Changes in isoprenoid lipid synthesis by gemfibrozil and clofibric acid in rat hepatocytes.

Science.gov (United States)

Hashimoto, F; Taira, S; Hayashi, H

2000-05-15

We studied whether gemfibrozil and clofibric acid alter isoprenoid lipid synthesis in rat hepatocytes. After incubation of the cells with the agent for 74 hr, [(14)C]acetate or [(3)H]mevalonate was added, and the cells were further incubated for 4 hr. Gemfibrozil and clofibric acid increased ubiquinone synthesis from [(14)C]acetate and [(3)H]mevalonate. The effect of gemfibrozil was greater than that of clofibric acid. Also, gemfibrozil decreased dolichol synthesis from [(14)C]acetate and [(3)H]mevalonate. However, clofibric acid increased dolichol synthesis from [(3)H]mevalonate. Gemfibrozil decreased cholesterol synthesis from [(14)C]acetate and [(3)H]mevalonate. Clofibric acid decreased cholesterol synthesis from [(14)C]acetate, but did not affect synthesis from [(3)H]mevalonate. These results suggest that both agents, at different rates, activate the synthetic pathway of ubiquinone, at least from mevalonate. Gemfibrozil may inhibit the synthetic pathway of dolichol, at least from mevalonate. Contrary to gemfibrozil, clofibric acid may activate the synthetic pathway of dolichol from mevalonate. Gemfibrozil may inhibit the synthetic pathway of cholesterol from mevalonate in addition to the pathway from acetate to mevalonate inhibited by both agents.

Can vaccinia virus be replaced by MVA virus for testing virucidal activity of chemical disinfectants?

Directory of Open Access Journals (Sweden)

Rapp Ingrid

2010-06-01

Full Text Available Abstract Background Vaccinia virus strain Lister Elstree (VACV is a test virus in the DVV/RKI guidelines as representative of the stable enveloped viruses. Since the potential risk of laboratory-acquired infections with VACV persists and since the adverse effects of vaccination with VACV are described, the replacement of VACV by the modified vaccinia Ankara strain (MVA was studied by testing the activity of different chemical biocides in three German laboratories. Methods The inactivating properties of different chemical biocides (peracetic acid, aldehydes and alcohols were tested in a quantitative suspension test according to the DVV/RKI guideline. All tests were performed with a protein load of 10% fetal calf serum with both viruses in parallel using different concentrations and contact times. Residual virus was determined by endpoint dilution method. Results The chemical biocides exhibited similar virucidal activity against VACV and MVA. In three cases intra-laboratory differences were determined between VACV and MVA - 40% (v/v ethanol and 30% (v/v isopropanol are more active against MVA, whereas MVA seems more stable than VACV when testing with 0.05% glutardialdehyde. Test accuracy across the three participating laboratories was high. Remarkably inter-laboratory differences in the reduction factor were only observed in two cases. Conclusions Our data provide valuable information for the replacement of VACV by MVA for testing chemical biocides and disinfectants. Because MVA does not replicate in humans this would eliminate the potential risk of inadvertent inoculation with vaccinia virus and disease in non-vaccinated laboratory workers.

Structural Basis for Nucleotide Binding and Reaction Catalysis in Mevalonate Diphosphate Decarboxylase

Energy Technology Data Exchange (ETDEWEB)

Barta, Michael L.; McWhorter, William J.; Miziorko, Henry M.; Geisbrecht, Brian V. (UMKC)

2012-09-17

Mevalonate diphosphate decarboxylase (MDD) catalyzes the final step of the mevalonate pathway, the Mg{sup 2+}-ATP dependent decarboxylation of mevalonate 5-diphosphate (MVAPP), producing isopentenyl diphosphate (IPP). Synthesis of IPP, an isoprenoid precursor molecule that is a critical intermediate in peptidoglycan and polyisoprenoid biosynthesis, is essential in Gram-positive bacteria (e.g., Staphylococcus, Streptococcus, and Enterococcus spp.), and thus the enzymes of the mevalonate pathway are ideal antimicrobial targets. MDD belongs to the GHMP superfamily of metabolite kinases that have been extensively studied for the past 50 years, yet the crystallization of GHMP kinase ternary complexes has proven to be difficult. To further our understanding of the catalytic mechanism of GHMP kinases with the purpose of developing broad spectrum antimicrobial agents that target the substrate and nucleotide binding sites, we report the crystal structures of wild-type and mutant (S192A and D283A) ternary complexes of Staphylococcus epidermidis MDD. Comparison of apo, MVAPP-bound, and ternary complex wild-type MDD provides structural information about the mode of substrate binding and the catalytic mechanism. Structural characterization of ternary complexes of catalytically deficient MDD S192A and D283A (k{sub cat} decreased 10{sup 3}- and 10{sup 5}-fold, respectively) provides insight into MDD function. The carboxylate side chain of invariant Asp{sup 283} functions as a catalytic base and is essential for the proper orientation of the MVAPP C3-hydroxyl group within the active site funnel. Several MDD amino acids within the conserved phosphate binding loop ('P-loop') provide key interactions, stabilizing the nucleotide triphosphoryl moiety. The crystal structures presented here provide a useful foundation for structure-based drug design.

Crystallization and preliminary X-ray diffraction analysis of mevalonate kinase from Methanosarcina mazei

International Nuclear Information System (INIS)

Zhuang, Ningning; Seo, Kyung Hye; Chen, Cong; Zhou, Jia; Kim, Seon Won; Lee, Kon Ho

2012-01-01

Recombinant mevalonate kinase from M. mazei has been crystallized. Diffraction data were collected to 2.08 Å resolution. Mevalonate kinase (MVK), which plays an important role in catalysing the biosynthesis of isoprenoid compounds derived from the mevalonate pathway, transforms mevalonate to 5-phosphomevalonate using ATP as a cofactor. Mevalonate kinase from Methanosarcina mazei (MmMVK) was expressed in Escherichia coli, purified and crystallized for structural analysis. Diffraction-quality crystals of MmMVK were obtained by the vapour-diffusion method using 0.32 M MgCl 2 , 0.08 M bis-tris pH 5.5, 16%(w/v) PEG 3350. The crystals belonged to space group P2 1 2 1 2, with unit-cell parameters a = 97.11, b = 135.92, c = 46.03 Å. Diffraction data were collected to 2.08 Å resolution

Barriers to Sustainable MVA Supply in Ghana: Challenges for the ...

African Journals Online (AJOL)

Multiple studies have demonstrated that manual vacuum aspiration (MVA) is ideal for surgical uterine evacuation in low-resource settings such as Ghana, but developing a sustainable supply to MVA has been challenging. In 2007 a situational analysis was conducted in Ghana to identify barriers to sustainable MVA supply.

Effects of 2,3-iminosqualene in cultured cells

International Nuclear Information System (INIS)

Popjak, G.; Meenan, A.; Nes, W.D.

1987-01-01

2,3-Iminosqualene added to culture media 10 ug/ml) of rat hepatoma (H4-II-E-C3) or Chinese hamster ovary (CHO) cells irreversibly inactivates the squalene-oxide: lanosterol cyclase, but it does not inhibit general polyprenyl synthesis either from [ 14 C]acetate or [ 14 C]mevalonate. Isq added to lipoprotein-containing media of H4 cells causes in 24 hr an over twofold rise in HMG-CoA reductase and abolishes the repressive effect of mevalonate (MVA) on the reductase. H4 cells synthesize from [2- 14 C]-MVA labelled squalene, squalene-2,3-oxide, squalene-2,3-22,23-dioxide, but very little sterol. The conversion of MVA to these polyprenyls in the presence of Isq is as efficient as its conversion to squalene and cholesterol in control cells. They conclude that the repressor of HMG-CoA reductase derived from MVA is a sterol - whatever might be the nature of that sterol - and not a nonsteroidal derivative of MVA metabolism. H4 cells exposed to Isq in lipid-depleted media die in 48-72 hr, but can be rescued by LDL, but not by free cholesterol or MVA. CHO cells are more resistant than H4 cells and succumb only after 8-9 days' exposure to Isq

Poly-MVA attenuates 7,12- dimethylbenz[a]anthracene initiated and croton oil promoted skin papilloma formation on mice skin.

Science.gov (United States)

Veena, Ravindran K; Ajith, Thekkuttuparambil A; Janardhanan, Kainoor K; Antonawich, Francis

2017-09-01

Chemopreventive agents which exhibit activities such as anti-inflammation, inhibition of carcinogen induced mutagenesis and scavenging of free radical might play a decisive role in the inhibition of chemical carcinogenesis either at the initiation or promotion stage. Many synthesized palladium (Pd) complexes tested experimentally for antitumor activity are found effective. Poly-MVA is a liquid blend preparation containing B complex vitamins, ruthenium with Pd complexed with alpha lipoic acid as the major ingredients. The antitumor effect of Poly-MVA was evaluated against 7,12-dimethylbenz[a] anthracene-initiated croton oil-promoted papilloma formation on mice skin. Skin tumor was initiated with a single application of 390 nmol of DMBA in 20 µl acetone. The effect of Poly-MVA against croton oil- induced inflammation and lipid peroxidation on the mice skin was also evaluated. Topical application of Poly-MVA (100 µl, twice weekly for 18 weeks) 30 minutes prior to each croton oil application, significantly decreased the tumor incidence (11%) and the average number of tumor per animals. Application of Poly-MVA (100 µl) before croton oil significantly (p < 0.05) protected the mouse skin from inflammation (36%) and lipid peroxidation (14%) when compared to the croton oil alone treated group. Experimental results indicate that Poly-MVA attenuate the tumor promoting effects of croton oil and the effect may probably be due to its anti-inflammatory and antioxidant activity.

Are pleiotropic effects of statins real?

Directory of Open Access Journals (Sweden)

Alberto Corsini

2007-11-01

Full Text Available Alberto Corsini, Nicola Ferri, Michele CortellaroDepartment of Pharmacological Sciences and Department of Clinical Sciences, “Luigi Sacco”, University of Milan, Milan, ItalyAbstract: The clinical benefits of statins are strongly related to their low density lipoproteincholesterol (LDL-C lowering properties. However, because mevalonic acid (MVA, the product of 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA reductase reaction, is the precursor not only of cholesterol but also of nonsteroidal isoprenoid compounds, the inhibition of HMG-CoA reductase may result in pleiotropic effects, independent of their hypocholesterolemic properties. The discrimination between the pleiotropic from LDL-C lowering effects may potentially be more evident during the early phase of treatment since plasma MVA levels drop up to 70% within 1–2 hours while a reduction of LDL-C, detectable after 24 hours, became significant after 6–7 days. Therefore, the deprivation of circulating MVA-derived isoprenoids in the early phase of treatment could be the main mechanism responsible for the atheroprotective effect of statins. This early window of protection in the absence of LDL-C lowering suggests that the anti-inflammatory and the pleiotropic properties of statins may have clinical importance. Therefore, acute coronary syndromes could represent a clinical condition for addressing the early benefits of statins therapy, ie, within 24 h of the event, independent of LDL-C lowering.Keywords: anti-inflammatory effects of statins, mevalonate pathway, LDL lowering, acute coronary syndrome, prenylated proteins

A Novel AT-Rich DNA Recognition Mechanism for Bacterial Xenogeneic Silencer MvaT.

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Pengfei Ding

2015-06-01

Full Text Available Bacterial xenogeneic silencing proteins selectively bind to and silence expression from many AT rich regions of the chromosome. They serve as master regulators of horizontally acquired DNA, including a large number of virulence genes. To date, three distinct families of xenogeneic silencers have been identified: H-NS of Proteobacteria, Lsr2 of the Actinomycetes, and MvaT of Pseudomonas sp. Although H-NS and Lsr2 family proteins are structurally different, they all recognize the AT-rich DNA minor groove through a common AT-hook-like motif, which is absent in the MvaT family. Thus, the DNA binding mechanism of MvaT has not been determined. Here, we report the characteristics of DNA sequences targeted by MvaT with protein binding microarrays, which indicates that MvaT prefers binding flexible DNA sequences with multiple TpA steps. We demonstrate that there are clear differences in sequence preferences between MvaT and the other two xenogeneic silencer families. We also determined the structure of the DNA-binding domain of MvaT in complex with a high affinity DNA dodecamer using solution NMR. This is the first experimental structure of a xenogeneic silencer in complex with DNA, which reveals that MvaT recognizes the AT-rich DNA both through base readout by an "AT-pincer" motif inserted into the minor groove and through shape readout by multiple lysine side chains interacting with the DNA sugar-phosphate backbone. Mutations of key MvaT residues for DNA binding confirm their importance with both in vitro and in vivo assays. This novel DNA binding mode enables MvaT to better tolerate GC-base pair interruptions in the binding site and less prefer A tract DNA when compared to H-NS and Lsr2. Comparison of MvaT with other bacterial xenogeneic silencers provides a clear picture that nature has evolved unique solutions for different bacterial genera to distinguish foreign from self DNA.

Development of 50 MVA superconducting generator

International Nuclear Information System (INIS)

Ueda, Kiyotaka; Maki, Naoki; Takahashi, Noriyoshi; Ogata, Hisanao; Sanematsu, Toshihiro.

1984-01-01

Superconducting synchronous generators are expected to be the large capacity turbogenerators of next generation, but they have the structural features considerably different from conventional generators, such as low temperature multiple cylinder rotors and air gap armature winding. For the purpose of grasping the performance of superconducting generators and establishing the fundamental technology for their practical use, Hitachi Ltd. manufactured a 50 MVA superconducting generator. As the results of test, the precooling operation was smoothly finished for about 40 hours, and the superconducting rotor rotated stably at 3000 rpm. The steady and transient electrical characteristics were able to be grasped. It is intended to reflect these results to the development of a practical generator of 500 MVA class expected as the next step. When the superconducting exciting winding cooled by liquid helium is used, the reduction of weight, the improvement of efficiency and the improvement of the stability of power system can be expected. The structural features and the function of superconducting generators, the present state of the development in the world, the outline of the 50 MVA generator, the test results and the problems and the prospect hereafter are reported. The superconducting winding was made of NbTiZr alloy multicore wires. (Kako, I.)

FWI and MVA the natural way

KAUST Repository

Alkhalifah, Tariq Ali

2014-01-01

Integrating migration velocity analysis (MVA) and full waveform inversion (FWI) can help reduce the high nonlinearity of the classic FWI objective function. The combination of inverting for the long and short wavelength components of the velocity model using a dual objective function that is sensitive to both components is still very expensive and have produced mixed results. We develop an approach that includes both components integrated to complement each other. We specifically utilize the image to generate reflections in our synthetic data only when the velocity model is not capable of producing such reflections. As a result, we get the MVA working when we need it, and mitigate it\\'s influence when the velocity model produces accurate reflections (possible first for the low frequencies). Applications to a layered model, as well as, the Marmousi model demonstrate some of the approach features.

Development and Test of a Prototype 100MVA Superconducting Generator

Energy Technology Data Exchange (ETDEWEB)

Fogarty, James M.; Bray, James W.

2007-05-25

In 2002, General Electric and the US Department of Energy (DOE) entered into a cooperative agreement for the development of a commercialized 100 MVA generator using high temperature superconductors (HTS) in the field winding. The intent of the program was to: • Identify and develop technologies that would be needed for such a generator. • Develop conceptual designs for generators with ratings of 100 MVA and higher using HTS technology. • Perform proof of concept tests at the 1.5 MW level for GE’s proprietary warm iron rotor HTS generator concept. • Design, build, and test a prototype of a commercially viable 100 MVA generator that could be placed on the power grid. This report summarizes work performed during the program and is provided as one of the final program deliverables.

Risk-Informed Monitoring, Verification and Accounting (RI-MVA). An NRAP White Paper Documenting Methods and a Demonstration Model for Risk-Informed MVA System Design and Operations in Geologic Carbon Sequestration

Energy Technology Data Exchange (ETDEWEB)

Unwin, Stephen D.; Sadovsky, Artyom; Sullivan, E. C.; Anderson, Richard M.

2011-09-30

This white paper accompanies a demonstration model that implements methods for the risk-informed design of monitoring, verification and accounting (RI-MVA) systems in geologic carbon sequestration projects. The intent is that this model will ultimately be integrated with, or interfaced with, the National Risk Assessment Partnership (NRAP) integrated assessment model (IAM). The RI-MVA methods described here apply optimization techniques in the analytical environment of NRAP risk profiles to allow systematic identification and comparison of the risk and cost attributes of MVA design options.

Possible regulation of sterol biosynthesis by phenolic acids

International Nuclear Information System (INIS)

Ranganathan, S.; Ramasarma, T.

1974-01-01

To test whether the phenolic acids, metabolites of tyrosine, regulate the biosynthesis of cholesterol, influence of phenolic acids on the incorporation of mevalonate-2- 14 C into sterols by rat liver and brain homogenate systems has been investigated in vitro. Results show that the combined presence of the aromatic ring and the carboxyl group in the compound under investigation inhibited the incorporation of labelled mevalonate. (M.G.B.)

Biosynthesis of sesquiterpenes in grape berry exocarp of Vitis vinifera L.: evidence for a transport of farnesyl diphosphate precursors from plastids to the cytosol.

Science.gov (United States)

May, Bianca; Lange, B Markus; Wüst, Matthias

2013-11-01

The participation of the mevalonic acid (MVA) and 1-deoxy-d-xylulose 5-phosphate/2-C-methyl-d-erythritol-4-phosphate (DOXP/MEP) pathways in sesquiterpene biosynthesis of grape berries was investigated. There is an increasing interest in this class of terpenoids, since the oxygenated sesquiterpene rotundone was identified as the peppery aroma impact compound in Australian Shiraz wines. To investigate precursor supply pathway utilization, in vivo feeding experiments were performed with the deuterium labeled, pathway specific, precursors [5,5-(2)H2]-1-deoxy-d-xylulose and [5,5-(2)H2]-mevalonic acid lactone. Head Space-Solid Phase Micro Extraction-Gas Chromatography-Mass Spectrometry (HS-SPME-GC-MS) analysis of the generated volatile metabolites demonstrated that de novo sesquiterpene biosynthesis is mainly located in the grape berry exocarp (skin), with no detectable activity in the mesocarp (flesh) of the Lemberger variety. Interestingly, precursors from both the (primarily) cytosolic MVA and plastidial DOXP/MEP pathways were incorporated into grape sesquiterpenes in the varieties Lemberger, Gewürztraminer and Syrah. Our labeling data provide evidence for a homogenous, cytosolic pool of precursors for sesquiterpene biosynthesis, indicating that a transport of precursors occurs mostly from plastids to the cytosol. The labeling patterns of the sesquiterpene germacrene D were in agreement with a cyclization mechanism analogous to that of a previously cloned enantioselective (R)-germacrene D synthase from Solidago canadensis. This observation was subsequently confirmed by enantioselective GC-MS analysis demonstrating the exclusive presence of (R)-germacrene D, and not the (S)-enantiomer, in grape berries. Copyright © 2013 Elsevier Ltd. All rights reserved.

1 MVA HTS-2G Generator for Wind Turbines

Science.gov (United States)

Kovalev, K. L.; Poltavets, V. N.; Ilyasov, R. I.; Verzhbitsky, L. G.; Kozub, S. S.

2017-10-01

The calculation, design simulations and design performance of 1 MVA HTS-2G (second-generation high-temperature superconductor) Generator for Wind Turbines were done in 2013-2014 [1]. The results of manufacturing and testing of 1 MVA generator are presented in the article. HTS-2G field coils for the rotor were redesigned, fabricated and tested. The tests have shown critical current of the coils, 41-45 A (self field within the ferromagnetic core, T = 77 K), which corresponds to the current of short samples at self field. Application of the copper inner frame on the pole has improved internal cooling conditions of HTS coil windings and reduced the magnetic field in the area, thereby increased the critical current value. The original construction of the rotor with a rotating cryostat was developed, which decreases the thermal in-flow to the rotor. The stator of 1 MW HTS-2G generator has been manufactured. In order to improve the specific weight of the generator, the wave (harmonic drive) multiplier was used, which provides increasing RPM from 15 RPM up to 600 RPM. The total mass of the multiplier and generator is significantly smaller compared to traditional direct-drive wind turbines generators [2-7]. Parameters of the multiplier and generator were chosen based on the actual parameters of wind turbines, namely: 15 RPM, power is 1 MVA. The final test of the assembled synchronous generator with HTS-2G field coils for Wind Turbines with output power 1 MVA was completed during 2015.

The candidate TB vaccine, MVA85A, induces highly durable Th1 responses.

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Michele Tameris

Full Text Available Vaccination against tuberculosis (TB should provide long-term protective immunity against Mycobacterium tuberculosis (M.tb. The current TB vaccine, Bacille Calmette-Guerin (BCG, protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. One potential reason for the limited durability of protection may be waning of immunity through gradual attrition of BCG-induced T cells. We determined if a MVA85A viral-vector boost could enhance the durability of mycobacteria-specific T cell responses above those induced by BCG alone.We describe a long-term follow-up study of persons previously vaccinated with MVA85A. We performed a medical history and clinical examination, a tuberculin skin test and measured vaccine-specific T cell responses in persons previously enrolled as adults, adolescents, children or infants into three different Phase II trials, between 2005 and 2011.Of 252 potential participants, 183 (72.6% consented and completed the study visit. Vaccine-induced Ag85A-specific CD4+ T cell responses were remarkably persistent in healthy, HIV-uninfected adults, adolescents, children and infants, up to 6 years after MVA85A vaccination. Specific CD4+ T cells expressed surface markers consistent with either CD45RA-CCR7+ central memory or CD45RA-CCR7- effector memory T cells. Similarly durable Ag85A-specific CD4+ T cell responses were detected in HIV-infected persons who were on successful antiretroviral therapy when MVA85A was administered. By contrast, Ag85A-specific CD4+ T cell frequencies in untreated MVA85A-vaccinated HIV-infected persons were mostly undetectable 3-5 years after vaccination.MVA85A induces remarkably durable T cell responses in immunocompetent persons. However, results from a recent phase IIb trial of MVA85A, conducted in infants from the same geographic area and study population, showed no vaccine efficacy, suggesting that these durable T cell responses do not

Alteration of Mevalonate Pathway in Rat Splenic Lymphocytes: Possible Role in Cytokines Secretion Regulated by L-Theanine

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Chengjian Li

2018-01-01

Full Text Available L-Theanine is a nonprotein amino acid in tea, and its immunomodulatory function has been confirmed. This study aimed to investigate the effect of L-theanine addition on cytokines secretion in rat splenic lymphocytes and explore its potential immunomodulatory effects on the mevalonate biosynthetic pathway. Our results showed that L-theanine treatment did not influence the proliferation and division indexes of the splenic lymphocytes subsets. Interestingly, L-theanine treatment had regulated the contents of IFN-γ, IL-2, IL-4, IL-10, IL-12, and TNF-α  (P<0.001 except IL-6 and upregulated the mRNA and protein expression of Ras-related protein Rap-1A (Rap1A, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR, and farnesyl diphosphate synthase (FDPs (P<0.001. Additionally, there was a positive correlation between Rap1A and HMGCR proteins expression and IFN-γ, IL-4, and IL-6 levels. In conclusion, L-theanine regulated the secretion of cytokines probably by activating expression of Rap1A and HMGCR proteins involved in the mevalonate biosynthetic pathway in rat splenic lymphocytes. Therefore, L-theanine might be a promising potential drug candidate as immunopotentiator.

Proteomic Analysis of Lettuce Seed Germination and Thermoinhibition by Sampling of Individual Seeds at Germination and Removal of Storage Proteins by Polyethylene Glycol Fractionation1

Science.gov (United States)

Song, Bin-Yan; Deng, Zhi-Jun; Wang, Yue; Liu, Shu-Jun; Møller, Ian Max; Song, Song-Quan

2015-01-01

Germination and thermoinhibition in lettuce (Lactuca sativa ‘Jianyexianfeng No. 1’) seeds were investigated by a proteomic comparison among dry seeds, germinated seeds at 15°C, at 15°C after imbibition at 25°C for 48 h, or at 25°C in KNO3 (all sampled individually at germination), and ungerminated seeds at 25°C, a thermoinhibitory temperature. Before two-dimensional gel electrophoresis analysis, storage proteins (greater than 50% of total extractable protein) were removed by polyethylene glycol precipitation, which significantly improved the detection of less abundant proteins on two-dimensional gels. A total of 108 protein spots were identified to change more than 2-fold (P lettuce seed germination and thermoinhibition. Accumulation of three proteins and expression of five genes participating in the mevalonate (MVA) pathway of isoprenoid biosynthesis correlated positively with seed germinability. Inhibition of this pathway by lovastatin delayed seed germination and increased the sensitivity of germination to abscisic acid. MVA pathway-derived products, cytokinins, partially reversed the lovastatin inhibition of germination and released seed thermoinhibition at 25°C. We conclude that the MVA pathway for isoprenoid biosynthesis is involved in lettuce seed germination and thermoinhibition. PMID:25736209

Regulation of the Mevalonate Pathway for the Prevention of Breast Cancer

National Research Council Canada - National Science Library

Archer, Michael

2000-01-01

...) can be accounted for by their inhibitory effect on the cholesterol biosynthesis (mevalonate) pathway. In Task 1, we have shown that the decrease in mammary gland HMG-CoA reductase seen in LDL-R -/- mice compared...

Biosynthesis of 2-methyl-3-buten-2-ol emitted from needles of Pinus ponderosa via the non-mevalonate DOXP/MEP pathway of isoprenoid formation.

Science.gov (United States)

Zeidler, J; Lichtenthaler, H K

2001-06-01

The volatile hemiterpene 2-methyl-3-buten-2-ol (MBO) is emitted from the needles of several pine species from the Western United States and contributes to ozone formation in the atmosphere. It is synthesised enzymatically from dimethylallyl diphosphate (DMAPP). We show here that needles of Pinus ponderosa Laws. incorporated [1-2H1]-1-deoxy-D-xylulose (d-DOX) into the emitted MBO, but not D,L-[2-13C]mevalonic acid lactone. Furthermore, MBO emission was inhibited by fosmidomycin, a specific inhibitor of the second enzyme of the mevalonate-independent pathway of isopentenyl diphosphate and DMAPP formation, i.e. the 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway. We thus prove that MBO emitted from needles of P. ponderosa is primarily formed via the DOXP/MEP pathway.

Genetic adjuvantation of recombinant MVA with CD40L potentiates CD8 T cell mediated immunity

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Henning eLauterbach

2013-08-01

Full Text Available Modified vaccinia Ankara (MVA is a safe and promising viral vaccine vector that is currently investigated in several clinical and pre-clinical trials. In contrast to inactivated or sub-unit vaccines, MVA is able to induce strong humoral as well as cellular immune responses. In order to further improve its CD8 T cell inducing capacity, we genetically adjuvanted MVA with the coding sequence of murine CD40L, a member of the tumor necrosis factor (TNF superfamily. Immunization of mice with this new vector led to strongly enhanced primary and memory CD8 T cell responses. Concordant with the enhanced CD8 T cell response, we could detect stronger activation of dendritic cells and higher systemic levels of innate cytokines (including IL-12p70 early after immunization. Interestingly, acquisition of memory characteristics (i.e., IL-7R expression was accelerated after immunization with MVA-CD40L in comparison to non-adjuvanted MVA. Furthermore, the generated CTLs also showed improved functionality as demonstrated by intracellular cytokine staining and in vivo killing activity. Importantly, the superior CTL response after a single MVA-CD40L immunization was able to protect B cell deficient mice against a fatal infection with ectromelia virus. Taken together, we show that genetic adjuvantation of MVA can change strength, quality and functionality of innate and adaptive immune responses. These data should facilitate a rational vaccine design with a focus on rapid induction of large numbers of CD8 T cells able to protect against specific diseases.

A benchmark report on MVA Berlin, the key element of waste management in Berlin; MVA Berlin als Herzstueck der Berliner Entsorgung im Vergleich mit der Wettbewerbs-Benchmark

Energy Technology Data Exchange (ETDEWEB)

Kempin, T. [Berliner Stadtreinigungsbetrieb, Berlin (Germany)

2004-07-01

The MVA Ruhleben incinerator has state-of-the-art technology, volume-dependent prime costs of 100-130 EUR/t, an acceptance payment of 63.70 EUR/t, employees covered by collective agreement system, disposal capacities of 500,000 tpa of residues, ecological sustainability, and customer-friendliness. Its importance will increase in the future as more than half of the expected waste volume of 983,000 tpa will be processed from 2005. (orig.) [German] Die MVA Ruhleben gewaehrleistet derzeit den Stand der Technik, mengenabhaengige Selbstkosten zwischen 100 EUR/t und 130 EUR/t, ein Annahmeentgelt von 63,70 EUR/t, soziale tarifgebundene Arbeitsplaetze, Entsorgungssicherheit, derzeit fuer 500.000 Tonnen Abfall pro Jahr, oekologische Nachhaltigkeit, Kundenfreundlichkeit. Die MVA Ruhleben wird zukuenftig fuer die Abfallentsorgung in Berlin eine noch groessere Bedeutung haben. Mit etwa 520.000 t/a Abfallentsorgungskapazitaet wird sie mehr als die Haelfte des erwarteten ueberlassungspflichtigen Restabfallaufkommens von 983.000 t/a ab 2005 verarbeiten. (orig.)

An overview of the non-mevalonate pathway for terpenoid

Indian Academy of Sciences (India)

Unknown

troversial role of isomerase via non-MVA route in which both IPP and DMAPP are reported to be synthe- ... chemical scheme was proposed with a head-to-head con- densation of ..... berry exocarp and mesocarp; Phytochemistry 60 451–459.

Diseño y construcción de vectores de transferencia para la obtención de virus vaccinia Ankara modificado (MVA recombinantes Design and construction of transfer vectors in order to obtain recombinant modified vaccinia virus Ankara (MVA

Directory of Open Access Journals (Sweden)

M. F. Ferrer

2007-09-01

Full Text Available El virus vaccinia Ankara modificado (MVA constituye un buen candidato para el desarrollo de vectores virales de expresión no replicativos porque no replica en la mayoría de las células de mamíferos. Para la producción de MVA recombinantes es fundamental disponer de vectores de transferencia que, por recombinación homóloga con el genoma viral, permitan introducir los genes de interés en regiones no esenciales para la replicación in vitro. En este trabajo se diseñaron y obtuvieron los vectores de transferencia denominados VT-MHA y VT-MTK que portan las regiones correspondientes a las posiciones 1-303 y 608-948 del gen MVA165R y 1-244 y 325-534 del gen MVA086R, respectivamente, las que flanquean un sitio de clonado múltiple para la inserción de los genes foráneos. En dichos vectores se clonaron los casetes para la expresión de los genes lac Z o uid A, y la actividad de las enzimas marcadoras b-galactosidasa y b-glucuronidasa se confirmó in situ. Además, utilizando el vector denominado VT-MTK-GUS, se obtuvieron y aislaron MVA recombinantes puros que portan y expresan el gen uid A. Los resultados obtenidos constituyen las herramientas básicas para establecer la metodología de obtención de MVA recombinantes, con el propósito de desarrollar localmente vectores virales no replicativos candidatos a vacunas.Modified Vaccinia virus Ankara (MVA constitutes a good candidate for the development of non-replicative expression viral vectors because it does not replicate in most of mammalian cells. It is essential, for the production of recombinant MVA, the availability of transfer vectors which allow the introduction of desired genes into non-essential regions for in vitro viral replication, by homologous recombination with the viral genome. In the present work, the transfer vectors named VT-MHA and VT-MTK were designed and obtained. They carried genomic regions corresponding to 1- 303 and 608-948 positions of the MVA165R gene and 1-244 and

The Regulation of the Mevalonate Pathway for the Prevention of Breast Cancer

National Research Council Canada - National Science Library

Archer, Michael

2001-01-01

...)can be accounted for by their inhibitory effect on the cholesterol biosynthesis (mevalonate) pathway. In Task 1, we have shown that the decrease in mammary gland HMG-CoA redustase seen in LDL-R -/- mice compared...

Conceptual Design of a Single Phase 33 MVA HTS Transformer with a Tertiary Winding

International Nuclear Information System (INIS)

Lee, S. W.; Kim, W. S.; Hahn, S. Y.; Hwang, Y. I.; Choi, K. D.

2006-01-01

We have proposed a 3 phase, 100 MVA, 154 kV class HTS transformer substituting for a 60 MVA conventional transformer. The power transformer of 154 kV class has a tertiary winding besides primary and secondary windings. So the HTS transformer should have the 3rd superconducting winding. In this paper, we designed conceptually the structure of the superconducting windings of a single phase 33 MVA transformer. The electrical characteristics of the HTS transformer such as % impedance and AC loss vary with the arrangement of the windings and gaps between windings. We analyzed the effects of the winding parameters, evaluated the cost of each design, and proposed a suitable HTS transformer model for future power distribution system.

Comparison of tissue adequacy for histologic examination from Ipas MVA plus and Wallach Endocell in women with abnormal uterine bleeding.

Science.gov (United States)

Wanijasombutti, Paphada; Imruetaicharoenchok, Arinporn; Tangjitgamol, Siriwan; Loharamtaweethong, Kongsak; Phuriputt, Napaporn; Phaloprakarn, Chadakarn

2015-08-01

The aim of this study was to compare endometrial tissue adequacy sampling by Wallach Endocell and manual vacuum aspiration (Ipas MVA plus) in women with abnormal uterine bleeding. Pain and immediate complications from each method were also compared. Two hundred and forty women with abnormal uterine bleeding were randomly assigned to two methods of endometrial sampling: MVA (n = 122) and Endocell (n = 118). The basic characteristic features of the women, the difficulty of the procedure, pain score by visual analogue scale, immediate complications, and treatment were recorded. Endometrial tissue adequacy and histopathologic diagnoses were evaluated. The adequacy of tissue samples was 81.1% in the MVA group and 85.6% in the Endocell group (P = 0.356). There was a significant difference in the rates of difficult procedure between the two groups (27.0% in MVA vs 14.4% in Endocell; P = 0.016). Moderate to severe pain was significantly higher in the MVA group compared to the Endocell group: 60.7% and 19.5%, respectively (P < 0.001). Other immediate minor complications were also observed to be significantly higher in the MVA group (44.3%) than in the Endocell group (30.5%) (P = 0.028). Although medication required for pain was higher in the MVA group (23.0%) than in the Endocell group (12.0%), the difference was not significant (P = 0.130). The two most common histopathologic findings obtained from MVA and Endocell specimens were proliferative endometrium (32.4%) and atrophic endometrium (27.1%). MVA was comparable to Endocell in terms of tissue adequacy. Moderate to severe pain was experienced significantly more in the MVA group; however, the requirement of pain treatment was not significantly different between the groups. © 2015 The Authors Journal of Obstetrics and Gynaecology Research © 2015 Japan Society of Obstetrics and Gynecology.

Additions of precursors and elicitors improve geranylgeraniol production in Croton stellatopilosus callus cultures

Directory of Open Access Journals (Sweden)

Juraithip Wungsintaweekul

2015-02-01

Full Text Available Strategies for enhancing GGOH production in Croton stellatopilosus callus culture included additions of precursors (sodium acetate-NA, sodium pyruvate-NP, mevalonic acid lactone-MVA and elicitors (methyl jasmonate-MJ, acetylsalicylic acid-ASA, yeast extract-YE. Treated cells were evaluated for their GGOH contents by GC-FID and compared with the nontreated cells as controls. Additions of NA (25 mg/L, NP (50 mg/L and MVA (100 mg/L resulted in an enhancement of GGOH productivity to 0.61 mg/g DW, 0.52 mg/g DW and 0.70 mg/g DW, respectively, compared to the control culture (0.29 mg/g DW. Callus cultures elicited with MJ at 30 mg/L for 24 h stimulated GGOH production to 0.35 mg/g DW compared to the control culture (0.07 mg/g DW. Cells also responded to ASA (20 mg/L, 2 days and YE (0.25 g/L, 4 days and produced GGOH contents of 0.46 mg/g DW and 1.37 mg/g DW, respectively. This study has shown that isoprenoid precursors and conventional elicitors enhanced GGOH production in the C. stellatopilosus callus culture.

Development and evaluation of recombinant MVA viruses expressing bohv-1 glycoprotein D

OpenAIRE

Ferrer, María Florencia

2010-01-01

El virus vaccinia Ankara modificado (MVA) es un virus altamente atenuado que se utiliza eficientemente como vector viral no replicativo para el desarrollo de nuevas vacunas. En este trabajo de Tesis se desarrolló un nuevo inmunógeno basado en MVA que expresa como antígeno de interés la glicoproteína D (versión secretada, gDs) del virus herpes bovino tipo I (BoHV-1), un agente infeccioso ampliamente distribuido en Argentina. Primeramente, se diseñó y construyó el vector de transferencia para o...

Effects of MVA85A vaccine on tuberculosis challenge in animals: systematic review

Science.gov (United States)

Kashangura, Rufaro; Sena, Emily S; Young, Taryn; Garner, Paul

2015-01-01

Background: The existing Bacillus Calmette–Guérin (BCG) vaccination provides partial protection against tuberculosis (TB). The modified vaccinia ankara virus-expressing antigen 85A (MVA85A) aims to boost BCG immunity. We evaluated the animal evidence supporting the testing of MVA85A in humans. Methods: Our protocol included in vivo preclinical studies of the MVA85A booster with BCG compared with BCG alone, followed by a TB challenge. We used standard methods for systematic review of animal studies, and summarized mortality, measures of pathology and lung bacterial load. The comprehensive literature search was to September 2014. Two independent investigators assessed eligibility and performed data extraction. We assessed study quality and pooled bacteria load using random effect meta-analysis. Findings: We included eight studies in 192 animals. Three experiments were in mice, two in guinea pigs, two in macaques and one in calves. Overall, study quality was low with no randomization, baseline comparability not described and blinding not reported. For animal death (including euthanasia due to severe morbidity), studies were underpowered, and overall no benefit demonstrated. No difference was shown for lung pathology measured on an ordinal scale or bacterial load. The largest mortality trial carried out in macaques had more deaths in the MVA85A vaccine group, and was published after a trial in South Africa had started recruiting children. Conclusions: This independent assessment of the animal data does not provide evidence to support efficacy of MVA85A as a BCG booster. More rigorous conduct and reporting of preclinical research are warranted, and we believe the results of studies should be publicly available before embarking on trials in humans, irrespective of the findings. PMID:26351306

Increasing production yield of tyrosine and mevalonate through inhibition of biomass formation

DEFF Research Database (Denmark)

Li, Songyuan; Jendresen, Christian Bille; Nielsen, Alex Toftgaard

2016-01-01

, in particular, resulted in an increase in mass yield of mevalonate and tyrosine by 80% and 50%, respectively. By tracking production and biomass concentrations, it was observed that the production was maintained for more than 10 h after inhibition of cell growth, despite cell maintenance requirements...

Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency

NARCIS (Netherlands)

Schneiders, Marit S.; Houten, Sander M.; Turkenburg, Marjolein; Wanders, Ronald J. A.; Waterham, Hans R.

2006-01-01

OBJECTIVE: In cells from patients with the autoinflammatory disorder mevalonate kinase (MK) deficiency, which includes the hyperimmunoglobulin D with periodic fever syndrome, MK becomes the rate-limiting enzyme in the isoprenoid biosynthesis pathway. This suggests that up-regulation of residual MK

Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging

NARCIS (Netherlands)

Sapir, Amir; Tsur, Assaf; Koorman, Thijs; Ching, Kaitlin; Mishra, Prashant; Bardenheier, Annabelle; Podolsky, Lisa; Bening-Abu-Shach, Ulrike; Boxem, Mike; Chou, Tsui-Fen; Broday, Limor; Sternberg, Paul W

2014-01-01

Many metabolic pathways are critically regulated during development and aging but little is known about the molecular mechanisms underlying this regulation. One key metabolic cascade in eukaryotes is the mevalonate pathway. It catalyzes the synthesis of sterol and nonsterol isoprenoids, such as

Rapid generation of markerless recombinant MVA vaccines by en passant recombineering of a self-excising bacterial artificial chromosome.

Science.gov (United States)

Cottingham, Matthew G; Gilbert, Sarah C

2010-09-01

The non-replicating poxviral vector modified vaccinia virus Ankara (MVA) is currently a leading candidate for development of novel recombinant vaccines against globally important diseases. The 1980s technology for making recombinant MVA (and other poxviruses) is powerful and robust, but relies on rare recombination events in poxviral-infected cells. In the 21st century, it has become possible to apply bacterial artificial chromosome (BAC) technology to poxviruses, as first demonstrated by B. Moss' lab in 2002 for vaccinia virus. A similar BAC clone of MVA was subsequently derived, but while recombination-mediated genetic engineering for rapid production was used of deletion mutants, an alternative method was required for efficient insertion of transgenes. Furthermore "markerless" viruses, which carry no trace of the selectable marker used for their isolation, are increasingly required for clinical trials, and the viruses derived via the new method contained the BAC sequence in their genomic DNA. Two methods are adapted to MVA-BAC to provide more rapid generation of markerless recombinants in weeks rather than months. "En passant" recombineering is applied to the insertion of a transgene expression cassette and the removal of the selectable marker in bacteria; and a self-excising variant of MVA-BAC is constructed, in which the BAC cassette region is rapidly and efficiently lost from the viral genome following rescue of the BAC into infectious virus. These methods greatly facilitate and accelerate production of recombinant MVA, including markerless constructs. Copyright 2010 Elsevier B.V. All rights reserved.

Side-by-side comparison of gene-based smallpox vaccine with MVA in nonhuman primates.

Science.gov (United States)

Golden, Joseph W; Josleyn, Matthew; Mucker, Eric M; Hung, Chien-Fu; Loudon, Peter T; Wu, T C; Hooper, Jay W

2012-01-01

Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.

Side-by-side comparison of gene-based smallpox vaccine with MVA in nonhuman primates.

Directory of Open Access Journals (Sweden)

Joseph W Golden

Full Text Available Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA. We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV nonhuman primate (NHP challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.

Double-Difference Tomography for Sequestration MVA

Energy Technology Data Exchange (ETDEWEB)

Westman, Erik

2008-12-31

Analysis of synthetic data was performed to determine the most cost-effective tomographic monitoring system for a geologic carbon sequestration injection site. Double-difference tomographic inversion was performed on 125 synthetic data sets: five stages of CO2 plume growth, five seismic event regions, and five geophone arrays. Each resulting velocity model was compared quantitatively to its respective synthetic velocity model to determine an accuracy value. The results were examined to determine a relationship between cost and accuracy in monitoring, verification, and accounting applications using double-difference tomography. The geophone arrays with widely-varying geophone locations, both laterally and vertically, performed best. Additionally, double difference seismic tomography was performed using travel time data from a carbon sequestration site at the Aneth oil field in southeast Utah as part of a Department of Energy initiative on monitoring, verification, and accounting (MVA) of sequestered CO2. A total of 1,211 seismic events were recorded from a borehole array consisting of 22 geophones. Artificial velocity models were created to determine the ease with which different CO2 plume locations and sizes can be detected. Most likely because of the poor geophone arrangement, a low velocity zone in the Desert Creek reservoir can only be detected when regions of test site containing the highest ray path coverage are considered. MVA accuracy and precision may be improved through the use of a receiver array that provides more comprehensive ray path coverage.

Executive compensation and the EVA and MVA performance of ...

African Journals Online (AJOL)

The media regularly report a growing incidence of non-alignment of executive pay and performance, and in some cases, no link between the two whatsoever. The advent of new measures of shareholder wealth such as economic value added (EVA) and market value added (MVA) have allowed some companies to link ...

Block of the Mevalonate Pathway Triggers Oxidative and Inflammatory Molecular Mechanisms Modulated by Exogenous Isoprenoid Compounds

Directory of Open Access Journals (Sweden)

Paola Maura Tricarico

2014-04-01

Full Text Available Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD. One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines’ release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3, cytokines and nitric oxide (NO]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

Recombination-mediated genetic engineering of a bacterial artificial chromosome clone of modified vaccinia virus Ankara (MVA.

Directory of Open Access Journals (Sweden)

Matthew G Cottingham

2008-02-01

Full Text Available The production, manipulation and rescue of a bacterial artificial chromosome clone of Vaccinia virus (VAC-BAC in order to expedite construction of expression vectors and mutagenesis of the genome has been described (Domi & Moss, 2002, PNAS99 12415-20. The genomic BAC clone was 'rescued' back to infectious virus using a Fowlpox virus helper to supply transcriptional machinery. We apply here a similar approach to the attenuated strain Modified Vaccinia virus Ankara (MVA, now widely used as a safe non-replicating recombinant vaccine vector in mammals, including humans. Four apparently full-length, rescuable clones were obtained, which had indistinguishable immunogenicity in mice. One clone was shotgun sequenced and found to be identical to the parent. We employed GalK recombination-mediated genetic engineering (recombineering of MVA-BAC to delete five selected viral genes. Deletion of C12L, A44L, A46R or B7R did not significantly affect CD8(+ T cell immunogenicity in BALB/c mice, but deletion of B15R enhanced specific CD8(+ T cell responses to one of two endogenous viral epitopes (from the E2 and F2 proteins, in accordance with published work (Staib et al., 2005, J. Gen. Virol.86, 1997-2006. In addition, we found a higher frequency of triple-positive IFN-gamma, TNF-alpha and IL-2 secreting E3-specific CD8+ T-cells 8 weeks after vaccination with MVA lacking B15R. Furthermore, a recombinant vaccine capable of inducing CD8(+ T cells against an epitope from Plasmodium berghei was created using GalK counterselection to insert an antigen expression cassette lacking a tandem marker gene into the traditional thymidine kinase locus of MVA-BAC. MVA continues to feature prominently in clinical trials of recombinant vaccines against diseases such as HIV-AIDS, malaria and tuberculosis. Here we demonstrate in proof-of-concept experiments that MVA-BAC recombineering is a viable route to more rapid and efficient generation of new candidate mutant and recombinant

Dendritic cells exposed to MVA-based HIV-1 vaccine induce highly functional HIV-1-specific CD8(+ T cell responses in HIV-1-infected individuals.

Directory of Open Access Journals (Sweden)

Núria Climent

Full Text Available Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B in human monocyte-derived dendritic cells (MDDC and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α. MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8(+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8(+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4(+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B.

Barriers to Sustainable MVA Supply in Ghana: Challenges for the ...

African Journals Online (AJOL)

Erah

2009-12-04

Dec 4, 2009 ... and the private health sectors, procuring MVA equipment has been particularly ... 1School of Public Health, University of California, Berkeley, USA; 2Alidor Maternity Home, PO Box ... identified as current employees for the ... acknowledged that lack of equipment ... nurse midwives working in lower-level.

Sterol-mediated regulation of mevalonic acid synthesis. Accumulation of 4-carboxysterols as the predominant sterols synthesized in a Chinese hamster ovary cell cholesterol auxotroph (mutant 215)

International Nuclear Information System (INIS)

Plemenitas, A.; Havel, C.M.; Watson, J.A.

1990-01-01

Chinese hamster ovary-215 (CHO-215) mutant cells are auxotrophic for cholesterol. Berry and Chang (Berry, D. J., and Chang, T. Y. (1982) Biochemistry 21, 573-580) suggested that the metabolic lesion was at the level of 4-methyl sterol oxidation. However, the observed cellular accumulation of lanosterol was not consistent with a defect at this metabolic site. With the use of a novel Silica Sep Pak sterol separation procedure, we demonstrated that 60-80% of the acetonesoluble lipid radioactivity in [5-3H]mevalonate-labeled CHO-215 cells was incorporated into acidic sterols. 7(8),Cholesten-4 beta-methyl,4 alpha-carboxy,3 beta-ol was the dominant end product. In addition to this acidic sterol, 7(8),24-cholestadien,4 beta-methyl,4 alpha-carboxy,3 beta-ol and 7(8),24-cholestadien,4 alpha-carboxy,3 beta-ol were also isolated. Incubation of cell-free extracts with [3H]7(8)-cholesten-4 beta-methyl, 4 alpha-carboxy,3 beta-ol and pyridine nucleotides confirmed that CHO-215 4-carboxysterol decarboxylase activity was less than 1% of that for wild type cells. Thus, a correspondence between decreased 4-carboxysterol decarboxylase activity and the spectrum of accumulated sterol products by intact CHO-215 cells was demonstrated. No detectable cholesterol was synthesized by CHO-215 cells. 3H-Product accumulation studies demonstrated that 7(8),24-cholestadien, 4 beta-methyl,4 alpha-carboxy,3 beta-ol increased prior to its subsequent saturation at the delta 24 carbon. Furthermore, the steady state ratio for delta 24-saturated acidic sterols/unsaturated acidic sterols was dependent on media cholesterol source and amount. Finally, the accumulated acidic sterol(s) were not regulatory signal molecules for the modulation of 3-hydroxy-3-methyl-glutaryl coenzyme. A reductase activity in response to cholesterol availability

Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults.

Science.gov (United States)

Pathan, Ansar A; Minassian, Angela M; Sander, Clare R; Rowland, Rosalind; Porter, David W; Poulton, Ian D; Hill, Adrian V S; Fletcher, Helen A; McShane, Helen

2012-08-17

A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG. Healthy BCG-vaccinated volunteers were vaccinated with either 1×10(7) or 1×10(8)PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5×10(7)PFU MVA85A had been administered. There were no serious adverse events recorded following administration of either 1×10(7) or 1×10(8)PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1×10(8)PFU of MVA85A when compared to either 5×10(7) or 1×10(7)PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1×10(8)PFU compared to the 5×10(7) and 1×10(7) doses. Additionally, a broader range of Ag85A epitopes are detected following 1×10(8)PFU of MVA85A. A higher dose of 1×10(8)PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected. Copyright © 2012 Elsevier Ltd. All rights reserved.

S-Carvone Suppresses Cellulase-Induced Capsidiol Production in Nicotiana tabacum by Interfering with Protein Isoprenylation1[C][W

Science.gov (United States)

Huchelmann, Alexandre; Gastaldo, Clément; Veinante, Mickaël; Zeng, Ying; Heintz, Dimitri; Tritsch, Denis; Schaller, Hubert; Rohmer, Michel; Bach, Thomas J.; Hemmerlin, Andréa

2014-01-01

S-Carvone has been described as a negative regulator of mevalonic acid (MVA) production by interfering with 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) activity, a key player in isoprenoid biosynthesis. The impact of this monoterpene on the production of capsidiol in Nicotiana tabacum, an assumed MVA-derived sesquiterpenoid phytoalexin produced in response to elicitation by cellulase, was investigated. As expected, capsidiol production, as well as early stages of elicitation such as hydrogen peroxide production or stimulation of 5-epi-aristolochene synthase activity, were repressed. Despite the lack of capsidiol synthesis, apparent HMGR activity was boosted. Feeding experiments using (1-13C)Glc followed by analysis of labeling patterns by 13C-NMR, confirmed an MVA-dependent biosynthesis; however, treatments with fosmidomycin, an inhibitor of the MVA-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) isoprenoid pathway, unexpectedly down-regulated the biosynthesis of this sesquiterpene as well. We postulated that S-carvone does not directly inhibit the production of MVA by inactivating HMGR, but possibly targets an MEP-derived isoprenoid involved in the early steps of the elicitation process. A new model is proposed in which the monoterpene blocks an MEP pathway–dependent protein geranylgeranylation necessary for the signaling cascade. The production of capsidiol was inhibited when plants were treated with some inhibitors of protein prenylation or by further monoterpenes. Moreover, S-carvone hindered isoprenylation of a prenylable GFP indicator protein expressed in N. tabacum cell lines, which can be chemically complemented with geranylgeraniol. The model was further validated using N. tabacum cell extracts or recombinant N. tabacum protein prenyltransferases expressed in Escherichia coli. Our study endorsed a reevaluation of the effect of S-carvone on plant isoprenoid metabolism. PMID:24367019

Design and Development of a 100 MVA HTS Generator for Commercial Entry

Energy Technology Data Exchange (ETDEWEB)

None

2007-06-07

In 2002, General Electric and the US Department of Energy (DOE) entered into a cooperative agreement for the development of a commercialized 100 MVA generator using high temperature superconductors (HTS) in the field winding. The intent of the program was to: (1) identify and develop technologies that would be needed for such a generator; (2) develop conceptual designs for generators with ratings of 100 MVA and higher using HTS technology; (3) perform proof of concept tests at the 1.5 MW level for GE's proprietary warm iron rotor HTS generator concept; and (4) design, build, and test a prototype of a commercially viable 100 MVA generator that could be placed on the power grid. This report summarizes work performed during the program and is provided as one of the final program deliverables. The design for the HTS generator was based on GE's warm iron rotor concept in which a cold HTS coil is wound around a warm magnetic iron pole. This approach for rotating HTS electrical machinery provides the efficiency benefits of the HTS technology while addressing the two most important considerations for power generators in utility applications: cost and reliability. The warm iron rotor concept uses the least amount of expensive HTS wire compared to competing concepts and builds on the very high reliability of conventional iron core stators and armature windings.

ANALISIS PENGARUH EVA DAN MVA TERHADAP RETURN SAHAM PADA INDUSTRI PROPERTI DI BURSA EFEK INDONESIA PERIODE 2007-2012

Directory of Open Access Journals (Sweden)

Ryan Pahlawan

2015-04-01

Full Text Available Abstrak: Tujuan dari penelitian ini adalah untuk mengetahui dan menganalisis: (1 pengaruh Economic Value Added (EVA terhadap return saham (2 pengaruh Market Value Added (MVA terhadap return saham (3 pengaruh Economic Value Added (EVA dan Market Value Added (MVA terhadap return saham antara variabel kinerja keuangan industri properti di Bursa Efek Indonesia pada periode 2007-2012. Kegunaan teoritis adalah untuk memberikan kontribusi tentang pengetahuan manajemen keuangan, yang dapat digunakan sebagai acuan untuk penelitian berikutnya kinerja keuangan terutama tentang industri properti di Bursa Efek Indonesia. Kegunaan praktis adalah untuk mengetahui pengaruh tingkat Economic Value Added (EVA dan Market Value Added (MVA terhadap kinerja keuangan untuk kontribusi memberi kepada manajemen properti umum dalam mengelola variabel kinerja industri properti Bursa Efek Indonesia.Penelitian ini menggunakan data sekunder yang dikumpulkan dari data Bursa Efek Indonesia, dan Departemen Riset menurut sifat laporan keuangan pada periode 2007-2012. Sampel adalah 54 variabel dan dianalisis dengan regresi berganda metode statistik linier. Total nilai determinasi adalah 0,368, artinya ini adalah 36,8% informasi dalam data dapat dijelaskan oleh model dan 63,2% di bawah variabel lain dan error. Kesimpulan dari penelitian ini adalah: (1 Variabel Economic Value Added (EVA berpengaruh positif terhadap return saham; (2 Variabel Market Value Added (MVA memiliki pengaruh negatif terhadap Return Saham; Mengacu pada kesimpulan penelitian diatas maka disarankan adalah: (1 Dioptimalkan Economic Value Added (EVA untuk mencapai pendapatan dan keuntungan dari return saham (2 Mengelola Variabel Market Value Added (MVA pada kondisi baik untuk menjaga stabilitas keuangan dan mendapatkan dipercaya dari investor Bursa Efek Indonesia (3 Fokus ke Manajemen Risiko, Jasa, perusahaan Visi & Misi, dan Active keterampilan dan pengetahuan karyawan perusahaan yang lebih tinggi untuk

Optimizing the coefficients of the leading terms of the Born Series: FWI+MVA+more

KAUST Repository

Alkhalifah, Tariq Ali

2017-05-26

The scattering series theoretically utilizes a model perturbation framework to explain the difference between the seismic modeled data corresponding to a background model and those measured in the field corresponding to the real Earth. These perturbations include short wavelength features like those predicted by full waveform inversion (FWI) gradients, and long wavelength features often constrained by migration velocity analysis (MVA) objectives. The Born series, however, is not a convergent series. If the perturbations are large, we probably will not be able to explain the data difference. Thus, using the leading terms of the Born in an iterative process, in which they are scaled properly, allows us to avoid such limitations and update the short and long wavelength components of the velocity model. In fact, the FWI update is manifested in the first term of the Born series, and the MVA update is represented by the transmission (first Fresnel zone) part of the second term. In this case, FWI and MVA are code names for dividing the optimized update to reflectivity based portions and those adequate for the background, respectively. Examples on synthetic and real data demonstrate this logic.

Market implementation of the MVA platform for pre-pandemic and pandemic influenza vaccines: A quantitative key opinion leader analysis.

Science.gov (United States)

Ramezanpour, Bahar; Pronker, Esther S; Kreijtz, Joost H C M; Osterhaus, Albert D M E; Claassen, E

2015-08-20

A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modified vaccinia virus Ankara (MVA) as a platform for pre-pandemic and pandemic influenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Key opinion leaders (KOLs) in the influenza vaccine field were interviewed to collect a unique dataset to evaluate the market potential of this platform. The purpose of this study, to evaluate commercial potential of the MVA platform for the development of novel generation pandemic influenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT-AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally important role that threats and opportunities of this platform play. This study further highlights unmet needs in the influenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great promise for this vector as vaccine platform for pre-pandemic and pandemic influenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials seem that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insufficiently effective vaccines, are available. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Biosynthetic origin of the isoprene units in chromenes of Piper aduncum (Piperaceae)

International Nuclear Information System (INIS)

Leite, Ana C.; Lopes, Adriana A.; Bolzani, Vanderlan da S.; Furlan, Maysa; Kato, Massuo J.

2007-01-01

Metabolic studies involving the incorporation of [1- 13 C]-D-glucose into intact leaves of Piper aduncum (Piperaceae) have indicated that both the mevalonate (MVA) and the pyruvate-triose (MEP) non-mevalonate pathways are implicated in the biosynthesis of isoprene moieties present in methyl 2,2-dimethyl-2H-1-chromene-6-carboxylate (1) and methyl 2,2-dimethyl-8-(3'-methyl- 2'-butenyl)-2H-1-chromene-6-carboxylate (2). The pattern of incorporation of label from [1- 13 C]-D-glucose into these chromenes was determined by quantitative 13 C NMR spectroscopy. The results confirmed that biosynthetic compartment of 1 and 2 could either be the plastid and/ or the cytosol or, possibly, an additional compartment such as the plastid inter-membrane space. (author)

Effect of Iminodiacetic Acid-Modified Nieuwland Catalyst on the Acetylene Dimerization Reaction

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Yanhe You

2017-12-01

Full Text Available The iminodiacetic acid-modified Nieuwland catalyst not only improves the conversion of acetylene but also increases the selectivity of monovinylacetylene (MVA. A catalyst system containing 4.5% iminodiacetic acid exhibited excellent performance, and the yield of MVA was maintained at 32% after 24 h, producing an increase in the yield by 12% relative to the Nieuwland catalyst system. Based on a variety of characterization methods analysis of the crystal precipitated from the catalyst solution, it can be inferred that the outstanding performance and lifetime of the catalyst system was due to the presence of iminodiacetic acid, which increases the electron density of Cu+ and adjusts the acidity of the catalytic solution.

Antitumor Effects of Palladium-α-Lipoic Acid Complex Formulation as an Adjunct in Radiotherapy.

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Veena, Ravindran Kalathil; Ajith, Thekkuttuparambil Ananthanarayanan; Janardhanan, Kainoor Krishnankutty; Antonawich, Francis

2016-01-01

Several investigations have been initiated to enhance the antitumor effect of radiation and ameliorate its adverse effects such as reducing blood cell counts and causing DNA damage in normal cells. Compounds that enhance the antitumor activity of radiation without reducing blood cell counts or damaging DNA in normal cells can be of immense use as an adjunct in radiotherapy. We evaluated the antitumor effect of a specific set of minerals, vitamins, and amino acids (Poly-MVA) (2 mL/kg, per os), with and without radiation, against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines that were transplanted in a solid-tumor model. Whole-body γ-radiation exposure (2 Gy) was performed using 60Co. Poly-MVA enhanced the antitumor effect of radiation when administered beforehand. Furthermore, Poly-MVA administered once daily for 2 wk, immediately after 4 Gy irradiation, protected DNA damage in peripheral blood. It also rendered protection against the radiation-induced reduction of platelet count. The unique electronic and redox properties of palladium-α-lipoic acid complex in Poly-MVA appear to be responsible for the exhibited effect. The results conclude that the antitumor-enhancing and normal cell-protective effect of Poly-MVA warrants additional studies for its potential clinical application.

Cellulose decomposition in a 50 MVA transformer

International Nuclear Information System (INIS)

Piechalak, B.W.

1992-01-01

Dissolved gas-in-oil analysis for carbon monoxide and carbon dioxide has been used for years to predict cellulose decomposition in a transformer. However, the levels at which these gases become significant have not been widely agreed upon. This paper evaluates the gas analysis results from the nitrogen blanket and the oil of a 50 MVA unit auxiliary transformer in terms of whether accelerated thermal breakdown or normal aging of the paper is occurring. Furthermore, this paper presents additional data on carbon monoxide and carbon dioxide levels in unit and system auxiliary transformers at generating stations and explains why their levels differ

Dynamics of Monoterpene Formation in Spike Lavender Plants

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Isabel Mendoza-Poudereux

2017-12-01

Full Text Available The metabolic cross-talk between the mevalonate (MVA and the methylerythritol phosphate (MEP pathways was analyzed in spike lavender (Lavandula latifolia Med on the basis of 13CO2-labelling experiments using wildtype and transgenic plants overexpressing the 3-hydroxy-3-methylglutaryl CoA reductase (HMGR, the first and key enzyme of the MVA pathway. The plants were labelled in the presence of 13CO2 in a gas chamber for controlled pulse and chase periods of time. GC/MS and NMR analysis of 1,8-cineole and camphor, the major monoterpenes present in their essential oil, indicated that the C5-precursors, isopentenyl diphosphate (IPP and dimethylallyl diphosphate (DMAPP of both monoterpenes are predominantly biosynthesized via the MEP pathway. Surprisingly, overexpression of HMGR did not have significant impact upon the crosstalk between the MVA and MEP pathways indicating that the MEP route is the preferred pathway for the synthesis of C5 monoterpene precursors in spike lavender.

Proteomic analysis of lettuce seed germination and thermoinhibition by sampling of individual seeds at germination and removal of storage proteins by polyethylene glycol fractionation.

Science.gov (United States)

Wang, Wei-Qing; Song, Bin-Yan; Deng, Zhi-Jun; Wang, Yue; Liu, Shu-Jun; Møller, Ian Max; Song, Song-Quan

2015-04-01

Germination and thermoinhibition in lettuce (Lactuca sativa 'Jianyexianfeng No. 1') seeds were investigated by a proteomic comparison among dry seeds, germinated seeds at 15°C, at 15°C after imbibition at 25°C for 48 h, or at 25°C in KNO3 (all sampled individually at germination), and ungerminated seeds at 25°C, a thermoinhibitory temperature. Before two-dimensional gel electrophoresis analysis, storage proteins (greater than 50% of total extractable protein) were removed by polyethylene glycol precipitation, which significantly improved the detection of less abundant proteins on two-dimensional gels. A total of 108 protein spots were identified to change more than 2-fold (Pseeds than in ungerminated 25°C seeds. Gene expression of 12 of those proteins correlated well with the protein accumulation. Methionine metabolism, ethylene production, lipid mobilization, cell elongation, and detoxification of aldehydes were revealed to be potentially related to lettuce seed germination and thermoinhibition. Accumulation of three proteins and expression of five genes participating in the mevalonate (MVA) pathway of isoprenoid biosynthesis correlated positively with seed germinability. Inhibition of this pathway by lovastatin delayed seed germination and increased the sensitivity of germination to abscisic acid. MVA pathway-derived products, cytokinins, partially reversed the lovastatin inhibition of germination and released seed thermoinhibition at 25°C. We conclude that the MVA pathway for isoprenoid biosynthesis is involved in lettuce seed germination and thermoinhibition. © 2015 American Society of Plant Biologists. All Rights Reserved.

A T cell-inducing influenza vaccine for the elderly: safety and immunogenicity of MVA-NP+M1 in adults aged over 50 years.

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Richard D Antrobus

Full Text Available Current influenza vaccines have reduced immunogenicity and are of uncertain efficacy in older adults. We assessed the safety and immunogenicity of MVA-NP+M1, a viral-vectored influenza vaccine designed to boost memory T cell responses, in a group of older adults.Thirty volunteers (aged 50-85 received a single intramuscular injection of MVA-NP+M1 at a dose of 1·5×10(8 plaque forming units (pfu. Safety and immunogenicity were assessed over a period of one year. The frequency of T cells specific for nucleoprotein (NP and matrix protein 1 (M1 was determined by interferon-gamma (IFN-γ ELISpot, and their phenotypic and functional properties were characterized by polychromatic flow cytometry. In a subset of M1-specific CD8(+ T cells, T cell receptor (TCR gene expression was evaluated using an unbiased molecular approach.Vaccination with MVA-NP+M1 was well tolerated. ELISpot responses were boosted significantly above baseline following vaccination. Increases were detected in both CD4(+ and CD8(+ T cell subsets. Clonality studies indicated that MVA-NP+M1 expanded pre-existing memory CD8(+ T cells, which displayed a predominant CD27(+CD45RO(+CD57(-CCR7(- phenotype both before and after vaccination.MVA-NP+M1 is safe and immunogenic in older adults. Unlike seasonal influenza vaccination, the immune responses generated by MVA-NP+M1 are similar between younger and older individuals. A T cell-inducing vaccine such as MVA-NP+M1 may therefore provide a way to circumvent the immunosenescence that impairs routine influenza vaccination.ClinicalTrials.gov NCT00942071.

Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway*

Science.gov (United States)

Onono, Fredrick; Subramanian, Thangaiah; Sunkara, Manjula; Subramanian, Karunai Leela; Spielmann, H. Peter; Morris, Andrew J.

2013-01-01

Mammalian cells can use exogenous isoprenols to generate isoprenoid diphosphate substrates for protein isoprenylation, but the mechanism, efficiency, and biological importance of this process are not known. We developed mass spectrometry-based methods using chemical probes and newly synthesized stable isotope-labeled tracers to quantitate incorporation of exogenously provided farnesol, geranylgeraniol, and unnatural analogs of these isoprenols containing an aniline group into isoprenoid diphosphates and protein isoprenylcysteines by cultured human cancer cell lines. We found that at exogenous isoprenol concentrations >10 μm, this process can generate as much as 50% of the cellular isoprenoid diphosphate pool used for protein isoprenylation. Mutational activation of p53 in MDA-MB-231 breast cancer cells up-regulates the mevalonate pathway to promote tumor invasiveness. p53 silencing or pharmacological inhibition of HMG-CoA reductase in these cells decreases protein isoprenylation from endogenously synthesized isoprenoids but enhances the use of exogenous isoprenols for this purpose, indicating that this latter process is regulated independently of the mevalonate pathway. Our observations suggest unique opportunities for design of cancer cell-directed therapies and may provide insights into mechanisms underlying pleiotropic therapeutic benefits and unwanted side effects of mevalonate pathway inhibition. PMID:23908355

Expression of Terpenoid Biosynthetic Genes and Accumulation of Chemical Constituents in Valeriana fauriei

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Yun Ji Park

2016-05-01

Full Text Available Valeriana fauriei (V. fauriei, which emits a characteristic and unpleasant odor, is important in traditional medicine. In this study, the expression of terpenoid biosynthetic genes was investigated in different organs that were also screened for volatile compounds including valerenic acid and its derivatives. Specific expression patterns from different parts of V. fauriei were observed using quantitative real-time PCR (qRT-PCR. The highest transcript levels of biosynthetic genes involved in mevalonic acid (MVA and methylerythritol phosphate (MEP production were found in the stem. Although the amounts of volatile compounds were varied by organ, most of the volatile terpenoids were accumulated in the root. Gas chromatography mass spectrometry (GC-MS analysis identified 128 volatile compounds, which represented 65.33% to 95.66% of total volatiles. Certain compounds were only found in specific organs. For example, isovalerenic acid and valerenic acid and its derivatives were restricted to the root. Organs with high transcript levels did not necessarily have high levels of the corresponding chemical constituents. According to these results, we hypothesize that translocation may occur between different organs in V. fauriei.

