Associations of Serum Uric Acid and SLC2A9 Variant with Depressive and Anxiety Disorders: A Population-Based Study.

BACKGROUND: Limited information exists regarding the association between serum uric acid (SUA) and psychiatric disorders. We explored the relationship between SUA and subtypes of major depressive disorder (MDD) and specific anxiety disorders. Additionally, we examined the association of SLC2A9 rs6855911 variant with anxiety disorders. METHODS: We conducted a cross-sectional analysis on 3,716 individuals aged 35-66 years previously selected for the population-based CoLaus survey and who agreed to undergo further psychiatric evaluation. SUA was measured using uricase-PAP method. The French translation of the semi-structured Diagnostic Interview for Genetic Studies was used to establish lifetime and current diagnoses of depression and anxiety disorders according to the DSM-IV criteria. RESULTS: Men reported significantly higher levels of SUA compared to women (357±74 µmol/L vs. 263±64 µmol/L). The prevalence of lifetime and current MDD was 44% and 18% respectively while the corresponding estimates for any anxiety disorders were 18% and 10% respectively. A quadratic hockey-stick shaped curve explained the relationship between SUA and social phobia better than a linear trend. However, with regards to the other specific anxiety disorders and other subtypes of MDD, there was no consistent pattern of association. Further analyses using SLC2A9 rs6855911 variant, known to be strongly associated with SUA, supported the quadratic relationship observed between SUA phenotype and social phobia. CONCLUSIONS: A quadratic relationship between SUA and social phobia was observed consistent with a protective effect of moderately elevated SUA on social phobia, which disappears at higher concentrations. Further studies are needed to confirm our observations.

Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy.

In 1980 the World Health Organization declared that smallpox was eradicated from the world, and routine smallpox vaccination was discontinued. Nevertheless, samples of the smallpox virus (variola virus) were retained for research purposes, not least because of fears that terrorist groups or rogue states might also have kept samples in order to develop a bioweapon. Variola virus represents an effective bioweapon because it is associated with high morbidity and mortality and is highly contagious. Since September 11, 2001, countries around the world have begun to develop policies and preparedness programs to deal with a bioterror attack, including stockpiling of smallpox vaccine. Smallpox vaccine itself may be associated with a number of serious adverse events, which can often be managed with vaccinia immune globulin (VIG). VIG may also be needed as prophylaxis in patients for whom pre-exposure smallpox vaccine is contraindicated (such as those with eczema or pregnant women), although it is currently not licensed in these cases. Two intravenous formulations of VIG (VIGIV Cangene and VIGIV Dynport) have been licensed by the FDA for the management of patients with progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and extensive body surface involvement or periocular implantation following inadvertent inoculation.

The novel ss469415590 variant predicts virological response to therapy in patients with chronic hepatitis C virus type 1 infection.

BACKGROUND: A novel dinucleotide variant TT/∆G (ss469415590) has been associated with hepatitis C virus clearance. AIM: To assess the role of the ss469415590 variant, compared with the known IL28B polymorphisms (rs8099917, rs12979860 and rs12980275) for predicting virological response to therapy in chronic hepatitis C, and its association with the CXCL10 chemokine serum levels - a surrogate marker of interferon-stimulated genes activation. METHODS: Multivariate analysis of factors predicting rapid and sustained virological response in 280 consecutive, treatment-naïve, nondiabetic, Caucasian patients with chronic hepatitis C treated with peginterferon alpha and ribavirin. RESULTS: In hepatitis C virus genotype 1, the OR (95% CI) for rapid and sustained virological response for the wild-type ss469415590 TT was 9.88 (1.99-48.99) and 7.25 (1.91-27.51), respectively, similar to those found for rs12979860 CC [9.55 (1.93-47.37) and 6.30 (1.71-23.13)] and for rs12980275 AA [9.62 (1.94-47.77] and 7.83 (2.02-30.34)], but higher than for rs8099917 TT [4.8 (1.73-13.33) and 4.75 (2.05-10.98)]. In hepatitis C virus genotype 1, mean (SD) CXCL10 levels in patients with the TT/TT, TT/∆G and ∆G/∆G variants were, respectively, 355.1 (240.6), 434.4 (247.4) and 569.9 (333.3) (P = 0.04). In patients with genotypes 2 and 3 no significant association was found for TT/∆G with viral response. The predictive value of ss469415590 was stronger in patients with advanced fibrosis. CONCLUSIONS: The novel IL28B variants at marker ss469415590 predict response to IFN alpha in chronic hepatitis C patients, especially in those with advanced fibrosis. Their determination may be superior to that of known IL28B variants for patient management using IFN-based regimens.

