Posted by: reganenosusd | October 31, 2014

October 2014

Gupta, M. K., J. Gulick, R. J. Liu, Xuejun Wang, J. D. Molkentin, & J. Robbins. (2014). Sumo E2 Enzyme UBC9 Is Required for Efficient Protein Quality Control in Cardiomyocytes. Circulation Research, 115(8), 721-+.

Rationale: Impairment of proteasomal function is pathogenic in several cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation, and although the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control is not fully understood. Objective: To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a small ubiquitin-like modifier-conjugating enzyme, in cardiomyocyte protein quality control. Methods and Results: Gain-and loss-of-function approaches were used to determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function in cardiomyocytes, whereas knockdown of UBC9 by small interfering RNA caused significant accumulations of aggregated protein. UPS function and relative activity was analyzed using a UPS reporter protein consisting of a short degron, CL1, fused to the COOH-terminus of green fluorescent protein (GFPu). Subsequently, the effects of UBC9 on UPS function were tested in a proteotoxic model of desmin-related cardiomyopathy, caused by cardiomyocyte-specific expression of a mutated alpha B crystallin, CryAB(R120G). CryAB(R120G) expression leads to aggregate formation and decreased proteasomal function. Coinfection of UBC9-adenovirus with CryABR120G virus reduced the proteotoxic sequelae, decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 significantly decreased UPS function in the model and resulted in increased aggregate levels. Conclusions: UBC9 plays a significant role in cardiomyocyte protein quality control, and its activity can be exploited to reduce toxic levels of misfolded or aggregated proteins in cardiomyopathy.

Baisc Biomedical Sciences, Vermillion Campus.

Klonoski, Joshua M., Heather R. Hurtig, Brian A. Juber, Margaret J. Schuneman, Thomas E. Bickett, Joshua M. Svendsen, . . . Victor C. Huber. (2014). Vaccination against the M protein of Streptococcus pyogenes prevents death after influenza virus:S. pyogenes super-infection. Vaccine, 32(40), 5241-5249.

Influenza virus infections are associated with a significant number of illnesses and deaths on an annual basis. Many of the deaths are due to complications from secondary bacterial invaders, including Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The beta-hemolytic bacteria S. pyogenes colonizes both skin and respiratory surfaces, and frequently presents clinically as strep throat or impetigo. However, when these bacteria gain access to normally sterile sites, they can cause deadly diseases including sepsis, necrotizing fasciitis, and pneumonia. We previously developed a model of influenza virus:S. pyogenes super-infection, which we used to demonstrate that vaccination against influenza virus can limit deaths associated with a secondary bacterial infection, but this protection was not complete. In the current study, we evaluated the efficacy of a vaccine that targets the M protein of S. pyogenes to determine whether immunity toward the bacteria alone would allow the host to survive an influenza virus:S. pyogenes super-infection. Our data demonstrate that vaccination against the M protein induces IgG antibodies, in particular those of the IgG1 and IgG2a isotypes, and that these antibodies can interact with macrophages. Ultimately, this vaccine-induced immunity eliminated death within our influenza virus:S. pyogenes super-infection model, despite the fact that all M protein-accinated mice showed signs of illness following influenza virus inoculation. These findings identify immunity against bacteria as an important component of protection against influenza virus:bacteria super-infection. (C) 2014 Elsevier Ltd. All rights reserved.

Basic Biomedical Sciences, Vermillion Campus.

Morecraft, Robert J., Kimberly S. Stilwell-Morecraft, Kathryn M. Solon-Cline, Jizhir Ge, & W. G. Darling. (2014). Cortical Innervation of the Hypoglossal Nucleus in the Non-Human Primate (Macaca mulatta). Journal of Comparative Neurology, 522(15), 3456-3484.

The corticobulbar projection to the hypoglossal nucleus was studied from the frontal, parietal, cingulate, and insular cortices in the rhesus monkey by using high-resolution anterograde tracers and stereology. The hypoglossal nucleus received bilateral input from the face/head region of the primary (M1), ventrolateral pre( LPMCv), supplementary (M2), rostral cingulate (M3), and caudal cingulate (M4) motor cortices. Additional bilateral corticohypoglossal projections were found from the dorsolateral premotor cortex (LPMCd), ventrolateral proisocortical motor area (ProM), ventrolateral primary somatosensory cortex (S1), rostral insula, and pregenual region of the anterior cingulate gyrus (areas 24/32). Dense terminal projections arose from the ventral region of M1, and moderate projections from LPMCv and rostral part of M2, with considerably fewer hypoglossal projections arising from the other cortical regions. These findings demonstrate that extensive regions of the non-human primate cerebral cortex innervate the hypoglossal nucleus. The widespread and bilateral nature of this corticobulbar connection suggests recovery of tongue movement after cortical injury that compromises a subset of these areas, may occur from spared corticohypoglossal projection areas located on the lateral, as well as medial surfaces of both hemispheres. Since functional imaging studies have shown that homologous cortical areas are activated in humans during tongue movement tasks, these corticobulbar projections may exist in the human brain. (C) 2014 Wiley Periodicals, Inc.

Basic Biomedical Sciences, Vermillion Campus.

Weltman, Nathan Y., K. Ojamaa, Evelyn H. Schlenker, Y. F. Chen, R. Zucchi, A. Saba, . . . A. M. Gerdes. (2014). Low-Dose T-3 Replacement Restores Depressed Cardiac T-3 Levels, Preserves Coronary Microvasculature and Attenuates Cardiac Dysfunction in Experimental Diabetes Mellitus. Molecular Medicine, 20, 302-312.

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 g/mL T-3; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T-3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T-3 and T-4 : 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T-3 replacement largely restored cardiac tissue TH levels (T-3 and T-4 : 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T-3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

Basic Biomedical Sciences, Vermillion Campus.

Kraus, J. M., D. M. Walters, Jeff S. Wesner, C. A. Stricker, T. S. Schmidt, & R. E. Zuellig. (2014). Metamorphosis Alters Contaminants and Chemical Tracers in Insects: Implications for Food Webs. Environmental Science & Technology, 48(18), 10957-10965.

Insects are integral to most freshwater and terrestrial food webs, but due to their accumulation of environmental pollutants they are also contaminant vectors that threaten reproduction, development, and survival of consumers. Metamorphosis from larvae to adult can cause large chemical changes in insects, altering contaminant concentrations and fractionation of chemical tracers used to establish contaminant biomagnification in food webs, but no framework exists for predicting and managing these effects. We analyzed data from 39 studies of 68 analytes (stable isotopes and contaminants), and found that metamorphosis effects varied greatly. delta N-15, widely used to estimate relative trophic position in biomagnification studies, was enriched by similar to 1 parts per thousand during metamorphosis, while delta C-13 used to estimate diet, was similar in larvae and adults. Metals and polycyclic aromatic hydrocarbons (PAHs) were predominantly lost during metamorphosis leading to similar to 2 to 125-fold higher larval concentrations and higher exposure risks for predators of larvae compared to predators of adults. In contrast, manufactured organic contaminants (such as polychlorinated biphenyls) were retained and concentrated in adults, causing up to similar to 3-fold higher adult concentrations and higher exposure risks to predators of adult insects. Both food web studies and contaminant management and mitigation strategies need to consider how metamorphosis affects the movement of materials between habitats and ecosystems, with special regard for aquatic-terrestrial linkages.