Phase I safety and immunogenicity evaluation of MVA-CMDR, a multigenic, recombinant modified vaccinia Ankara-HIV-1 vaccine candidate.

Science.gov (United States)

Currier, Jeffrey R; Ngauy, Viseth; de Souza, Mark S; Ratto-Kim, Silvia; Cox, Josephine H; Polonis, Victoria R; Earl, Patricia; Moss, Bernard; Peel, Sheila; Slike, Bonnie; Sriplienchan, Somchai; Thongcharoen, Prasert; Paris, Robert M; Robb, Merlin L; Kim, Jerome; Michael, Nelson L; Marovich, Mary A

2010-11-15

We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand. MVA-CMDR or placebo was administered intra-muscularly (IM; 10(7) or 10(8) pfu) or intradermally (ID; 10(6) or 10(7) pfu) at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10∶2). Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFNγ Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a (51)Cr-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i) moderate in magnitude (median IFNγ Elispot of 78 SFC/10(6) PBMC at 10(8) pfu IM), but high in response rate (70% (51)Cr-release positive; 90% Elispot positive; 100% ICS positive, at 10(8) pfu IM); (ii) predominantly HIV Env-specific CD4(+) T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route); (iv) dose- and route-dependent with 10(8) pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 10(8) pfu IM). MVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses

Phase I safety and immunogenicity evaluation of MVA-CMDR, a multigenic, recombinant modified vaccinia Ankara-HIV-1 vaccine candidate.

Directory of Open Access Journals (Sweden)

Jeffrey R Currier

2010-11-01

Full Text Available We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand.MVA-CMDR or placebo was administered intra-muscularly (IM; 10(7 or 10(8 pfu or intradermally (ID; 10(6 or 10(7 pfu at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10∶2. Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFNγ Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a (51Cr-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i moderate in magnitude (median IFNγ Elispot of 78 SFC/10(6 PBMC at 10(8 pfu IM, but high in response rate (70% (51Cr-release positive; 90% Elispot positive; 100% ICS positive, at 10(8 pfu IM; (ii predominantly HIV Env-specific CD4(+ T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route; (iv dose- and route-dependent with 10(8 pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 10(8 pfu IM.MVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

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Paola Maura Tricarico

2017-03-01

Full Text Available Background/Aims: Mevalonate Kinase Deficiency (MKD, is a hereditary disease due to mutations in mevalonate kinase gene (MVK. MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA, the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. Methods: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. Results: MVK mutants’ over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. Conclusions: We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation.

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency.

Science.gov (United States)

Tricarico, Paola Maura; Romeo, Alessandra; Gratton, Rossella; Crovella, Sergio; Celsi, Fulvio

2017-01-01

Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. MVK mutants' over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation. © 2017 The Author(s)Published by S. Karger AG, Basel.

Biosynthetic origin of the isoprene units in chromenes of Piper aduncum (Piperaceae)

Energy Technology Data Exchange (ETDEWEB)

Leite, Ana C.; Lopes, Adriana A.; Bolzani, Vanderlan da S.; Furlan, Maysa [UNESP, Araraquara, SP (Brazil). Inst. de Quimica]. E-mail: maysaf@iq.unesp.br; Kato, Massuo J. [Universidade de Sao Paulo (USP), SP (Brazil). Inst. de Quimica

2007-07-01

Metabolic studies involving the incorporation of [1-{sup 13}C]-D-glucose into intact leaves of Piper aduncum (Piperaceae) have indicated that both the mevalonate (MVA) and the pyruvate-triose (MEP) non-mevalonate pathways are implicated in the biosynthesis of isoprene moieties present in methyl 2,2-dimethyl-2H-1-chromene-6-carboxylate (1) and methyl 2,2-dimethyl-8-(3'-methyl- 2'-butenyl)-2H-1-chromene-6-carboxylate (2). The pattern of incorporation of label from [1- {sup 13}C]-D-glucose into these chromenes was determined by quantitative {sup 13}C NMR spectroscopy. The results confirmed that biosynthetic compartment of 1 and 2 could either be the plastid and/ or the cytosol or, possibly, an additional compartment such as the plastid inter-membrane space. (author)

Estudio preliminar sobre micorriza versículo – Arbuscular (MVA en lulo (Solanum quitoense Lam

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Sieverding Ewald

1986-12-01

Full Text Available En el estudio se determinó el carácter (obligado o facultativo de la asociación micorrícica y se evaluó la eficiencia de nueve cepas de micorriza en dos tipos de oxisoles con fertilidad baja y moderada y en presencia de tres niveles de fósforo (0,50 Y 100 kg/ha. El lulo es una especie micotrófica facultativa, ya que con adecuados niveles de fósforo asimilable en el suelo su desarrollo no depende de la asociación micorrícica, mientras que con bajos niveles sucede lo contrario. En general, la inoculación con MVA incrementó el desarrollo del lulo tanto en semilleros como en plántulas. Los mejores aislamientos de MVA fueron una mezcla de Acaulospora spp y Glomus sp y Entrophospora colombiana. En general, la efectividad de la MVA incrementó con niveles bajos y medios de fósforo y se deprimió con el nivel alto, El desarrollo del lulo y la efectividad de la micorriza fue mayor en la localidad más cálida (1050 m, 24°C y 60 % HR que en la más templada (2100 m, 14°C Y 80 % HR.A preliminary study to determine the character (obligate or facultative of the mycorrhizal association in, "naranjilla" (Solanum quitoense L. and an evaluation of nine mycorrhiza stock, was carried out at Palmira (1050 m, 24°C and R.H. of 60 % and Jamundí (2100 m, 14°C and R.H. of 80 %. The trial was held on two oxyzole having a lowand moderate fertility, with 3 levels of phosphorus (0,50 Y 100 kq/ha. The "naranjilla" is a facultative mycotrophic specie. In general, the inoculation with MVA fungi, increased the development of the "naranjilla" in seed beds as well as transplanted seed lings. The effectivity of MVA was dependent on the fungus specie, its origin, the phosphorus levels in the soil and the weather of both Iocalities. The development of the "naranjilla" and the effectivity of the mycorrhiza was superior at the locality (14°C. In general, the isolations which showed the best behavior were a mixture of Acaulospora spp and Glomus sp, and

MVA E2 recombinant vaccine in the treatment of human papillomavirus infection in men presenting intraurethral flat condyloma: a phase I/II study.

Science.gov (United States)

Albarran Y Carvajal, Antonio; de la Garza, Alfonso; Cruz Quiroz, Benitez Jose Cecilio; Vazquez Zea, Eduardo; Díaz Estrada, Ismael; Mendez Fuentez, Ernesto; López Contreras, Mario; Andrade-Manzano, Alejandro; Padilla, Santiago; Varela, Axel Ramírez; Rosales, Ricardo

2007-01-01

Human papillomavirus (HPV) is the etiologic agent for warts and cervical cancer. In Mexico, the death rate from cervical cancer is extremely high, and statistical data show that since 1990 the number of deaths is increasing. Condylomas and cancer of the penis are the most common lesions presented in men; bladder and prostate cancer in men are also associated with the presence of HPV. Since HPV is transmitted by sexual intercourse, treating both partners is necessary in order to eliminate the virus in the population. Approaches to this include preventative vaccines such as Gardasil, and therapeutic vaccines to treat established infections in both men and women. This will be the only way to decrease the numbers of deaths due to this malignancy. We conducted a phase I/II clinical trial to evaluate the potential use of the recombinant vaccinia viral vaccine MVA E2 (composed of modified vaccinia virus Ankara [MVA] expressing the E2 gene of bovine papillomavirus) to treat flat condyloma lesions associated with oncogenic HPV in men. Fifty male patients with flat condyloma lesions were treated with either MVA E2 therapeutic vaccine or fluorouracil (5-fluorouracil). Thirty men received the therapeutic vaccine, at a total of 10(6) virus particles per dose, administered directly into the urethra once every week over a 4-week period. Twenty control patients were treated with 5% fluorouracil 1mL twice weekly over a 4-week period directly into the urethra. Reduction of lesions or absence of papillomavirus infection was monitored by colposcopy and histologic analysis. The immune response after MVA E2 treatment was determined by measuring the antibodies against the MVA E2 virus and by analyzing the lymphocyte cytotoxic activity against cancer cells bearing oncogenic papillomavirus. Presence of papillomavirus was determined by the Hybrid Capture method. Twenty-eight of 30 patients showed no lesion or presence of papillomavirus as diagnosed by colposcopy and brush histologic

Heterologous prime-boost vaccination with DNA and MVA vaccines, expressing HIV-1 subtype C mosaic Gag virus-like particles, is highly immunogenic in mice.

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Ros Chapman

Full Text Available In an effort to make affordable vaccines suitable for the regions most affected by HIV-1, we have constructed stable vaccines that express an HIV-1 subtype C mosaic Gag immunogen (BCG-GagM, MVA-GagM and DNA-GagM. Mosaic immunogens have been designed to address the tremendous diversity of this virus. Here we have shown that GagM buds from cells infected and transfected with MVA-GagM and DNA-GagM respectively and forms virus-like particles. Previously we showed that a BCG-GagM prime MVA-GagM boost generated strong cellular immune responses in mice. In this study immune responses to the DNA-GagM and MVA-GagM vaccines were evaluated in homologous and heterologous prime-boost vaccinations. The DNA homologous prime boost vaccination elicited predominantly CD8+ T cells while the homologous MVA vaccination induced predominantly CD4+ T cells. A heterologous DNA-GagM prime MVA-GagM boost induced strong, more balanced Gag CD8+ and CD4+ T cell responses and that were predominantly of an effector memory phenotype. The immunogenicity of the mosaic Gag (GagM was compared to a naturally occurring subtype C Gag (GagN using a DNA homologous vaccination regimen. DNA-GagN expresses a natural Gag with a sequence that was closest to the consensus sequence of subtype C viruses sampled in South Africa. DNA-GagM homologous vaccination induced cumulative HIV-1 Gag-specific IFN-γ ELISPOT responses that were 6.5-fold higher than those induced by the DNA-GagN vaccination. Similarly, DNA-GagM vaccination generated 7-fold higher levels of cytokine-positive CD8+ T cells than DNA-GagN, indicating that this subtype C mosaic Gag elicits far more potent immune responses than a consensus-type Gag. Cells transfected and infected with DNA-GagM and MVA-GagM respectively, expressed high levels of GagM and produced budding virus-like particles. Our data indicates that a heterologous prime boost regimen using DNA and MVA vaccines expressing HIV-1 subtype C mosaic Gag is highly

The SUD1 gene encodes a putative E3 ubiquitin ligase and is a positive regulator of 3-hydroxy-3-methylglutaryl coenzyme a reductase activity in Arabidopsis.

Science.gov (United States)

Doblas, Verónica G; Amorim-Silva, Vítor; Posé, David; Rosado, Abel; Esteban, Alicia; Arró, Montserrat; Azevedo, Herlander; Bombarely, Aureliano; Borsani, Omar; Valpuesta, Victoriano; Ferrer, Albert; Tavares, Rui M; Botella, Miguel A

2013-02-01

The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme catalyzes the major rate-limiting step of the mevalonic acid (MVA) pathway from which sterols and other isoprenoids are synthesized. In contrast with our extensive knowledge of the regulation of HMGR in yeast and animals, little is known about this process in plants. To identify regulatory components of the MVA pathway in plants, we performed a genetic screen for second-site suppressor mutations of the Arabidopsis thaliana highly drought-sensitive drought hypersensitive2 (dry2) mutant that shows decreased squalene epoxidase activity. We show that mutations in SUPPRESSOR OF DRY2 DEFECTS1 (SUD1) gene recover most developmental defects in dry2 through changes in HMGR activity. SUD1 encodes a putative E3 ubiquitin ligase that shows sequence and structural similarity to yeast Degradation of α factor (Doα10) and human TEB4, components of the endoplasmic reticulum-associated degradation C (ERAD-C) pathway. While in yeast and animals, the alternative ERAD-L/ERAD-M pathway regulates HMGR activity by controlling protein stability, SUD1 regulates HMGR activity without apparent changes in protein content. These results highlight similarities, as well as important mechanistic differences, among the components involved in HMGR regulation in plants, yeast, and animals.

MVA recombinants expressing the fusion and hemagglutinin genes of PPRV protects goats against virulent challenge.

Science.gov (United States)

Chandran, Dev; Reddy, Kolli Bhaktavatsala; Vijayan, Shahana Pallichera; Sugumar, Parthasarthy; Rani, Gudavalli Sudha; Kumar, Ponsekaran Santha; Rajendra, Lingala; Srinivasan, Villuppanoor Alwar

2010-09-01

Peste des Petits Ruminants (PPR) is a highly contagious animal disease caused by the Peste des Petits Ruminants virus (PPRV) belonging to the genus morbillivirus and family Paramyxoviridae. The disease results in high morbidity and mortality in goats, sheep and in some small wild ruminants. The presence of large number of small ruminants reared in endemic areas makes PPR a notorious disease threatening the livelihood of poor farmers. Conventional vaccination using a live, attenuated vaccine gives adequate protection but cannot be used in case of eradication of the disease due to difficulty in differentiation of infected animals from the vaccinated ones.In the present study, we constructed two recombinant viruses using attenuated Modified Vaccinia virus Ankara virus (MVA) namely MVA-F and MVA-H expressing the full length PPRV fusion (F) and hemagglutinin (H) glycoproteins, respectively. Goats were vaccinated intramuscularly with 105 plaque forming units (PFU) each of the recombinant viruses and a live attenuated vaccine (RAKSHA PPR) and challenged 4 months later with PPRV challenge virus (10(3) goat LD(50)). All goats were completely protected from the clinical disease. This study gave an indication that mass vaccination of small ruminants with either of the above or both recombinant inexpensive virus vaccines could help in possible eradication of PPRV from endemic countries like India and subsequent seromonitoring of the disease for differentiation of infected animals from vaccinated ones.

HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial.

Directory of Open Access Journals (Sweden)

Charlotta Nilsson

Full Text Available We compared safety and immunogenicity of intradermal (ID vaccination with and without electroporation (EP in a phase I randomized placebo-controlled trial of an HIV-DNA prime HIV-MVA boost vaccine in healthy Swedish volunteers.HIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and B and RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteers received vaccine using a needle-free device (ZetaJet with (n=16 or without (n=9 ID EP (Dermavax. Five volunteers were placebo recipients. Boosting with recombinant MVA-CMDR expressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA or placebo was performed at weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 protein boost together with HIV-MVA.The ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statistically significant difference was seen in the IFN-γ ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33% and HIV-DNA ID recipients (1/7, 14%, p=0.6158. The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-γ ELISpot response rate to 18/19 (95%. CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrable in 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and 71% responders, respectively. IFN-γ and IL-2 dominated the CD4+ T cell response to Gag and Env. The CD8+ response to Gag was broader with expression of IFN-γ, IL-2, MIP-1β and/or CD107. No differences were seen between DNA vaccine groups. Binding antibodies were induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env, with the highest titers among EP/gp140 recipients.Intradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediated immune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen, with or without intradermal electroporation use.International Standard Randomised Controlled Trial Number (ISRCTN 60284968.

HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial.

Science.gov (United States)

Nilsson, Charlotta; Hejdeman, Bo; Godoy-Ramirez, Karina; Tecleab, Teghesti; Scarlatti, Gabriella; Bråve, Andreas; Earl, Patricia L; Stout, Richard R; Robb, Merlin L; Shattock, Robin J; Biberfeld, Gunnel; Sandström, Eric; Wahren, Britta

2015-01-01

We compared safety and immunogenicity of intradermal (ID) vaccination with and without electroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA prime HIV-MVA boost vaccine in healthy Swedish volunteers. HIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and B and RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteers received vaccine using a needle-free device (ZetaJet) with (n=16) or without (n=9) ID EP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVA-CMDR expressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performed at weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 protein boost together with HIV-MVA. The ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statistically significant difference was seen in the IFN-γ ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV-DNA ID recipients (1/7, 14%, p=0.6158). The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-γ ELISpot response rate to 18/19 (95%). CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrable in 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and 71% responders, respectively. IFN-γ and IL-2 dominated the CD4+ T cell response to Gag and Env. The CD8+ response to Gag was broader with expression of IFN-γ, IL-2, MIP-1β and/or CD107. No differences were seen between DNA vaccine groups. Binding antibodies were induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env, with the highest titers among EP/gp140 recipients. Intradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediated immune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen, with or without intradermal electroporation use. International Standard Randomised Controlled Trial Number (ISRCTN) 60284968.

A 220 MVA turbo-generator for the TCV tokamak power supplies

International Nuclear Information System (INIS)

Perez, A.; Canay, I.M.; Simond, J.-J.; Morf, J.-J; Pahud, J.-D; Seysen, R.

1989-01-01

A new 220 MVA, 120 Hz, 4 pole turbo-generator will be used as a pulsed power source to supply the toroidal and poloidal power supplies of the TCV tokamak, which is being built at the Ecole Polytechnique Federale de Lausanne in Switzerland. The paper describes the particular requirements of the TCV poloidal power supplies and the main electrical and mechanical features of the turbo-generator and its principal auxillaries. (author). 6 figs.; 1 tab

A Study on the Operation of 1 MVA Distribution STATCON

Energy Technology Data Exchange (ETDEWEB)

Park, S.T.; Jeon, Y.S.; Yoon, J.S.; Oh, K.I. [Korea Electric Power Research Institute, Taejeon (Korea)

2001-07-01

The objective of this study is to develop the power system operational technology of 1 MVA STATCON device, which was installed at Gaya Substation in Changwon Power Transmission District Office to improve the power quality by FACTS(Flexible AC Transmission Systems). This report presents the contents as follow; The development of EMTDC simulator to analyze the operating effect of STATCON, analysis of compensation effect when increasing the capacity of STATCON, and analysis of the controlling reactive power by STATCON. (author). 27 figs., 6 tabs.

Design of double-fed control system for J-TEXT 100 MVA pulse generator unit

International Nuclear Information System (INIS)

Fang, Jianming; Yu, Kexun; Zhang, Ming; Zhuang, Ge; Xiao, Zhiguo; Jiang, Guozhong; Yang, Cheng; Xu, Jiayu

2013-01-01

Highlights: ► A double-fed control system is designed for J-TEXT 100 MVA pulse generator unit. ► The double-fed system can control the motor speed and reactive power individually. ► Experiment on a prototype motor shows a good control result. -- Abstract: The 100 MVA pulse generator unit is the main power supply of J-TEXT. This unit supplies energy for the toroidal coil, the ohmic heat coil and the divertor coil, with the maximum stored energy 185 MJ. For the difference of grid frequency between China and USA, the rotational speed and stored energy of this unit are less than the designed value. A double-fed control system for the unit is designed to raise them. This double-fed system has applied a control method using a rotational reference frame oriented by stator flux. With this control system, the speed and reactive power of motor could be controlled individually. Experiments on a prototype motor show a good control result

Double-Difference Tomography for Sequestration MVA [monitoring, verification, and accounting

Energy Technology Data Exchange (ETDEWEB)

Westman, Erik [Virginia Polytechnic Inst. and State Univ. (Virginia Tech), Blacksburg, VA (United States)

2012-12-31

Analysis of synthetic data was performed to determine the most cost-effective tomographic monitoring system for a geologic carbon sequestration injection site. Double-difference tomographic inversion was performed on 125 synthetic data sets: five stages of CO2 plume growth, five seismic event regions, and five geophone arrays. Each resulting velocity model was compared quantitatively to its respective synthetic velocity model to determine an accuracy value. The results were examined to determine a relationship between cost and accuracy in monitoring, verification, and accounting applications using double-difference tomography. The geophone arrays with widely-varying geophone locations, both laterally and vertically, performed best. Additionally, double difference seismic tomography was performed using travel time data from a carbon sequestration site at the Aneth oil field in southeast Utah as part of a Department of Energy initiative on monitoring, verification, and accounting (MVA) of sequestered CO2. A total of 1,211 seismic events were recorded from a borehole array consisting of 22 geophones. Artificial velocity models were created to determine the ease with which different CO2 plume locations and sizes can be detected. Most likely because of the poor geophone arrangement, a low velocity zone in the Desert Creek reservoir can only be detected when regions of test site containing the highest ray path coverage are considered. MVA accuracy and precision may be improved through the use of a receiver array that provides more comprehensive ray path coverage.

A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects.

Science.gov (United States)

Greenberg, Richard N; Hay, Christine M; Stapleton, Jack T; Marbury, Thomas C; Wagner, Eva; Kreitmeir, Eva; Röesch, Siegfried; von Krempelhuber, Alfred; Young, Philip; Nichols, Richard; Meyer, Thomas P; Schmidt, Darja; Weigl, Josef; Virgin, Garth; Arndtz-Wiedemann, Nathaly; Chaplin, Paul

2016-01-01

Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56-80 years old population. MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56-80 year old vaccinia-experienced subjects (N = 120). Subjects received either two injections of MVA (MM group) or one injection of Placebo and one injection of MVA (PM group) four weeks apart. Safety was evaluated by assessment of adverse events (AE), focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT) before and at different time points after vaccination. Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4) were as follows: Seroconversion (SC) rates (doubling of titers from baseline) in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%]), and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]). Geometric mean titers (GMT) measured by ELISA two weeks after the final vaccination for Group

An MVA Approach to Missing $E_T$

CERN Document Server

Herwig, Theodor Christian

2013-01-01

We present an overview of an analysis of the missing transverse energy (MET) resolution in the CMS detector studying $Z\\to\\mu\\mu$ decay events as a part of the University of Michigan Summer REU Program. We make use of boosted decision trees and specialized recoil variables in an attempt to isolate separate effects contributing to the detector resolution such as pileup, the underlying event, and detector inefficiencies. A metric is developed to study the body of high-MET events in the distribution. Emphasis is placed on constructing a multivariate analysis that effectively models and corrects these `tail' regions, resulting in an overall improvement in our MET resolution. In Monte-Carlo simulation, we see an improvement from a mean value of MET = 18.12 GeV to MET= 8.14 GeV with full MVA corrections.

TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome

Science.gov (United States)

Ochiai, Hiroshi; Miyamoto, Tatsuo; Kanai, Akinori; Hosoba, Kosuke; Sakuma, Tetsushi; Kudo, Yoshiki; Asami, Keiko; Ogawa, Atsushi; Watanabe, Akihiro; Kajii, Tadashi; Yamamoto, Takashi; Matsuura, Shinya

2014-01-01

Cancer-prone syndrome of premature chromatid separation with mosaic variegated aneuploidy [PCS (MVA) syndrome] is a rare autosomal recessive disorder characterized by constitutional aneuploidy and a high risk of childhood cancer. We previously reported monoallelic mutations in the BUB1B gene (encoding BUBR1) in seven Japanese families with the syndrome. No second mutation was found in the opposite allele of any of the families studied, although a conserved BUB1B haplotype and a decreased transcript were identified. To clarify the molecular pathology of the second allele, we extended our mutational search to a candidate region surrounding BUB1B. A unique single nucleotide substitution, G > A at ss802470619, was identified in an intergenic region 44 kb upstream of a BUB1B transcription start site, which cosegregated with the disorder. To examine whether this is the causal mutation, we designed a transcription activator-like effector nuclease–mediated two-step single-base pair editing strategy and biallelically introduced this substitution into cultured human cells. The cell clones showed reduced BUB1B transcripts, increased PCS frequency, and MVA, which are the hallmarks of the syndrome. We also encountered a case of a Japanese infant with PCS (MVA) syndrome carrying a homozygous single nucleotide substitution at ss802470619. These results suggested that the nucleotide substitution identified was the causal mutation of PCS (MVA) syndrome. PMID:24344301

Analyzing the structural aspects of Isoprenoid biosynthesis pathway proteins in Ocimum species

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Muktesh Chandra

2017-10-01

Full Text Available Generally thought that the extremely diverse array of secondary metabolites observed within Ocimum species defends against a comparable diverse array of biotic pests, pathogens and herbivores encountered around its natural range. Along with defense the diverse array of secondary metabolite also leads to the therapeutic and remedial property which justifies Ocimum as natural medicinal and aromatic casket. Many of the defense compounds, aroma compounds and medicinal derivatives are secondary metabolites isolated from trichome glands, mainly consist of terpenoids as well as phenylpropanoids. Various pathways fabricating these compounds are known viz. mevalonate pathway (MVA, phenylpropanoid pathway and MEP pathways. The enzyme cascade responsible for various secondary metabolites, need to be explored in various aspects. Here we had studied the MVA pathway enzymes in O. basilicum and O. gratissimum to figure out variations in enzyme structures due to speciation. Hence, in depth analysis of the transcriptome of O. basilicum and O. gratissimum, varrying in qualitative and quantitative aspects of essential oil were carried out. The transcriptome data from NCBI server was assembled using bioinformatic approaches. nr database at NCBI repository used for annotation, which assigned 60% contigs to known functions. Contigs corresponding to Mevalonate pathway enzymes are isolated using perl pipelines developed in our lab, which were further assembled using CLC workbench to remove redundancy and make larger stretch of sequence. Blastx of these larger sequences assigned them function and they are mapped to validated sequences to make full length. Data from both species led us to overall seven enzymes (total 14 of MVA pathway. These enzymes are studied in detail for various physio-chemical properties, steriochemical properties and motif/domain for protein-protein interaction (PPI study. Homolog models of all enzymes were predicted, against templates from RCSB

Vectores recombinantes basados en el virus modificado de ankara (MVA) como vacunas preventivas y terapéuticas contra el SIDA

OpenAIRE

Heeney, Jonathan L.; Mooij, Petra; Nájera García, José Luis; Jiménez, Victoria; Esteban, Mariano; Gómez, Carmen E.

2005-01-01

Vectores Recombinantes basados en el Virus Modificado de Ankara (MVA) como Vacunas Preventivas y Terapéuticas contra el SIDA. Losvirus recombinantes de la invención contienen secuencias que se encuentran insertadas en el mismo sitio de inserción del MVA y permiten la expresión simultánea de varios antígenos, una proteína Env del VIH-I consistente en una proteína gpl20 carente de secuencias correspondientes a la proteína gp41, y una proteína quiméricade fusión de Gag, Pol y Nef. Son virus esta...

Environmental and genetic factors associated with solanesol accumulation in potato leaves

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Raymond Campbell

2016-08-01

Full Text Available Solanesol is a high value 45-carbon, unsaturated, all-trans-nonaprenol isoprenoid. Recently solanesol has received particular attention because of its utility, both in its own right and as a precursor in the production of numerous compounds used in the treatment of disease states. Solanesol is found mainly in solanaceous crops such as potato, tomato, tobacco and pepper where it accumulates in the foliage. There is considerable potential to explore the extraction of solanesol from these sources as a valuable co-product. In this study we have characterised the genetic variation in leaf solanesol content in a biparental, segregating diploid potato population. We demonstrate that potato leaf solanesol content is genetically controlled and identify several quantitative trait loci associated with leaf solanesol content. Transient over-expression of genes from the methylerythritol 4-phosphate (MEP and mevalonic acid (MVA pathways, either singly or in combination, resulted in enhanced accumulation of solanesol in leaves of Nicotiana benthamiana, providing insights for genetically engineering the pathway. We also demonstrate that in potato, leaf solanesol content is enhanced by up to six-fold on exposure to moderately elevated temperature and show corresponding changes in expression patterns of MEP and MVA genes. Our combined approaches offer new insights into solanesol accumulation and strategies for developing a bio-refinery approach to potato production.

Up-regulation of an N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase enhances production of essential oils and sterols in transgenic Lavandula latifolia.

Science.gov (United States)

Muñoz-Bertomeu, Jesús; Sales, Ester; Ros, Roc; Arrillaga, Isabel; Segura, Juan

2007-11-01

Spike lavender (Lavandula latifolia) essential oil is widely used in the perfume, cosmetic, flavouring and pharmaceutical industries. Thus, modifications of yield and composition of this essential oil by genetic engineering should have important scientific and commercial applications. We generated transgenic spike lavender plants expressing the Arabidopsis thaliana HMG1 cDNA, encoding the catalytic domain of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR1S), a key enzyme of the mevalonic acid (MVA) pathway. Transgenic T0 plants accumulated significantly more essential oil constituents as compared to controls (up to 2.1- and 1.8-fold in leaves and flowers, respectively). Enhanced expression of HMGR1S also increased the amount of the end-product sterols, beta-sitosterol and stigmasterol (average differences of 1.8- and 1.9-fold, respectively), but did not affect the accumulation of carotenoids or chlorophylls. We also analysed T1 plants derived from self-pollinated seeds of T0 lines that flowered after growing for 2 years in the greenhouse. The increased levels of essential oil and sterols observed in the transgenic T0 plants were maintained in the progeny that inherited the HMG1 transgene. Our results demonstrate that genetic manipulation of the MVA pathway increases essential oil yield in spike lavender, suggesting a contribution for this cytosolic pathway to monoterpene and sesquiterpene biosynthesis in leaves and flowers of the species.

Crosstalk between MAV and MEP pathways in vitro grape plants exposed to UV-B radiation

International Nuclear Information System (INIS)

Gil, M.; Bottini, R.; Piccoli, P.; Pontin, M.

2010-01-01

The synthesis of terpenoids from IPP (isopentenyl diphosphate) proceeds in plants throughout two pathways, the MVA (mevalonic acid) in cytosol and the MEP (2-C-methyl-D-erythritol 4-phosphate) in plastids. Ultraviolet-B (UV-B) radiation induced the synthesis of terpenes in in vitro grape plants according to the fluence rate. Low intensity UV-B promoted the MVA pathway while high intensity UV-B stimulated the MEP pathway. Mevastatin is known to inhibit the enzyme HMG-CoA reductase blocking terpene synthesis in cytosol. In vitro plants growing 45 days under 16 h-photoperiod (100 μmol m - 2 s - 1) were fed at the apex with mevastatin and then exposed to an UV-B dose administrated at two intensities: low UV-B (8.25 μW cm - 2,16 h) or high UV-B (33 μW cm - 2,4 h). Methanol: chloroform extracts were analyzed by GC-EIMS and compared with controls without mevastatin. Levels of γ-Sitosterol and Stigmasterol were significantly increased under low intensity UV-B in the controls. The plants treated with the inhibitor showed a significant decrease of both sterols and a decrease in the plastidial terpenes but sterols were higher under UV-B. These results suggest an IPP crosstalk between the MAV and MEP pathways under restrictive conditions. (authors)

High-throughput enzyme screening platform for the IPP-bypass mevalonate pathway for isopentenol production

DEFF Research Database (Denmark)

Kang, Aram; Meadows, Corey W.; Canu, Nicolas

2017-01-01

Isopentenol (or isoprenol, 3-methyl-3-buten-1-ol) is a drop-in biofuel and a precursor for commodity chemicals such as isoprene. Biological production of isopentenol via the mevalonate pathway has been optimized extensively in Escherichia coli, yielding 70% of its theoretical maximum. However, high...... ATP requirements and isopentenyl diphosphate (IPP) toxicity pose immediate challenges for engineering bacterial strains to overproduce commodities utilizing IPP as an intermediate. To overcome these limitations, we developed an “IPP-bypass� isopentenol pathway using the promiscuous activity...

Flywheel for a 167 MVA surge power motor-generator set

International Nuclear Information System (INIS)

Mertens, H.

1975-01-01

Flywheels to be subjected to major speed fluctuations are designed on the basis of both the usual strength analysis and fracture mechanics considerations, and the testing and operating instructions have to allow for this. Appropriate test units are used to determine the fracture toughness of the material. Residual stresses are measured and extensive ultrasonic and magnetic particle tests performed to enable the permissible number of stress cycles to be predicted. The article deals with these problems by reference to the flywheel of a 167 MVA surge power motor-generator set for the Max Planck Insitute for Plasma Physics in Garching. (orig.) [de

Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis

Energy Technology Data Exchange (ETDEWEB)

Barta, Michael L.; Skaff, D. Andrew; McWhorter, William J.; Herdendorf, Timothy J.; Miziorko, Henry M.; Geisbrecht, Brian V. (UMKC)

2011-10-28

The polyisoprenoid compound undecaprenyl phosphate is required for biosynthesis of cell wall peptidoglycans in Gram-positive bacteria, including pathogenic Enterococcus, Streptococcus, and Staphylococcus spp. In these organisms, the mevalonate pathway is used to produce the precursor isoprenoid, isopentenyl 5-diphosphate. Mevalonate diphosphate decarboxylase (MDD) catalyzes formation of isopentenyl 5-diphosphate in an ATP-dependent irreversible reaction and is therefore an attractive target for inhibitor development that could lead to new antimicrobial agents. To facilitate exploration of this possibility, we report the crystal structure of Staphylococcus epidermidis MDD (1.85 {angstrom} resolution) and, to the best of our knowledge, the first structures of liganded MDD. These structures include MDD bound to the mevalonate 5-diphosphate analogs diphosphoglycolyl proline (2.05 {angstrom} resolution) and 6-fluoromevalonate diphosphate (FMVAPP; 2.2 {angstrom} resolution). Comparison of these structures provides a physical basis for the significant differences in K{sub i} values observed for these inhibitors. Inspection of enzyme/inhibitor structures identified the side chain of invariant Ser{sup 192} as making potential contributions to catalysis. Significantly, Ser {yields} Ala substitution of this side chain decreases k{sub cat} by {approx}10{sup 3}-fold, even though binding interactions between FMVAPP and this mutant are similar to those observed with wild type MDD, as judged by the 2.1 {angstrom} cocrystal structure of S192A with FMVAPP. Comparison of microbial MDD structures with those of mammalian counterparts reveals potential targets at the active site periphery that may be exploited to selectively target the microbial enzymes. These studies provide a structural basis for previous observations regarding the MDD mechanism and inform future work toward rational inhibitor design.

Analisis Perbandingan Kinerja Keuangan Sebelum Dan Sesudah Merger Dengan Menggunakan Metode Economic Value Added (Eva Dan Market Value Added (Mva Pada Pt Unilever Indonesia Tbk

Directory of Open Access Journals (Sweden)

Rakhmi Ayu Zulvina

2010-04-01

Full Text Available Merger is a decision to combine or merge two or more companies into one new company. One of the merged company in Indonesia is PT Unilever Indonesia Tbk with PT Knorr Indonesia in 2004. To identify and analyze it, EVA and MVA method is used, then the results of the calculations tested using normality test statistical tool kolmogorov smirnov, and carried out by means of differential test paired samples T-test.The increase of  EVA before and after the merger worth 125.30%. While the increase in MVA before and after the merger worth 227.33%. Increasing the value of MVA was more due to the company's market value, which is reflected in the share price and listed share, although not free from invested capital in the company

1300MVA steam-turbine generators for Kansai Electric Power's Oi Nuclear Power Station

Energy Technology Data Exchange (ETDEWEB)

Oishi, N; Amagasa, N; Ito, H; Yagi, K [Mitsubishi Electric Corp., Kobe (Japan). Kobe Works

1977-06-01

Mitsubishi Electric has completed two 1300 MVA generators, equipped with 5500kW brushless exciters, that will be the No. 1 and No. 2 generators of the Oi plant. They are among the largest anywhere, and incorporate such technological innovations as water cooling of the stator coil and asymmetrical arrangement of the rotor slots. The article discusses generator specifications and construction, the brushless exciter, and the results of factory tests.

Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania☆,☆☆

Science.gov (United States)

Bakari, Muhammad; Aboud, Said; Nilsson, Charlotta; Francis, Joel; Buma, Deus; Moshiro, Candida; Aris, Eric A.; Lyamuya, Eligius F.; Janabi, Mohamed; Godoy-Ramirez, Karina; Joachim, Agricola; Polonis, Victoria R.; Bråve, Andreas; Earl, Patricia; Robb, Merlin; Marovich, Mary; Wahren, Britta; Pallangyo, Kisali; Biberfeld, Gunnel; Mhalu, Fred; Sandström, Eric

2016-01-01

Background We conducted a phase I/II randomized placebo-controlled trial with the aim of exploring whether priming with a low intradermal dose of a multiclade, multigene HIV-1 DNA vaccine could improve the immunogenicity of the same vaccine given intramuscularly prior to boosting with a heterologous HIV-1 MVA among healthy adults in Dar es Salaam, Tanzania. Methods Sixty HIV-uninfected volunteers were randomized to receive DNA plasmid vaccine 1 mg intradermally (id), n = 20, or 3.8 mg intramuscularly (im), n = 20, or placebo, n = 20, using a needle-free injection device. DNA plasmids encoding HIV-1 genes gp160 subtype A, B, C; rev B; p17/p24 gag A, B and Rtmut B were given at weeks 0, 4 and 12. Recombinant MVA (108 pfu) expressing HIV-1 Env, Gag, Pol of CRF01_AE or placebo was administered im at month 9 and 21. Results The vaccines were well tolerated. Two weeks after the third HIV-DNA injection, 22/38 (58%) vaccinees had IFN-γ ELISpot responses to Gag. Two weeks after the first HIV-MVA boost all 35 (100%) vaccinees responded to Gag and 31 (89%) to Env. Two to four weeks after the second HIV-MVA boost, 28/29 (97%) vaccinees had IFN-γ ELISpot responses, 27 (93%) to Gag and 23 (79%) to Env. The id-primed recipients had significantly higher responses to Env than im recipients. Intracellular cytokine staining for Gag-specific IFN-γ/IL-2 production showed both CD8+ and CD4+ T cell responses. All vaccinees had HIV-specific lymphoproliferative responses. All vaccinees reacted in diagnostic HIV serological tests and 26/29 (90%) had antibodies against gp160 after the second HIV-MVA boost. Furthermore, while all of 29 vaccinee sera were negative for neutralizing antibodies against clade B, C and CRF01 AE pseudoviruses in the TZM-bl neutralization assay, in a PBMC assay, the response rate ranged from 31% to 83% positives, depending upon the clade B or CRF01_AE virus tested. This vaccine approach is safe and highly immunogenic. Low dose, id HIV-DNA priming elicited higher

Newborn Mice Vaccination with BCG.HIVA222 + MVA.HIVA Enhances HIV-1-Specific Immune Responses: Influence of Age and Immunization Routes

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Narcís Saubi

2011-01-01

Full Text Available We have evaluated the influence of age and immunization routes for induction of HIV-1- and M. tuberculosis-specific immune responses after neonatal (7 days old and adult (7 weeks old BALB/c mice immunization with BCG.HIVA222 prime and MVA.HIVA boost. The specific HIV-1 cellular immune responses were analyzed in spleen cells. The body weight of the newborn mice was weekly recorded. The frequencies of HIV-specific CD8+ T cells producing IFN-γ were higher in adult mice vaccinated intradermally and lower in adult and newborn mice vaccinated subcutaneously. In all cases the IFN-γ production was significantly higher when mice were primed with BCG.HIVA222 compared with BCGwt. When the HIV-specific CTL activity was assessed, the frequencies of specific killing were higher in newborn mice than in adults. The prime-boost vaccination regimen which includes BCG.HIVA222 and MVA.HIVA was safe when inoculated to newborn mice. The administration of BCG.HIVA222 to newborn mice is safe and immunogenic and increased the HIV-specific responses induced by MVA.HIVA vaccine. It might be a good model for infant HIV and Tuberculosis bivalent vaccine.

Newborn Mice Vaccination with BCG.HIVA222 + MVA.HIVA Enhances HIV-1-Specific Immune Responses: Influence of Age and Immunization Routes

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Saubi, Narcís; Im, Eung-Jun; Fernández-Lloris, Raquel; Gil, Olga; Cardona, Pere-Joan; Gatell, Josep Maria; Hanke, Tomáš; Joseph, Joan

2011-01-01

We have evaluated the influence of age and immunization routes for induction of HIV-1- and M. tuberculosis-specific immune responses after neonatal (7 days old) and adult (7 weeks old) BALB/c mice immunization with BCG.HIVA222 prime and MVA.HIVA boost. The specific HIV-1 cellular immune responses were analyzed in spleen cells. The body weight of the newborn mice was weekly recorded. The frequencies of HIV-specific CD8+ T cells producing IFN-γ were higher in adult mice vaccinated intradermally and lower in adult and newborn mice vaccinated subcutaneously. In all cases the IFN-γ production was significantly higher when mice were primed with BCG.HIVA222 compared with BCGwt. When the HIV-specific CTL activity was assessed, the frequencies of specific killing were higher in newborn mice than in adults. The prime-boost vaccination regimen which includes BCG.HIVA222 and MVA.HIVA was safe when inoculated to newborn mice. The administration of BCG.HIVA222 to newborn mice is safe and immunogenic and increased the HIV-specific responses induced by MVA.HIVA vaccine. It might be a good model for infant HIV and Tuberculosis bivalent vaccine. PMID:21603216

Recombination-mediated genetic engineering of a bacterial artificial chromosome clone of modified vaccinia virus Ankara (MVA)

DEFF Research Database (Denmark)

Cottingham, Matthew G; Andersen, Rikke F; Spencer, Alexandra J

2008-01-01

-length, rescuable clones were obtained, which had indistinguishable immunogenicity in mice. One clone was shotgun sequenced and found to be identical to the parent. We employed GalK recombination-mediated genetic engineering (recombineering) of MVA-BAC to delete five selected viral genes. Deletion of C12L, A44L, A...

Enhanced cell surface expression, immunogenicity and genetic stability resulting from a spontaneous truncation of HIV Env expressed by a recombinant MVA

International Nuclear Information System (INIS)

Wyatt, Linda S.; Belyakov, Igor M.; Earl, Patricia L.; Berzofsky, Jay A.; Moss, Bernard

2008-01-01

During propagation of modified vaccinia virus Ankara (MVA) encoding HIV 89.6 Env, a few viral foci stained very prominently. Virus cloned from such foci replicated to higher titers than the parent and displayed enhanced genetic stability on passage. Sequence analysis showed a single nucleotide deletion in the 89.6 env gene of the mutant that caused a frame shift and truncation of 115 amino acids from the cytoplasmic domain. The truncated Env was more highly expressed on the cell surface, induced higher antibody responses than the full-length Env, reacted with HIV neutralizing monoclonal antibodies and mediated CD4/co-receptor-dependent fusion. Intramuscular (IM), intradermal (ID) needleless, and intrarectal (IR) catheter inoculations gave comparable serum IgG responses. However, intraoral (IO) needleless injector route gave the highest IgA in lung washings and IR gave the highest IgA and IgG responses in fecal extracts. Induction of CTL responses in the spleens of individual mice as assayed by intracellular cytokine staining was similar with both the full-length and truncated Env constructs. Induction of acute and memory CTL in the spleens of mice immunized with the truncated Env construct by ID, IO, and IR routes was comparable and higher than by the IM route, but only the IR route induced CTL in the gut-associated lymphoid tissue. Thus, truncation of Env enhanced genetic stability as well as serum and mucosal antibody responses, suggesting the desirability of a similar modification in MVA-based candidate HIV vaccines

A genomics resource for investigating regulation of essential oil production in Lavandula angustifolia.

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Lane, Alexander; Boecklemann, Astrid; Woronuk, Grant N; Sarker, Lukman; Mahmoud, Soheil S

2010-03-01

We are developing Lavandula angustifolia (lavender) as a model system for investigating molecular regulation of essential oil (a mixture of mono- and sesquiterpenes) production in plants. As an initial step toward building the necessary 'genomics toolbox' for this species, we constructed two cDNA libraries from lavender leaves and flowers, and obtained sequence information for 14,213 high-quality expressed sequence tags (ESTs). Based on homology to sequences present in GenBank, our EST collection contains orthologs for genes involved in the 1-deoxy-D: -xylulose-5-phosphate (DXP) and the mevalonic acid (MVA) pathways of terpenoid biosynthesis, and for known terpene synthases and prenyl transferases. To gain insight into the regulation of terpene metabolism in lavender flowers, we evaluated the transcriptional activity of the genes encoding for 1-deoxy-D: -xylulose-5-phosphate synthase (DXS) and HMG-CoA reductase (HMGR), which represent regulatory steps of the DXP and MVA pathways, respectively, in glandular trichomes (oil glands) by real-time PCR. While HMGR transcripts were barely detectable, DXS was heavily expressed in this tissue, indicating that essential oil constituents are predominantly produced through the DXP pathway in lavender glandular trichomes. As anticipated, the linalool synthase (LinS)-the gene responsible for the production of linalool, a major constituent of lavender essential oil-was also strongly expressed in glands. Surprisingly, the most abundant transcript in floral glandular trichomes corresponded to a sesquiterpene synthase (cadinene synthase, CadS), although sesquiterpenes are minor constituents of lavender essential oils. This result, coupled to the weak activity of the MVA pathway (the main route for sesquiterpene production) in trichomes, indicates that precursor supply may represent a bottleneck in the biosynthesis of sesquiterpenes in lavender flowers.

Sterol partitioning by HMGR and DXR for routing intermediates toward withanolide biosynthesis.

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Singh, Shefali; Pal, Shaifali; Shanker, Karuna; Chanotiya, Chandan Singh; Gupta, Madan Mohan; Dwivedi, Upendra Nath; Shasany, Ajit Kumar

2014-12-01

Withanolides biosynthesis in the plant Withania somnifera (L.) Dunal is hypothesized to be diverged from sterol pathway at the level of 24-methylene cholesterol. The conversion and translocation of intermediates for sterols and withanolides are yet to be characterized in this plant. To understand the influence of mevalonate (MVA) and 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways on sterols and withanolides biosynthesis in planta, we overexpressed the WsHMGR2 and WsDXR2 in tobacco, analyzed the effect of transient suppression through RNAi, inhibited MVA and MEP pathways and fed the leaf tissue with different sterols. Overexpression of WsHMGR2 increased cycloartenol, sitosterol, stigmasterol and campesterol compared to WsDXR2 transgene lines. Increase in cholesterol was, however, marginally higher in WsDXR2 transgenic lines. This was further validated through transient suppression analysis, and pathway inhibition where cholesterol reduction was found higher due to WsDXR2 suppression and all other sterols were affected predominantly by WsHMGR2 suppression in leaf. The transcript abundance and enzyme analysis data also correlate with sterol accumulation. Cholesterol feeding did not increase the withanolide content compared to cycloartenol, sitosterol, stigmasterol and campesterol. Hence, a preferential translocation of carbon from MVA and MEP pathways was found differentiating the sterols types. Overall results suggested that MVA pathway was predominant in contributing intermediates for withanolides synthesis mainly through the campesterol/stigmasterol route in planta. © 2014 Scandinavian Plant Physiology Society.

Metabolic plasticity for isoprenoid biosynthesis in bacteria.

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Pérez-Gil, Jordi; Rodríguez-Concepción, Manuel

2013-05-15

Isoprenoids are a large family of compounds synthesized by all free-living organisms. In most bacteria, the common precursors of all isoprenoids are produced by the MEP (methylerythritol 4-phosphate) pathway. The MEP pathway is absent from archaea, fungi and animals (including humans), which synthesize their isoprenoid precursors using the completely unrelated MVA (mevalonate) pathway. Because the MEP pathway is essential in most bacterial pathogens (as well as in the malaria parasites), it has been proposed as a promising new target for the development of novel anti-infective agents. However, bacteria show a remarkable plasticity for isoprenoid biosynthesis that should be taken into account when targeting this metabolic pathway for the development of new antibiotics. For example, a few bacteria use the MVA pathway instead of the MEP pathway, whereas others possess the two full pathways, and some parasitic strains lack both the MVA and the MEP pathways (probably because they obtain their isoprenoids from host cells). Moreover, alternative enzymes and metabolic intermediates to those of the canonical MVA or MEP pathways exist in some organisms. Recent work has also shown that resistance to a block of the first steps of the MEP pathway can easily be developed because several enzymes unrelated to isoprenoid biosynthesis can produce pathway intermediates upon spontaneous mutations. In the present review, we discuss the major advances in our knowledge of the biochemical toolbox exploited by bacteria to synthesize the universal precursors for their essential isoprenoids.

A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE in 18-40 Year Old Subjects with Diagnosed Atopic Dermatitis.

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Richard N Greenberg

Full Text Available Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD. Prior studies evaluating Modified Vaccinia Ankara virus (MVA, a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers.This Phase II study compared the safety and immunogenicity of MVA enrolling groups of 350 subjects with AD (SCORAD ≤ 30 and 282 healthy subjects.Subjects were vaccinated twice with MVA, each dose given subcutaneously 4 weeks apart. Adverse events, cardiac parameters, and the development of vaccinia virus humoral immune responses were monitored.The overall safety of the vaccine was similar in both groups. Adverse events affecting skin were experienced significantly more often in subjects with AD, but the majority of these events were mild to moderate in intensity. Seroconversion rates and geometric mean titers for total and neutralizing vaccinia-specific antibodies in the AD group were non-inferior compared to the healthy subjects.The size of the study population limited the detection of serious adverse events occurring at a frequency less than 1%.MVA has a favorable safety profile and the ability to elicit vaccinia-specific immune responses in subjects with AD.ClinicalTrials.gov NCT00316602.

Utilization of biodiesel by-product as substrate for high-production of β-farnesene via relatively balanced mevalonate pathway in Escherichia coli.

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You, Shengping; Yin, Qingdian; Zhang, Jianye; Zhang, Chengyu; Qi, Wei; Gao, Lan; Tao, Zhiping; Su, Rongxin; He, Zhimin

2017-11-01

Farnesene has been identified as suitable jet fuel substitutes and metabolic engineering for microbial production of farnesene is an alternative and attractive route. In this study, due to accumulation of toxic intermediate isopentenyl pyrophosphate (IPP), an engineered Escherichia coli strain harboring heterologous mevalonate pathway produced only 4.11mg/L β-farnesene. Through higher-level expression of isopentenyl diphosphate isomerase and farnesyl diphosphate synthase to minimize the accumulated IPP, another engineered strain with relatively balanced mevalonate pathway was constructed and had the highest production of β-farnesene to date (8.74g/L) by Escherichia coli in a lab bioreactor. Furthermore, this is the first report on utilization of biodiesel by-product (simple purification) as substrate for high-production of β-farnesene by the engineered strain optimized and β-farnesene concentration reached 2.83g/L in a lab bioreactor. Therefore, the engineered strain optimized could be used as a platform host for high-production of other terpenoids using biodiesel by-product as substrate. Copyright © 2017 Elsevier Ltd. All rights reserved.

MVA and NYVAC as vaccines against emergent infectious diseases and cancer.

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Gómez, Carmen E; Nájera, José L; Krupa, Magdalena; Perdiguero, Beatriz; Esteban, Mariano

2011-06-01

Recombinants based on poxviruses have been used extensively as gene delivery systems to study many biological functions of foreign genes and as vaccines against many pathogens, particularly in the veterinary field. Based on safety record, efficient expression and ability to trigger specific immune responses, two of the most promising poxvirus vectors for human use are the attenuated modified vaccinia virus Ankara (MVA) and the Copenhagen derived NYVAC strains. Because of the scientific and clinical interest in these two vectors, here we review their biological characteristics, with emphasis on virus-host cell interactions, viral immunomodulators, gene expression profiling, virus distribution in animals, and application as vaccines against different pathogens and tumors.

DNA/MVA Vaccines for HIV/AIDS

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Smita S. Iyer

2014-02-01

Full Text Available Since the initial proof-of-concept studies examining the ability of antigen-encoded plasmid DNA to serve as an immunogen, DNA vaccines have evolved as a clinically safe and effective platform for priming HIV-specific cellular and humoral responses in heterologous “prime-boost” vaccination regimens. Direct injection of plasmid DNA into the muscle induces T- and B-cell responses against foreign antigens. However, the insufficient magnitude of this response has led to the development of approaches for enhancing the immunogenicity of DNA vaccines. The last two decades have seen significant progress in the DNA-based vaccine platform with optimized plasmid constructs, improved delivery methods, such as electroporation, the use of molecular adjuvants and novel strategies combining DNA with viral vectors and subunit proteins. These innovations are paving the way for the clinical application of DNA-based HIV vaccines. Here, we review preclinical studies on the DNA-prime/modified vaccinia Ankara (MVA-boost vaccine modality for HIV. There is a great deal of interest in enhancing the immunogenicity of DNA by engineering DNA vaccines to co-express immune modulatory adjuvants. Some of these adjuvants have demonstrated encouraging results in preclinical and clinical studies, and these data will be examined, as well.

A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants.

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Muhammed O Afolabi

Full Text Available A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1 during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia.Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1.From March to October 2010, 48 infants (24 vaccine and 24 no-treatment were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9% and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms.A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and

HPLC Determination of α-Keto Acids from Human Serum Using 2, 3-Diamino-2, 3- Dimethyl Butane as Derivatizing Reagent

International Nuclear Information System (INIS)

Mahar, K.P.; Shar, G.Q.; Khuhawar, M.Y.; Abbasi, K.U.; Azmat, R.; Jameel Ahmed Biag, J.A.

2013-01-01

Seven α-keto acids, pyruvic acid (PYR), 2-oxobutyric acid (KB), 3-methyl-2-oxobutyric acid (MKBA), 3-methyl-2-oxovaleric acid (K3MVA), 4-methyl-2-oxovaleric acid (K4MVA), 2-oxoglutaric acid (KG) and Phenyl pyruvic acid (PPY) as derivatives of 2,3-diamino-2,3-dimethybutane (DDB) were separated by HPLC column Zorbax C-18 (4.6x150 mm-id). The compounds were eluted with methanol-water-acetonitrile (40:58:2 V/V/V) with flow rate 1 ml/min. UV detection was carried out by photodiode array at 255 nm. Linear calibration plots were obtained with 0.1 to 60 μg/ml with limits of detection (LoD) within 0.04-0.4 μg/ml. The method was applied for the analysis of α-keto acids from serum of diabetic patients with blood glucose level 430-458 mg/dl and healthy volunteers. The amounts of α-keto acids observed 3.24-9.71 μg/ml with RSD 1.1-1.9 percentage in diabetic patients were higher than healthy volunteer's 0.11-1.3 μg/ml with RSD 0.9-2.6 percentage. (author)

MvaT Family Proteins Encoded on IncP-7 Plasmid pCAR1 and the Host Chromosome Regulate the Host Transcriptome Cooperatively but Differently.

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Yun, Choong-Soo; Takahashi, Yurika; Shintani, Masaki; Takeda, Toshiharu; Suzuki-Minakuchi, Chiho; Okada, Kazunori; Yamane, Hisakazu; Nojiri, Hideaki

2016-02-01

MvaT proteins are members of the H-NS family of proteins in pseudomonads. The IncP-7 conjugative plasmid pCAR1 carries an mvaT-homologous gene, pmr. In Pseudomonas putida KT2440 bearing pCAR1, pmr and the chromosomally carried homologous genes, turA and turB, are transcribed at high levels, and Pmr interacts with TurA and TurB in vitro. In the present study, we clarified how the three MvaT proteins regulate the transcriptome of P. putida KT2440(pCAR1). Analyses performed by a modified chromatin immunoprecipitation assay with microarray technology (ChIP-chip) suggested that the binding regions of Pmr, TurA, and TurB in the P. putida KT2440(pCAR1) genome are almost identical; nevertheless, transcriptomic analyses using mutants with deletions of the genes encoding the MvaT proteins during the log and early stationary growth phases clearly suggested that their regulons were different. Indeed, significant regulon dissimilarity was found between Pmr and the other two proteins. Transcription of a larger number of genes was affected by Pmr deletion during early stationary phase than during log phase, suggesting that Pmr ameliorates the effects of pCAR1 on host fitness more effectively during the early stationary phase. Alternatively, the similarity of the TurA and TurB regulons implied that they might play complementary roles as global transcriptional regulators in response to plasmid carriage. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Alphavirus replicon DNA expressing HIV antigens is an excellent prime for boosting with recombinant modified vaccinia Ankara (MVA or with HIV gp140 protein antigen.

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Maria L Knudsen

Full Text Available Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells and antibodies. Studies in humans have shown that DNA vaccines are safe, but their immunogenicity needs further improvement. As a step towards this goal, we have previously demonstrated that immunogenicity is increased with the use of an alphavirus DNA-launched replicon (DREP vector compared to conventional DNA vaccines. In this study, we investigated the effect of varying the dose and number of administrations of DREP when given as a prime prior to a heterologous boost with poxvirus vector (MVA and/or HIV gp140 protein formulated in glucopyranosyl lipid A (GLA-AF adjuvant. The DREP and MVA vaccine constructs encoded Env and a Gag-Pol-Nef fusion protein from HIV clade C. One to three administrations of 0.2 μg DREP induced lower HIV-specific T cell and IgG responses than the equivalent number of immunizations with 10 μg DREP. However, the two doses were equally efficient as a priming component in a heterologous prime-boost regimen. The magnitude of immune responses depended on the number of priming immunizations rather than the dose. A single low dose of DREP prior to a heterologous boost resulted in greatly increased immune responses compared to MVA or protein antigen alone, demonstrating that a mere 0.2 μg DREP was sufficient for priming immune responses. Following a DREP prime, T cell responses were expanded greatly by an MVA boost, and IgG responses were also expanded when boosted with protein antigen. When MVA and protein were administered simultaneously following multiple DREP primes, responses were slightly compromised compared to administering them sequentially. In conclusion, we have demonstrated efficient priming of HIV-specific T cell and IgG responses with a low dose of DREP, and shown that the priming effect depends on number of primes administered rather than dose.

Client preferences and acceptability for medical abortion and MVA as early pregnancy termination method in Northwest Ethiopia

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White Mary T

2011-06-01

Full Text Available Abstract Background Increasing access to safe abortion services is the most effective way of preventing the burden of unsafe abortion, which is achieved by increasing safe choices for pregnancy termination. Medical abortion for termination of early abortion is said to safe, effective, and acceptable to women in several countries. In Ethiopia, however, medical methods have, until recently, never been used. For this reason it is important to assess women's preferences and the acceptability of medical abortion and manual vacuum aspiration (MVA in the early first trimester pregnancy termination and factors affecting acceptability of medical and MVA abortion services. Methods A prospective study was conducted in two hospitals and two clinics from March 2009 to November 2009. The study population consisted of 414 subjects over the age of 18 with intrauterine pregnancies of up to 63 days' estimated gestation. Of these 251 subjects received mifepristone and misoprostol and 159 subjects received MVA. Questionnaires regarding expectations and experiences were administered before the abortion and at the 2-week follow-up visit. Results The study groups were similar with respect to age, marital status, educational status, religion and ethnicity. Their mean age was about 23, majority in both group completed secondary education and about half were married. Place of residence and duration of pregnancy were associated with method choice. Subjects undergoing medical abortions reported significantly greater satisfaction than those undergoing surgical abortions (91.2% vs 82.4%; P Conclusions Women receiving medical abortion were more satisfied with their method and more likely to choose the same method again than were subjects undergoing surgical abortion. We conclude that medical abortion can be used widely as an alternative method for early pregnancy termination.

Simulation of double-fed speed regulation system for 125 MVA motor-generator set

International Nuclear Information System (INIS)

Wang Fen; Wang Shujing; Li Huajun

2007-01-01

A simulation modeling of double-fed motor speed regulation for 125 MVA AC pulsed M-G set of HL-2A is built using Matlab. Some parameters of the project are obtained by the pre-simulation, and the process of start-up is analyzed. In the Matlab simulation the motor model in Simulink can not be connected directly to the cycloconverter model. This problem is solved by adding an ideal transformer model between them, and the satisfactory result is obtained. A new method of control switching two cycloconverter without circulating current has been introduced. (authors)

Ultrasound for critical care physicians: hypotension after a MVA

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Schmitz E

2014-03-01

Full Text Available No abstract available. Article truncated after first page. A 25 year old woman was a restrained driver in a rollover motor vehicle accident (MVA and suffered a C5-C6 fracture-dislocation with spinal cord injury. She was lucid and able to follow commands and could move her upper extremities but not her lower extremities. She was given approximately 6 liters of fluid but required vasopressors to maintain her blood pressure. Initial ECG revealed a normal sinus rhythm without significant ST changes (Figure 1. Upon initial evaluation her blood pressure was low. Bedside ultrasound of the left anterior second intercostal space revealed a sliding lung sign and a 4 chamber view of her heart was performed (Figure 2. Which of the following is the most likely cause of her hypotension? 1. Blunt cardiac injury; 2. Intravascular volume depletion; 3. Neurogenic stunned myocardium; 4. Pericardial tamponade; 5. Pneumothorax ...

MVA power flow and loss analysis for electricity market

International Nuclear Information System (INIS)

Wu, Z.Q.; Chen, G.Z.

2001-01-01

MVA power-flow and loss analysis is the basis for allocating the fixed costs and power losses under electricity-market deregulation. It is pointed out that the decomposition allocation of active and reactive power losses is not reasonable. The theory of active and reactive loss allocation and branch-power-flow decomposition has been proposed. Various contributory factors have been deduced. These contributory factors include the contribution factors of the active and reactive generation power, load-power-to-branch flows, the contribution factors of active and reactive generation power to active and reactive load power, the contribution factors of active and reactive load power to generation power, and the contribution factors of active and reactive load power and active and reactive generation power to line power losses. The detailed calculation results are presented and analysed, demonstrating that the theory presented provides a good charging algorithm for all the market participants. (Author)

HIV-1 Subtype C Mosaic Gag Expressed by BCG and MVA Elicits Persistent Effector T Cell Responses in a Prime-Boost Regimen in Mice.

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Tsungai Ivai Jongwe

Full Text Available Over 90% of HIV/AIDS positive individuals in sub-Saharan Africa are infected with highly heterogeneous HIV-1 subtype C (HIV-1C viruses. One of the best ways to reduce the burden of this disease is the development of an affordable and effective prophylactic vaccine. Mosaic immunogens are computationally designed to overcome the hurdle of HIV diversity by maximizing the expression of potential T cell epitopes. Mycobacterium bovis BCG ΔpanCD auxotroph and modified vaccinia Ankara (MVA vaccines expressing HIV-1C mosaic Gag (GagM were tested in a prime-boost regimen to demonstrate immunogenicity in a mouse study. The BCG-GagM vaccine was stable and persisted 11.5 weeks post vaccination in BALB/c mice. Priming with BCG-GagM and boosting with MVA-GagM elicited higher Gag-specific IFN-γ ELISPOT responses than the BCG-GagM only and MVA-GagM only homologous vaccination regimens. The heterologous vaccination also generated a more balanced and persistent CD4+ and CD8+ T cell Gag-specific IFN-γ ELISPOT response with a predominant effector memory phenotype. A Th1 bias was induced by the vaccines as determined by the predominant secretion of IFN-γ, TNF-α, and IL-2. This study shows that a low dose of MVA (104 pfu can effectively boost a BCG prime expressing the same mosaic immunogen, generating strong, cellular immune responses against Gag in mice. Our data warrants further evaluation in non-human primates. A low dose vaccine would be an advantage in the resource limited countries of sub-Saharan Africa and India (where the predominating virus is HIV-1 subtype C.

MVA-based H5N1 vaccine affords cross-clade protection in mice against influenza A/H5N1 viruses at low doses and after single immunization.

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Joost H C M Kreijtz

Full Text Available Human infections with highly pathogenic avian influenza viruses of the H5N1 subtype, frequently reported since 2003, result in high morbidity and mortality. It is feared that these viruses become pandemic, therefore the development of safe and effective vaccines is desirable. MVA-based H5N1 vaccines already proved to be effective when two immunizations with high doses were used. Dose-sparing strategies would increase the number of people that can be vaccinated when the amount of vaccine preparations that can be produced is limited. Furthermore, protective immunity is induced ideally after a single immunization. Therefore the minimal requirements for induction of protective immunity with a MVA-based H5N1 vaccine were assessed in mice. To this end, mice were vaccinated once or twice with descending doses of a recombinant MVA expressing the HA gene of influenza virus A/Vietnam/1194/04. The protective efficacy was determined after challenge infection with the homologous clade 1 virus and a heterologous virus derived from clade 2.1, A/Indonesia/5/05 by assessing weight loss, virus replication and histopathological changes. It was concluded that MVA-based vaccines allowed significant dose-sparing and afford cross-clade protection, also after a single immunization, which are favorable properties for an H5N1 vaccine candidate.

Overexpressing 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR in the lactococcal mevalonate pathway for heterologous plant sesquiterpene production.

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Adelene Ai-Lian Song

Full Text Available Isoprenoids are a large and diverse group of metabolites with interesting properties such as flavour, fragrance and therapeutic properties. They are produced via two pathways, the mevalonate pathway or the 2-C-methyl-D-erythritol-4-phosphate (MEP pathway. While plants are the richest source of isoprenoids, they are not the most efficient producers. Escherichia coli and yeasts have been extensively studied as heterologous hosts for plant isoprenoids production. In the current study, we describe the usage of the food grade Lactococcus lactis as a potential heterologous host for the production of sesquiterpenes from a local herbaceous Malaysian plant, Persicaria minor (synonym Polygonum minus. A sesquiterpene synthase gene from P. minor was successfully cloned and expressed in L. lactis. The expressed protein was identified to be a β-sesquiphellandrene synthase as it was demonstrated to be functional in producing β-sesquiphellandrene at 85.4% of the total sesquiterpenes produced based on in vitro enzymatic assays. The recombinant L. lactis strain developed in this study was also capable of producing β-sesquiphellandrene in vivo without exogenous substrates supplementation. In addition, overexpression of the strain's endogenous 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR, an established rate-limiting enzyme in the eukaryotic mevalonate pathway, increased the production level of β-sesquiphellandrene by 1.25-1.60 fold. The highest amount achieved was 33 nM at 2 h post-induction.

Jasmonate-induced biosynthesis of andrographolide in Andrographis paniculata.

Science.gov (United States)

Sharma, Shiv Narayan; Jha, Zenu; Sinha, Rakesh Kumar; Geda, Arvind Kumar

2015-02-01

Andrographolide is a prominent secondary metabolite found in Andrographis paniculata that exhibits enormous pharmacological effects. In spite of immense value, the normal biosynthesis of andrographolide results in low amount of the metabolite. To induce the biosynthesis of andrographolide, we attempted elicitor-induced activation of andrographolide biosynthesis in cell cultures of A. paniculata. This was carried out by using methyl jasmonate (MeJA) as an elicitor. Among the various concentrations of MeJA tested at different time periods, 5 µM MeJA yielded 5.25 times more andrographolide content after 24 h of treatment. The accumulation of andrographolide was correlated with the expression level of known regulatory genes (hmgs, hmgr, dxs, dxr, isph and ggps) of mevalonic acid (MVA) and 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways. These results established the involvement of MeJA in andrographolide biosynthesis by inducing the transcription of its biosynthetic pathways genes. The coordination of isph, ggps and hmgs expression highly influenced the andrographolide biosynthesis. © 2014 Scandinavian Plant Physiology Society.