A natural structural variant of the mouse TCR beta-chain displays intrinsic receptor function and antigen specificity.

The Cbeta0 alternate cassette exon is located between the Jbeta1 and Cbeta1 genes in the mouse TCR beta-locus. In T cells with a VDJbeta1 rearrangement, the Cbeta0 exon may be included in TCRbeta transcripts (herein called TCRbeta-Cbeta0 transcripts), potentially inserting an additional 24 aa between the V and C domains of the TCR beta-chain. These TCRbeta splice isoforms may be differentially regulated after Ag activation, because we detected TCRbeta-Cbeta0 transcripts in a high proportion (>60%) of immature and mature T cells having VDJbeta1 rearrangements but found a substantially reduced frequency (<35%) of TCRbeta-Cbeta0 expression among CD8 T cells selected by Ag in vivo. To study the potential activity of the TCRbeta-Cbeta0 splice variant, we cloned full-length TCR cDNAs by single-cell RT-PCR into retroviral expression vectors. We found that the TCRbeta-Cbeta0 splice isoform can function during an early stage of T cell development normally dependent on TCR beta-chain expression. We also demonstrate that T hybridoma-derived cells expressing a TCRbeta-Cbeta0 isoform together with the clonally associated TCR alpha-chain recognize the same cognate peptide-MHC ligand as the corresponding normal alphabetaTCR. This maintenance of receptor function and specificity upon insertion of the Cbeta0 peptide cassette signifies a remarkable adaptability for the TCR beta-chain, and our findings open the possibility that this splice isoform may function in vivo.

Autologous stem cell transplantation: leukapheresis product has anti-angiogenic effects in vivo correlating with neutrophil-derived VEGFR1.

BACKGROUND: High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is used for the treatment of hemato-oncologic malignancies. In this study, we measured the effect of HDC/ASCT on plasma concentrations of antiangiogenic soluble vascular endothelial growth factor receptor 1 (sVEGFR1) and of leukapheresis products (LP) and patient serum on chick chorioallantoic (CAM) angiogenesis. MATERIALS AND METHODS: VEGFR1- and CD34-expressing cells of leukapheresis products were analyzed by flow cytometry. Alternatively spliced isoforms of VEGFR1 mRNA were quantified using reverse transcription PCR. RESULTS: Plasma concentrations of sVEGFR1 decreased after HDC, but significantly increased after ASCT. In the CAM assay, sera of patients elicited a proangiogenic effect before and after HDC, but a strong antiangiogenic response after ASCT, comparable to that of bevacizumab at therapeutic concentrations. LP contains high concentrations of sVEGFR1, and high density of VEGFR1(+) neutrophilic granulocytes, in which mRNA expression is shifted toward the soluble VEGFR1 isoform. CONCLUSION: Neutrophil-derived antiangiogenic sVEGFR1 within the LP may contribute to the therapeutic efficacy of ASCT.