Biology Department.

Swanson, David, Yufeng Zhang, & Marisa King. (2014). Mechanistic Drivers of Flexibility in Summit Metabolic Rates of Small Birds. Plos One, 9(7), 9.

Flexible metabolic phenotypes allow animals to adjust physiology to better fit ecological or environmental demands, thereby influencing fitness. Summit metabolic rate (M-sum = maximal thermogenic capacity) is one such flexible trait. Skeletal muscle and heart masses and myocyte metabolic intensity are potential drivers of M-sum flexibility in birds. We examined correlations of skeletal muscle and heart masses and pectoralis muscle citrate synthase (CS) activity (an indicator of cellular metabolic intensity) with M-sum in house sparrows (Passer domesticus) and dark-eyed juncos (Junco hyemalis) to determine whether these traits are associated with M-sum variation. Pectoralis mass was positively correlated with M-sum for both species, but no significant correlation remained for either species after accounting for body mass (M-b) variation. Combined flight and leg muscle masses were also not significantly correlated with M-sum for either species. In contrast, heart mass was significantly positively correlated with M-sum for juncos and nearly so (P = 0.054) for sparrows. Mass-specific and total pectoralis CS activities were significantly positively correlated with M-sum for sparrows, but not for juncos. Thus, myocyte metabolic intensity influences M-sum variation in house sparrows, although the stronger correlation of total (r = 0.495) than mass-specific (r = 0.378) CS activity with M-sum suggests that both pectoralis mass and metabolic intensity impact M-sum. In contrast, neither skeletal muscle masses nor pectoralis metabolic intensity varied with M-sum in juncos. However, heart mass was associated with M-sum variation in both species. These data suggest that drivers of metabolic flexibility are not uniform among bird species.

Biology Department.

Wesner, Jeff S., J. M. Kraus, T. S. Schmidt, D. M. Walters, & W. H. Clements. (2014). Metamorphosis Enhances the Effects of Metal Exposure on the Mayfly, Centroptilum triangulifer. Environmental Science & Technology, 48(17), 10415-10422.

The response of larval aquatic insects to stressors such as metals is used to assess the ecological condition of streams worldwide. However, nearly all larval insects metamorphose from aquatic larvae to winged adults, and recent surveys indicate that adults may be a more sensitive indicator of stream metal toxicity than larvae. One hypothesis to explain this pattern is that insects exposed to elevated metal in their larval stages have a reduced ability to successfully complete metamorphosis. To test this hypothesis we exposed late-instar larvae of the mayfly, Centroptilum triangulifer, to an aqueous Zn gradient (32-476 mu g/L) in the laboratory. After 6 days of exposure, when metamorphosis began, larval survival was unaffected by zinc. However, Zn reduced wingpad development at concentrations above 139 mu g/L. In contrast, emergence of subimagos and imagos tended to decline with any increase in Zn. At Zn concentrations below 105 mu g/L (hardness-adjusted aquatic life criterion), survival between the wingpad and subimago stages declined 5-fold across the Zn gradient. These results support the hypothesis that metamorphosis may be a survival bottleneck, particularly in contaminated streams. Thus, death during metamorphosis may be a key mechanism explaining how stream metal contamination can impact terrestrial communities by reducing aquatic insect emergence.

Biology Department.

Ghimire, Niranjan, Jie Luo, Ruogu Tang, Yuyu Sun, & Ying Deng. (2014). Novel anti-infective activities of chitosan immobilized titanium surface with enhanced osteogenic properties. Colloids & Surfaces B: Biointerfaces, 122, 126-133.

We have covalently immobilized chitosan onto a titanium (Ti) surface to manage implant-related infection and poor osseointegration, two of the major complications of orthopedic implants. The Ti surface was first treated with sulfuric acid (SA) and then covalently grafted with chitosan. Surface roughness, contact angle and surface zeta potential of the samples were markedly increased by the sulfuric acid treatment and the subsequent chitosan immobilization. The chitosan-immobilized Ti (SA-CS-Ti) showed two novel antimicrobial roles: it (a) prevented the invasion and internalization of bacteria into the osteoblast-like cells, and (b) significantly increased the susceptibility of adherent bacteria to antibiotics. In addition, the sulfuric acid-treated Ti (SA-Ti) and SA-CS-Ti led to significantly increased ( P < 0.05) osteoblast-like cell attachment, enhanced cell proliferation, and better osteogenic differentiation and mineralization of osteoblast-like cells.

Biomedical Engineering, Sioux Falls Campus.

Banerjee, Subhash, Soumen Payra, Arijit Saha, & Grigoriy Sereda. (2014). ZnO nanoparticles: a green efficient catalyst for the room temperature synthesis of biologically active 2-aryl-1,3-benzothiazole and 1,3-benzoxazole derivatives. Tetrahedron Letters: International Organ for the Rapid Publication of Preliminary Communications in Organic Chemistry, 55(40), 5515-5520.

A facile synthetic protocol for the synthesis of 2-aryl-1,3-benzothiazoles and 1,3-benzoxazoles has been demonstrated using ZnO nanoparticles as a mild and efficient heterogeneous catalyst. The reactions using ZnO nanoparticles were very fast (<8 min) and provided excellent yields (>90%) of the products. The catalyst was recycled and reused up to eight times without significant loss of catalytic activity. The potential application of 2-(4-hydroxyphenyl)-1,3-benzothiazole as new acid–base indicator has also been demonstrated in this Letter.

Chemistry Department.

Bartholomew, Catherine, Ashish Chakradhar, U. W. E. Burghaus, Chia-Ming Wu, R. U. I. Peng, Srujan Mishra, & Ranjit T. Koodali. (2014). REACTIVITY AND MORPHOLOGY OF , , AND – OXIDE CLUSTERS SUPPORTED ON MCM-48 TOWARD THIOPHENE HYDRODESULPHURIZATION. Surface Review & Letters, 21(5), -1.

In this paper, the morphology, chemical composition and reactivity of MCM-48 powders impregnated with , or both toward hydrodesulphurization (HDS) of thiophene were characterized. The reactivity of the catalyst was quantitatively compared with a standard industrial catalyst (from HaldorTopsoe, Denmark) and a novel 2 nanotube-based catalysts (from R. Tenne, Israel). Morphology and chemical composition were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), and EDX elemental maps. Reactivity was determined in a gas-chromatograph based mini flow reactor using thiophene as a probe molecule. The sulfided MCM-48 supported catalyst showed the largest HDS activity with turnover frequencies (TOF) about half as large as for the commercial system under the test conditions used here. Presulfiding did increase activity of all MCM-48 catalysts.