Aspects regarding the Calculation of the Dielectric Loss Angle Tangent between the Windings of a Rated 40 MVA Transformer

Directory of Open Access Journals (Sweden)

Cristinel Popescu

2015-09-01

Full Text Available The paper aims to identify how to determine the dielectric loss angle tangent of the electric transformers from the transformer stations. Autors of the paper managed a case study on the dielectric established between high respectively medium voltage windings of an electrical rated 40 MVA transformer.

Effect of light on 2H/1H fractionation in lipids from continuous cultures of the diatom Thalassiosira pseudonana

Science.gov (United States)

Sachs, Julian P.; Maloney, Ashley E.; Gregersen, Joshua

2017-07-01

Continuous cultures of the marine diatom Thalassiosira pseudonana were grown at irradiances between 6 and 47 μmol m-2 s-1 in order to evaluate the effect of light on hydrogen isotope fractionation in lipids. δ2H values increased with irradiance in phytol by 1.1‰ (μmol m-2 s-1)-1 and by 0.3‰ (μmol m-2 s-1)-1 in the C14:0 fatty acid, but decreased by 0.8‰ (μmol m-2 s-1)-1 in the sterol 24-methyl-cholesta-5,24(28)-dien-3β-ol (C28Δ5,24(28)). The anticorrelation between δ2H values in C28Δ5,24(28) and irradiance is attributed to enhanced sterol precursor synthesis via the plastidic methylerythritol phosphate (MEP) pathway at high irradiance, relative to the cytosolic mevalonic acid (MVA) pathway, and the supposition that MEP precursors are 2H-depleted compared to MVA precursors because they incorporate a greater proportion of hydrogen from photosynthetically produced NADPH. Increasing δ2H values of phytol and C14:0 with irradiance is attributed to a greater proportion of pyruvate, the last common precursor to both lipids, being sourced from glycolysis in the mitochondria and cytosol, where enhanced incorporation of metabolic NADPH and further hydrogen exchange with cell water can enrich pyruvate with 2H relative to pyruvate from the chloroplast. Irrespective of the biosynthetic mechanisms responsible for the 2H/1H fractionation response to light, the high sensitivity of lipid δ2H values in T. pseudonana continuous cultures would result in -30‰ to +40‰ variations in δ2H over a 40 μmol m-2 s-1 range in sub-saturating irradiance if expressed in the environment, depending on the lipid.

Deletion of A44L, A46R and C12L Vaccinia Virus Genes from the MVA Genome Improved the Vector Immunogenicity by Modifying the Innate Immune Response Generating Enhanced and Optimized Specific T-Cell Responses

Directory of Open Access Journals (Sweden)

María Pía Holgado

2016-05-01

Full Text Available MVA is an attenuated vector that still retains immunomodulatory genes. We have previously reported its optimization after deleting the C12L gene, coding for the IL-18 binding-protein. Here, we analyzed the immunogenicity of MVA vectors harboring the simultaneous deletion of A44L, related to steroid synthesis and A46R, a TLR-signaling inhibitor (MVAΔA44L-A46R; or also including a deletion of C12L (MVAΔC12L/ΔA44L-A46R. The absence of biological activities of the deleted genes in the MVA vectors was demonstrated. Adaptive T-cell responses against VACV epitopes, evaluated in spleen and draining lymph-nodes of C57Bl/6 mice at acute/memory phases, were of higher magnitude in those animals that received deleted MVAs compared to MVAwt. MVAΔC12L/ΔA44L-A46R generated cellular specific memory responses of higher quality characterized by bifunctionality (CD107a/b+/IFN-γ+ and proliferation capacity. Deletion of selected genes from MVA generated innate immune responses with higher levels of determining cytokines related to T-cell response generation, such as IL-12, IFN-γ, as well as IL-1β and IFN-β. This study describes for the first time that simultaneous deletion of the A44L, A46R and C12L genes from MVA improved its immunogenicity by enhancing the host adaptive and innate immune responses, suggesting that this approach comprises an appropriate strategy to increase the MVA vaccine potential.

Analysis of acyl CoA ester intermediates of the mevalonate pathway in Saccharomyces cerevisiae

DEFF Research Database (Denmark)

Seker, Tamay; Møller, Kasper; Nielsen, Jens

2005-01-01

The mevalonate pathway plays an important role in providing the cell with a number of essential precursors for the synthesis of biomass constituents. With respect to their chemical structure, the metabolites of this pathway can be divided into two groups: acyl esters [acetoacetyl CoA, acetyl Co......A, hydroxymethylglutaryl (HMG) CoA] and phosphorylated metabolites (isopentenyl pyrophosphate, dimethylallyl pyrophosphate, geranyl pyrophosphate, farnesyl pyrophosphate). In this study, we developed a method for the precise analysis of the intracellular concentration of acetoacetyl CoA, acetyl CoA and HMG CoA; and we...... used this method for quantification of these metabolites in Saccharomyces cerevisiae, both during batch growth on glucose and on galactose and in glucose-limited chemostat cultures operated at three different dilution rates. The level of the metabolites changed depending on the growth phase...

The role of leucine in isoprenoid metabolism. Incorporation of [3-13C]leucine and of [2-3H,4-14C]-β,β-dimethyl-acrylic acid into phytosterols by tissue cultures of Andrographis paniculata

International Nuclear Information System (INIS)

Anastasis, P.; Freer, I.; Overton, K.; Rycroft, D.; Singh, S.B.

1985-01-01

[3- 13 C]Leucine is incorporated into phytosterols by tissue cultures of Andrographis paniculata by breakdown to acetyl-CoA and its subsequent incorporation via (3S)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) and mevalonic acid; [2- 3 H,4- 14 C]-β,β-dimethylacrylic acid also is not incorporated intact. (author)

Retinoid production using metabolically engineered Escherichia coli with a two-phase culture system.

Science.gov (United States)

Jang, Hui-Jeong; Yoon, Sang-Hwal; Ryu, Hee-Kyung; Kim, Jung-Hun; Wang, Chong-Long; Kim, Jae-Yean; Oh, Deok-Kun; Kim, Seon-Won

2011-07-29

Retinoids are lipophilic isoprenoids composed of a cyclic group and a linear chain with a hydrophilic end group. These compounds include retinol, retinal, retinoic acid, retinyl esters, and various derivatives of these structures. Retinoids are used as cosmetic agents and effective pharmaceuticals for skin diseases. Retinal, an immediate precursor of retinoids, is derived by β-carotene 15,15'-mono(di)oxygenase (BCM(D)O) from β-carotene, which is synthesized from the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Retinoids are chemically unstable and biologically degraded via retinoic acid. Although extensive studies have been performed on the microbial production of carotenoids, retinoid production using microbial metabolic engineering has not been reported. Here, we report retinoid production using engineered Escherichia coli that express exogenous BCM(D)O and the mevalonate (MVA) pathway for the building blocks synthesis in combination with a two-phase culture system using a dodecane overlay. Among the BCM(D)O tested in E. coli, the synthetic retinoid synthesis protein (SR), based on bacteriorhodopsin-related protein-like homolog (Blh) of the uncultured marine bacteria 66A03, showed the highest β-carotene cleavage activity with no residual intracellular β-carotene. By introducing the exogenous MVA pathway, 8.7 mg/L of retinal was produced, which is 4-fold higher production than that of augmenting the MEP pathway (dxs overexpression). There was a large gap between retinal production and β-carotene consumption using the exogenous MVA pathway; therefore, the retinal derivatives were analyzed. The derivatives, except for retinoic acid, that formed were identified, and the levels of retinal, retinol, and retinyl acetate were measured. Amounts as high as 95 mg/L retinoids were obtained from engineered E. coli DH5α harboring the synthetic SR gene and the exogenous MVA pathway in addition to dxs overexpression, which

Vectores recombinantes basados en el virus modificado de ankara (MVA), con deleción en el gen C6L, como vacunas contra el VIH/SIDA y otras enfermedades

OpenAIRE

García-Arriaza, J.; Gómez, Carmen E.; Esteban, Mariano

2011-01-01

[ES] La presente invención engloba dentro de los campos de la biología molecular y de la biotecnología. Especificamente se refiere a virus recombinantes basados en el virus modificado de Ankara (MVA) que expresan los antigenos gp120 y Gag-Pol-Nef del virus de la inmunodeficienciahumana (VIH-1) de subtipo B (MVA-B), sobre los que see ha delecionado el gen de vaccinia C6L, y que han sido diseñados para utilizarse como vacunas contra el VIH/SIDA y otras enfermedades.

Vectores recombinantes basados en el virus modificado de Ankara (MVA), con deleción en el gen C6L, como vacunas contra el VIH/SIDA y otras enfermedades

OpenAIRE

García-Arriaza, J.; Gómez, Carmen E.; Esteban, Mariano

2011-01-01

La presente invención se engloba dentro de los campos de la biología molecular y de la biotecnología. Específicamente se refiere a virus recombinantes basados en el virus modificado de Ankara (MVA) que expresan los antígenos gp120 y Gag-Pol-Nef del virus de la inmunodeficiencia humana (VIH-1) de subtipo B (MVA-B), sobre los que se ha delecionado el gen de vaccinia C6L, y que han sido diseñados para utilizarse como vacunas contra el VIH/SIDA y otras enfermedades.

Role of leucine in isoprenoid metabolism. Incorporation of (3-/sup 13/C)leucine and of (2-/sup 3/H,4-/sup 14/C)-. beta. ,. beta. -dimethyl-acrylic acid into phytosterols by tissue cultures of Andrographis paniculata

Energy Technology Data Exchange (ETDEWEB)

Anastasis, P; Freer, I; Overton, K; Rycroft, D; Singh, S B [Glasgow Univ. (UK). Dept. of Chemistry

1985-02-01

(3-/sup 13/C)Leucine is incorporated into phytosterols by tissue cultures of Andrographis paniculata by breakdown to acetyl-CoA and its subsequent incorporation via (3S)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) and mevalonic acid; (2-/sup 3/H,4-/sup 14/C)-..beta..,..beta..-dimethylacrylic acid also is not incorporated intact.

Vectores recombinantes basados en el virus Vaccinia modificado de Ankara (MVA) como vacunas contra la leishmaniasis

OpenAIRE

Pérez Jiménez, Eva; Larraga, Vicente; Esteban, Mariano

2005-01-01

Vectores recombinantes basados en el virus vaccinia modificado de Ankara (MVA) como vacunas contra la leishmaniasis. Los vectores de la invención contienen secuencias codificantes de la proteína LACK, preferentemente insertadas en el locus de hemaglutinina del virus y bajo el control de un promotor que permite su expresión a lo largo del ciclo de infección del virus. Son vectores seguros, estables, que dan lugar a una potente respuesta inmune que confiere protección frente a la leishmaniasis,...

Modeling of Electric Field Around 100 MVA 150/20 KV Power Transformator Using Charge Simulation Method

OpenAIRE

Rachman, Noviadi Arief; Risdiyanto, Agus; Ramdan, Ade

2013-01-01

Charge Simulation Method is one of the field theory that can be used as an approach to calculate the electromagnetic distribution on the electrical conductor. This paper discussed electric field modeling around power transformator by using Matlab to find the safety distance. The safe distance threshold of the electric field to human health refers to WHO and SNI was 5 kV/m. The specification of the power transformator was three phases, 150/20 kV, and 100 MVA. The basic concept is to change the...

An examination of the Apo-1/Fas promoter Mva I polymorphism in Japanese patients with multiple sclerosis

Directory of Open Access Journals (Sweden)

Yabe Ichiro

2002-08-01

Full Text Available Abstract Background The Apo-1/Fas (CD95 molecule is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor (TNF receptor family. Both Fas and Fas ligand (FasL are expressed in activated mature T cells, and prolonged cell activation induces susceptibility to Fas-mediated apoptosis. The Apo-1/Fas gene is located in a chromosomal region that shows linkage in multiple sclerosis (MS genome screens, and studies indicate that there is aberrant expression of the Apo-1/Fas molecule in MS. Methods Mva I polymorphism on the Apo-1/Fas promoter gene was detected by PCR-RFLP from the DNA of 114 Japanese patients with conventional MS and 121 healthy controls. We investigated the association of the Mva I polymorphism in Japanese MS patients using a case-control association study design. Results We found no evidence that the polymorphism contributes to susceptibility to MS. Furthermore, there was no association between Apo-1/Fas gene polymorphisms and clinical course (relapsing-remitting course or secondary-progressive course. No significant association was observed between Apo-1/Fas gene polymorphisms and the age at disease onset. Conclusions Overall, our findings suggest that Apo-1/Fas promoter gene polymorphisms are not conclusively related to susceptibility to MS or the clinical characteristics of Japanese patients with MS.

Field testing of a 1,300MVA turbine generator for the Oi nuclear-power station

International Nuclear Information System (INIS)

Inoue, Toshiaki; Tajiri, Yoshiaki; Ito, Hiroyuki; Fukuda, Mitsuo.

1980-01-01

The first Mitsubishi 1,300MVA turbine generator for this power station was put into commercial operation in March 1979, and the second unit in December of that year. The turbine generators use new technology in a variety of areas, including the cooling system, to achieve great increases in capacity over previously designed generators, and are destined to become the worldwide standard for large-scale generators of this type. Valuable experience was gained in the installation and testing of the generators. The outline of the tests performed on the generators with respect to heating and vibration are described in the article. (author)

A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector

International Nuclear Information System (INIS)

Wang, Z.; Zhou, W.; Srivastava, T.; La Rosa, C.; Mandarino, A.; Forman, S.J.; Zaia, J.A.; Britt, W.J.; Diamond, D.J.

2008-01-01

A therapeutic CMV vaccine incorporating an antigenic repertoire capable of eliciting a cellular immune response has yet to be successfully implemented for patients who already have acquired an infection. To address this problem, we have developed a vaccine candidate derived from modified vaccinia Ankara (MVA) that expresses three immunodominant antigens (pp65, IE1, IE2) from CMV. The novelty of this vaccine is the fusion of two adjacent exons from the immediate-early region of CMV, their successful expression in MVA, and robust immunogenicity in both primary and memory response models. Evaluation of the immunogenicity of the viral vaccine in mouse models shows that it can stimulate primary immunity against all three antigens in both the CD4 + and CD8 + T cell subsets. Evaluation of human PBMC from healthy CMV-positive donors or patients within 6 months of receiving hematopoietic cell transplant shows robust stimulation of existing CMV-specific CD4 + and CD8 + T cell subsets

Amo 1618 effects on incorporation of 14C-MVA and 14C-acetate into sterols in Nicotiana and Digitalis seedlings and cell-free preparations from Nicotiana

International Nuclear Information System (INIS)

Douglas, T.J.; Paleg, L.G.

1978-01-01

Incorporation of radioactivity from acetate-[ 14 C] and MVA-[ 14 C] into sterols and sterol precursors in tobacco was inhibited by Amo 1618; differing patterns of accumulation were obtained with the two precursors, suggesting more than one point of inhibition. This was borne out with cell-free preparations with which it was demonstrated that both HMG-CoA reductase and squalene-2,3-epoxide cyclase were inhibited, the latter more strongly than the former. GLC analysis of gross sterol and hydrocarbon fractions confirmed previous indications that incorporation of radioactivity into individual sterols was inhibited by Amo 1618. Finally, incorporation of MVA-[ 14 C] into sterols and sterol precursors of Digitalis was significantly altered by the retardant, thus expanding the generality of the relationship between sterol (particularly 4-desmethylsterol) biosynthesis inhibition and retardant effect. (author)

MVA amplifier used for plasma position control in the WEGA tokamak

International Nuclear Information System (INIS)

Schenk, G.

1982-02-01

A new amplifier has been developed for the control of the plasma positron in the WEGA III tokomak acting on the vertical magnetic field. In the high power domain thyristor choppers are usually applied. Unfortunately their response time is quite long and does not yet correspond to the WEGA demand. Therefore transistors have been used to build a fast switching amplifier of the H-bridge type, delivering a power of 1 MVA, by switching 2500 A at 400 V. Because of the duty cycle of the plasma (0,12 s every 240 s) the necessary average power to the amplifier supply is only 500 VA. An intermediate energy storage in an electrolytic capacitor bank is therefore used. As the switching transistors must operate under extreme conditions of voltage and current, precautions must be taken to limit the overvoltage and the overcurrent, to prevent oscillations and to assure power and control equilibrium among the transistors

Short-circuit tests of 1650 and 96 MVA transformers for 1300 MW french nuclear power plants

International Nuclear Information System (INIS)

Mailhot, M.

1989-01-01

Power evacuation and feeding of the auxiliaries directly from the 400 kV grid are sensitive points governing the security of 1300 MW PWR Nuclear Power Plants of the French Program. These two different functions are provided by two specific types of transformers. - Banks of 3 single-phase 550 MVA - 400 kV/20 kV transformers. - Three-phase 96 MVA - 400 kV / 3 x 6.8 kV transformers. These passive elements must have a never failing reliability and assure a continuous service in spite of electric, thermal and mechanical stresses that may occur during the lifetime of the power plant. Dielectric and thermal tests carried out in the manufacturers test floors insure these stresses withstand capabilities of transformers. In France, high short-circuit power for the 400 kV network added to often low impedance voltages for transformers impose on them very high stresses during short-circuits. Calculation and experimentation on scale or partial models are not sufficient to insure short-circuit currents withstand capabilities of transformers. The margin of uncertainty dependent on obligatory extrapolations for this kind of complex systems [steel, magnetic sheets, copper, oil, paper and transformerboard] can be reduced in a significant way only by real scale tests on prototypes. These tests that need both high power and voltage cannot be performed in manufacturers test floors. So, in France they are carried out at the EDF Les Renardieres Laboratory. Following paper deals with SHELL TYPE TRANSFORMERS which, particularly thanks to their interleaved rectangular windings display a great resistance to short-circuit stresses

The effect of O-acetylsalicylic acid on lipid synthesis by guinea pig gastric mucosa in vitro

International Nuclear Information System (INIS)

Spohn, M.; McColl, I.

1987-01-01

The aim of this work was to investigate the involvement of lipids as possible components of the gastric mucosal barrier by studying the synthesis and secretion of lipids by the epithelial cell lining of gastric mucosa and the effect of salicylate on these processes. O-Acetylsalicylic acid reversibly reduced in vitro incorporation of (U- 14 C) and of DL-(2- 14 C) mevalonic acid into lipids by isolated epithelial cells and by intact mucosa of guinea pig stomach, indicating reversible inhibition of lipid synthesis by the tissue in the presence of the drug. Inhibition of incorporation of both precursors into total lipids, into their fatty acid components, and into cholesterol is demonstrated

Virus-Induced Silencing of Key Genes Leads to Differential Impact on Withanolide Biosynthesis in the Medicinal Plant, Withania somnifera.

Science.gov (United States)

Agarwal, Aditya Vikram; Singh, Deeksha; Dhar, Yogeshwar Vikram; Michael, Rahul; Gupta, Parul; Chandra, Deepak; Trivedi, Prabodh Kumar

2018-02-01

Withanolides are a collection of naturally occurring, pharmacologically active, secondary metabolites synthesized in the medicinally important plant, Withania somnifera. These bioactive molecules are C28-steroidal lactone triterpenoids and their synthesis is proposed to take place via the mevalonate (MVA) and 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways through the sterol pathway using 24-methylene cholesterol as substrate flux. Although the phytochemical profiles as well as pharmaceutical activities of Withania extracts have been well studied, limited genomic information and difficult genetic transformation have been a major bottleneck towards understanding the participation of specific genes in withanolide biosynthesis. In this study, we used the Tobacco rattle virus (TRV)-mediated virus-induced gene silencing (VIGS) approach to study the participation of key genes from MVA, MEP and triterpenoid biosynthesis for their involvement in withanolide biosynthesis. TRV-infected W. somnifera plants displayed unique phenotypic characteristics and differential accumulation of total Chl as well as carotenoid content for each silenced gene suggesting a reduction in overall isoprenoid synthesis. Comprehensive expression analysis of putative genes of withanolide biosynthesis revealed transcriptional modulations conferring the presence of complex regulatory mechanisms leading to withanolide biosynthesis. In addition, silencing of genes exhibited modulated total and specific withanolide accumulation at different levels as compared with control plants. Comparative analysis also suggests a major role for the MVA pathway as compared with the MEP pathway in providing substrate flux for withanolide biosynthesis. These results demonstrate that transcriptional regulation of selected Withania genes of the triterpenoid biosynthetic pathway critically affects withanolide biosynthesis, providing new horizons to explore this process further, in planta.

Investigation of slot discharge on a 239 MVA hydro generator stator winding

Energy Technology Data Exchange (ETDEWEB)

Li, S.; Hong, W. [BC Hydro and Power Authority, Vancouver, BC (Canada)

2009-07-01

This paper discussed a slot discharge investigation conducted on a 239 MVA generator stator winding. The generator in which the winding was located had experienced core split distortion, stator winding phase-to-phase failures, winding failures during Hipot testing, and high partial discharge (PD) activity. The results of on-line PD testing data were evaluated. The stator winding was subjected to visual inspections, bar dissections, and failure mechanism analyses. Eleven winding bars were removed from the stator slots in order to assess groundwall insulation conditions and identify the cause of the slot discharge activity. It was determined that the root cause of the slot discharge was a loose, non-uniform bar in the slot. The vibrating bar caused the semi-conductive coating to wear out and degraded the armour tape. Results of the study demonstrated the importance of on-line PD monitoring for detecting slot PD activity. 4 refs., 3 tabs., 11 figs.

Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap.

Science.gov (United States)

Gray, Glenda E; Mayer, Kenneth H; Elizaga, Marnie L; Bekker, Linda-Gail; Allen, Mary; Morris, Lynn; Montefiori, David; De Rosa, Stephen C; Sato, Alicia; Gu, Niya; Tomaras, Georgia D; Tucker, Timothy; Barnett, Susan W; Mkhize, Nonhlanhla N; Shen, Xiaoying; Downing, Katrina; Williamson, Carolyn; Pensiero, Michael; Corey, Lawrence; Williamson, Anna-Lise

2016-06-01

A phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 10(9) PFU (months 4 and 5) (n = 40) or of a placebo (n = 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4(+) T-cell and CD8(+) T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4(+) T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4(+) T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.). Copyright © 2016 Gray et al.

Isoprenoid biosynthesis in eukaryotic phototrophs: A spotlight on algae

Energy Technology Data Exchange (ETDEWEB)

Lohr M.; Schwender J.; Polle, J. E. W.

2012-04-01

Isoprenoids are one of the largest groups of natural compounds and have a variety of important functions in the primary metabolism of land plants and algae. In recent years, our understanding of the numerous facets of isoprenoid metabolism in land plants has been rapidly increasing, while knowledge on the metabolic network of isoprenoids in algae still lags behind. Here, current views on the biochemistry and genetics of the core isoprenoid metabolism in land plants and in the major algal phyla are compared and some of the most pressing open questions are highlighted. Based on the different evolutionary histories of the various groups of eukaryotic phototrophs, we discuss the distribution and regulation of the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways in land plants and algae and the potential consequences of the loss of the MVA pathway in groups such as the green algae. For the prenyltransferases, serving as gatekeepers to the various branches of terpenoid biosynthesis in land plants and algae, we explore the minimal inventory necessary for the formation of primary isoprenoids and present a preliminary analysis of their occurrence and phylogeny in algae with primary and secondary plastids. The review concludes with some perspectives on genetic engineering of the isoprenoid metabolism in algae.

Phylogenomic reconstruction of archaeal fatty acid metabolism

Science.gov (United States)

Dibrova, Daria V.; Galperin, Michael Y.; Mulkidjanian, Armen Y.

2014-01-01

While certain archaea appear to synthesize and/or metabolize fatty acids, the respective pathways still remain obscure. By analyzing the genomic distribution of the key lipid-related enzymes, we were able to identify the likely components of the archaeal pathway of fatty acid metabolism, namely, a combination of the enzymes of bacterial-type β-oxidation of fatty acids (acyl-CoA-dehydrogenase, enoyl-CoA hydratase, and 3-hydroxyacyl-CoA dehydrogenase) with paralogs of the archaeal acetyl-CoA C-acetyltransferase, an enzyme of the mevalonate biosynthesis pathway. These three β-oxidation enzymes working in the reverse direction could potentially catalyze biosynthesis of fatty acids, with paralogs of acetyl-CoA C-acetyltransferase performing addition of C2 fragments. The presence in archaea of the genes for energy-transducing membrane enzyme complexes, such as cytochrome bc complex, cytochrome c oxidase, and diverse rhodopsins, was found to correlate with the presence of the proposed system of fatty acid biosynthesis. We speculate that because these membrane complexes functionally depend on fatty acid chains, their genes could have been acquired via lateral gene transfer from bacteria only by those archaea that already possessed a system of fatty acid biosynthesis. The proposed pathway of archaeal fatty acid metabolism operates in extreme conditions and therefore might be of interest in the context of biofuel production and other industrial applications. PMID:24818264

Proposal for the Award of a Contract for the Supply of 18kV Power Transformers Rated 464 kVA to 2 MVA

CERN Document Server

2002-01-01

This document concerns the award of a contract for the supply of thirty-five 18 kV cast-resin rectifier power transformers rated 464 kVA to 2 MVA and 26 protective enclosures. Following a market survey (MS-2920/SL/LHC) carried out among 56 firms in sixteen Member States, a call for tenders (IT-3007/SL/LHC) was sent on 12 August 2002 to eight firms in five Member States. By the closing date, CERN had received three tenders from three firms in three Member States. The Finance Committee is invited to agree to the negotiation of a contract with TRASFOR (CH), the lowest bidder, for the supply of 35 power transformers rated 464 kVA to 2 MVA and 26 protective enclosures for a total amount of 1 398 500 Swiss francs, not subject to revision, with an option for three additional transformers and protective enclosures, for an additional amount of 107 650 Swiss francs, subject to revision for inflation from 1 January 2005, bringing the total amount to 1 506 150 Swiss francs subject to revision for inflation from 1 January...

Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

Science.gov (United States)

Biswas, Sumi; Choudhary, Prateek; Elias, Sean C; Miura, Kazutoyo; Milne, Kathryn H; de Cassan, Simone C; Collins, Katharine A; Halstead, Fenella D; Bliss, Carly M; Ewer, Katie J; Osier, Faith H; Hodgson, Susanne H; Duncan, Christopher J A; O'Hara, Geraldine A; Long, Carole A; Hill, Adrian V S; Draper, Simon J

2014-01-01

The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases

Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

Directory of Open Access Journals (Sweden)

Sumi Biswas

Full Text Available The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i ChAd63-MVA immunization, ii immunization and CHMI, and iii primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i total IgG responses before and after CHMI, ii responses to allelic variants of MSP1 and AMA1, iii functional growth inhibitory activity (GIA, iv IgG avidity, and v isotype responses (IgG1-4, IgA and IgM. These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other

Comparative glandular trichome transcriptome-based gene characterization reveals reasons for differential (-)-menthol biosynthesis in Mentha species.

Science.gov (United States)

Akhtar, Md Qussen; Qamar, Nida; Yadav, Pallavi; Kulkarni, Pallavi; Kumar, Ajay; Shasany, Ajit Kumar

2017-06-01

The genes involved in menthol biosynthesis are reported earlier in Mentha × piperita. But the information on these genes is not available in Mentha arvensis. To bridge the gap in knowledge on differential biosynthesis of monoterpenes leading to compositional variation in the essential oil of these species, a comparative transcriptome analysis of the glandular trichome (GT) was carried out. In addition to the mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathway genes, about 210 and 196 different terpene synthases (TPSs) transcripts were identified from annotation in M. arvensis and M. × piperita, respectively, and correlated to several monoterpenes present in the essential oil. Six isoforms of (-)-menthol dehydrogenases (MD), the last enzyme of the menthol biosynthetic pathway, were identified, cloned and characterized from the transcriptome data (three from each species). Varied expression levels and differential enzyme kinetics of these isoforms indicated the nature and composition of the product, as these isoforms generate both (-)-menthol and (+)-neomenthol from (-)-menthone and converts (-)-menthol to (-)-menthone in the reverse reaction, and hence together determine the quantity of (-)-menthol in the essential oil in these two species. Several genes for high value minor monoterpenes could also be identified from the transcriptome data. © 2017 Scandinavian Plant Physiology Society.

Influence of adenovirus and MVA vaccines on the breadth and hierarchy of T cell responses.

Science.gov (United States)

Rollier, Christine S; Hill, Adrian V S; Reyes-Sandoval, Arturo

2016-08-31

Viral-vectored vaccines are in clinical development for several infectious diseases where T-cell responses can mediate protection, and responses to sub-dominant epitopes is needed. Little is known about the influence of MVA or adenoviral vectors on the hierarchy of the dominant and sub-dominant T-cell epitopes. We investigated this aspect in mice using a malaria immunogen. Our results demonstrate that the T-cell hierarchy is influenced by the timing of analysis, rather than by the vector after a single immunization, with hierarchy changing over time. Repeated homologous immunization reduced the breadth of responses, while heterologous prime-boost induced the strongest response to the dominant epitope, albeit with only modest response to the sub-dominant epitopes. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dynamic control of gene expression in Saccharomyces cerevisiae engineered for the production of plant sesquitepene α-santalene in a fed-batch mode

DEFF Research Database (Denmark)

Scalcinati, Gionata; Knuf, Christoph; Partow, Siavash

2012-01-01

-santalene, the precursor of a commercially interesting compound, was constructed through a rationally designed metabolic engineering approach. Optimal sesquiterpene production was obtained by modulating the expression of one of the key metabolic steps of the mevalonate (MVA) pathway, squalene synthase (Erg9). To couple......Microbial cells engineered for efficient production of plant sesquiterpenes may allow for sustainable and scalable production of these compounds that can be used as e.g. perfumes and pharmaceuticals. Here, for the first time a Saccharomyces cerevisiae strain capable of producing high levels of α...... ERG9 expression to glucose concentration its promoter was replaced by the HXT1 promoter. In a second approach, the HXT2 promoter was used to express an ERG9 antisense construct. Using the HXT1 promoter to control ERG9 expression, it was possible to divert the carbon flux from sterol synthesis towards...

Mevalonate-derived quinonemethide triterpenoid from in vitro roots of Peritassa laevigata and their localization in root tissue by MALDI imaging

Science.gov (United States)

Pina, Edieidia S.; Silva, Denise B.; Teixeira, Simone P.; Coppede, Juliana S.; Furlan, Maysa; França, Suzelei C.; Lopes, Norberto P.; Pereira, Ana Maria S.; Lopes, Adriana A.

2016-03-01

Biosynthetic investigation of quinonemethide triterpenoid 22β-hydroxy-maytenin (2) from in vitro root cultures of Peritassa laevigata (Celastraceae) was conducted using 13C-precursor. The mevalonate pathway in P. laevigata is responsible for the synthesis of the quinonemethide triterpenoid scaffold. Moreover, anatomical analysis of P. laevigata roots cultured in vitro and in situ showed the presence of 22β-hydroxy-maytenin (2) and maytenin (1) in the tissues from transverse or longitudinal sections with an intense orange color. MALDI-MS imaging confirmed the distribution of (2) and (1) in the more distal portions of the root cap, the outer cell layers, and near the vascular cylinder of P. laevigata in vitro roots suggesting a role in plant defense against infection by microorganisms as well as in the root exudation processes.

P53- and mevalonate pathway–driven malignancies require Arf6 for metastasis and drug resistance

Science.gov (United States)

Hashimoto, Ari; Oikawa, Tsukasa; Hashimoto, Shigeru; Sugino, Hirokazu; Yoshikawa, Ayumu; Otsuka, Yutaro; Handa, Haruka; Onodera, Yasuhito; Nam, Jin-Min; Oneyama, Chitose; Okada, Masato; Fukuda, Mitsunori

2016-01-01

Drug resistance, metastasis, and a mesenchymal transcriptional program are central features of aggressive breast tumors. The GTPase Arf6, often overexpressed in tumors, is critical to promote epithelial–mesenchymal transition and invasiveness. The metabolic mevalonate pathway (MVP) is associated with tumor invasiveness and known to prenylate proteins, but which prenylated proteins are critical for MVP-driven cancers is unknown. We show here that MVP requires the Arf6-dependent mesenchymal program. The MVP enzyme geranylgeranyl transferase II (GGT-II) and its substrate Rab11b are critical for Arf6 trafficking to the plasma membrane, where it is activated by receptor tyrosine kinases. Consistently, mutant p53, which is known to support tumorigenesis via MVP, promotes Arf6 activation via GGT-II and Rab11b. Inhibition of MVP and GGT-II blocked invasion and metastasis and reduced cancer cell resistance against chemotherapy agents, but only in cells overexpressing Arf6 and components of the mesenchymal program. Overexpression of Arf6 and mesenchymal proteins as well as enhanced MVP activity correlated with poor patient survival. These results provide insights into the molecular basis of MVP-driven malignancy. PMID:27044891

Proteomic analysis of lettuce seed germination and thermoinhibition by sampling of individual seeds at germination and removal of storage proteins by polyethylene glycol fractionation

DEFF Research Database (Denmark)

Wang, Wei-Qing; Song, Bin-Yan; Deng, Zhi-Jun

2015-01-01

the sensitivity of germination to abscisic acid. MVA pathway-derived products, cytokinins, partially reversed the lovastatin inhibition of germination and released seed thermoinhibition at 25°C. We conclude that the MVA pathway for isoprenoid biosynthesis is involved in lettuce seed germination...

Electron microscopy of hydrocarbon production in parthenium argentatum (guayule)

Energy Technology Data Exchange (ETDEWEB)

Bauer, Thomas E. [Univ. of California, Berkeley, CA (United States)

1977-11-01

The electron microscope was used to study the biological processes involved in hydrocarbon production. The little desert shrub Guayule (Parthenium argentatum) was selected for study. This shrub can produce hydrocarbons (rubber) in concentrations up to 1/4 of its dry weight. It grows on semi-arid land and has been extensively studied. The potential of Guayule is described in detail. Results of an investigation into the morphology of Guayule at the electron microscope level are given. Experiments, which would allow the biosynthesis of hydrocarbon in Guayule to be followed, were designed. In order to do this, knowledge of the biochemistry of rubber formation was used to select a tracer, mevalonic acid. Mevalonic acid is the precursor of all the terpenoids, a large class of hydrocarbons which includes rubber. It was found that when high enough concentrations of mevalonic acid are administered to seedling Guayule plants, build-ups of metabolized products are found within the chloroplasts of the seedlings. Also, tritium labeled mevalonic acid was used as a precursor, and its metabolic progress was followed by using the technique of electron microscope autoradiography. The results of these experiments also implicated chloroplasts of the Guayule plant in hydrocarbon production. The final task was the development of a system to produce three-dimensional stereo reconstructions of organelles suspected of involvement in hydrocarbon biosynthesis in Guayule. The techniques are designed to reconstruct an object from serial sections of that object. The techniques use stereo imaging both to abstract information for computer processing, and also in the computer produced reconstruction.

Diseño del sistema de control y protección de una central hidráulica de 37 MVA

OpenAIRE

Feliz Juárez, Javier Fernando

2013-01-01

El presente Proyecto Fin de Carrera tiene como objetivo el estudio, diseño y valoración técnica y económica del Sistema de Control y Protección de Grupo de una central hidroeléctrica de 37 MVA. Este Sistema está compuesto por el conjunto de equipos eléctricos, electrónicos y mecánicos encargados del control y protección de los dispositivos e instalaciones existentes en la central y necesarias para el correcto funcionamiento de la unidad Turbina- Generador de la misma. Se han...

Vectores recombinantes basados en el virus modificado de Ankara (MVA) com vacunas preventivas y terapeúticas contra la hepatitis C

OpenAIRE

Esteban, Mariano; Gómez, Carmen E.; Perdiguero, Beatriz

2014-01-01

[ES] Los virus recombinantes de la invención contienen secuencias que se encuentran insertadas en el mismo sitio de inserción del MVA y que permiten la expresión simultáneamente de varios antígenos del VHC, concretamente las proteínas maduras estructurales (Core, E1, E2 y p7) y no estructurales (NS2, NS3, NS4A, NS4B, NS5A más los 201 aminoácidos de la región N-terminal de NS5B). Con ello se consiguen virus recombinantes estables, que permiten el desencadenamiento de una respuesta inmune contr...

DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus.

Directory of Open Access Journals (Sweden)

Melanie Thompson

Full Text Available GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA boost vaccine (GOVX-B11, was undertaken in HIV infected participants on antiretroviral treatment (ART to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI. Nine men who began antiretroviral therapy (ART within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.clinicaltrials.gov NCT01378156.

DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus.

Science.gov (United States)

Thompson, Melanie; Heath, Sonya L; Sweeton, Bentley; Williams, Kathy; Cunningham, Pamela; Keele, Brandon F; Sen, Sharon; Palmer, Brent E; Chomont, Nicolas; Xu, Yongxian; Basu, Rahul; Hellerstein, Michael S; Kwa, Suefen; Robinson, Harriet L

2016-01-01

GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine. clinicaltrials.gov NCT01378156.

ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans.

Science.gov (United States)

Sheehy, Susanne H; Duncan, Christopher J A; Elias, Sean C; Choudhary, Prateek; Biswas, Sumi; Halstead, Fenella D; Collins, Katharine A; Edwards, Nick J; Douglas, Alexander D; Anagnostou, Nicholas A; Ewer, Katie J; Havelock, Tom; Mahungu, Tabitha; Bliss, Carly M; Miura, Kazutoyo; Poulton, Ian D; Lillie, Patrick J; Antrobus, Richard D; Berrie, Eleanor; Moyle, Sarah; Gantlett, Katherine; Colloca, Stefano; Cortese, Riccardo; Long, Carole A; Sinden, Robert E; Gilbert, Sarah C; Lawrie, Alison M; Doherty, Tom; Faust, Saul N; Nicosia, Alfredo; Hill, Adrian V S; Draper, Simon J

2012-12-01

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

Mevalonosomes: specific vacuoles containing the mevalonate pathway in Plocamium brasiliense cortical cells (Rhodophyta).

Science.gov (United States)

Paradas, Wladimir Costa; Crespo, Thalita Mendes; Salgado, Leonardo Tavares; de Andrade, Leonardo Rodrigues; Soares, Angélica Ribeiro; Hellio, Claire; Paranhos, Ricardo Rogers; Hill, Lilian Jorge; de Souza, Geysa Marinho; Kelecom, Alphonse Germaine Albert Charles; Da Gama, Bernardo Antônio Perez; Pereira, Renato Crespo; Amado-Filho, Gilberto Menezes

2015-04-01

This paper has identified, for the first time in a member of the Rhodophyta, a vacuolar organelle containing enzymes that are involved in the mevalonate pathway-an important step in red algal isoprenoid biosynthesis. These organelles were named mevalonosomes (Mev) and were found in the cortical cells (CC) of Plocamium brasiliense, a marine macroalgae that synthesizes several halogenated monoterpenes. P. brasiliense specimens were submitted to a cytochemical analysis of the activity of the 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS). Using transmission electron microscopy (TEM), we confirmed the presence of HMGS activity within the Mev. Because HMGS is necessary for the biosynthesis of halogenated monoterpenes, we isolated a hexanic fraction (HF) rich in halogenated monoterpenes from P. brasiliense that contained a pentachlorinated monoterpene as a major metabolite. Because terpenes are often related to chemical defense, the antifouling (AF) activity of pentachlorinated monoterpene was tested. We found that the settlement of the mussel Perna perna was reduced by HF treatment (2.25 times less than control; 40% and 90% of fouled surface, respectively; P = 0.001; F9,9 = 1.13). The HF (at 10 μg · mL(-1) ) also inhibited three species of fouling microalgae (Chlorarachnion reptans, Cylindrotheca cloisterium, and Exanthemachrysis gayraliae), while at a higher concentration (50 μg · mL(-1) ), it inhibited the bacteria Halomonas marina, Polaribacter irgensii, Pseudoalteromonas elyakovii, Shewanella putrefaciens, and Vibrio aestuarianus. The AF activity of P. brasiliense halogenated monoterpenes and the localization of HMGS activity inside Mev suggest that this cellular structure found in CC may play a role in thallus protection against biofouling. © 2015 Phycological Society of America.

Study on the secondary metabolic regulation of callus of Panax quinquefolium L

International Nuclear Information System (INIS)

Zhang Meiping; Wang Yi; Sun Chunyu; Li Xianggao

2003-01-01

The effects of precursors with different kind, concentration, growth phase, time and different ATP, nicotinic acid concentration on the callus growth and saponin formation with the buds of Panax quinquefolium L. has been studied. The results showed that 0.1% mevalonic acid inhibited the callus growth but promoted the saponin formation; L-leucine of 100 mg/L had no obvious effects on callus growth, but promoted the saponin formation; Mg(Ac) 2 of 444 mg/L promoted both the callus growth and saponin content. The optimum time for precursor feeding is at the beginning of regeneration. The optimum time for mevalonic acid is 6h; ATP of 160 mg/L promoted both the callus growth and saponin formation. Nicotinic acid of 1.0 mg/L promoted callus growth and saponin formation. With 4000 Gy of 60 Co γ-rays, the saponin content has been increased 1 time compared with nonirradiation

Production of 3-Oxo-2-(2'-pentenyl)-cyclopentane-1-octanoic Acid in the Fungus Aspergillus oryzae: A Step Towards Heterologous Production of Pyrethrins in Fungi.

Science.gov (United States)

Mohamed, Maged E; Pahirulzaman, Khomaizon A K; Lazarus, Colin M

2016-03-01

Pyrethrins are natural insecticides, which accumulate to high concentrations in pyrethrum (Chrysanthemum cinerariaefolium) flowers. Synthetic pyrethroids are more stable, more efficacious and cheaper, but contemporary requirements for safe and environmentally friendly pesticides encourage a return to the use of natural pyrethrins, and this would be favoured by development of an efficient route to their production by microbial fermentation. The biosynthesis of pyrethrins involves ester linkage between an acid moiety (chrysanthemoyl or pyrethroyl, synthesised via the mevalonic acid pathway from glucose), and an alcohol (pyrethrolone). Pyrethrolone is generated from 3-oxo-2-(2'-pentenyl)-cyclopentane-1-octanoic acid, which originates from α-linolenic acid via the jasmonic acid biosynthetic cascade. The first four genes in this cascade, encoding lipoxygenase 2, allene-oxide synthase, allene-oxide cyclase 2 and 12-oxophytodienoic acid reductase 3, were amplified from an Arabidopsis thaliana cDNA library, cloned in a purpose-built fungal multigene expression vector and expressed in Aspergillus oryzae. HPLC-MS analysis of the transgenic fungus homogenate gave good evidence for the presence of 3-oxo-2-(2'-pentenyl)-cyclopentane-1-octanoic acid.

[In vitro study over statins effects on cellular growth curves and its reversibility with mevalonate].

Science.gov (United States)

Millan Núñez-Cortés, Jesús; Alvarez Rodriguez, Ysmael; Alvarez Novés, Granada; Recarte Garcia-Andrade, Carlos; Alvarez-Sala Walther, Luis

2014-01-01

HMG-CoA-Reductase inhibitors, also known as statins, are currently the most powerful cholesterol-lowering drugs available on the market. Clinical trials and experimental evidence suggest that statins have heavy anti-atherosclerotic effects. These are in part consequence of lipid lowering but also result from pleiotropic actions of the drugs. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL-c reduction or via a direct effect on cellular functions. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. So, although statins typically have similar effects on LDL-c levels, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects. In this paper we analize the in vitro effects of different statins over different cell lines from cells implicated in atherosclerotic process: endothelial cells, fibroblasts, and vascular muscular cells. In relation with our results we can proof that the effects of different dosis of different statins provides singular effects over growth curves of different cellular lines, a despite of a class-dependent effects. So, pleiotropic effects and its reversibility with mevalonate are different according with the molecule and the dosis. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

Combination of intratumoral injections of vaccinia virus MVA expressing GM-CSF and immunization with DNA vaccine prolongs the survival of mice bearing HPV16 induced tumors with downregulated expression of MHC class I molecules

Czech Academy of Sciences Publication Activity Database

Němečková, Š.; Šmahel, M.; Hainz, P.; Macková, J.; Zurková, K.; Gabriel, P.; Indrová, Marie; Kutinová, L.

2007-01-01

Roč. 54, č. 4 (2007), s. 326-333 ISSN 0028-2685 R&D Projects: GA MZd NR8004 Institutional research plan: CEZ:AV0Z50520514 Keywords : vaccinia virus MVA expressing GM- CSF * DNA vaccine * HPV16 induced tumors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.208, year: 2007

Synthetic addiction extends the productive life time of engineered Escherichia coli populations

DEFF Research Database (Denmark)

Rugbjerg, Peter; Sarup-Lytzen, Kira; Nagy, Mariann

2018-01-01

range of genetic variants that disrupt the biosynthetic capacity of the engineered organism. Synthetic product addiction that couples high-yield production of a desired metabolite to expression of nonconditionally essential genes could offer a solution to this problem by selectively favoring cells...... with biosynthetic capacity in the population without constraining the medium. We constructed such synthetic product addiction by controlling the expression of two nonconditionally essential genes with a mevalonic acid biosensor. The product-addicted production organism retained high-yield mevalonic acid production...... through 95 generations of cultivation, corresponding to the number of cell generations required for >200-m3 industrial-scale production, at which time the nonaddicted strain completely abolished production. Using deep DNA sequencing, we find that the product-addicted populations do not accumulate genetic...

The effect of current Schistosoma mansoni infection on the immunogenicity of a candidate TB vaccine, MVA85A, in BCG-vaccinated adolescents: An open-label trial.

Directory of Open Access Journals (Sweden)

Anne Wajja

2017-05-01

Full Text Available Helminth infection may affect vaccine immunogenicity and efficacy. Adolescents, a target population for tuberculosis booster vaccines, often have a high helminth burden. We investigated effects of Schistosoma mansoni (Sm on the immunogenicity and safety of MVA85A, a model candidate tuberculosis vaccine, in BCG-vaccinated Ugandan adolescents.In this phase II open label trial we enrolled 36 healthy, previously BCG-vaccinated adolescents, 18 with no helminth infection detected, 18 with Sm only. The primary outcome was immunogenicity measured by Ag85A-specific interferon gamma ELISpot assay. Tuberculosis and schistosome-specific responses were also assessed by whole-blood stimulation and multiplex cytokine assay, and by antibody ELISAs.Ag85A-specific cellular responses increased significantly following immunisation but with no differences between the two groups. Sm infection was associated with higher pre-immunisation Ag85A-specific IgG4 but with no change in antibody levels following immunisation. There were no serious adverse events. Most reactogenicity events were of mild or moderate severity and resolved quickly.The significant Ag85A-specific T cell responses and lack of difference between Sm-infected and uninfected participants is encouraging for tuberculosis vaccine development. The implications of pre-existing Ag85A-specific IgG4 antibodies for protective immunity against tuberculosis among those infected with Sm are not known. MVA85A was safe in this population.ClinicalTrials.gov NCT02178748.

Does limited virucidal activity of biocides include duck hepatitis B virucidal action?

Directory of Open Access Journals (Sweden)

Sauerbrei Andreas

2012-10-01

Full Text Available Abstract Background There is agreement that the infectivity assay with the duck hepatitis B virus (DHBV is a suitable surrogate test to validate disinfectants for hepatitis B virucidal activity. However, since this test is not widely used, information is necessary whether disinfectants with limited virucidal activity also inactivate DHBV. In general, disinfectants with limited virucidal activity are used for skin and sensitive surfaces while agents with full activity are more aggressive. The present study compares the activity of five different biocides against DHBV and the classical test virus for limited virucidal activity, the vaccinia virus strain Lister Elstree (VACV or the modified vaccinia Ankara strain (MVA. Methods Virucidal assay was performed as suspension test according to the German DVV/RKI guideline. Duck hepatitis B virus obtained from congenitally infected Peking ducks was propagated in primary duck embryonic hepatocytes and was detected by indirect immunofluorescent antigen staining. Results The DHBV was inactivated by the use of 40% ethanol within 1-min and 30% isopropanol within 2-min exposure. In comparison, 40% ethanol within 2-min and 40% isopropanol within 1-min exposure were effective against VACV/MVA. These alcohols only have limited virucidal activity, while the following agents have full activity. 0.01% peracetic acid inactivated DHBV within 2 min and a concentration of 0.005% had virucidal efficacy against VACV/MVA within 1 min. After 2-min exposure, 0.05% glutardialdehyde showed a comparable activity against DHBV and VACV/MVA. This is also the case for 0.7% formaldehyde after a contact time of 30 min. Conclusions Duck hepatitis B virus is at least as sensitive to limited virucidal activity as VACV/MVA. Peracetic acid is less effective against DHBV, while the alcohols are less effective against VACV/MVA. It can be expected that in absence of more direct tests the results may be extrapolated to HBV.

Modeling of Electric Field Around 100 MVA 150/20 kV Power Transformator using Charge Simulation Method

Directory of Open Access Journals (Sweden)

Noviadi Arief Rachman

2013-07-01

Full Text Available Charge Simulation Method is one of the field theory that can be used as an approach to calculate the electromagnetic distribution on the electrical conductor. This paper discussed electric field modeling around power transformator by using Matlab to find the safety distance. The safe distance threshold of the electric field to human health refers to WHO and SNI was 5 kV/m. The specification of the power transformator was three phases, 150/20 kV, and 100 MVA. The basic concept is to change the distribution charge on the conductor or dielectric polarization charge with a set of discrete fictitious charge. The value of discrete fictitious charge was equivalent to the potential value of the conductor, and became a reference to calculate the electric field around the surface contour of the selected power transformator. The measurement distance was 5 meter on each side of the transformator surface. The results showed that the magnitude of the electric field at the front side was 5541 V/m, exceeding the safety limits.

On the mechanism for the formation of indole alkalois in Penicillium concavo-rugulosum

International Nuclear Information System (INIS)

Ohmomo, Sadahiro; Miyazaki, Kenji; Ohashi, Tsutomu; Abe, Matazo

1977-01-01

Experiments on the biosynthesis and microbiological conversion of indole alkaloids in Penicillium concavo-rugulosum were carried out with the growing and resting mycelia, respectively, of a selected strain of the same mold. The former experiments were performed by the use of DL-tryptophan-3- 14 C or DL-mevalonic acid-2- 14 C-lactone as a precursor, while the latter experiments by the use of rugulovasine A- 3 H, dihydrorugulovasine A- 3 H, 4-[γ,γ-dimethylallyl]-tryptophan- 3 H, chanoclavine-[I]- 3 H or the other tritiated ergoline alkaloids. The results of these experiments suggested that in the Penicillium mold employed there exist the following biosynthetic route: tryptophan+mevalonic acid → 4-[γ,γ-dimethylallyl]-tryptophan → rugulovasine A → dihydrorugulovasine A → dihydrorugulovasine A-lactam. (auth.)

Expression of the mevalonate pathway enzymes in the Lutzomyia longipalpis (Diptera: Psychodidae) sex pheromone gland demonstrated by an integrated proteomic approach.

Science.gov (United States)

González-Caballero, Natalia; Rodríguez-Vega, Andrés; Dias-Lopes, Geovane; Valenzuela, Jesus G; Ribeiro, Jose M C; Carvalho, Paulo Costa; Valente, Richard H; Brazil, Reginaldo P; Cuervo, Patricia

2014-01-16

In Latin America, Lutzomyia longipalpis is the main vector of the protozoan parasite Leishmania infantum, which is the causal agent of American Visceral Leishmaniasis. This insect uses male-produced pheromones for mate recognition. Elucidation of pheromone biogenesis or its regulation may enable molecular strategies for mating disruption and, consequently, the vector's population management. Motivated by our recent results of the transcriptomic characterization of the L. longipalpis pheromone gland, we performed a proteomic analysis of this tissue combining SDS-PAGE, and mass spectrometry followed by an integrative data analysis. Considering that annotated genome sequences of this sand fly are not available, we designed an alternative workflow searching MS/MS data against two customized databases using three search engines: Mascot, OMSSA and ProLuCID. A total of 542 proteins were confidently characterized, 445 of them using a Uniref100-insect protein database, and 97 using a transcript translated database. In addition, use of PEAKS for de novo peptide sequencing of MS/MS data confirmed ~90% identifications made with the combination of the three search engines. Our results include the identification of six of the seven enzymes of the mevalonate-pathway, plus the enzymes involved in sesquiterpenoid biosynthesis, all of which are proposed to be involved in pheromone production in L. longipalpis. L. longipalpis is the main vector of the protozoan parasite L. infantum, which is the causal agent of American Visceral Leishmaniasis. One of the control measures of such disease is focused on vector population control. As this insect uses male-produced pheromones for mate recognition, the elucidation of pheromone biogenesis or its regulating process may enable molecular strategies for mating disruption and, consequently, this vector's population management. On this regard, in this manuscript we report expression evidence, at the protein level, of several molecules potentially

The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells

Science.gov (United States)

Castella, Barbara; Kopecka, Joanna; Sciancalepore, Patrizia; Mandili, Giorgia; Foglietta, Myriam; Mitro, Nico; Caruso, Donatella; Novelli, Francesco; Riganti, Chiara; Massaia, Massimo

2017-01-01

Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation. PMID:28580927

TLR1/2 activation during heterologous prime-boost vaccination (DNA-MVA enhances CD8+ T Cell responses providing protection against Leishmania (Viannia.

Directory of Open Access Journals (Sweden)

Asha Jayakumar

2011-06-01

Full Text Available Leishmania (Viannia parasites present particular challenges, as human and murine immune responses to infection are distinct from other Leishmania species, indicating a unique interaction with the host. Further, vaccination studies utilizing small animal models indicate that modalities and antigens that prevent infection by other Leishmania species are generally not protective.Using a newly developed mouse model of chronic L. (Viannia panamensis infection and the heterologous DNA prime - modified vaccinia virus Ankara (MVA boost vaccination modality, we examined whether the conserved vaccine candidate antigen tryparedoxin peroxidase (TRYP could provide protection against infection/disease.Heterologous prime - boost (DNA/MVA vaccination utilizing TRYP antigen can provide protection against disease caused by L. (V. panamensis. However, protection is dependent on modulating the innate immune response using the TLR1/2 agonist Pam3CSK4 during DNA priming. Prime-boost vaccination using DNA alone fails to protect. Prior to infection protectively vaccinated mice exhibit augmented CD4 and CD8 IFNγ and memory responses as well as decreased IL-10 and IL-13 responses. IL-13 and IL-10 have been shown to be independently critical for disease in this model. CD8 T cells have an essential role in mediating host defense, as CD8 depletion reversed protection in the vaccinated mice; vaccinated mice depleted of CD4 T cells remained protected. Hence, vaccine-induced protection is dependent upon TLR1/2 activation instructing the generation of antigen specific CD8 cells and restricting IL-13 and IL-10 responses.Given the general effectiveness of prime-boost vaccination, the recalcitrance of Leishmania (Viannia to vaccine approaches effective against other species of Leishmania is again evident. However, prime-boost vaccination modality can with modulation induce protective responses, indicating that the delivery system is critical. Moreover, these results suggest that

Hydrocarbons in the millipede Graphidostreptus tumuliporus (Karsch) (Myriapoda: Diplopoda)—I. In vivo incorporation of 14C-labelled precursors into the hydrocarbon fraction

NARCIS (Netherlands)

Oudejans, R.C.H.M.

1972-01-01

1. 1. Biosynthesis of hydrocarbons in male and female specimens of the millipede Graphidostreptus tumuliporus was investigated after injection of the following precursors: 1-14C-acetate, 16-14C- and 1-14C-palmitic acid, isoleucine-14C(U), valine-14C(U) and mevalonic-2-14C acid. 2. 2. Both sexes

Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models.

Science.gov (United States)

Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin-Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

2015-10-15

Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. ©2015 American Association for Cancer Research.

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis.

Science.gov (United States)

Leung-Theung-Long, Stéphane; Coupet, Charles-Antoine; Gouanvic, Marie; Schmitt, Doris; Ray, Aurélie; Hoffmann, Chantal; Schultz, Huguette; Tyagi, Sandeep; Soni, Heena; Converse, Paul J; Arias, Lilibeth; Kleinpeter, Patricia; Sansas, Benoît; Mdluli, Khisimuzi; Vilaplana, Cristina; Cardona, Pere-Joan; Nuermberger, Eric; Marchand, Jean-Baptiste; Silvestre, Nathalie; Inchauspé, Geneviève

2018-01-01

Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host's immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA) virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections.

Draft genome sequence of Actinotignum schaalii DSM 15541T: Genetic insights into the lifestyle, cell fitness and virulence.

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Atteyet F Yassin

Full Text Available The permanent draft genome sequence of Actinotignum schaalii DSM 15541T is presented. The annotated genome includes 2,130,987 bp, with 1777 protein-coding and 58 rRNA-coding genes. Genome sequence analysis revealed absence of genes encoding for: components of the PTS systems, enzymes of the TCA cycle, glyoxylate shunt and gluconeogensis. Genomic data revealed that A. schaalii is able to oxidize carbohydrates via glycolysis, the nonoxidative pentose phosphate and the Entner-Doudoroff pathways. Besides, the genome harbors genes encoding for enzymes involved in the conversion of pyruvate to lactate, acetate and ethanol, which are found to be the end products of carbohydrate fermentation. The genome contained the gene encoding Type I fatty acid synthase required for de novo FAS biosynthesis. The plsY and plsX genes encoding the acyltransferases necessary for phosphatidic acid biosynthesis were absent from the genome. The genome harbors genes encoding enzymes responsible for isoprene biosynthesis via the mevalonate (MVA pathway. Genes encoding enzymes that confer resistance to reactive oxygen species (ROS were identified. In addition, A. schaalii harbors genes that protect the genome against viral infections. These include restriction-modification (RM systems, type II toxin-antitoxin (TA, CRISPR-Cas and abortive infection system. A. schaalii genome also encodes several virulence factors that contribute to adhesion and internalization of this pathogen such as the tad genes encoding proteins required for pili assembly, the nanI gene encoding exo-alpha-sialidase, genes encoding heat shock proteins and genes encoding type VII secretion system. These features are consistent with anaerobic and pathogenic lifestyles. Finally, resistance to ciprofloxacin occurs by mutation in chromosomal genes that encode the subunits of DNA-gyrase (GyrA and topisomerase IV (ParC enzymes, while resistant to metronidazole was due to the frxA gene, which encodes NADPH

High security of supply thanks to a mains-coupling transformer; Hoehere Versorgungssicherheit durch Netzkupplungstransformator. 400-MVA-Transformatorengruppe mit Laengs- und Querregelung

Energy Technology Data Exchange (ETDEWEB)

Aschwanden, T. [Kraftwerke Oberhasli AG (KWO), Innertkirchen (Switzerland); Jaeggi, F. [BKW FMB Energie AG, Berne (Switzerland)

2006-07-01

This article discusses how the coupling between the 380-kV and 132-kV grids in Bassecourt, Switzerland, was realised using a 400 MVA transformer and thus assures the quality of supply in the Cantons of Basel and Jura as well as in western Switzerland in general. This direct coupling eases the load on existing 380/220-kV transforming equipment in Bassecourt on the Swiss-French border. Details on the Bassecourt transformer station are given and the concept behind the new installation is discussed. In particular, the new transformer's ability to influence power and reactive power flows between the 380-kV grid and the 132-kV mains is described. The transformer's physical and electrical construction is discussed in detail. The purchasing process and the transformer's protective systems are described. A review of first operational experience gained is presented.

Mevalonate Pathway Antagonist Inhibits Proliferation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

Science.gov (United States)

Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin- Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

2015-01-01

Purpose Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Since TP53 mutations occur in almost all of the ovarian high-grade serous carcinoma, we determined if statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design Two ovarian cancer mouse models were employed. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously develop serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the anti-tumor effects of lovastatin were also investigated. Results Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced anti-proliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusion The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. PMID:26109099

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis.

Directory of Open Access Journals (Sweden)

Stéphane Leung-Theung-Long

Full Text Available Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG vaccine, infection by Mycobacterium tuberculosis (Mtb remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host's immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections.

Investigations on the isoprenoid biosynthesis in the green alga Scenedesmus obliquus by using the 13C-labelling technique

International Nuclear Information System (INIS)

Schwender, J.

1995-01-01

The biosynthesis of several prenyllipids (isoprenoid lipids) of the green alga Scendesmus obliquus was investigated. The aim was to verify, whether the biosynthesis of isopentenyl diphosphate (IPP) in Scenedesmus proceeds according to the classical acetate mevalonate pathway or to an alternative pathway. An alternative pathway for IPP formation has recently been detected in some eubacteria by the group of Prof. M. Rohmer. Some inhibition tests were performed with mevinolin, a specific inhibitor of HMG-CoA reductase which yields mevalonic acid. Mevinolin should block the biosynthesis of such isoprenoids which are formed via the acetate mevalonate pathway. Scenedesmus was grown heterotrophically on 13 C-labelled glucose or acetate. After isolation and purification of 13 C-labelled phytol (side chains of chlorophylls), β-carotene, lutein, plastoquinone-9 and three sterol compounds, the enrichment of 13 C at different carbon-positions of the labelled compounds was determined. This was achieved by the 13 C-NMR technique in cooperation with Miriam Seemann of the group of Prof. M. Rohmer in Mullhouse/France. (orig.) [de

Report on acoustic and vibration measurements on 250 MVA transformer at St. Vital Station, Winnipeg, Manitoba

International Nuclear Information System (INIS)

Weissman, K.; McLoughlin, M.; Schott, R.; Tennese, G.; Daneryd, A.

1998-09-01

Vibroacoustic behaviour of a power transformer was characterized prior to employing active noise control (ANC) to control transformer noise. The effect of changes in temperature and loading conditions on the vibration pattern of the transformer tank received particular attention. The transformer quieting technology has been developed and implemented by QuietPower Systems of New York and Noise Cancellation Technologies Inc., of Maryland. Results of the study will be used to ensure that actuator placement is appropriate for each of the seasons experienced throughout the year, as well as to build boundary element and finite element models of the tank vibration and the associated radiated noise. Boundary element results show that the first four harmonics are the primary contributors to radiated noise. The finite element model used to examine the modal response of the tank structure showed high modal densities, even around the lower order harmonics (120 Hz). This can be interpreted to mean that statistical techniques normally associated with high frequency noise problems may be applicable here because of the high modal density. Results of the completed summer and winter measurements permit an evaluation of the effects of loading conditions, temperature and other environmental factors on transformer noise. Appendix B contains the results of numerical simulations on a 250 MVA transformer. 3 refs., 72 figs., 2 appendices

Phase II trial of Modified Vaccinia Ankara (MVA virus expressing 5T4 and high dose Interleukin-2 (IL-2 in patients with metastatic renal cell carcinoma

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Mitcham Josephine

2009-01-01

Full Text Available Abstract Background Interleukin-2 (IL-2 induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC but the antigen(s responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity. Methods 25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses. Results There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12% were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48% had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261. All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs. Conclusion Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients. Trial registration number ISRCTN83977250

Inhibition of Rho and Rac geranylgeranylation by atorvastatin is critical for preservation of endothelial junction integrity.

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Hongbing Xiao

Full Text Available BACKGROUND: Small GTPases (guanosine triphosphate, GTP are involved in many critical cellular processes, including inflammation, proliferation, and migration. GTP loading and isoprenylation are two important post-translational modifications of small GTPases, and are critical for their normal function. In this study, we investigated the role of post-translational modifications of small GTPases in regulating endothelial cell inflammatory responses and junctional integrity. METHODS AND RESULTS: Confluent human umbilical vein endothelial cell (HUVECs treated with atorvastatin demonstrated significantly decreased lipopolysaccharide (LPS-mediated IL-6 and IL-8 generation. The inhibitory effect of atorvastatin (Atorva was attenuated by co-treatment with 100 µM mevalonate (MVA or 10 µM geranylgeranyl pyrophosphate (GGPP, but not by 10 µM farnesyl pyrophosphate (FPP. Atorvastatin treatment of HUVECs produced a time-dependent increase in GTP loading of all Rho GTPases, and induced the translocation of small Rho GTPases from the cellular membrane to the cytosol, which was reversed by 100 µM MVA and 10 µM GGPP, but not by 10 µM FPP. Atorvastatin significantly attenuated thrombin-induced HUVECs permeability, increased VE-cadherin targeting to cell junctions, and preserved junction integrity. These effects were partially reversed by GGPP but not by FPP, indicating that geranylgeranylation of small GTPases plays a major role in regulating endothelial junction integrity. Silencing of small GTPases showed that Rho and Rac, but not Cdc42, play central role in HUVECs junction integrity. CONCLUSIONS: In conclusion, our studies show that post-translational modification of small GTPases plays a vital role in regulating endothelial inflammatory response and endothelial junction integrity. Atorvastatin increased GTP loading and inhibited isoprenylation of small GTPases, accompanied by reduced inflammatory response and preserved cellular junction integrity.

The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells [v1; ref status: indexed, http://f1000r.es/yx

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Michael Hartmann

2013-08-01

Full Text Available We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL. By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP pathway with known inhibitors like oxoclomazone and fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1, shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL.

The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells

Science.gov (United States)

Bach, Thomas J

2013-01-01

We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL). By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP) pathway with known inhibitors like oxoclomazone and fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1), shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA) pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL. PMID:24555083

Characterization and regulation of Leishmania major 3-hydroxy-3-methylglutaryl-CoA reductase

DEFF Research Database (Denmark)

Montalvetti, A; Pena Diaz, Javier; Hurtado, R

2000-01-01

In eukaryotes the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase catalyses the synthesis of mevalonic acid, a common precursor to all isoprenoid compounds. Here we report the isolation and overexpression of the gene coding for HMG-CoA reductase from Leishmania major. The protein from L...

Inhibition of Prenylation Promotes Caspase 3 Activation, Lamin B Degradation and Loss in Metabolic Cell Viability in Pancreatic β-Cells

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Khadija G. Syeda

2017-10-01

Full Text Available Background/Aims: Lamins are intermediate filament proteins that constitute the main components of the lamina underlying the inner-nuclear membrane and serve to organize chromatin. Lamins (e.g., lamin B undergo posttranslational modifications (e.g., isoprenylation at their C-terminal cysteine residues. Such modifications are thought to render optimal association of lamins with the nuclear envelop. Using human islets, rodent islets, and INS-1 832/13 cells, we recently reported significant metabolic defects under glucotoxic and endoplasmic reticulum (ER stress conditions, including caspase 3 activation and lamin B degradation. The current study is aimed at further understanding the regulatory roles of protein prenylation in the induction of the aforestated metabolic defects. Methods: Subcellular phase partitioning assay was done using Triton X-114. Cell morphology and metabolic cell viability assays were carried out using standard methodologies. Results: We report that exposure of pancreatic β-cells to Simvastatin, an inhibitor of mevalonic acid (MVA biosynthesis, and its downstream isoprenoid derivatives, or FTI-277, an inhibitor of farnesyltransferase that mediates farnesylation of lamins, leads to activation of caspase 3 and lamin B degradation. Furthermore, Simvastatin-treatment increased activation of p38MAPK (a stress kinase and inhibited ERK1/2 (regulator of cell proliferation. Inhibition of farnesylation also resulted in the release of degraded lamin B into the cytosolic fraction and promoted loss in metabolic cell viability. Conclusion: Based on these findings we conclude that protein prenylation plays key roles in islet β-cell function. These findings affirm further support to the hypothesis that defects in prenylation pathway induce caspase-3 activation and nuclear lamin degradation in pancreatic β-cells under the duress of metabolic stress (e.g., glucotoxicity.