Associations of serum uric acid and SLC2A9 variant with depressive and anxiety disorders: a population-based study

Background: Limited information exists regarding the association between serum uric acid (SUA) and psychiatric disorders. We explored the relationship between SUA and subtypes of major depressive disorder (MDD) and specific anxiety disorders. Additionally, we examined the association of SLC2A9 rs6855911 variant with anxiety disorders. Methods: We conducted a cross-sectional analysis on 3,716 individuals aged 35-66 years previously selected for the population-based CoLaus survey and who agreed to undergo further psychiatric evaluation. SUA was measured using uricase-PAP method. The French translation of the semi-structured Diagnostic Interview for Genetic Studies was used to establish lifetime and current diagnoses of depression and anxiety disorders according to the DSM-IV criteria. Results: Men reported significantly higher levels of SUA compared to women (357}74 μmol/L vs. 263}64 μmol/L). The prevalence of lifetime and current MDD was 44% and 18% respectively while the corresponding estimates for any anxiety disorders were 18% and 10% respectively. A quadratic hockey-stick shaped curve explained the relationship between SUA and social phobia better than a linear trend. However, with regards to the other specific anxiety disorders and other subtypes of MDD, there was no consistent pattern of association. Further analyses using SLC2A9 rs6855911 variant, known to be strongly associated with SUA, supported the quadratic relationship observed between SUA phenotype and social phobia. Conclusions: A quadratic relationship between SUA and social phobia was observed consistent with a protective effect of moderately elevated SUA on social phobia, which disappears at higher concentrations. Further studies are needed to confirm our observations.

Linker insertion mutagenesis based on IS21 transposition: isolation of an AMP-insensitive variant of catabolic ornithine carbamoyltransferase from Pseudomonas aeruginosa.

The bacterial insertion sequence IS21 when repeated in tandem efficiently promotes non-replicative cointegrate formation in Escherichia coli. An IS21-IS21 junction region which had been engineered to contain unique SalI and BglII sites close to the IS21 termini was not affected in the ability to form cointegrates with target plasmids. Based on this finding, a novel procedure of random linker insertion mutagenesis was devised. Suicide plasmids containing the engineered junction region (pME5 and pME6) formed cointegrates with target plasmids in an E.coli host strain expressing the IS21 transposition proteins in trans. Cointegrates were resolved in vitro by restriction with SalI or BglII and ligation; thus, insertions of four or 11 codons, respectively, were created in the target DNA, practically at random. The cloned Pseudomonas aeruginosa arcB gene encoding catabolic ornithine carbamoyltransferase was used as a target. Of 20 different four-codon insertions in arcB, 11 inactivated the enzyme. Among the remaining nine insertion mutants which retained enzyme activity, three enzyme variants had reduced affinity for the substrate ornithine and one had lost recognition of the allosteric activator AMP. The linker insertions obtained illustrate the usefulness of the method in the analysis of structure-function relationships of proteins.

Production of Acetic Acid by Fermentation with Propionibacteria, HR-321, 1993

This project was undertaken jointly with a project supported by the Iowa Corn Promotion Board. Together the projects aimed at producing the organic acids, propionic acid and acetic acid, by fermentation. The impacts were to provide agriculturally-based alternatives to production of these acids, currently produced mainly as petrochemicals. The potentially high-demand use for acetic acid is as the "acetate" in Calcium Magnesium Acetate (CMA), the non-corrosive road deicer. Fermentation was, however, far from being an economically acceptable alternative. Gains were made in this work toward making this a feasible route. These advances included (1) development of a variant strain of propionibacteria capable of producing higher concentrations of acids; (2) comparison of conditions for several ways of cultivating free cells and establishment of the relative benefits of each; (3) achievement of the highest productivity in fermentations using immobilized cells; (4) identification of corn steep liquor as a lower cost substrate for the fermentation; (5) application of a membrane extraction system for acid recovery and reduction of product inhibition; and (6) initial use of more detailed economic analysis of process alternatives to guide in the identification of where the greatest payback potential is for future research. At this point, the fermentation route to these acids using the propionibacteria is technically feasible, but economically unfeasible. Future work with integration of the above process improvements can be expected to lead to further gains in economics. However, such work can not be expected to make CMA a less expensive deicer than common road salt.