Chemistry Department.

Blumenthal, Tyler, Jeevan Meruga, Jon Kellar, William Cross, Krishnamraju Ankireddy, Swathi Vunnam, . . . QuocAnh N. Luu. (2012). Patterned direct-write and screen-printing of NIR-to-visible upconverting inks for security applications. Nanotechnology, 23(18), 1-1.

Two methods of direct-write printing for producing highly resolved features of a polymer impregnated with luminescent upconversion phosphors for security applications are presented. The printed polymer structures range in shape from features to text. The thin polymer features were deposited by direct-write printing of atomized material as well as by screen-printing techniques. These films contain highly luminescent lanthanide-doped, rare-earth nanocrystals, β-NaYF4:3%Er, 17%Yb, which are capped with oleic acid. This capping agent allows the nanocrystals to disperse throughout the films for full detailing of printed features. Upconversion of deposited features was obtained using a 980 nm wavelength laser with emission of upconverted light in the visible region at both 540 and 660 nm. Features were deposited onto high bond paper, Kapton®, and glass to demonstrate possible covert and forensic security printing applications, as they are printed in various features and invisible to ‘naked-eye’ viewing at low concentrations of nanocrystals.

Chemistry Department.

Huang, Shuping, T. M. Inerbaev, & Dmitri S. Kilin. (2014). Excited State Dynamics of Ru-10 Cluster Interfacing Anatase TiO2(101) Surface and Liquid Water. Journal of Physical Chemistry Letters, 5(16), 2823-2829.

Charge transfer dynamics at the interface of supported metal nanocluster and liquid water by GGA+U calculations combined with density matrix formalism is considered. The Rum duster introduces new states into the band gap of TiO2 surface, narrows the band gap of TiO2, and enhances the absorption strength. The H2O adsorption significantly enhances the intensity of photon absorption, which is due to the formation of Ti-O(water) and Ru-O(water) bonds at the interfaces. The Ruff, cluster promotes the dissociation of water, facilitates charge transfer, and increases the relaxation rates of holes and electrons. We expect that our results are helpful in understanding basic processes contributing to photoelectrochemical water splitting.

Chemistry Department.

Huang, Shuping, & Dmitri S. Kilin. (2014). Charge Transfer, Luminescence, and Phonon Bottleneck in TiO2 Nanowires Computed by Eigenvectors of Liouville Superoperator. Journal of Chemical Theory and Computation, 10(9), 3996-4005.

A nonadiabatic excited state dynamics study of ?001? anatase TiO2 nanowire is obtained by combining density matrix in LiouvilleRedfield formalism and ab initio electronic structure calculations. The properties of eigenvectors of LiouvilleRedfield superoperator are investigated. The time evolutions of KohnSham orbital populations are obtained for different electronic excitations. The numerical solutions of the population changes over time are in agreement with the analytical results. The analytical and numerical results on the electron and hole relaxation rates are compared. The electron nonradiative relaxation to the bottom of conduction band involves Ti 3d orbitals, whereas the hole nonradiative relaxation to the top of valence band is mainly localized in surface O 2p orbitals. The rate of relaxation in nanowire is slower than in bulk TiO2 demonstrating phonon-bottleneck effect. Calculated emission spectrum has vanishing contribution from lowest energy excitation, which indicates charge transfer.

Chemistry Department.

Kibombo, Harrison S., Vagulejan Balasanthiran, Chia-Ming Wu, Rui Peng, & Ranjit T. Koodali. (2014). Exploration of room temperature synthesis of palladium containing cubic MCM-48 mesoporous materials. Microporous and Mesoporous Materials, 198, 1-8.


Pd-MCM-48 mesoporous materials were synthesized by a modified Stober synthesis method in 4 h at room temperature. Pd nanoparticles were prepared by using Na-2[PdCl4] and Pd(acac)(2) as Pd precursors, and their influence in the preparation of the cubic MCM-48 mesoporous phase was investigated. In addition, Pd(0) nanoparticles was prepared separately and added to the synthesis gel. The influence of varying the Pd precursor, solvent media, the time of addition of Pd precursor, and the concentration of NaBH4 reducing agent used for preparation of Pd(0) and its effect for the formation of the cubic phase were investigated. These resultant materials were characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-Visible spectroscopy, nitrogen physisorption, and CO-Pulse titration. Reusability studies assessing a material prepared using Pd(0)-DMAP encapsulated nanoparticles that were reduced with 0.1 N NaBH4 i.e. 3%Pd-MCM-48-D-N01 indicate that the yields for the hydrogenation of trans-cinnamic acid are greater than 95% even after 8 catalytic cycles, and at which the cubic phase was maintained under our experimental conditions. (C) 2014 Elsevier Inc. All rights reserved.

Chemistry Department.

Meruga, Jeevan M., William M. Cross, P. Stanley  May, QuocAnh Luu, Grant A. Crawford, & Jon J. Kellar. (2012). Security printing of covert quick response codes using upconverting nanoparticle inks. Nanotechnology, 23(39), 1-1.

Counterfeiting costs governments and private industries billions of dollars annually due to loss of value in currency and other printed items. This research involves using lanthanide doped β-NaYF4 nanoparticles for security printing applications. Inks comprised of Yb3+/Er3+ and Yb3+/Tm3+ doped β-NaYF4 nanoparticles with oleic acid as the capping agent in toluene and methyl benzoate with poly(methyl methacrylate) (PMMA) as the binding agent were used to print quick response (QR) codes. The QR codes were made using an AutoCAD file and printed with Optomec direct-write aerosol jetting®. The printed QR codes are invisible under ambient lighting conditions, but are readable using a near-IR laser, and were successfully scanned using a smart phone. This research demonstrates that QR codes, which have been used primarily for information sharing applications, can also be used for security purposes. Higher levels of security were achieved by printing both green and blue upconverting inks, based on combinations of Er3+/Yb3+ and Tm3+/Yb3+, respectively, in a single QR code. The near-infrared (NIR)-to-visible upconversion luminescence properties of the two-ink QR codes were analyzed, including the influence of NIR excitation power density on perceived color, in term of the CIE 1931 chromaticity index. It was also shown that this security ink can be optimized for line width, thickness and stability on different substrates.

Chemistry Department.

Sathe, Ajay, Matthea A. Peck, Choumini Balasanthiran, Marjorie A. Langell, Robert M. Rioux, & James D. Hoefelmeyer. (2014). X-ray photoelectron spectroscopy of transition metal ions attached to the surface of rod-shape anatase TiO2 nanocrystals. Inorganica Chimica Acta, 422, 8-13.

