In vivo and in vitro characterization of site-specific recombination of a novel serine integrase from the temperate phage EFC-1

International Nuclear Information System (INIS)

Yoon, Bohyun; Kim, Inki; Nam, Ja-Ae; Chang, Hyo-Ihl; Ha, Chang Hoon

2016-01-01

EFC-1 integrase is a site-specific recombinase that belongs to the large family of serine recombinase. In previously study, we isolated the temperate phage EFC-1, and characterized its genomic sequence. Within its genome, Orf28 was predicted encode a 464 amino acid of a putative integrase gene. In this study, EFC-1 integrase was characterized in vitro and in vivo. In vitro assay was performed using purified His-tag fusion integrase. Also, to identify which serine is involved in the catalytic domain, we used site-directed mutagenesis and analyzed by a recombination assay in vitro. In vivo assay involved PCR and confocal microscopy in HEK293 cells, and determined the minimal lengths of attP and attB sites. According to our results, the EFC-1 integrase-mediated recombination was site-specific and unidirectional system in vitro and in vivo. Serine 21 of EFC-1 integrase plays a major role in the catalytic domain, and minimal sizes of attB and attP was defined 48 and 54 bp. Our finding may help develop a useful tool for gene therapy and gene delivery system. - Highlights: • EFC-1 integrase-mediated recombination was site-specific and unidirectional system. • Serine 21 of EFC-1 integrase plays a major role in the catalytic domain. • The functional minimal sizes of attB and attP was defined 48 and 54 bp.

Efficient site-specific integration in Plasmodium falciparum chromosomes mediated by mycobacteriophage Bxb1 integrase.

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Nkrumah, Louis J; Muhle, Rebecca A; Moura, Pedro A; Ghosh, Pallavi; Hatfull, Graham F; Jacobs, William R; Fidock, David A

2006-08-01

Here we report an efficient, site-specific system of genetic integration into Plasmodium falciparum malaria parasite chromosomes. This is mediated by mycobacteriophage Bxb1 integrase, which catalyzes recombination between an incoming attP and a chromosomal attB site. We developed P. falciparum lines with the attB site integrated into the glutaredoxin-like cg6 gene. Transfection of these attB(+) lines with a dual-plasmid system, expressing a transgene on an attP-containing plasmid together with a drug resistance gene and the integrase on a separate plasmid, produced recombinant parasites within 2 to 4 weeks that were genetically uniform for single-copy plasmid integration. Integrase-mediated recombination resulted in proper targeting of parasite proteins to intra-erythrocytic compartments, including the apicoplast, a plastid-like organelle. Recombinant attB x attP parasites were genetically stable in the absence of drug and were phenotypically homogeneous. This system can be exploited for rapid genetic integration and complementation analyses at any stage of the P. falciparum life cycle, and it illustrates the utility of Bxb1-based integrative recombination for genetic studies of intracellular eukaryotic organisms.

HIV-1 integrase inhibitor resistance among treatment naïve patients in the West of Scotland.

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Bradley-Stewart, A; Urcia, C; MacLean, A; Aitken, C; Gunson, R

2017-07-01

Transmitted integrase inhibitor resistance is rare, with only a small number of cases reported world-wide to date. The aim of this study was to assess whether transmitted integrase inhibitor resistance has occurred in Scotland and if so, could there be a case for performing genotypic integrase resistance testing at baseline. The study population consisted of 106 treatment naïve, newly diagnosed, HIV positive patients. The patient samples were collected between October 2015 and March 2016 at the time of HIV diagnosis and prior to initiation of anti-retroviral therapy. The integrase region was amplified and sequenced. We detected integrase inhibitor resistance (T66I/T) at baseline in one patient sample. This is a non-polymorphic mutation seen in patients receiving elvitegravir which confers high-level resistance to elvitegravir and intermediate resistance to raltegravir. A further 10 patients had accessory mutations which have minimal or no effect on susceptibility to integrase inhibitors. Transmitted integrase inhibitor resistance remains rare. The results of the present study do not support performing integrase resistance testing at baseline. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Nucleic acid amplification of HIV-1 integrase sequence subtypes CRF01_AE and B for development of HIV anti-integrase drug resistance genotyping assay

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Adlar, F. R.; Bela, B.

2017-08-01

To anticipate the potential use of anti-integrase drugs in Indonesia for treatment of HIV-1 infection, the development of a drug resistance genotyping assay for anti-integrase is crucial in identifying the genetic drug resistance profile of Indonesian HIV-1 strains. This experiment aimed to amplify a target region in the integrase gene of Indonesian HIV-1 subtypes CRF01_AE and B that contain genetic mutations known to confer resistance to anti-integrase drug. Eleven archived plasma samples from individuals living with HIV-1 were obtained from the Virology and Cancer Pathobiology Research Center for Health Service (VCPRC FKUI-RSCM) laboratory. One of the plasma samples contained HIV-1 subtype B, and the remaining plasma samples contained subtype CRF01_AE. The target regions for all samples were amplified through RT-PCR, with an annealing temperature of 55 °C, using the primer pair AE_POL 4086F and AE_POL 5232R that were designed by VCPRC FKUI-RSCM. The results of this experiment show that 18.2% (2/11) of the samples were successfully amplified using the one-step RT-PCR. While the primer pair was effective in amplifying the target region in the integrase gene sequence for subtype B (100%; 1/1), it had a low efficacy (10%, 1/10) for subtype CRF01_AE. In conclusion, the primer pair can be used to amplify the target region in Indonesian HIV-1 strain subtypes CRF01_AE and B. However, optimization of the PCR condition and an increased number of samples would help to determine an accurate representation of the efficacy of the primer pair.

Inhibition of HIV-1 Integrase gene expression by 10-23 DNAzyme

Indian Academy of Sciences (India)

We have designed three novel DNAzymes, DIN54, DIN116, and DIN152, against HIV-1 Integrase gene using Mfold software and evaluated them for target site cleavage activity on the in vitro transcribed mRNA. All DNAzymes were tested for its inhibition of expression of HIV Integrase protein in the transiently transfected cell ...

Integrase of Mason-Pfizer monkey virus

Czech Academy of Sciences Publication Activity Database

Snášel, Jan; Krejčík, Zdeněk; Jenčová, Věra; Rosenberg, Ivan; Ruml, Tomáš; Alexandratos, J.; Gustchina, A.; Pichová, Iva

2005-01-01

Roč. 272, č. 1 (2005), s. 203-216 ISSN 1742-464X R&D Projects: GA AV ČR(CZ) IAA4055304 Institutional research plan: CEZ:AV0Z4055905 Keywords : integrase * Mason-Pfizer monkey virus * HIV-1 Subject RIV: CE - Biochemistry

A novel function for spumaretrovirus integrase: an early requirement for integrase-mediated cleavage of 2 LTR circles

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Mouscadet Jean-François

2005-05-01

Full Text Available Abstract Retroviral integration is central to viral persistence and pathogenesis, cancer as well as host genome evolution. However, it is unclear why integration appears essential for retrovirus production, especially given the abundance and transcriptional potential of non-integrated viral genomes. The involvement of retroviral endonuclease, also called integrase (IN, in replication steps apart from integration has been proposed, but is usually considered to be accessory. We observe here that integration of a retrovirus from the spumavirus family depends mainly on the quantity of viral DNA produced. Moreover, we found that IN directly participates to linear DNA production from 2-LTR circles by specifically cleaving the conserved palindromic sequence found at LTR-LTR junctions. These results challenge the prevailing view that integrase essential function is to catalyze retroviral DNA integration. Integrase activity upstream of this step, by controlling linear DNA production, is sufficient to explain the absolute requirement for this enzyme. The novel role of IN over 2-LTR circle junctions accounts for the pleiotropic effects observed in cells infected with IN mutants. It may explain why 1 2-LTR circles accumulate in vivo in mutants carrying a defective IN while their linear and integrated DNA pools decrease; 2 why both LTRs are processed in a concerted manner. It also resolves the original puzzle concerning the integration of spumaretroviruses. More generally, it suggests to reassess 2-LTR circles as functional intermediates in the retrovirus cycle and to reconsider the idea that formation of the integrated provirus is an essential step of retrovirus production.