Asphalt Cement Concrete Longitudinal Joint Adhesive Crafco PN 34524 (Iowa DOT New Product C-98-7), HR-2084, 2000

The joint between two lanes of asphalt pavement is often the first area of a roadway which shows signs of deterioration and requires maintenance. As the final lift of hot asphalt is being placed in a construction project, it is being forced p against the adjoining lane of cold asphalt, forming the longitudinal joint. The mating of the two lanes, to form a high quality seal, is often not fully successful and later results in premature stripping or raveling as water enters the unsealed joint. The application of a hot poured rubberized asphaltic joint sealant along the joint face in the final stage of construction should help to form a watertight joint seal. A new product, especially formulated for the longitudinal joint in asphalt pavements was proposed to improve joint sealing. The following describes the experimental application of the new product, Crafco, PN 34524.

Role of β-TrCP1, variant and homologue in HIV-1 life cycle

Summary The CD4 molecule plays a key role in AIDS pathogenesis, it is required for entry of the virus into permissive cells and its subsequent down-modulation of the cell surface is a hallmark of HN-1 infected cells. The virus encodes no less than three proteins that participate in this process: Nef, Vpu and Env. Vpu protein interacts with CD4 within the endoplasmic reticulum of infected cells, where it targets CD4 for degradation through the interaction with a cellular protein named ß-TrCP1. This F-box protein functions as the substrate recognition subunit of the SCF ß-Trcr E3 ubiquitin ligase, which normally induce the ubiquitination and subsequent degradation of various proteins such as ß-catenin and IxBa. Mammals possess a homologue of ß-TrCP1, HOS, also named ß-TrCP2 which has a cytoplasmic subcellular distribution. Structural analysis of the ligand-binding domain of both homologues shows striking surface similarities. Both F-box proteins have a redundant role in a number of cellular processes; however the potential role of ß-TrCP2 in HIV-1 infected cells has not been evaluated. In the present study, we assessed the existence of génetic variants of BRTC, encoding ß-TrCP1, and evaluated whether these variants would affect CD4 down-modulation. Additionally, we determined whether ß-TrCP2 shares with its homologue structural and functional properties that would allow it to bind Vpu, modulate CD4 expression, and thus participate in HN-1 pathogenesis. We identified a single nucleotide polymorphism present in the human population with an allelic frequency of 0.03 that leads to the substitution of alanine 507 by a serine. However, we showed by transient transfection in HeLa CD4+ cells that this variant behaves as ß-TrCP1 with respect to CD4 down-modulation. We established transient expression systems in HeLa CD4+ cells to test whether ß-TrCP2 is implicated in Vpu-mediated CD4 down-modulation. We show by coimmunoprecipitation experiments that ß-TrCP2 binds Vpu and is able to induce CD4 down-modulation as efficiently as ß-TrCP1. In two different cell lines, HeLa CD4+ and Jurkat, Vpu-mediated CD4 down-modulation could not be completely reversed through the silencing of endogenous ß-TrCP 1 or ß-TrCP2 individually, but required both genes to be silenced simultaneously. We evaluated the role of ß-TrCP1 and ß-TrCP2 in HIV-1 life cycle using silencing prior to actual viral infection. Both ß-TrCP1 and ß-TrCP2 contributed to CD4 down-modulation during aone-cycle viral infection iri Ghost cells. In addition, the combined silencing of both homologues in the absence of env and nef reversed CD4 down-modulation, showing that ß-TrCP 1 and ß-TrCP2 represent the main and additive effectors of HIV-1 encoded Vpu. In addition, we showed that silencing of ß-TrCPI but not ß-TrCP2 induced a decrease of HIV-1 LTR-driven expression. In a transient transfection system with Tat and a LTR luciferase reporter, both homologues modulated LTR-driven expression. The present study revealed that ß-TrCP2 represents a novel protein participating in HIV-1 cycle and complete comprehension of the complex interplay occurring between the two F-Box will improve our understanding of HIV-1 infection. Résumé La molécule CD4 joue un rôle clef dans la pathogenèse du SIDA ; elle est requise pour l'entrée du virus dans les cellules permissives et la