X-ray photoelectron spectra were obtained for a series of M–TiO 2 samples in which transition metal ions are directly attached to the surface of anatase TiO 2 nanocrystals. The samples were prepared using CrCl 3 · n H 2 O, MnCl 2 · n H 2 O, FeCl 2 · n H 2 O, CoCl 2 · n H 2 O, NiCl 2 · n H 2 O, and CuCl 2 · n H 2 O as metal sources. We observed spontaneous air oxidation of the metal for the Mn–TiO 2 and Fe–TiO 2 samples as indicated by rapid color changes. X-ray photoelectron spectroscopy (XPS) data confirms the oxidation states of the metals Cr, Co, and Ni are unchanged from the precursor, Mn and Fe are oxidized, and Cu is in a more reduced state. The reduction of Cu likely arises during the XPS experiment – a phenomenon well-documented in the literature; whereas UV–Vis data of the Cu–TiO 2 dispersions are consistent with Cu 2+ .

Chemistry Department.

Carley, Tamara L., Calvin F. Miller, Joseph L. Wooden, …., & Brennan T. Jordan. (2014). Iceland is not a magmatic analog for the Hadean: Evidence from the zircon record. Earth & Planetary Science Letters, 405, 85-97.

Tangible evidence of Earth’s earliest (Hadean; >4.0 Ga) crust, and the processes and materials that contributed to its formation, exists almost entirely in a record of detrital zircon from Jack Hills, Western Australia, and a few other locations. Iceland, with its thick, juvenile, basaltic crust and relatively abundant silicic rocks, is considered a potential modern analog for the Hadean magmatic environment where >4 Ga zircon formed. We present the first extensive dataset for Icelandic zircon, with trace element and oxygen isotope compositions from samples that span the island’s history and full range of tectonic settings. This statistically robust zircon-based comparison between Iceland and the early Earth reveals distinctions in chemistry that suggest fundamental differences in magmatic environments. Whereas the δ 18 O signature of Hadean zircons generally exceed that of zircons equilibrated with mantle-derived magma ( 85 % ≥ 5.3 ‰ ; median 6‰), almost all Icelandic zircons are characterized by a “light” oxygen signature ( 98 % ≤ 5.3 ‰ ; median 3‰). Deviations from “juvenile” oxygen values indicate that many Hadean zircons and almost all Icelandic zircons grew from magmas with substantial contributions from materials that had interacted with surface waters. In the Hadean case, the interaction occurred at low temperatures, while in Iceland, it was a high-temperature interaction. Icelandic and Hadean zircons are also distinct in their Ti concentrations (Icelandic median concentration 12 ppm, Hadean median 5 ppm). Titanium in zircon correlates positively with temperature of crystallization, and this difference in median Ti concentration suggests a temperature difference of at least 50 °C. Other differences in trace elements compositions are consistent with the interpretation that Icelandic and Hadean zircons grew in magmas with very different origins and histories (e.g., the heavy rare earth element Yb is almost an order of magnitude higher in Icelandic zircon). A comparison with elemental data for Phanerozoic zircon from different environments demonstrates that the Hadean population is unusually depleted in Ti, but otherwise similar to zircons from continental arc settings. Zircons from Iceland, and from modern evolving rift environments where oceanic lithosphere and upwelling asthenosphere are replacing continental lithosphere, are compositionally intermediate between mid-ocean ridge and continental arc zircon populations. The elemental distinctions are consistent with fractionation of zircon-bearing magmas under hotter and drier conditions in Icelandic, mid-ocean ridge, and evolving rift environments and cooler and wetter conditions in arc and, especially, Hadean environments.

Earth Sciences Department.

Chowell, Gerardo, Lone Simonsen, Jose Flores, Mark A. Miller, & Cécile Viboud. (2014). Death Patterns during the 1918 Influenza Pandemic in Chile. Emerging Infectious Diseases, 20(11), 1803-1811.

Scarce information about the epidemiology of historical influenza pandemics in South America prevents complete understanding of pandemic patterns throughout the continent and across different climatic zones. To fill gaps with regard to spatiotemporal patterns of deaths associated with the 1918 influenza pandemic in Chile, we reviewed archival records. We found evidence that multiple pandemic waves at various times of the year and of varying intensities occurred during 1918-1921 and that influenza-related excess deaths peaked during July-August 1919. Pandemic-associated mortality rates were elevated for all age groups, including for adults ≥50 years of age; elevation from baseline was highest for young adults. Overall, the rate of excess deaths from the pandemic was estimated at 0.94% in Chile, similar to rates reported elsewhere in Latin America, but rates varied ≈10-fold across provinces. Patterns of death during the pandemic were affected by variation in host-specific susceptibility, population density, baseline death rate, and climate.

Mathematics Department.

Dutkay, Dorin E., & Gabriel Picioroaga. (2014). Generalized Walsh Bases and Applications. Acta Applicandae Mathematicae, 133(1), 1-18.

We investigate convergence properties of generalized Walsh series associated with signals faL (1)[0,1]. We also show how the dependence of the generalized Walsh bases on NxN unitary matrices allows for applications in signal encoding and encryption, provided the signals are piece-wise constant on N-adic subintervals of [0,1].

Mathematics Department.

Borrego, Maura, Daniel Boden, & Lynita K. Newswander. (2014). Sustained Change: Institutionalizing Interdisciplinary Graduate Education. Journal of Higher Education, 85(6), 858-885.

We employ Scott’s three pillars of institutions (regulative, normative, and cultural-cognitive) to investigate how higher education organizations change to support interdisciplinary graduate education. Using document analysis and case study approaches, we illustrate how strategies which address both policies and cultural norms are most successful.

Political Science Department.

Emery, Noah N., Jeffrey S. Simons, C. Joseph Clarke, & Raluca M. Gaher. (2014). Emotion differentiation and alcohol-related problems: The mediating role of urgency. Addictive Behaviors, 39(10), 1459-1463.

Deficits in emotional and behavioral regulation figure prominently in etiological models of alcohol-related problems. This study tests a model linking poor differentiation of emotion to alcohol-related problems via urgency. The sample consisted of 102 undergraduates between the ages 18 and 24 who reported moderate to heavy alcohol consumption. As hypothesized, negative urgency mediated the relationship between negative emotion differentiation and alcohol-related problems. However, contrary to hypothesis, positive urgency was not associated with either positive emotion differentiation or alcohol-related problems and the indirect effect of positive emotion differentiation via positive urgency was not significant. Instead, positive emotion differentiation exhibited a significant direct effect on alcohol-related problems. This study provides an initial examination of connections between specificity in labeling emotions, behavioral disinhibition, and problematic alcohol use. These findings suggest that poor differentiation of negative emotion may foster impulsive behavior when negatively aroused. Whereas, impulsive behavior when positively aroused may reflect heightened sensitivity to positive reinforcement, which may not be related to reflective processes underlying emotion differentiation. (C) 2014 Elsevier Ltd. All rights reserved.

Psychology Department.