Observational Study of a French and Belgian Multicenter Cohort of 23 Patients Diagnosed in Adulthood With Mevalonate Kinase Deficiency.

Science.gov (United States)

Durel, Cécile-Audrey; Aouba, Achille; Bienvenu, Boris; Deshayes, Samuel; Coppéré, Brigitte; Gombert, Bruno; Acquaviva-Bourdain, Cécile; Hachulla, Eric; Lecomte, Frédéric; Touitou, Isabelle; Ninet, Jacques; Philit, Jean-Baptiste; Messer, Laurent; Brouillard, Marc; Girard-Madoux, Marie-Hélène; Moutschen, Michel; Raison-Peyron, Nadia; Hutin, Pascal; Duffau, Pierre; Trolliet, Pierre; Hatron, Pierre-Yves; Heudier, Philippe; Cevallos, Ramiro; Lequerré, Thierry; Brousse, Valentine; Lesire, Vincent; Audia, Sylvain; Maucort-Boulch, Delphine; Cuisset, Laurence; Hot, Arnaud

2016-03-01

The aim of this study was to describe the clinical and biological features of Mevalonate kinase deficiency (MKD) in patients diagnosed in adulthood. This is a French and Belgian observational retrospective study from 2000 to 2014. To constitute the cohort, we cross-check the genetic and biochemical databases. The clinical, enzymatic, and genetic data were gathered from medical records. Twenty-three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission. MKD diagnosed in adulthood shared clinical and genetic features with classical pediatric disease. An elevated IgD concentration is a good marker for MKD in adults. Despite a decrease of severity and frequency of attacks with age, only one-third of patients achieved spontaneous remission.

Investigation of the Correlation Between Neurocognitive Function with Advanced Magnetic Resonance Imaging (MRI), Electroencephalography (EEG) in Patients with Traumatic Brain Injury Exposure: Neurocognitive function and advanced MRI and EEG

Science.gov (United States)

2011-01-01

child (MVA007), pneumonia (MVA017), urinary infection (MVA018), appendix (MVA026), a leg fracture (MVA008), and tonsils and fractures (MVA019). The...Toronto CR 2011-015 59 Glossary ..... DTI – diffusion tensor imaging EEG – electroencephalography FLAIR – fluid-attenuated inversion recovery

IL-12 and GM-CSF in DNA/MVA immunizations against HIV-1 CRF12_BF Nef induced T-cell responses with an enhanced magnitude, breadth and quality.

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Ana María Rodríguez

Full Text Available In Argentina, the HIV epidemic is characterized by the co-circulation of subtype B and BF recombinant viral variants. Nef is an HIV protein highly variable among subtypes, making it a good tool to study the impact of HIV variability in the vaccine design setting. We have previously reported a specific cellular response against NefBF with low cross-reactivity to NefB in mice. The aim of this work was to analyze whether the co-administration of IL-12 and GM-CSF, using DNA and MVA vaccine vectors, could improve the final cellular response induced. Mice received three DNA priming doses of a plasmid that express NefBF plus DNAs expressing IL-12 and/or GM-CSF. Afterwards, all the groups were boosted with a MVAnefBF dose. The highest increase in the magnitude of the NefBF response, compared to that induced in the control was found in the IL-12 group. Importantly, a response with higher breadth was detected in groups which received IL-12 or GM-CSF, evidenced as an increased frequency of recognition of homologous (BF and heterologous (B Nef peptides, as well as a higher number of other Nef peptide pools representing different viral subtypes. However, these improvements were lost when both DNA cytokines were simultaneously administered, as the response was focused against the immunodominant peptide with a detrimental response towards subdominant epitopes. The pattern of cytokines secreted and the specific-T-cell proliferative capacity were improved in IL-12 and IL-12+GM-CSF groups. Importantly IL-12 generated a significant higher T-cell avidity against a B heterologous peptide.This study indicates that the incorporation of DNA expressing IL-12 in DNA/MVA schemes produced the best results in terms of improvements of T-cell-response key properties such as breadth, cross-reactivity and quality (avidity and pattern of cytokines secreted. These relevant results contribute to the design of strategies aimed to induce T-cell responses against HIV antigens with

A Clinical Study on Management of Incomplete Abortion by Manual Vacuum Aspiration (MVA

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Arifa Akter Jahan

2012-07-01

Full Text Available Background: Abortion is an important social and public health issue. In Bangladesh complication from unsafe abortion is one of the leading causes of maternal mortality. It is a serious health problem. World Health Organisation estimates that 14% of maternal deaths which occur every year in the countries of South Asia including Bangladesh are due to abortion. Study shows manual vacuum aspiration procedure is safe and effective in incomplete abortion. Very few clinical trials were carried out in Bangladesh to assess the safety and effectivity of manual vacuum aspiration in managing incomplete abortion. Objective: To find out the outcome of manual vacuum aspiration in the management of patients of incomplete abortion. Materials and Methods: This observational descriptive study was conducted in the department of Obstetrics & Gynaecology, Dhaka Medical College & Hospital from June to December, 2004. One hundred cases of diagnosed incomplete abortion up to 12 weeks of gestation were managed by manual vacuum aspiration during this period. A data recording sheet was designed for this purpose. Haemodynamically stable patients with no history of induced abortion and fever were enrolled. Results: Procedure time of manual vacuum aspiration was short, average duration was 7 minutes. Bleeding was minimum (20-30 mL in 67% cases and weighted mean was 29.80 mL. Eighty three percent patients were stable during the procedure and only 3% needed blood transfusion. Nonnarcotic analgesics were used in 59% cases and 33% needed only proper counselling. Average duration of hospital stay was 2 hours. Effectiveness of the procedure was about 98% with very low post procedure complication rate (2%. Conclusion: MVA procedure is a safe and effective technique of uterine evacuation in incomplete abortion. It is quick, less expensive, effective and less painful. Hospital stay and chance of perforation of uterus is less. So this procedure should be considered by health care

Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?

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Malachy I. Okeke

2017-10-01

Full Text Available Modified vaccinia virus Ankara (MVA is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines.

Mechanisms of action and medicinal applications of abscisic Acid.

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Bassaganya-Riera, J; Skoneczka, J; Kingston, D G J; Krishnan, A; Misyak, S A; Guri, A J; Pereira, A; Carter, A B; Minorsky, P; Tumarkin, R; Hontecillas, R

2010-01-01

Since its discovery in the early 1960's, abscisic acid (ABA) has received considerable attention as an important phytohormone, and more recently, as a candidate medicinal in humans. In plants it has been shown to regulate important physiological processes such as response to drought stress, and dormancy. The discovery of ABA synthesis in animal cells has generated interest in the possible parallels between its role in plant and animal systems. The importance of this molecule has prompted the development of several methods for the chemical synthesis of ABA, which differ significantly from the biosynthesis of ABA in plants through the mevalonic acid pathway. ABA recognition in plants has been shown to occur at both the intra- and extracellularly but little is known about the perception of ABA by animal cells. A few ABA molecular targets have been identified in vitro (e.g., calcium signaling, G protein-coupled receptors) in both plant and animal systems. A unique finding in mammalian systems, however, is that the peroxisome proliferator-activated receptor, PPAR gamma, is upregulated by ABA in both in vitro and in vivo studies. Comparison of the human PPAR gamma gene network with Arabidopsis ABA-related genes reveal important orthologs between these groups. Also, ABA can ameliorate the symptoms of type II diabetes, targeting PPAR gamma in a similar manner as the thiazolidinediones class of anti-diabetic drugs. The use of ABA in the treatment of type II diabetes, offers encouragement for further studies concerning the biomedical applications of ABA.

Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.

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Tapia, Milagritos D; Sow, Samba O; Lyke, Kirsten E; Haidara, Fadima Cheick; Diallo, Fatoumata; Doumbia, Moussa; Traore, Awa; Coulibaly, Flanon; Kodio, Mamoudou; Onwuchekwa, Uma; Sztein, Marcelo B; Wahid, Rezwanul; Campbell, James D; Kieny, Marie-Paule; Moorthy, Vasee; Imoukhuede, Egeruan B; Rampling, Tommy; Roman, Francois; De Ryck, Iris; Bellamy, Abbie R; Dally, Len; Mbaya, Olivier Tshiani; Ploquin, Aurélie; Zhou, Yan; Stanley, Daphne A; Bailer, Robert; Koup, Richard A; Roederer, Mario; Ledgerwood, Julie; Hill, Adrian V S; Ballou, W Ripley; Sullivan, Nancy; Graham, Barney; Levine, Myron M

2016-01-01

The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo). In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18-65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18-50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 10(10) viral particle units (pu), 2·5 × 10(10) pu, 5 × 10(10) pu, or 1 × 10(11) pu; US participants received 1 × 10(10) pu or 1 × 10(11) pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 10(8) plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured

Pengaruh Pemberian Mikoriza Vesikula Arbuskula (MVA Campuran terhadap Kemunculan Penyakit Layu Fusarium pada Tanaman Melon (Cucumis melo L.

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Najmah Farhati

2017-09-01

Full Text Available Melon (Cucumis melo L. has economic potential to be cultivated because the fruit contains protein, fat, carbohydrate, calcium, phosphor, fiber, iron, vitamin A, vitamin B1, vitamin B2, vitamin C, and niacin. Fusarium wilt caused by Fusarium oxysporum will decrease melon crop production. One of controlling method to Fusarium wilt diseases on melon plants which safe for environtmental by using biological control. One of microorganisms which can be biological control agent is Vesicular Arbuscular Mycorrhiza (VAM. This research use experimental method with a Completely Randomized Design (CRD. The experimental treatment consists of two types of treatment which combine 5 doses of VAM mixture ( 0 g/plant, 10 g/plant, 12,5 g/plant, 15 g/plant, 17,5 g/plant and two inoculation method VAM is inoculated when seeds are planted and inoculation when the seedlings are replanted. Each treatment was repeated 3 times and each unit consist of three plant, so there are 30 units of experiments or 90 plants. The main variabels are observed consist of the incubation periode of the disease and the intensity of fusarium wilt and the supporting variabels consist of pH, temperature, humidity, and the scale of infection. The mixed MVA 15 g/plant dosage inoculated when seeds are planted and 15 g/plant dosage inoculated when the seedlings are replanted is the most effective to suppress incubation period of Fusarium wilt disease.

E3L and F1L Gene Functions Modulate the Protective Capacity of Modified Vaccinia Virus Ankara Immunization in Murine Model of Human Smallpox

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Asisa Volz

2018-01-01

Full Text Available The highly attenuated Modified Vaccinia virus Ankara (MVA lacks most of the known vaccinia virus (VACV virulence and immune evasion genes. Today MVA can serve as a safety-tested next-generation smallpox vaccine. Yet, we still need to learn about regulatory gene functions preserved in the MVA genome, such as the apoptosis inhibitor genes F1L and E3L. Here, we tested MVA vaccine preparations on the basis of the deletion mutant viruses MVA-ΔF1L and MVA-ΔE3L for efficacy against ectromelia virus (ECTV challenge infections in mice. In non-permissive human tissue culture the MVA deletion mutant viruses produced reduced levels of the VACV envelope antigen B5. Upon mousepox challenge at three weeks after vaccination, MVA-ΔF1L and MVA-ΔE3L exhibited reduced protective capacity in comparison to wildtype MVA. Surprisingly, however, all vaccines proved equally protective against a lethal ECTV infection at two days after vaccination. Accordingly, the deletion mutant MVA vaccines induced high levels of virus-specific CD8+ T cells previously shown to be essential for rapidly protective MVA vaccination. These results suggest that inactivation of the anti-apoptotic genes F1L or E3L modulates the protective capacity of MVA vaccination most likely through the induction of distinct orthopoxvirus specific immunity in the absence of these viral regulatory proteins.

Loss of HMG-CoA reductase in C. elegans causes defects in protein prenylation and muscle mitochondria.

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Parmida Ranji

Full Text Available HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway and the target of cholesterol-lowering statins. We characterized the C. elegans hmgr-1(tm4368 mutant, which lacks HMG-CoA reductase, and show that its phenotypes recapitulate that of statin treatment, though in a more severe form. Specifically, the hmgr-1(tm4368 mutant has defects in growth, reproduction and protein prenylation, is rescued by exogenous mevalonate, exhibits constitutive activation of the UPRer and requires less mevalonate to be healthy when the UPRmt is activated by a constitutively active form of ATFS-1. We also show that different amounts of mevalonate are required for different physiological processes, with reproduction requiring the highest levels. Finally, we provide evidence that the mevalonate pathway is required for the activation of the UPRmt.

[MVK gene abnormality and new approach to treatment of hyper IgD syndrome and periodic fever syndrome].

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Naruto, Takuya

2007-04-01

Hyper IgD and periodic fever syndrome (HIDS; OMIM 260920) is one of the hereditary autoinflammatory syndromes characterized by recurrent episodes of fever and inflammation.. HIDS is an autosomal recessive disorder characterized by recurrent fever attacks in early childhood. HIDS caused by mevalonate kinase (MK) mutations, also that is the gene of mevalonic aciduria (OMIM 251170). During febrile episodes, urinary mevalonate concentrations were found to be significantly elevated in patients. Diagnosis of HIDS was retrieving gene or measurement of the enzyme activity in peripheral blood lymphocyte in general. This of HIDS is an activity decline of MK, and a complete deficiency of MK becomes a mevalonic aciduria with a nervous symptom. The relation between the fever and inflammation of mevalonate or isoprenoid products are uncertain. The therapy attempt with statins, which is inhibited the next enzyme after HMG-CoA reductase, or inhibit the proinflammatory cytokines.

Three-Year Durability of Immune Responses Induced by HIV-DNA and HIV-Modified Vaccinia Virus Ankara and Effect of a Late HIV-Modified Vaccinia Virus Ankara Boost in Tanzanian Volunteers.

Science.gov (United States)

Joachim, Agricola; Munseri, Patricia J; Nilsson, Charlotta; Bakari, Muhammad; Aboud, Said; Lyamuya, Eligius F; Tecleab, Teghesti; Liakina, Valentina; Scarlatti, Gabriella; Robb, Merlin L; Earl, Patricia L; Moss, Bernard; Wahren, Britta; Mhalu, Fred; Ferrari, Guido; Sandstrom, Eric; Biberfeld, Gunnel

2017-08-01

We explored the duration of immune responses and the effect of a late third HIV-modified vaccinia virus Ankara (MVA) boost in HIV-DNA primed and HIV-MVA boosted Tanzanian volunteers. Twenty volunteers who had previously received three HIV-DNA and two HIV-MVA immunizations were given a third HIV-MVA immunization 3 years after the second HIV-MVA boost. At the time of the third HIV-MVA, 90% of the vaccinees had antibodies to HIV-1 subtype C gp140 (median titer 200) and 85% to subtype B gp160 (median titer 100). The majority of vaccinees had detectable antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, 70% against CRF01_AE virus-infected cells (median titer 239) and 84% against CRF01_AE gp120-coated cells (median titer 499). A high proportion (74%) of vaccinees had IFN-γ ELISpot responses, 63% to Gag and 42% to Env, 3 years after the second HIV-MVA boost. After the third HIV-MVA, there was an increase in Env-binding antibodies and ADCC-mediating antibodies relative to the response seen at the time of the third HIV-MVA vaccination, p < .0001 and p < .05, respectively. The frequency of IFN-γ ELISpot responses increased to 95% against Gag or Env and 90% to both Gag and Env, p = .064 and p = .002, respectively. In conclusion, the HIV-DNA prime/HIV-MVA boost regimen elicited potent antibody and cellular immune responses with remarkable durability, and a third HIV-MVA immunization significantly boosted both antibody and cellular immune responses relative to the levels detected at the time of the third HIV-MVA, but not to higher levels than after the second HIV-MVA.

An insight into structural and functional characteristics of 3-hydoxy 3-methyl glutarylCoA reductase from Ocimum species

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Shilpi Bansal

2017-10-01

Full Text Available Secondary metabolites, the biological compounds secreted by plants as an aid to support their growth and development under stress conditions or as a part of their defense mechanism, now hold equal importance for mankind who employs it immensely for medication, flavorings, aroma, etc. Wide applicability of these compounds instigates one to understand the biosynthesis, structure and regulation of these bioactive molecules. Terpenoids form the largest group of secondary metabolites which comprise of a wide range of structurally and functionally distinct metabolites synthesized either via mevalonate pathway or non-mevalonate pathway. Targeting a key regulatory enzyme of this pathway, modulation of which would alter the carbon flux would be beneficial to enhance our knowledge about the above issue. For this the transcriptome (from SRA of different Ocimum species was mined out for important pathway genes using various bioinformatics approaches. Amongst them 3-hydoxy 3-methyl glutaryl CoA reductase (HMGR was selected which is the rate limiting enzyme in mevalonate pathway which controls the conversion of HMG-CoA to mevalonic acid. Isolation, cloning, protein expression, purification, etc. would be discussed in detail in the meeting. Full length protein was also characterized through bioinformatics tools to study its structure, properties, conserved domains, etc. Increase in secondary metabolite production by alteration of HMGR pool along with transcript modulation studies in planta revealed that HMGR gene governs the biosynthesis of secondary metabolites. Transcriptome mapping of different HMGR homologs which on comparison within member of same genus revealed its divergent nature which could account to its multifunctional role in different plants. Besides, providing a deep insight about the enzyme function combination of such molecular, transgenic and bioinformatics tools would help to develop strategies to engineer the HMGR mediated flux and also

Terpenoid biosynthesis in Euphorbia lathyris and Copaifera spp

Energy Technology Data Exchange (ETDEWEB)

Skrukrud, C.L.

1987-07-01

Biosynthesis of triterpenoids by isolated latex of Euphorbia lathyris was investigated. The rate of in vitro incorporation of mevalonic acid into triterpenoids was thirty times greater than acetate incorporation indicating that the rate-limiting step in the pathway occurs prior to mevalonate. Both HMG-CoA reductase (EC 1.1.1.34) and HMG-CoA lyase (EC 4.1.3.4) activities were detected in isolated latex. HMG-CoA reductase was localized to a membrane-bound fraction of a 5000g pellet of latex. The rate of conversion of HMG-CoA to mevalonate by this enzyme is comparable to the overall rate of acetate incorporation into the triterpenoids suggesting that this enzyme is rate-determining in the biosynthesis of triterpenoids in E. lathyris latex. HMG-CoA reductase of E. lathyris vegetative tissue was localized to the membrane-bound portion of a particulate fraction (18,000g), and was solubilized by treatment with 2% polyoxyethylene ether W-1. Differences in the optimal pH for activity of HMG-CoA reductase from the latex and vegetative tissue suggest that isozymes of the enzyme may be present in the two tissue types. Studies of the incorporation of various precursors into leaf discs and cuttings taken from Copaifera spp. show differences in the rate of incorporation into Copaifera sesquiterpenes suggesting that the site of sesquiterpene biosynthesis may differ in its accessibility to the different substrates and/or reflecting the metabolic controls on carbon allocation to the terpenes. Mevalonate incorporation by Copaifera langsdorfii cuttings into sesquiterpenes was a hundred-fold greater than either acetate or glucose incorporation, however, its incorporation into squalene and triterpenoids was also a hundred-fold greater than the incorporation into sesquiterpenes. 119 refs., 58 figs., 16 tabs.

Terpenoid biosynthesis in Euphorbia lathyris and Copaifera spp

International Nuclear Information System (INIS)

Skrukrud, C.L.

1987-07-01

Biosynthesis of triterpenoids by isolated latex of Euphorbia lathyris was investigated. The rate of in vitro incorporation of mevalonic acid into triterpenoids was thirty times greater than acetate incorporation indicating that the rate-limiting step in the pathway occurs prior to mevalonate. Both HMG-CoA reductase (EC 1.1.1.34) and HMG-CoA lyase (EC 4.1.3.4) activities were detected in isolated latex. HMG-CoA reductase was localized to a membrane-bound fraction of a 5000g pellet of latex. The rate of conversion of HMG-CoA to mevalonate by this enzyme is comparable to the overall rate of acetate incorporation into the triterpenoids suggesting that this enzyme is rate-determining in the biosynthesis of triterpenoids in E. lathyris latex. HMG-CoA reductase of E. lathyris vegetative tissue was localized to the membrane-bound portion of a particulate fraction (18,000g), and was solubilized by treatment with 2% polyoxyethylene ether W-1. Differences in the optimal pH for activity of HMG-CoA reductase from the latex and vegetative tissue suggest that isozymes of the enzyme may be present in the two tissue types. Studies of the incorporation of various precursors into leaf discs and cuttings taken from Copaifera spp. show differences in the rate of incorporation into Copaifera sesquiterpenes suggesting that the site of sesquiterpene biosynthesis may differ in its accessibility to the different substrates and/or reflecting the metabolic controls on carbon allocation to the terpenes. Mevalonate incorporation by Copaifera langsdorfii cuttings into sesquiterpenes was a hundred-fold greater than either acetate or glucose incorporation, however, its incorporation into squalene and triterpenoids was also a hundred-fold greater than the incorporation into sesquiterpenes. 119 refs., 58 figs., 16 tabs

Propiconazole-enhanced hepatic cell proliferation is associated with dysregulation of the cholesterol biosynthesis pathway leading to activation of Erk1/2 through Ras farnesylation

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Murphy, Lynea A.; Moore, Tanya; Nesnow, Stephen, E-mail: nesnow.stephen@epa.gov

2012-04-15

Propiconazole is a mouse hepatotumorigenic fungicide designed to inhibit CYP51, a key enzyme in the biosynthesis of ergosterol in fungi and is widely used in agriculture to prevent fungal growth. Metabolomic studies in mice revealed that propiconazole increased levels of hepatic cholesterol metabolites and bile acids, and transcriptomic studies revealed that genes within the cholesterol biosynthesis, cholesterol metabolism and bile acid biosyntheses pathways were up-regulated. Hepatic cell proliferation was also increased by propiconazole. AML12 immortalized hepatocytes were used to study propiconazole's effects on cell proliferation focusing on the dysregulation of cholesterol biosynthesis and resulting effects on Ras farnesylation and Erk1/2 activation as a primary pathway. Mevalonate, a key intermediate in the cholesterol biosynthesis pathway, increases cell proliferation in several cancer cell lines and tumors in vivo and serves as the precursor for isoprenoids (e.g. farnesyl pyrophosphate) which are crucial in the farnesylation of the Ras protein by farnesyl transferase. Farnesylation targets Ras to the cell membrane where it is involved in signal transduction, including the mitogen-activated protein kinase (MAPK) pathway. In our studies, mevalonic acid lactone (MVAL), a source of mevalonic acid, increased cell proliferation in AML12 cells which was reduced by farnesyl transferase inhibitors (L-744,832 or manumycin) or simvastatin, an HMG-CoA reductase inhibitor, indicating that this cell system responded to alterations in the cholesterol biosynthesis pathway. Cell proliferation in AML12 cells was increased by propiconazole which was reversed by co-incubation with L-744,832 or simvastatin. Increasing concentrations of exogenous cholesterol muted the proliferative effects of propiconazole and the inhibitory effects of L-733,832, results ascribed to reduced stimulation of the endogenous cholesterol biosynthesis pathway. Western blot analysis of subcellular

Triterpenoid biosynthesis in Euphorbia lathyris latex

International Nuclear Information System (INIS)

Hawkins, D.R.

1987-11-01

The structures of triterpenols, not previously been known, from Euphorbia lathyris latex are reported. A method for quantifying very small amounts of these compounds was developed. Concerning the biochemistry of the latex, no exogenous cofactors were required for the biosynthesis and the addition of compounds such as NADPAH and ATP do not stimulate the biosynthesis. The addition of DTE or a similar anti-oxidant was found to help reduce the oxidation of the latex, thus increasing the length of time that the latex remains active. The requirement of a divalent cation and the preference for Mn in the pellet was observed. The effect of several inhibitors on the biosynthesis of the triterpenoids was examined. Mevinolin was found to inhibit the biosynthesis of the triterpenoids from acetate, but not mevalonate. A dixon plot of the inhibition of acetate incorporation showed an I 50 concentration of 3.2 μM. Fenpropimorph was found to have little or no effect on the biosynthesis. Tridemorph was found to inhibit the biosynthesis of all of the triterpenoids with an I 50 of 4 μM. It was also observed that the cyclopropyl containing triterpenols, cycloartenol and 24-methylenecycloartenol were inhibited much more strongly than those containing an 8-9 double bond, lanosterol and 24-methylenelanosterol. The evidence indicates, but does not definetely prove, that lanosterol and 24-methylenelanosterol are not made from cycloartenol and 24-methylenecycloartenol via a ring-opening enzyme such as cycloeucalenol-obtusifoliol isomerase. The possibilty that cycloartenol is made via lanosterol was investigated by synthesizing 4-R-4- 3 H-mevalonic acid and incubating latex with a mixture of this and 14 C-mevalonic acid. From the 3 H/ 14 C ratio it was shown that cycloartenol and 24-methylenecycloartenol are not made via an intermediate containing as 8-9 double bond. 88 refs., 15 figs., 30 tabs

Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia Ankara vaccines: a systematic review.

Science.gov (United States)

Elizaga, Marnie L; Vasan, Sandhya; Marovich, Mary A; Sato, Alicia H; Lawrence, Dale N; Chaitman, Bernard R; Frey, Sharon E; Keefer, Michael C

2013-01-01

Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines. Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. 'Routine cardiac investigations' (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and 'Symptom-driven cardiac investigations' are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine. Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine. Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants. ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337.

Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia Ankara vaccines: a systematic review.

Directory of Open Access Journals (Sweden)

Marnie L Elizaga

Full Text Available Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines.Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. 'Routine cardiac investigations' (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls, and 'Symptom-driven cardiac investigations' are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine.Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12% had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine.Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants.ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337.

Differential control of the cholesterol biosynthetic pathway in tumor versus liver: evidence for decontrolled tumor cholesterogenesis in a cell-free system

International Nuclear Information System (INIS)

Azrolan, N.

1987-01-01

Cholesterol biosynthesis was characterized in cell-free post-mitochondrial supernatant (PMS) systems prepared from both normal rat liver and Morris hepatoma 3924A. Per cell, the rate of cholesterol synthesis from either 14 C-citrate of 14 -acetate in the hepatoma system was 9-fold greater than that observed in the liver system. Furthermore, the ratio of sterol-to-fatty acid synthesis rates from 14 C-citrate was more than 3-fold greater in the tumor than in the normal liver system. Incubations using radiolabeled acetate and mevalonate have demonstrated the loss of a normally rate-limiting control site within the early portion of the cholesterol biosynthetic pathway in the tumor system. Upon analysis of the steady-state levels of early lipogenic intermediates, the specific site of decontrol in the tumor was identified as the 3-hydroxy-3-methylglutaryl-CoA → mevalonate site of this pathway. In contrast, this reaction appeared to retain its rate-limiting properties in the cell-free system from normal liver

Use of [2-14C]mevalonate and saponin-bound [14C]-3-hydroxy-3-methylglutaric acid for the biosynthesis of terpenoids in leaves of Dioscorea deltoidea

International Nuclear Information System (INIS)

Gurielidze, K.G.; Paseshnichenko, V.A.; Vasil'eva, I.S.

1986-01-01

After the introduction of [2- 14 C]acetate into leaves of Dioscorea deltoidea, a radioactive furonanalog of deltafolin - protodeltofolin, containing two-thirds of the label in the 3-hydroxy-3-methylglutaryl portion - was isolated from them. Radioactive β-careotene and sterols were isolated from cut young leaves of Dioscorea 24 h after the introduction of [ 14 C] protodeltofolin into them, using chromatography on a column of silica gel and precipitation of sterols in the form of digitonins for this purpose. The incorporation of radioactivity from [ 14 C]-3-hydroxy-3-methyl-glutaric acid, bound in the form of a saponin, and β-carotene came to 0.18-0.80%, while incorporation into sterols came to 0.07-2.86% of the radioactivity of the alcohol extract. Thereby it was shown that 3-hydroxyl-3-methylglutaric acid, bound in the form of the saponin, can be used to form terpenoids in Dioscorea leaves. It was suggested that the binding of hydroxymethylglutaric acid to saponin represents one of the mechanisms of regulation of the rate of terpenoid biosynthesis in Dioscorea leaves

A mitral annulus tracking approach for navigation of off-pump beating heart mitral valve repair.

Science.gov (United States)

Li, Feng P; Rajchl, Martin; Moore, John; Peters, Terry M

2015-01-01

To develop and validate a real-time mitral valve annulus (MVA) tracking approach based on biplane transesophageal echocardiogram (TEE) data and magnetic tracking systems (MTS) to be used in minimally invasive off-pump beating heart mitral valve repair (MVR). The authors' guidance system consists of three major components: TEE, magnetic tracking system, and an image guidance software platform. TEE provides real-time intraoperative images to show the cardiac motion and intracardiac surgical tools. The magnetic tracking system tracks the TEE probe and the surgical tools. The software platform integrates the TEE image planes and the virtual model of the tools and the MVA model on the screen. The authors' MVA tracking approach, which aims to update the MVA model in near real-time, comprises of three steps: image based gating, predictive reinitialization, and registration based MVA tracking. The image based gating step uses a small patch centered at each MVA point in the TEE images to identify images at optimal cardiac phases for updating the position of the MVA. The predictive reinitialization step uses the position and orientation of the TEE probe provided by the magnetic tracking system to predict the position of the MVA points in the TEE images and uses them for the initialization of the registration component. The registration based MVA tracking step aims to locate the MVA points in the images selected by the image based gating component by performing image based registration. The validation of the MVA tracking approach was performed in a phantom study and a retrospective study on porcine data. In the phantom study, controlled translations were applied to the phantom and the tracked MVA was compared to its "true" position estimated based on a magnetic sensor attached to the phantom. The MVA tracking accuracy was 1.29 ± 0.58 mm when the translation distance is about 1 cm, and increased to 2.85 ± 1.19 mm when the translation distance is about 3 cm. In the study on

Activation of cross-reactive mucosal T and B cell responses in human nasopharynx-associated lymphoid tissue in vitro by Modified Vaccinia Ankara-vectored influenza vaccines.

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Mullin, Jennifer; Ahmed, Muhammed S; Sharma, Ravi; Upile, Navdeep; Beer, Helen; Achar, Priya; Puksuriwong, Suttida; Ferrara, Francesca; Temperton, Nigel; McNamara, Paul; Lambe, Teresa; Gilbert, Sarah C; Zhang, Qibo

2016-03-29

Recent efforts have been focused on the development of vaccines that could induce broad immunity against influenza virus, either through T cell responses to conserved internal antigens or B cell response to cross-reactive haemagglutinin (HA). We studied the capacity of Modified Vaccinia Ankara (MVA)-vectored influenza vaccines to induce cross-reactive immunity to influenza virus in human nasopharynx-associated lymphoid tissue (NALT) in vitro. Adenotonsillar cells were isolated and stimulated with MVA vaccines expressing either conserved nucleoprotein (NP) and matrix protein 1 (M1) (MVA-NP-M1) or pandemic H1N1 HA (MVA-pdmH1HA). The MVA vaccine uptake and expression, and T and B cell responses were analyzed. MVA-vectored vaccines were highly efficient infecting NALT and vaccine antigens were highly expressed by B cells. MVA-NP-M1 elicited T cell response with greater numbers of IFNγ-producing CD4+ T cells and tissue-resident memory T cells than controls. MVA-pdmH1HA induced cross-reactive anti-HA antibodies to a number of influenza subtypes, in an age-dependent manner. The cross-reactive antibodies include anti-avian H5N1 and mainly target HA2 domain. MVA vaccines are efficient in infecting NALT and the vaccine antigen is highly expressed by B cells. MVA vaccines expressing conserved influenza antigens induce cross-reactive T and B cell responses in human NALT in vitro, suggesting the potential as mucosal vaccines for broader immunity against influenza. Copyright © 2016 Elsevier Ltd. All rights reserved.

Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway.

Directory of Open Access Journals (Sweden)

Peihong Dai

2014-04-01

Full Text Available Modified vaccinia virus Ankara (MVA is an attenuated poxvirus that has been engineered as a vaccine against infectious agents and cancers. Our goal is to understand how MVA modulates innate immunity in dendritic cells (DCs, which can provide insights to vaccine design. In this study, using murine bone marrow-derived dendritic cells, we assessed type I interferon (IFN gene induction and protein secretion in response to MVA infection. We report that MVA infection elicits the production of type I IFN in murine conventional dendritic cells (cDCs, but not in plasmacytoid dendritic cells (pDCs. Transcription factors IRF3 (IFN regulatory factor 3 and IRF7, and the positive feedback loop mediated by IFNAR1 (IFN alpha/beta receptor 1, are required for the induction. MVA induction of type I IFN is fully dependent on STING (stimulator of IFN genes and the newly discovered cytosolic DNA sensor cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase. MVA infection of cDCs triggers phosphorylation of TBK1 (Tank-binding kinase 1 and IRF3, which is abolished in the absence of cGAS and STING. Furthermore, intravenous delivery of MVA induces type I IFN in wild-type mice, but not in mice lacking STING or IRF3. Treatment of cDCs with inhibitors of endosomal and lysosomal acidification or the lysosomal enzyme Cathepsin B attenuated MVA-induced type I IFN production, indicating that lysosomal enzymatic processing of virions is important for MVA sensing. Taken together, our results demonstrate a critical role of the cGAS/STING-mediated cytosolic DNA-sensing pathway for type I IFN induction in cDCs by MVA. We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs.

Nitrogen-containing bisphosphonate, YM529/ONO-5920 (a novel minodronic acid), inhibits RANKL expression in a cultured bone marrow stromal cell line ST2

International Nuclear Information System (INIS)

Nishida, Shozo; Tsubaki, Masanobu; Hoshino, Mayumi; Namimatsu, Ayumi; Uji, Hiromi; Yoshioka, Shohei; Tanimori, Yoshihiro; Yanae, Masashi; Iwaki, Masahiro; Irimajiri, Kiyohiro

2005-01-01

Increase in bone resorption by osteoclasts can cause metabolic bone diseases, such as osteoporosis. Recent attention has been paid to the receptor activator of the NF-κB ligand (RANKL), an accelerator of osteoclast differentiation. RANKL is expressed on the bone marrow-derived stromal cell membrane and induces the differentiation of osteoclasts by binding to RANK expressed on the osteoclast precursor cell membrane. Since the inhibition of RANKL expression can lead to the inhibition of osteoclastic bone resorption, the clinical application of RANKL inhibition could be expected to have a major effect on metabolic bone disease therapy. In this study, we investigated whether or not YM529/ONO-5920, a nitrogen-containing bisphosphonate (a novel minodronic acid), inhibits RANKL expression in a bone marrow-derived stromal cell line (ST2 cells). Reverse transcription-polymerase chain reaction revealed that the administration of YM529/ONO-5920 to ST2 cells inhibited RANKL mRNA expression and reduced RANKL proteins as assessed by Western blot analysis. The inhibition of RANKL mRNA expression was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination. Furthermore, YM529/ONO-5920 reduced phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and similarly, U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, inhibited RANKL expression. Pretreatment with GGPP reversed the YM529/ONO-5920-induced decrease in phosphorylation of ERK. Furthermore, YM529/ONO-5920 decreased TRAP-positive cells in co-culture of ST2 cells and an osteoclast cell line, C7 cells, and this decrease was inhibited by pretreatment with GGPP. This indicates that YM529/ONO-5920 inhibits GGPP biosynthesis in the mevalonate pathway and then signal transduction in the Ras-mitogen-activated protein kinase pathway, thereby inhibiting RANKL expression on ST2 cells. These results suggest a newly elucidated action of bisphosphonates in

Inhibition of Mevalonate Pathway and Synthesis of the Storage Lipids in Human Liver-Derived and Non-liver Cell Lines by Lippia alba Essential Oils.

Science.gov (United States)

Montero-Villegas, Sandra; Polo, Mónica; Galle, Marianela; Rodenak-Kladniew, Boris; Castro, María; Ves-Losada, Ana; Crespo, Rosana; García de Bravo, Margarita

2017-01-01

The essential oils (EOs) of Lippia alba, an herb extensively used as a folk medicine in Latin America, are today promoted as an effective means of eliminating problems caused by hyperlipemia. We hypothesized that L.alba EOs inhibited cholesterol and triacylglycerols synthesis and decreased the intracellular depots of those lipids (lipid droplets), mechanisms involving the induction of a hypolipidemic response. Our aim was, therefore, to evaluate the hypolipogenic capability of the EOs of four L. alba chemotypes on liver-derived (HepG2) and non-liver (A549) human cell lines and to identify the potential biochemical targets of those chemotypes, particularly within the mevalonate pathway (MP). [ 14 C]Acetate was used as radioactive precursor for assays. Lipid analyses were performed by thin-layer and capillary gas chromatography, lipid droplets analyzed by fluorescence microscopy, and HMGCR levels determined by Western blot. In both cell lines, all four chemotypes exerted hypocholesterogenic effects within a concentration range of 3.2-32 µg/mL. Nonsaponifiable lipids manifested a decrease in incorporation of [ 14 C]acetate into squalene, lanosterol, lathosterol, and cholesterol, but not into ubiquinone, thus suggesting an inhibition of enzymes in the MP downstream from farnesyl pyrophosphate. The tagetenone chemotype, the most efficacious hypocholesterogenic L. alba EO, lowered HMGCR protein levels; inhibited triacylglycerols, cholesteryl esters, and phospholipids synthesis; and diminished lipid droplets in size and volume. These results revealed that L. alba EOs inhibited different lipogenic pathways and such lipid-lowering effects could prove essential to prevent cardiovascular diseases.

Hydrochemistry of the Mahomet Bedrock Valley Aquifer, East-Central Illinois: indicators of recharge and ground-water flow

Science.gov (United States)

Panno, S.V.; Hackley, Keith C.; Cartwright, K.; Liu, Chao-Li

1994-01-01

A conceptual model of the ground-water flow and recharge to the Mahomet Bedrock Valley Aquifer (MVA), east-central Illinois, was developed using major ion chemistry and isotope geochemistry. The MVA is a 'basal' fill in the east-west trending buried bedrock valley composed of clean, permeable sand and gravel to thicknesses of up to 61 m. It is covered by a thick sequence of glacial till containing thinner bodies of interbedded sand and gravel. Ground water from the MVA was found to be characterized by clearly defined geochemical regions with three distinct ground-water types. A fourth ground-water type was found at the confluence of the MVA and the Mackinaw Bedrock Valley Aquifer (MAK) to the west. Ground water in the Onarga Valley, a northeastern tributary of the MVA, is of two types, a mixed cation-SO42- type and a mixed cation-HCO3- type. The ground water is enriched in Na+, Ca2+, Mg2+, and SO42- which appears to be the result of an upward hydraulic gradient and interaction of deeper ground water with oxidized pyritic coals and shale. We suggest that recharge to the Onarga Valley and overlying aquifers is 100% from bedrock (leakage) and lateral flow from the MVA to the south. The central MVA (south of the Onarga Valley) is composed of relatively dilute ground water of a mixed cation-HCO3- type, with low total dissolved solids, and very low concentrations of Cl- and SO42-. Stratigraphic relationships of overlying aquifers and ground-water chemistry of these and the MVA suggest recharge to this region of the MVA (predominantly in Champaign County) is relatively rapid and primarily from the surface. Midway along the westerly flow path of the MVA (western MVA), ground water is a mixed cation-HCO3- type with relatively high Cl-, where Cl- increases abruptly by one to ??? two orders of magnitude. Data suggest that the increase in Cl- is the result of leakage of saline ground water from bedrock into the MVA. Mass-balance calculations indicate that approximately 9.5% of

Strategies to obtain multiple recombinant modified vaccinia Ankara vectors. Applications to influenza vaccines.

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Barbieri, Andrea; Panigada, Maddalena; Soprana, Elisa; Di Mario, Giuseppina; Gubinelli, Francesco; Bernasconi, Valentina; Recagni, Marta; Donatelli, Isabella; Castrucci, Maria R; Siccardi, Antonio G

2018-01-01

As a vaccination vector, MVA has been widely investigated both in animal models and humans. The construction of recombinant MVA (rMVA) relies on homologous recombination between an acceptor virus and a donor plasmid in infected/transfected permissive cells. Our construction strategy "Red-to-Green gene swapping" - based on the exchange of two fluorescent markers within the flanking regions of MVA deletion ΔIII, coupled to fluorescence activated cell sorting - is here extended to a second insertion site, within the flanking regions of MVA deletion ΔVI. Exploiting this strategy, both double and triple rMVA were constructed, expressing as transgenes the influenza A proteins HA, NP, M1, and PB1. Upon validation of the harbored transgenes co-expression, double and triple recombinants rMVA(ΔIII)-NP-P2A-M1 and rMVA(ΔIII)-NP-P2A-M1-(ΔVI)-PB1 were assayed for in vivo immunogenicity and protection against lethal challenge. In vivo responses were identical to those obtained with the reported combinations of single recombinants, supporting the feasibility and reliability of the present improvement and the extension of Red-to-Green gene swapping to insertion sites other than ΔIII. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of Percutaneous Edge-to-Edge Repair on Mitral Valve Area and Its Association With Pulmonary Hypertension and Outcomes.

Science.gov (United States)

Utsunomiya, Hiroto; Itabashi, Yuji; Kobayashi, Sayuki; Rader, Florian; Hussaini, Asma; Makar, Moody; Trento, Alfredo; Siegel, Robert J; Kar, Saibal; Shiota, Takahiro

2017-08-15

Percutaneous edge-to-edge repair using the MitraClip system causes reduction in mitral valve area (MVA). However, its clinical impact is not fully elucidated. This study assessed the impact of postprocedural MVA reduction on pulmonary hypertension and outcomes. A total of 92 patients with grades 3 to 4 + mitral regurgitation (MR) who underwent MitraClip therapy were retrospectively reviewed. Using intraprocedural, 3-dimensional transesophageal echocardiography, postprocedural MVA was obtained by 2 optimized planes through the medial and lateral orifices of the repaired valve. MVA was reduced by 60.1% immediately after MitraClip procedure (p <0.001). Postprocedural MVA correlated moderately with mean transmitral pressure gradient (TMPG) in the majority of patients (r = -0.56, p <0.001), but discordance of MVA and TMPG was observed in 40% of patients. In multivariable linear regression analysis, postprocedural MVA ≤1.94 cm 2 was independently associated with a blunted decrease in systolic pulmonary artery pressure at 1-month follow-up (β-estimate -4.63, 95% confidence interval -9.71 to -0.15, p = 0.042). Postprocedural MVA ≤1.94 cm 2 was an independent predictor of all-cause mortality and heart failure hospitalization after MitraClip (hazard ratio 4.28, 95% confidence interval 1.56 to 11.7, p = 0.005) even after adjustment for age, gender, atrial fibrillation, cause of MR, left ventricular systolic function, pre-existing pulmonary hypertension, and residual MR. After further adjustment for TMPG ≥5 mm Hg, postprocedural MVA ≤1.94 cm 2 remained predictive for adverse outcomes (p = 0.048). In conclusion, the intraprocedural assessment of MVA by 3-dimensional transesophageal echocardiography can predict hemodynamic response and postprocedural prognosis after MitraClip therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development.

Science.gov (United States)

Volz, A; Sutter, G

2017-01-01

Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional smallpox vaccination. Adapted to growth in avian cells MVA lost the ability to replicate in mammalian hosts and lacks many of the genes orthopoxviruses use to conquer their host (cell) environment. As a biologically well-characterized mutant virus, MVA facilitates fundamental research to elucidate the functions of poxvirus host-interaction factors. As extremely safe viral vectors MVA vaccines have been found immunogenic and protective in various preclinical infection models. Multiple recombinant MVA currently undergo clinical testing for vaccination against human immunodeficiency viruses, Mycobacterium tuberculosis or Plasmodium falciparum. The versatility of the MVA vector vaccine platform is readily demonstrated by the swift development of experimental vaccines for immunization against emerging infections such as the Middle East Respiratory Syndrome. Recent advances include promising results from the clinical testing of recombinant MVA-producing antigens of highly pathogenic avian influenza virus H5N1 or Ebola virus. This review summarizes our current knowledge about MVA as a unique strain of vaccinia virus, and discusses the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology. © 2017 Elsevier Inc. All rights reserved.

Analysis of iridoids content and expression studies of genes encoding early enzymes in the indol terpenoid biosynthesis pathway in Catharanthus roseus Análisis de iridoides y expresión de genes que codifican enzimas tempranas en la síntesis de alcaloides indol terpenoicos en Catharanthus roseus

OpenAIRE

Leech Mark; Palacios-Rojas Natalia

2004-01-01

Terpenoid indole alkaloids (TIA) are of pharmaceutical importance, however the industrial use of these compouds is very limited because its accumulation is very low in plant tissues. TIA are derived f rom the shikimate and terpenoid pathways, which supply secologanin and tryptamine, the indole and iridoid moieties, respectively. Secololganin is a terpenoid which is belived to be synthesised the MEP pathway rather than by the acetate/mevalonic acid pathway. Secologanin is thought to be a limit...

Intraoperative assessment of mitral valve area after mitral valve repair: comparison of different methods.

Science.gov (United States)

Maslow, Andrew; Gemignani, Anthony; Singh, Arun; Mahmood, Feroze; Poppas, Athena

2011-04-01

In the present study, 3 different methods to measure the mitral valve area (MVA) after mitral valve repair (MVRep) were studied. Data obtained immediately after repair were compared with postoperative data. The objective was to determine the feasibility and correlation between intraoperative and postoperative MVA data. A prospective study. A tertiary care medical center. Twenty-five elective adult surgical patients scheduled for MVRep. Echocardiographic data included MVAs obtained using the pressure half-time (PHT), 2-dimensional planimetry (2D-PLAN), and the continuity equation (CE). These data were obtained immediately after cardiopulmonary bypass and were compared with data obtained before hospital discharge (transthoracic echocardiogram 1) and 6 to 12 months after surgery (transthoracic echocardiogram 2). Intraoperative care was guided by hemodynamic goals designed to optimize cardiac function. The data show good agreement and correlation between MVA obtained with PHT and 2D-PLAN within and between each time period. MVA data obtained with the CE in the postoperative period were lower than and did not correlate or agree as well with other MVA data. The MVA recorded immediately after valve repair, using PHT, correlated and agreed with MVA data obtained in the postoperative period. These results contrast with previously published data and could highlight the impact of hemodynamic function during the assessment of MVA. Copyright © 2011 Elsevier Inc. All rights reserved.

Reconstructed image of human heart for total artificial heart implantation, based on MR image and cast silicone model of heart

International Nuclear Information System (INIS)

Komoda, Takashi; Maeta, Hajime; Uyama, Chikao.

1991-01-01

Based on transverse (TRN) and LV long axis (LAX) MR images of two cadaver hearts, three-dimensional (3-D) computer models of the connecting interface between remaining heart and total artificial heart, i.e., mitral and tricuspid valvular annuli (MVA and TVA), ascending aorta (Ao) and pulmonary artery (PA), were reconstructed to compare the shape and the size of MVA and those of TVA, the distance between the center of MVA and TVA (D G ), the angle between the plane of MVA and that of TVA (R T ), and the angles of Ao and PA, respectively, to the plane of MVA (R A , R P ), with those obtained in cast silicone models. It was found that based on LAX rather than TRN MR image, MVA and TVA might be more precisely reconstructed. The data obtained in 3-D images of MVA, TVA, Ao and PA based on silicone models of 32 hearts were as follows: D G (cm): 4.17±0.43, R T (degrees): 22.1±11.3, R A (degrees): 54.9±15.3, R P (degrees): 30.8±17.1. (author)

Identification and preliminary characterization of protein-cysteine farnesyltransferase

International Nuclear Information System (INIS)

Manne, V.; Roberts, D.; Tobin, A.; O'Rourke, E.; Barbacid, M.; De Virgilio, M.; Meyers, C.; Ahmed, N.; Kurz, B.; Resh, M.; Kung, Hsiang-Fu

1990-01-01

Ras proteins must be isoprenylated at a conserved cysteine residue near the carboxyl terminus in order to exert their biological activity. Previous studies indicate that an intermediate in the mevalonate pathway, most likely farnesyl pyrophosphate, is the donor of this isoprenyl group. Inhibition of mevalonate synthesis reverts the abnormal phenotypes induced by the mutant RAS2 Valendash19 gene in Saccharomyces cerevisiae and blocks the maturation of Xenopus oocytes induced by an onocogenic Ras p21 protein of human origin. These results have raised the possibility of using inhibitors of the mevalonate pathway to block the transforming properties of ras oncogenes. Unfortunately, mevalonate is a precursor of various end products essential to mammalian cells, such as dolichols, ubiquinones, heme A, and cholesterol. In this study, the authors describe an enzymatic activity(ies) capable of catalyzing the farnesylation of unprocessed Ras p21 proteins in vitro at the correct (Cys-186) residue. Gel filtration analysis of a partially purified preparation of protein farnesyltransferase revealed two peaks of activity at 250-350 kDa and 80-130 kDa. Availability of an in vitro protein farnesyltransferase assay should be useful in screening for potential inhibitors of ras oncogene function that will not interfere with other aspects of the mevalonate pathway

Triterpenoid biosynthesis in Euphorbia lathyris latex

Energy Technology Data Exchange (ETDEWEB)

Hawkins, D.R.

1987-11-01

The structures of triterpenols, not previously been known, from Euphorbia lathyris latex are reported. A method for quantifying very small amounts of these compounds was developed. Concerning the biochemistry of the latex, no exogenous cofactors were required for the biosynthesis and the addition of compounds such as NADPAH and ATP do not stimulate the biosynthesis. The addition of DTE or a similar anti-oxidant was found to help reduce the oxidation of the latex, thus increasing the length of time that the latex remains active. The requirement of a divalent cation and the preference for Mn in the pellet was observed. The effect of several inhibitors on the biosynthesis of the triterpenoids was examined. Mevinolin was found to inhibit the biosynthesis of the triterpenoids from acetate, but not mevalonate. A dixon plot of the inhibition of acetate incorporation showed an I/sub 50/ concentration of 3.2 ..mu..M. Fenpropimorph was found to have little or no effect on the biosynthesis. Tridemorph was found to inhibit the biosynthesis of all of the triterpenoids with an I/sub 50/ of 4 ..mu..M. It was also observed that the cyclopropyl containing triterpenols, cycloartenol and 24-methylenecycloartenol were inhibited much more strongly than those containing an 8-9 double bond, lanosterol and 24-methylenelanosterol. The evidence indicates, but does not definetely prove, that lanosterol and 24-methylenelanosterol are not made from cycloartenol and 24-methylenecycloartenol via a ring-opening enzyme such as cycloeucalenol-obtusifoliol isomerase. The possibilty that cycloartenol is made via lanosterol was investigated by synthesizing 4-R-4-/sup 3/H-mevalonic acid and incubating latex with a mixture of this and /sup 14/C-mevalonic acid. From the /sup 3/H//sup 14/C ratio it was shown that cycloartenol and 24-methylenecycloartenol are not made via an intermediate containing as 8-9 double bond. 88 refs., 15 figs., 30 tabs.

Using Multimedia Vocabulary Annotations in L2 Reading and Listening Activities

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Jing Xu

2010-01-01

This paper reviews the role of multimedia vocabulary annotation (MVA) in facilitating second language (L2) reading and listening activities. It examines the multimedia learning and multimedia language learning theories that underlie the MVA research, synthesizes the findings on MVA in the last decade, and identifies three underresearched areas on…

[Construction and Function Verification of a Novel Shuttle Vector Containing a Marker Gene Self-deletion System].

Science.gov (United States)

Li, Lili; Wang, Zhan; Zhou, Yubai; Zhang, Fang; Shen, Sisi; Li, Zelin; Zeng, Yi

2015-09-01

For rapid and accurate screening of recombinant modified vaccinia virus Ankara (rMVA) that satisfied the quality standards of clinical trials, a novel shuttle vector that can delete the marker gene automatically during virus propagation was construted: pZL-EGFP. To construct the pZL-EGFP, the original shuttle vector pSC11 was modified by replacing the LacZ marker gene with enhanced green fluorescent protein (EGFP) and then inserting homologous sequences of TKL into the flank regions of EGFP. Baby hamster kidney (BHK)-21 cells were cotransfected with pZL-EGFP and MVA, and underwent ten passages and one plaque screening to obtain the EGFP-free rMVA carrying the exogenous gene. Resulting rMVA was tested by polymerase chain reaction and western blotting to verify pZL-EGFP function. A novel shuttle vector pZL-EGFP containing an EGFP marker gene which could be deleted automatically was constructed. This gene deletion had no effect on the activities of rMVA, and the exogenous gene could be expressed stably. These results suggest that rMVA can be packaged efficiently by homologous recombination between pZL-EGFP and MVA in BHK-21 cells, and that the carried EGFP gene can be removed automatically by intramolecular homologous recombination during virus passage. Meanwhile, the gene deletion had no influence on the activities of rMVA and the expression of exogenous target gene. This study lays a solid foundation for the future research.

Enhanced protein and biochemical production using CRISPRi-based growth switches

DEFF Research Database (Denmark)

Li, Songyuan; Jendresen, Christian Bille; Grünberger, Alexander

2016-01-01

functionality of the growth switches. Decoupling of growth from production of biochemicals was demonstrated for mevalonate, a precursor for isoprenoid compounds. Mass yield of mevalonate was increased by 41%, and production was maintained for more than 45 h after activation of the pyrF-based growth switch...

Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4

Science.gov (United States)

Foresti, Ombretta; Ruggiano, Annamaria; Hannibal-Bach, Hans K; Ejsing, Christer S; Carvalho, Pedro

2013-01-01

Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate pathway. As HMGR acts at the beginning of the pathway, its regulation affects the synthesis of sterols and of other essential mevalonate-derived metabolites, such as ubiquinone or dolichol. Here, we describe a novel, evolutionarily conserved feedback system operating at a sterol-specific step of the mevalonate pathway. This involves the sterol-dependent degradation of squalene monooxygenase mediated by the yeast Doa10 or mammalian Teb4, a ubiquitin ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Since the other branch of ERAD is required for HMGR regulation, our results reveal a fundamental role for ERAD in sterol homeostasis, with the two branches of this pathway acting together to control sterol biosynthesis at different levels and thereby allowing independent regulation of multiple products of the mevalonate pathway. DOI: http://dx.doi.org/10.7554/eLife.00953.001 PMID:23898401

Mucosal immunization with PLGA-microencapsulated DNA primes a SIV-specific CTL response revealed by boosting with cognate recombinant modified vaccinia virus Ankara

International Nuclear Information System (INIS)

Sharpe, Sally; Hanke, Tomas; Tinsley-Bown, Anne; Dennis, Mike; Dowall, Stuart; McMichael, Andrew; Cranage, Martin

2003-01-01

Systemically administered DNA encoding a recombinant human immunodeficiency virus (HIV) derived immunogen effectively primes a cytotoxic T lymphocyte (CTL) response in macaques. In this further pilot study we have evaluated mucosal delivery of DNA as an alternative priming strategy. Plasmid DNA, pTH.HW, encoding a multi-CTL epitope gene, was incorporated into poly(D,L-lactic-co-glycolic acid) microparticles of less than 10 μm in diameter. Five intrarectal immunizations failed to stimulate a circulating vaccine-specific CTL response in 2 Mamu-A*01 + rhesus macaques. However, 1 week after intradermal immunization with a cognate modified vaccinia virus Ankara vaccine MVA.HW, CTL responses were detected in both animals that persisted until analysis postmortem, 12 weeks after the final boost. In contrast, a weaker and less durable response was seen in an animal vaccinated with the MVA construct alone. Analysis of lymphoid tissues revealed a disseminated CTL response in peripheral and regional lymph nodes but not the spleen of both mucosally primed animals

STEVIOSIDE SYNTHESIS IN STEVIA (Stevia rebaudiana Bert

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Alfredo Jarma Orozco

2010-01-01

Full Text Available Stevia rebaudiana Bert. is a subtropical wild plant of Paraguay, that possesses a potent sweetener up to 300 times higher than sucrose and has no calories. The molecules responsible for these characteristics are diterpen glycosides, found in leaves and synthesized at least, at initial states, which use the same pathway of the gibberellic acid in which the shiquimic acid gives origin to many aromatic compounds. The acetate is the precursor of the terpens or isoprenoids through the acetate-mevalonate pathway, where steviosides are found. Although in this article, an alternative route is discussed. This updating pretends to contribute tools for the understanding of the main pathways of steviol glycosides synthesis.

Hydrocarbons and energy from plants: Final report, 1984-1987

Energy Technology Data Exchange (ETDEWEB)

Calvin, M.; Otvos, J.; Taylor, S.E.; Nemethy, E.K.; Skrukrud, C.L.; Hawkins, D.R.; Lago, R.

1988-08-01

Plant hydrocarbon (isoprenoid) production was investigated as an alternative source to fossil fuels. Because of their high triterpenoid (hydrocarbon) content of 4--8%, Euphorbia lathyris plants were used as a model system for this study. The structure of the E. lathyris triterpenoids was determined, and triterpenoid biosynthesis studied to better understand the metabolic regulation of isoprenoid production. Triterpenoid biosynthesis occurs in two distinct tissue types in E. lathyris plants: in the latex of the laticifer cells; and in the mesophyll cells of the leaf and stem. The latex has been fractionated by centrifugation, and it has been determined that the later steps of isoprenoid biosynthesis, the conversion of mevalonic acid to the triterpenes, are compartmentized within a vacuole. Also identified was the conversion of hydroxymethyl glutaryl-CoA to mevalonic acid, catalyzed by the enzyme Hydroxymethyl glutaryl-CoA Reductase, as a key rate limiting step in isoprenoid biosynthesis. At least two isozymes of this enzyme, one in the latex and another in the leaf plastids, have been identified. Environmental stress has been applied to plants to study changes in carbon allocation. Salinity stress caused a large decrease in growth, smaller decreases in photosynthesis, resulting in a larger allocation of carbon to both hydrocarbon and sugar production. An increase in Hydroxymethyl glutaryl-CoA Reductase activity was also observed when isoprenoid production increased. Other species where also screened for the production of hydrogen rich products such as isoprenoids and glycerides, and their hydrocarbon composition was determined.

Molecular cloning and functional expression of geranylgeranyl pyrophosphate synthase from Coleus forskohlii Briq

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Kawamukai Makoto

2004-11-01

Full Text Available Abstract Background Isopentenyl diphosphate (IPP, a common biosynthetic precursor to the labdane diterpene forskolin, has been biosynthesised via a non-mevalonate pathway. Geranylgeranyl diphosphate (GGPP synthase is an important branch point enzyme in terpenoid biosynthesis. Therefore, GGPP synthase is thought to be a key enzyme in biosynthesis of forskolin. Herein we report the first confirmation of the GGPP synthase gene in Coleus forskohlii Briq. Results The open reading frame for full-length GGPP synthase encodes a protein of 359 amino acids, in which 1,077 nucleotides long with calculated molecular mass of 39.3 kDa. Alignments of C. forskohlii GGPP synthase amino acid sequences revealed high homologies with other plant GGPP synthases. Several highly conserved regions, including two aspartate-rich motifs were identified. Transient expression of the N-terminal region of C. forskohlii GGPP synthase-GFP fusion protein in tobacco cells demonstrated subcellular localization in the chloroplast. Carotenoid production was observed in Escherichia coli harboring pACCAR25ΔcrtE from Erwinia uredovora and plasmid carrying C. forskohlii GGPP synthase. These results suggested that cDNA encoded functional GGPP synthase. Furthermore, C. forskohlii GGPP synthase expression was strong in leaves, decreased in stems and very little expression was observed in roots. Conclusion This investigation proposed that forskolin was synthesised via a non-mevalonate pathway. GGPP synthase is thought to be involved in the biosynthesis of forskolin, which is primarily synthesised in the leaves and subsequently accumulates in the stems and roots.

Effect of chlorpromazine on rat arterial lipid synthesis, in vitro

International Nuclear Information System (INIS)

Bell, F.P.; Hubert, E.V.

1982-01-01

The effect of chlorpromazine, a major tranquilizer, on arterial lipid metabolism was studied in vitro in rat aortas incubated with [ 14 C]acetate and [ 14 C]mevalonate as lipid precursors. Chlorpromazine at a level of 0.25 mM in the incubation medium significantly reduced the incorporation of [ 14 C]acetate into free fatty acids (p less than 0.01) and total phospholipids (p less than 0.001) but not triglycerides. Chlorpromazine also altered the pattern of arterial phospholipids synthesized from [ 14 C]acetate by significantly increasing the relative proportion of phosphatidylinositol plus phosphatidylserine (p less than 0.02) and reducing the relative proportion of sphingomyelin (p less than 0.001). [ 14 C] Acetate incorporation into the combined fractions of steryl esters plus hydrocarbons and sterols plus diglycerides was also significantly reduced (p less than 0.001) by 0.25 mM chlorpromazine. Studies with [ 14 C]mevalonate showed that chlorpromazine is also an inhibitor of sterol biosynthesis in arterial tissues as evidenced by 35-40% reductions (p less than 0.05) in the formation of 14 C-labeled squalene and C27 sterols

The Immunogenicity of the Tumor-Associated Antigen α-Fetoprotein Is Enhanced by a Fusion with a Transmembrane Domain

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Lucile Tran

2012-01-01

Full Text Available Aim. To investigate the ability of recombinant modified vaccinia virus Ankara (rMVA vector to induce an immune response against a well-tolerated self-antigen. Methods. rMVA vectors expressing different form of α-fetoprotein (AFP were produced and characterized. Naïve mice were vaccinated with MVA vectors expressing the AFP antigen in either a secreted, or a membrane-bound, or an intracellular form. The immune response was monitored by an IFNΓ ELISpot assay and antibody detection. Results. Vaccination with the membrane-associated form of AFP induced a stronger CD8+ T-cell response compared to the ones obtained with the MVA encoding the secreted or the intracellular forms of AFP. Moreover, the vaccination with the membrane-bound AFP elicited the production of AFP-specific antibodies. Conclusions. The AFP transmembrane form is more immunogenic. Expressing a membrane-bound form in the context of an MVA vaccination could enhance the immunogenicity of a self-antigen.

“Right tool,” wrong “job”: Manual vacuum aspiration, post-abortion care and transnational population politics in Senegal

Science.gov (United States)

Suh, Siri

2015-01-01

The “rightness” of a technology for completing a particular task is negotiated by medical professionals, patients, state institutions, manufacturing companies, and non-governmental organizations. This paper shows how certain technologies may challenge the meaning of the “job” they are designed to accomplish. Manual vacuum aspiration (MVA) is a syringe device for uterine evacuation that can be used to treat complications of incomplete abortion, known as post-abortion care (PAC), or to terminate pregnancy. I explore how negotiations over the rightness of MVA as well as PAC unfold at the intersection of national and global reproductive politics during the daily treatment of abortion complications at three hospitals in Senegal, where PAC is permitted but induced abortion is legally prohibited. Although state health authorities have championed MVA as the “preferred” PAC technology, the primary donor for PAC, the United States Agency for International Development, does not support the purchase of abortifacient technologies. I conducted an ethnography of Senegal's PAC program between 2010 and 2011. Data collection methods included interviews with 49 health professionals, observation of PAC treatment and review of abortion records at three hospitals, and a review of transnational literature on MVA and PAC. While MVA was the most frequently employed form of uterine evacuation in hospitals, concerns about off-label MVA practices contributed to the persistence of less effective methods such as dilation and curettage (D&C) and digital curettage. Anxieties about MVA's capacity to induce abortion have constrained its integration into routine obstetric care. This capacity also raises questions about what the “job,” PAC, represents in Senegalese hospitals. The prioritization of MVA's security over women's access to the preferred technology reinforces gendered inequalities in health care. PMID:25948127

"Right tool," wrong "job": Manual vacuum aspiration, post-abortion care and transnational population politics in Senegal.

Science.gov (United States)

Suh, Siri

2015-06-01

The "rightness" of a technology for completing a particular task is negotiated by medical professionals, patients, state institutions, manufacturing companies, and non-governmental organizations. This paper shows how certain technologies may challenge the meaning of the "job" they are designed to accomplish. Manual vacuum aspiration (MVA) is a syringe device for uterine evacuation that can be used to treat complications of incomplete abortion, known as post-abortion care (PAC), or to terminate pregnancy. I explore how negotiations over the rightness of MVA as well as PAC unfold at the intersection of national and global reproductive politics during the daily treatment of abortion complications at three hospitals in Senegal, where PAC is permitted but induced abortion is legally prohibited. Although state health authorities have championed MVA as the "preferred" PAC technology, the primary donor for PAC, the United States Agency for International Development, does not support the purchase of abortifacient technologies. I conducted an ethnography of Senegal's PAC program between 2010 and 2011. Data collection methods included interviews with 49 health professionals, observation of PAC treatment and review of abortion records at three hospitals, and a review of transnational literature on MVA and PAC. While MVA was the most frequently employed form of uterine evacuation in hospitals, concerns about off-label MVA practices contributed to the persistence of less effective methods such as dilation and curettage (D&C) and digital curettage. Anxieties about MVA's capacity to induce abortion have constrained its integration into routine obstetric care. This capacity also raises questions about what the "job," PAC, represents in Senegalese hospitals. The prioritization of MVA's security over women's access to the preferred technology reinforces gendered inequalities in health care. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biofuel and chemical production by recombinant microorganisms via fermentation of proteinaceous biomass

Science.gov (United States)

Liao, James C.; Cho, Kwang Myung; Yan, Yajun; Huo, Yixin

2016-03-15

Provided herein are metabolically modified microorganisms characterized by having an increased keto-acid flux when compared with the wild-type organism and comprising at least one polynucleotide encoding an enzyme that when expressed results in the production of a greater quantity of a chemical product when compared with the wild-type organism. The recombinant microorganisms are useful for producing a large number of chemical compositions from various nitrogen containing biomass compositions and other carbon sources. More specifically, provided herein are methods of producing alcohols, acetaldehyde, acetate, isobutyraldehyde, isobutyric acid, n-butyraldehyde, n-butyric acid, 2-methyl-1-butyraldehyde, 2-methyl-1-butyric acid, 3-methyl-1-butyraldehyde, 3-methyl-1-butyric acid, ammonia, ammonium, amino acids, 2,3-butanediol, 1,4-butanediol, 2-methyl-1,4-butanediol, 2-methyl-1,4-butanediamine, isobutene, itaconate, acetoin, acetone, isobutene, 1,5-diaminopentane, L-lactic acid, D-lactic acid, shikimic acid, mevalonate, polyhydroxybutyrate (PHB), isoprenoids, fatty acids, homoalanine, 4-aminobutyric acid (GABA), succinic acid, malic acid, citric acid, adipic acid, p-hydroxy-cinnamic acid, tetrahydrofuran, 3-methyl-tetrahydrofuran, gamma-butyrolactone, pyrrolidinone, n-methylpyrrolidone, aspartic acid, lysine, cadeverine, 2-ketoadipic acid, and/or S-adenosyl-methionine (SAM) from a suitable nitrogen rich biomass.