Raltegravir: first in class HIV integrase inhibitor

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Zelalem Temesgen

2008-06-01

Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

A historical sketch of the discovery and development of HIV-1 integrase inhibitors.

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Savarino, Andrea

2006-12-01

The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor 'integration' of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the beta-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review reconstructs (in the general context of the history of AIDS research) the principal steps that led to the integrase inhibitors currently in clinical trials, and discusses possible future directions.

HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland

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Parczewski Miłosz

2012-12-01

Full Text Available Abstract Background HIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross-resistance among representatives of this class of antiretrovirals. The aim of this study was to analyse integrase sequence variability among antiretroviral treatment naive and experienced patients with no prior integrase inhibitor (InI exposure and investigate development of the InI drug resistance mutations following the virologic failure of the raltegravir containing regimen. Methods Sequencing of HIV-1 integrase region from plasma samples of 80 integrase treatment naive patients and serial samples from 12 patients with observed virologic failure on raltegravir containing treatment whenever plasma vireamia exceeded >50 copies/ml was performed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor variants. For subtyping bootstrapped phylogenetic analysis was used; Bayesian Monte Carlo Marcov Chain (MCMC model was implemented to infer on the phylogenetic relationships between the serial sequences from patients failing on raltegravir. Results Majority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, as well as CRF01_AE , CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI-treatment naive patients. In 30 (38.5% cases polymorphic variation with predominance of the E157Q mutation was observed. This mutation was more common among subtype B (26 cases, 54.2% than non-B sequences (5 cases, 16.7%, p=0.00099, OR: 5.91 (95% CI:1.77-22.63]. Other variants included L68V, L74IL, T97A, E138D, V151I, R263K. Among 12 (26.1% raltegravir treated patients treatment failure was observed; major InI drug resistance mutations (G140S, Q148H and N155H, V151I, E92EQ, V151I, G163R were noted in four of these cases (8.3% of the total InI-treated patients. Time to the development of drug resistance ranged

Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

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Thomas S Peat

Full Text Available A fragment-based screen against human immunodeficiency virus type 1 (HIV integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

Recombinase-mediated reprogramming and dystrophin gene addition in mdx mouse induced pluripotent stem cells.

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Chunli Zhao

Full Text Available A cell therapy strategy utilizing genetically-corrected induced pluripotent stem cells (iPSC may be an attractive approach for genetic disorders such as muscular dystrophies. Methods for genetic engineering of iPSC that emphasize precision and minimize random integration would be beneficial. We demonstrate here an approach in the mdx mouse model of Duchenne muscular dystrophy that focuses on the use of site-specific recombinases to achieve genetic engineering. We employed non-viral, plasmid-mediated methods to reprogram mdx fibroblasts, using phiC31 integrase to insert a single copy of the reprogramming genes at a safe location in the genome. We next used Bxb1 integrase to add the therapeutic full-length dystrophin cDNA to the iPSC in a site-specific manner. Unwanted DNA sequences, including the reprogramming genes, were then precisely deleted with Cre resolvase. Pluripotency of the iPSC was analyzed before and after gene addition, and ability of the genetically corrected iPSC to differentiate into myogenic precursors was evaluated by morphology, immunohistochemistry, qRT-PCR, FACS analysis, and intramuscular engraftment. These data demonstrate a non-viral, reprogramming-plus-gene addition genetic engineering strategy utilizing site-specific recombinases that can be applied easily to mouse cells. This work introduces a significant level of precision in the genetic engineering of iPSC that can be built upon in future studies.

Ethyl malonate amides: a diketo acid offspring fragment for HIV integrase inhibition.

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Serafin, Katarzyna; Mazur, Pawel; Bak, Andrzej; Laine, Elodie; Tchertanov, Luba; Mouscadet, Jean-François; Polanski, Jaroslaw

2011-08-15

While searching for new HIV integrase inhibitors we discovered that some ethyl malonate amides (EMA) are active against this enzyme. Surprisingly, the main function can only very rarely be found among the reported drug candidates. We synthesised a series of compounds in order to establish and analyse the structure-activity relationship. The similarity to the important classes of HIV integrase inhibitors as well as the synthetic availability of the different targets including this pharmacophore makes EMA compounds an interesting object of investigations. Copyright © 2011 Elsevier Ltd. All rights reserved.

Lack of integrase inhibitors associated resistance mutations among HIV-1C isolates.

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Mulu, Andargachew; Maier, Melanie; Liebert, Uwe Gerd

2015-12-01

Although biochemical analysis of HIV-1 integrase enzyme suggested the use of integrase inhibitors (INIs) against HIV-1C, different viral subtypes may favor different mutational pathways potentially leading to varying levels of drug resistance. Thus, the aim of this study was to search for the occurrence and natural evolution of integrase polymorphisms and/or resistance mutations in HIV-1C Ethiopian clinical isolates prior to the introduction of INIs. Plasma samples from chronically infected drug naïve patients (N = 45), of whom the PR and RT sequence was determined previously, were used to generate population based sequences of HIV-1 integrase. HIV-1 subtype was determined using the REGA HIV-1 subtyping tool. Resistance mutations were interpreted according to the Stanford HIV drug resistance database ( http://hivdb.stanford.edu ) and the updated International Antiviral Society (IAS)-USA mutation lists. Moreover, rates of polymorphisms in the current isolates were compared with South African and global HIV-1C isolates. All subjects were infected with HIV-1C concordant to the protease (PR) and reverse transcriptase (RT) regions. Neither major resistance-associated IN mutations (T66I/A/K, E92Q/G, T97A, Y143HCR, S147G, Q148H/R/K, and N155H) nor silent mutations known to change the genetic barrier were observed. Moreover, the DDE-catalytic motif (D64G/D116G/E152 K) and signature HHCC zinc-binding motifs at codon 12, 16, 40 and 43 were found to be highly conserved. However, compared to other South African subtype C isolates, the rate of polymorphism was variable at various positions. Although the sample size is small, the findings suggest that this drug class could be effective in Ethiopia and other southern African countries where HIV-1C is predominantly circulating. The data will contribute to define the importance of integrase polymorphism and to improve resistance interpretation algorithms in HIV-1C isolates.

A Mos1 transposase in vivo assay to screen new HIV-1 integrase inhibitors.

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Cancian, Mariana; Loreto, Elgion L S

2018-04-01

The integrase and transposase enzymes of retrovirus and transposons, respectively, share the catalytic DDE domain. In vitro assays showed that inhibitors of HIV-1 integrase generally inhibit the mariner Mos1 transposase. Using a Drosophila strain in which the mobilisation of the mariner element can be quantified by mosaic eyes, we showed that flies maintained in medium containing 210 µM to 4 mM of raltegravir, or 1 or 2 mM of dolutegravir, which are HIV-1 integrase inhibitor used in AIDS treatment, have 23-33% less somatic mobilisation in mosaic eyes when treated with raltegravir and 28-32% when treated with dolutegravir. The gene expression of the mariner transposase gene, estimated by qPCR, is similar among treated and control flies. The results suggest that in vivo assays using Drosophila can be used as a primary screening of inhibitory drugs for transposase and retroviral integrase. The advantages of this assay are that it is easy, quick, cheap and is an in vivo test, meaning that the tested substance has to have been taken in by cells and has arrived at the target site, which is not the case when in vitro assays are applied.