Robles, Elias, Noah N. Emery, Perla A. Vargas, Araceli Moreno, Brent Marshall, Richard C. Grove, & Huateng Zhang. (2014). Patterns of responding on a balloon analogue task reveal individual differences in overall risk-taking: Choice between guaranteed and uncertain cash. Journal of General Psychology, 141(3), 207-227.

We explored the utility of analyzing within- and between-balloon response patterns on a balloon analogue task (BAT) in relation to overall risk scores, and to a choice between a small guaranteed cash reward and an uncertain reward of the same expected value. Young adults (n = 61) played a BAT, and then were offered a choice between $5 in cash and betting to win $0 to $15. Between groups, pumping was differentially influenced by explosions and by the number of successive unexploded balloons, with risk takers responding increasingly on successive balloons after an explosion. Within-balloons, risk takers showed a characteristic pattern of constant high rate, while non-risk takers showed a characteristic variable lower rate. Overall, results show that the higher number of pumps and explosions that characterize risk takers at a molar level, result from particular forms of adaptation to the positive and negative outcomes of choices seen at a molecular level. (PsycINFO Database Record (c) 2014 APA, all rights reserved). (journal abstract)

Psychology Department.

Wang, X. T., S. Li, & L. L. Rao. (2014). Conservation combats exploitation: Choices within an evolutionary framework. Behavioral and Brain Sciences, 37(4), 437-438.

Intentional change when viewed as making a risky or intertemporal choice with evolutionary relevance helps us understand its successes and its failures. To promote future-oriented ecological rationality requires establishing a linkage between nongenetic, cultural, and symbolic selections and genetic adaptations. Coupled with biophilic instinct, intentional conservation is more likely to prevail against evolved desires of environmental exploitation.

Psychology Department.

Askelson, N. M., D. L. Chi, E. Momany, R. Kuthy, C. Ortiz, Jessica D. Hanson, & P. Damiano. (2014). Encouraging early preventive dental visits for preschool-aged children enrolled in Medicaid: using the Extended Parallel Process Model to conduct formative research. Journal of Public Health Dentistry, 74(1), 64-70.

Objective: Preventive dental visits for preschool-aged children can result in better oral health outcomes, especially for children from lower income families. Many children, however, still do not see a dentist for preventive visits. This qualitative study examined the potential for the Extended Parallel Process Model (EPPM) to be used to uncover potential antecedents to parents’ decisions about seeking preventive dental care. Methods: Seventeen focus groups including 41 parents were conducted. The focus group protocol centered on constructs (perceived severity, perceived susceptibility, perceived self-efficacy, and perceived response efficacy) of the EPPM. Transcripts were analyzed by three coders who employed closed coding strategies. Results: Parents’ perceptions of severity of dental issues were high, particularly regarding negative health and appearance outcomes. Parents perceived susceptibility of their children to dental problems as low, primarily because most children in this study received preventive care, which parents viewed as highly efficacious. Parents’ self-efficacy to obtain preventive care for their children was high. However, they were concerned about barriers including lack of dentists, especially dentists who are good with young children. Conclusions: Findings were consistent with EPPM, which suggests this model is a potential tool for understanding parents’ decisions about seeking preventive dental care for their young children. Future research should utilize quantitative methods to test this model.

Sanford School of Medicine, Sioux Falls Campus.

Bergeron, Michael F. (2014). Heat Stress and Thermal Strain Challenges in Running. Journal of Orthopaedic & Sports Physical Therapy, 44(10), 831-838.


SYNOPSIS: Running well and safely in the heat is challenging for all runners, from recreational to elite. As environmental heat stress (heat stress modulated or augmented by air temperature, humidity, wind speed, and solar radiation) and the intensity and duration of a training run or race increase, so are metabolic heat production, the parallel need for heat transfer from the body to maintain thermal equilibrium, the consequent increase in blood flow to the skin, and the concomitant sweating response progressively and proportionally amplified. An accumulating total body-water deficit from extensive sweating and escalating level of cardiovascular and thermal strain will, in due course, considerably challenge a runner’s physiology, perception of effort, and on-course well-being and performance. However, with the appropriate preparation and modifications to planned running intensity and distance, runners can safely tolerate and effectively train and compete in a wide range of challenging environmental conditions. Clinicians play a key role in this regard as an effective resource for providing the most effective guidelines and making the best overall individual recommendations regarding training and competing in the heat.

Sanford School of Medicine, Sioux Falls Campus.

Ferris, D., R. Samakoses, S. L. Block, E. Lazcano-Ponce, J. A. Restrepo, K. S. Reisinger, . . . A. Saah. (2014). Long-term Study of a Quadrivalent Human Papillomavirus Vaccine. Pediatrics, 134(3), E657-E665.


BACKGROUND: We present a long-term safety, immunogenicity, and effectiveness study of a quadrivalent human papillomavirus (HPV4) vaccine. METHODS: Sexually naive boys and girls aged 9 to 15 years (N = 1781) were assigned (2:1) to receive HPV4 vaccine or saline placebo at day 1 and months 2 and 6. At month 30, the placebo group (n = 482) received HPV4 vaccine following the same regimen and both cohorts were followed through month 96. Subjects >= 16 years were eligible for effectiveness evaluations. The primary objective was to evaluate the long-term anti-HPV6/11/16/18 serological levels. The secondary objective was to estimate vaccine effectiveness against HPV6/11/16/18-related persistent infection or disease. RESULTS: For each of the HPV4 vaccine types, vaccination-induced anti-HPV response persisted through month 96. Among 429 subjects who received HPV4 vaccine at a mean age of 12, none developed HPV6/11/16/18-related disease or persistent infection of >= 12 months’ duration. Acquisition of new sexual partners (among those >= 16 years) was similar to 1 per year. Subjects receiving HPV4 vaccine at month 30 (mean age 15 years) had a similar baseline rate of seropositivity to >= 1 of the 4 HPV types to those vaccinated at day 1 (mean age 12 years; 1.9% [9 of 474] vs 1.7% [20 of 1157]); however, 4 of the 9 subjects vaccinated at the later age were seropositive to 3 vaccine types, indicating previous HPV exposure. No new significant serious adverse events were observed for 8 years postvaccination in both genders. CONCLUSIONS: When administered to adolescents, the HPV4 vaccine demonstrated durability in clinically effective protection and sustained antibody titers over 8 years.

Sanford School of Medicine, Sioux Falls Campus.

Finn, R., C. C. Evans, & Lance Lee. (2014). Strain-dependent brain defects in mouse models of primary ciliary dyskinesia with mutations in Pcdp1 and Spef2. Neuroscience, 277, 552-567.