A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma

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Jamil MO

2017-06-01

Full Text Available Muhammad Omer Jamil, Mary S Jerome, Deborah Miley, Katri S Selander, Francisco Robert Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA Purpose: Malignant pleural mesothelioma (MPM is a rare malignancy with a dismal median survival of <12 months with current therapy. Single and combination chemotherapy regimens have shown only modest clinical benefit. In preclinical studies, nitrogen-containing bisphosphonates (zoledronic acid inhibit growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells.Patients and methods: We investigated the role of zoledronic acid in a pilot, single-arm trial of MPM patients with Eastern Cooperative Oncology Group (ECOG performance status (PS 0–2 who had progressed on prior treatments or had not received systemic therapy due to poor PS. Primary end point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG positron emission tomography criteria. Secondary end points were progression-free survival (PFS and overall survival (OS. Exploratory end points include the effect of zoledronic acid therapy on vascular endothelial growth factor (VEGF, basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels.Results: Eight male patients (median age of 62 years with the following clinical characteristics were treated; ECOG PS was 0–2, 75% with epithelioid type, and 62% had prior chemotherapy. Overall composite response rate was 12.5% and the clinical benefit rate (response + stable disease was 37.5%. Median PFS was 2 months (0.5–21 months and median OS was

Masked Visual Analysis: Minimizing Type I Error in Visually Guided Single-Case Design for Communication Disorders.

Science.gov (United States)

Byun, Tara McAllister; Hitchcock, Elaine R; Ferron, John

2017-06-10

Single-case experimental designs are widely used to study interventions for communication disorders. Traditionally, single-case experiments follow a response-guided approach, where design decisions during the study are based on participants' observed patterns of behavior. However, this approach has been criticized for its high rate of Type I error. In masked visual analysis (MVA), response-guided decisions are made by a researcher who is blinded to participants' identities and treatment assignments. MVA also makes it possible to conduct a hypothesis test assessing the significance of treatment effects. This tutorial describes the principles of MVA, including both how experiments can be set up and how results can be used for hypothesis testing. We then report a case study showing how MVA was deployed in a multiple-baseline across-subjects study investigating treatment for residual errors affecting rhotics. Strengths and weaknesses of MVA are discussed. Given their important role in the evidence base that informs clinical decision making, it is critical for single-case experimental studies to be conducted in a way that allows researchers to draw valid inferences. As a method that can increase the rigor of single-case studies while preserving the benefits of a response-guided approach, MVA warrants expanded attention from researchers in communication disorders.

Kinerja Keuangan Berbasis Penciptaan Nilai, Faktor Makroekonomi dan Pengaruhnya Terhadap Return Saham Sektor Pertanian

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Arif Kurniadi

2013-01-01

Full Text Available Stock return is the main indicator of performance for investors in assessing the effectiveness of the invested capital. The volatility of stock price index of the agricultural sector during 2005 - 2011 has resulted in an annualized return was the second-lowest sector after mining sector. The use of value creation-based performance analysis (EVA, MVA, and Q-Tobin can help companies create corporate value highly associated with stock returns. In addition, external factors may also affect stock returns. The purposes of this study are: (1 to analyze the financial performance of companies in the agricultural sector by using EVA, MVA, and Q-Tobin, (2 to analyze the influence of EVA, MVA, Q-Tobin and macroeconomic factors (inflation and exchange rates on stock returns agricultural sector, and (3 to develop managerial implications of the results of analyzes performed. Data was collected from eight companies agricultural sector, which listed in Indonesia Stock Exchange before 2005. Descriptive analysis is used to analyze EVA, MVA, and Q-Tobin for each company and data panel is used to find out influence of EVA, MVA, Q-Tobin, and macroeconomic factors on stock returns. The study showed that most companies gained a negative EVA. Tthe MVA analysis showed that most companies gained more positive MVA. The Q-Tobin result shows that most companies gained value q<1. Based on REM analysis, only found MVARET and Q-TobinRET have significant effect on stock returns. EVARET, inflation, an exchange rate, and dummy crisis have insignificant effect on stock returns.

Assessment of tumor blood flow and its correlation with histopathologic features in skull base meningiomas and schwannomas by using pseudo-continuous arterial spin labeling images

International Nuclear Information System (INIS)

Yamamoto, Tatsuya; Takeuchi, Hiroaki; Kinoshita, Kazuyuki; Kosaka, Nobuyuki; Kimura, Hirohiko

2014-01-01

Objective: We aimed to investigate whether pseudo-continuous arterial spin labeling (pcASL)-MRI can adequately evaluate tumor perfusion even if the tumors are located in the skull base region and evaluate the correlation between tumor blood flow (TBF) and the histopathologic features of skull base meningiomas and schwannomas. Materials and methods: We enrolled 31 patients with skull base meningioma (n = 14) and schwannoma (n = 17) who underwent surgical resection. TBF was calculated from pcASL. Tissue sections were stained with CD34 to evaluate microvessel area (MVA). TBF and MVA ratio were compared between meningiomas and schwannomas using Mann–Whitney U-test. The correlations between MVA ratio and TBF were evaluated in each tumor by using single linear regression analysis and Spearman's rank correlation coefficients (r s ). Results: MVA ratio and TBF were significantly higher in meningioma than in schwannoma (both p < 0.01). Correlation analyses revealed significant positive correlations between MVA ratio and both mean and max TBF for meningiomas (r s = 0.89, 0.81, both p < 0.01). There was a weak positive correlation between MVA ratio and mean TBF for schwannomas (r s = 0.43, p = 0.04). However, no significant correlation was found between MVA ratio and max TBF for schwannoma. Conclusions: pcASL-MRI is useful for evaluating tumor perfusion even if the tumors are located in the skull base region. Moreover, pcASL-TBF was significantly higher in most meningiomas compared to schwannomas, which can help in the differential diagnosis of the 2 tumor types even without the use of contrast material

Hyper-immunoglobulin D syndrome with novel mutations in an afebrile infant.

Science.gov (United States)

Cadmus, Simi D; Green, Reid; Carrasco, Ruy; Levy, Moise L; Diaz, Lucia Z

2018-03-30

Hyper-immunoglobulin D syndrome is a rare autosomal-recessive autoinflammatory syndrome in which a mevalonate kinase deficiency results due to mutations of the mevalonate kinase gene. We report a case of an Asian male infant who was found to have hyper-immunoglobulin D syndrome in the absence of fever. His skin manifestations included cephalic pustulosis as well recurrent transient and fixed pink plaques and nodules on the face and extremities. Subsequent examination revealed hyper-immunoglobulin D syndrome with two novel allelic mutations in the mevalonate kinase gene: c.895G > A (p.D299N) and c.1168C > T (p.Q390). It is important for dermatologists to recognize the varied cutaneous presentations of hyper-immunoglobulin D syndrome because rapid diagnosis and treatment can significantly affect outcomes. © 2018 Wiley Periodicals, Inc.

Engineering a functional 1-deoxy-D-xylulose 5-phosphate (DXP) pathway in Saccharomyces cerevisiae

DEFF Research Database (Denmark)

Kirby, James; Dietzel, Kevin L.; Wichmann, Gale

2016-01-01

Isoprenoids are used in many commercial applications and much work has gone into engineering microbial hosts for their production. Isoprenoids are produced either from acetyl-CoA via the mevalonate pathway or from pyruvate and glyceraldehyde 3-phosphate via the 1-deoxy-D-xylulose 5-phosphate (DXP......) pathway. Saccharomyces cerevisiae exclusively utilizes the mevalonate pathway to synthesize native isoprenoids and in fact the alternative DXP pathway has never been found or successfully reconstructed in the eukaryotic cytosol. There are, however, several advantages to isoprenoid synthesis via the DXP...... time, functional expression of the DXP pathway in S. cerevisiae. Under low aeration conditions, an engineered strain relying solely on the DXP pathway for isoprenoid biosynthesis achieved an endpoint biomass 80% of that of the same strain using the mevalonate pathway....

Sequential Immunization with gp140 Boosts Immune Responses Primed by Modified Vaccinia Ankara or DNA in HIV-Uninfected South African Participants.

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Gavin Churchyard

Full Text Available The safety and immunogenicity of SAAVI DNA-C2 (4 mg IM, SAAVI MVA-C (2.9 x 109 pfu IM and Novartis V2-deleted subtype C gp140 (100 mcg with MF59 adjuvant in various vaccination regimens was evaluated in HIV-uninfected adults in South Africa.Participants at three South African sites were randomized (1:1:1:1 to one of four vaccine regimens: MVA prime, sequential gp140 protein boost (M/M/P/P; concurrent MVA/gp140 (MP/MP; DNA prime, sequential MVA boost (D/D/M/M; DNA prime, concurrent MVA/gp140 boost (D/D/MP/MP or placebo. Peak HIV specific humoral and cellular responses were measured.184 participants were enrolled: 52% were female, all were Black/African, median age was 23 years (range, 18-42 years and 79% completed all vaccinations. 159 participants reported at least one adverse event, 92.5% were mild or moderate. Five, unrelated, serious adverse events were reported. The M/M/P/P and D/D/MP/MP regimens induced the strongest peak neutralizing and binding antibody responses and the greatest CD4+ T-cell responses to Env. All peak neutralizing and binding antibody responses decayed with time. The MVA, but not DNA, prime contributed to the humoral and cellular immune responses. The D/D/M/M regimen was poorly immunogenic overall but did induce modest CD4+ T-cell responses to Gag and Pol. CD8+ T-cell responses to any antigen were low for all regimens.The SAAVI DNA-C2, SAAVI MVA-C and Novartis gp140 with MF59 adjuvant in various combinations were safe and induced neutralizing and binding antibodies and cellular immune responses. Sequential immunization with gp140 boosted immune responses primed by MVA or DNA. The best overall immune responses were seen with the M/M/P/P regimen.ClinicalTrials.gov NCT01418235.

Safety and immunogenicity of a modified-vaccinia-virus-Ankara-based influenza A H5N1 vaccine: a randomised, double-blind phase 1/2a clinical trial.

Science.gov (United States)

Kreijtz, Joost H C M; Goeijenbier, Marco; Moesker, Fleur M; van den Dries, Lennert; Goeijenbier, Simone; De Gruyter, Heidi L M; Lehmann, Michael H; Mutsert, Gerrie de; van de Vijver, David A M C; Volz, Asisa; Fouchier, Ron A M; van Gorp, Eric C M; Rimmelzwaan, Guus F; Sutter, Gerd; Osterhaus, Albert D M E

2014-12-01

Modified vaccinia virus Ankara (MVA) is a promising viral vector platform for the development of an H5N1 influenza vaccine. Preclinical assessment of MVA-based H5N1 vaccines showed their immunogenicity and safety in different animal models. We aimed to assess the safety and immunogenicity of the MVA-haemagglutinin-based H5N1 vaccine MVA-H5-sfMR in healthy individuals. In a single-centre, double-blind phase 1/2a study, young volunteers (aged 18-28 years) were randomly assigned with a computer-generated list in equal numbers to one of eight groups and were given one injection or two injections intramuscularly at an interval of 4 weeks of a standard dose (10(8) plaque forming units [pfu]) or a ten times lower dose (10(7) pfu) of the MVA-H5-sfMR (vector encoding the haemagglutinin gene of influenza A/Vietnam/1194/2004 virus [H5N1 subtype]) or MVA-F6-sfMR (empty vector) vaccine. Volunteers and physicians who examined and administered the vaccine were masked to vaccine assignment. Individuals who received the MVA-H5-sfMR vaccine were eligible for a booster immunisation 1 year after the first immunisation. Primary endpoint was safety. Secondary outcome was immunogenicity. The trial is registered with the Dutch Trial Register, number NTR3401. 79 of 80 individuals who were enrolled completed the study. No serious adverse events were identified. 11 individuals reported severe headache and lightheadedness, erythema nodosum, respiratory illness (accompanied by influenza-like symptoms), sore throat, or injection-site reaction. Most of the volunteers had one or more local (itch, pain, redness, and swelling) and systemic reactions (rise in body temperature, headache, myalgia, arthralgia, chills, malaise, and fatigue) after the first, second, and booster immunisations. Individuals who received the 10(7) dose had fewer systemic reactions. The MVA-H5-sfMR vaccine at 10(8) pfu induced significantly higher antibody responses after one and two immunisations than did 10(7) pfu when

Static electrification testing of Texas Utilities 345-20.9 kV, 650 MVA generator step-up transformer under controlled factory conditions

International Nuclear Information System (INIS)

Crofts, D.W.; Moore, H.

1995-01-01

Comanche Peak Nuclear Power Plant, with two 1150 Megawatt units, has two 345-20.9 kV, three-phase, 650 MVA transformers connected in parallel. The transformers have had a long history of hydrogen generation, and one of the Unit No. 2 transformers failed in 1983 while energized from the system for plant construction power. The failed unit was repaired and returned to Comanche Peak, and there was no evidence of static electrification involvement in the failure. During the time from installation to commercial operation in 1990 for Unit No. 1 and 1992 for Unit No. 2, the transformers were backfed from the system as needed to provide construction power. There was little regard paid to the operation of the cooling systems other than assuring the cooling was running. The transformers on unit No. 1 were subjected to several unusual electrical events - ferroresonance in 1981 and over excitation in 1983, with the generation of gasses of great concern. The decision was made to install a new transformer and return the old unit to the factory for diagnostic testing to determine the cause for the generation of combustible gas, primarily hydrogen. The dielectric integrity of the transformer could be quantified and decisions made concerning the replacement of the remaining transformers. After testing, the transformer was disassembled for forensic evaluation and rebuilt for return as a spare or to replace another transformer while undergoing repairs. Deformation of the bottom of the tank was discovered with large dents in the bottom protruding inward approximately one and one-half inches. With the concern of decreased clearances or displaced flux shields in the tank, an inspection opening was cut in the end of the transformer near the bottom. While investigating the deformation, evidence of partial discharge activity was discovered at the bottom of the high-to-low insulation; a location where static electrification damage has been observed in other large shell-form transformers

Motor vehicle accidents: How should cirrhotic patients be managed?

Institute of Scientific and Technical Information of China (English)

Takumi Kawaguchi; Eitaro Taniguchi; Michio Sata

2012-01-01

Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs.Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit,which frequently occurs in cirrhotic patients independent of severity of liver disease.Although MHE is known as a risk factor for MVAs,the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown.Recently,Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT),and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs,Besides the ICT and lactulose,there are various diagnostic tools and therapeutic strategies for MHE.In this commentary,we discussed a current issue of diagnostic tools for MHE,including neuropsychological tests.We also discussed the advantages of the other therapeutic strategies for MHE,such as intake of a regular breakfast and coffee,and supplementation with zinc and branched chain amino acids,on the MVA-related societal costs.

Isoprenylation is required for the processing of the lamin A precursor

International Nuclear Information System (INIS)

Beck, L.A.; Hosick, T.J.; Sinensky, M.

1990-01-01

The nuclear lamina proteins, prelamin A, lamin B, and a 70-kD lamina-associated protein, are posttranslationally modified by a metabolite derived from mevalonate. This modification can be inhibited by treatment with (3-R,S)-3-fluoromevalonate, demonstrating that it is isoprenoid in nature. We have examined the association between isoprenoid metabolism and processing of the lamin A precursor in human and hamster cells. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by mevinolin (lovastatin) specifically depletes endogenous isoprenoid pools and inhibits the conversion of prelamin A to lamin A. Prelamin A processing is also blocked by mevalonate starvation of Mev-1, a CHO cell line auxotrophic for mevalonate. Moreover, inhibition of prelamin A processing by mevinolin treatment is rapidly reversed by the addition of exogenous mevalonate. Processing of prelamin A is, therefore, dependent on isoprenoid metabolism. Analysis of the conversion of prelamin A to lamin A by two independent methods, immunoprecipitation and two-dimensional nonequilibrium pH gel electrophoresis, demonstrates that a precursor-product relationship exists between prelamin A and lamin A. Analysis of R,S-[5-3H(N)]mevalonate-labeled cells shows that the rate of turnover of the isoprenoid group from prelamin A is comparable to the rate of conversion of prelamin A to lamin A. These results suggest that during the proteolytic maturation of prelamin A, the isoprenylated moiety is lost. A significant difference between prelamin A processing, and that of p21ras and the B-type lamins that undergo isoprenylation-dependent proteolytic maturation, is that the mature form of lamin A is no longer isoprenylated

Applications of high-Tc-superconductors to power engineering. Manufacture of YBCO plate-type conductors and construction of a HTS current limiter model up to 1 MVA nominal power. Final report

International Nuclear Information System (INIS)

Utz, B.; Schmidt, W.; Schilling, W.; Fischperer, I.; Kraemer, H.P.; Wacker, B.; Gromoll, B.; Neumueller, H.W.; Arndt, A.; Karras, B.; Krueger, U.; Pyritz, U.; Schiewe, H.; Schiller, H.P.; Volkmar, R.R.; Hering, U.; Roessler, R.; Freyhardt, H.C.; Sievers, S.; Hoffmann, J.; Dzich, J.; Kinder, H.; Hoffmann, C.; Lindmayer, M.; Grundmann, J.; Woerdenweber, R.; Hollmann, E.; Kutzner, R.; Klein, W.; Bunte, S.; Kuhn, M.

2002-06-01

In terms of materials, the main focus of the work was on the manufacture of large-area YBCO plate-type conductors with homogeneous properties and maximum current densities of j c >1 MA/cm 2 . j c values of better than 3 MA/cm 2 were achieved reproducibly on sapphire substrates of 100 mm diameter and 10 x 20 cm 2 in size with a homogeneity of 10%; on polycrystalline substrates of 10 x 20 cm 2 in size, homogeneous j c values of up to 2 MA/cm 2 were also successfully demonstrated. Of the total of four methods of coating available at the start of the project, thermal co-evaporation (TCE) proved best for YBCO thin films and the IBAD method best for quasi single-crystal buffer films. The latter are necessary to achieve high j c on polycrystalline substrates such as ZrO 2 (Y), glass and Al 2 O 3 . Polycrystalline substrates are essential in order to make the HTS current limiter as a future product commercially feasible. The favoured solutions ZrO 2 (Y) and glass have not come up to expectations, because present investigations into quench propagation are showing that, with this approach, the high values of power density required for the switching process (1600 VA/cm 2 ) cannot be achieved. Towards the end of the project, polycrystalline Al 2 O 3 began to be seen as a successful alternative; the work is being pursued further within the context of a follow-on project. The coating processes were stabilized successfully and, when combined with strict quality control, allowed the yield of tested, ready-to-use plate-type conductors to be improved to 85%. This success was an essential prerequisite for the building of a 3-phase, 1.2 MVA model (7.2 kV) comprising a total of sixty-three 100 mm plate-type conductors. At the Berlin factory the model has been successfully tested up to a prospective short-circuit current of 5 kV. This has demonstrated the basic suitability of HTS thin-film technology for use in current limiters. So far the model has been switched a total of 43 times

How Genes Evolve

Indian Academy of Sciences (India)

focus on ecological and evolutionary genetics of ... construction of phylogenetic trees from molecular data. More recently, use of ... 500 MVA- Bony fishes. Ca 100 MVA - .... functional or structural domain of the proteins e.g. tropomysine chain ...

Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4

DEFF Research Database (Denmark)

Foresti, Ombretta; Ruggiano, Annamaria; Hannibal-Bach, Hans K

2013-01-01

Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate pathway. As HMGR acts at the beginning of the pathway, its regulation affects the synthesis of sterols and of other essential mevalonate......-derived metabolites, such as ubiquinone or dolichol. Here, we describe a novel, evolutionarily conserved feedback system operating at a sterol-specific step of the mevalonate pathway. This involves the sterol-dependent degradation of squalene monooxygenase mediated by the yeast Doa10 or mammalian Teb4, a ubiquitin...... ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Since the other branch of ERAD is required for HMGR regulation, our results reveal a fundamental role for ERAD in sterol homeostasis, with the two branches of this pathway acting together...

Hyper-IgD syndrome with novel mutation in a Japanese girl.

Science.gov (United States)

Naruto, Takuya; Nakagishi, Yasuo; Mori, Masaaki; Miyamae, Takako; Imagawa, Tomoyuki; Yokota, Shumpei

2009-01-01

Hyperimmunoglobulin D and periodic fever syndrome (HIDS) is an autosomal recessive auto-inflammatory disorder characterized by recurrent febrile attacks with lymphadenopathy, abdominal distress, skin eruptions and joint involvement. We discuss the case of a 15-year-old Japanese girl who had presented with periodic fever, hepatosplenomegaly and intractable diarrhea from seven weeks of age. At first, undifferentiated autoimmune disorder was suspected, and she was treated with prednisolone and, in turn, with immunosuppressants such as cyclosporine, methotrexate, cyclophosphamide and rituximab or with plasma exchange. However, these trials failed to relieve her symptoms, and so she was transferred to our hospital when she was 15 years old. Her parents and elder brother had no history of recurrent fever, prolonged abdominal pain or diarrhea of unknown origin. The patient had extremely elevated levels of mevalonic aciduria and had homozygosity as a novel mutation in the MVK gene (G326R). Finally, HIDS was diagnosed. She was treated with simvastatin, which resulted in a moderate decrease of the urinary mevalonic acid concentration and good clinical course. This is the first case in which homozygosity for the mutation of the MVK gene has been reported in an Asian patient, and indicated a need for differentiation.

Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses.

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Hodge, James W; Poole, Diane J; Aarts, Wilhelmina M; Gómez Yafal, Alicia; Gritz, Linda; Schlom, Jeffrey

2003-11-15

Cancer vaccine regimens use various strategies to enhance immune responses to specific tumor-associated antigens (TAAs), including the increasing use of recombinant poxviruses [vaccinia (rV) and fowlpox (rF)] for delivery of the TAA to the immune system. However, the use of replication competent vectors with the potential of adverse reactions have made attenuation a priority for next-generation vaccine strategies. Modified vaccinia Ankara (MVA) is a replication defective form of vaccinia virus. Here, we investigated the use of MVA encoding a tumor antigen gene, carcinoembryonic antigen (CEA), in addition to multiple costimulatory molecules (B7-1, intercellular adhesion molecule-1, and lymphocyte function-associated antigen-3 designated TRICOM). Vaccination of mice with MVA-CEA/TRICOM induced potent CD4+ and CD8+ T-cell responses specific for CEA. MVA-CEA/TRICOM could be administered twice in vaccinia naïve mice and only a single time in vaccinia-immune mice before being inhibited by antivector-immune responses. The use of MVA-CEA/TRICOM in a diversified prime and boost vaccine regimen with rF-CEA/TRICOM, however, induced significantly greater levels of both CD4+ and CD8+ T-cell responses specific for CEA than that seen with rV-CEA/TRICOM prime and rF-CEA/TRICOM boost. In a self-antigen tumor model, the diversified MVA-CEA/TRICOM/rF-CEA/ TRICOM vaccination regimen resulted in a significant therapeutic antitumor response as measured by increased survival, when compared with the diversified prime and boost regimen, rV-CEA/TRICOM/rF-CEA/TRICOM. The studies reported here demonstrate that MVA, when used as a prime in a diversified vaccination, is clearly comparable with the regimen using the recombinant vaccinia in both the induction of cellular immune responses specific for the "self"-TAA transgene and in antitumor activity.

THE EFFECT OF LEVERAGE AND ECONOMIC VALUE ADDED ON MARKET VALUE ADDED

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Kristína Jančovičová BOGNÁROVÁ

2018-05-01

Full Text Available Economic value added (EVA is a performance measure developed by Stern Stewart & Co. that attempts to measure the true economic profit produced by a company. Such a metric is useful for investors who wish to determine how well a company has produced value for its investors, and it can be compared against the company's peers for a quick analysis of how well the company is operating in its industry. Market value added (MVA, on the other hand, is simply the difference between the current total market value of a company and the capital contributed by investors (including both shareholders and bondholders. It is typically used for companies that are larger and publicly-traded. MVA is not a performance metric like EVA, but instead is a wealth metric, measuring the level of value a company has accumulated over time. In order to maximise the value for shareholders, companies should strive towards maximising MVA and not necessarily their total market value. It is believed, that the best way to do so is to maximize EVA, which reflects a company’s ability to earn returns above the cost of capital. The leverage available to companies that incur fixed costs and use borrowed capital with a fixed interest charge has been known and quantified by financial managers for some time. In this research the effect of leverage and EVA on MVA as the measure of shareholder wealth creation was analysed. Leverage and EVA have been used as the independent variables whereas MVA has been used as the measure of shareholder wealth creation. Correlation and regression methods have been employed to find out in what way financial managers can practice the effects of leverage and EVA to maximize MVA. The results showed that EVA and leverage have no profound impact on MVA of the selected Slovak companies

The frames of reference of the motor-visual aftereffect.

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Guido Barchiesi

Full Text Available Repeatedly performing similar motor acts produces short-term adaptive changes in the agent's motor system. One striking use-dependent effect is the motor-to-visual aftereffect (MVA, a short-lasting negative bias in the conceptual categorization of visually-presented training-related motor behavior. The MVA is considered the behavioral counterpart of the adaptation of visuomotor neurons that code for congruent executed and observed motor acts. Here we characterize which features of the motor training generate the MVA, along 3 main dimensions: a the relative role of motor acts vs. the semantics of the task-set; b the role of muscular-specific vs. goal-specific training and c the spatial frame of reference with respect to the whole body. Participants were asked to repeatedly push or pull some small objects in a bowl as we varied different components of adapting actions across three experiments. The results show that a the semantic value of the instructions given to the participant have no role in generating the MVA, which depends only on the motor meaning of the training act; b both intrinsic body movements and extrinsic action goals contribute simultaneously to the genesis of the MVA and c changes in the relative position of the acting hand compared to the observed hand, when they do not involve changes to the movement performed or to the action meaning, do not have an effect on the MVA. In these series of experiments we confirm that recent motor experiences produce measurable changes in how humans see each others' actions. The MVA is an exquisite motor effect generated by two distinct motor sub-systems, one operating in an intrinsic, muscular specific, frame of reference and the other operating in an extrinsic motor space.

Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants.

Science.gov (United States)

Melamed, Sharon; Wyatt, Linda S; Kastenmayer, Robin J; Moss, Bernard

2013-09-23

Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture, (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production. Published by Elsevier Ltd.

[Risk factors for presence of complications of the mechanical ventilatory assistance in the newborn].

Science.gov (United States)

Tapia-Rombo, Carlos Antonio; Domínguez-Martínez, Rosalba; Saucedo-Zavala, Victor Joel; Cuevas-Urióstegui, Maria Luisa

2004-01-01

The mechanical ventilatory assistance (MVA) is a procedure that is used very often in the neonatal intensive care units but its use its linked to a lot of complications. The objective of this study was to determine the risk factors for the presence of complications of the MVA in the newborns infants. One hundred thirty five medical records from January 98 to June 2000 of newborns that had been discharged by amelioration or death were reviewed retrospectively. All of them had been received MVA; twenty medical record were excluded. They were divided in two groups: group A, neonates that had presented complications during MVA, composed of 40 patients (cases) and B, neonates with MVA, but that had not presented complications due to the procedure of 75 patients (controls). In group A there were 39 preterm neonates and in B, 58 preterm neonates, the rest were term neonates. It was used descriptive and inferential statistics. Odds ratio (OR) and multivariate analysis were used to study risk factors with confidence interval (CI) of 95%. Statistical significance was considered at p newborn patients critically ill, with low birth weight, low gestational age, with RDS, who need more ventilatory support will be more liable to have complications and, as consequence, the mortality will be increased. For this reason it is essential a close monitoring of this group of patients for not over supporting them in IOF, PIP and cycles, thus avoiding as far as possible, the complications of the MVA.

Minimally invasive mitral valve annuloplasty confers a long-term survival benefit compared with state-of-the-art treatment in heart failure with functional mitral regurgitation.

Science.gov (United States)

Penicka, Martin; Kotrc, Martin; Ondrus, Tomas; Mo, Yujing; Casselman, Filip; Vanderheyden, Marc; Van Camp, Guy; Van Praet, Frank; Bartunek, Jozef

2017-10-01

Clinical impact of the minimally invasive surgical mitral valve annuloplasty (MVA) of functional mitral regurgitation (FMR) in systolic heart failure on top of the state-of-the-art standards of care remains controversial. Therefore, we aimed to compare clinical outcomes of isolated MVA using the mini-invasive videothoracoscopic approach versus the state-of-the-art (CON=conservative) treatment in patients with chronic systolic heart failure and symptomatic FMR. The study population consisted of 379 patients (age 68.9±11.0years, 62.8% males) with left ventricular (LV) systolic dysfunction, symptomatic FMR and previous heart failure hospitalization. A total of 167 patients underwent undersized MVA and 212 patients were treated conservatively. A concomitant MAZE was performed in 53 (31.7%) patients. In the MVA group, the periprocedural and the 30-day mortality were 1.2% and 4.8%, respectively. During the median follow-up of 7.1years (IQR 3.5-9.8years) a total of 74 (44.3%) and 138 (65.1%) died in the MVA and the CON group, respectively (pstate-of-the-art treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Involvement of 2-C-methyl-D-erythritol-4-phosphate pathway in biosynthesis of aphidicolin-like tetracyclic diterpene of Scoparia dulcis.

Science.gov (United States)

Nkembo, Marguerite Kasidimoko; Lee, Jung-Bum; Nakagiri, Takeshi; Hayashi, Toshimitsu

2006-05-01

Specific inhibitors of the MVA pathway (pravastatin) and the MEP pathway (fosmidomycin) were used to interfere with the biosynthetic flux which leads to the production of aphidicolin-like diterpene in leaf organ cultures of Scoparia dulcis. Treatment of leaf organs with fosmidomycin resulted in dose dependent inhibition of chlorophylls, carotenoids, scopadulcic acid B (SDB) and phytol production, and no effect on sterol production was observed. In response to the pravastatin treatment, a significant decrease in sterol and perturbation of SDB production was observed.

Metabolic Profiling of Lactococcus lactis Under Different Culture Conditions

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Normah Mohd Noor

2012-07-01

Full Text Available Gas chromatography mass spectrometry (GC-MS and headspace gas chromatography mass spectrometry (HS/GC-MS were used to study metabolites produced by Lactococcus lactis subsp. cremoris MG1363 grown at a temperature of 30 °C with and without agitation at 150 rpm, and at 37 °C without agitation. It was observed that L. lactis produced more organic acids under agitation. Primary alcohols, aldehydes, ketones and polyols were identified as the corresponding trimethylsilyl (TMS derivatives, whereas amino acids and organic acids, including fatty acids, were detected through methyl chloroformate derivatization. HS analysis indicated that branched-chain methyl aldehydes, including 2-methylbutanal, 3-methylbutanal, and 2-methylpropanal are degdradation products of isoleucine, leucine or valine. Multivariate analysis (MVA using partial least squares discriminant analysis (PLS-DA revealed the major differences between treatments were due to changes of amino acids and fermentation products.

Metabolic reconstructions identify plant 3-methylglutaconyl-CoA hydratase that is crucial for branched-chain amino acid catabolism in mitochondria.

Science.gov (United States)

Latimer, Scott; Li, Yubing; Nguyen, Thuong T H; Soubeyrand, Eric; Fatihi, Abdelhak; Elowsky, Christian G; Block, Anna; Pichersky, Eran; Basset, Gilles J

2018-05-09

The proteinogenic branched-chain amino acids (BCAAs) leucine, isoleucine and valine are essential nutrients for mammals. In plants, BCAAs double as alternative energy sources when carbohydrates become limiting, the catabolism of BCAAs providing electrons to the respiratory chain and intermediates to the tricarboxylic acid cycle. Yet, the actual architecture of the degradation pathways of BCAAs is not well understood. In this study, gene network modeling in Arabidopsis and rice, and plant-prokaryote comparative genomics detected candidates for 3-methylglutaconyl-CoA hydratase (4.2.1.18), one of the missing plant enzymes of leucine catabolism. Alignments of these protein candidates sampled from various spermatophytes revealed non-homologous N-terminal extensions that are lacking in their bacterial counterparts, and green fluorescent protein-fusion experiments demonstrated that the Arabidopsis protein, product of gene At4g16800, is targeted to mitochondria. Recombinant At4g16800 catalyzed the dehydration of 3-hydroxymethylglutaryl-CoA into 3-methylglutaconyl-CoA, and displayed kinetic features similar to those of its prokaryotic homolog. When at4g16800 knockout plants were subjected to dark-induced carbon starvation, their rosette leaves displayed accelerated senescence as compared to control plants, and this phenotype was paralleled by a marked increase in the accumulation of free and total leucine, isoleucine and valine. The seeds of the at4g16800 mutant showed a similar accumulation of free BCAAs. These data suggest that 3-methylglutaconyl-CoA hydratase is not solely involved in the degradation of leucine, but is also a significant contributor to that of isoleucine and valine. Furthermore, evidence is shown that unlike the situation observed in Trypanosomatidae, leucine catabolism does not contribute to the formation of the terpenoid precursor mevalonate. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights

Posttraumatic Stress Disorder among Motor Vehicle Accident Victims

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Marina Yuabova

2013-05-01

Full Text Available Motor vehicle accidents (MVA have been a leading contributor to posttraumatic stress disorder (PTSD. Given the high rate of MVA incidents, it is of crucial importance to detect and diagnose PTSD in primary care. Assessing PTSD requires detecting and treating physiologic responses associated with MVA incidents. Responses such as elevated heart rate and blood pressure following an incident as well as psychological processes have been found to predict the likelihood of developing PTSD months or years after the occurrence. Screening for PTSD requires the implementation of multiple assessment tools to accurately detect the presence of PTSD. Clinicians chose assessment tools based on scales used to screen for anxiety, social dysfunction, somatic complaints and depression. Indeed, it cannot be overstated that clinicians must conduct early assessment and diagnosis of PTSD while evaluating the multiple factors that impact upon whether or not an individual will develop PTSD after a MVA.

Vaccination directed against the human endogenous retrovirus-K envelope protein inhibits tumor growth in a murine model system.

Science.gov (United States)

Kraus, Benjamin; Fischer, Katrin; Büchner, Sarah M; Wels, Winfried S; Löwer, Roswitha; Sliva, Katja; Schnierle, Barbara S

2013-01-01

Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer.

Middle east respiratory syndrome coronavirus spike protein delivered by modified vaccinia virus ankara efficiently induces virus-neutralizing antibodies

NARCIS (Netherlands)

F. Song (Fei); R. Fux (Robert); L.B.V. Provacia (Lisette); A. Volz (Asisa); M. Eickmann; S. Becker (Stephan); A.D.M.E. Osterhaus (Albert); B.L. Haagmans (Bart); G. Suttera (Gerd)

2013-01-01

textabstractMiddle East respiratory syndrome coronavirus (MERS-CoV) has recently emerged as a causative agent of severe respiratory disease in humans. Here, we constructed recombinant modified vaccinia virus Ankara (MVA) expressing full-length MERS-CoV spike (S) protein (MVA-MERS-S). The genetic

PTSD symptom severity and psychiatric comorbidity in recent motor vehicle accident victims: a latent class analysis.

Science.gov (United States)

Hruska, Bryce; Irish, Leah A; Pacella, Maria L; Sledjeski, Eve M; Delahanty, Douglas L

2014-10-01

We conducted a latent class analysis (LCA) on 249 recent motor vehicle accident (MVA) victims to examine subgroups that differed in posttraumatic stress disorder (PTSD) symptom severity, current major depressive disorder and alcohol/other drug use disorders (MDD/AoDs), gender, and interpersonal trauma history 6-weeks post-MVA. A 4-class model best fit the data with a resilient class displaying asymptomatic PTSD symptom levels/low levels of comorbid disorders; a mild psychopathology class displaying mild PTSD symptom severity and current MDD; a moderate psychopathology class displaying severe PTSD symptom severity and current MDD/AoDs; and a severe psychopathology class displaying extreme PTSD symptom severity and current MDD. Classes also differed with respect to gender composition and history of interpersonal trauma experience. These findings may aid in the development of targeted interventions for recent MVA victims through the identification of subgroups distinguished by different patterns of psychiatric problems experienced 6-weeks post-MVA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Changes in the use of manual vacuum aspiration for postabortion care within the public healthcare service network in Honduras.

Science.gov (United States)

Chinchilla, Ana Ligia; Flores, Ivo Flores; Morales, Alma Fabiola; de Gil, Marina Padilla

2014-07-01

Honduras is one of the 17 priority countries included in the International Federation of Gynecology and Obstetrics (FIGO) Initiative for the Prevention of Unsafe Abortion and its Consequences. The priority category enables the country to request emergency funding to acquire services or commodities that could contribute toward achieving the objectives laid out in its plan of action. These objectives include improving postabortion care by increasing the use of manual vacuum aspiration (MVA) as an outpatient procedure with minimal human and material resources. Since the Ministry of Health lacked funding, use of the emergency fund was approved for the purchase and distribution of MVA kits nationwide to ensure continuity and the hope of increasing MVA use. Eleven hospitals participating in this initiative provided data for analysis of the outcome. These data show no increase in MVA use; however, as discussed in the article, further investigation provided valuable information on the reasons behind these results. Copyright © 2014. Published by Elsevier Ireland Ltd.

A pandemic influenza H1N1 live vaccine based on modified vaccinia Ankara is highly immunogenic and protects mice in active and passive immunizations.

Directory of Open Access Journals (Sweden)

Annett Hessel

Full Text Available BACKGROUND: The development of novel influenza vaccines inducing a broad immune response is an important objective. The aim of this study was to evaluate live vaccines which induce both strong humoral and cell-mediated immune responses against the novel human pandemic H1N1 influenza virus, and to show protection in a lethal animal challenge model. METHODOLOGY/PRINCIPAL FINDINGS: For this purpose, the hemagglutinin (HA and neuraminidase (NA genes of the influenza A/California/07/2009 (H1N1 strain (CA/07 were inserted into the replication-deficient modified vaccinia Ankara (MVA virus--a safe poxviral live vector--resulting in MVA-H1-Ca and MVA-N1-Ca vectors. These live vaccines, together with an inactivated whole virus vaccine, were assessed in a lung infection model using immune competent Balb/c mice, and in a lethal challenge model using severe combined immunodeficient (SCID mice after passive serum transfer from immunized mice. Balb/c mice vaccinated with the MVA-H1-Ca virus or the inactivated vaccine were fully protected from lung infection after challenge with the influenza H1N1 wild-type strain, while the neuraminidase virus MVA-N1-Ca induced only partial protection. The live vaccines were already protective after a single dose and induced substantial amounts of neutralizing antibodies and of interferon-gamma-secreting (IFN-gamma CD4- and CD8 T-cells in lungs and spleens. In the lungs, a rapid increase of HA-specific CD4- and CD8 T cells was observed in vaccinated mice shortly after challenge with influenza swine flu virus, which probably contributes to the strong inhibition of pulmonary viral replication observed. In addition, passive transfer of antisera raised in MVA-H1-Ca vaccinated immune-competent mice protected SCID mice from lethal challenge with the CA/07 wild-type virus. CONCLUSIONS/SIGNIFICANCE: The non-replicating MVA-based H1N1 live vaccines induce a broad protective immune response and are promising vaccine candidates for

The impact of cardiac rhythm on the mitral valve area and gradient in patients with mitral stenosis.

Science.gov (United States)

Arı, Hasan; Arı, Selma; Karakuş, Alper; Camcı, Sencer; Doğanay, Kübra; Tütüncü, Ahmet; Melek, Mehmet; Bozat, Tahsin

2017-08-01

The aim of this study was to evaluate the effect of cardiac rhythm on the echocardiographic mitral valve area (MVA) and transmitral gradient calculation in relation to net atrioventricular compliance (Cn). Patients (n=22) with mild or moderate pure rheumatic mitral stenosis (MS) (MVA 1 cm2) and atrial fibrillation (AF) were evaluated. All patients underwent transthoracic electrical DC cardioversion under amiodarone treatment. Nineteen of the 22 patients were successfully converted to sinus rhythm (SR). The patients were evaluated with transthoracic echocardiography before and two to three days after DC cardioversion. In order to deal with variable R-R intervals, the measurements were averaged on five to eight consecutive beats in AF. Cn was calculated with a previously validated equation [Cn (mL/mm Hg)=1.270 x MVA/E-wave downslope]. The Cn difference between AF and SR was calculated as follows: [(AF Cn-SR Cn)/AF Cn] x 100. The percentage gradient (mean or maximal) difference between AF and SR was calculated as follows: [AF gradient (mean or maximal) - SR gradient (mean or maximal)]/[AF gradient (mean or maximal)] x 100. The MVA was lower (MVA planimetric; 1.62±0.29 vs. 1.54±0.27; p=.003, MVA PHT; 1.66±0.30 vs. 1.59±0.26; p=0.01) but transmitral gradient (mean gradient; 6.49±2.51 vs. 8.89±3.52; p=0.001, maximal gradient: 16.94±5.11 vs. 18.57±4.54; p=0.01) and Cn values (5.37±0.77 vs. 6.26±0.64; pgradient difference (mean and maximal) (Cn difference-mean gradient difference; r=0.46; p=0.05; Cn difference-maximal gradient difference; r=0.72; p=0.001). Cardiac rhythm has a significant impact on echocardiographic evaluation of MVA, transmitral gradient, and Cn in patients with MS.

Mean value analysis for polling systems

NARCIS (Netherlands)

Winands, E.M.M.; Adan, I.J.B.F.; Houtum, van G.J.J.A.N.

2005-01-01

The present paper deals with the problem of calculating mean delays in polling systems with either exhaustive or gated service. We develop a mean value analysis (MVA) to compute these delay figures. The merits of MVA are in its intrinsic simplicity and its intuitively appealing derivation. As a

Mean value analysis for polling systems

NARCIS (Netherlands)

Winands, E.M.M.; Adan, I.J.B.F.; Houtum, van G.J.J.A.N.

2006-01-01

The present paper deals with the problem of calculating mean delays in polling systems with either exhaustive or gated service. We develop a mean value analysis (MVA) to compute these delay figures. The merits of MVA are in its intrinsic simplicity and its intuitively appealing derivation. As a

Role of plastidic pyruvate dehydrogenase complex (pl. PDC) in chloroplast metabolism of spinach

International Nuclear Information System (INIS)

Schulze-Siebert, D.; Homeyer, U.; Schultz, G.

1986-01-01

Labeling experiments of chloroplasts in the light ( 14 CO 2 , 2- 14 C-pyruvate etc.) revealed that pl. PDC is predominantly involved in the synthesis of branched chain amino acids and pl. isoprenoids (carotenes, PQ, α-T). In this context, pl. phosphoglycerate mutase as missing link in the C 3 → C 2 metabolism of chloroplasts was identified by latency experiments. This indicates a direct pathway from Calvin cycle to pl. PDC. Using protoplasts, maximal rates in pl. PDC metabolism were obtained. On the other hand, mitochondrial PDC in protoplasts is mainly involved in fatty acid synthesis by known mechanism. Additionally, cytosolic-ER-isoprenoids were formed (e.g. sterols). When 14 CO 2 was simultaneously applied with unlabeled acetate to protoplasts in the light an isotopic dilution of fatty acids were found but not of pl. isoprenoids. This may indicate an partially channeling of pl. PDC and mevalonate pathway for pl. isoprenoid synthesis. Inhibitory studies with DCMU point in the same direction

Increasing Growth and Yield of Upland Rice by Application of Vesicular Arbuscular Mycorrhizae and Potassium Fertilizer

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Dedi Natawijaya

2012-01-01

Full Text Available Field experiment with a split plot design has been carried out in order to assess the growth characteristics andyields, and effectiveness of MVA upland rice which were given potassium fertilizer in two growing seasons. MVAinoculation consisted of three treatments (without MVA, Glomus sp. and Gigaspora sp. while potassium fertilizerconsisted of five levels (0, 12.5, 25, 37.5, and 50 kg ha-1 K. The results showed that plant growth variable which wasinoculated by MVA at any levels of K fertilizer was higher in the dry season than that in the wet season, whereas theopposite occurred for net assimilation rate. Potassium content of leaf tissue, shoot/root ratio, and grain weight perhill was determined and mutually dependent on genus MVA, dosages of K fertilizer, and growing season. Harvestindex and grain dry weight per hill were influenced by the growing season and the genus MVA but the effect did notdepend on each other. At all dosages of K fertilizer and any MVA genera, Gigaspora sp. inoculation was better thanthat of Glomus sp. Dry weight of grains per hill was affected by the contribution of grain content per hill, weight of1000 grains and number of productive seedlings per hill. The optimum dosage of K fertilizer in the dry season was32.4 kg ha-1 K with grain yield 3.12 Mg ha-1 for inoculation of Gigaspora sp., whereas the optimum dosage in the wetseason was 34.2 kg ha-1 K for the treatment Glomus sp. inoculation with Gigaspora sp. in the wet season did notreach dosages of optimum K fertilizer.

Calculation of Mitral Valve Area in Mitral Stenosis: Comparison of Continuity Equation and Pressure Half Time With Two-Dimensional Planimetry in Patients With and Without Associated Aortic or Mitral Regurgitation or Atrial Fibrillation

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Roya Sattarzadeh

2018-01-01

Full Text Available Accurate measurement of Mitral Valve Area (MVA is essential to determining the Mitral Stenosis (MS severity and to achieving the best management strategies for this disease. The goal of the present study is to compare mitral valve area (MVA measurement by Continuity Equation (CE and Pressure Half-Time (PHT methods with that of 2D-Planimetry (PL in patients with moderate to severe mitral stenosis (MS. This comparison also was performed in subgroups of patients with significant Aortic Insufficiency (AI, Mitral Regurgitation (MR and Atrial Fibrillation (AF. We studied 70 patients with moderate to severe MS who were referred to echocardiography clinic. MVA was determined by PL, CE and PHT methods. The agreement and correlations between MVA’s obtained from various methods were determined by kappa index, Bland-Altman analysis, and linear regression analysis. The mean values for MVA calculated by CE was 0.81 cm (±0.27 and showed good correlation with those calculated by PL (0.95 cm, ±0.26 in whole population (r=0.771, P<0.001 and MR subgroup (r=0.763, P<0.001 and normal sinus rhythm and normal valve subgroups (r=0.858, P<0.001 and r=0.867, P<0.001, respectively. But CE methods didn’t show any correlation in AF and AI subgroups. MVA measured by PHT had a good correlation with that measured by PL in whole population (r=0.770, P<0.001 and also in NSR (r=0.814, P<0.001 and normal valve subgroup (r=0.781, P<0.001. Subgroup with significant AI and those with significant MR showed moderate correlation (r=0.625, P=0.017 and r=0.595, P=0.041, respectively. Bland Altman Analysis showed that CE would estimate MVA smaller in comparison with PL in the whole population and all subgroups and PHT would estimate MVA larger in comparison with PL in the whole population and all subgroups. The mean bias for CE and PHT are 0.14 cm and -0.06 cm respectively. In patients with moderate to severe mitral stenosis, in the absence of concomitant AF, AI or MR, the accuracy

Planning for Sustainable Access to Technology: An Essential ...

African Journals Online (AJOL)

The clinic managers were pleased to be providing the improved services in accordance with new national protocols prescribing that sharp curettage services be replaced with MVA. The clinic staff worked with members of the local community to explain that MVA procedures are simple and safe and that women could now ...

Homeless Liaisons' Awareness about the Implementation of the McKinney-Vento Act

Science.gov (United States)

Wilkins, Brittany Taylor; Mullins, Mary H.; Mahan, Amber; Canfield, James P.

2016-01-01

The federal government enacted the McKinney--Vento Homeless Assistance Act (MVA) to equip schools with services to help alleviate the many barriers students experiencing homelessness face in pursuit of educational opportunities. Educational agencies use federally mandated liaisons to uphold the provisions of the MVA. Despite the homeless liaisons'…

Mevalonates, Ras and Breast Cancer

National Research Council Canada - National Science Library

White, Michael

2001-01-01

.... This selective inhibition appears to be a consequence of expression of oncogenic Ras. Here we are evaluating the ability of Fmev to selectively interfere with proliferation of breast cancer cells...

Sleep apnea-related risk of motor vehicle accidents is reduced by continuous positive airway pressure: Swedish Traffic Accident Registry data.

Science.gov (United States)

Karimi, Mahssa; Hedner, Jan; Häbel, Henrike; Nerman, Olle; Grote, Ludger

2015-03-01

Obstructive sleep apnea (OSA) is associated with an increased risk of motor vehicle accidents (MVAs). The rate of MVAs in patients suspected of having OSA was determined and the effect of continuous positive airway pressure (CPAP) was investigated. MVA rate in patients referred for OSA was compared to the rate in the general population using data from the Swedish Traffic Accident Registry (STRADA), stratified for age and calendar year. The risk factors for MVAs, using demographic and polygraphy data, and MVA rate before and after CPAP were evaluated in the patient group. Clinical sleep laboratory and population based control (n = 635,786). There were 1,478 patients, male sex 70.4%, mean age 53.6 (12.8) y. CPAP. The number of accidents (n = 74) among patients was compared with the expected number (n = 30) from a control population (STRADA). An increased MVA risk ratio of 2.45 was found among patients compared with controls (P accident risk was most prominent in the elderly patients (65-80 y, seven versus two MVAs). In patients, driving distance (km/y), EDS (Epworth Sleepiness score ≥ 16), short habitual sleep time (≤5 h/night), and use of hypnotics were associated with increased MVA risk (odds ratios 1.2, 2.1, 2.7 and 2.1, all P ≤ 0.03). CPAP use ≥ 4 h/night was associated with a reduction of MVA incidence (7.6 to 2.5 accidents/1,000 drivers/y). The MVA risk in this large cohort of unselected patients with OSA suggests a need for accurate tools to identify individuals at risk. Sleep apnea severity (e.g., apnea-hypopnea index) failed to identify patients at risk. © 2015 Associated Professional Sleep Societies, LLC.

Modified Vaccinia Virus Ankara Vector Induces Specific Cellular and Humoral Responses in the Female Reproductive Tract, the Main HIV Portal of Entry.

Science.gov (United States)

Marlin, Romain; Nugeyre, Marie-Thérèse; Tchitchek, Nicolas; Parenti, Matteo; Hocini, Hakim; Benjelloun, Fahd; Cannou, Claude; Dereuddre-Bosquet, Nathalie; Levy, Yves; Barré-Sinoussi, Françoise; Scarlatti, Gabriella; Le Grand, Roger; Menu, Elisabeth

2017-09-01

The female reproductive tract (FRT) is one of the major mucosal invasion sites for HIV-1. This site has been neglected in previous HIV-1 vaccine studies. Immune responses in the FRT after systemic vaccination remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized specific immune responses in all compartments of the FRT of nonhuman primates after systemic vaccination. Memory T cells were preferentially found in the lower tract (vagina and cervix), whereas APCs and innate lymphoid cells were mainly located in the upper tract (uterus and fallopian tubes). This compartmentalization of immune cells in the FRT was supported by transcriptomic analyses and a correlation network. Polyfunctional MVA-specific CD8 + T cells were detected in the blood, lymph nodes, vagina, cervix, uterus, and fallopian tubes. Anti-MVA IgG and IgA were detected in cervicovaginal fluid after a second vaccine dose. Thus, systemic vaccination with an MVA vector elicits cellular and Ab responses in the FRT. Copyright © 2017 by The American Association of Immunologists, Inc.

Comparison of manual vacuum aspiration and misoprostol in the management of incomplete abortion

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Gabkika Bray Madoue

2016-11-01

Full Text Available Background: Incomplete abortions can be managed expectantly, surgically and medically (using misoprostol. Expectant management is safe in places where women have access to information, appropriate care and follow-up; however, in isolated and poor areas women who come for help need an intervention. Objective: To compare the efficiency of manual vacuum aspiration (MVA and misoprostol in the treatment of incomplete abortion. Patients and method: This was a prospective study over five months from March to August 2015. All patients admitted with a diagnosis of incomplete abortion were recruited into the study. Results: 308 patients with incomplete abortion were randomized into two treatment groups - MVA (done under local anaesthesia and misoprostol (400 micrograms by the vaginal route. MVA was successfully performed for all patients. Two patients presented with anaemia. In the misoprostol group, 23 patients had vaginal bleeding, and 10 persistence of incomplete abortion. Conclusion: MVA is more effective than misoprostol with less complications in the treatment of incomplete abortion when it is done by a trained person.

Metabolomics Analysis of the Toxic Effects of the Production of Lycopene and Its Precursors

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April M. Miguez

2018-05-01

Full Text Available Using cells as microbial factories enables highly specific production of chemicals with many advantages over chemical syntheses. A number of exciting new applications of this approach are in the area of precision metabolic engineering, which focuses on improving the specificity of target production. In recent work, we have used precision metabolic engineering to design lycopene-producing Escherichia coli for use as a low-cost diagnostic biosensor. To increase precursor availability and thus the rate of lycopene production, we heterologously expressed the mevalonate pathway. We found that simultaneous induction of these pathways increases lycopene production, but induction of the mevalonate pathway before induction of the lycopene pathway decreases both lycopene production and growth rate. Here, we aim to characterize the metabolic changes the cells may be undergoing during expression of either or both of these heterologous pathways. After establishing an improved method for quenching E. coli for metabolomics analysis, we used two-dimensional gas chromatography coupled to mass spectrometry (GCxGC-MS to characterize the metabolomic profile of our lycopene-producing strains in growth conditions characteristic of our biosensor application. We found that the metabolic impacts of producing low, non-toxic levels of lycopene are of much smaller magnitude than the typical metabolic changes inherent to batch growth. We then used metabolomics to study differences in metabolism caused by the time of mevalonate pathway induction and the presence of the lycopene biosynthesis genes. We found that overnight induction of the mevalonate pathway was toxic to cells, but that the cells could recover if the lycopene pathway was not also heterologously expressed. The two pathways appeared to have an antagonistic metabolic effect that was clearly reflected in the cells’ metabolic profiles. The metabolites homocysteine and homoserine exhibited particularly interesting

Analysis of variola and vaccinia virus neutralization assays for smallpox vaccines.

Science.gov (United States)

Hughes, Christine M; Newman, Frances K; Davidson, Whitni B; Olson, Victoria A; Smith, Scott K; Holman, Robert C; Yan, Lihan; Frey, Sharon E; Belshe, Robert B; Karem, Kevin L; Damon, Inger K

2012-07-01

Possible smallpox reemergence drives research for third-generation vaccines that effectively neutralize variola virus. A comparison of neutralization assays using different substrates, variola and vaccinia (Dryvax and modified vaccinia Ankara [MVA]), showed significantly different 90% neutralization titers; Dryvax underestimated while MVA overestimated variola neutralization. Third-generation vaccines may rely upon neutralization as a correlate of protection.

Vaccination directed against the human endogenous retrovirus-K (HERV-K) gag protein slows HERV-K gag expressing cell growth in a murine model system.

Science.gov (United States)

Kraus, Benjamin; Fischer, Katrin; Sliva, Katja; Schnierle, Barbara S

2014-03-26

Human endogenous retroviruses (HERVs) are remnants of ancestral infections and chromosomally integrated in all cells of an individual, are transmitted only vertically and are defective in viral replication. However enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed inter-alia in HIV-infected individuals and tumor patients. Therefore HERV-K might serve as a tumor-specific antigen or even as a constant target for the development of an HIV vaccine. To verify our hypothesis, we tested the immunogenicity of HERV-K Gag by using a recombinant vaccinia virus (MVA-HKcon) expressing the HERV-K Gag protein and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) and the HERV-K Gag protein (RLZ-HKGag cells). Subcutaneous application of RLZ-HKGag cells into syngenic BALB/c mice resulted in the formation of local tumors in MVA vaccinated mice. MVA-HKcon vaccination reduced the tumor growth. Furthermore, intravenous injection of RLZ-HKGag cells led to the formation of pulmonary metastases. Vaccination of tumor-bearing mice with MVA-HKcon drastically reduced the number of pulmonary RLZ-HKGag tumor nodules compared to vaccination with wild-type MVA. The data demonstrate that HERV-K Gag is a useful target for vaccine development and might offer new treatment opportunities for cancer patients.

Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone

International Nuclear Information System (INIS)

Johnson, Timothy E.; Zhang, Xiaohua; Bleicher, Kimberly B.; Dysart, Gary; Loughlin, Amy F.; Schaefer, William H.; Umbenhauer, Diane R.

2004-01-01

Statins are widely used to treat lipid disorders. These drugs are safe and well tolerated; however, in <1% of patients, myopathy and/or rhabdomyolysis can develop. To better understand the mechanism of statin-induced myopathy, we examined the ability of structurally distinct statins to induce apoptosis in an optimized rat myotube model. Compound A (a lactone) and Cerivastatin (an open acid) induced apoptosis, as measured by TUNEL and active caspase 3 staining, in a concentration- and time-dependent manner. In contrast, an epimer of Compound A (Compound B) exhibited a much weaker apoptotic response. Statin-induced apoptosis was completely prevented by mevalonate or geranylgeraniol, but not by farnesol. Zaragozic acid A, a squalene synthase inhibitor, caused no apoptosis on its own and had no effect on Compound-A-induced myotoxicity, suggesting the apoptosis was not a result of cholesterol synthesis inhibition. The geranylgeranyl transferase inhibitors GGTI-2133 and GGTI-2147 caused apoptosis in myotubes; the farnesyl transferase inhibitor FTI-277 exhibited a much weaker effect. In addition, the prenylation of rap1a, a geranylgeranylated protein, was inhibited by Compound A in myotubes at concentrations that induced apoptosis. A similar statin-induced apoptosis profile was seen in human myotube cultures but primary rat hepatocytes were about 200-fold more resistant to statin-induced apoptosis. Although the statin-induced hepatotoxicity could be attenuated with mevalonate, no effect was found with either geranylgeraniol or farnesol. In studies assessing ubiquinone levels after statin treatment in rat and human myotubes, there was no correlation between ubiquinone levels and apoptosis. Taken together, these observations suggest that statins cause apoptosis in myotube cultures in part by inhibiting the geranylgeranylation of proteins, but not by suppressing ubiquinone concentration. Furthermore, the data from primary hepatocytes suggests a cell-type differential

Simvastatin Inhibits IL-5-Induced Chemotaxis and CCR3 Expression of HL-60-Derived and Human Primary Eosinophils.

Science.gov (United States)

Fu, Chia-Hsiang; Tsai, Wan-Chun; Lee, Ta-Jen; Huang, Chi-Che; Chang, Po-Hung; Su Pang, Jong-Hwei

2016-01-01

IL-5-induced chemotaxis of eosinophils is an important feature of allergic airway inflammatory diseases. Simvastatin, a lipid lowering agent, has been shown to exhibit anti-inflammatory and anti-allergic effects. Our aim was to investigate the effect of simvastatin on IL-5-induced eosinophil chemotaxis and its regulatory mechanisms. Eosinophils were derived by treating HL-60 clone 15 (HC15) cells with butyric acid (BA) in an alkaline condition or through direct isolation from human peripheral blood. The expressions of CC chemokine receptor 3 (CCR3) and interleukin (IL)-5 receptors (IL5Rα and β) were analyzed using RT/real-time PCR. The granular proteins were stained using fast green. Eotaxin-induced chemotaxis was measured using a transwell migration assay. CCR3 protein expression was revealed by immunocytochemistry. An animal model of allergic rhinitis was established by challenging Sprague-Dawley® rats repeatedly with ovalbumin. Butyric acid significantly increased the expression of IL5Rα and IL5Rβ, CCR3 and granular proteins in HC15 cells, indicating the maturation of eosinophils (BA-E cells). IL-5 further enhanced the CCR3 expression at both the mRNA and protein levels and the eotaxin-induced chemotaxis of BA-E cells. Simvastatin inhibited the effects of IL-5 on BA-E cells, but not in the presence of mevalonate. Similar results were also exhibited in human primary eosinophils. In vivo animal studies further confirmed that oral simvastatin could significantly suppress the infiltration of eosinophils into turbinate tissues of allergic rats. Therefore, simvastatin was demonstrated to inhibit IL-5-induced CCR3 expression and chemotaxis of eosinophils mediated via the mevalonate pathway. We confirmed that simvastatin also reduced eosinophilic infiltration in allergic rhinitis.

Interacción micorriza vesiculo-arbuscular, Rhizobium leguminosa en un oxisol de los Llanos Orientales de Colombia

Directory of Open Access Journals (Sweden)

Satizabal E. Jorge H.

1987-03-01

Full Text Available En los dos primeros trabajos (la y lb, se evaluó la interacción entre cepas seleccionadas de Rhizobium (apropiadas para la leguminosa forrajera tropical Centrosema macrocarpum y especies (Entrophospora colombiana, Acaulospora longula, Glomus manihotis de micorriza vesiculo arbuscular (MVA, en un suelo esterilizado, fijador de P. Los experimentos se diferenciaron por las fuentes de P utilizadas. Por su mayor producción de materia seca, absorción de minerales, nodulación y infección por MVA, se destacaron las plantas inoculadas con cuales quiera de las cepas de FIlizobiumy Glomus manihotis (Experimento la o Acaulospora longula (Experimento lb. En la tercera investigación (Experimento II, se evalúo en Centrosema la interacción MVA, Rhizobiumo N-químico (niveles equivalentes a 0, 30,55, 105,0 + Rhiz. y 30 + Rhiz. kg N ha-1 y dosis de P (0, 20, 40 y 80 kg ha-1. Es aconsejable aplicar pequeñas dosis (30 kg ha-1 de N al momento de la siembra e inocular con Rhizobium. Plantas inoculadas con MVA presentaron su óptimo crecimiento con 40 kg P ha-1. Dosis de 80 kg P ha-1 favoreció la eficiencia de la bacteria más no la del hongo.In the first two works (la and lb we evaluated the interation between selected stumps of Rhizobium (appropiate for the tropical forage legumes Centrosema macrocarpum and species (Entrophospora colombiana, Acaulospora longula, Glomus manihotis of vesicular-arbuscular mycorrhiza (MVA, in a sterelize soil fixer of P. The two experiments are different because we used different P sources. For the best production of dry matter, absorption of minerals, nodulation and infection for MVA; rebounded the plants with the inoculation with any of the Rhizobium´s stumps and Glomus manihotis (Experiment la of Acaulospora longula (Experiment lb. In the third investigation (Experiment II we evaluated in Centrosema the interaction MVA. Rhizobium and chemical N (levels equivalent to 0,30. 55, 105, O + Rhizobium and 30 + Rhizobium kg N ha

Simvastatin Inhibits Goblet Cell Hyperplasia and Lung Arginase in a Mouse Model of Allergic Asthma: A Novel Treatment for Airway Remodeling?

Science.gov (United States)

Zeki, Amir A.; Bratt, Jennifer M.; Rabowsky, Michelle; Last, Jerold A.; Kenyon, Nicholas J.

2010-01-01

Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function, and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. The statins are cholesterol-lowering drugs that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting step of cholesterol biosynthesis in the mevalonate pathway. These drugs have been associated with improved respiratory health and ongoing clinical trials are testing their therapeutic potential in asthma. We hypothesized that simvastatin treatment of ovalbumin-exposed mice would attenuate early features of airway remodeling, by a mevalonate-dependent mechanism. BALB/c mice were initially sensitized to ovalbumin, and then exposed to 1% ovalbumin aerosol for 2 weeks after sensitization for a total of six exposures. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) were injected intraperitoneally before each ovalbumin exposure. Treatment with simvastatin attenuated goblet cell hyperplasia, arginase-1 protein expression, and total arginase enzyme activity, but did not alter airway hydroxyproline content or transforming growth factor-β1. Inhibition of goblet cell hyperplasia by simvastatin was mevalonate-dependent. No appreciable changes to airway smooth muscle cells were observed in any of the control or treatment groups. In conclusion, in an acute mouse model of allergic asthma, simvastatin inhibited early hallmarks of airway remodeling, indicators that can lead to airway thickening and fibrosis. Statins are potentially novel treatments for airway remodeling in asthma. Further studies utilizing sub-chronic or chronic allergen exposure models are needed to extend these initial findings. PMID:21078495

Morphologic and Biochemical Changes in Dogs After Portacaval Shunt Plus Bile Fistula or Ileal Bypass: Failure of Bile Fistula or Ileal Bypass to Prevent Hepatocyte Atrophy

Science.gov (United States)

Thompson, Jon S.; Porter, Kendrick A.; Hayashida, Nobuo; McNamara, Donald J.; Parker, Thomas S.; Russell, William J. I.; Francavilla, Antonio; Starzl, Thomas E.

2010-01-01

External biliary fistula (BF) or ileal bypass (IB) was performed in dogs at the time of or 2 weeks after portacaval shunt (PCS). The pathologic changes in the dog livers 2 to 4 weeks later were compared to those caused by PCS alone. Histopathologic differences between PCS alone vs. PCS plus BF or IB could not be found. Thus, the experiments did not confirm recent observations by others in rats that BF prevents or reverses the hepatic injury of PCS. As estimated by plasma mevalonic acid determinations, the increase in hepatic cholesterol synthesis that is characteristic after BF or IB was suppressed in animals with PCS. BF and IB reduced but did not eliminate the postprandial elevation in serum bile acid that occurs after PCS. The findings have possible relevance in planning the treatment of patients with familial hypercholesterolemia with the combined use of PCS and IB. PMID:6862371

Zeatin is indispensable for the G2-M transition in tobacco BY-2 cells.

Science.gov (United States)

Laureys, F; Dewitte, W; Witters, E; Van Montagu, M; Inzé, D; Van Onckelen, H

1998-04-10

The importance of N6-isoprenoid cytokinins in the G2-M transition of Nicotiana tabacum BY-2 cells was investigated. Both cytokinin biosynthesis and entry in mitosis were partially blocked by application at early or late G2 of lovastatin (10 microM), an inhibitor of mevalonic acid synthesis. LC-MS/MS quantification of endogenous cytokinins proved that lovastatin affects cytokinin biosynthesis by inhibiting HMG-CoA reductase. Out of eight different aminopurines and a synthetic auxin tested for their ability to override lovastatin inhibition of mitosis, only zeatin was active. Our data point to a key role for a well-defined cytokinin (here, zeatin) in the G2-M transition of tobacco BY-2 cells.

Trauma history characteristics and subsequent PTSD symptoms in motor vehicle accident victims.

Science.gov (United States)

Irish, Leah; Ostrowski, Sarah A; Fallon, William; Spoonster, Eileen; Dulmen, Manfred van; Sledjeski, Eve M; Delahanty, Douglas L

2008-08-01

The present study examined the relationship between trauma history characteristics (number and type of traumas, age at first trauma, and subjective responses to prior traumas) and the development of posttraumatic stress disorder (PTSD) symptoms following a motor vehicle accident (MVA). One hundred eighty-eight adult MVA victims provided information about prior traumatization and were evaluated for PTSD symptoms 6 weeks and one year following the MVA. Results indicated that after controlling for demographics and depression, prior trauma history characteristics accounted for a small, but significant amount of the variance in PTSD symptoms. Distress from prior trauma and number of types of prior traumas were the most meaningful trauma history predictors. Results encourage further evaluation of trauma history as a multifaceted construct.

Reduction of Radiation-Induced Changes in Biophysical Properties of Erythrocytes

International Nuclear Information System (INIS)

El-Marakby, S.M.A.