Developing a Dynamic Pharmacophore Model for HIV-1 Integrase

International Nuclear Information System (INIS)

Carlson, Heather A.; Masukawa, Keven M.; Rubins, Kathleen; Bushman, Frederic; Jorgensen, William L.; Lins, Roberto; Briggs, James; Mccammon, Andy

2000-01-01

We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of ''dynamic'' pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy minimization method, available in the BOSS program; it is used to determine binding regions for probe molecules containing functional groups that complement the active site. All protein conformations from the MD are overlaid, and conserved binding regions for the probe molecules are identified. Those conserved binding regions define the dynamic pharmacophore model. Here, the dynamic model is compared to known inhibitors of the integrase as well as a three-point, ligand-based pharmacophore model from the literature. Also, a ''static'' pharmacophore model was determined in the standard fashion, using a single crystal structure. Inhibitors thought to bind in the active site of HIV-1 integrase fit the dynamic model but not the static model. Finally, we have identified a set of compounds from the Available Chemicals Directory that fit the dynamic pharmacophore model, and experimental testing of the compounds has confirmed several new inhibitors

Structural and Functional Insights into Foamy Viral Integrase

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Cha-Gyun Shin

2013-07-01

Full Text Available Successful integration of retroviral DNA into the host chromosome is an essential step for viral replication. The process is mediated by virally encoded integrase (IN and orchestrated by 3'-end processing and the strand transfer reaction. In vitro reaction conditions, such as substrate specificity, cofactor usage, and cellular binding partners for such reactions by the three distinct domains of prototype foamy viral integrase (PFV-IN have been described well in several reports. Recent studies on the three‑dimensional structure of the interacting complexes between PFV-IN and DNA, cofactors, binding partners, or inhibitors have explored the mechanistic details of such interactions and shown its utilization as an important target to develop anti-retroviral drugs. The presence of a potent, non-transferable nuclear localization signal in the PFV C-terminal domain extends its use as a model for investigating cellular trafficking of large molecular complexes through the nuclear pore complex and also to identify novel cellular targets for such trafficking. This review focuses on recent advancements in the structural analysis and in vitro functional aspects of PFV-IN.

Tight regulation of the intS gene of the KplE1 prophage: a new paradigm for integrase gene regulation.

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Gaël Panis

2010-10-01

Full Text Available Temperate phages have the ability to maintain their genome in their host, a process called lysogeny. For most, passive replication of the phage genome relies on integration into the host's chromosome and becoming a prophage. Prophages remain silent in the absence of stress and replicate passively within their host genome. However, when stressful conditions occur, a prophage excises itself and resumes the viral cycle. Integration and excision of phage genomes are mediated by regulated site-specific recombination catalyzed by tyrosine and serine recombinases. In the KplE1 prophage, site-specific recombination is mediated by the IntS integrase and the TorI recombination directionality factor (RDF. We previously described a sub-family of temperate phages that is characterized by an unusual organization of the recombination module. Consequently, the attL recombination region overlaps with the integrase promoter, and the integrase and RDF genes do not share a common activated promoter upon lytic induction as in the lambda prophage. In this study, we show that the intS gene is tightly regulated by its own product as well as by the TorI RDF protein. In silico analysis revealed that overlap of the attL region with the integrase promoter is widely encountered in prophages present in prokaryotic genomes, suggesting a general occurrence of negatively autoregulated integrase genes. The prediction that these integrase genes are negatively autoregulated was biologically assessed by studying the regulation of several integrase genes from two different Escherichia coli strains. Our results suggest that the majority of tRNA-associated integrase genes in prokaryotic genomes could be autoregulated and that this might be correlated with the recombination efficiency as in KplE1. The consequences of this unprecedented regulation for excessive recombination are discussed.

Generation of chickens expressing Cre recombinase.

Science.gov (United States)

Leighton, Philip A; Pedersen, Darlene; Ching, Kathryn; Collarini, Ellen J; Izquierdo, Shelley; Jacob, Roy; van de Lavoir, Marie-Cecile

2016-10-01

Cre recombinase has been extensively used for genome engineering in transgenic mice yet its use in other species has been more limited. Here we describe the generation of transgenic chickens expressing Cre recombinase. Green fluorescent protein (GFP)-positive chicken primordial germ cells were stably transfected with β-actin-Cre-recombinase using phiC31 integrase and transgenic chickens were generated. Cre recombinase activity was verified by mating Cre birds to birds carrying a floxed transgene. Floxed sequences were only excised in offspring from roosters that inherited the Cre recombinase but were excised in all offspring from hens carrying the Cre recombinase irrespective of the presence of the Cre transgene. The Cre recombinase transgenic birds were healthy and reproductively normal. The Cre and GFP genes in two of the lines were closely linked whereas the genes segregated independently in a third line. These founders allowed development of GFP-expressing and non-GFP-expressing Cre recombinase lines. These lines of birds create a myriad of opportunities to study developmentally-regulated and tissue-specific expression of transgenes in chickens.

Generation of Driver and Reporter Constructs for the GAL4 Expression System in Drosophila.

Science.gov (United States)

Southall, Tony D; Brand, Andrea H

2008-07-01

INTRODUCTIONThe GAL4 system is a method for ectopic gene expression that allows the selective activation of any cloned gene in a wide variety of tissue- and cell-specific patterns. This protocol describes the generation of driver and reporter lines for use with the GAL4 system in Drosophila. A promoter-GAL4 fusion is constructed using a P-element transformable vector, and a GAL4-responsive target gene is created via generation of an upstream activation sequence (UAS)-reporter construct. An alternative strategy for integration using the phiC31 system is also provided. Transformant lines are generated using standard procedures for microinjection.

[Isolation, idetification and anti-HIV-1 integrase activity of culturable endophytic fungi from Tibetan medicinal plant Phlomis younghusbandii Mukerjee].

Science.gov (United States)

Zhang, Da-Wei; Zhao, Ming-Ming; Chen, Juan; Li, Chao; Guo, Shun-Xing

2013-05-01

A total of 52 endophytic fungi were isolated from roots and stems of Tibetan medicinal plant Phlomis younghusbandii Mukerjee. These fungal isolates were molecularly identified based on ITS sequnces and 28S sequences distributed to 12 genera, including Phoma, Chaetosphaeronema, Fusarium and Leptosphaeria, etc. Among them, the dominant genus was Phoma. Extracts of all strains were evaluated for anti-HIV-1 integrase activity by using soluable integrase expressed in E. coli BL21 (DE3). The results showed that seven samples from five fungal endophytes PHY-24, PHY-38, PHY-40, PHY-51, PHY-53, which belonged to genus Chaetosphaeronema, inhibited strand transfer reaction catalyzed by HIV-1 integrase with IC50 values, of 6.60, 5.20, 2.86, 7.86, 4.47, 4.56 and 3.23 microg x mL(-1) respectively. In conclusion, the endophytic fungi of Phlomis younghusbandii Mukerjee are valuable for further screening anti-HIV-1 integrase agents.

Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis, Biological Activities and Mechanism of Action

Science.gov (United States)

Di Santo, Roberto; Costi, Roberta; Roux, Alessandra; Artico, Marino; Lavecchia, Antonio; Marinelli, Luciana; Novellino, Ettore; Palmisano, Lucia; Andreotti, Mauro; Amici, Roberta; Galluzzo, Clementina Maria; Nencioni, Lucia; Palamara, Anna Teresa; Pommier, Yves; Marchand, Christophe

2008-01-01

The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the β-diketo acids (DKAs) represent a major lead for anti-HIV-1drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3′-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-crosslinking experiments. PMID:16539381

Development of a novel in vitro assay for the evaluation of integron DNA integrase activity

Directory of Open Access Journals (Sweden)

Fatemeh Tohidi

2016-05-01

Full Text Available Integrons play an important role in multidrug resistance. The integron platform codes for integrase (intI that is required for gene cassette integration through site-specific recombination. The recombination crossover occurs between the G and TT nucleotides in non-palindromic attI and palindromic attC sites. The aim of this study was to establish an efficient in vitro assay for integrase purification and activity detection. To this end, the intI gene was cloned into the pET-22b plasmid. Then, the resulting recombinant plasmid was transformed into Escherichia coli Origami™ strain. The recombinant protein expression was confirmed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE and western blot assays. The recombinant intI protein was purified by nickel–nitrilotriacetic acid (Ni–NTA affinity chromatography, and its activity was measured by a newly introduced assay. Briefly, specific primers for each side of attI and attC were used, thereby, a polymerase chain reaction would be performed, if a fused plasmid containing both attI and attC sites was created upon recombination. SDS-PAGE and western blotting confirmed the presence of a 38-kDa recombinant protein. Optimum conditions were established for the measurement of the integrase activity and a new model assay was conducted to analyse the recombination activity in vitro. Although the electrophoretic mobility shift assay is an efficient and reliable method, the newly introduced assay provided new or enhanced capability to determine the integrase activity, suggesting that there is no need for expensive and advanced equipment.