Hydrocephalus is caused by the accumulation of cerebrospinal fluid (CSF) in the cerebral ventricular system which results in an enlargement of the cranium due to increased intraventricular pressure. The increase in pressure within the brain typically results in sloughing of ciliated ependymal cells, loss of cortical gray matter, and increased gliosis. Congenital hydrocephalus is associated with several syndromes including primary ciliary dyskinesia (PCD), a rare, genetically heterogeneous, pediatric syndrome that results from defects in motile cilia and flagella. We have examined the morphological and physiological defects in the brains of two mouse models of PCD, nm1054 and bgh , which have mutations in Pcdp1 (also known as Cfap221 ) and Spef2 , respectively. Histopathological and immunohistochemical analyses of mice with these mutations on the C57BL/6J and 129S6/SvEvTac genetic backgrounds demonstrate strain-dependent morphological brain damage. Alterations in astrocytosis, microglial activation, myelination, and the neuronal population were identified and are generally more severe on the C57BL/6J background. Analysis of ependymal ciliary clearance ex vivo and CSF flow in vivo demonstrate a physiological defect in nm1054 and bgh mice on both genetic backgrounds, indicating that abnormal cilia-driven flow is not the sole determinant of the severity of hydrocephalus in these models. These results suggest that genetic modifiers play an important role in susceptibility to severe PCD-associated hydrocephalus.

Sanford School of Medicine, Sioux Falls Campus.

Flock, M. R., A. C. Skulas-Ray, William S. Harris, T. L. Gaugler, J. A. Fleming, & P. M. Kris-Etherton. (2014). Effects of supplemental long-chain omega-3 fatty acids and erythrocyte membrane fatty acid content on circulating inflammatory markers in a randomized controlled trial of healthy adults. Prostaglandins Leukotrienes and Essential Fatty Acids, 91(4), 161-168.

The long-chain omega-3 polyunsaturated (n-3 PUFA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), may have anti-inflammatory effects. We evaluated the dose-response effect of EPA+DHA supplementation on circulating TNF-alpha, IL-6, and CRP and explored associations between red blood cell (RBC) membrane PUFA content and TNF-alpha, IL-6, and CRP. Young adults with low fish intake (n= 116) received one of five doses (0, 300, 600, 900, or 1,800 mg/d EPA+DHA) for 5 months. There were no significant effects of supplemental EPA+DHA on IL-6 or CRP; however, there was a marginal treatment effect for TNF-alpha (p < 0.08). At baseline, higher quartiles of RBC DHA were associated with lower TNF-alpha (p=0.001); higher quartiles of arachidonic acid were associated with higher TNF-alpha (p=0.005). EPA+DHA supplementation had no dose-response effect on TNF-alpha, IL-6, or CRP in healthy young adults; however, associations between inflammatory markers and RBC PUFA warrant further investigation. (C) 2014 Elsevier Ltd. All rights reserved.

Sanford School of Medicine, Sioux Falls Campus.

Floen, Miranda J., Benjamin J. Forred, Elliot J. Bloom, & Peter F. Vitiello. (2014). Thioredoxin-1 redox signaling regulates cell survival in response to hyperoxia. Free Radical Biology & Medicine, 75, 167-177.


The most common form of newborn chronic lung disease, bronchopulmonary dysplasia (BPD), is thought to be caused by oxidative disruption of lung morphogenesis, which results in decreased pulmonary vasculature and alveolar simplification. Although cellular redox status is known to regulate cellular proliferation and differentiation, redox-sensitive pathways associated with these processes in developing pulmonary epithelium are unknown. Redox-sensitive pathways are commonly regulated by cysteine thiol modifications. Therefore two thiol oxidoreductase systems, thioredoxin and glutathione, were chosen to elucidate the roles of these pathways on cell death. Studies herein indicate that thiol oxidation contributes to cell death through impaired activity of glutathione-dependent and thioredoxin (Trx) systems and altered signaling through redox-sensitive pathways. Free thiol content decreased by 71% with hyperoxic (95% oxygen) exposure. Increased cell death was observed during oxygen exposure when either the Trx or the glutathione-dependent system was pharmacologically inhibited with aurothioglucose (ATG) or buthionine sulfoximine, respectively. However, inhibition of the Trx system yielded the smallest decrease in free thiol content (1.44% with ATG treatment vs 21.33% with BSO treatment). Although Trx1 protein levels were unchanged, Trx1 function was impaired during hyperoxic treatment as indicated by progressive cysteine oxidation. Overexpression of Trx1 in H1299 cells utilizing an inducible construct increased cell survival during hyperoxia, whereas siRNA knockdown of Trx1 during oxygen treatment reduced cell viability. Overall, this indicated that a comparatively small pool of proteins relies on Trx redox functions to mediate cell survival in hyperoxia, and the protective functions of Trx1 are progressively lost by its oxidative inhibition. To further elucidate the role of Trx1, potential Trx1 redox protein–protein interactions mediating cytoprotection and cell survival pathways were determined by utilizing a substrate trap (mass action trapping) proteomics approach. With this method, known Trx1 targets were detected, including peroxiredoxin-1 as well as novel targets, including two HSP90 isoforms (HSP90AA1 and HSP90AB1). Reactive cysteines within the structure of HSP90 are known to modulate its ATPase-dependent chaperone activity through disulfide formation and S-nitrosylation. Whereas HSP90 expression is unchanged at the protein level during hyperoxic exposure, siRNA knockdown significantly increased hyperoxic cell death by 2.5-fold, indicating cellular dependence on HSP90 chaperone functions in response to hyperoxic exposure. These data support the hypothesis that hyperoxic impairment of Trx1 has a negative impact on HSP90-oxidative responses critical to cell survival, with potential implications for pathways implicated in lung development and the pathogenesis of BPD.

Sanford School of Medicine, Sioux Falls Campus.

Griffin, Kurt J., Paul A. Thompson, M. Gottschalk, J. H. Kyllo, & Alex Rabinovitch. (2014). Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial. Lancet Diabetes & Endocrinology, 2(9), 710-718.