2014-01-01

The increase in uses of nuclear technologies in power production, medical and industrial applications enhanced the probability of accidental radiation exposure to occupational workers, patients and public, thereafter increasing hazardous health effects. In comparison with planned radiation exposure during diagnosis and therapy, the management of accidental radiation exposure is relatively complicated due to uncertainties in dose, duration, organs involved in radiation exposure. Although radiation accidents are not common, human error, failure to follow safety precautions and inadequate control and regulation of radiation sources have led to deaths and significant exposures among workers and members of the public. Treatment of the victim in this case needs information and measurements that may take time in order to determine the suitable therapeutic strategy for its case. However, after the event of the radiation accident, it will be important to provide an agent that would mitigate the effects of exposure to ionizing radiation and can promote or increase the efficiency of the treatment. Ideally this agent would be long-lasting, be easily administered (preferably orally) and possesses low toxicity. Development of agents for prophylaxis, mitigation and treatment of radiation injury is an important task for radiological studies. The aim of the present work is to study the prophylactic and mitigation effect of poly-MVA (a dietary supplement of Palladiumlipoic acid nano-complex) against acute whole body gamma irradiation through measurements of biophysical changes in blood erythrocytes of rats. Adult male rats were exposed to 6 Gy single dose from Cs- 137 source. The animals received daily oral administration of 2ml/Kg body weight of poly-MVA with three different time intervals. The prophylactic effect was examined by two modes of administration: first mode was uptake of poly-MVA for two weeks before irradiation then the administration was stopped and the second animal

Superconducting generator technology--an overview

International Nuclear Information System (INIS)

Edmonda, J.S.

1979-01-01

Application of superconducting technology to field windings of large ac generators provides virtually unlimited field capability without incurring resistive losses in the winding. Several small-scale superconducting generators have been built and tested demonstrating the feasibility of such concepts. For machines of much larger capacity, conceptual designs for 300 Mva and 1200 Mva have been completed. The development of a 300 Mva generator is projected. Designed, engineered and fabricated as a turbo generator, the superconducting machine is to be installed in a power plant, tested and operated in concert with a prime mover, the steam generator and the auxiliary support systems of the power plant. This will provide answers to the viability of operating a superconducting machine and its cryogenic handling systems in a full time, demanding environment. 21 refs

Dose-dependent dual effects of cholesterol and desmosterol on J774 macrophage proliferation

International Nuclear Information System (INIS)

Rodriguez-Acebes, Sara; Cueva, Paloma de la; Ferruelo, Antonio J.; Fernandez-Hernando, Carlos; Lasuncion, Miguel A.; Martinez-Botas, Javier; Gomez-Coronado, Diego

2008-01-01

We addressed the ability of native, oxidized and acetylated low-density lipoproteins (nLDL, oxLDL and acLDL, respectively) and desmosterol to act as sources of sterol for the proliferation of J774A.1 macrophages. Treatment with 0.5 μM lovastatin and lipoprotein-deficient serum suppressed cell proliferation. This inhibition was effectively prevented by nLDL, but only to a lesser extent by oxLDL. AcLDL, despite its ability to deliver a higher amount of cholesterol to J774 macrophages than the other LDLs, was dependent on mevalonate supply to sustain cell proliferation. Similarly, exogenous desmosterol, which is not converted into cholesterol in J774 cells, required the simultaneous addition of mevalonate to support optimal cell growth. Expression of hydroxymethyl glutaryl coenzyme A reductase mRNA was potently down-regulated by acLDL and exogenous desmosterol, but the effect was weaker with other sterol sources. We conclude that nLDL is more efficient than modified LDL in sustaining macrophage proliferation. Despite the requirement of cholesterol or desmosterol for J774 cell proliferation, excessive provision of either sterol limits mevalonate availability, thus suppressing cell proliferation.

Dose-dependent dual effects of cholesterol and desmosterol on J774 macrophage proliferation

Energy Technology Data Exchange (ETDEWEB)

Rodriguez-Acebes, Sara [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain); Cueva, Paloma de la; Ferruelo, Antonio J; Fernandez-Hernando, Carlos [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); Lasuncion, Miguel A [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain); Departamento de Bioquimica y Biologia Molecular, Universidad de Alcala, Alcala de Henares (Spain); Martinez-Botas, Javier [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain); Gomez-Coronado, Diego [Servicio de Bioquimica-Investigacion, Hospital Ramon y Cajal, Carretera de Colmenar, km 9, 28034 Madrid (Spain); CIBER de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid (Spain)], E-mail: diego.gomez@hrc.es

2008-12-12

We addressed the ability of native, oxidized and acetylated low-density lipoproteins (nLDL, oxLDL and acLDL, respectively) and desmosterol to act as sources of sterol for the proliferation of J774A.1 macrophages. Treatment with 0.5 {mu}M lovastatin and lipoprotein-deficient serum suppressed cell proliferation. This inhibition was effectively prevented by nLDL, but only to a lesser extent by oxLDL. AcLDL, despite its ability to deliver a higher amount of cholesterol to J774 macrophages than the other LDLs, was dependent on mevalonate supply to sustain cell proliferation. Similarly, exogenous desmosterol, which is not converted into cholesterol in J774 cells, required the simultaneous addition of mevalonate to support optimal cell growth. Expression of hydroxymethyl glutaryl coenzyme A reductase mRNA was potently down-regulated by acLDL and exogenous desmosterol, but the effect was weaker with other sterol sources. We conclude that nLDL is more efficient than modified LDL in sustaining macrophage proliferation. Despite the requirement of cholesterol or desmosterol for J774 cell proliferation, excessive provision of either sterol limits mevalonate availability, thus suppressing cell proliferation.

Development of a novel, guinea pig-specific IFN-γ ELISPOT assay and characterization of guinea pig cytomegalovirus GP83-specific cellular immune responses following immunization with a modified vaccinia virus Ankara (MVA)-vectored GP83 vaccine.

Science.gov (United States)

Gillis, Peter A; Hernandez-Alvarado, Nelmary; Gnanandarajah, Josephine S; Wussow, Felix; Diamond, Don J; Schleiss, Mark R

2014-06-30

The guinea pig (Cavia porcellus) provides a useful animal model for studying the pathogenesis of many infectious diseases, and for preclinical evaluation of vaccines. However, guinea pig models are limited by the lack of immunological reagents required for characterization and quantification of antigen-specific T cell responses. To address this deficiency, an enzyme-linked immunospot (ELISPOT) assay for guinea pig interferon (IFN)-γ was developed to measure antigen/epitope-specific T cell responses to guinea pig cytomegalovirus (GPCMV) vaccines. Using splenocytes harvested from animals vaccinated with a modified vaccinia virus Ankara (MVA) vector encoding the GPCMV GP83 (homolog of human CMV pp65 [gpUL83]) protein, we were able to enumerate and map antigen-specific responses, both in vaccinated as well as GPCMV-infected animals, using a panel of GP83-specific peptides. Several potential immunodominant GP83-specific peptides were identified, including one epitope, LGIVHFFDN, that was noted in all guinea pigs that had a detectable CD8+ response to GP83. Development of a guinea pig IFN-γ ELISPOT should be useful in characterization of additional T cell-specific responses to GPCMV, as well as other pathogens. This information in turn can help focus future experimental evaluation of immunization strategies, both for GPCMV as well as for other vaccine-preventable illnesses studied in the guinea pig model. Copyright © 2014 Elsevier Ltd. All rights reserved.

Increased population density of neurosurgeons associated with decreased risk of death from motor vehicle accidents in the United States.

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Desai, Atman; Bekelis, Kimon; Zhao, Wenyan; Ball, Perry A

2012-09-01

Motor vehicle accidents (MVAs) are a leading cause of death and disability in young people. Given that a major cause of death from MVAs is traumatic brain injury, and neurosurgeons hold special expertise in this area relative to other members of a trauma team, the authors hypothesized that neurosurgeon population density would be related to reduced mortality from MVAs across US counties. The Area Resource File (2009-2010), a national health resource information database, was retrospectively analyzed. The primary outcome variable was the 3-year (2004-2006) average in MVA deaths per million population for each county. The primary independent variable was the density of neurosurgeons per million population in the year 2006. Multiple regression analysis was performed, adjusting for population density of general practitioners, urbanicity of the county, and socioeconomic status of the county. The median number of annual MVA deaths per million population, in the 3141 counties analyzed, was 226 (interquartile range [IQR] 151-323). The median number of neurosurgeons per million population was 0 (IQR 0-0), while the median number of general practitioners per million population was 274 (IQR 175-410). Using an unadjusted analysis, each increase of 1 neurosurgeon per million population was associated with 1.90 fewer MVA deaths per million population (p neurosurgeon per million population was associated with 1.01 fewer MVA deaths per million population (p neurosurgeons is associated with a significant reduction in deaths from MVAs, a major cause of death nationally. This suggests that the availability of local neurosurgeons is an important factor in the overall likelihood of survival from an MVA, and therefore indicates the importance of promoting neurosurgical education and practice throughout the country.

THE INFLUENCE OF CORPORATE FINANCIAL PERFORMANCE ON SHARE RETURN

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Ghulam Nurul Huda

2015-09-01

Full Text Available This study was conducted to examine the effect of financial performances of Economic Value Added (EVA, Market Value Added (MVA as well as financial ratios (Fixed Asset Turnover, Return on Investment, Debt to Equity Ratio, Price to Book Value, Total Asset Turnover on Stock Return. This study used the data of six representative palm oil companies which were listed in Indonesia Stock Exchange. The analysis models that were used included three multiple regression equations for EVA, MVA and Stock Return. The results indicate that DER significantly influences EVA and PBV, and TATO significantly influences MVA. Return Shares are significantly only affected by EVA. The company's fundamentals, especially EVA, PBV, TATO and DER were used by investors to predict the Stock Return in Indonesia Stock Exchange in 2009–2014 period. This study confirmed the previous studies that these variables are involved on regression model to predict the Stock Return. The results of the analysis of the company's financial performance with EVA and MVA and financial fundamental variables provide a better alternative picture on the achievement of the company so that the benefits in investing in the palm oil business in Indonesia can be maximally managed.Keywords: Indonesia Stock Exchange, investor, market, multiple regression, stock

Vasospastic angina and microvascular angina are differentially influenced by PON1 A632G polymorphism in the Japanese.

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Mashiba, Junko; Koike, George; Kamiunten, Hitoshi; Ikeda, Manami; Sunagawa, Kenji

2005-12-01

Ethnicity and smoking are well-known risk factors for the pathogenesis of coronary vasospasm. Oxidative stress induced by smoking plays a crucial role in coronary vasospasm, but is not enough to account for the pathogenesis of coronary vasospasm, indicating that genetic factors are strongly involved. The study group comprised 162 vasospastic angina patients (VSAs), 61 microvascular angina patients (MVAs) and 61 non-responders (NRs) diagnosed by acetylcholine provocation test. Four polymorphisms of the oxidative stress related genes, cytochrome b-245, alpha polypeptide gene (CYBA) C242T and A640G, paraoxonase 1 gene (PON1) A632G, phospholipase A2 group VII gene (PLA2G7) G994T were genotyped. Allele frequency of PON1 632-G was significantly higher in both the VSA with dominant fashion and the MVA with recessive fashion compared with NR. This association was strongly influenced by gender in the MVA only. There were no significant associations between the other polymorphisms and coronary vasospasm. In addition, the allele frequency of PON1 632-G in the Japanese was higher than in Caucasians. There was a significant association between PON1 A632G polymorphism and MVA as well as VSA, but the impact of this on VSA and MVA is different in the Japanese.

Contrast-enhanced ultrasonography of hepatocellular carcinoma: Correlation between quantitative parameters and arteries in neoangiogenesis or sinusoidal capillarization

International Nuclear Information System (INIS)

Pei Xiaoqing; Liu Longzhong; Zheng Wei; Cai Muyan; Han Feng; He Jiehua; Li Anhua; Chen Minshan

2012-01-01

Objective: The quantitative parameters in contrast-enhanced ultrasonography-time–intensity curve of hepatocellular carcinoma (HCC) were studied to explore their potential importance in monitoring the effects of anti-angiogenic therapy for HCC. Methods: 115 HCC patients were studied with contrast-enhanced ultrasonography-time–intensity curve (CEUS-TIC) and with immunohistochemical analysis of tissue sections. The CEUS images were analyzed off-line to obtained quantitative parameters including maximum of intensity (IMAX), rise time (RT), time to peak (TTP), mean transit time (mTT), rise slope (RS), and washout time (WT). Monoclonal antibodies specific for smooth muscle actin and anti-CD34 were used to observe unpaired arteries (UAs) and microvessel area (MVA) of sinusoidal capillarization, respectively. The UAs and MVA of 82 HCC cases were successfully stained. Results: The number of UAs had moderate correlation with RT (r = −0.446), TTP (r = −0.432), and RS (r = 0.431) (P < 0.05), and it had mild correlation with IMAX (r = 0.303) and WT (r = 0.285) (P < 0.05). MVA of sinusoidal capillarization had no correlation with perfusion parameters. Conclusion: Quantitative CEUS-TIC parameters reflecting hemodynamics of tumors are correlated with UAs, but not with MVA, and they might be used to monitor the effects of anti-angiogenic therapy on HCC.

The intracellular cholesterol landscape: dynamic integrator of the immune response

Science.gov (United States)

Fessler, Michael B.

2016-01-01

Cholesterol has typically been considered an exogenous, disease-related factor in immunity; however, recent literature suggests that a paradigm shift is in order. Sterols are now recognized to ligate several immune receptors. Altered flux through the mevalonic acid synthesis pathway also appears to be a required event in the antiviral interferon response of macrophages and in the activation, proliferation, and differentiation of T cells. In this review, evidence is discussed that suggests an intrinsic, ‘professional’ role for sterols and oxysterols in macrophage and T cell immunity. Host defense may have been the original selection pressure behind the development of mechanisms for intracellular cholesterol homeostasis. Functional coupling between sterol metabolism and immunity has fundamental implications for health and disease. PMID:27692616

INDICATORI DE PERFORMANŢĂ ÎN CONTEXTUL REGLEMENTĂRILOR CONTABILE INTERNAŢIONALE

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Neculai Tabara

2007-05-01

Full Text Available Performance Accounting and Analysis provides metrics definitions, compliance tracking, costaccounting by task order, functional area for full-cost accounting with reporting tools for management, alongwith a complete array of data-extraction methods. The comprehensive income is a project which addressesbroadly the issues related to the display and presentation in the financial statements of all recognized changes inassets and liabilities from transactions or other events except those related to transactions with owners asowners (sometimes called comprehensive income. The other two measures of financial performance that arebeing applied increasingly in investor-owned and not-for-profit healthcare organizations are market valueadded (MVA and economic value added (EVA. Unlike traditional profitability measures, both MVA and EVAmeasures take into account the cost of equity capital. MVA is most appropriate for investor-owned healthcareorganizations and EVA is the best measure for not-for-profit organizations.

The investment in scent: time-resolved metabolic processes in developing volatile-producing Nigella sativa L. seeds.

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Wentao Xue

Full Text Available The interplay of processes in central and specialized metabolisms during seed development of Nigella sativa L. was studied by using a high-throughput metabolomics technology and network-based analysis. Two major metabolic shifts were identified during seed development: the first was characterized by the accumulation of storage lipids (estimated as total fatty acids and N-compounds, and the second by the biosynthesis of volatile organic compounds (VOCs and a 30% average decrease in total fatty acids. Network-based analysis identified coordinated metabolic processes during development and demonstrated the presence of five network communities. Enrichment analysis indicated that different compound classes, such as sugars, amino acids, and fatty acids, are largely separated and over-represented in certain communities. One community displayed several terpenoids and the central metabolites, shikimate derived amino acids, raffinose, xylitol and glycerol-3-phosphate. The latter are related to precursors of the mevalonate-independent pathway for VOC production in the plastid; also plastidial fatty acid 18∶3n-3 abundant in "green" seeds grouped with several major terpenes. The findings highlight the interplay between the components of central metabolism and the VOCs. The developmental regulation of Nigella seed metabolism during seed maturation suggests a substantial re-allocation of carbon from the breakdown of fatty acids and from N-compounds, probably towards the biosynthesis of VOCs.

Genetics Home Reference: mevalonate kinase deficiency

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... cellular functions, such as cell growth, cell maturation (differentiation), formation of the cell's structural framework (the cytoskeleton), gene activity (expression), and protein production and modification. Most MVK gene mutations that cause ...

Isoprenoid biosynthesis and mevalonate kinase deficiency

NARCIS (Netherlands)

Henneman, L.

2011-01-01

Mevalonaat Kinase Deficiëntie (MKD) is een aangeboren ziekte geassocieerd met heftige koortsaanvallen die drie tot vier dagen aanhouden en gepaard gaan met koude rillingen, gewrichtsklachten, huiduitslag, hoofdpijn, duizeligheid, buikpijn, braken en diarree. De koortsaanvallen treden gemiddeld eens

In vitro toxicology of respirable Montserrat volcanic ash.

Science.gov (United States)

Wilson, M R; Stone, V; Cullen, R T; Searl, A; Maynard, R L; Donaldson, K

2000-11-01

In July 1995 the Soufriere Hills volcano on the island of Montserrat began to erupt. Preliminary reports showed that the ash contained a substantial respirable component and a large percentage of the toxic silica polymorph, cristobalite. In this study the cytotoxicity of three respirable Montserrat volcanic ash (MVA) samples was investigated: M1 from a single explosive event, M2 accumulated ash predominantly derived from pyroclastic flows, and M3 from a single pyroclastic flow. These were compared with the relatively inert dust TiO(2) and the known toxic quartz dust, DQ12. Surface area of the particles was measured with the Brunauer, Emmet, and Teller (BET) adsorption method and cristobalite content of MVA was determined by x ray diffraction (XRD). After exposure to particles, the metabolic competence of the epithelial cell line A549 was assessed to determine cytotoxic effects. The ability of the particles to induce sheep blood erythrocyte haemolysis was used to assess surface reactivity. Treatment with either MVA, quartz, or titanium dioxide decreased A549 epithelial cell metabolic competence as measured by ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On addition of mannitol, the cytotoxic effect was significantly less with M1, quartz, and TiO(2). All MVA samples induced a dose dependent increase in haemolysis, which, although less than the haemolysis induced by quartz, was significantly greater than that induced by TiO(2). Addition of mannitol and superoxide dismutase (SOD) significantly reduced the haemolytic activity only of M1, but not M2 or M3, the samples derived from predominantly pyroclastic flow events. Neither the cristobalite content nor the surface area of the MVA samples correlated with observed in vitro reactivity. A role for reactive oxygen species could only be shown in the cytotoxicity of M1, which was the only sample derived from a purely explosive event. These results suggest that in general the

Power system for tokamak fusion experiments. Motor generator with flywheel effect

International Nuclear Information System (INIS)

Miyachi, Kengo

1997-01-01

JT-60 requires an enormous electric power pulse about 1,300 MVA periodically for its plasma initiation, containment and heating. JT-60 could not receive all electric power from a commercial line for plasma experiment except about 160 MVA because the 275 kV commercial line has some limitations. Therefore JT-60 needs huge electric power sources. The power supply system of JT-60 has 3 motor generators (MG). The total capacity of MG is 1,115 MVA that consists of a toroidal MG (TMG), poloidal MG (PMG) and Heating power supply MG (HMG), and each MG has a huge flywheel effect. For example, TMG has a 4.02 GJ energy yield that consists of 6 disk flywheel. The total weight of flywheel of TMG is 650 ton. This report describes the structure, operating system, and maintenance history of 3 types of MG. (author)

Treatment algorithm based on the multivariate survival analyses in patients with advanced hepatocellular carcinoma treated with trans-arterial chemoembolization.

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Hasmukh J Prajapati

Full Text Available To develop the treatment algorithm from multivariate survival analyses (MVA in patients with Barcelona clinic liver cancer (BCLC C (advanced Hepatocellular carcinoma (HCC patients treated with Trans-arterial Chemoembolization (TACE.Consecutive unresectable and non-tranplantable patients with advanced HCC, who received DEB TACE were studied. A total of 238 patients (mean age, 62.4yrs was included in the study. Survivals were analyzed according to different parameters from the time of the 1st DEB TACE. Kaplan Meier and Cox Proportional Hazard model were used for survival analysis. The SS was constructed from MVA and named BCLC C HCC Prognostic (BCHP staging system (SS.Overall median survival (OS was 16.2 months. In HCC patients with venous thrombosis (VT of large vein [main portal vein (PV, right or left PV, hepatic vein, inferior vena cava] (22.7% versus small vein (segmental/subsegmental PV (9.7% versus no VT had OSs of 6.4 months versus 20 months versus 22.8 months respectively (p<0.001. On MVA, the significant independent prognostic factors (PFs of survival were CP class, eastern cooperative oncology group (ECOG performance status (PS, single HCC<5 cm, site of VT, metastases, serum creatinine and serum alpha-feto protein. Based on these PFs, the BCHP staging system was constructed. The OSs of stages I, II and III were 28.4 months, 11.8 months and 2.4 months accordingly (p<0.001. The treatment plan was proposed according to the different stages.On MVA of patients with advanced HCC treated with TACE, significant independent prognostic factors (PFs of survival were CP class, ECOG PS, single HCC<5 cm or others, site of VT, metastases, serum creatinine and serum alpha-feto protein. New BCHP SS was proposed based on MVA data to identify the suitable advanced HCC patients for TACE treatments.

Modified vaccinia virus Ankara expressing the hemagglutinin of pandemic (H1N1) 2009 virus induces cross-protective immunity against Eurasian 'avian-like' H1N1 swine viruses in mice.

Science.gov (United States)

Castrucci, Maria R; Facchini, Marzia; Di Mario, Giuseppina; Garulli, Bruno; Sciaraffia, Ester; Meola, Monica; Fabiani, Concetta; De Marco, Maria A; Cordioli, Paolo; Siccardi, Antonio; Kawaoka, Yoshihiro; Donatelli, Isabella

2014-05-01

To examine cross-reactivity between hemagglutinin (HA) derived from A/California/7/09 (CA/09) virus and that derived from representative Eurasian "avian-like" (EA) H1N1 swine viruses isolated in Italy between 1999 and 2008 during virological surveillance in pigs. Modified vaccinia virus Ankara (MVA) expressing the HA gene of CA/09 virus (MVA-HA-CA/09) was used as a vaccine to investigate cross-protective immunity against H1N1 swine viruses in mice. Two classical swine H1N1 (CS) viruses and four representative EA-like H1N1 swine viruses previously isolated during outbreaks of respiratory disease in pigs on farms in Northern Italy were used in this study. Female C57BL/6 mice were vaccinated with MVA/HA/CA/09 and then challenged intranasally with H1N1 swine viruses. Cross-reactive antibody responses were determined by hemagglutination- inhibition (HI) and virus microneutralizing (MN) assays of sera from MVA-vaccinated mice. The extent of protective immunity against infection with H1N1 swine viruses was determined by measuring lung viral load on days 2 and 4 post-challenge. Systemic immunization of mice with CA/09-derived HA, vectored by MVA, elicited cross-protective immunity against recent EA-like swine viruses. This immune protection was related to the levels of cross-reactive HI antibodies in the sera of the immunized mice and was dependent on the similarity of the antigenic site Sa of H1 HAs. Our findings suggest that the herd immunity elicited in humans by the pandemic (H1N1) 2009 virus could limit the transmission of recent EA-like swine HA genes into the influenza A virus gene pool in humans. © 2013 The Authors Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Enhancement of carotenoid production by disrupting the C22-sterol desaturase gene (CYP61 in Xanthophyllomyces dendrorhous

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Loto Iris

2012-10-01

Full Text Available Abstract Background Xanthophyllomyces dendrorhous is a basidiomycetous yeast that synthesizes astaxanthin, which is a carotenoid with a great biotechnological impact. The ergosterol and carotenoid synthesis pathways are derived from the mevalonate pathway, and in both pathways, cytochrome P450 enzymes are involved. Results In this study, we isolated and described the X. dendrorhous CYP61 gene, which encodes a cytochrome P450 involved in ergosterol biosynthesis. This gene is composed of nine exons and encodes a 526 amino acid polypeptide that shares significant percentages of identity and similitude with the C22-sterol desaturase, CYP61, from other fungi. Mutants derived from different parental strains were obtained by disrupting the CYP61 gene with an antibiotic selection marker. These mutants were not able to produce ergosterol and accumulated ergosta-5,8,22-trien-3-ol and ergosta-5,8-dien-3-ol. Interestingly, all of the mutants had a more intense red color phenotype than their respective parental strains. The carotenoid composition was qualitatively and quantitatively analyzed by RP-HPLC, revealing that the carotenoid content was higher in the mutant strains without major changes in their composition. The expression of the HMGR gene, which encodes an enzyme involved in the mevalonate pathway (3-hydroxy-3-methylglutaryl-CoA reductase, was analyzed by RT-qPCR showing that its transcript levels are higher in the CYP61 mutants. Conclusions These results suggest that in X. dendrorhous, ergosterol regulates HMGR gene expression by a negative feedback mechanism and in this way; it contributes in the regulation of the carotenoid biosynthesis.

Selective inhibition of the demethylation at C-14 in ergosterol biosynthesis by the fungicide, Denmert (S-1358)

International Nuclear Information System (INIS)

Kato, Toshiro; Kawase, Yasuo

1976-01-01

A direct evidence of the inhibitory effect in a cell-free system of S. cerevisiae was experimentally studied, and the site of action of Denmert (S-n-butyl S'-p-tert-butylbenzyl N-3-pyridyldithiocarbon-imidate) in sterol biosynthesis was examined. 14 C-labeled lanosterol and 14-desmethyl-lanosterol were biosynthetically prepared. DL-mevalonate-2- 14 C was incubated with yeast cell-free homogenates for 3 hr at 28 deg C while being shaked vigorously in atmospheric oxygen. The resultant 14 C-labeled sterol was extracted and chromatographed on a silicic acid-Hyflo Super Cel column. 4,4-dimethyl sterol thus obtained was acetylated with acetic anhydride and pyridine. The separation of lanosteryl acetate and 14-desmethyl lanosteryl acetate was accomplished on alumina thin-layer plates. After the saponification of each steryl acetate, the quantity of the sterol was assessed by gas chromatography with cholesterol as an internal standard. The incubation of the 14 C-labeled sterol was achieved under the same conditions as those for the DL-mevalonate-2- 14 C except the addition of the substrate which was dispersed in 0.1M phosphate buffer. Denmert inhibited the conversion of 14 C-labeled lanosterol to 4-desmethyl sterol, while the conversion of 14 C-labeled 14-desmethyl lanosterol to 4-desmethyl sterol was hardly affected by the fungicide. Therefore, Denmert is a potent selective inhibitor of the demethylation at the C-14 position in ergosterol biosynthesis. The fungicide, triarimol, exhibited the same effect on sterol biosynthesis as that of Denmert. (Iwakiri, K.)

Engineering a functional 1-deoxy-D-xylulose 5-phosphate (DXP) pathway in Saccharomyces cerevisiae

Energy Technology Data Exchange (ETDEWEB)

Kirby, James [Univ. of California, Berkeley, CA (United States). California Institute of Quantitative Biosciences (QB3); Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Dietzel, Kevin L. [Amyris, inc., Emeryville, CA (United States); Wichmann, Gale [Amyris, inc., Emeryville, CA (United States); Chan, Rossana [Univ. of California, Berkeley, CA (United States). California Institute of Quantitative Biosciences (QB3); Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Antipov, Eugene [Amyris, inc., Emeryville, CA (United States); Moss, Nathan [Amyris, inc., Emeryville, CA (United States); Baidoo, Edward E. K. [Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Jackson, Peter [Amyris, inc., Emeryville, CA (United States); Gaucher, Sara P. [Amyris, inc., Emeryville, CA (United States); Gottlieb, Shayin [Amyris, inc., Emeryville, CA (United States); LaBarge, Jeremy [Amyris, inc., Emeryville, CA (United States); Mahatdejkul, Tina [Amyris, inc., Emeryville, CA (United States); Hawkins, Kristy M. [Amyris, inc., Emeryville, CA (United States); Muley, Sheela [Amyris, inc., Emeryville, CA (United States); Newman, Jack D. [Amyris, inc., Emeryville, CA (United States); Liu, Pinghua [Boston Univ., MA (United States). Dept. of Chemistry; Keasling, Jay D. [Univ. of California, Berkeley, CA (United States). California Institute of Quantitative Biosciences (QB3); Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Univ. of California, Berkeley, CA (United States). Depts. of Chemical & Biomolecular Engineering and Bioengineering; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems & Engineering Div.; Technical Univ. of Denmark, Hoesholm (Denmark). Novo Nodisk Foundation Center for Biosustainability; Zhao, Lishan [Amyris, inc., Emeryville, CA (United States)

2016-10-27

Isoprenoids are made by all free-living organisms and range from essential metabolites like sterols and quinones to more complex compounds like pinene and rubber. They are used in many commercial applications and much work has gone into engineering microbial hosts for their production. Isoprenoids are produced either from acetyl-CoA via the mevalonate pathway or from pyruvate and glyceraldehyde 3-phosphate via the 1-deoxy-D-xylulose 5-phosphate (DXP) pathway. Saccharomyces cerevisiae exclusively utilizes the mevalonate pathway to synthesize native isoprenoids and in fact the alternative DXP pathway has never been found or successfully reconstructed in the eukaryotic cytosol. There are, however, several advantages to isoprenoid synthesis via the DXP pathway, such as a higher theoretical yield, and it has long been a goal to transplant the pathway into yeast. In this work, we investigate and address barriers to DXP pathway functionality in S. cerevisiae using a combination of synthetic biology, biochemistry and metabolomics. We report, for the first time, functional expression of the DXP pathway in S. cerevisiae. Under low aeration conditions, an engineered strain relying solely on the DXP pathway for isoprenoid biosynthesis achieved an endpoint biomass 80% of that of the same strain using the mevalonate pathway.

Molecular docking and NMR binding studies to identify novel inhibitors of human phosphomevalonate kinase

Energy Technology Data Exchange (ETDEWEB)

Boonsri, Pornthip [Chemical Proteomics Facility at Marquette, Department of Chemistry, Marquette University, Milwaukee, WI 53201 (United States); Department of Chemistry, NANOTEC Center of Nanotechnology, National Nanotechnology Center, Faculty of Science, Kasetsart University, Bangkok 10900 (Thailand); Neumann, Terrence S.; Olson, Andrew L.; Cai, Sheng [Chemical Proteomics Facility at Marquette, Department of Chemistry, Marquette University, Milwaukee, WI 53201 (United States); Herdendorf, Timothy J.; Miziorko, Henry M. [Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110 (United States); Hannongbua, Supa [Department of Chemistry, NANOTEC Center of Nanotechnology, National Nanotechnology Center, Faculty of Science, Kasetsart University, Bangkok 10900 (Thailand); Sem, Daniel S., E-mail: daniel.sem@cuw.edu [Chemical Proteomics Facility at Marquette, Department of Chemistry, Marquette University, Milwaukee, WI 53201 (United States)

2013-01-04

Highlights: Black-Right-Pointing-Pointer Natural and synthetic inhibitors of human phosphomevalonate kinase identified. Black-Right-Pointing-Pointer Virtual screening yielded a hit rate of 15%, with inhibitor K{sub d}'s of 10-60 {mu}M. Black-Right-Pointing-Pointer NMR studies indicate significant protein conformational changes upon binding. -- Abstract: Phosphomevalonate kinase (PMK) phosphorylates mevalonate-5-phosphate (M5P) in the mevalonate pathway, which is the sole source of isoprenoids and steroids in humans. We have identified new PMK inhibitors with virtual screening, using autodock. Promising hits were verified and their affinity measured using NMR-based {sup 1}H-{sup 15}N heteronuclear single quantum coherence (HSQC) chemical shift perturbation and fluorescence titrations. Chemical shift changes were monitored, plotted, and fitted to obtain dissociation constants (K{sub d}). Tight binding compounds with K{sub d}'s ranging from 6-60 {mu}M were identified. These compounds tended to have significant polarity and negative charge, similar to the natural substrates (M5P and ATP). HSQC cross peak changes suggest that binding induces a global conformational change, such as domain closure. Compounds identified in this study serve as chemical genetic probes of human PMK, to explore pharmacology of the mevalonate pathway, as well as starting points for further drug development.

Synergistic Radioprotection by Gamma-Tocotrienol and Pentoxifylline: Role of cAMP Signaling

International Nuclear Information System (INIS)

Kulkarni, Shilpa; Chakraborty, Kushal; Kumar, K. Sree; Kao, Tzu-Cheg; Hauer-Jensen, Martin; Ghosh, Sanchita P.

2013-01-01

Purpose. This study was designed to determine the efficacy and mechanisms of radioprotection by the combination of gamma-tocotrienol (GT3) and pentoxifylline (PTX) against acute radiation injury. Materials and Methods. Post-irradiation survival was monitored to determine the most efficacious dose and time of administration of PTX. Dose reduction factor (DRF) was calculated to compare the radioprotective efficacy of the combination. To determine the mechanism of synergistic radioprotection by the combination, mevalonate or calmodulin were coadministered with the GT3-PTX combination. Mevalonate was used to reverse the inhibitory effect of GT3 on 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), and calmodulin was used to reverse the inhibition of phosphodiesterase (PDE) by PTX. Results. The combination was most effective when 200 mg/kg of PTX was administered 15 min before irradiation along with 200 mg/kg of GT3 (−24 h) and resulted in a DRF of 1.5. White blood cells and neutrophil counts showed accelerated recovery in GT3-PTX-treated groups compared to GT3. Mevalonate had no effect on the radioprotection of GT3-PTX; calmodulin abrogated the synergistic radioprotection by GT3-PTX. Conclusion. The mechanism of radioprotection by GT3-PTX may involve PDE inhibition

Engineering a Synthetic Microbial Consortium for Comprehensive Conversion of Algae Biomass into Terpenes for Advanced Biofuels and Bioproducts

Energy Technology Data Exchange (ETDEWEB)

Wu, Weihua [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Wu, Benjamin Chiau-Pin [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Davis, Ryan Wesley [Sandia National Lab. (SNL-CA), Livermore, CA (United States)

2015-10-01

Recent strategies for algae-based biofuels have primarily focused on biodiesel production by exploiting high algal lipid yields under nutrient stress conditions. However, under conditions supporting robust algal biomass accumulation, carbohydrate and proteins typically comprise up to ~80% of the ash-free dry weight of algae biomass. Therefore, comprehensive utilization of algal biomass for production of multipurpose intermediate- to high-value bio-based products will promote scale-up of algae production and processing to commodity volumes. Terpenes are hydrocarbon and hydrocarbon-like (C:O>10:1) compounds with high energy density, and are therefore potentially promising candidates for the next generation of value added bio-based chemicals and “drop-in” replacements for petroleum-based fuels. In this study, we demonstrated the feasibility of bioconversion of proteins into sesquiterpene compounds as well as comprehensive bioconversion of algal carbohydrates and proteins into biofuels. To achieve this, the mevalonate pathway was reconstructed into an E. coli chassis with six different terpene synthases (TSs). Strains containing the various TSs produced a spectrum of sesquiterpene compounds in minimal medium containing amino acids as the sole carbon source. The sesquiterpene production was optimized through three different regulation strategies using chamigrene synthase as an example. The highest total terpene titer reached 166 mg/L, and was achieved by applying a strategy to minimize mevalonate accumulation in vivo. The highest yields of total terpene were produced under reduced IPTG induction levels (0.25 mM), reduced induction temperature (25°C), and elevated substrate concentration (20 g/L amino acid mixture). A synthetic bioconversion consortium consisting of two engineering E. coli strains (DH1-TS and YH40-TS) with reconstructed terpene biosynthetic pathways was designed for comprehensive single-pot conversion of algal carbohydrates and proteins to

EMDR therapy for PTSD after motor vehicle accidents: meta-analytic evidence for specific treatment

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Maddalena eBoccia

2015-04-01

Full Text Available Motor vehicle accident (MVA victims may suffer both acute and post-traumatic stress disorders (PTSD. With PTSD affecting social, interpersonal and occupational functioning, clinicians as well as the National Institute of Health are very interested in identifying the most effective psychological treatment to reduce PTSD. From research findings, eye movement desensitization and reprocessing (EMDR therapy is considered as one of the effective treatment of PTSD. In this paper, we present the results of a meta-analysis of fMRI studies on PTSD after MVA through activation likelihood estimation. We found that PTSD following MVA is characterized by neural modifications in the anterior cingulate cortex (ACC, a cerebral structure involved in fear-conditioning mechanisms. Basing on previous findings in both humans and animals, which demonstrate that desensitization techniques and extinction protocols act on the limbic system, the effectiveness of EMDR and of cognitive behavioral therapies (CBT may be related to the fact that during these therapies the ACC is stimulated by desensitization.

A large capacity turbine generator for nuclear power generation

International Nuclear Information System (INIS)

Maeda, Susumu; Miki, Takahiro; Suzuki, Kazuichi

2000-01-01

In future large capacity nuclear power plant, capacity of a generator to be applied will be 1800 MVA of the largest class in the world. In response to this, the Mitsubishi Electric Co., Ltd. began to carry out element technology verification of a four-pole large capacity turbine generator mainly using upgrading technique of large capacity, since 1994 fiscal year. And, aiming at reliability verification of the 1800 MVA class generator, a model generator with same cross-section as that of an actual one was manufactured, to carry out some verifications on its electrified tests, and so on. Every performance evaluation result of tests on the model generator were good, and high reliability to design and manufacturing technique of the 1800 MVA class generator could be verified. In future, on the base of these technologies, further upgrading of reliability on the large capacity turbine generator for nuclear power generation is intended to be carried out. (G.K.)

EMDR therapy for PTSD after motor vehicle accidents: meta-analytic evidence for specific treatment

Science.gov (United States)

Boccia, Maddalena; Piccardi, Laura; Cordellieri, Pierluigi; Guariglia, Cecilia; Giannini, Anna Maria

2015-01-01

Motor vehicle accident (MVA) victims may suffer both acute and post-traumatic stress disorders (PTSD). With PTSD affecting social, interpersonal and occupational functioning, clinicians as well as the National Institute of Health are very interested in identifying the most effective psychological treatment to reduce PTSD. From research findings, eye movement desensitization and reprocessing (EMDR) therapy is considered as one of the effective treatment of PTSD. In this paper, we present the results of a meta-analysis of fMRI studies on PTSD after MVA through activation likelihood estimation. We found that PTSD following MVA is characterized by neural modifications in the anterior cingulate cortex (ACC), a cerebral structure involved in fear-conditioning mechanisms. Basing on previous findings in both humans and animals, which demonstrate that desensitization techniques and extinction protocols act on the limbic system, the effectiveness of EMDR and of cognitive behavioral therapies (CBT) may be related to the fact that during these therapies the ACC is stimulated by desensitization. PMID:25954183

Regulation of carbon partitioning into carotenes by MPTA, a substituted tertiary amine

Energy Technology Data Exchange (ETDEWEB)

Madhavan, S.; Rosenfield, C.L.; Benedict, C.R.

1986-04-01

In mature citrus fruits, synthesis and turnover of carotenes appears to be low. Treatment of lemon pieces with the substituted tertiary amine, 2-(4-methylphenoxyl)triethylamine, MPTA, induces the synthesis of carotenes. Exposure of tissue slices (lemon flavedo) to MPTA for 72 hrs results in the production of 29.6 ..mu..g gfrwt/sup -1/ lycopene whereas control slices showed only trace amounts of lycopene. An identical incorporation of /sup 14/C-glucose into sugars, amino acids and organic acids, in both treated and control tissue slices indicates the non-disturbance of fruit respiration by MPTA treatment. Incorporation of /sup 14/C-glucose into carotenes is negligible in mature citrus fruits, but in MPTA treated tissue slices there is a pronounced incorporation of /sup 14/C-glucose into carotenes. MPTA treatment induces the synthesis of carotene enzymes, thus effecting an increased partitioning of glucose into the MVA pathway for carotene synthesis.

Regulation of carbon partitioning into carotenes by MPTA, a substituted tertiary amine

International Nuclear Information System (INIS)

Madhavan, S.; Rosenfield, C.L.; Benedict, C.R.

1986-01-01

In mature citrus fruits, synthesis and turnover of carotenes appears to be low. Treatment of lemon pieces with the substituted tertiary amine, 2-(4-methylphenoxyl)triethylamine, MPTA, induces the synthesis of carotenes. Exposure of tissue slices (lemon flavedo) to MPTA for 72 hrs results in the production of 29.6 μg gfrwt -1 lycopene whereas control slices showed only trace amounts of lycopene. An identical incorporation of 14 C-glucose into sugars, amino acids and organic acids, in both treated and control tissue slices indicates the non-disturbance of fruit respiration by MPTA treatment. Incorporation of 14 C-glucose into carotenes is negligible in mature citrus fruits, but in MPTA treated tissue slices there is a pronounced incorporation of 14 C-glucose into carotenes. MPTA treatment induces the synthesis of carotene enzymes, thus effecting an increased partitioning of glucose into the MVA pathway for carotene synthesis

Statins: pros and cons.

Science.gov (United States)

Pinal-Fernandez, Iago; Casal-Dominguez, Maria; Mammen, Andrew L

2018-05-23

Statins inhibit the critical step of cholesterol synthesis in which 3-hydroxy-3-methylglutaryl coenzyme A (HMGC) is transformed to mevalonate by the enzyme HMGC reductase. By doing so, they have a potent lipid-lowering effect that reduces cardiovascular risk and decreases mortality. Since the mevalonate pathway also influences endothelial function, the inflammatory response, and coagulation, the effects of statins reach well beyond their cholesterol lowering properties. As with all drugs, statins may have adverse effects; these include musculoskeletal symptoms, increased risk of diabetes, and higher rates of hemorrhagic stroke. However, the frequency of adverse effects is extremely low and, in selected patient populations, the benefits of statins considerably outweigh the potential risks. Published by Elsevier España, S.L.U.

The Relationship between “Protection of” and “Violence Against” Infants and Young Children: The U.S. Experience, 1940–2005

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Jack E. Riggs

2014-08-01

Full Text Available Between 1940 and 2005, in the United States, the rate of unnatural death declined about 75 percent in infant and young child boys and girls; a remarkable indicator of successful child protection. During this same period, the rate of reported homicide in infant boys increased 64.0 percent, in infant girls increased 43.5 percent, in young child boys increased 333.3 percent, and in young child girls increased 300.0 percent, a dismal and disturbing indicator of failed child protection. Can these simultaneously encouraging and discouraging observations be reconciled? The four categories of unnatural death, homicide, suicide, motor vehicle accident (MVA, and non-MVA, are mutually exclusive classifications. Correlations between the four categories of unnatural death among U.S. men and woman in all age groups for the years 1940 through 2005 were calculated. A negative correlation between homicide and non-MVA death rates was shown for all age groups, encompassing the entire human lifespan, in both genders. This consistently observed negative correlation was only observed between homicide and non-MVA death rates, and was not demonstrated between other causes of unnatural deaths. Moreover, this negative correlation was strongest (less than −0.7 in infants and young children. These observations are consistent with the suggestion that as the rate of unnatural death in infants and young children dramatically declined, society gave greater scrutiny to those fewer occurring unnatural deaths and demonstrated an increasing propensity to assign blame for those fewer deaths.

Categorical and dimensional study of the predictive factors of the development of a psychotrauma in victims of car accidents.

Science.gov (United States)

Berna, G; Vaiva, G; Ducrocq, F; Duhem, S; Nandrino, J L

2012-01-01

This study aimed to evaluate the predictive factors of the emergence of complete PTSD and subsyndromal PTSD (defined as individuals exposed to a traumatic event with at least one psychopathological impact, such as hyperarousal, avoidance or persistent re-experiencing) following a motor vehicle accident (MVA). We recruited 155 adult MVA patients, physically injured and admitted to trauma service, over two years. In the week following the accident, patients were asked to complete questionnaires assessing their social situation (sex, age, marital and employment status, prior MVA or trauma), comorbidity (MINI), distress (PDI) and dissociation (PDEQ) experienced during and immediately after the trauma. An evaluation using the CAPS was conducted six months after the trauma to assess a possible PTSD. At six months, 25.8% of the participants developed subsyndromal symptoms and 7.74% developed complete PTSD. The three symptoms that best discriminated the groups were dysphoric emotion, perceived life threat and dissociation. Logistic regression results showed that the strongest predictor of PTSD was the perceived life threat. In addition, a dimensional approach to the results revealed significant correlations between (1) peritraumatic distress and persistent re-experiencing or hyperarousal and (2) dissociation score and avoidance strategy. The presence of a prior traumatic event reinforces avoidance strategies. Our results stress that peritraumatic factors (especially the perception of a life threat) are good predictors of PTSD development. A dimensional perspective allows better identification of psychological complications following an MVA. Copyright © 2011 Elsevier Ltd. All rights reserved.

Spinal cord gliomas: A multi-institutional retrospective analysis

International Nuclear Information System (INIS)

Abdel-Wahab, May; Etuk, Blessing; Palermo, James; Shirato, Hiroki; Kresl, John; Yapicier, Ozlem; Walker, Gail; Scheithauer, Bernd W.; Shaw, Edward; Lee, Charles; Curran, Walter; Thomas, Terry; Markoe, Arnold

2006-01-01

Purpose: To determine the impact of postoperative radiation therapy (POXRT) on outcome in spinal cord gliomas. Patients and Methods: Data from 242 patients were collected retrospectively from six institutions using a standardized data sheet. Pathology specimens, when available, were centrally reviewed. Results: A total of 183 patients were analyzed: 82 received surgery alone as initial treatment, whereas 101 had surgery and POXRT. Demographic, diagnostic, and treatment factors were analyzed for impact on progression-free (PFS) and overall survival (OS). PFS in ependymoma patients was 74%, 60%, and 35% at 5, 10, 15 years, respectively, and was significantly influenced by treatment type, race, age, tumor grade, and type of surgery on univariate analysis, with age being the only significant factor on multivariate analysis (MVA) (p = 0.01). OS of ependymoma patients was 91%, 84%, and 75% at 5, 10, and 15 years, respectively, and was significantly influenced by both complete resection (p = 0.04) and age (p = 0.03) on MVA. In astrocytomas, PFS was 42%, 29%, and 15% at 5, 10, and 15 years, and was significantly influenced by POXRT in low- and intermediate-grade tumors on MVA (p = 0.02). OS at 5, 10, and 15 years was 59%, 53%, and 32%, respectively, and was significantly influenced by grade on MVA (p < 0.01). Conclusion: Postoperative radiation therapy reduced disease progression in low- and moderate-grade astrocytomas. In ependymomas, complete resection significantly influenced OS

PENGARUH KINERJA BERBASIS PENCIPTAAN NILAI DAN VARIABEL MAKROEKONOMI TERHADAP RETURN SAHAM INDUSTRI PAKAN TERNAK

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Evi Karmilah

2016-07-01

Full Text Available The creation of value-based performance measurement can be an alternative in measuring the company's financial performance. Results can be used as indicators of assessments by investors, and these indicators can influence the stock returns. Besides, macroeconomic variables also affect stock returns. This study aimed to analyze the financial performance of companies in the process of creation of value-added with EVA, MVA, and Tobin's Q approach. Impacts of these performance measurements and macroeconomic variables (exchange rates, interest rates, and inflation on stock returns of the subsector animal feed industry were studied. Descriptive analysis was applied in analyzing the company's financial performance. The impacts of the company financial performance and macroeconomic variables were assessed by using panel data regression analysis. The results related to the company's performance showed that 1 EVA performance dominantly obtained a positive EVA value; 2 MVA performance predominantly produced a positive MVA value in 3 companies and a negative MVA value in the other company; 3 Tobin’s Q performance predominantly generated a value of Q>1 in 2 companies and a value of Q<1 in the other 2 companies. The results of the panel data regression analysis concluded the independent variables influencing the stock return were the performance variables while the macroeconomic variables had no effects on stock return.Keywords: macroeconomic variables, panel data regression, stock return, subsector of animal feed, value-based performance

Routine training is not enough: structured training in family planning and abortion improves residents' competency scores and intentions to provide abortion after graduation more than ad hoc training.

Science.gov (United States)

Macisaac, Laura; Vickery, Zevidah

2012-03-01

Abortion provision remains threatened by the paucity of physicians trained to provide them. Lack of training during residency has been cited by obstetrician and gynecologist (ob-gyn) physicians as a reason for not including abortion in their practice. We administered surveys on interest, competency and intention to provide abortions to two groups of ob-gyn residents: one experiencing a new comprehensive and structured family planning rotation, and another group at our affiliate hospital's residency program receiving "ad hoc" training during their routine gynecology rotations. Surveys were anonymous and blinded to investigator. The structured family planning rotation group compared to the ad hoc group reported significantly increased competency score using a Likert scale in manual vacuum aspiration (MVA) (4.5 vs. 1; p=.003) and had a higher proportion reporting intent to provide office MVA postresidency (100% vs. 39%; p=.01) and being trained to 22.5 weeks' vs. 12 weeks' gestation (p=.005). In bivariate analysis, competency in MVA was associated with higher intentions to provide MVA after residency (p=.007). A structured rotation in family planning and abortion for obstetrics/gynecology residents results in increases in competency and intentions to provide abortion, and an association between the two. In-hospital structured training proved to be superior to ad hoc training in our affiliate institution in improving competency and intention to provide abortion after residency. Copyright © 2012 Elsevier Inc. All rights reserved.

Postprandial metabolomics: A pilot mass spectrometry and NMR study of the human plasma metabolome in response to a challenge meal

Energy Technology Data Exchange (ETDEWEB)

Karimpour, Masoumeh; Surowiec, Izabella; Wu, Junfang [Computational Life Science Cluster (CLiC), Department of Chemistry, Umeå University, 90187 Umeå (Sweden); Gouveia-Figueira, Sandra [Computational Life Science Cluster (CLiC), Department of Chemistry, Umeå University, 90187 Umeå (Sweden); Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå (Sweden); Pinto, Rui [Computational Life Science Cluster (CLiC), Department of Chemistry, Umeå University, 90187 Umeå (Sweden); Bioinformatics Infrastructure for Life Sciences (Sweden); Trygg, Johan [Computational Life Science Cluster (CLiC), Department of Chemistry, Umeå University, 90187 Umeå (Sweden); Zivkovic, Angela M. [Department of Nutrition, University of California, Davis, One Shields Ave, CA 95616 (United States); Nording, Malin L., E-mail: malin.nording@umu.se [Computational Life Science Cluster (CLiC), Department of Chemistry, Umeå University, 90187 Umeå (Sweden)

2016-02-18

The study of postprandial metabolism is relevant for understanding metabolic diseases and characterizing personal responses to diet. We combined three analytical platforms – gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) – to validate a multi-platform approach for characterizing individual variation in the postprandial state. We analyzed the postprandial plasma metabolome by introducing, at three occasions, meal challenges on a usual diet, and 1.5 years later, on a modified background diet. The postprandial response was stable over time and largely independent of the background diet as revealed by all three analytical platforms. Coverage of the metabolome between NMR and GC-MS included more polar metabolites detectable only by NMR and more hydrophobic compounds detected by GC-MS. The variability across three separate testing occasions among the identified metabolites was in the range of 1.1–86% for GC-MS and 0.9–42% for NMR in the fasting state at baseline. For the LC-MS analysis, the coefficients of variation of the detected compounds in the fasting state at baseline were in the range of 2–97% for the positive and 4–69% for the negative mode. Multivariate analysis (MVA) of metabolites detected with GC-MS revealed that for both background diets, levels of postprandial amino acids and sugars increased whereas those of fatty acids decreased at 0.5 h after the meal was consumed, reflecting the expected response to the challenge meal. MVA of NMR data revealed increasing postprandial levels of amino acids and other organic acids together with decreasing levels of acetoacetate and 3-hydroxybutanoic acid, also independent of the background diet. Together these data show that the postprandial response to the same challenge meal was stable even though it was tested 1.5 years apart, and that it was largely independent of background diet. This work demonstrates the efficacy of a

Postprandial metabolomics: A pilot mass spectrometry and NMR study of the human plasma metabolome in response to a challenge meal

International Nuclear Information System (INIS)

Karimpour, Masoumeh; Surowiec, Izabella; Wu, Junfang; Gouveia-Figueira, Sandra; Pinto, Rui; Trygg, Johan; Zivkovic, Angela M.; Nording, Malin L.

2016-01-01

The study of postprandial metabolism is relevant for understanding metabolic diseases and characterizing personal responses to diet. We combined three analytical platforms – gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) – to validate a multi-platform approach for characterizing individual variation in the postprandial state. We analyzed the postprandial plasma metabolome by introducing, at three occasions, meal challenges on a usual diet, and 1.5 years later, on a modified background diet. The postprandial response was stable over time and largely independent of the background diet as revealed by all three analytical platforms. Coverage of the metabolome between NMR and GC-MS included more polar metabolites detectable only by NMR and more hydrophobic compounds detected by GC-MS. The variability across three separate testing occasions among the identified metabolites was in the range of 1.1–86% for GC-MS and 0.9–42% for NMR in the fasting state at baseline. For the LC-MS analysis, the coefficients of variation of the detected compounds in the fasting state at baseline were in the range of 2–97% for the positive and 4–69% for the negative mode. Multivariate analysis (MVA) of metabolites detected with GC-MS revealed that for both background diets, levels of postprandial amino acids and sugars increased whereas those of fatty acids decreased at 0.5 h after the meal was consumed, reflecting the expected response to the challenge meal. MVA of NMR data revealed increasing postprandial levels of amino acids and other organic acids together with decreasing levels of acetoacetate and 3-hydroxybutanoic acid, also independent of the background diet. Together these data show that the postprandial response to the same challenge meal was stable even though it was tested 1.5 years apart, and that it was largely independent of background diet. This work demonstrates the efficacy of a

Synthetic protein scaffolds based on peptide motifs and cognate adaptor domains for improving metabolic productivity

Directory of Open Access Journals (Sweden)

Anselm H.C. Horn

2015-11-01

Full Text Available The efficiency of many cellular processes relies on the defined interaction among different proteins within the same metabolic or signaling pathway. Consequently, a spatial colocalization of functionally interacting proteins has frequently emerged during evolution. This concept has been adapted within the synthetic biology community for the purpose of creating artificial scaffolds. A recent advancement of this concept is the use of peptide motifs and their cognate adaptor domains. SH2, SH3, GBD, and PDZ domains have been used most often in research studies to date. The approach has been successfully applied to the synthesis of a variety of target molecules including catechin, D-glucaric acid, H2, hydrochinone, resveratrol, butyrate, gamma-aminobutyric acid, and mevalonate. Increased production levels of up to 77-fold have been observed compared to non-scaffolded systems. A recent extension of this concept is the creation of a covalent linkage between peptide motifs and adaptor domains, which leads to a more stable association of the scaffolded systems and thus bears the potential to further enhance metabolic productivity.

Review of Quantitative Monitoring Methodologies for Emissions Verification and Accounting for Carbon Dioxide Capture and Storage for California’s Greenhouse Gas Cap-and-Trade and Low-Carbon Fuel Standard Programs

Energy Technology Data Exchange (ETDEWEB)

Oldenburg, Curtis M. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Earth Sciences Division; Birkholzer, Jens T. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Earth Sciences Division

2014-12-23

The Cap-and-Trade and Low Carbon Fuel Standard (LCFS) programs being administered by the California Air Resources Board (CARB) include Carbon Dioxide Capture and Storage (CCS) as a potential means to reduce greenhouse gas (GHG) emissions. However, there is currently no universal standard approach that quantifies GHG emissions reductions for CCS and that is suitable for the quantitative needs of the Cap-and-Trade and LCFS programs. CCS involves emissions related to the capture (e.g., arising from increased energy needed to separate carbon dioxide (CO₂) from a flue gas and compress it for transport), transport (e.g., by pipeline), and storage of CO₂ (e.g., due to leakage to the atmosphere from geologic CO₂ storage sites). In this project, we reviewed and compared monitoring, verification, and accounting (MVA) protocols for CCS from around the world by focusing on protocols specific to the geologic storage part of CCS. In addition to presenting the review of these protocols, we highlight in this report those storage-related MVA protocols that we believe are particularly appropriate for CCS in California. We find that none of the existing protocols is completely appropriate for California, but various elements of all of them could be adopted and/or augmented to develop a rigorous, defensible, and practical surface leakage MVA protocol for California. The key features of a suitable surface leakage MVA plan for California are that it: (1) informs and validates the leakage risk assessment, (2) specifies use of the most effective monitoring strategies while still being flexible enough to accommodate special or site-specific conditions, (3) quantifies stored CO₂, and (4) offers defensible estimates of uncertainty in monitored properties. California’s surface leakage MVA protocol needs to be applicable to the main CO₂ storage opportunities (in California and in other states with entities participating in California�

78 FR 20029 - Castor Oil, Polymer With Adipic Acid, Linoleic Acid, Oleic Acid and Ricinoleic Acid; Tolerance...

Science.gov (United States)

2013-04-03

..., Polymer With Adipic Acid, Linoleic Acid, Oleic Acid and Ricinoleic Acid; Tolerance Exemption AGENCY... from the requirement of a tolerance for residues of castor oil, polymer with adipic acid, linoleic acid... pesticide formulation. Advance Polymer Technology submitted a petition to EPA under the Federal Food, Drug...

Reference: 507 [Arabidopsis Phenome Database[Archive

Lifescience Database Archive (English)

Full Text Available Keiko et al. 2007 Feb. Plant Cell Physiol. 48(2):322-31. Higher plants have two metabolic pathways for isopr...espite the compartmentalization of these two pathways, metabolic flow occurs betw...een them. However, little is known about the mechanisms that regulate the two pathways and the metabolic cro...lomazone, inhibitors of the MVA and MEP pathways, respectively. The accumulation of the major products of these pathways...be involved in isoprenoid biosynthesis in both the MVA and MEP pathways. Lovastatin insensitive 1, a Novel p

A viral vectored prime-boost immunization regime targeting the malaria Pfs25 antigen induces transmission-blocking activity.

Directory of Open Access Journals (Sweden)

Anna L Goodman

Full Text Available The ookinete surface protein Pfs25 is a macrogamete-to-ookinete/ookinete stage antigen of Plasmodium falciparum, capable of exerting high-level anti-malarial transmission-blocking activity following immunization with recombinant protein-in-adjuvant formulations. Here, this antigen was expressed in recombinant chimpanzee adenovirus 63 (ChAd63, human adenovirus serotype 5 (AdHu5 and modified vaccinia virus Ankara (MVA viral vectored vaccines. Two immunizations were administered to mice in a heterologous prime-boost regime. Immunization of mice with AdHu5 Pfs25 at week 0 and MVA Pfs25 at week 10 (Ad-MVA Pfs25 resulted in high anti-Pfs25 IgG titers, consisting of predominantly isotypes IgG1 and IgG2a. A single priming immunization with ChAd63 Pfs25 was as effective as AdHu5 Pfs25 with respect to ELISA titers at 8 weeks post-immunization. Sera from Ad-MVA Pfs25 immunized mice inhibited the transmission of P. falciparum to the mosquito both ex vivo and in vivo. In a standard membrane-feeding assay using NF54 strain P. falciparum, oocyst intensity in Anopheles stephensi mosquitoes was significantly reduced in an IgG concentration-dependent manner when compared to control feeds (96% reduction of intensity, 78% reduction in prevalence at a 1 in 5 dilution of sera. In addition, an in vivo transmission-blocking effect was also demonstrated by direct feeding of immunized mice infected with Pfs25DR3, a chimeric P. berghei line expressing Pfs25 in place of endogenous Pbs25. In this assay the density of Pfs25DR3 oocysts was significantly reduced when mosquitoes were fed on vaccinated as compared to control mice (67% reduction of intensity, 28% reduction in prevalence and specific IgG titer correlated with efficacy. These data confirm the utility of the adenovirus-MVA vaccine platform for the induction of antibodies with transmission-blocking activity, and support the continued development of this alternative approach to transmission-blocking malaria subunit

Sleep Apnea Related Risk of Motor Vehicle Accidents is Reduced by Continuous Positive Airway Pressure: Swedish Traffic Accident Registry Data

Science.gov (United States)

Karimi, Mahssa; Hedner, Jan; Häbel, Henrike; Nerman, Olle; Grote, Ludger

2015-01-01

Study Objectives: Obstructive sleep apnea (OSA) is associated with an increased risk of motor vehicle accidents (MVAs). The rate of MVAs in patients suspected of having OSA was determined and the effect of continuous positive airway pressure (CPAP) was investigated. Design: MVA rate in patients referred for OSA was compared to the rate in the general population using data from the Swedish Traffic Accident Registry (STRADA), stratified for age and calendar year. The risk factors for MVAs, using demographic and polygraphy data, and MVA rate before and after CPAP were evaluated in the patient group. Setting: Clinical sleep laboratory and population based control (n = 635,786). Patients: There were 1,478 patients, male sex 70.4%, mean age 53.6 (12.8) y. Interventions: CPAP. Measurements and Results: The number of accidents (n = 74) among patients was compared with the expected number (n = 30) from a control population (STRADA). An increased MVA risk ratio of 2.45 was found among patients compared with controls (P accident risk was most prominent in the elderly patients (65–80 y, seven versus two MVAs). In patients, driving distance (km/y), EDS (Epworth Sleepiness score ≥ 16), short habitual sleep time (≤ 5 h/night), and use of hypnotics were associated with increased MVA risk (odds ratios 1.2, 2.1, 2.7 and 2.1, all P ≤ 0.03). CPAP use ≥ 4 h/night was associated with a reduction of MVA incidence (7.6 to 2.5 accidents/1,000 drivers/y). Conclusions: The motor vehicle accident risk in this large cohort of unselected patients with obstructive sleep apnea suggests a need for accurate tools to identify individuals at risk. Sleep apnea severity (e.g., apnea-hypopnea index) failed to identify patients at risk. Citation: Karimi M, Hedner J, Häbel H, Nerman O, Grote L. Sleep apnea related risk of motor vehicle accidents is reduced by continuous positive airway pressure: Swedish traffic accident registry data. SLEEP 2015;38(3):341–349. PMID:25325460

Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

International Nuclear Information System (INIS)

Martirosyan, Anna; Clendening, James W; Goard, Carolyn A; Penn, Linda Z

2010-01-01

Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action. The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches. We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis. The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism. Moreover, we also show lovastatin synergizes

[Studies on interaction of acid-treated nanotube titanic acid and amino acids].

Science.gov (United States)

Zhang, Huqin; Chen, Xuemei; Jin, Zhensheng; Liao, Guangxi; Wu, Xiaoming; Du, Jianqiang; Cao, Xiang

2010-06-01

Nanotube titanic acid (NTA) has distinct optical and electrical character, and has photocatalysis character. In accordance with these qualities, NTA was treated with acid so as to enhance its surface activity. Surface structures and surface groups of acid-treated NTA were characterized and analyzed by Transmission Electron Microscope (TEM) and Fourier Transform Infrared Spectrometry (FT-IR). The interaction between acid-treated NTA and amino acids was investigated. Analysis results showed that the lengths of acid-treated NTA became obviously shorter. The diameters of nanotube bundles did not change obviously with acid-treating. Meanwhile, the surface of acid-treated NTA was cross-linked with carboxyl or esterfunction. In addition, acid-treated NTA can catch amino acid residues easily, and then form close combination.

Ibotenic acid and thioibotenic acid

DEFF Research Database (Denmark)

Hermit, Mette B; Greenwood, Jeremy R; Nielsen, Birgitte

2004-01-01

In this study, we have determined and compared the pharmacological profiles of ibotenic acid and its isothiazole analogue thioibotenic acid at native rat ionotropic glutamate (iGlu) receptors and at recombinant rat metabotropic glutamate (mGlu) receptors expressed in mammalian cell lines....... Thioibotenic acid has a distinct pharmacological profile at group III mGlu receptors compared with the closely structurally related ibotenic acid; the former is a potent (low microm) agonist, whereas the latter is inactive. By comparing the conformational energy profiles of ibotenic and thioibotenic acid...... with the conformations preferred by the ligands upon docking to mGlu1 and models of the other mGlu subtypes, we propose that unlike other subtypes, group III mGlu receptor binding sites require a ligand conformation at an energy level which is prohibitively expensive for ibotenic acid, but not for thioibotenic acid...

Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study.

Directory of Open Access Journals (Sweden)

Yoshie Hasegawa

Full Text Available Zoledronic acid (ZOL is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT.Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95 or the CTZ group (n = 93 from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2, followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug.This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8% was doubled to CT group (7.7%, respectively (one-sided chi-square test, p = 0.068, though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071, and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112. Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and

[Acids in coffee. XI. The proportion of individual acids in the total titratable acid].

Science.gov (United States)

Engelhardt, U H; Maier, H G

1985-07-01

22 acids in ground roast coffees and instant coffees were determined by GLC of their silyl derivatives (after preseparation by gel electrophoresis) or isotachophoresis. The contribution to the total acidity (which was estimated by titration to pH 8 after cation exchange of the coffee solutions) was calculated for each individual acid. The mentioned acids contribute with 67% (roast coffee) and 72% (instant coffee) to the total acidity. In the first place citric acid (12.2% in roast coffee/10.7% in instant coffee), acetic acid (11.2%/8.8%) and the high molecular weight acids (8%/9%) contribute to the total acidity. Also to be mentioned are the shares of chlorogenic acids (9%/4.8%), formic acid (5.3%/4.6%), quinic acid (4.7%/5.9%), malic acid (3.9%/3%) and phosphoric acid (2.5%/5.2%). A notable difference in the contribution to total acidity between roast and instant coffee was found for phosphoric acid and pyrrolidonecarboxylic acid (0.7%/1.9%). It can be concluded that those two acids are formed or released from e.g. their esters in higher amounts than other acids during the production of instant coffee.

Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans

DEFF Research Database (Denmark)

Mörck, Catarina; Elmelund-Præstekær, Louise Cathrine Braun; Kurth, Caroline

2009-01-01

of lipid moieties for protein prenylation. The nematode Caenorhabditis elegans possesses a mevalonate pathway that lacks the branch leading to cholesterol synthesis, and thus represents an ideal organism to specifically study the noncholesterol roles of the pathway. Inhibiting HMG-CoA reductase in C....... elegans using statins or RNAi leads to developmental arrest and loss of membrane association of a GFP-based prenylation reporter. The unfolded protein response (UPR) is also strongly activated, suggesting that impaired prenylation of small GTPases leads to the accumulation of unfolded proteins and ER...... and fatty acid composition were unaffected in statin-treated worms, even though they showed reduced staining with Nile red. We conclude that inhibitors of HMG-CoA reductase or of farnesyl transferases induce the UPR by inhibiting the prenylation of M57.2 substrates, resulting in developmental arrest in C...

Cardiac Computed Tomography versus Echocardiography in the Assessment of Stenotic Rheumatic Mitral Valve.