Postexposure protection of macaques from vaginal SHIV infection by topical integrase inhibitors.

Science.gov (United States)

Dobard, Charles; Sharma, Sunita; Parikh, Urvi M; West, Rolieria; Taylor, Andrew; Martin, Amy; Pau, Chou-Pong; Hanson, Debra L; Lipscomb, Jonathan; Smith, James; Novembre, Francis; Hazuda, Daria; Garcia-Lerma, J Gerardo; Heneine, Walid

2014-03-12

Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure.

Sketching the historical development of pyrimidones as the inhibitors of the HIV integrase

Czech Academy of Sciences Publication Activity Database

Patel, Rahul V.; Keum, Y.S.; Park, S.W.

2015-01-01

Roč. 97, JUN 5 (2015), s. 649-663 ISSN 0223-5234 Institutional support: RVO:61389030 Keywords : Pyrimidones * Anti-HIV * Integrase inhibitors Subject RIV: CE - Biochemistry Impact factor: 3.902, year: 2015

Molecular dynamics simulation studies of the wild type and E92Q/N155H mutant of Elvitegravir-resistance HIV-1 integrase.

Science.gov (United States)

Chen, Qi; Cheng, Xiaolin; Wei, Dongqing; Xu, Qin

2015-03-01

Although Elvitegravir (EVG) is a newly developed antiretrovirals drug to treat the acquired immunodeficiency syndrome (AIDS), drug resistance has already been found in clinic, such as E92Q/N155H and Q148H/G140S. Several structural investigations have already been reported to reveal the molecular mechanism of the drug resistance. As full length crystal structure for HIV-1 integrase is still unsolved, we herein use the crystal structure of the full length prototype foamy virus (PFV) in complex with virus DNA and inhibitor Elvitegravir as a template to construct the wild type and E92Q/N155H mutant system of HIV-1 integrase. Molecular dynamic simulations was used to revel the binding mode and the drug resistance of the EVG ligand in E92Q/N155H. Several important interactions were discovered between the mutated residues and the residues in the active site of the E92Q/N155H double mutant pattern, and cross correlation and clustering methods were used for detailed analysis. The results from the MD simulation studies will be used to guide the experimental efforts of developing novel inhibitors against drug-resistant HIV integrase mutants.

The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome

NARCIS (Netherlands)

van Bel, Nikki; van der Velden, Yme; Bonnard, Damien; Le Rouzic, Erwann; Das, Atze T.; Benarous, Richard; Berkhout, Ben

2014-01-01

The viral integrase (IN) is an essential protein for HIV-1 replication. IN inserts the viral dsDNA into the host chromosome, thereby aided by the cellular co-factor LEDGF/p75. Recently a new class of integrase inhibitors was described: allosteric IN inhibitors (ALLINIs). Although designed to

Comparison Between Several Integrase-defective Lentiviral Vectors Reveals Increased Integration of an HIV Vector Bearing a D167H Mutant

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Muhammad Qamar Saeed

2014-01-01

Full Text Available HIV-1 derived vectors are among the most efficient for gene transduction in mammalian tissues. As the parent virus, they carry out vector genome insertion into the host cell chromatin. Consequently, their preferential integration in transcribed genes raises several conceptual and safety issues. To address part of these questions, HIV-derived vectors have been engineered to be nonintegrating. This was mainly achieved by mutating HIV-1 integrase at functional hotspots of the enzyme enabling the development of streamlined nuclear DNA circles functional for transgene expression. Few integrase mutant vectors have been successfully tested so far for gene transfer. They are cleared with time in mitotic cells, but stable within nondividing retina cells or neurons. Here, we compared six HIV vectors carrying different integrases, either wild type or with different mutations (D64V, D167H, Q168A, K186Q+Q214L+Q216L, and RRK262-264AAH shown to modify integrase enzymatic activity, oligomerization, or interaction with key cellular cofactor of HIV DNA integration as LEDGF/p75 or TNPO3. We show that these mutations differently affect the transduction efficiency as well as rates and patterns of integration of HIV-derived vectors suggesting their different processing in the nucleus. Surprisingly and most interestingly, we report that an integrase carrying the D167H substitution improves vector transduction efficiency and integration in both HEK-293T and primary CD34+ cells.

Targeted Gene Knockin in Porcine Somatic Cells Using CRISPR/Cas Ribonucleoproteins

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Ki-Eun Park

2016-05-01

Full Text Available The pig is an ideal large animal model for genetic engineering applications. A relatively short gestation interval and large litter size makes the pig a conducive model for generating and propagating genetic modifications. The domestic pig also shares close similarity in anatomy, physiology, size, and life expectancy, making it an ideal animal for modeling human diseases. Often, however, the technical difficulties in generating desired genetic modifications such as targeted knockin of short stretches of sequences or transgenes have impeded progress in this field. In this study, we have investigated and compared the relative efficiency of CRISPR/Cas ribonucleoproteins in engineering targeted knockin of pseudo attP sites downstream of a ubiquitously expressed COL1A gene in porcine somatic cells and generated live fetuses by somatic cell nuclear transfer (SCNT. By leveraging these knockin pseudo attP sites, we have demonstrated subsequent phiC31 integrase mediated integration of green fluorescent protein (GFP transgene into the site. This work for the first time created an optimized protocol for CRISPR/Cas mediated knockin in porcine somatic cells, while simultaneously creating a stable platform for future transgene integration and generating transgenic animals.

Molecular features related to HIV integrase inhibition obtained from structure- and ligand-based approaches.

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Luciana L de Carvalho

Full Text Available Among several biological targets to treat AIDS, HIV integrase is a promising enzyme that can be employed to develop new anti-HIV agents. The aim of this work is to propose a mechanistic interpretation of HIV-1 integrase inhibition and to rationalize the molecular features related to the binding affinity of studied ligands. A set of 79 HIV-1 integrase inhibitors and its relationship with biological activity are investigated employing 2D and 3D QSAR models, docking analysis and DFT studies. Analyses of docking poses and frontier molecular orbitals revealed important features on the main ligand-receptor interactions. 2D and 3D models presenting good internal consistency, predictive power and stability were obtained in all cases. Significant correlation coefficients (r(2 = 0.908 and q(2= 0.643 for 2D model; r(2= 0.904 and q(2= 0.719 for 3D model were obtained, indicating the potential of these models for untested compounds. The generated holograms and contribution maps revealed important molecular requirements to HIV-1 IN inhibition and several evidences for molecular modifications. The final models along with information resulting from molecular orbitals, 2D contribution and 3D contour maps should be useful in the design of new inhibitors with increased potency and selectivity within the chemical diversity of the data.