Background Type 1 diabetes results from autoimmune destruction of pancreatic beta cells. Findings from preclinical studies suggest that dipeptidyl peptidase-4 inhibitors and proton-pump inhibitors might enhance beta-cell survival and regeneration. We postulated that sitagliptin and lansoprazole would preserve beta-cell function in patients with recentonset type 1 diabetes. Methods We did a double-blind, placebo-controlled, phase 2 trial (REPAIR-T1D). Participants aged 11-36 years, diagnosed with type 1 diabetes within the past 6 months were recruited from Sanford Health Systems (Sioux Falls, SD, USA; Fargo, ND, USA), Children’s Hospitals and Clinics of Minnesota (St Paul, MN, USA), and Rady Children’s Hospital (San Diego, CA, USA). Participants were randomly assigned (2: 1) to receive oral sitagliptin (100 mg for participants >= 18 years, 50 mg for those <18 years) and lansoprazole (60 mg for participants >= 18 years, 30 mg for those <18 years) or matched placebo for 12 months. Randomisation was done by a blocked randomisation process (blocks of three and six), with separate streams for younger (<18 years) and older (>= 18 years) participants, and males and females. All participants and personnel remained masked until after the completion of the final 12 month visit, at which time data were unmasked to the analysis team. The primary endpoint was C-peptide response to a mixed meal challenge at 12 months measured as 2 h area under curve. Analysis was by intention to treat. This trial is registered with, number NCT01155284. Findings Between Sept 21, 2010, and May 29, 2012, 46 participants were randomly assigned to the treatment group and 22 to the placebo group; of whom 40 participants in the treatment group and 18 in the placebo group completed the 12-month treatment. At 12 months, the mean change in C-peptide area under curve was -229 pmol/L (95% CI -316 to -142) for the treatment group and -253 pmol/L (-383 to -123) for the placebo group; this difference was not significant (p= 0.77). No adverse or serious adverse events were probably or definitely related to the study treatment. Interpretation Although the expected change in the primary endpoint was not achieved, not all participants had increases in glucagon-like peptide-1 and gastrin concentrations that were expected with treatment. Although participants did not have adverse events related to study drugs, the study is not powered to address safety definitively. Further trials including these drugs might be warranted, but should be designed to ensure appropriate selection of participants and increases in these intermediary hormones.

Sanford School of Medicine, Sioux Falls Campus.

Gupta, Brij, Diane Maher, Mara Ebeling, Phillip Stephenson, Susan Puumala, Michael Koch, . . . Subhash Chauhan. (2014). Functions and regulation of MUC13 mucin in colon cancer cells. Journal of Gastroenterology, 49(10), 1378-1391.

Background: MUC13 is overexpressed and aberrantly localized in colon cancer tissue; however, the specific functions and regulation of MUC13 expression are unknown. Methods: Stable cell lines with either overexpressed or suppressed MUC13 levels were analyzed to determine cell growth, colony formation, cell migration, and cell invasion assays. The molecular mechanisms involved in MUC13 regulation were elucidated via chromatin immunoprecipitation (ChIP) and analysis of interleukin 6 (IL6) treatments. Colon cancer tissues were analyzed by immunohistochemistry (IHC) for the protein levels of MUC13 and P-STAT5 in colon cancer cells. Results: Overexpression of MUC13 increased cell growth, colony formation, cell migration, and invasion. In concordance, MUC13 silencing decreased these tumorigenic features. Overexpression of MUC13 also modulated various cancer-associated proteins, including telomerase reverse transcriptase, sonic hedgehog, B cell lymphoma murine like site 1, and GATA like transcription factor 1. Additionally, MUC13-overexpressing cells showed increased HER2 and P-ERK expression. ChIP analysis revealed binding of STAT5 to the predicted MUC13 promoter. IL6 treatment of colon cancer cells increased the expression of MUC13 via activation of the JAK2/STAT5 signaling pathway. Suppression of JAK2 and STAT5 signaling by chemical inhibitors abolished IL6-induced MUC13 expression. IHC analysis showed increased expression of both P-STAT5 and MUC13 in colon cancer as compared to adjacent normal tissue. Conclusions: The results of this study, for the first time, suggest functional roles of MUC13 in colon cancer progression and provide information regarding the regulation of MUC13 expression via JAK2/STAT5 which may reveal promising therapeutic approaches for colon cancer treatment.

Sanford School of Medicine, Sioux Falls Campus.

Haugrud, Allison B., Yongxian Zhuang, Joseph D. Coppock, & W. Keith Miskimins. (2014). Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Research and Treatment, 147(3), 539-550.


The unique metabolism of breast cancer cells provides interest in exploiting this phenomenon therapeutically. Metformin, a promising breast cancer therapeutic, targets complex I of the electron transport chain leading to an accumulation of reactive oxygen species (ROS) that eventually lead to cell death. Inhibition of complex I leads to lactate production, a metabolic byproduct already highly produced by reprogrammed cancer cells and associated with a poor prognosis. While metformin remains a promising cancer therapeutic, we sought a complementary agent to increase apoptotic promoting effects of metformin while attenuating lactate production possibly leading to greatly improved efficacy. Dichloroacetate (DCA) is a well-established drug used in the treatment of lactic acidosis which functions through inhibition of pyruvate dehydrogenase kinase (PDK) promoting mitochondrial metabolism. Our purpose was to examine the synergy and mechanisms by which these two drugs kill breast cancer cells. Cell lines were subjected to the indicated treatments and analyzed for cell death and various aspects of metabolism. Cell death and ROS production were analyzed using flow cytometry, Western blot analysis, and cell counting methods. Images of cells were taken with phase contrast microscopy or confocal microscopy. Metabolism of cells was analyzed using the Seahorse XF24 analyzer, lactate assays, and pH analysis. We show that when DCA and metformin are used in combination, synergistic induction of apoptosis of breast cancer cells occurs. Metformin-induced oxidative damage is enhanced by DCA through PDK1 inhibition which also diminishes metformin promoted lactate production. We demonstrate that DCA and metformin combine to synergistically induce caspase-dependent apoptosis involving oxidative damage with simultaneous attenuation of metformin promoted lactate production. Innovative combinations such as metformin and DCA show promise in expanding breast cancer therapies.

Sanford School of Medicine, Sioux Falls Campus.

Miedema, Jayson, Daniel C. Zedek, Brian Z. Rayala, & E. Eugene Bain Iii. (2014). 9 tips to help prevent derm biopsy mistakes. Journal of Family Practice, 63(10), 559-564.


The article offers 9 tips for family physicians on how to prevent errors in conducting skin biopsy among patients.

Sanford School of Medicine, Sioux Falls Campus.

Novak, Jeanne, Wendy Parent-Johnson, Laura A. Owens, & Patricia Keul. (2014). National certification initiative for employment support professionals: Promoting quality integrated employment services. Journal of Vocational Rehabilitation, 40(2), 99-107.


This article describes a recent certification initiative to build an international network of professionals who have the knowledge and skills to provide quality integrated employment services to individuals with a variety of disabilities. An overview of the history and conceptual framework guiding the development of the Employment Support Professional Certification Program will be followed by a presentation of findings from a preliminary survey study of 93 professionals who have been certified. Survey respondents identified both personal and professional motivations for pursuing the Certified Employment Support Professional (CESP) designation, including the desire to (a) achieve a sense of accomplishment and personal satisfaction, (b) demonstrate a professional standard of competence and commitment to the profession, and (c) garner professional credibility and enhanced opportunities for career advancement. The authors describe ongoing efforts and recommendations for validating the credentialing program and for increasing the number of certified professionals equipped to establish and expand equitable employment opportunities for individuals with disabilities. (PsycINFO Database Record (c) 2014 APA, all rights reserved). (journal abstract)

Sanford School of Medicine, Sioux Falls Campus.