Science.gov (United States)

Unal Aksu, Hale; Gorgulu, Sevket; Diker, Mustafa; Celik, Omer; Aksu, Huseyin; Ozturk, Derya; Kırıs, Adem; Kalkan, Ali Kemal; Erturk, Mehmet; Bakır, İhsan

2016-03-01

There are different clinical cardiac applications of dual source computed tomography (DSCT). Here, we aimed to compare the DSCT with the transthoracic echocardiography (TTE) for evaluating the Wilkins score and planimetric mitral valve area (MVA) of a rheumatic stenotic mitral valve. We prospectively evaluated mitral valvular structure and function in 31 patients with known mitral stenosis undergoing electrocardiogram-gated, second-generation DSCT, in our heart center for different indications. Mitral valve was evaluated using Wilkins score, and also, the planimetric MVA was assessed. We found a significant difference between MVAs determined by DSCT (average 1.42 ± 0.44 cm2) and MVAs determined by TTE (average 1.35 ± 0.43 cm2 ; difference 0.07 ± 0.16 cm2; P = 0.018). Linear regression analysis revealed a good correlation between the two techniques (r = 0.934; P < 0.0001). The limits of agreement for DSCT and TTE in the Bland-Altman analysis were ±0.31 cm2 . DSCT using TTE as the reference enabled good discrimination between mild and moderate-to-severe stenosis and had an area under the ROC curve of 0.967 (CI 0.912-1.023; P < 0.0001). Wilkins scores obtained by DSCT (7.51 ± 1.17, range 5-10) and TTE (8.16 ± 1.27, range 6-10) had a moderate correlation (r = 0.686; P < 0.0001). We found that planimetric MVA measurements assessed by DSCT were closely correlated with MVA calculations by TTE. The moderate correlation was observed for the Wilkins score. © 2015, Wiley Periodicals, Inc.

Longitudinal Associations Between PTSD Symptoms and Dyadic Conflict Communication Following a Severe Motor Vehicle Accident.

Science.gov (United States)

Fredman, Steffany J; Beck, J Gayle; Shnaider, Philippe; Le, Yunying; Pukay-Martin, Nicole D; Pentel, Kimberly Z; Monson, Candice M; Simon, Naomi M; Marques, Luana

2017-03-01

There are well-documented associations between posttraumatic stress disorder (PTSD) symptoms and intimate relationship impairments, including dysfunctional communication at times of relationship conflict. To date, the extant research on the associations between PTSD symptom severity and conflict communication has been cross-sectional and focused on military and veteran couples. No published work has evaluated the extent to which PTSD symptom severity and communication at times of relationship conflict influence each other over time or in civilian samples. The current study examined the prospective bidirectional associations between PTSD symptom severity and dyadic conflict communication in a sample of 114 severe motor vehicle accident (MVA) survivors in a committed intimate relationship at the time of the accident. PTSD symptom severity and dyadic conflict communication were assessed at 4 and 16weeks post-MVA, and prospective associations were examined using path analysis. Total PTSD symptom severity at 4weeks prospectively predicted greater dysfunctional communication at 16weeks post-MVA but not vice versa. Examination at the level of PTSD symptom clusters revealed that effortful avoidance at 4weeks prospectively predicted greater dysfunctional communication at 16weeks, whereas dysfunctional communication 4weeks after the MVA predicted more severe emotional numbing at 16weeks. Findings highlight the role of PTSD symptoms in contributing to dysfunctional communication and the importance of considering PTSD symptom clusters separately when investigating the dynamic interplay between PTSD symptoms and relationship functioning over time, particularly during the early posttrauma period. Clinical implications for the prevention of chronic PTSD and associated relationship problems are discussed. Copyright © 2016. Published by Elsevier Ltd.

Identifying Clinical Factors Which Predict for Early Failure Patterns Following Resection for Pancreatic Adenocarcinoma in Patients Who Received Adjuvant Chemotherapy Without Chemoradiation.

Science.gov (United States)

Walston, Steve; Salloum, Joseph; Grieco, Carmine; Wuthrick, Evan; Diaz, Dayssy A; Barney, Christian; Manilchuk, Andrei; Schmidt, Carl; Dillhoff, Mary; Pawlik, Timothy M; Williams, Terence M

2018-05-04

The role of radiation therapy (RT) in resected pancreatic cancer (PC) remains incompletely defined. We sought to determine clinical variables which predict for local-regional recurrence (LRR) to help select patients for adjuvant RT. We identified 73 patients with PC who underwent resection and adjuvant gemcitabine-based chemotherapy alone. We performed detailed radiologic analysis of first patterns of failure. LRR was defined as recurrence of PC within standard postoperative radiation volumes. Univariate analyses (UVA) were conducted using the Kaplan-Meier method and multivariate analyses (MVA) utilized the Cox proportional hazard ratio model. Factors significant on UVA were used for MVA. At median follow-up of 20 months, rates of local-regional recurrence only (LRRO) were 24.7%, LRR as a component of any failure 68.5%, metastatic recurrence (MR) as a component of any failure 65.8%, and overall disease recurrence (OR) 90.5%. On UVA, elevated postoperative CA 19-9 (>90 U/mL), pathologic lymph node positive (pLN+) disease, and higher tumor grade were associated with increased LRR, MR, and OR. On MVA, elevated postoperative CA 19-9 and pLN+ were associated with increased MR and OR. In addition, positive resection margin was associated with increased LRRO on both UVA and MVA. About 25% of patients with PC treated without adjuvant RT develop LRRO as initial failure. The only independent predictor of LRRO was positive margin, while elevated postoperative CA 19-9 and pLN+ were associated with predicting MR and overall survival. These data may help determine which patients benefit from intensification of local therapy with radiation.

The acidic functional groups of humic acid

Energy Technology Data Exchange (ETDEWEB)

Shanxiang, Li; Shuhe, Sun; Zhai Zongxi, Wu Qihu

1983-09-01

The acidic functional groups content, pK value, DELTAH and DELTAS of humic acid (HA) and nitro-humic acid (NHA) were determined by potentiometry, conductometry and calorimetric titration. The thermodynamic parameters of carboxylic groups and phenolic hydroxyl groups of humic acid are similar to that of simple hydroxy-benzoic acid. The configuration sites of acidic functional groups in humic acid from different coals are different. The carbonyl groups on aromatic rings are probably ortho to phenolic -OH for HA and NHA extracted from Huangxian's brown coal and Japanese lignite, while those from Lingshi's weathered coal are not. The weak -COOH groups of the latter possess higher chemical activity. The -COOH content in HA increases, phenolic -OH group decreases and the chemical acidity of acidic functional groups increases when HA is oxidized by nitric acid. (14 refs.)

A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; final results of the fluvastatin angiographic restenosis (FLARE) trial

NARCIS (Netherlands)

J. Shepherd; H. Suryapranata (Harry); P.J. Pfister; P.J. de Feyter (Pim); G.A. van Es (Gerrit Anne); R. Melkert (Rein); G. Jackson (Graham); J.J.R.M. Bonnier (Hans); C.M. Miguel (Carlos); M.C. Vrolix (Mathias); A. Branzi (Angelo); P.W.J.C. Serruys (Patrick); D.P. Foley (David)

1999-01-01

textabstractBACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors competitively inhibit biosynthesis of mevalonate, a precursor of non-sterol compounds involved in cell proliferation. Experimental evidence suggests that fluvastatin may, independent of

Development of an image-based screening system for inhibitors of the plastidial MEP pathway and of protein geranylgeranylation

Science.gov (United States)

Hartmann, Michael; Gas-Pascual, Elisabet; Hemmerlin, Andrea; Rohmer, Michel; Bach, Thomas J.

2015-01-01

In a preceding study we have recently established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, which involves expressing a dexamethasone-inducible GFP fused to the prenylable, carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL). By using pathway-specific inhibitors it was there demonstrated that inhibition of the methylerythritol phosphate (MEP) pathway with oxoclomazone and fosmidomycin, as well as inhibition of protein geranylgeranyl transferase type 1 (PGGT-1), shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA) pathway with mevinolin did not affect this localization. Furthermore, in this initial study complementation assays with pathway-specific intermediates confirmed that the precursors for the cytosolic isoprenylation of this fusion protein are predominantly provided by the MEP pathway. In order to optimize this visualization system from a more qualitative assay to a statistically trustable medium or a high-throughput screening system, we established now new conditions that permit culture and analysis in 96-well microtiter plates, followed by fluorescence microscopy. For further refinement, the existing GFP-BD-CVIL cell line was transformed with an estradiol-inducible vector driving the expression of a RFP protein, C-terminally fused to a nuclear localization signal (NLS-RFP). We are thus able to quantify the total number of viable cells versus the number of inhibited cells after various treatments. This approach also includes a semi-automatic counting system, based on the freely available image processing software. As a result, the time of image analysis as well as the risk of user-generated bias is reduced to a minimum. Moreover, there is no cross-induction of gene expression by dexamethasone and estradiol, which is an

Studi Pengaruh Pemasangan NGR 40 Ohm pada Uprating Transformator 2 GI Gianyar Terhadap Gangguan Hubung Singkat 1 Phasa Tanah

Directory of Open Access Journals (Sweden)

Arya Surya Darma

2017-08-01

Full Text Available Along with the development of ever-increasing burden on the GI Gianyar then the transformer unit 2 with a capacity of 30 MVA will be uprating with a capacity of 60 MVA transformer. To maintain the continuity and reliability of the flow of electrical power to the consumer , NGR (Neutral Grounding Resistance and relay SBEF is used as the safety equipment of the short circuit 1 phase to ground was not in to the neutral point of the transformer. Uprating of transformers that have been done changes on 1 phase fault current to ground when using a direct earthing systems with a value to become 1838.21 A. While the value of the short-circuit current 1 phase to ground after pairing NGR 40 Ohm value is fixed at 288.675 A, so that the current setting and time relay SBEF fixed at 90 A and 7.067 seconds. The analysis result from the effect of installation NGR and rele SBEF on the transformer 60 MVA against short circuit 1 phase to ground has the ability good protection for the value of the fault current is able to be reduced from 1838,21 A into 288.675 A after pairing NGR 40 Ohm and time is needed SBEF to handle distractions 7.067 seconds. Intisari- Seiring dengan perkembangan beban yang terus meningkat di GI Gianyar maka transformator unit 2 berkapasitas 30 MVA akan di lakukan uprating (penggantian dengan transformator berkapasitas 60 MVA. Untuk menjaga kontinyuitas dan keandalan aliran daya listrik sampai ke konsumen (beban, NGR (Neutral Grounding Resistance dan rele SBEF dipergunakan sebagai peralatan pengaman dari gangguan hubung singkat phasa tanah agar arus gangguan 1 phasa ke tanah tidak sampai mengalir ke titik netral transformator. Dari uprating transformator yang sudah di lakukan terjadi perubahan pada arus gangguan 1 phasa ke tanah jika menggunakan sistem pentanahan langsung (solid grounding menjadi 1838,21 A. Sedangkan nilai dari arus hubung singkat 1 phasa ke tanah setelah dipasangkan NGR 40 Ohm nilainya tetap sebesar 288,675 A

Mechanism of inhibitory effect of atorvastatin on resistin expression induced by tumor necrosis factor-α in macrophages

Directory of Open Access Journals (Sweden)

Chua Su-Kiat

2009-05-01

Full Text Available Abstract Atorvastatin has been shown to reduce resistin expression in macrophages after pro-inflammatory stimulation. However, the mechanism of reducing resistin expression by atorvastatin is not known. Therefore, we sought to investigate the molecular mechanisms of atorvastatin for reducing resistin expression after proinflammatory cytokine, tumor necrosis factor-α (TNF-α stimulation in cultured macrophages. Cultured macrophages were obtained from human peripheral blood mononuclear cells. TNF-α stimulation increased resistin protein and mRNA expression and atorvastatin inhibited the induction of resistin by TNF-α. Addition of mevalonate induced resistin protein expression similar to TNF-α stimulation. However, atorvastatin did not have effect on resistin protein expression induced by mevalonate. SP600125 and JNK small interfering RNA (siRNA completely attenuated the resistin protein expression induced by TNF-α and mevalonate. TNF-α induced phosphorylation of Rac, while atorvastatin and Rac-1 inhibitor inhibited the phosphorylation of Rac induced by TNF-α. The gel shift and promoter activity assay showed that TNF-α increased AP-1-binding activity and resistin promoter activity, while SP600125 and atorvastatin inhibited the AP-1-binding activity and resistin promoter activity induced by TNF-α. Recombinant resistin and TNF-α significantly reduced glucose uptake in cultured macrophages, while atorvastatin reversed the reduced glucose uptake by TNF-α. In conclusion, JNK and Rac pathway mediates the inhibitory effect of atorvastatin on resistin expression induced by TNF-α.

Statins and protein prenylation in cancer cell biology and therapy.

Science.gov (United States)

Garcia-Ruiz, Carmen; Morales, Albert; Fernandez-Checa, Jose C

2012-05-01

The use of statins has scaled up to become one of the most prescribed medicines in the world and have been very useful in the manegement of cardiovascular diseases and related mortality. The disclosure of their chemical structure similar to that of hydroxy methyl glutaryl-CoA (HMG-CoA) revealed their ability to compete with and inhibit the rate-limiting enzyme HMG-CoA reductase that catalyzes the synthesis of mevalonate, which then serves as the precursor for isoprenoids and cholesterol in the mevalonate pathway. While most of the effects of statins are associated with the lowering of cellular cholesterol levels, it is clear that they also blunt the non-sterol branch of the mevalonate pathway, decreasing formation of isoprenoids and altering protein-prenylation, a critical event in the posttranslational modulation of proteins involved in the regulation of cell cycle progression, proliferation and signaling pathways. Randomized controlled trials for the prevention of cardiovascular diseases indicated that statins elicited provocative and unexpected benefits for reducing a number of different types of cancers, including colorectal carcinoma, melanoma, prostate and hepatocellular carcinoma, although in other cancer types the preclinical expectations of statins were dissapointing. In this review, we will describe the evidence and mechanisms underlying the potential beneficial use of statins and the role of protein prenylation in cancer prevention. Of relevance, the combination of statins with other anti cancer drugs may be a significant asset in malignancies resistant to current therapy.

The Acid-Base Titration of a Very Weak Acid: Boric Acid

Science.gov (United States)

Celeste, M.; Azevedo, C.; Cavaleiro, Ana M. V.

2012-01-01

A laboratory experiment based on the titration of boric acid with strong base in the presence of d-mannitol is described. Boric acid is a very weak acid and direct titration with NaOH is not possible. An auxiliary reagent that contributes to the release of protons in a known stoichiometry facilitates the acid-base titration. Students obtain the…

Usnic acid controls the acidity tolerance of lichens

International Nuclear Information System (INIS)

Hauck, Markus; Juergens, Sascha-Rene

2008-01-01

The hypotheses were tested that, firstly, lichens producing the dibenzofuran usnic acid colonize substrates characterized by specific pH ranges, secondly, this preferred pH is in a range where soluble usnic acid and its corresponding anion occur in similar concentrations, and thirdly, usnic acid makes lichens vulnerable to acidity. Lichens with usnic acid prefer an ambient pH range between 3.5 and 5.5 with an optimum between 4.0 and 4.5. This optimum is close to the pK a1 value of usnic acid of 4.4. Below this optimum pH, dissolved SO 2 reduces the chlorophyll fluorescence yield more in lichens with than without their natural content of usnic acid. This suggests that usnic acid influences the acidity tolerance of lichens. The putative mechanism of the limited acidity tolerance of usnic acid-containing lichens is the acidification of the cytosol by molecules of protonated usnic acid shuttling protons through the plasma membrane at an apoplastic pH a1 . - Combined field and experimental data suggest that usnic acid makes lichens sensitive to acidity at pH <3.5

Structure of active IspH enzyme from escherichia coli provides mechanistic insights into substrate reduction

KAUST Repository

Grä wert, Tobias; Rohdich, Felix; Span, Lngrid; Backer, Adelbert; Eisenreich, Wolfgang; Eppinger, Jö rg; Groll, Michael

2009-01-01

The terminal step of the non-mevalonate pathway of terpene biosynthesis is catalyzed by IspH (see scheme). In the crystal structure of IspH from E. coli, a bound inorganic diphosphate ligand occupies the position of the diphosphate residue

Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers

NARCIS (Netherlands)

Federici, Silvia; Sormani, Maria Pia; Ozen, Seza; Lachmann, Helen J; Amaryan, Gayane; Woo, Patricia; Koné-Paut, Isabelle; Dewarrat, Natacha; Cantarini, Luca; Insalaco, Antonella; Uziel, Yosef; Rigante, Donato; Quartier, Pierre; Demirkaya, Erkan; Herlin, Troels; Meini, Antonella; Fabio, Giovanna; Kallinich, Tilmann; Martino, Silvana; Butbul, Aviel Yonatan; Olivieri, Alma; Kuemmerle-Deschner, Jasmin; Neven, Benedicte; Simon, Anna; Ozdogan, Huri; Touitou, Isabelle; Frenkel, Joost; Hofer, Michael; Martini, Alberto; Ruperto, Nicolino; Gattorno, Marco

2015-01-01

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor

Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response

NARCIS (Netherlands)

Simon, A.; Bijzet, J.; Voorbij, H.A.M.; Mantovani, A.; Van Der Meer, J.W.M.; Drenth, J.P.H.

2004-01-01

Background. Classical type hyper-immunoglobulin D (IgD) syndrome (HTDS) is an hereditary autoinflammatory disorder, characterized by recurrent episodes of fever, lymphadenopathy, abdominal distress and a high serum concentration of IgD. It is caused by mevalonate kinase deficiency. Objective. To

Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation

NARCIS (Netherlands)

Houten, S. M.; Frenkel, J.; Waterham, H. R.

2003-01-01

Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its

[Teichoic acids from lactic acid bacteria].

Science.gov (United States)

Livins'ka, O P; Harmasheva, I L; Kovalenko, N K

2012-01-01

The current view of the structural diversity of teichoic acids and their involvement in the biological activity of lactobacilli has been reviewed. The mechanisms of effects of probiotic lactic acid bacteria, in particular adhesive and immunostimulating functions have been described. The prospects of the use of structure data of teichoic acid in the assessment of intraspecific diversity of lactic acid bacteria have been also reflected.

Preparation of fulvic acid and low-molecular organic acids by oxidation of weathered coal humic acid

Energy Technology Data Exchange (ETDEWEB)

Shinozuka, T.; Ito, A.; Sasaki, O.; Yazawa, Y.; Yamaguchi, T. [Chiba Institute of Technolgy, Chiba (Japan). Dept. of Industrial Chemistry

2002-07-01

Weathered coal contains much humic acid and a little fulvic acid. Therefore, the production of fulvic acid, the most valuable humic substance because of its water-solubility, was examined by ozone and hydrogen peroxide oxidation of humic acid extracted form Xinjiang (China) weathered coal. The resulting products of the oxidation were water soluble fulvic acid and organic acids, mainly formic acid and oxalic acid. The product yield of fulvic acid was 20 (C%) and that of organic acids were 39 (C%) for formic and acid 13 (C%) for oxalic acid. The formed fulvic acid showed a higher content of oxygen and carboxyl groups, than those of the extracted one from the original weathered coal.

Unlocking interpretation in near infrared multivariate calibrations by orthogonal partial least squares.

Science.gov (United States)

Stenlund, Hans; Johansson, Erik; Gottfries, Johan; Trygg, Johan

2009-01-01

Near infrared spectroscopy (NIR) was developed primarily for applications such as the quantitative determination of nutrients in the agricultural and food industries. Examples include the determination of water, protein, and fat within complex samples such as grain and milk. Because of its useful properties, NIR analysis has spread to other areas such as chemistry and pharmaceutical production. NIR spectra consist of infrared overtones and combinations thereof, making interpretation of the results complicated. It can be very difficult to assign peaks to known constituents in the sample. Thus, multivariate analysis (MVA) has been crucial in translating spectral data into information, mainly for predictive purposes. Orthogonal partial least squares (OPLS), a new MVA method, has prediction and modeling properties similar to those of other MVA techniques, e.g., partial least squares (PLS), a method with a long history of use for the analysis of NIR data. OPLS provides an intrinsic algorithmic improvement for the interpretation of NIR data. In this report, four sets of NIR data were analyzed to demonstrate the improved interpretation provided by OPLS. The first two sets included simulated data to demonstrate the overall principles; the third set comprised a statistically replicated design of experiments (DoE), to demonstrate how instrumental difference could be accurately visualized and correctly attributed to Wood's anomaly phenomena; the fourth set was chosen to challenge the MVA by using data relating to powder mixing, a crucial step in the pharmaceutical industry prior to tabletting. Improved interpretation by OPLS was demonstrated for all four examples, as compared to alternative MVA approaches. It is expected that OPLS will be used mostly in applications where improved interpretation is crucial; one such area is process analytical technology (PAT). PAT involves fewer independent samples, i.e., batches, than would be associated with agricultural applications; in

Antigenicity of Leishmania-Activated C-Kinase Antigen (LACK in Human Peripheral Blood Mononuclear Cells, and Protective Effect of Prime-Boost Vaccination With pCI-neo-LACK Plus Attenuated LACK-Expressing Vaccinia Viruses in Hamsters

Directory of Open Access Journals (Sweden)

Laura Fernández

2018-04-01

Full Text Available Leishmania-activated C-kinase antigen (LACK is a highly conserved protein among Leishmania species and is considered a viable vaccine candidate for human leishmaniasis. In animal models, prime-boost vaccination with LACK-expressing plasmids plus attenuated vaccinia viruses (modified vaccinia Ankara [MVA] and mutant M65 expressing LACK, has been shown to protect against cutaneous leishmaniasis (CL. Further, LACK demonstrated to induce the production of protective cytokines in patients with active CL or cured visceral leishmaniasis, as well as in asymptomatic individuals from endemic areas. However, whether LACK is capable to trigger cytokine release by peripheral blood mononuclear cells from patients cured of CL due to Leishmania infantum (L. infantum or induce protection in L. infantum-infected hamsters [visceral leishmaniasis (VL model], has not yet been analyzed. The present work examines the ex vivo immunogenicity of LACK in cured VL and CL patients, and asymptomatic subjects from an L. infantum area. It also evaluates the vaccine potential of LACK against L. infantum infection in hamsters, in a protocol of priming with plasmid pCI-neo-LACK (DNA-LACK followed by a booster with the poxvirus vectors MVA-LACK or M65-LACK. LACK-stimulated PBMC from both asymptomatic and cured subjects responded by producing IFN-γ, TNF-α, and granzyme B (Th1-type response. Further, 78% of PBMC samples that responded to soluble Leishmania antigen showed IFN-γ secretion following stimulation with LACK. In hamsters, the protocol of DNA-LACK prime/MVA-LACK or M65-LACK virus boost vaccination significantly reduced the amount of Leishmania DNA in the liver and bone marrow, with no differences recorded between the use of MVA or M65 virus vector options. In summary, the Th1-type and cytotoxic responses elicited by LACK in PBMC from human subjects infected with L. infantum, and the parasite protective effect of prime/boost vaccination in hamsters with DNA-LACK/MVA

Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Morris, W. James, E-mail: jmorris@bccancer.bc.ca [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Tyldesley, Scott [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Rodda, Sree [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Halperin, Ross [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Centre for the Southern Interior, Vancouver, British Columbia (Canada); Pai, Howard [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Island Centre, Vancouver, British Columbia (Canada); McKenzie, Michael; Duncan, Graeme [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Morton, Gerard [Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Hamm, Jeremy [Department of Population Oncology, BC Cancer Agency, Vancouver, British Columbia (Canada); Murray, Nevin [BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Department of Medicine, University of British Columbia, Vancouver, British Columbia (Canada)

2017-06-01

Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.

Acid Rain

Science.gov (United States)

Bricker, Owen P.; Rice, Karen C.

1995-01-01

Although acid rain is fading as a political issue in the United States and funds for research in this area have largely disappeared, the acidity of rain in the Eastern United States has not changed significantly over the last decade, and it continues to be a serious environmental problem. Acid deposition (commonly called acid rain) is a term applied to all forms of atmospheric deposition of acidic substances - rain, snow, fog, acidic dry particulates, aerosols, and acid-forming gases. Water in the atmosphere reacts with certain atmospheric gases to become acidic. For example, water reacts with carbon dioxide in the atmosphere to produce a solution with a pH of about 5.6. Gases that produce acids in the presence of water in the atmosphere include carbon dioxide (which converts to carbonic acid), oxides of sulfur and nitrogen (which convert to sulfuric and nitric acids}, and hydrogen chloride (which converts to hydrochloric acid). These acid-producing gases are released to the atmosphere through natural processes, such as volcanic emissions, lightning, forest fires, and decay of organic matter. Accordingly, precipitation is slightly acidic, with a pH of 5.0 to 5.7 even in undeveloped areas. In industrialized areas, most of the acid-producing gases are released to the atmosphere from burning fossil fuels. Major emitters of acid-producing gases include power plants, industrial operations, and motor vehicles. Acid-producing gases can be transported through the atmosphere for hundreds of miles before being converted to acids and deposited as acid rain. Because acids tend to build up in the atmosphere between storms, the most acidic rain falls at the beginning of a storm, and as the rain continues, the acids "wash out" of the atmosphere.

Symptoms and beyond: Self-concept among sexually assaulted women.

Science.gov (United States)

Keshet, Hadar; Gilboa-Schechtman, Eva

2017-09-01

The unique characteristics of sexual assault (SA)-a toxic mix of an interpersonal harm, a violent exploitation of one's body, and a transformation of an act of connectedness into an act of submission-are postulated to negatively affect the self-concept. We sought to deepen the understanding of self-concept impairments among sexually assaulted women with varying levels of posttraumatic distress. To this end, we compared women with a main trauma of SA to women with a main trauma of motor-vehicle accident (MVA) and to nontraumatized (NT) women on several self-concept aspects. Our main hypotheses were (a) sexually assaulted women without PTSD exhibit impaired self-concept as compared with NT women and (b) SA is related to greater self-concept impairments as compared with MVA, even when posttraumatic distress is statistically controlled. Women (N = 235: NT = 69, MVA = 87, SA = 79) completed a web-based survey including measures designed to assess the global and domain-specific contents and structure of the self-concept as well as background and clinical questionnaires. Sexually assaulted women without PTSD reported impaired self-concept as compared with NT women. Furthermore, SA was related to greater self-concept impairments as compared with MVA, even when considering participants' levels of posttraumatic distress. SA is related to unique self-concept impairments that extend beyond symptoms, emphasizing the need to assess and address self-concept impairments in sexually assaulted women. The importance of adopting a multifaceted conceptualization of the self to gain a deeper understanding of the aftermath of trauma is highlighted. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Improving monoterpene geraniol production through geranyl diphosphate synthesis regulation in Saccharomyces cerevisiae.

Science.gov (United States)

Zhao, Jianzhi; Bao, Xiaoming; Li, Chen; Shen, Yu; Hou, Jin

2016-05-01

Monoterpenes have wide applications in the food, cosmetics, and medicine industries and have recently received increased attention as advanced biofuels. However, compared with sesquiterpenes, monoterpene production is still lagging in Saccharomyces cerevisiae. In this study, geraniol, a valuable acyclic monoterpene alcohol, was synthesized in S. cerevisiae. We evaluated three geraniol synthases in S. cerevisiae, and the geraniol synthase Valeriana officinalis (tVoGES), which lacked a plastid-targeting peptide, yielded the highest geraniol production. To improve geraniol production, synthesis of the precursor geranyl diphosphate (GPP) was regulated by comparing three specific GPP synthase genes derived from different plants and the endogenous farnesyl diphosphate synthase gene variants ERG20 (G) (ERG20 (K197G) ) and ERG20 (WW) (ERG20 (F96W-N127W) ), and controlling endogenous ERG20 expression, coupled with increasing the expression of the mevalonate pathway by co-overexpressing IDI1, tHMG1, and UPC2-1. The results showed that overexpressing ERG20 (WW) and strengthening the mevalonate pathway significantly improved geraniol production, while expressing heterologous GPP synthase genes or down-regulating endogenous ERG20 expression did not show positive effect. In addition, we constructed an Erg20p(F96W-N127W)-tVoGES fusion protein, and geraniol production reached 66.2 mg/L after optimizing the amino acid linker and the order of the proteins. The best strain yielded 293 mg/L geraniol in a fed-batch cultivation, a sevenfold improvement over the highest titer previously reported in an engineered S. cerevisiae strain. Finally, we showed that the toxicity of geraniol limited its production. The platform developed here can be readily used to synthesize other monoterpenes.

Enzymatic formation of hexadecenoic acid from palmitic acid

International Nuclear Information System (INIS)

Nakano, Masao; Fujino, Yasuhiko

1975-01-01

Desaturation of palmitic acid was investigated in an enzyme system prepared from rat liver. 2-trans-Hexadecenoic acid as well as 9-cis-gexadecenoic acid (palmitoleic acid) were found to be formed as monoenoic acid in this system. (author)

Improved survival in rhesus macaques immunized with modified vaccinia virus Ankara recombinants expressing simian immunodeficiency virus envelope correlates with reduction in memory CD4+ T-cell loss and higher titers of neutralizing antibody.

Science.gov (United States)

Ourmanov, Ilnour; Kuwata, Takeo; Goeken, Robert; Goldstein, Simoy; Iyengar, Ranjani; Buckler-White, Alicia; Lafont, Bernard; Hirsch, Vanessa M

2009-06-01

Previous studies demonstrated that immunization of macaques with simian immunodeficiency virus (SIV) Gag-Pol and Env recombinants of the attenuated poxvirus modified vaccinia virus Ankara (MVA) provided protection from high viremia and AIDS following challenge with a pathogenic strain of SIV. Although all animals became infected, plasma viremia was significantly reduced in animals that received the MVA-SIV recombinant vaccines compared with animals that received nonrecombinant MVA. Most importantly, the reduction in viremia resulted in a significant increase in median and cumulative survival. Continued analysis of these animals over the subsequent 9 years has shown that they maintain a survival advantage, although all but two of the macaques have progressed to AIDS. Importantly, improved survival correlated with preservation of memory CD4(+) T cells in the peripheral blood. The greatest survival advantage was observed in macaques immunized with regimens containing SIV Env, and the titer of neutralizing antibodies to the challenge virus prior to or shortly following challenge correlated with preservation of CD4(+) T cells. These data are consistent with a role for neutralizing antibodies in nonsterilizing protection from high viremia and associated memory CD4(+) T-cell loss.

Diabetes and driving safety: science, ethics, legality and practice.

Science.gov (United States)

Cox, Daniel J; Singh, Harsimran; Lorber, Daniel

2013-04-01

Diabetes affects over 25 million people in the United States, most of whom are over the age of 16 and many of whom are licensed to drive a motor vehicle. Safe operation of a motor vehicle requires complex interactions of cognitive and motor functions and medical conditions that affect these functions often will increase the risk of motor vehicle accidents (MVA). In the case of diabetes, hypoglycemia is the most common factor that has been shown to increase MVA rates. When people with diabetes are compared with nondiabetic controls, systematic analyses show that the relative risk of MVA is increased by between 12% and 19% (Relative Risk Ratio 1.12-1.19). In comparison, the RRR for attention deficit hyperactivity disorder is 4.4 and for sleep apnea is 2.4. Epidemiologic research suggests that patients at risk for hypoglycemia-related MVAs may have some characteristics in common, including a history of severe hypoglycemia or of hypoglycemia-related driving mishaps. Experimental studies also have shown that people with a history of hypoglycemia-related driving mishaps have abnormal counter-regulatory responses to hypoglycemia and greater cognitive impairments during moderate hypoglycemia.

Sequential injection redox or acid-base titration for determination of ascorbic acid or acetic acid.

Science.gov (United States)

Lenghor, Narong; Jakmunee, Jaroon; Vilen, Michael; Sara, Rolf; Christian, Gary D; Grudpan, Kate

2002-12-06

Two sequential injection titration systems with spectrophotometric detection have been developed. The first system for determination of ascorbic acid was based on redox reaction between ascorbic acid and permanganate in an acidic medium and lead to a decrease in color intensity of permanganate, monitored at 525 nm. A linear dependence of peak area obtained with ascorbic acid concentration up to 1200 mg l(-1) was achieved. The relative standard deviation for 11 replicate determinations of 400 mg l(-1) ascorbic acid was 2.9%. The second system, for acetic acid determination, was based on acid-base titration of acetic acid with sodium hydroxide using phenolphthalein as an indicator. The decrease in color intensity of the indicator was proportional to the acid content. A linear calibration graph in the range of 2-8% w v(-1) of acetic acid with a relative standard deviation of 4.8% (5.0% w v(-1) acetic acid, n=11) was obtained. Sample throughputs of 60 h(-1) were achieved for both systems. The systems were successfully applied for the assays of ascorbic acid in vitamin C tablets and acetic acid content in vinegars, respectively.

Glycosyltransferase glycosylating flavokermesic acid and/or kermesic acid

DEFF Research Database (Denmark)

2016-01-01

An isolated glycosyltransferase (GT) polypeptide capable of: (I) : conjugating glucose to flavokermesic acid (FK); and/or (II) : conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid.......An isolated glycosyltransferase (GT) polypeptide capable of: (I) : conjugating glucose to flavokermesic acid (FK); and/or (II) : conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid....

GLYCOSYLTRANSFERASE GLYCOSYLATING FLAVOKERMESIC ACID AND/OR KERMESIC ACID

DEFF Research Database (Denmark)

2015-01-01

An isolated glycosyltransferase (GT) polypeptide capable of: (I): conjugating glucose to flavokermesic acid (FK); and/or (II): conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid.......An isolated glycosyltransferase (GT) polypeptide capable of: (I): conjugating glucose to flavokermesic acid (FK); and/or (II): conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid....

Nonorthologous gene displacement of phosphomevalonate kinase

NARCIS (Netherlands)

Houten, S. M.; Waterham, H. R.

2001-01-01

Phosphomevalonate kinase (PMK; EC 2.7.4.2) catalyzes the phosphorylation of 5-phosphomevalonate into 5-diphosphomevalonate, an essential step in isoprenoid biosynthesis via the mevalonate pathway. So far, two nonorthologous genes encoding PMK have been described, the Saccharomyces cerevisiae ERG8

Effect of inflammatory attacks in the classical type hyper-IgD syndrome on immunoglobulin D, cholesterol and parameters of the acute phase response.

NARCIS (Netherlands)

Simon, A.; Bijzet, J.; Voorbij, H.A.; Mantovani, A.; Meer, J.W.M. van der; Drenth, J.P.H.

2004-01-01

BACKGROUND: Classical type hyper-immunoglobulin D (IgD) syndrome (HIDS) is an hereditary auto-inflammatory disorder, characterized by recurrent episodes of fever, lymphadenopathy, abdominal distress and a high serum concentration of IgD. It is caused by mevalonate kinase deficiency. OBJECTIVE: To

Statin Resistance and Export

DEFF Research Database (Denmark)

Ley, Ana

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the key enzyme in the mevalonate pathway that leads to the synthesis of cholesterol and ergosterol in animal and fungal cells, respectively. Their extensiveuse in treatment and prevention of cardiovascular diseases...

Specific bile acid radioimmunoassays for separate determinations of unconjugated cholic acid, conjugated cholic acid and conjugated deoxycholic acid in serum and their clinical application

International Nuclear Information System (INIS)

Matern, S.; Gerok, W.

1977-01-01

Specific radioimmunoassays for separate determinations of serum unconjugated cholic, conjugated cholic and conjugated deoxycholic acids have been developed. Prior to the radioimmunoassay, extraction of serum bile acids was performed with Amberlite XAD-2. Unconjugated cholic acid was separated from glyco- and taurocholic acids by thin-layer chromatography. At 50% displacement of bound labeled glyco[ 3 H]cholic acid using antiserum obtained after immunization with cholic acid-bovine serum albumin-conjugate the cross-reactivity of taurocholic acid was 100%, cholic acid 80%, glycochenodeoxycholic acid 10%, chenodeoxycholic acid 7%, conjugated deoxycholic acid 3%, and conjugated lithocholic acid 3 H]cholic acid was linear on a logit-log plot from 5 to 80 pmol of unlabeled glycocholic acid. Fasting serum conjugated cholic acid in healthy subjects was 0.68 +- 0.34 μmol/l. Unconjugated cholic acid was determined by a solid phase radioimmunoassay using the cholic acid antibody chemically bound to Sepharose. The displacement curve of [ 3 H]cholic acid in the solid phase radioimmunoassay was linear on a logit-log plot from 5 to 200 pmol of unlabeled cholic acid. The coefficient of variation between samples was 5%. Fasting serum conjugated deoxycholic acid concentrations in 10 healthy subjects ranged from 0.18 to 0.92 μmol/l determined by a radioimmunoassay using antiserum obtained after immunization with deoxycholic acid-bovine serum albumin-conjugate. The clinical application of these bile acid radioimmunoassays is shown by an 'oral cholate tolerance test' as a sensitive indicator of liver function and by an 'oral cholyglycine tolerance test' as a useful test for bile acid absorption. (orig.) [de

Amino acids in the sedimentary humic and fulvic acids

Digital Repository Service at National Institute of Oceanography (India)

Sardessai, S.

acids in the coastal Arabian Sea sediments: whereas amino acids content of fulvic acids was lower than that of humic acids in the coastal sediments of Bay of Bengal. Slope sedimentary humic acids were relatively enriched in amino acids as compared...

Effect of propionic acid on citric acid fermentation in an integrated citric acid-methane fermentation process.

Science.gov (United States)

Xu, Jian; Bao, Jia-Wei; Su, Xian-Feng; Zhang, Hong-Jian; Zeng, Xin; Tang, Lei; Wang, Ke; Zhang, Jian-Hua; Chen, Xu-Sheng; Mao, Zhong-Gui

2016-03-01

In this study, an integrated citric acid-methane fermentation process was established to solve the problem of wastewater treatment in citric acid production. Citric acid wastewater was treated through anaerobic digestion and then the anaerobic digestion effluent (ADE) was further treated and recycled for the next batch citric acid fermentation. This process could eliminate wastewater discharge and reduce water resource consumption. Propionic acid was found in the ADE and its concentration continually increased in recycling. Effect of propionic acid on citric acid fermentation was investigated, and results indicated that influence of propionic acid on citric acid fermentation was contributed to the undissociated form. Citric acid fermentation was inhibited when the concentration of propionic acid was above 2, 4, and 6 mM in initial pH 4.0, 4.5 and, 5.0, respectively. However, low concentration of propionic acid could promote isomaltase activity which converted more isomaltose to available sugar, thereby increasing citric acid production. High concentration of propionic acid could influence the vitality of cell and prolong the lag phase, causing large amount of glucose still remaining in medium at the end of fermentation and decreasing citric acid production.

Metabolic engineering of Escherichia coli for limonene and perillyl alcohol production.

Science.gov (United States)

Alonso-Gutierrez, Jorge; Chan, Rossana; Batth, Tanveer S; Adams, Paul D; Keasling, Jay D; Petzold, Christopher J; Lee, Taek Soon

2013-09-01

Limonene is a valuable monoterpene used in the production of several commodity chemicals and medicinal compounds. Among them, perillyl alcohol (POH) is a promising anti-cancer agent that can be produced by hydroxylation of limonene. We engineered E. coli with a heterologous mevalonate pathway and limonene synthase for production of limonene followed by coupling with a cytochrome P450, which specifically hydroxylates limonene to produce POH. A strain containing all mevalonate pathway genes in a single plasmid produced limonene at titers over 400mg/L from glucose, substantially higher than has been achieved in the past. Incorporation of a cytochrome P450 to hydroxylate limonene yielded approximately 100mg/L of POH. Further metabolic engineering of the pathway and in situ product recovery using anion exchange resins would make this engineered E. coli a potential production platform for any valuable limonene derivative. © 2013 Elsevier Inc. All rights reserved.

A Direct, Biomass-Based Synthesis of Benzoic Acid: Formic Acid-Mediated Deoxygenation of the Glucose-Derived Materials Quinic Acid and Shikimic Acid

Energy Technology Data Exchange (ETDEWEB)

Arceo, Elena; Ellman, Jonathan; Bergman, Robert

2010-05-03

An alternative biomass-based route to benzoic acid from the renewable starting materials quinic acid and shikimic acid is described. Benzoic acid is obtained selectively using a highly efficient, one-step formic acid-mediated deoxygenation method.

Catalytic acetoxylation of lactic acid to 2-acetoxypropionic acid, en route to acrylic acid

NARCIS (Netherlands)

Beerthuis, R.; Granollers, M.; Brown, D.R.; Salavagione, H.J.; Rothenberg, G.; Shiju, N.R.

2015-01-01

We present an alternative synthetic route to acrylic acid, starting from the platform chemical lactic acid and using heterogeneous catalysis. To improve selectivity, we designed an indirect dehydration reaction that proceeds via acetoxylation of lactic acid to 2-acetoxypropionic acid. This

[Lipid synthesis by an acidic acid tolerant Rhodotorula glutinis].

Science.gov (United States)

Lin, Zhangnan; Liu, Hongjuan; Zhang, Jian'an; Wang, Gehua

2016-03-01

Acetic acid, as a main by-product generated in the pretreatment process of lignocellulose hydrolysis, significantly affects cell growth and lipid synthesis of oleaginous microorganisms. Therefore, we studied the tolerance of Rhodotorula glutinis to acetic acid and its lipid synthesis from substrate containing acetic acid. In the mixed sugar medium containing 6 g/L glucose and 44 g/L xylose, and supplemented with acetic acid, the cell growth was not:inhibited when the acetic acid concentration was below 10 g/L. Compared with the control, the biomass, lipid concentration and lipid content of R. glutinis increased 21.5%, 171% and 122% respectively when acetic acid concentration was 10 g/L. Furthermore, R. glutinis could accumulate lipid with acetate as the sole carbon source. Lipid concentration and lipid yield reached 3.20 g/L and 13% respectively with the initial acetic acid concentration of 25 g/L. The lipid composition was analyzed by gas chromatograph. The main composition of lipid produced with acetic acid was palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid, including 40.9% saturated fatty acids and 59.1% unsaturated fatty acids. The lipid composition was similar to that of plant oil, indicating that lipid from oleaginous yeast R. glutinis had potential as the feedstock of biodiesel production. These results demonstrated that a certain concentration of acetic acid need not to be removed in the detoxification process when using lignocelluloses hydrolysate to produce microbial lipid by R. glutinis.

Production of jet fuel precursor monoterpenoids from engineered Escherichia coli

DEFF Research Database (Denmark)

Mendez-Perez, Daniel; Alonso-Gutierrez, Jorge; Hu, Qijun

2017-01-01

). FPP biosynthesis diverts the carbon flux from monoterpene production to C15 products and quinone biosynthesis. In this study, we tested a chromosomal mutation of Escherichia coli's native FPP synthase (IspA) to improve GPP availability for the production of monoterpenes using a heterologous mevalonate...

Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome

NARCIS (Netherlands)

Frenkel, Joost; Rijkers, Ger T.; Mandey, Saskia H. L.; Buurman, Sandra W. M.; Houten, Sander M.; Wanders, Ronald J. A.; Waterham, Hans R.; Kuis, Wietse

2002-01-01

OBJECTIVE: To investigate whether the increased interleukin-1beta (IL-1beta) secretion in hyperimmunoglobulinemia D and periodic fever syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds. METHODS:

[Regulating acid stress resistance of lactic acid bacteria--a review].

Science.gov (United States)

Wu, Chongde; Huang, Jun; Zhou, Rongqing

2014-07-04

As cell factories, lactic acid bacteria are widely used in food, agriculture, pharmaceutical and other industries. Acid stress is one the important survival challenges encountered by lactic acid bacteria both in fermentation process and in the gastrointestinal tract. Recently, the development of systems biology and metabolic engineering brings unprecedented opportunity for further elucidating the acid tolerance mechanisms and improving the acid stress resistance of lactic acid bacteria. This review addresses physiological mechanisms of lactic acid bacteria during acid stress. Moreover, strategies to improve the acid stress resistance of lactic acid were proposed.

Preparation and characterization Al3+-bentonite Turen Malang for esterification fatty acid (palmitic acid, oleic acid and linoleic acid)

Science.gov (United States)

Abdulloh, Abdulloh; Aminah, Nanik Siti; Triyono, Mudasir, Trisunaryanti, Wega

2016-03-01

Catalyst preparation and characterization of Al3+-bentonite for esterification of palmitic acid, oleic acid and linoleic acid has been done. Al3+-bentonite catalyst was prepared from natural bentonite of Turen Malang through cation exchange reaction using AlCl3 solution. The catalysts obtained were characterized by XRD, XRF, pyridine-FTIR and surface area analyser using the BET method. Catalyst activity test of Al3+-bentonite for esterification reaction was done at 65°C using molar ratio of metanol-fatty acid of 30:1 and 0.25 g of Al3+-bentonite catalyst for the period of ½, 1, 2, 3, 4 and 5 hours. Based on the characterization results, the Al3+-bentonite Turen Malang catalyst has a d-spacing of 15.63 Ǻ, acid sites of Brönsted and Lewis respectively of 230.79 µmol/g and 99.39 µmol/g, surface area of 507.3 m2/g and the average of radius pore of 20.09 Å. GC-MS analysis results of the oil phase after esterification reaction showed the formation of biodiesel (FAME: Fatty acid methyl ester), namely methyl palmitate, methyl oleate and methyl linoleate. The number of conversions resulted in esterification reaction using Al3+-bentonite Turen Malang catalyst was 74.61%, 37.75%, and 20, 93% for the esterification of palmitic acid, oleic acid and linoleic acid respectively.

Efficacy of Lactic Acid, Lactic Acid-Acetic Acid Blends, and Peracetic Acid To Reduce Salmonella on Chicken Parts under Simulated Commercial Processing Conditions.

Science.gov (United States)

Ramirex-Hernandez, Alejandra; Brashears, Mindy M; Sanchez-Plata, Marcos X

2018-01-01

The poultry processing industry has been undergoing a series of changes as it modifies processing practices to comply with new performance standards for chicken parts and comminuted poultry products. The regulatory approach encourages the use of intervention strategies to prevent and control foodborne pathogens in poultry products and thus improve food safety and protect human health. The present studies were conducted to evaluate the efficacy of antimicrobial interventions for reducing Salmonella on inoculated chicken parts under simulated commercial processing conditions. Chicken pieces were inoculated by immersion in a five-strain Salmonella cocktail at 6 log CFU/mL and then treated with organic acids and oxidizing agents on a commercial rinsing conveyor belt. The efficacy of spraying with six different treatments (sterile water, lactic acid, acetic acid, buffered lactic acid, acetic acid in combination with lactic acid, and peracetic acid) at two concentrations was evaluated on skin-on and skin-off chicken thighs at three application temperatures. Skinless chicken breasts were used to evaluate the antimicrobial efficacy of lactic acid and peracetic acid. The color stability of treated and untreated chicken parts was assessed after the acid interventions. The lactic acid and buffered lactic acid treatments produced the greatest reductions in Salmonella counts. Significant differences between the control and water treatments were identified for 5.11% lactic acid and 5.85% buffered lactic acid in both skin-on and skin-off chicken thighs. No significant effect of treatment temperature for skin-on chicken thighs was found. Lactic acid and peracetic acid were effective agents for eluting Salmonella cells attached to chicken breasts.

Molecular interaction of pinic acid with sulfuric acid

DEFF Research Database (Denmark)

Elm, Jonas; Kurtén, Theo; Bilde, Merete

2014-01-01

We investigate the molecular interactions between the semivolatile α-pinene oxidation product pinic acid and sulfuric acid using computational methods. The stepwise Gibbs free energies of formation have been calculated utilizing the M06-2X functional, and the stability of the clusters is evaluated...... cluster. The involvement of more than one pinic acid molecule in a single cluster is observed to lead to the formation of favorable (pinic acid)2(H2SO4) and (pinic acid)2(H2SO4)2 clusters. The identified most favorable growth paths starting from a single pinic acid molecule lead to closed structures...

Effect of acetic acid on citric acid fermentation in an integrated citric acid-methane fermentation process.

Science.gov (United States)

Xu, Jian; Chen, Yang-Qiu; Zhang, Hong-Jian; Tang, Lei; Wang, Ke; Zhang, Jian-Hua; Chen, Xu-Sheng; Mao, Zhong-Gui

2014-09-01

An integrated citric acid-methane fermentation process was proposed to solve the problem of extraction wastewater in citric acid fermentation process. Extraction wastewater was treated by anaerobic digestion and then recycled for the next batch of citric acid fermentation to eliminate wastewater discharge and reduce water resource consumption. Acetic acid as an intermediate product of methane fermentation was present in anaerobic digestion effluent. In this study, the effect of acetic acid on citric acid fermentation was investigated and results showed that lower concentration of acetic acid could promote Aspergillus niger growth and citric acid production. 5-Cyano-2,3-ditolyl tetrazolium chloride (CTC) staining was used to quantify the activity of A. niger cells, and the results suggested that when acetic acid concentration was above 8 mM at initial pH 4.5, the morphology of A. niger became uneven and the part of the cells' activity was significantly reduced, thereby resulting in deceasing of citric acid production. Effects of acetic acid on citric acid fermentation, as influenced by initial pH and cell number in inocula, were also examined. The result indicated that inhibition by acetic acid increased as initial pH declined and was rarely influenced by cell number in inocula.

New Acid Combination for a Successful Sandstone Acidizing

Science.gov (United States)

Shafiq, M. U.; Mahmud, H. K. B.; Rezaee, R.

2017-05-01

With the development of new enhanced oil recovery techniques, sandstone acidizing has been introduced and played a pivotal role in the petroleum industry. Different acid combinations have been applied, which react with the formation, dissolve the soluble particles; thus increase the production of hydrocarbons. To solve the problems which occurred using current preflush sandstone acidizing technology (hydrochloric acid); a new acid combination has been developed. Core flooding experiments on sandstone core samples with dimensions 1.5 in. × 3 in. were conducted at a flow rate of 2 cm3/min. A series of hydrochloric-acetic acid mixtures with different ratios were tested under 150°F temperature. The core flooding experiments performed are aimed to dissolve carbonate, sodium, potassium and calcium particles from the core samples. These experiments are followed by few important tests which include, porosity-permeability, pH value, Inductively Coupled Plasma (ICP) analysis and Nuclear Magnetic Resonance (NMR measurements). All the results are compared with the results of conventional hydrochloric acid technology. NMR and porosity analysis concluded that the new acid combination is more effective in creating fresh pore spaces and thus increasing the reservoir permeability. It can be seen from the pore distribution before and after the acidizing. Prior applying acid; the large size of pores appears most frequently in the pore distribution while with the applied acid, it was found that the small pore size is most the predominant of the pore distribution. These results are validated using ICP analysis which shows the effective removal of calcium and other positive ions from the core sample. This study concludes that the combination of acetic-hydrochloric acid can be a potential candidate for the preflush stage of sandstone acidizing at high temperature reservoirs.

Intradermal HIV-1 DNA Immunization Using Needle-Free Zetajet Injection Followed by HIV-Modified Vaccinia Virus Ankara Vaccination Is Safe and Immunogenic in Mozambican Young Adults: A Phase I Randomized Controlled Trial.

Science.gov (United States)

Viegas, Edna Omar; Tembe, Nelson; Nilsson, Charlotta; Meggi, Bindiya; Maueia, Cremildo; Augusto, Orvalho; Stout, Richard; Scarlatti, Gabriella; Ferrari, Guido; Earl, Patricia L; Wahren, Britta; Andersson, Sören; Robb, Merlin L; Osman, Nafissa; Biberfeld, Gunnel; Jani, Ilesh; Sandström, Eric

2017-11-27

We assessed the safety and immunogenicity of HIV-DNA priming using Zetajet™, a needle-free device intradermally followed by intramuscular HIV-MVA boosts, in 24 healthy Mozambicans. Volunteers were randomized to receive three immunizations of 600 μg (n = 10; 2 × 0.1 ml) or 1,200 μg (n = 10; 2 × 0.2 ml) of HIV-DNA (3 mg/ml), followed by two boosts of 10 8 pfu HIV-MVA. Four subjects received placebo saline injections. Vaccines and injections were safe and well tolerated with no difference between the two priming groups. After three HIV-DNA immunizations, IFN-γ ELISpot responses to Gag were detected in 9/17 (53%) vaccinees, while none responded to Envelope (Env). After the first HIV-MVA, the overall response rate to Gag and/or Env increased to 14/15 (93%); 14/15 (93%) to Gag and 13/15 (87%) to Env. There were no significant differences between the immunization groups in frequency of response to Gag and Env or magnitude of Gag responses. Env responses were significantly higher in the higher dose group (median 420 vs. 157.5 SFC/million peripheral blood mononuclear cell, p = .014). HIV-specific antibodies to subtype C gp140 and subtype B gp160 were elicited in all vaccinees after the second HIV-MVA, without differences in titers between the groups. Neutralizing antibody responses were not detected. Two (13%) of 16 vaccinees, one in each of the priming groups, exhibited antibodies mediating antibody-dependent cellular cytotoxicity to CRF01_AE. In conclusion, HIV-DNA vaccine delivered intradermally in volumes of 0.1-0.2 ml using Zetajet was safe and well tolerated. Priming with the 1,200 μg dose of HIV-DNA generated higher magnitudes of ELISpot responses to Env.

Postoperative Chemoradiation Therapy in High-Risk Cervical Cancer: Re-evaluating the Findings of Gynecologic Oncology Group Study 109 in a Large, Population-Based Cohort

Energy Technology Data Exchange (ETDEWEB)

Trifiletti, Daniel M. [Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia (United States); Swisher-McClure, Samuel [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Showalter, Timothy N. [Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia (United States); Hegarty, Sarah E. [Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Grover, Surbhi, E-mail: Surbhi.grover@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

2015-12-01

Purpose: To review the National Cancer Database (NCDB) to evaluate postoperative high-risk cervical cancer patients for factors associated with a benefit from chemoradiation therapy (CRT) over external beam radiation therapy alone (EBRT). Methods and Materials: The National Cancer Database was queried for women with cervical cancer treated with hysterectomy and adjuvant EBRT from 2002 to 2012. Only patients with pathologic lymph node involvement (LN+), positive surgical margins, and/or parametrial invasion were included in our analysis (on the basis of Peter's criteria). Univariable and multivariable analyses (MVA) were performed, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to investigate for factors associated with of CRT utilization and overall survival (OS). Results: A total of 3053 patients met inclusion criteria, and 2479 received adjuvant CRT (81%), whereas 574 (19%) received EBRT alone. Factors associated with increased CRT utilization on MVA included age <69 years, year of diagnosis ≥2008, non-adenocarcinoma histology, and LN+. Use of CRT improved OS among the entire cohort on MVA (HR 0.76, CI 0.601-0.962; P=.022). On MVA, CRT improved OS in patients with LN+ as their sole Peter's criteria (HR 0.58, CI 0.413-0.814; P=.002). Chemoradiation therapy did not improve OS in patients with only positive margins (P=.73), only parametrial invasion (P=.95), or any combination of these 2 factors without LN+ (P=.63). Conclusions: The use of adjuvant CRT after hysterectomy improves OS in patients with high-risk cervical cancer compared with EBRT alone, but this benefit seems to be restricted to patients with LN+. The benefits of adjuvant CRT over EBRT alone in patients with parametrial invasion and/or positive margins (without nodal involvement) are unknown.

A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer.

Science.gov (United States)

Taylor, Graham S; Jia, Hui; Harrington, Kevin; Lee, Lip Wai; Turner, James; Ladell, Kristin; Price, David A; Tanday, Manjit; Matthews, Jen; Roberts, Claudia; Edwards, Ceri; McGuigan, Lesley; Hartley, Andrew; Wilson, Steve; Hui, Edwin P; Chan, Anthony T C; Rickinson, Alan B; Steven, Neil M

2014-10-01

Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses. Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations. Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively. MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials. ©2014 American Association for Cancer Research.

Infectivity of attenuated poxvirus vaccine vectors and immunogenicity of a raccoonpox vectored rabies vaccine in the Brazilian Free-tailed bat (Tadarida brasiliensis)

Science.gov (United States)

Stading, Benjamin; Osorio, Jorge E.; Velasco-Villa, Andres; Smotherman, Michael; Kingstad-Bakke, Brock; Rocke, Tonie E.

2016-01-01

Bats (Order Chiroptera) are an abundant group of mammals with tremendous ecological value as insectivores and plant dispersers, but their role as reservoirs of zoonotic diseases has received more attention in the last decade. With the goal of managing disease in free-ranging bats, we tested modified vaccinia Ankara (MVA) and raccoon poxvirus (RCN) as potential vaccine vectors in the Brazilian Free-tailed bat (Tadarida brasiliensis), using biophotonic in vivo imaging and immunogenicity studies. Animals were administered recombinant poxviral vectors expressing the luciferase gene (MVA-luc, RCN-luc) through oronasal (ON) or intramuscular (IM) routes and subsequently monitored for bioluminescent signal indicative of viral infection. No clinical illness was noted after exposure to any of the vectors, and limited luciferase expression was observed. Higher and longer levels of expression were observed with the RCN-luc construct. When given IM, luciferase expression was limited to the site of injection, while ON exposure led to initial expression in the oral cavity, often followed by secondary replication at another location, likely the gastric mucosa or gastric associated lymphatic tissue. Viral DNA was detected in oral swabs up to 7 and 9 days post infection (dpi) for MVA and RCN, respectively. While no live virus was detected in oral swabs from MVA-infected bats, titers up to 3.88 x 104 PFU/ml were recovered from oral swabs of RCN-infected bats. Viral DNA was also detected in fecal samples from two bats inoculated IM with RCN, but no live virus was recovered. Finally, we examined the immunogenicity of a RCN based rabies vaccine (RCN-G) following ON administration. Significant rabies neutralizing antibody titers were detected in the serum of immunized bats using the rapid fluorescence focus inhibition test (RFFIT). These studies highlight the safety and immunogenicity of attenuated poxviruses and their potential use as vaccine vectors in bats.

Viral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosis.

Science.gov (United States)

Vordermeier, H Martin; Villarreal-Ramos, Bernardo; Cockle, Paul J; McAulay, Martin; Rhodes, Shelley G; Thacker, Tyler; Gilbert, Sarah C; McShane, Helen; Hill, Adrian V S; Xing, Zhou; Hewinson, R Glyn

2009-08-01

Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin (BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after M. bovis challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.

The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone

Directory of Open Access Journals (Sweden)

Martin Boegemann

2017-02-01

Full Text Available The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS and overall survival (OS was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR <5 and 17 with NLR >5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months (HR: 1.6 (95%CI:0.9–2.8; p = 0.11. After multivariate adjustment (MVA, ECOG > 0–1, baseline LDH>upper limit of normal (UNL and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months (HR: 2.3 (95%CI:1.3–4.0; p < 0.01. In MVA, ECOG > 0–1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to <5 prognosticated worse PFS (five versus 12 months (HR: 4.1 (95%CI:1.1–15.8; p = 0.04. MVA showed a trend towards worse PFS for NLR-change to <5 (p = 0.11. NLR-change to <5 led to non-significant shorter median OS (seven versus 16 months (HR: 2.3 (95%CI:0.7–7.1; p = 0.15. MVA showed non-significant difference for OS. We concluded baseline NLR <5 is associated with improved survival. In contrast, in patients with baseline NLR >5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully.

Application of citric acid in acid stimulation treatments

Energy Technology Data Exchange (ETDEWEB)

Alkhaldi, M.H.; Sarma, H.K. [Adelaide Univ., Adelaide (Australia); Nasr-el-Din, H.A. [Texas A and M Univ., College Station, TX (United States)

2009-07-01

A rotating disk apparatus was used to investigate mass transfer during the reaction of citric acid with calcite. The study evaluated the effects of initial acid concentrations, temperature, and disk rotational speed on the effective diffusion coefficient of citric acid. The diffusion coefficient was calculated at 25, 40, and 50 degrees C using various citric acid concentrations. The study indicated that the coefficient was a function of the interactions between calcium citrate precipitation and counter calcium ions. At high acid concentrations, the effects of calcium citrate precipitation and counter calcium ions were significant. The calculated citric acid diffusion coefficients were not comparable with measured effective diffusion coefficients using the rotating disk. At lower initial citric acid concentrations, the effects of both calcium citrate precipitation and counter calcium ions on citric acid diffusivity were minimal. It was concluded that temperature effects on the diffusion coefficient followed Arrhenius law. Activation energy was equal to 37.9 kJ/mol. 34 refs., 4 tabs., 13 figs.

Acid distribution in phosphoric acid fuel cells

Energy Technology Data Exchange (ETDEWEB)

Okae, I.; Seya, A.; Umemoto, M. [Fuji Electric Co., Ltd., Chiba (Japan)

1996-12-31

Electrolyte acid distribution among each component of a cell is determined by capillary force when the cell is not in operation, but the distribution under the current load conditions had not been clear so far. Since the loss of electrolyte acid during operation is inevitable, it is necessary to store enough amount of acid in every cell. But it must be under the level of which the acid disturbs the diffusion of reactive gases. Accordingly to know the actual acid distribution during operation in a cell is very important. In this report, we carried out experiments to clarify the distribution using small single cells.

Determination of dissociation constants or propionic acid and lactic acid (2-hydroxypropionic acid) by potentiometry and conductometry

International Nuclear Information System (INIS)

Saeeduddin; Khanzada, A.W.K.

2004-01-01

Dissociation constants of propionic acid and 2-hydroxypropionic acid (lactic acid) have been studied at different temperatures between 25 to 50 deg. C interval. Propionic acid is analyzed by conductometry while 2-hydroxypropionic acid is analyzed by potentiometry. Both investigated compounds are symmetrical carboxylic acids having same length of carbon chain but are markedly different in ionic behavior. We were interested to see how the hydroxyl group (-OH) induction in propionic acid affects on pKa values of 2-hydroxypropionic acid. We observed that as temperature increases pKa values increase. The increase is observed for both the investigated compounds. PKa values of 2-hydroxypropionic acid are lower as compared to propionic acid because of electron withdrawing (-OH). (author)

Acid Rain, pH & Acidity: A Common Misinterpretation.

Science.gov (United States)

Clark, David B.; Thompson, Ronald E.

1989-01-01

Illustrates the basis for misleading statements about the relationship between pH and acid content in acid rain. Explains why pH cannot be used as a measure of acidity for rain or any other solution. Suggests that teachers present acidity and pH as two separate and distinct concepts. (RT)

Chlorogenic acid and caffeic acid are absorbed in humans

NARCIS (Netherlands)

Olthof, Margreet R.; Hollman, Peter C H; Katan, Martijn B.

2001-01-01

Chlorogenic acid, an ester of caffeic acid and quinic acid, is a major phenolic compound in coffee; daily intake in coffee drinkers is 0.5-1 g. Chlorogenic acid and caffeic acid are antioxidants in vitro and might therefore contribute to the prevention of cardiovascular disease. However, data on the

Improvement on control of waste disposal system at Genkai Nuclear Power Station No.1 and No.2 unit

International Nuclear Information System (INIS)

Morooka, Masatoshi; Tsutsumi, Akria

1989-01-01

At Genkai Nuclear Power Station, the operational and control systems of the boric acid evaporator, waste liquid evaporator and gaseous waste disposal system were converted from general purpose analong systems to computer instrumentation and control systems in order to improve their operability and controllability. The equipments were operated by batch processing system, so plant operators were required to operate them manually. By introducing the computer instrumentation and control systems, the automatic operation of the equipments has become possible. Furthermore, it has become possible to monitor the relevant parameters intensively with a CRT in the operating room, and it contributes to the improvement of reliability and labor saving. The operation of No.1 plant was begun in October, 1975, and No.2 plant in March, 1981. Both are the PWR plants of 625 MVA capacity. The outline of the power station facilities, the background of the reconstruction, the problems and the plan of reconstruction for the boric acid recovery facility, waste liquid evaporator and gas compressor, the peculiarity of the reconstruction works, and the effect of introducing the new systems are reported. (Kako, I.)

Note: a high-sensitivity current sensor based on piezoelectric ceramic Pb(Zr,Ti)O3 and ferromagnetic materials.

Science.gov (United States)

He, Wei; Li, Ping; Wen, Yumei; Zhang, Jitao; Yang, Aichao; Lu, Caijiang

2014-02-01

An electric current sensor using piezoelectric ceramic Pb(Zr,Ti)O3 (PZT) sandwiched between two high permeability cuboids and two NdFeB magnets is presented. The magnetic field originating from an electric wire is augmented by the high permeability cuboids. The PZT plate experiences an enhanced magnetic force and generates voltage output. When placed with a distance of d = 5.0 mm from the wire, the sensor shows a flat sensitivity of ∼5.7 mV/A in the frequency range of 30 Hz-80 Hz and an average sensitivity of 5.6 mV/A with highly linear behavior in the current range of 1 A-10 A at 50 Hz.

Kinetic properties and inhibition of Trypanosoma cruzi 3-hydroxy-3-methylglutaryl CoA reductase

DEFF Research Database (Denmark)

Hurtado-Guerrrero, Ramón; Pena Diaz, Javier; Montalvetti, Andrea

2002-01-01

A detailed kinetic analysis of the recombinant soluble enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) from Trypanosoma cruzi has been performed. The enzyme catalyzes the normal anabolic reaction and the reductant is NADPH. It also catalyzes the oxidation of mevalonate but at a lower propo...

Comparison of Buffer Effect of Different Acids During Sandstone Acidizing

International Nuclear Information System (INIS)

Shafiq, Mian Umer; Mahmud, Hisham Khaled Ben; Hamid, Mohamed Ali

2015-01-01

The most important concern of sandstone matrix acidizing is to increase the formation permeability by removing the silica particles. To accomplish this, the mud acid (HF: HCl) has been utilized successfully for many years to stimulate the sandstone formations, but still it has many complexities. This paper presents the results of laboratory investigations of different acid combinations (HF: HCl, HF: H 3 PO 4 and HF: HCOOH). Hydrofluoric acid and fluoboric acid are used to dissolve clays and feldspar. Phosphoric and formic acids are added as a buffer to maintain the pH of the solution; also it allows the maximum penetration of acid into the core sample. Different tests have been performed on the core samples before and after the acidizing to do the comparative study on the buffer effect of these acids. The analysis consists of permeability, porosity, color change and pH value tests. There is more increase in permeability and porosity while less change in pH when phosphoric and formic acids were used compared to mud acid. From these results it has been found that the buffer effect of phosphoric acid and formic acid is better than hydrochloric acid. (paper)

Electrolytic nature of aqueous sulfuric acid. 2. Acidity.

Science.gov (United States)

Fraenkel, Dan

2012-09-27

In part 1 of this study, I reported that the Debye-Hückel limiting law and the smaller-ion shell (SiS) model of strong electrolyte solutions fit nicely with the experimental mean ionic activity coefficient (γ(±)) of aqueous sulfuric acid as a function of concentration and of temperature when the acid is assumed to be a strong 1-3 electrolyte. Here, I report that the SiS-derived activity coefficient of H(+), γ(H(+)), of the 1-3 acid is comparable to that of aqueous HCl. This agrees with titration curves showing, as well-known, that sulfuric acid in water is parallel in strength to aqueous HCl. The calculated pH is in good accord with the Hammett acidity function, H(0), of aqueous sulfuric acid at low concentration, and differences between the two functions at high concentration are discussed and explained. This pH-H(0) relation is consistent with the literature showing that the H(0) of sulfuric acid (in the 1-9 M range) is similar to those of HCl and the other strong mineral monoprotic acids. The titration of aqueous sulfuric acid with NaOH does not agree with the known second dissociation constant of 0.010 23; rather, the constant is found to be ~0.32 and the acid behaves upon neutralization as a strong diprotic acid practically dissociating in one step. A plausible reaction pathway is offered to explain how the acid may transform, upon base neutralization, from a dissociated H(4)SO(5) (as 3H(+) and HSO(5)(3-)) to a dissociated H(2)SO(4) even though the equilibrium constant of the reaction H(+) + HSO(5)(3-) ↔ SO(4)(2-) + H(2)O, at 25 °C, is 10(-37) (part 1).