Molecular dynamics simulation studies of the wild type and E92Q/N155H mutant of Elvitegravir-resistance HIV-1 integrase

Energy Technology Data Exchange (ETDEWEB)

Chen, Qi [Shanghai Jiao Tong Univ., Shanghai (China). State Key Lab. of Microbial Metabolism and College of Life Science and Biotechnology; Cheng, Xiaolin [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology; Wei, Dongqing [Shanghai Jiao Tong Univ., Shanghai (China). State Key Lab. of Microbial Metabolism and College of Life Science and Biotechnology; Xu, Qin [Shanghai Jiao Tong Univ., Shanghai (China). State Key Lab. of Microbial Metabolism and College of Life Science and Biotechnology

2014-11-06

Although Elvitegravir (EVG) is a newly developed antiretrovirals drug to treat the acquired immunodeficiency syndrome (AIDS), drug resistance has already been found in clinic, such as E92Q/N155H and Q148H/G140S. Several structural investigations have already been reported to reveal the molecular mechanism of the drug resistance. As full length crystal structure for HIV-1 integrase is still unsolved, we use in this paper the crystal structure of the full length prototype foamy virus (PFV) in complex with virus DNA and inhibitor Elvitegravir as a template to construct the wild type and E92Q/N155H mutant system of HIV-1 integrase. Molecular dynamic simulations was used to revel the binding mode and the drug resistance of the EVG ligand in E92Q/N155H. Several important interactions were discovered between the mutated residues and the residues in the active site of the E92Q/N155H double mutant pattern, and cross correlation and clustering methods were used for detailed analysis. The results from the MD simulation studies will be used to guide the experimental efforts of developing novel inhibitors against drug-resistant HIV integrase mutants.

Lead Screening for HIV-1 Integrase (IN Inhibited by Traditional Chinese Medicine

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Tzu-Chieh Hung

2014-01-01

Full Text Available Human immunodeficiency virus causes the acquired immunodeficiency syndrome (AIDS and becomes a serious world-wide problem because of this disease's rapid propagation and incurability. Integrase strand transfer inhibitors (INSTIs supports HIV have rapid drug resistance for antitreatment. Screening the traditional Chinese medicine (TCM database by simulating molecular docking and molecular dynamics may select molecular compounds to inhibit INSTIs against HIV drug resistance. (S-cathinone and (1S,2S-norpseudoephedrine are selected based on structure and ligand-based drugs are designed and then get higher bioactivity predicted score from SVM than Raltegravir and other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. According to the docking poses, hydrophobic interactions and hydrogen bond variations define the main regions of important amino acids in integrase. In addition to the detection of TCM compound efficacy, we suggest (1S,2S-norpseudoephedrine is better than the others based on the analysis of interaction and the effect on the structural variation.

Real-time monitoring of disintegration activity of catalytic core domain of HIV-1 integrase using molecular beacon.

Science.gov (United States)

Zhang, Da-wei; Zhao, Ming-ming; He, Hong-qiu; Guo, Shun-xing

2013-09-15

HIV-1 integrase, an essential enzyme for retroviral replication, is a validated target for anti-HIV therapy development. The catalytic core domain of integrase (IN-CCD) is capable of catalyzing disintegration reaction. In this work, a hairpin-shaped disintegration substrate was designed and validated by enzyme-linked immunosorbent assay; a molecular beacon-based assay was developed for disintegration reaction of IN-CCD. Results showed that the disintegration substrate could be recognized and catalyzed by IN-CCD, and the disintegration reaction can be monitored according to the increase of fluorescent signal. The assay can be applied to real-time detection of disintegration with advantages of simplicity, high sensitivity, and excellent specificity. Copyright © 2013 Elsevier Inc. All rights reserved.

Cloning, purification and structure determination of the HIV integrase-binding domain of lens epithelium-derived growth factor.

Science.gov (United States)

Hannon, Clare; Cruz-Migoni, Abimael; Platonova, Olga; Owen, Robin L; Nettleship, Joanne E; Miller, Ami; Carr, Stephen B; Harris, Gemma; Rabbitts, Terence H; Phillips, Simon E V

2018-03-01

Lens epithelium-derived growth factor (LEDGF)/p75 is the dominant binding partner of HIV-1 integrase in human cells. The crystal structure of the HIV integrase-binding domain (IBD) of LEDGF has been determined in the absence of ligand. IBD was overexpressed in Escherichia coli, purified and crystallized by sitting-drop vapour diffusion. X-ray diffraction data were collected at Diamond Light Source to a resolution of 2.05 Å. The crystals belonged to space group P2 1 , with eight polypeptide chains in the asymmetric unit arranged as an unusual octamer composed of four domain-swapped IBD dimers. IBD exists as a mixture of monomers and dimers in concentrated solutions, but the dimers are unlikely to be biologically relevant.

HIV-2 integrase polymorphisms and longitudinal genotypic analysis of HIV-2 infected patients failing a raltegravir-containing regimen.

Science.gov (United States)

Cavaco-Silva, Joana; Abecasis, Ana; Miranda, Ana Cláudia; Poças, José; Narciso, Jorge; Águas, Maria João; Maltez, Fernando; Almeida, Isabel; Germano, Isabel; Diniz, António; Gonçalves, Maria de Fátima; Gomes, Perpétua; Cunha, Celso; Camacho, Ricardo Jorge

2014-01-01

To characterize the HIV-2 integrase gene polymorphisms and the pathways to resistance of HIV-2 patients failing a raltegravir-containing regimen, we studied 63 integrase strand transfer inhibitors (INSTI)-naïve patients, and 10 heavily pretreated patients exhibiting virological failure while receiving a salvage raltegravir-containing regimen. All patients were infected by HIV-2 group A. 61.4% of the integrase residues were conserved, including the catalytic motif residues. No INSTI-major resistance mutations were detected in the virus population from naïve patients, but two amino acids that are secondary resistance mutations to INSTIs in HIV-1 were observed. The 10 raltegravir-experienced patients exhibited resistance mutations via three main genetic pathways: N155H, Q148R, and eventually E92Q - T97A. The 155 pathway was preferentially used (7/10 patients). Other mutations associated to raltegravir resistance in HIV-1 were also observed in our HIV-2 population (V151I and D232N), along with several novel mutations previously unreported. Data retrieved from this study should help build a more robust HIV-2-specific algorithm for the genotypic interpretation of raltegravir resistance, and contribute to improve the clinical monitoring of HIV-2-infected patients.

Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

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Neamati Nouri

2009-04-01

Full Text Available Abstract Correction to Erik Serrao, Srinivas Odde, Kavya Ramkumar and Nouri Neamati: Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 2009, 6:25. Since the recent publication of our article (Neamati, Retrovirology 2009, 6:25, we have noticed an error which we would like to correct and we would like to apologise to the readers for this mistake.

Contribution of HIV minority variants to drug resistance in an integrase strand transfer inhibitor-based therapy

Czech Academy of Sciences Publication Activity Database

Weber, Jan; Gibson, R. M.; Meyer, A. M.; Winner, D.; Robertson, D. L.; Miller, M. D.; Quinones-Mateu, M. E.

2013-01-01

Roč. 18, Suppl. 1 (2013), A66-A66 ISSN 1359-6535. [International Workshop on HIV & Hepatitis Virus Drug Resistance Curative Strategies. 04.06.2013-08.06.2013, Toronto] Institutional support: RVO:61388963 Keywords : HIV minority variants * integrase inhibitor * replicative fitness Subject RIV: CE - Biochemistry

Integrase-Deficient Lentiviral Vector as an All-in-One Platform for Highly Efficient CRISPR/Cas9-Mediated Gene Editing

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Pavel I. Ortinski

2017-06-01

Full Text Available The CRISPR/Cas9 systems have revolutionized the field of genome editing by providing unprecedented control over gene sequences and gene expression in many species, including humans. Lentiviral vectors (LVs are one of the primary delivery platforms for the CRISPR/Cas9 system due to their ability to accommodate large DNA payloads and sustain robust expression in a wide range of dividing and non-dividing cells. However, long-term expression of LV-delivered Cas9/guide RNA may lead to undesirable off-target effects characterized by non-specific RNA-DNA interactions and off-target DNA cleavages. Integrase-deficient lentiviral vectors (IDLVs present an attractive means for delivery of CRISPR/Cas9 components because: (1 they are capable of transducing a broad range of cells and tissues, (2 have superior packaging capacity compared to other vectors (e.g., adeno-associated viral vectors, and (3 they are expressed transiently and demonstrate very weak integration capability. In this manuscript, we aimed to establish IDLVs as a means for safe and efficient delivery of CRISPR/Cas9. To this end, we developed an all-in-one vector cassette with increased production efficacy and demonstrated that CRISPR/Cas9 delivered by the improved IDLV vectors can mediate rapid and robust gene editing in human embryonic kidney (HEK293T cells and post-mitotic brain neurons in vivo, via transient expression and with higher gene-targeting specificity than the corresponding integrase-competent vectors.

Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. Integrase inhibition

International Nuclear Information System (INIS)

Lee-Huang, Sylvia; Huang, Philip Lin; Zhang Dawei; Lee, Jae Wook; Bao Ju; Sun Yongtao; Chang, Young-Tae; Zhang, John; Huang, Paul Lee

2007-01-01

We have identified oleuropein (Ole) and hydroxytyrosol (HT) as a unique class of HIV-1 inhibitors from olive leaf extracts effective against viral fusion and integration. We used molecular docking simulation to study the interactions of Ole and HT with viral targets. We find that Ole and HT bind to the conserved hydrophobic pocket on the surface of the HIV-gp41 fusion domain by hydrogen bonds with Q577 and hydrophobic interactions with I573, G572, and L568 on the gp41 N-terminal heptad repeat peptide N36, interfering with formation of the gp41 fusion-active core. To test and confirm modeling predications, we examined the effect of Ole and HT on HIV-1 fusion complex formation using native polyacrylamide gel electrophoresis and circular dichroism spectroscopy. Ole and HT exhibit dose-dependent inhibition on HIV-1 fusion core formation with EC 50 s of 66-58 nM, with no detectable toxicity. Our findings on effects of HIV-1 integrase are reported in the subsequent article

Docking studies on a new human immunodeficiency virus integrase-Mg-DNA complex: phenyl ring exploration and synthesis of 1H-benzylindole derivatives through fluorine substitutions.

Science.gov (United States)

Ferro, Stefania; De Luca, Laura; Barreca, Maria Letizia; Iraci, Nunzio; De Grazia, Sara; Christ, Frauke; Witvrouw, Myriam; Debyser, Zeger; Chimirri, Alba

2009-01-22

A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been built. It was used to study the binding mode of integrase strand transfer inhibitor 1 (CHI-1043) and other fluorine analogues. Molecular modeling results prompted us to synthesize the designed derivatives which showed potent enzymatic inhibition at nanomolar concentration, high antiviral activity, and low toxicity. Microwave assisted organic synthesis (MAOS) was employed in several steps of the synthetic pathway, thus reducing reaction times and improving yields.

The ΦBT1 large serine recombinase catalyzes DNA integration at pseudo-attB sites in the genus Nocardia

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Marion Herisse

2018-05-01

Full Text Available Plasmid vectors based on bacteriophage integrases are important tools in molecular microbiology for the introduction of foreign DNA, especially into bacterial species where other systems for genetic manipulation are limited. Site specific integrases catalyze recombination between phage and bacterial attachment sites (attP and attB, respectively and the best studied integrases in the actinomycetes are the serine integrases from the Streptomyces bacteriophages ΦC31 and ΦBT1. As this reaction is unidirectional and highly stable, vectors containing phage integrase systems have been used in a number of genetic engineering applications. Plasmids bearing the ΦBT1 integrase have been used to introduce DNA into Streptomyces and Amycolatopsis strains; however, they have not been widely studied in other actinobacterial genera. Here, we show that vectors based on ΦBT1 integrase can stably integrate into the chromosomes of a range of Nocardia species, and that this integration occurs despite the absence of canonical attB sites in these genomes. Furthermore, we show that a ΦBT1 integrase-based vector can insert at multiple pseudo-attB sites within a single strain and we determine the sequence of a pseudo-attB motif. These data suggest that ΦBT1 integrase-based vectors can be used to readily and semi-randomly introduce foreign DNA into the genomes of a range of Nocardia species. However, the precise site of insertion will likely require empirical determination in each species to avoid unexpected off-target effects.

Primary resistance to integrase strand transfer inhibitors in patients infected with diverse HIV-1 subtypes in sub-Saharan Africa

NARCIS (Netherlands)

Inzaule, Seth C.; Hamers, Raph L.; Noguera-Julian, Marc; Casadellà, Maria; Parera, Mariona; Rinke de Wit, Tobias F.; Paredes, Roger

2018-01-01

To investigate the prevalence and patterns of major and accessory resistance mutations associated with integrase strand transfer inhibitors (INSTIs), across diverse HIV-1 subtypes in sub-Saharan Africa. pol gene sequences were obtained using Illumina next-generation sequencing from 425 INSTI-naive

BF integrase genes of HIV-1 circulating in São Paulo, Brazil, with a recurrent recombination region.

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Atila Iamarino

Full Text Available Although some studies have shown diversity in HIV integrase (IN genes, none has focused particularly on the gene evolving in epidemics in the context of recombination. The IN gene in 157 HIV-1 integrase inhibitor-naïve patients from the São Paulo State, Brazil, were sequenced tallying 128 of subtype B (23 of which were found in non-B genomes, 17 of subtype F (8 of which were found in recombinant genomes, 11 integrases were BF recombinants, and 1 from subtype C. Crucially, we found that 4 BF recombinant viruses shared a recurrent recombination breakpoint region between positions 4900 and 4924 (relative to the HXB2 that includes 2 gRNA loops, where the RT may stutter. Since these recombinants had independent phylogenetic origin, we argue that these results suggest a possible recombination hotspot not observed so far in BF CRF in particular, or in any other HIV-1 CRF in general. Additionally, 40% of the drug-naïve and 45% of the drug-treated patients had at least 1 raltegravir (RAL or elvitegravir (EVG resistance-associated amino acid change, but no major resistance mutations were found, in line with other studies. Importantly, V151I was the most common minor resistance mutation among B, F, and BF IN genes. Most codon sites of the IN genes had higher rates of synonymous substitutions (dS indicative of a strong negative selection. Nevertheless, several codon sites mainly in the subtype B were found under positive selection. Consequently, we observed a higher genetic diversity in the B portions of the mosaics, possibly due to the more recent introduction of subtype F on top of an ongoing subtype B epidemics and a fast spread of subtype F alleles among the B population.

D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75

International Nuclear Information System (INIS)

Du Li; Zhao Yaxue; Chen, Jing; Yang Liumeng; Zheng Yongtang; Tang Yun; Shen Xu; Jiang Hualiang

2008-01-01

Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. In this work, we reported that a benzoic acid derivative, 4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl) -1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)methyl]benzoic acid (D77) could potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution thus exhibiting antiretroviral activity. Molecular docking with site-directed mutagenesis analysis and surface plasmon resonance (SPR) binding assays has clarified possible binding mode of D77 against HIV-1 integrase. As the firstly discovered small molecular compound targeting HIV-1 integrase interaction with LEDGF/p75, D77 might supply useful structural information for further anti-HIV agent discovery

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

Science.gov (United States)

Schreier, John D; Embrey, Mark W; Raheem, Izzat T; Barbe, Guillaume; Campeau, Louis-Charles; Dubost, David; McCabe Dunn, Jamie; Grobler, Jay; Hartingh, Timothy J; Hazuda, Daria J; Klein, Daniel; Miller, Michael D; Moore, Keith P; Nguyen, Natalie; Pajkovic, Natasa; Powell, David A; Rada, Vanessa; Sanders, John M; Sisko, John; Steele, Thomas G; Wai, John; Walji, Abbas; Xu, Min; Coleman, Paul J

2017-05-01

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structure-property relationships for n-alkyl-isocyanate-containing polymers

Science.gov (United States)