Radichev, Ilian A., Lilia V. Maneva-Radicheva, Christina Amatya, Camille Parker, Jacob Ellefson, Clive Wasserfall, . . . Alexei Y. Savinov. (2014). Nardilysin-Dependent Proteolysis of Cell-Associated VTCN1 (B7-H4) Marks Type 1 Diabetes Development. Diabetes, 63(10), 3470-3482.

T-cell responses directed against insulin-secreting pancreatic β-cells are the key events highlighting type 1 diabetes (T1D). Therefore, a defective control of T-cell activation is thought to underlie T1D development. Recent studies implicated a B7-like negative costimulatory protein, V-set domain-containing T-cell activation inhibitor-1 (VTCN1), as a molecule capable of inhibiting T-cell activation and, potentially, an important constituent in experimental models of T1D. Here, we unravel a general deficiency within the VTCN1 pathway that is shared between diabetes-prone mice and a subset of T1D patients. Gradual loss of membrane-tethered VTCN1 from antigen-presenting cells combined with an increased release of soluble VTCN1 (sVTCN1) occurs in parallel to natural T1D development, potentiating hyperproliferation of diabeto-genic T cells. Mechanistically, we demonstrate that the loss of membrane-tethered VTCN1 is linked to proteolytic cleavage mediated by the metalloproteinase nardilysin. The cleaved sVTCN1 fragment was detected at high levels in the peripheral blood of 53% T1D patients compared with only 9% of the healthy subjects. Elevated blood sVTCN1 levels appeared early in the disease progression and correlated with the aggressive pace of disease, highlighting the potential use of sVTCN1 as a new T1D biomarker, and identifying nardilysin as a potential therapeutic target.

Sanford School of Medicine, Sioux Falls Campus.

Savinova, Olga V., Kristi Fillaus, L. Jing, William S. Harris, & Gregory C. Shearer. (2014). Reduced Apolipoprotein Glycosylation in Patients with the Metabolic Syndrome. Plos One, 9(8), 9.

Objective: The purpose of this study was to compare the apolipoprotein composition of the three major lipoprotein classes in patients with metabolic syndrome to healthy controls. Methods: Very low density (VLDL), intermediate/low density (IDL/LDL, hereafter LDL), and high density lipoproteins (HDL) fractions were isolated from plasma of 56 metabolic syndrome subjects and from 14 age-sex matched healthy volunteers. The apolipoprotein content of fractions was analyzed by one-dimensional (1D) gel electrophoresis with confirmation by a combination of mass spectrometry and biochemical assays. Results: Metabolic syndrome patients differed from healthy controls in the following ways: (1) total plasma – apoA1 was lower, whereas apoB, apoC2, apoC3, and apoE were higher; (2) VLDL – apoB, apoC3, and apoE were increased; (3) LDL – apoC3 was increased, (4) HDL -associated constitutive serum amyloid A protein (SAA4) was reduced (p<0.05 vs. controls for all). In patients with metabolic syndrome, the most extensively glycosylated (di-sialylated) isoform of apoC3 was reduced in VLDL, LDL, and HDL fractions by 17%, 30%, and 25%, respectively (p<0.01 vs. controls for all). Similarly, the glycosylated isoform of apoE was reduced in VLDL, LDL, and HDL fractions by 15%, 26%, and 37% (p<0.01 vs. controls for all). Finally, glycosylated isoform of SAA4 in HDL fraction was 42% lower in patients with metabolic syndrome compared with controls (p<0.001). Conclusions: Patients with metabolic syndrome displayed several changes in plasma apolipoprotein composition consistent with hypertriglyceridemia and low HDL cholesterol levels. Reduced glycosylation of apoC3, apoE and SAA4 are novel findings, the pathophysiological consequences of which remain to be determined.

Sanford School of Medicine, Sioux Falls Campus.

Simpson, N. A., E. D. Wheeler, & David A. Pearce. (2014). Screening, diagnosis and epidemiology of Batten disease. Expert Opinion on Orphan Drugs, 2(9), 903-910.

Introduction: Batten disease, also called neuronal ceroid lipofuscinosis, describes a heterogeneous group of lysosomal storage disorders that are the most common inherited progressive neurodegenerative disorders in children. The disease is caused by mutations in the neuronal ceroid lipofusinoses (CLN) genes, which are mostly inherited in an autosomal recessive manner. Areas covered: Screening guidelines and diagnostic tools have been developed for Batten disease, and although improvements have been made to these tools they may not be widely available or accessible. While certain studies have investigated the epidemiology of Batten disease in certain geographic locations, the global prevalence of Batten disease is not well established. Expert opinion: An international patient registry may provide a mechanism to gather important data on individuals diagnosed with Batten disease and may serve as a resource that could help investigators better understand the epidemiology of the disease.

Sanford School of Medicine, Sioux Falls Campus.

Stewart, Brandie M., Jason P. Gallivan, Lee A. Baugh, & J. Randall Flanagan. (2014). Motor, not visual, encoding of potential reach targets. Current Biology, 24(19), R953-R954.

Summary We often encounter situations in which there are multiple potential targets for action, as when, for example, we hear the request “could you pass the …” at the dinner table. It has recently been shown that, in such situations, activity in sensorimotor brain areas represents competing reach targets in parallel prior to deciding between, and then reaching towards, one of these targets [1] . One intriguing possibility, consistent with the influential notion of action ‘affordances’ [2] , is that this activity reflects movement plans towards each potential target [3] . However, an equally plausible explanation is that this activity reflects an encoding of the visual properties of the potential targets (for example, their locations or directions), prior to any target being selected and the associated movement plan being formed. Notably, previous work showing spatial averaging behaviour during reaching, in which initial movements are biased towards the midpoint of the spatial distribution of potential targets [4–6] , remains equally equivocal concerning the motor versus visual encoding of reach targets. Here, using a rapid reaching task that disentangles these two competing accounts, we show that reach averaging behaviour reflects the parallel encoding of multiple competing motor plans. This provides direct evidence for theories proposing that the brain prepares multiple available movements before selecting between them [3] .

Sanford School of Medicine, Sioux Falls Campus.

Jang, Yuri, Soonhee Roh, & David A. Chiriboga. (2014). The impact of acculturation on depressive symptoms: A comparison of older Korean Americans in two areas. Asian American Journal of Psychology, 5(3), 200-205.

This study examined how the impact of acculturation on depressive symptoms varied between two samples of older Korean Americans. One sample was from west central Florida (low Korean density area; n = 672), and the other from the New York City metropolitan area (high Korean density area; n = 420). The average level of acculturation was lower among older Korean Americans in New York, compared to those living in Florida. In the hierarchical regression models with the New York sample, acculturation was initially significant in predicting depressive symptoms; however, its impact was gradually attenuated and eventually became nonsignificant with the sequential entry of control variables. On the other hand, in the Florida sample, the impact of acculturation on depressive symptoms remained significant throughout the models. The results suggest that the level and importance of acculturation may differ by geographic locations and invite further contextual research in immigrant populations.

School of Health Sciences.


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