Aspartic acid

Science.gov (United States)

... we eat. Aspartic acid is also called asparaginic acid. Aspartic acid helps every cell in the body work. It ... release Normal nervous system function Plant sources of aspartic acid include: avocado, asparagus, and molasses. Animal sources of ...

Incorporation and distribution of dihomo-gamma-linolenic acid, arachidonic acid, and eicosapentaenoic acid in cultured human keratinocytes

International Nuclear Information System (INIS)

Punnonen, K.; Puustinen, T.; Jansen, C.T.

1986-01-01

Human keratinocytes in culture were labelled with 14 C-dihomo-gamma-linolenic acid, 14 C-arachidonic acid or 14 C-eicosapentaenoic acid. All three eicosanoid precursor fatty acids were effectively incorporated into the cells. In phospholipids most of the radioactivity was recovered, in neutral lipids a substantial amount, and as free unesterified fatty acids only a minor amount. Most of the radioactivity was found in phosphatidylethanolamine which was also the major phospholipid as measured by phosphorous assay. The incorporation of dihomo-gamma-linolenic acid and arachidonic acid into lipid subfractions was essentially similar. Eicosapentaenoic acid was, however, much less effectively incorporated into phosphatidylinositol + phosphatidylserine and, correspondingly, more effectively into triacylglycerols as compared to the two other precursor fatty acids. Once incorporated, the distribution of all three precursor fatty acids was relatively stable, and only minor amounts of fatty acids were released into the culture medium during short term culture (two days). Our study demonstrates that eicosanoid precursor fatty acids are avidly taken up by human keratinocytes and esterified into membrane lipids. The clinical implication of this finding is that dietary manipulations might be employed to cause changes in the fatty acid composition of keratinocytes

Role of membrane sterols and cortical microtubules in gravity resistance in plants

Science.gov (United States)

Hoson, T.; Koizumi, T.; Matsumoto, S.; Kumasaki, S.; Soga, K.; Wakabayashi, K.; Sakaki, T.

Resistance to the gravitational force is a principal graviresponse in plants comparable to gravitropism Nevertheless only limited information has been obtained for this graviresponse We have examined mechanisms of signal perception transformation and transduction of the perceived signal and response to the transduced signal in gravity resistance using hypergravity conditions produced by centrifugation In Arabidopsis hypocotyls hypergravity treatment greatly increased the expression level of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase HMGR which catalyzes a reaction producing mevalonic acid a key precursor of terpenoids such as membrane sterols Geranyl diphosphate synthase gene was also up-regulated by hypergravity whereas the expression of other genes involved in membrane lipid metabolism was not influenced Hypergravity caused an increase in sterol content in azuki bean epicotyls but not in phospholipid glycolipid or fatty acid content Also hypergravity did not influence fatty acid composition in any lipid class Thus the effect of hypergravity on membrane lipid metabolism was specific for sterol synthesis On the other hand alpha- and beta-tubulin genes were up-regulated by hypergravity treatment in Arabidopsis hypocotyls Hypergravity also induced reorientation of cortical microtubules in azuki epicotyls the percentage of epidermal cells with transverse microtubles was decreased whereas that with longitudinal microtubules was increased Inhibitors of HMGR action and microtubule-disrupting agents completely prevented the gravity resistance

Multiserotype protection elicited by a combinatorial prime-boost vaccination strategy against bluetongue virus.

Directory of Open Access Journals (Sweden)

Eva Calvo-Pinilla

Full Text Available Bluetongue virus (BTV belongs to the genus Orbivirus within the family Reoviridae. The development of vector-based vaccines expressing conserved protective antigens results in increased immune activation and could reduce the number of multiserotype vaccinations required, therefore providing a cost-effective product. Recent recombinant DNA technology has allowed the development of novel strategies to develop marker and safe vaccines against BTV. We have now engineered naked DNAs and recombinant modified vaccinia virus Ankara (rMVA expressing VP2, VP7 and NS1 proteins from BTV-4. IFNAR((-/- mice inoculated with DNA/rMVA-VP2,-VP7-NS1 in an heterologous prime boost vaccination strategy generated significant levels of antibodies specific of VP2, VP7, and NS1, including those with neutralizing activity against BTV-4. In addition, vaccination stimulated specific CD8(+ T cell responses against these three BTV proteins. Importantly, the vaccine combination expressing NS1, VP2 and VP7 proteins of BTV-4, elicited sterile protection against a lethal dose of homologous BTV-4 infection. Remarkably, the vaccine induced cross-protection against lethal doses of heterologous BTV-8 and BTV-1 suggesting that the DNA/rMVA-VP2,-VP7,-NS1 marker vaccine is a promising multiserotype vaccine against BTV.

Uracil in formic acid hydrolysates of deoxyribonucleic acid

Science.gov (United States)

Schein, Arnold H.

1966-01-01

1. When DNA is hydrolysed with formic acid for 30min. at 175° and the hydrolysate is chromatographed on paper with propan-2-ol–2n-hydrochloric acid, in addition to expected ultraviolet-absorbing spots corresponding to guanine, adenine, cytosine and thymine, an ultraviolet-absorbing region with RF similar to that of uracil can be detected. Uracil was separated from this region and identified by its spectra in acid and alkali, and by its RF in several solvent systems. 2. Cytosine, deoxyribocytidine and deoxyribocytidylic acid similarly treated with formic acid all yielded uracil, as did a mixture of deoxyribonucleotides. 3. Approx. 4% of deoxyribonucleotide cytosine was converted into uracil by the formic acid treatment. ImagesFig. 1. PMID:5949371

Pertumbuhan Cabai Merah (Capsicum annuum L. pada Tanah Masam yang Diinokulasi Mikoriza Vesikula Arbuskula (MVA Campuran dan Pupuk Fosfat

Directory of Open Access Journals (Sweden)

Maryam Jamilah

2017-06-01

Full Text Available This research aimed to find out the interaction effect between mixed Vesicular Arbuscular Mycorrhiza (VAM and phosphate fertilizer to the growth of red chili (C. annuum in acid soil, and to fnd out the best combination of mixed VAM and phosphate fertilizer to the growth of red chili (C. annuum in acid soil. This research used an experimental method with Completely Randomized Design (CRD in a factorial pattern with two factors. The first factor was mixed VAM dosages consisted of four levels: 0; 10; 15; 20 g/plant. The second factor was phosphate fertilizer dosages consisted of four levels:  0; 0,2; 0,4; 0,6 g/plant. Each combination treatment had three replication. The parameters were observed in the form of plant height, stem diameter, plant top dry weight, degree of VAM infection, and P content of plant tissue. Data obtained from the observation was analyzed with Analysis of Variance (ANOVA at an error rate of 5% and 1%, treatment that showed significant or very significant result, then followed with Honestly Significant Difference (HSD test. The result showed that interaction between mixed Vesicular Arbuscular Mycorrhiza (VAM and phosphate fertilizer did not increase the plant height, stem diameter, and plant top dry weight, but each factor increased the plant height, stem diameter, and plant top dry weight. VAM dosage inoculation of 20 g/plant without phosphate fertilizer is the most effective combination in increasing the degree of VAM infection.

Reactive extraction and recovery of levulinic acid, formic acid and furfural from aqueous solutions containing sulphuric acid

NARCIS (Netherlands)

Brouwer, Thomas; Blahusiak, Marek; Babic, Katarina; Schuur, Boelo

2017-01-01

Levulinic acid (LA) can be produced from lignocellulosic materials via hydroxylation followed by an acid-catalyzed conversion of hexoses. Inorganic homogeneous catalysts are mostly used, in particular sulphuric acid, yielding a mixture of LA with sulphuric acid, formic acid (FA) and furfural.

8MVA modulator/regulator for neutral beams

International Nuclear Information System (INIS)

Remsen, D.B. Jr.; Overett, T.H.

1980-05-01

This paper describes very generally the modulator/regulator (Mod/Reg) being built for Transrex by Systems, Science and Software for use on the neutral beam power supplies that Transrex is building for General Atomic Company to power the neutral beam heating systems that will be used on the Doublet III fusion device. The Mod/Reg is required to provide an 80 kV, 100 A pulse for a second every 90 sec. The voltage is to be regulated to 3%, and in case of fault the pulse must be interrupted within 10 μsec. An additional requirement was that the total system have very low capacity such that the total energy stored would be less than 15 joules. This is a restriction imposed by the source designer to prevent destroying the source in case of an arc within the source

Well acidizing

Energy Technology Data Exchange (ETDEWEB)

Street, E H

1980-01-23

The apparatus relates in particular to a well-treating process in which an aqueous acid solution having a pH of < 2 is injected into a subterranean reservoir in a manner such that materials that contain ferric ions are present in the acid and, as the acid reacts within the reservoir and attains a pH exceeding 3, tend to be precipitated as ferric ion-containing solid materials that may plug the pores of the reservoir. Such a precipitation is prevented by dissolving in the acid solution an amount of 5-sulfosalicylic acid which is at least sufficient to sequester significant proportions of ferric ions when the pH of the acid is from 0.5 to 3 but is less than enough to cause a significant salting-out of solid materials, and an amount of citric acid which is at least sufficient to sequester significant proportions of ferric ions when the pH of the acid is from 3 to 6 but is less than enough to precipitate a significant amount of calcium citrate. The amount of the 5-sulfosalicylic acid may be from 0.01 to 0.05 moles/l and the amount of citric acid is from 0.001 to 0.009 moles/l. 11 claims.

Chemistry and electrochemistry in trifluoroacetic acid. Comparison with acetic acid

International Nuclear Information System (INIS)

Petit, Gerard

1972-01-01

As the trifluoroacetic acid is, with the acetic acid, one of most often used carboxylic acids as solvent, notably in organic chemistry, this research thesis addresses some relatively simple complexing and redox reactions to highlight the peculiar feature of this acid, and to explain its very much different behaviour with respect to acetic acid. The author develops the notion of acidity level in solvents of low dielectric constant. The second part addresses a specific solvent: BF 3 (CH 3 COOH) 2 . The boron trifluoride strengthens the acidity of acetic acid and modifies its chemical and physical-chemical properties. In the third part, the author compares solvent properties of CF 3 COOH and CH 3 COOH. Noticed differences explain why the trifluoroacetic acid is a more interesting reaction environment than acetic acid for reactions such as electrophilic substitutions or protein solubilisation [fr

Deuterium incorporation experiments from (3R)- and (3S)-[3-2H]leucine into characteristic isoprenoidal lipid-core of halophilic archaea suggests the involvement of isovaleryl-CoA dehydrogenase.

Science.gov (United States)

Yamauchi, Noriaki; Tanoue, Ryo

2017-11-01

The stereochemical reaction course for the two C-3 hydrogens of leucine to produce a characteristic isoprenoidal lipid in halophilic archaea was observed using incubation experiments with whole cell Halobacterium salinarum. Deuterium-labeled (3R)- and (3S)-[3- 2 H]leucine were freshly prepared as substrates from 2,3-epoxy-4-methyl-1-pentanol. Incorporation of deuterium from (3S)-[3- 2 H]leucine and loss of deuterium from (3R)-[3- 2 H]leucine in the lipid-core of H. salinarum was observed. Taken together with the results of our previous report, involving the incubation of chiral-labeled [5- 2 H]leucine, these results strongly suggested an involvement of isovaleryl-CoA dehydrogenase in leucine conversion to isoprenoid lipid in halophilic archaea. The stereochemical course of the reaction (anti-elimination) might have been the same as that previously reported for mammalian enzyme reactions. Thus, these results suggested that branched amino acids were metabolized to mevalonate in archaea in a manner similar to other organisms.

Role of sialic acid in synaptosomal transport of amino acid transmitters

International Nuclear Information System (INIS)

Zaleska, M.M.; Erecinska, M.

1987-01-01

Active, high-affinity, sodium-dependent uptake of [ 14 C]-aminobutyric acid and of the acidic amino acid D-[ 3 H]-aspartate was inhibited by pretreatment of synaptosomes with neuraminidase from Vibrio cholerae. Inhibition was of a noncompetitive type and was related to the amount of sialic acid released. The maximum accumulation ratios of both amino acids (intracellular [amino acid]/extracellular [amino acid]) remained largely unaltered. Treatment with neuraminidase affected neither the synaptosomal energy levels nor the concentration of internal potassium. It is suggested that the γ-aminobutyric acid and acidic amino acid transporters are glycosylated and that sialic acid is involved in the operation of the carrier proteins directly and not through modification of driving forces responsible for amino acid uptake

Distillation Separation of Hydrofluoric Acid and Nitric Acid from Acid Waste Using the Salt Effect on Vapor-Liquid Equilibrium

Science.gov (United States)

Yamamoto, Hideki; Sumoge, Iwao

2011-03-01

This study presents the distillation separation of hydrofluoric acid with use of the salt effect on the vapor-liquid equilibrium for acid aqueous solutions and acid mixtures. The vapor-liquid equilibrium of hydrofluoric acid + salt systems (fluorite, potassium nitrate, cesium nitrate) was measured using an apparatus made of perfluoro alkylvinylether. Cesium nitrate showed a salting-out effect on the vapor-liquid equilibrium of the hydrofluoric acid-water system. Fluorite and potassium nitrate showed a salting-in effect on the hydrofluoric acid-water system. Separation of hydrofluoric acid from an acid mixture containing nitric acid and hydrofluoric acid was tested by the simple distillation treatment using the salt effect of cesium nitrate (45 mass%). An acid mixture of nitric acid (5.0 mol · dm-3) and hydrofluoric acid (5.0 mol · dm-3) was prepared as a sample solution for distillation tests. The concentration of nitric acid in the first distillate decreased from 5.0 mol · dm-3 to 1.13 mol · dm-3, and the concentration of hydrofluoric acid increased to 5.41 mol · dm-3. This first distillate was further distilled without the addition of salt. The concentrations of hydrofluoric acid and nitric acid in the second distillate were 7.21 mol · dm-3 and 0.46 mol · dm-3, respectively. It was thus found that the salt effect on vapor-liquid equilibrium of acid mixtures was effective for the recycling of acids from acid mixture wastes.

17,21-Secohopanoic acids, 25-norhopanoic acids, and 28-norhopanoic acids in source rocks and crude oils

Energy Technology Data Exchange (ETDEWEB)

Xueming Pan; Philp, R.P. [University of Oklahoma, Norman, OK (United States). School of Geology and Geophysics

2006-09-15

The presence of three families of hopanoic acids, 17,21-secohopanoic acids, 25-norhopanoic acids, and 28-norhopanoic acids, is discussed. Oils from West Siberia and tar balls from the Seychelles Islands were found to contain relatively high proportions of 17,21-secohopanoic acids. These acids have not been previously reported in any oils or source rocks. A heavily biodegraded West Siberian oil, was found to contain an homologous series of 25-norhopanoic acids co-occurring with the 25-norhopanes as previously reported in only a small number of oils from Campos Basin, Brazil. 28-Norhopanoic acids have been reported in various sediments and extracts of the Monterey Shale, but in this study their occurrence has been extended to oils, degraded oils, and tar balls sourced from the Monterey Shale. The primary purpose herein is to report the occurrence of these acids and possible relationships between the acids and corresponding hydrocarbons. (Author)

Process for the preparation of lactic acid and glyceric acid

Science.gov (United States)

Jackson, James E [Haslett, MI; Miller, Dennis J [Okemos, MI; Marincean, Simona [Dewitt, MI

2008-12-02

Hexose and pentose monosaccharides are degraded to lactic acid and glyceric acid in an aqueous solution in the presence of an excess of a strongly anionic exchange resin, such as AMBERLITE IRN78 and AMBERLITE IRA400. The glyceric acid and lactic acid can be separated from the aqueous solution. Lactic acid and glyceric acid are staple articles of commerce.

The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing.

Science.gov (United States)

Mroz, Magdalena S; Lajczak, Natalia K; Goggins, Bridie J; Keely, Simon; Keely, Stephen J

2018-03-01

The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T 84 cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl - channels, whereas inhibition of CFTR activity with either CFTR- inh -172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes

Biosynthesis of furanochromones in Pimpinella monoica

Indian Academy of Sciences (India)

polyketide origin of their aromatic and pyrone rings while the furan ring originates via an acetate-mevalonate pathway. The plant also utilises glycine and leucine as substrate via acetate. Biotransformation of 3-H-visnagin to (6) but not to (2) was also observed. Keywords. Biosynthesis; furochromones; polyketide origin; ...

Effects of dietary conjugated linoleic acid and linoleic:linolenic acid ratio on polyunsaturated fatty acid status in laying hens.

Science.gov (United States)

Du, M; Ahn, D U; Sell, J L

2000-12-01

A study was conducted to determine the effects of dietary conjugated linoleic acid (CLA) and the ratio of linoleic:linolenic acid on long-chain polyunsaturated fatty acid status. Thirty-two 31-wk-old White Leghorn hens were randomly assigned to four diets containing 8.2% soy oil, 4.1% soy oil + 2.5% CLA (4.1% CLA source), 4.1% flax oil + 2.5% CLA, or 4.1% soy oil + 4.1% flax oil. Hens were fed the diets for 3 wk before eggs and tissues were collected for the study. Lipids were extracted from egg yolk and tissues, classes of egg yolk lipids were separated, and fatty acid concentrations of total lipids, triglyceride, phosphatidylethanolamine, and phosphatidylcholine were analyzed by gas chromatography. The concentrations of monounsaturated fatty acids and non-CLA polyunsaturated fatty acids were reduced after CLA feeding. The amount of arachidonic acid was decreased after CLA feeding in linoleic acid- and linolenic acid-rich diets, but amounts of eicosapentaenoic acid and docosahexaenoic acid were increased in the linolenic-rich diet, indicating that the synthesis or deposition of long-chain n-3 fatty acids was accelerated after CLA feeding. The increased docosahexaenoic acid and eicosapentaenoic acid contents in lipid may be compensation for the decreased arachidonic acid content. Dietary supplementation of linoleic acid increased n-6 fatty acid levels in lipids, whereas linolenic acid increased n-3 fatty acid levels. Results also suggest that CLA might not be elongated to synthesize long-chain fatty acids in significant amounts. The effect of CLA in reducing the level of n-6 fatty acids and promoting the level of n-3 fatty acids could be related to the biological effects of CLA.

Potential of tocotrienols in the prevention and therapy of Alzheimer's disease.

Science.gov (United States)

Xia, Weiming; Mo, Huanbiao

2016-05-01

Currently there is no cure for Alzheimer's disease (AD); clinical trials are underway to reduce amyloid generation and deposition, a neuropathological hallmark in brains of AD patients. While genetic factors and neuroinflammation contribute significantly to AD pathogenesis, whether increased cholesterol level is a causative factor or a result of AD is equivocal. Prenylation of proteins regulating neuronal functions requires mevalonate-derived farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The observation that the levels of FPP and GGPP, but not that of cholesterol, are elevated in AD patients is consistent with the finding that statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, reduce FPP and GGPP levels and amyloid β protein production in preclinical studies. Retrospective studies show inverse correlations between incidence of AD and the intake and serum levels of the HMG CoA reductase-suppressive tocotrienols; tocopherols show mixed results. Tocotrienols, but not tocopherols, block the processing and nuclear localization of sterol regulatory element binding protein-2, the transcriptional factor for HMG CoA reductase and FPP synthase, and enhance the degradation of HMG CoA reductase. Consequently, tocotrienols deplete the pool of FPP and GGPP and potentially blunt prenylation-dependent AD pathogenesis. The antiinflammatory activity of tocotrienols further contributes to their protection against AD. The mevalonate- and inflammation-suppressive activities of tocotrienols may represent those of an estimated 23,000 mevalonate-derived plant secondary metabolites called isoprenoids, many of which are neuroprotective. Tocotrienol-containing plant foods and tocotrienol derivatives and formulations with enhanced bioavailability may offer a novel approach in AD prevention and treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Classical bile acids in animals, beta-phocaecholic acid in ducks.

Science.gov (United States)

Jirsa, M; Klinot, J; Klinotová, E; Ubik, K; Kucera, K

1989-01-01

1. Bile samples of different animals were analysed and the percentage content of classical bile acids was determined. 2. Herbivorous birds mostly excreted a large proportion of chenodeoxycholic acid. 3. The anteater (Myrmecophaga tridactyla) excreted deoxycholic acid most probably as a primary bile acid. 4. In the bile of ducks (Anas platyrhynchos) a large amount of (23R)3 alpha, 7 alpha, 23-trihydroxy-5 beta-cholan-24-oic acid (beta-phocaecholic acid) was found.

Decontamination effectiveness of mixtures of citric acid, oxalic acid and EDTA

International Nuclear Information System (INIS)

Speranzini, R.A.

1990-01-01

An experimental study of the decontamination effectiveness of citric acid, oxalic acid and EDTA mixtures was conducted to assess whether oxalic acid could be removed from decontamination solutions to minimize corrosion. In loop experiments, radioactive specimens from two boiling water reactors and one pressurized water reactor were suspended in solutions of single acids or in mixtures of reagents at total reagent concentrations of less than 0.1 wt% under conditions similar to those used to decontaminate reactor systems. Rate constants for dissolution of oxides and decontamination factors were measured. Based on the results, it was concluded that under certain conditions, oxalic acid was the most effective reagent for the dissolution of oxides. It was also found, however, that conditions under which effective dissolution occurred in solutions of oxalic acid and/or citric acid were difficult to define and control. EDTA was found to be an effective reagent for dissolution of oxides such that rates of dissolution in EDTA containing solutions at 117 degrees Celsius were comparable to rates in oxalic acid containing solutions. At 90 degrees Celsius, EDTA acted synergistically with oxalic acid such that the rate of dissolution of oxides in citric-acid/oxalic-acid/EDTA solutions was higher than in citric-acid/EDTA solutions. The rates of dissolution of oxides were significantly reduced when 60 mg/kg of ferric ion was added to the citric-acid/oxalic-acid, citric-acid/EDTA and citric-acid/oxalic-acid/EDTA solutions. It was concluded that effective decontaminations of BWR and PWR systems could be achieved with mixtures of citric acid and EDTA

Radioimmunoassay of conjugated cholic acid, chenodeoxycholic acid, and deoxycholic acid from human serum, with use of 125I-labeled ligands

International Nuclear Information System (INIS)

Maeentausta, O.; Jaenne, O.

1979-01-01

We describe a method for radioimmunoassay of conjugated cholic acid, chenodeoxycholic acid, and deoxycholic acid in serum. In the method, 125 I-labeled bile acid conjugates are used as the tracers along with antibodies raised against individual bile acid-bovine serum albumin conjugates. Antibody-bound and free bile acids were separated by polyethylene glycol precipitation (final concentration, 125 g/L). The lowest measurable amounts of the bile acids, expressed as pmol/tube, were: cholic acid conjugates, 2; chenodeoxycholic acid conjugates, 0.5; and deoxycholic acid conjugates, 2. Analytical recovery of bile acids added to bile acid-free serum ranged from 85 to 110%; intra-assay and inter-assay CVs ranged from 8.3 to 5.3% and from 5.3 to 12.2%, respectively. Concentrations (mean +- SD) of the bile acid conjugates in serum from apparently healthy women and men (in μmol/L) were: cholic acid conjugates, 0.43 +- 0.17 (n=126); chenodeoxycholic acid conjugates, 0.47 +- 0.23 (n=111); and deoxycholic acid conjugates, 0.33 +- 0.11 (n=96). The values for primary bile acids were greatly increased in patients with various hepatobiliary diseases

A Comparative Study of the Radical-scavenging Activity of the Phenolcarboxylic Acids Caffeic Acid, p-Coumaric Acid, Chlorogenic Acid and Ferulic Acid, With or Without 2-Mercaptoethanol, a Thiol, Using the Induction Period Method

Directory of Open Access Journals (Sweden)

Seiichiro Fujisawa

2008-10-01

Full Text Available Phenolcarboxylic acid antioxidants do not act in vivo as radical-scavengers in isolation, but rather together with GSH (glutathione, a coantioxidant, they constitute an intricate antioxidant network. Caffeic acid, p-coumaric acid, ferulic acid and chlorogenic acid with or without 2-mercaptoethanol (ME, as a substitute for GSH, was investigated by the induction period (IP method for polymerization of methyl methacrylate (MMA initiated by thermal decomposition of 2,2'-azobisisobutyronitrile (AIBN, a source of alkyl radicals, R. and benzoyl peroxide (BPO, a source of peroxy radicals, PhCOO. using differential scanning calorimetry (DSC. Upon PhCOO. radical scavenging, the stoichiometric factors (n, number of free radical trapped by one mole of antioxidant for caffeic acid, ferulic acid, p-coumaric acid and chlorogenic acid were 2.4, 1.8, 1.7 and 0.9, whereas upon R. radical scavenging, the corresponding values were 1.3, 1.2, 1.0 and 0.8, respectively. Antioxidants with n values close to 2 suggest the stepwise formation of semiquinone radicals and quinones. By contrast, those with n values close to 1 suggest the formation of dimers after single-electron oxidation, possibly due to recombination of corresponding aryloxy radicals. The ratio of the rate constant of inhibition to that of propagation (kinh/kp declined in the order chlorogenic acid > p-coumaric acid > ferulic acid > caffeic acid. The ratio of the observed IP for the phenolcarboxylic acid/2-mercapto-ethanol (ME mixture (1:1 molar ratio (A to the calculated IP (the simple sum of phenol acid antioxidant and ME (B was investigated. Upon R. scavenging, the caffeic acid or p-coumaric acid/ME mixture was A/B > 1, particularly the former was 1.2, suggesting a synergic effect. By contrast, upon PhCOO. scavenging, the corresponding mixture was A/B < 1, particularly the latter was 0.7, suggesting an antagonistic effect. Upon both radicals scavenging, the A/B for the ferulic acid or chlorogenic acid

Catalyzed oxidation reactions. IV. Picolinic acid catalysis of chromic acid oxidations

International Nuclear Information System (INIS)

Rocek, J.; Peng, T.Y.

1977-01-01

Picolinic acid and several closely related acids are effective catalysts in the chromic acid oxidation of primary and secondary alcohols; the oxidation of other substrates is accelerated only moderately. The reaction is first order in chromium-(VI), alcohol, and picolinic acid; it is second order in hydrogen ions at low acidity and approaches acidity independence at high perchloric acid concentrations. A primary deuterium kinetic isotope effect is observed at high but not at low acidities. At low acidity the reaction has a considerably lower activation energy and more negative activation entropy than at higher acidities. The reactive intermediate in the proposed mechanism is a negatively charged termolecular complex formed from chromic acid, picolinic acid, and alcohol. The rate-limiting step of the reaction changes with the acidity of the solution. At higher acidities the intermediate termolecular complex is formed reversibly and the overall reaction rate is determined by the rate of its decomposition into reaction products; at low acidities the formation of the complex is irreversible and hence rate limiting. Picolinic acids with a substituent in the 6 position show a greatly reduced catalytic activity. This observation is interpreted as suggesting a square pyramidal or octahedral structure for the reactive chromium (VI) intermediate. The temperature dependence of the deuterium isotope effect has been determined and the significance of the observed large values for E/sub a//sup D/ - E/sub a//sup H/ and A/sup D//A/sup H/ is discussed

Generators for Miranda

Energy Technology Data Exchange (ETDEWEB)

Angiolini, G.; Borgna, H.; Garcia, A.; Fernandez, M.; Piriz, H.; Verdu, C. [IMPSA Hydrogenerators (Argentina)

2000-10-01

The three generators at the Miranda hydroelectric power plant on the Araguari river northwest of Belo Horizonte in the state of Minas Gerais began operation in 1998. All the electromechanical equipment for the project was supplied by IMPSA. The generators, which are driven by Francis turbines, are vertical shaft, three-phase, salient-pole synchronous machines with an output of 137 MVA. The generators successfully completed a series of studies and trials before commercial operation began and Companhia Energetica de Minas Gerais (CEMIG) is considering increasing the operation power to 150 MVA. The specification and design of the electrical aspects, stator winding, rotor, bearings, shaft line, generator cooling system, excitation system and monitoring systems are described. Electromagnetic requirements and acceptance testing results are given in two summary tables.

Important conventional island design features: generators

International Nuclear Information System (INIS)

Fritsch, Th.

1985-01-01

To-day, maximum reactor capacity is setting a provisional limit to the MW race. The latest nuclear generators in manufacturing are rated 1530 MW - 1710 MVA and are doubtless the most powerful ones in the world. The target to be aimed at in designing large turbogenerators may be defined by the following points: 1) meeting the rated load conditions without overpassing maximum admissible temperatures in any part of the machine; 2) keeping losses as small as possible; 3) keeping overall size small enough to allow rail transportation from the works to the site; 4) choosing well experienced solutions in order to set a highly reliable machine with maximum maintenance. In this report the main features of nuclear generators in the 1000-2000 MVA range are described. (Auth.)

Targeted metabolomics analysis reveals the association between maternal folic acid supplementation and fatty acids and amino acids profiles in rat pups.

Science.gov (United States)

Liu, Zhipeng; Liu, Rui; Chou, Jing; Yu, Jiaying; Liu, Xiaowei; Sun, Changhao; Li, Ying; Liu, Liyan

2018-07-15

Maternal diet during pregnancy can influence offspring's health by affecting development and metabolism. This study aimed to analyze the influence of maternal folic acid (FA) supplementation on the metabolism of rat pups using targeted metabolomics. Twenty female rats were randomly assigned to a FA supplementation (FAS group, n = 10) or control group (n = 10), which were fed AIN93G diet with 2 or 10 mg/kg FA, respectively. We then measured amino acids and their derivatives, biogenic amines, and fatty acids in the female rats and their pups by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC/MS-MS) and gas chromatography-mass spectrometry (GC/MS-MS). In maternal rats, the significant changes of three metabolites (proline, γ-aminobutyric acid and esterified octadecatetraenoic acid, P acids (leucine, isoleucine, serine, proline) were obtained in FAS pups. Furthermore, there were the decreased esterified fatty acids (arachidonic acid, eicosapentaenoic acid, and docosatetraenoic acid) and free fatty acids (oleic acid, linoleic acid, γ-linolenic acid, octadecatetraenoic acid, arachidonic acid, eicosapentaenoic acid and selacholeic acid) in FAS pups. Metabolic changes in the FAS pups were characterized by changes in fatty acids and amino acids. These results suggested that FA supplementation during pregnancy influenced amino acids and fatty acids metabolism in rat pups. This study provides new insights into the regulation of amino acids and fatty acids metabolism during early life. Copyright © 2018 Elsevier B.V. All rights reserved.

Understanding Acid Rain

Science.gov (United States)

Damonte, Kathleen

2004-01-01

The term acid rain describes rain, snow, or fog that is more acidic than normal precipitation. To understand what acid rain is, it is first necessary to know what an acid is. Acids can be defined as substances that produce hydrogen ions (H+), when dissolved in water. Scientists indicate how acidic a substance is by a set of numbers called the pH…

Validation of a multi-analyte HPLC-DAD method for determination of uric acid, creatinine, homovanillic acid, niacinamide, hippuric acid, indole-3-acetic acid and 2-methylhippuric acid in human urine.

Science.gov (United States)

Remane, Daniela; Grunwald, Soeren; Hoeke, Henrike; Mueller, Andrea; Roeder, Stefan; von Bergen, Martin; Wissenbach, Dirk K

2015-08-15

During the last decades exposure sciences and epidemiological studies attracts more attention to unravel the mechanisms for the development of chronic diseases. According to this an existing HPLC-DAD method for determination of creatinine in urine samples was expended for seven analytes and validated. Creatinine, uric acid, homovanillic acid, niacinamide, hippuric acid, indole-3-acetic acid, and 2-methylhippuric acid were separated by gradient elution (formate buffer/methanol) using an Eclipse Plus C18 Rapid Resolution column (4.6mm×100mm). No interfering signals were detected in mobile phase. After injection of blank urine samples signals for the endogenous compounds but no interferences were detected. All analytes were linear in the selected calibration range and a non weighted calibration model was chosen. Bias, intra-day and inter-day precision for all analytes were below 20% for quality control (QC) low and below 10% for QC medium and high. The limits of quantification in mobile phase were in line with reported reference values but had to be adjusted in urine for homovanillic acid (45mg/L), niacinamide 58.5(mg/L), and indole-3-acetic acid (63mg/L). Comparison of creatinine data obtained by the existing method with those of the developed method showing differences from -120mg/L to +110mg/L with a mean of differences of 29.0mg/L for 50 authentic urine samples. Analyzing 50 authentic urine samples, uric acid, creatinine, hippuric acid, and 2-methylhippuric acid were detected in (nearly) all samples. However, homovanillic acid was detected in 40%, niacinamide in 4% and indole-3-acetic acid was never detected within the selected samples. Copyright © 2015 Elsevier B.V. All rights reserved.

Disease: H00206 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available MVA show the symptoms, including dysmorphic features, cataracts, neurologic symptoms. The majority of patien...ts with HIDS experience only recurrent febrile crises, without any neurologic abnormalities or dysmorphic

Removal of sulfamic acid from plutonium sulfamate--sulfamic acid solution

International Nuclear Information System (INIS)

Gray, L.W.

1978-10-01

Plutonium metal can be readily dissolved in aqueous solutions of sulfamic acid. When the plutonium sulfamate--sulfamic acid solutions are added to normal purex process streams, the sulfamate ion is oxidized by addition of sodium nitrite. This generates sodium sulfate which must be stored as radioactive waste. When recovery of ingrown 241 Am or storage of the dissolved plutonium must be considered, the sulfamate ion poses major and undesirable precipitation problems in the process streams. The present studies show that 40 to 80% of the sulfamate present in the dissolver solutions can be removed by precipitation as sulfamic acid by the addition of concentrated nitric acid. Addition of 64% nitric acid allows precipitation of 40 to 50% of the sulfamate; addition of 72% nitric acid allows precipitation of 50 to 60% of the sulfamate. If the solutions are chilled, additional sulfamic acid will precipitate. If the solutions are chilled to -10 0 C, about 70 to 80% of the orginal sulfamic acid in the dissolver will precipitate. A single, low-volume wash of the sulfamic acid crystals with concentrated nitric acid will decontaminate the crystals to a plutonium content of 5 dis/(min-gram)

Acid-functionalized polyolefin materials and their use in acid-promoted chemical reactions

Science.gov (United States)

Oyola, Yatsandra; Tian, Chengcheng; Bauer, John Christopher; Dai, Sheng

2016-06-07

An acid-functionalized polyolefin material that can be used as an acid catalyst in a wide range of acid-promoted chemical reactions, wherein the acid-functionalized polyolefin material includes a polyolefin backbone on which acid groups are appended. Also described is a method for the preparation of the acid catalyst in which a precursor polyolefin is subjected to ionizing radiation (e.g., electron beam irradiation) of sufficient power and the irradiated precursor polyolefin reacted with at least one vinyl monomer having an acid group thereon. Further described is a method for conducting an acid-promoted chemical reaction, wherein an acid-reactive organic precursor is contacted in liquid form with a solid heterogeneous acid catalyst comprising a polyolefin backbone of at least 1 micron in one dimension and having carboxylic acid groups and either sulfonic acid or phosphoric acid groups appended thereto.

Stream chemistry in the eastern United States. 2. Current sources of acidity in acidic and low acid-neutralizing-capacity streams

International Nuclear Information System (INIS)

Herlihy, A.T.; Kaufmann, P.R.; Mitch, M.E.

1991-01-01

The authors examined anion composition in National Stream Survey (NSS) data in order to evaluate the most probable sources of current acidity in acidic and low acid neutralizing capacity (ANC) streams in the eastern United States. Acidic streams that had almost no organic influence (less than 10% of total anions) and sulfate and nitrate concentrations indicative of evaporative concentration of atmospheric deposition were classified as acidic due to acidic deposition. These acidic streams were located in small forested watersheds in the Mid-Atlantic Highlands (an estimated 1950 km of stream length) and in the Mid-Atlantic Coastal Plain (1250 km). Acidic streams affected primarily by acidic deposition but also influenced by naturally occurring organic anions accounted for another 1180 km of acidic stream length and were located in the New Jersey Pine Barrens, plateau tops in the Mid-Atlantic and Southeast Highlands, and the Florida Panhandle. The total length of streams acidic due to acid mine drainage in the NSS (4590 km) was about the same as the total length of acidic streams likely affected by acidic deposition (4380 km). Acidic streams whose acid anion composition was dominated by organics were located in Florida and the Mid-Atlantic Coastal Plain. In Florida, most of the acidic streams were organic dominated, whereas about half of the streams in the Mid-Atlantic Coastal Plain were organic dominated. Organic-dominated acidic streams were not observed in the Mid-Atlantic and Southeast Highlands

15N NMR spectroscopic investigation of nitrous and nitric acids in sulfuric acid solutions of varying acidities

International Nuclear Information System (INIS)

Prakash, G.K.S.; Heiliger, L.; Olah, G.A.

1990-01-01

Both nitrous and nitric acids were studied in sulfuric acid solutions of varying acid strengths by 15 N NMR spectroscopy. The study gives new insights into the nature of intermediates present at different acid strengths. Furthermore, we have also discovered a novel redox reaction between NO 2 + and NO + ions involving the intermediacy of their respective acids. A mechanism is proposed to explain the observed results. 13 refs., 2 figs., 1 tab

Serum n-3 Tetracosapentaenoic Acid and Tetracosahexaenoic Acid Increase Following Higher Dietary α-Linolenic Acid but not Docosahexaenoic Acid.

Science.gov (United States)

Metherel, Adam H; Domenichiello, Anthony F; Kitson, Alex P; Lin, Yu-Hong; Bazinet, Richard P

2017-02-01

n-3 Tetracosapentaenoic acid (24:5n-3, TPAn-3) and tetracosahexaenoic acid (24:6n-3, THA) are believed to be important intermediates to docosahexaenoic acid (DHA, 22:6n-3) synthesis. The purpose of this study is to report for the first time serum concentrations of TPAn-3 and THA and their response to changing dietary α-linolenic acid (18:3n-3, ALA) and DHA. The responses will then be used in an attempt to predict the location of these fatty acids in relation to DHA in the biosynthetic pathway. Male Long Evans rats (n = 6 per group) were fed either a low (0.1% of total fatty acids), medium (3%) or high (10%) ALA diet with no added DHA, or a low (0%), medium (0.2%) or high (2%) DHA diet with a background of 2% ALA for 8 weeks post-weaning. Serum n-3 and n-6 polyunsaturated fatty acid (PUFA) concentrations (nmol/mL ± SEM) were determined by gas chromatography-mass spectrometry. Serum THA increases from low (0.3 ± 0.1) to medium (5.8 ± 0.7) but not from medium to high (4.6 ± 0.9) dietary ALA, while serum TPAn-3 increases with increasing dietary ALA from 0.09 ± 0.04 to 0.70 ± 0.09 to 1.23 ± 0.14 nmol/mL. Following DHA feeding, neither TPAn-3 or THA change across all dietary DHA intake levels. Serum TPAn-3 demonstrates a similar response to dietary DHA. In conclusion, this is the first study to demonstrate that increases in dietary ALA but not DHA increase serum TPAn-3 and THA in rats, suggesting that both fatty acids are precursors to DHA in the biosynthetic pathway.

Parabanic acid is the singlet oxygen specific oxidation product of uric acid.

Science.gov (United States)

Iida, Sayaka; Ohkubo, Yuki; Yamamoto, Yorihiro; Fujisawa, Akio

2017-11-01

Uric acid quenches singlet oxygen physically or reacts with it, but the oxidation product has not been previously characterized. The present study determined that the product is parabanic acid, which was confirmed by LC/TOFMS analysis. Parabanic acid was stable at acidic pH (acid at neutral or alkaline pH. The total yields of parabanic acid and oxaluric acid based on consumed uric acid were ~100% in clean singlet oxygen production systems such as UVA irradiation of Rose Bengal and thermal decomposition of 3-(1,4-dihydro-1,4-epidioxy-4-methyl-1-naphthyl)propionic acid. However, the ratio of the amount of uric acid consumed to the total amount of singlet oxygen generated was less than 1/180, indicating that most of the singlet oxygen was physically quenched. The total yields of parabanic acid and oxaluric acid were high in the uric acid oxidation systems with hydrogen peroxide plus hypochlorite or peroxynitrite. They became less than a few percent in peroxyl radical-, hypochlorite- or peroxynitrite-induced oxidation of uric acid. These results suggest that parabanic acid could be an in vivo probe of singlet oxygen formation because of the wide distribution of uric acid in human tissues and extracellular spaces. In fact, sunlight exposure significantly increased human skin levels of parabanic acid.

A GC-ECD method for estimation of free and bound amino acids, gamma-aminobutyric acid, salicylic acid, and acetyl salicylic acid from Solanum lycopersicum (L.).

Science.gov (United States)

Meher, Hari Charan; Gajbhiye, Vijay T; Singh, Ghanendra

2011-01-01

A gas chromatograph with electron capture detection method for estimation of selected metabolites--amino acids (free and bound), gamma-aminobutyric acid (GABA), salicylic acid (SA), and acetyl salicylic acid (ASA) from tomato--is reported. The method is based on nitrophenylation of the metabolites by 1-fluoro-2, 4-dinitrobenzene under aqueous alkaline conditions to form dinitophenyl derivatives. The derivatives were stable under the operating conditions of GC. Analysis of bound amino acids comprised perchloric acid precipitation of protein, alkylation (carboxymethylation) with iodoacetic acid, vapor-phase hydrolysis, and derivatization with 1-fluoro-2,4-dinitrobenzene in that order. The metabolites were resolved in 35 min, using a temperature-programmed run. The method is rapid, sensitive, and precise. It easily measured the typical amino acids (aspartate, asparagine, glutamate, glutamine, alanine, leucine, lysine, and phenylalanine) used for identification and quantification of a protein, resolved amino acids of the same mass (leucine and isoleucine), satisfactorily measured sulfur amino acid (methionine, cystine, and cysteine), and quantified GABA, SA, and ASA, as well. The developed method was validated for specificity, linearity, and precision. It has been applied and recommended for estimation of 25 metabolites from Solanum lycopersicum (L.).

Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids

DEFF Research Database (Denmark)

Conti, Paola; De Amici, Marco; Joppolo Di Ventimiglia, Samuele

2003-01-01

Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them...

Post traumatic stress disorder among motor vehicle accident ...

African Journals Online (AJOL)

PTSD) and associated risk factors among motor vehicle accident (MVA) survivors attending the orthopaedic and trauma clinic at Kenyatta National Hospital, Nairobi. Design: A cross-sectional study. Setting: Kenyatta National Hospital, Nairobi.

Crystal growth and physical characterization of picolinic acid cocrystallized with dicarboxylic acids

Science.gov (United States)

Somphon, Weenawan; Haller, Kenneth J.

2013-01-01

Pharmaceutical cocrystals are multicomponent materials containing an active pharmaceutical ingredient with another component in well-defined stoichiometry within the same unit cell. Such cocrystals are important in drug design, particularly for improving physicochemical properties such as solubility, bioavailability, or chemical stability. Picolinic acid is an endogenous metabolite of tryptophan and is widely used for neuroprotective, immunological, and anti-proliferative effects within the body. In this paper we present cocrystallization experiments of a series of dicarboxylic acids, oxalic acid, succinic acid, DL-tartaric acid, pimelic acid, and phthalic acid, with picolinic acid. Characterization by FT-IR and Raman spectroscopy, DSC and TG/DTG analysis, and X-ray powder diffraction show that new compounds are formed, including a 1:1 picolinium tartrate monohydrate, a 2:1 monohydrate adduct of picolinic acid and oxalic acid, and a 2:1 picolinic acid-succinic acid monohydrate cocrystal.

40 CFR 721.3620 - Fatty acid amine condensate, polycarboxylic acid salts.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Fatty acid amine condensate... Specific Chemical Substances § 721.3620 Fatty acid amine condensate, polycarboxylic acid salts. (a... a fatty acid amine condensate, polycarboxylic acid salts. (PMN P-92-445) is subject to reporting...

Bifidobacterium breve with α-linolenic acid and linoleic acid alters fatty acid metabolism in the maternal separation model of irritable bowel syndrome.

Science.gov (United States)

Barrett, Eoin; Fitzgerald, Patrick; Dinan, Timothy G; Cryan, John F; Ross, R Paul; Quigley, Eamonn M; Shanahan, Fergus; Kiely, Barry; Fitzgerald, Gerald F; O'Toole, Paul W; Stanton, Catherine

2012-01-01

The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15) were orally gavaged with either B. breve DPC6330 (10(9) microorganisms/day) alone or in combination with 0.5% (w/w) linoleic acid & 0.5% (w/w) α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11) in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (pbreve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11) in adipose tissue and palmitoleic acid in the prefrontal cortex (pbreve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (pbreve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (pbreve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (pbreve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated rats significantly modified the palmitoleic acid, arachidonic acid and docosahexaenoic acid contents in tissues. The effect was not observed in non-separated animals.

A novel approach in acidic disinfection through inhibition of acid resistance mechanisms; Maleic acid-mediated inhibition of glutamate decarboxylase activity enhances acid sensitivity of Listeria monocytogenes.

Science.gov (United States)

Paudyal, Ranju; Barnes, Ruth H; Karatzas, Kimon Andreas G

2018-02-01

Here it is demonstrated a novel approach in disinfection regimes where specific molecular acid resistance systems are inhibited aiming to eliminate microorganisms under acidic conditions. Despite the importance of the Glutamate Decarboxylase (GAD) system for survival of Listeria monocytogenes and other pathogens under acidic conditions, its potential inhibition by specific compounds that could lead to its elimination from foods or food preparation premises has not been studied. The effects of maleic acid on the acid resistance of L. monocytogenes were investigated and found that it has a higher antimicrobial activity under acidic conditions than other organic acids, while this could not be explained by its pKa or Ka values. The effects were found to be more pronounced on strains with higher GAD activity. Maleic acid affected the extracellular GABA levels while it did not affect the intracellular ones. Maleic acid had a major impact mainly on GadD2 activity as also shown in cell lysates. Furthermore, it was demonstrated that maleic acid is able to partly remove biofilms of L. monocytogenes. Maleic acid is able to inhibit the GAD of L. monocytogenes significantly enhancing its sensitivity to acidic conditions and together with its ability to remove biofilms, make a good candidate for disinfection regimes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acid Deposition Phenomena

International Nuclear Information System (INIS)

Ramadan, A.E.K.

2004-01-01

Acid deposition, commonly known as acid rain, occurs when emissions from the combustion of fossil fuels and other industrial processes undergo complex chemical reactions in the atmosphere and fall to the earth as wet deposition (rain, snow, cloud, fog) or dry deposition (dry particles, gas). Rain and snow are already naturally acidic, but are only considered problematic when less than a ph of 5.0 The main chemical precursors leading to acidic conditions are atmospheric concentrations of sulfur dioxide (SO 2 ) and nitrogen oxides (NO x ). When these two compounds react with water, oxygen, and sunlight in the atmosphere, the result is sulfuric (H 2 SO 4 ) and nitric acids (HNO 3 ), the primary agents of acid deposition which mainly produced from the combustion of fossil fuel and from petroleum refinery. Airborne chemicals can travel long distances from their sources and can therefore affect ecosystems over broad regional scales and in locations far from the sources of emissions. According to the concern of petroleum ministry with the environment and occupational health, in this paper we will discussed the acid deposition phenomena through the following: Types of acidic deposition and its components in the atmosphere Natural and man-made sources of compounds causing the acidic deposition. Chemical reactions causing the acidic deposition phenomenon in the atmosphere. Factors affecting level of acidic deposition in the atmosphere. Impact of acid deposition. Procedures for acidic deposition control in petroleum industry

Bifidobacterium breve with α-linolenic acid and linoleic acid alters fatty acid metabolism in the maternal separation model of irritable bowel syndrome.

Directory of Open Access Journals (Sweden)

Eoin Barrett

Full Text Available The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15 were orally gavaged with either B. breve DPC6330 (10(9 microorganisms/day alone or in combination with 0.5% (w/w linoleic acid & 0.5% (w/w α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11 in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (p<0.05. Administration of B. breve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11 in adipose tissue and palmitoleic acid in the prefrontal cortex (p<0.05, whereas feeding B. breve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (p<0.05 compared with the NS un-supplemented controls. Administration of B. breve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (p<0.01 and α-linolenic acid in adipose tissue (p<0.001, whereas feeding B. breve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (p<0.05, and α-linolenic acid in adipose tissue (p<0.001. B. breve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated

Aminocaproic Acid and Tranexamic Acid Fail to Reverse Dabigatran-Induced Coagulopathy.

Science.gov (United States)

Levine, Michael; Huang, Margaret; Henderson, Sean O; Carmelli, Guy; Thomas, Stephen H

In recent years, dabigatran has emerged as a popular alternative to warfarin for treatment of atrial fibrillation. If rapid reversal is required, however, no reversal agent has clearly been established. The primary purpose of this manuscript was to evaluate the efficacy of tranexamic acid and aminocaproic acid as agents to reverse dabigatran-induced coagulopathy. Rats were randomly assigned to 6 groups. Each rat received either dabigatran or oral placebo, followed by saline, tranexamic acid, or aminocaproic acid. An activated clotting test was used to measure the coagulopathy. Neither tranexamic acid nor aminocaproic acid successfully reversed dabigatran-induced coagulopathy. In this rodent model of dabigatran-induced coagulopathy, neither tranexamic acid nor aminocaproic acid were able to reverse the coagulopathy.

Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates

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Angiolo Pierantoni

Full Text Available Respiratory Syncytial Virus (RSV is a leading cause of severe respiratory disease in infants and the elderly. No vaccine is presently available to address this major unmet medical need. We generated a new genetic vaccine based on chimpanzee Adenovirus (PanAd3-RSV and Modified Vaccinia Ankara RSV (MVA-RSV encoding the F, N, and M2-1 proteins of RSV, for the induction of neutralizing antibodies and broad cellular immunity. Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN and intramuscular (M administration for safety, immunogenicity, and efficacy in different species. A single IN or IM vaccination completely protected BALB/c mice and cotton rats against RSV replication in the lungs. However, only IN administration could prevent infection in the upper respiratory tract. IM vaccination with MVA-RSV also protected cotton rats from lower respiratory tract infection in the absence of detectable neutralizing antibodies. Heterologous prime boost with PanAd3-RSV and MVA-RSV elicited high neutralizing antibody titers and broad T-cell responses in nonhuman primates. In addition, animals primed in the nose developed mucosal IgA against the F protein. In conclusion, we have shown that our vectored RSV vaccine induces potent cellular and humoral responses in a primate model, providing strong support for clinical testing.

Enhanced vaccine-induced CD8+ T cell responses to malaria antigen ME-TRAP by fusion to MHC class ii invariant chain.

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Alexandra J Spencer

Full Text Available The orthodox role of the invariant chain (CD74; Ii is in antigen presentation to CD4+ T cells, but enhanced CD8+ T cells responses have been reported after vaccination with vectored viral vaccines encoding a fusion of Ii to the antigen of interest. In this study we assessed whether fusion of the malarial antigen, ME-TRAP, to Ii could increase the vaccine-induced CD8+ T cell response. Following single or heterologous prime-boost vaccination of mice with a recombinant chimpanzee adenovirus vector, ChAd63, or recombinant modified vaccinia virus Ankara (MVA, higher frequencies of antigen-specific CD4+ and CD8+ T cells were observed, with the largest increases observed following a ChAd63-MVA heterologous prime-boost regimen. Studies in non-human primates confirmed the ability of Ii-fusion to augment the T cell response, where a 4-fold increase was maintained up to 11 weeks after the MVA boost. Of the numerous different approaches explored to increase vectored vaccine induced immunogenicity over the years, fusion to the invariant chain showed a consistent enhancement in CD8+ T cell responses across different animal species and may therefore find application in the development of vaccines against human malaria and other diseases where high levels of cell-mediated immunity are required.

Acidizing reservoirs while chelating iron with sulfosalicylic acid

Energy Technology Data Exchange (ETDEWEB)

McLaughlin, W A; Berkshire, D C

1980-09-30

A well treating process is described in which an aqueous solution of a strong acid capable of dissolving solids in a manner increasing the permeability of a subterranean earth formation is injected into a subterranean reservoir that contains an asphaltenic oil. At least the first injected portion of the aqueous acid and a solution or homogeneous dispersion of at least enough 5-sulfosalicylic acid to chelate with and prevent the formation of iron-asphaltene solids are included with substantially all of the ferric ions that become dissolved within the strong acid solution that enters the earth formation. 10 claims.

Acids and bases solvent effects on acid-base strenght

CERN Document Server

Cox, Brian G

2013-01-01

Acids and bases are ubiquitous in chemistry. Our understanding of them, however, is dominated by their behaviour in water. Transfer to non-aqueous solvents leads to profound changes in acid-base strengths and to the rates and equilibria of many processes: for example, synthetic reactions involving acids, bases and nucleophiles; isolation of pharmaceutical actives through salt formation; formation of zwitter- ions in amino acids; and chromatographic separation of substrates. This book seeks to enhance our understanding of acids and bases by reviewing and analysing their behaviour in non-aqueous solvents. The behaviour is related where possible to that in water, but correlations and contrasts between solvents are also presented.

Alkyl phosphonic acids and sulfonic acids in the Murchison meteorite

Science.gov (United States)

Cooper, George W.; Onwo, Wilfred M.; Cronin, John R.

1992-01-01

Homologous series of alkyl phosphonic acids and alkyl sulfonic acids, along with inorganic orthophosphate and sulfate, are identified in water extracts of the Murchison meteorite after conversion to their t-butyl dimethylsilyl derivatives. The methyl, ethyl, propyl, and butyl compounds are observed in both series. Five of the eight possible alkyl phosphonic acids and seven of the eight possible alkyl sulfonic acids through C4 are identified. Abundances decrease with increasing carbon number as observed of other homologous series indigenous to Murchison. Concentrations range downward from approximately 380 nmol/gram in the alkyl sulfonic acid series, and from 9 nmol/gram in the alkyl phosphonic acid series.

21 CFR 172.350 - Fumaric acid and salts of fumaric acid.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Fumaric acid and salts of fumaric acid. 172.350... HUMAN CONSUMPTION Special Dietary and Nutritional Additives § 172.350 Fumaric acid and salts of fumaric acid. Fumaric acid and its calcium, ferrous, magnesium, potassium, and sodium salts may be safely used...

Heart and bile acids - Clinical consequences of altered bile acid metabolism.

Science.gov (United States)

Vasavan, Tharni; Ferraro, Elisa; Ibrahim, Effendi; Dixon, Peter; Gorelik, Julia; Williamson, Catherine

2018-04-01

Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids. Copyright © 2018 Elsevier B.V. All rights reserved.

Docosahexaenoic Acid-Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties.

Science.gov (United States)

Kuda, Ondrej; Brezinova, Marie; Rombaldova, Martina; Slavikova, Barbora; Posta, Martin; Beier, Petr; Janovska, Petra; Veleba, Jiri; Kopecky, Jan; Kudova, Eva; Pelikanova, Terezie; Kopecky, Jan

2016-09-01

White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids-lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans. © 2016 by the American Diabetes Association.

A small antigenic determinant of the Chikungunya virus E2 protein is sufficient to induce neutralizing antibodies which are partially protective in mice.

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Christopher Weber

2015-04-01

Full Text Available The mosquito-borne Chikungunya virus (CHIKV causes high fever and severe joint pain in humans. It is expected to spread in the future to Europe and has recently reached the USA due to globalization, climate change and vector switch. Despite this, little is known about the virus life cycle and, so far, there is no specific treatment or vaccination against Chikungunya infections. We aimed here to identify small antigenic determinants of the CHIKV E2 protein able to induce neutralizing immune responses.E2 enables attachment of the virus to target cells and a humoral immune response against E2 should protect from CHIKV infections. Seven recombinant proteins derived from E2 and consisting of linear and/or structural antigens were created, and were expressed in and purified from E. coli. BALB/c mice were vaccinated with these recombinant proteins and the mouse sera were screened for neutralizing antibodies. Whereas a linear N-terminally exposed peptide (L and surface-exposed parts of the E2 domain A (sA alone did not induce neutralizing antibodies, a construct containing domain B and a part of the β-ribbon (called B+ was sufficient to induce neutralizing antibodies. Furthermore, domain sA fused to B+ (sAB+ induced the highest amount of neutralizing antibodies. Therefore, the construct sAB+ was used to generate a recombinant modified vaccinia virus Ankara (MVA, MVA-CHIKV-sAB+. Mice were vaccinated with MVA-CHIKV-sAB+ and/or the recombinant protein sAB+ and were subsequently challenged with wild-type CHIKV. Whereas four vaccinations with MVA-CHIKV-sAB+ were not sufficient to protect mice from a CHIKV infection, protein vaccination with sAB+ markedly reduced the viral titers of vaccinated mice.The recombinant protein sAB+ contains important structural antigens for a neutralizing antibody response in mice and its formulation with appropriate adjuvants might lead to a future CHIKV vaccine.

A novel multi-antigen virally vectored vaccine against Mycobacterium avium subspecies paratuberculosis.

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Tim J Bull

Full Text Available BACKGROUND: Mycobacterium avium subspecies paratuberculosis causes systemic infection and chronic intestinal inflammation in many species including primates. Humans are exposed through milk and from sources of environmental contamination. Hitherto, the only vaccines available against Mycobacterium avium subspecies paratuberculosis have been limited to veterinary use and comprised attenuated or killed organisms. METHODS: We developed a vaccine comprising a fusion construct designated HAV, containing components of two secreted and two cell surface Mycobacterium avium subspecies paratuberculosis proteins. HAV was transformed into DNA, human Adenovirus 5 (Ad5 and Modified Vaccinia Ankara (MVA delivery vectors. Full length expression of the predicted 95 kDa fusion protein was confirmed. PRINCIPAL FINDINGS: Vaccination of naïve and Mycobacterium avium subspecies paratuberculosis infected C57BL/6 mice using DNA-prime/MVA-boost or Ad5-prime/MVA-boost protocols was highly immunogenic resulting in significant IFN-gamma ELISPOT responses by splenocytes against recombinant vaccine antigens and a range of HAV specific peptides. This included strong recognition of a T-cell epitope GFAEINPIA located near the C-terminus of the fusion protein. Antibody responses to recombinant vaccine antigens and HAV specific peptides but not GFAEINPIA, also occurred. No immune recognition of vaccine antigens occurred in any sham vaccinated Mycobacterium avium subspecies paratuberculosis infected mice. Vaccination using either protocol significantly attenuated pre-existing Mycobacterium avium subspecies paratuberculosis infection measured by qPCR in spleen and liver and the Ad5-prime/MVA-boost protocol also conferred some protection against subsequent challenge. No adverse effects of vaccination occurred in any of the mice. CONCLUSIONS/SIGNIFICANCE: A range of modern veterinary and clinical vaccines for the treatment and prevention of disease caused by Mycobacterium avium

A novel multi-antigen virally vectored vaccine against Mycobacterium avium subspecies paratuberculosis.

Science.gov (United States)

Bull, Tim J; Gilbert, Sarah C; Sridhar, Saranya; Linedale, Richard; Dierkes, Nicola; Sidi-Boumedine, Karim; Hermon-Taylor, John

2007-11-28

Mycobacterium avium subspecies paratuberculosis causes systemic infection and chronic intestinal inflammation in many species including primates. Humans are exposed through milk and from sources of environmental contamination. Hitherto, the only vaccines available against Mycobacterium avium subspecies paratuberculosis have been limited to veterinary use and comprised attenuated or killed organisms. We developed a vaccine comprising a fusion construct designated HAV, containing components of two secreted and two cell surface Mycobacterium avium subspecies paratuberculosis proteins. HAV was transformed into DNA, human Adenovirus 5 (Ad5) and Modified Vaccinia Ankara (MVA) delivery vectors. Full length expression of the predicted 95 kDa fusion protein was confirmed. Vaccination of naïve and Mycobacterium avium subspecies paratuberculosis infected C57BL/6 mice using DNA-prime/MVA-boost or Ad5-prime/MVA-boost protocols was highly immunogenic resulting in significant IFN-gamma ELISPOT responses by splenocytes against recombinant vaccine antigens and a range of HAV specific peptides. This included strong recognition of a T-cell epitope GFAEINPIA located near the C-terminus of the fusion protein. Antibody responses to recombinant vaccine antigens and HAV specific peptides but not GFAEINPIA, also occurred. No immune recognition of vaccine antigens occurred in any sham vaccinated Mycobacterium avium subspecies paratuberculosis infected mice. Vaccination using either protocol significantly attenuated pre-existing Mycobacterium avium subspecies paratuberculosis infection measured by qPCR in spleen and liver and the Ad5-prime/MVA-boost protocol also conferred some protection against subsequent challenge. No adverse effects of vaccination occurred in any of the mice. A range of modern veterinary and clinical vaccines for the treatment and prevention of disease caused by Mycobacterium avium subspecies paratuberculosis are needed. The present vaccine proved to be highly

Conceptual design of the KSTAR Motor Generator

Energy Technology Data Exchange (ETDEWEB)

Kim, Chang-Hwan, E-mail: kch2004@nfri.re.kr [National Fusion Research Institute, 169-148 Gwahangno, Yusung-gu, Daejeon 305-333 (Korea, Republic of); Kong, Jong-Dea; Eom, Dae-Young; Joung, Nam-Young; Lee, Woo-Jin; Kim, Yang-Soo; Kwon, Myeun [National Fusion Research Institute, 169-148 Gwahangno, Yusung-gu, Daejeon 305-333 (Korea, Republic of); Han, Chul-Woo; Lee, Sel-Ki [Vitzrotech Co. Ltd, 605-2 Seonggok-dong, Danwon-gu, Ansan, Gyeonggi-do 425-833 (Korea, Republic of); Parker, F.J.; Hopkinson, D.; Le Flem, G.D. [Converteam UK Ltd, Leicester Road, Rugby, Warwickshire CV21 1BD (United Kingdom)

2012-09-15

Highlights: Black-Right-Pointing-Pointer The design of the MG which is required to allow the PF MPS to operate at its full power rating has been completed. Black-Right-Pointing-Pointer This system will increase the supply capability to the MPS to 200 MVA, 1.6 GJ and will supply reactive power to the MPS. Black-Right-Pointing-Pointer A VVVF of 12 MW will control the MG and will supply additional active power to the PF MPS in parallel with the MG. Black-Right-Pointing-Pointer The MG will be installed in August 2012. Black-Right-Pointing-Pointer The dummy coil testing will commence in December 2012 with superconducting coil testing scheduled for 2013. - Abstract: The Korean Superconducting Tokamak Advanced Research (KSTAR) superconducting magnet power supply is composed of a Poloidal Field Magnet Power Supply (PF MPS) and a Toroidal Field Magnet Power Supply (TF MPS). When the PF MPS is operated, it requires a large amount of power instantaneously from the KSTAR electric power system. To achieve the KSTAR operational goal, with a long pulse scenario, a peak power of 200 MVA is required and the total power demand for the KSTAR system can exceed 200 MVA. The available grid power is only 100 MVA at the KSTAR site. Increasing the available grid power was uneconomical and inefficient which is why NFRI are installing a Motor Generator (MG). National Fusion Research Institute (NFRI) has made a contract with Vitzrotech and Converteam to design, manufacture and install the MG. Converteam has designed the electromagnetic and mechanical specification of the MG and Variable Voltage Variable Frequency (VVVF) converter. In this paper we discuss the conceptual design, including energy saving and electrical capacity of the MG system and the performance of the MG to satisfy the KSTAR 300 s operation scenario. In addition, the manufacturing and installation plan for the KSTAR MG is discussed.

Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults

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L. Coughlan

2018-03-01

Full Text Available Background: T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP and matrix protein-1 (M1. We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. Methods: We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46 years and 24 subjects aged 50 years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18 months. Findings: Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP + M1 vaccination was significantly higher compared to ChAdOx1 NP + M1. In a mixed regression model, T-cell responses over 18 months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP + M1. Interpretation: A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. Funding Source: Medical Research Council UK, NIHR BMRC Oxford. Keywords: Influenza, T-cell responses, Influenza vaccines, Viral vectors, Adults, Older adults

Studies on the complexes of uranium(IV), thorium(IV) and lanthanum(III) acetates with p-aminobenzoic acid, m-aminobenzoic acid, benzilic acid and phthalic acid

International Nuclear Information System (INIS)

Singh, Mangal; Singh, Ajaib

1979-01-01

Complexes of acetates of U(IV), Th(IV) and La(III) with the ligands p-aminobenzoic acid, m-aminobenzoic acid, benzilic acid and phthalic acid have been prepared. Colour and chemical analytical data are recorded. They are characterised on the basis of IR and reflectance spectra and magnetic susceptibility data. (M.G.B.)

Incorporation of oxygen into abscisic acid and phaseic acid for molecular oxygen

International Nuclear Information System (INIS)

Creelman, R.A.; Zeevaart, J.A.D.

1984-01-01

Abscisic acid accumulates in detached, wilted leaves of Xanthium strumariu. When these leaves are subsequently rehydrated, phaseic acid, a catabolite of abscisic acid, accumulates. Analysis by gas chromatography-mass spectrometry of phaseic acid isolated from stressed and subsequently rehydrated leaves placed in an atmosphere containing 20% 18 O 2 and 80% N 2 indicates that one atom of 18 O is incorporated in the 6'-hydroxymethyl group of phaseic acid. This suggests that the enzyme that converts abscisic acid to phaseic acid is an oxygenase. Analysis by gas chromatography-mass spectrometry of abscisic acid isolated from stressed leaves kept in an atmosphere containing 18 O 2 indicates that one atom of 18 O is presented in the carboxyl group of abscisic acid. Thus, when abscisic acid accumulates in water-streesed leaves, only one of the four oxygens present in the abscisic acid molecule is derived from molecular oxygen. This suggest that either (a) the oxygen present in the 1'-, 4'-, and one of the two oxygens at the 1-position of abscisic acid arise from water, or (b) there exists a stored precursor with oxygen atoms already present in the 1'- and 4'-positions of abscisic acid which is converted to abscisic acid under conditions of water stress. 17 references, 2 figures, 1 tables

Incorporation of oxygen into abscisic Acid and phaseic Acid from molecular oxygen.

Science.gov (United States)

Creelman, R A; Zeevaart, J A

1984-05-01

Abscisic acid accumulates in detached, wilted leaves of Xanthium strumarium. When these leaves are subsequently rehydrated, phaseic acid, a catabolite of abscisic acid, accumulates. Analysis by gas chromatography-mass spectrometry of phaseic acid isolated from stressed and subsequently rehydrated leaves placed in an atmosphere containing 20% (18)O(2) and 80% N(2) indicates that one atom of (18)O is incorporated in the 6'-hydroxymethyl group of phaseic acid. This suggests that the enzyme that converts abscisic acid to phaseic acid is an oxygenase.Analysis by gas chromatography-mass spectrometry of abscisic acid isolated from stressed leaves kept in an atmosphere containing (18)O(2) indicates that one atom of (18)O is present in the carboxyl group of abscisic acid. Thus, when abscisic acid accumulates in water-stressed leaves, only one of the four oxygens present in the abscisic acid molecule is derived from molecular oxygen. This suggests that either (a) the oxygen present in the 1'-, 4'-, and one of the two oxygens at the 1-position of abscisic acid arise from water, or (b) there exists a stored precursor with oxygen atoms already present in the 1'- and 4'-positions of abscisic acid which is converted to abscisic acid under conditions of water stress.