Aronson, Carl Lawrence

Poly(n-hexyl isocyanate) (PHIC), poly(n-butyl-isocyanate) (PBIC), poly(n-butyl-co-cyclohexyl isocyanate) (PBCHIC), poly(n-hexyl isocyanate-b-isoprene) (HI), poly(n-butyl isocyanate-b-isoprene) (BI) and poly(n-hexyl isocyanate-b-isoprene- b-styrene) (MS) were synthesized and characterized with respect to composition, molecular Weight and polydispersity. PHIC, HI and HIS were found to be lyotropic liquid crystalline whereas PBIC, PBCHIC and BI were found to be non-lyotropic. A lyotropic-nematic liquid crystalline phase diagram was determined for the PHIC/xylene system. A novel and reversible electric-field-induced biphasic-paranematic phase transition was found for the PHIC/xylene system from the dynamics of topological defects. The electric-field-induced phase diagram for PHIC/xylene agreed with the theoretically predicted field-induced phase diagram of Khokhlov and Semenov for semiflexible-persistent polymers. The dielectric characteristics, steady-state electrically induced birefringence and steady-state electroheological (ER) activity of PHIC, PBIC and PBCHIC solutions were compared as a function of polymer concentration. The role of lyotropic liquid crystalline ordering in the functional ER mechanism of poly( n-hexyl isocyanate) solutions is presented. PBCHIC was found to thermally decompose by a first-order rate process which became slower with increasing cyclohexyl isocyanate content from thermal gravimetric analysis. Competition between monomer dissociation and degradative trimerization as well as a non-alternating sequence distribution were determined for PBCHIC from direct pyrolysis/mass spectrometry. The Arrhenius activation energy, pre-exponential factor and entropy for diffusion and evaporation of xylene from PHIC, were found to be functions of initial polymer concentration whereas the intrinsic diffusion coefficient of the solvent was found to be independent of initial polymer concentration. The cross polarized/magic angle spinning solid state 13C

Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors.

Science.gov (United States)

Latham, Catherine F; La, Jennifer; Tinetti, Ricky N; Chalmers, David K; Tachedjian, Gilda

2016-01-01

Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.

Study of Structure-active Relationship for Inhibitors of HIV-1 Integrase LEDGF/p75 Interaction by Machine Learning Methods.

Science.gov (United States)

Li, Yang; Wu, Yanbin; Yan, Aixia

2017-07-01

HIV-1 integrase (IN) is a promising target for anti-AIDS therapy, and LEDGF/p75 is proved to enhance the HIV-1 integrase strand transfer activity in vitro. Blocking the interaction between IN and LEDGF/p75 is an effective way to inhibit HIV replication infection. In this work, 274 LEDGF/p75-IN inhibitors were collected as the dataset. Support Vector Machine (SVM), Decision Tree (DT), Function Tree (FT) and Random Forest (RF) were applied to build several computational models for predicting whether a compound is an active or weakly active LEDGF/p75-IN inhibitor. Each compound is represented by MACCS fingerprints and CORINA Symphony descriptors. The prediction accuracies for the test sets of all the models are over 70 %. The best model Model 3B built by FT obtained a prediction accuracy and a Matthews Correlation Coefficient (MCC) of 81.08 % and 0.62 on test set, respectively. We found that the hydrogen bond and hydrophobic interactions are important for the bioactivity of an inhibitor. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A quantitative structure–activity relationship study on HIV-1 integrase inhibitors using genetic algorithm, artificial neural networks and different statistical methods

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Ghasem Ghasemi

2016-09-01

Full Text Available In this work, quantitative structure–activity relationship (QSAR study has been done on tricyclic phthalimide analogues acting as HIV-1 integrase inhibitors. Forty compounds were used in this study. Genetic algorithm (GA, artificial neural network (ANN and multiple linear regressions (MLR were utilized to construct the non-linear and linear QSAR models. It revealed that the GA–ANN model was much better than other models. For this purpose, ab initio geometry optimization performed at B3LYP level with a known basis set 6–31G (d. Hyperchem, ChemOffice and Gaussian 98W softwares were used for geometry optimization of the molecules and calculation of the quantum chemical descriptors. To include some of the correlation energy, the calculation was done with the density functional theory (DFT with the same basis set and Becke’s three parameter hybrid functional using the LYP correlation functional (B3LYP/6–31G (d. For the calculations in solution phase, the polarized continuum model (PCM was used and also included optimizations at gas-phase B3LYP/6–31G (d level for comparison. In the aqueous phase, the root–mean–square errors of the training set and the test set for GA–ANN model using jack–knife method, were 0.1409, 0.1804, respectively. In the gas phase, the root–mean–square errors of the training set and the test set for GA–ANN model were 0.1408, 0.3103, respectively. Also, the R2 values in the aqueous and the gas phase were obtained as 0.91, 0.82, respectively.

Removal of bacterial cells, antibiotic resistance genes and integrase genes by on-site hospital wastewater treatment plants: surveillance of treated hospital effluent quality

KAUST Repository

Timraz, Kenda Hussain Hassan; Xiong, Yanghui; Al Qarni, Hamed; Hong, Pei-Ying

2016-01-01

This study aims to evaluate the removal efficiency of microbial contaminants, including total cell counts, antibiotic-resistant bacteria (ARB), antibiotic resistance genes (ARGs, e.g. tetO, tetZ, sul1 and sul2) and integrase genes (e.g. intl1

Design and Synthesis of Bis-amide and Hydrazide-containing Derivatives of Malonic Acid as Potential HIV-1 Integrase Inhibitors

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Nouri Neamati

2008-10-01

Full Text Available HIV-1 integrase (IN is an attractive and validated target for the development of novel therapeutics against AIDS. In the search for new IN inhibitors, we designed and synthesized three series of bis-amide and hydrazide-containing derivatives of malonic acid. We performed a docking study to investigate the potential interactions of the title compounds with essential amino acids on the IN active site.

6-(1-Benzyl-1H-pyrrol-2-yl)-2,4-dioxo-5-hexenoic acids as dual inhibitors of recombinant HIV-1 integrase and ribonuclease H, synthesized by a parallel synthesis approach.

Science.gov (United States)

Costi, Roberta; Métifiot, Mathieu; Esposito, Francesca; Cuzzucoli Crucitti, Giuliana; Pescatori, Luca; Messore, Antonella; Scipione, Luigi; Tortorella, Silvano; Zinzula, Luca; Novellino, Ettore; Pommier, Yves; Tramontano, Enzo; Marchand, Christophe; Di Santo, Roberto

2013-11-14

The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug-drug interactions warrant the development of new anti-HIV agents. We previously discovered hit 6, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, 7a-y and 8a-y, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds 7b, 7u, and 8g were the most active against the RNase H activity of reverse-transcriptase, with IC50 values of 3, 3, and 2.5 μM, respectively. Compound 8g was also the most potent integrase inhibitor with an IC50 value of 26 nM.

Evidence for the horizontal transfer of an integrase gene from a fusellovirus to a pRN-like plasmid within a single strain of Sulfolobus and the implications for plasmid survival

DEFF Research Database (Denmark)

Peng, Xu

2008-01-01

of the integrase gene occurs in the viral attachment site (attP), which corresponds to the anticodon region of the targeted tRNA gene in the host chromosome. This point mutation confers on pXZ1 the ability to integrate into the tRNA(Glu)[CUC] gene, which differs from the integration site of SSV4, t......RNA(Glu)[UUC]. SSV4 and pXZ1 were also shown experimentally to integrate into separate sites on the host chromosome. This is believed to be the first report of a pRN plasmid sharing its natural host with a fusellovirus and carrying a highly similar integrase gene....