diminution de sa concentration au niveau de la surface cellulaire est une importante caractéristique des cellules infectées par le VIH-1. Le virus encode pas moins de trois protéines qui participent à ce processus Nef, Vpu et Env. La protéine Vpu lie CD4 au niveau du réticulum endoplasmique et induit sa dégradation en interagissant avec une protéine cellulaire nommée ß-TrCP 1. Cette protéine de type F-Box est une sous unité du complexe ubiquitine-ligase E3 SCFß-TrCP. Elle permet la reconnaissance du substrat par le complexe qui induit l'ubiquitination et la subséquente dégradation de diverses protéines cellulaires comme la ß-catenin ou IκBα. Les mammifères possèdent un homologue à ß-TrCP1appelé ß-TrCP2 (ou HOS). L'analyse comparative du domaine permettant la reconnaissance des substrats des deux homologues montre de frappantes similarités. Le rôle de ß-TrCP2 dans le cycle viral du VIH-1 n'a pas encore été évalué. Lors de cette étude, nous avons recherché l'existence de variants génétique de BTRC (codant pour ß-TrCP1) et nous avons évalué si ces variants pourraient affecter la dégradation des molécules CD4 induite par le virus. Nous avons ainsi identifié un polymorphisme présent dans la population humaine avec une fréquence allélique de 0.03 qui consiste en une substitution de l'alanine 507 par une sérine. Nous avons cependant montré par transfection dans des cellules HeLa CD4+ que ce variant se comporte comme ß-TrCP 1 en ce qui concerne la modulation de CD4. De plus, nous avons déterminé si ß-TrCP2 partageait avec son homologue des propriétés structurelles et fonctionnelles qui lui permettraient de lier Vpu, moduler la concentration de CD4 et ainsi prendre part à la pathogenèse du SIDA. Pour ce faire, nous avons établi un système d'expression temporaire dans des cellules HeLa CD4+. Par co-immunoprécipitation, nous avons montré que ß-TrCP2 lie Vpu et est capable d'induire la dégradation de CD4 aussi efficacement que ß-TrCP1. Dans deux différentes lignées cellulaires, HeLa CD4+ et Jurkat, la dégradation de CD4 n'a pu être complètement inhibée par le silencing individuel de ß-TrCP 1 ou ß-TrCP2, mais nécessitait le silencing simultané des 2 gènes. Nous avons évalué le rôle des deux homologues dans le cycle viral du VIH-1 en infectant des cellules Ghost avec le virus après avoir effectué un silencing des deux protéines. Nous avons ainsi montré que ß-TrCP 1 et ß-TrCP2 contribuent de manière additive à la dégradation de CD4 induite par une infection du VIH-1. Le silencing combiné des deux homologues inhiba complètement cette dégradation en l'absence de env et nef, prouvant qu'aucune autre voie ne participe à ce processus: En outre, nous avons montré que le silencing de ß-TrCP 1 mais pas celui de ß-TrCP2 induisait une diminution de l'expression virale sous contrôle du LTR. Nous n'avons cependant pas été en mesure de reconstituer cet effet en exprimant Tat et un gène reporteur sous contrôle du LTR dans des cellules HeLa CD4+. Le présent travail révèle que ß-TrCP2 représente une nouvelle protéine participant dans le cycle viral du VIH-1. Une complète compréhension de l'effet de chacun des deux homologues sur le cycle viral permettra d'améliorer notre compréhension de l'infection par le VIH-1.

Development of an Improved Agricultural-Based Deicing Product, TR-581, 2010

Snow and ice removal on public streets is a critical part of the work of departments of transportation in northern U.S. states, including Iowa. Iowa is also a state rich in agricultural resources, some of which undergo industrial processes that generate a number of byproducts, e.g., in converting corn to ethanol or soy to biodiesel. It would be desirable to find those that, with a minimum of additional processing, can be used as a deicing compound, either alone or in combination with products currently in use. The focus of this work is therefore to investigate by-products from agricultural processes that may be suitable for use as deicing applications. This topic has been investigated in the past by others, with many patented products described in the literature. An initial screening was carried out to assess the potential acceptability of selected commercial products, as well as a glycerol developed for this project. Based on the variety of parameters tested, the product combination that shows the greatest promise for future application consists of 80% glycerol with 20% NaCl.