Novel 3′-Processing Integrase Activity Assay by Real-Time PCR for Screening and Identification of HIV-1 Integrase Inhibitors

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Supachai Sakkhachornphop

2015-01-01

Full Text Available The 3′-end processing (3′P of each viral long terminal repeat (LTR during human immunodeficiency virus type-1 (HIV-1 integration is a vital step in the HIV life cycle. Blocking the 3′P using 3′P inhibitor has recently become an attractive strategy for HIV-1 therapeutic intervention. Recently, we have developed a novel real-time PCR based assay for the detection of 3′P activity in vitro. The methodology usually involves biotinylated HIV-1 LTR, HIV-1 integrase (IN, and specific primers and probe. In this novel assay, we designed the HIV-1 LTR substrate based on a sequence with a homology to HIV-1 LTR labeled at its 3′ end with biotin on the sense strand. Two nucleotides at the 3′ end were subsequently removed by IN activity. Only two nucleotides labeled biotin were captured on an avidin-coated tube; therefore, inhibiting the binding of primers and probe results in late signals in the real-time PCR. This novel assay has successfully detected both the 3′P activity of HIV-1 IN and the anti-IN activity by Raltegravir and sodium azide agent. This real-time PCR assay has been shown to be effective and inexpensive for a high-throughput screening of novel IN inhibitors.

Integrase-independent HIV-1 infection is augmented under conditions of DNA damage and produces a viral reservoir

International Nuclear Information System (INIS)

Ebina, Hirotaka; Kanemura, Yuka; Suzuki, Yasutsugu; Urata, Kozue; Misawa, Naoko; Koyanagi, Yoshio

2012-01-01

HIV-1 possesses a viral protein, integrase (IN), which is necessary for its efficient integration in target cells. However, it has been reported that an IN-defective HIV strain is still capable of integration. Here, we assessed the ability of wild type (WT) HIV-1 to establish infection in the presence of IN inhibitors. We observed a low, yet clear infection of inhibitor-incubated cells infected with WT HIV which was identical to cells infected with IN-deficient HIV, D64A. Furthermore, the IN-independent integration could be enhanced by the pretreatment of cells with DNA-damaging agents suggesting that integration is mediated by a DNA repair system. Moreover, significantly faster viral replication kinetics with augmented viral DNA integration was observed after infection in irradiated cells treated with IN inhibitor compared to nonirradiated cells. Altogether, our results suggest that HIV DNA has integration potential in the presence of an IN inhibitor and may serve as a virus reservoir.

Integrase-independent HIV-1 infection is augmented under conditions of DNA damage and produces a viral reservoir

Energy Technology Data Exchange (ETDEWEB)

Ebina, Hirotaka, E-mail: hebina@virus.kyoto-u.ac.jp; Kanemura, Yuka; Suzuki, Yasutsugu; Urata, Kozue; Misawa, Naoko; Koyanagi, Yoshio

2012-05-25

HIV-1 possesses a viral protein, integrase (IN), which is necessary for its efficient integration in target cells. However, it has been reported that an IN-defective HIV strain is still capable of integration. Here, we assessed the ability of wild type (WT) HIV-1 to establish infection in the presence of IN inhibitors. We observed a low, yet clear infection of inhibitor-incubated cells infected with WT HIV which was identical to cells infected with IN-deficient HIV, D64A. Furthermore, the IN-independent integration could be enhanced by the pretreatment of cells with DNA-damaging agents suggesting that integration is mediated by a DNA repair system. Moreover, significantly faster viral replication kinetics with augmented viral DNA integration was observed after infection in irradiated cells treated with IN inhibitor compared to nonirradiated cells. Altogether, our results suggest that HIV DNA has integration potential in the presence of an IN inhibitor and may serve as a virus reservoir.

A novel system for simultaneous or sequential integration of multiple gene-loading vectors into a defined site of a human artificial chromosome.

Science.gov (United States)

Suzuki, Teruhiko; Kazuki, Yasuhiro; Oshimura, Mitsuo; Hara, Takahiko

2014-01-01

Human artificial chromosomes (HACs) are gene-delivery vectors suitable for introducing large DNA fragments into mammalian cells. Although a HAC theoretically incorporates multiple gene expression cassettes of unlimited DNA size, its application has been limited because the conventional gene-loading system accepts only one gene-loading vector (GLV) into a HAC. We report a novel method for the simultaneous or sequential integration of multiple GLVs into a HAC vector (designated as the SIM system) via combined usage of Cre, FLP, Bxb1, and φC31 recombinase/integrase. As a proof of principle, we first attempted simultaneous integration of three GLVs encoding EGFP, Venus, and TdTomato into a gene-loading site of a HAC in CHO cells. These cells successfully expressed all three fluorescent proteins. Furthermore, microcell-mediated transfer of HACs enabled the expression of those fluorescent proteins in recipient cells. We next demonstrated that GLVs could be introduced into a HAC one-by-one via reciprocal usage of recombinase/integrase. Lastly, we introduced a fourth GLV into a HAC after simultaneous integration of three GLVs by FLP-mediated DNA recombination. The SIM system expands the applicability of HAC vectors and is useful for various biomedical studies, including cell reprogramming.

A novel system for simultaneous or sequential integration of multiple gene-loading vectors into a defined site of a human artificial chromosome.

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Teruhiko Suzuki

Full Text Available Human artificial chromosomes (HACs are gene-delivery vectors suitable for introducing large DNA fragments into mammalian cells. Although a HAC theoretically incorporates multiple gene expression cassettes of unlimited DNA size, its application has been limited because the conventional gene-loading system accepts only one gene-loading vector (GLV into a HAC. We report a novel method for the simultaneous or sequential integration of multiple GLVs into a HAC vector (designated as the SIM system via combined usage of Cre, FLP, Bxb1, and φC31 recombinase/integrase. As a proof of principle, we first attempted simultaneous integration of three GLVs encoding EGFP, Venus, and TdTomato into a gene-loading site of a HAC in CHO cells. These cells successfully expressed all three fluorescent proteins. Furthermore, microcell-mediated transfer of HACs enabled the expression of those fluorescent proteins in recipient cells. We next demonstrated that GLVs could be introduced into a HAC one-by-one via reciprocal usage of recombinase/integrase. Lastly, we introduced a fourth GLV into a HAC after simultaneous integration of three GLVs by FLP-mediated DNA recombination. The SIM system expands the applicability of HAC vectors and is useful for various biomedical studies, including cell reprogramming.

6 CFR 5.31 - Security of systems of records.

Science.gov (United States)

2010-01-01

... 6 Domestic Security 1 2010-01-01 2010-01-01 false Security of systems of records. 5.31 Section 5.31 Domestic Security DEPARTMENT OF HOMELAND SECURITY, OFFICE OF THE SECRETARY DISCLOSURE OF RECORDS AND INFORMATION Privacy Act § 5.31 Security of systems of records. (a) In general. Each component...

Plasmid integration in a wide range of bacteria mediated by the integrase of Lactobacillus delbrueckii bacteriophage mv4.

Science.gov (United States)

Auvray, F; Coddeville, M; Ritzenthaler, P; Dupont, L

1997-01-01

Bacteriophage mv4 is a temperate phage infecting Lactobacillus delbrueckii subsp. bulgaricus. During lysogenization, the phage integrates its genome into the host chromosome at the 3' end of a tRNA(Ser) gene through a site-specific recombination process (L. Dupont et al., J. Bacteriol., 177:586-595, 1995). A nonreplicative vector (pMC1) based on the mv4 integrative elements (attP site and integrase-coding int gene) is able to integrate into the chromosome of a wide range of bacterial hosts, including Lactobacillus plantarum, Lactobacillus casei (two strains), Lactococcus lactis subsp. cremoris, Enterococcus faecalis, and Streptococcus pneumoniae. Integrative recombination of pMC1 into the chromosomes of all of these species is dependent on the int gene product and occurs specifically at the pMC1 attP site. The isolation and sequencing of pMC1 integration sites from these bacteria showed that in lactobacilli, pMC1 integrated into the conserved tRNA(Ser) gene. In the other bacterial species where this tRNA gene is less or not conserved; secondary integration sites either in potential protein-coding regions or in intergenic DNA were used. A consensus sequence was deduced from the analysis of the different integration sites. The comparison of these sequences demonstrated the flexibility of the integrase for the bacterial integration site and suggested the importance of the trinucleotide CCT at the 5' end of the core in the strand exchange reaction. PMID:9068626

The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity

NARCIS (Netherlands)

Amadori, Céline; Ubeles van der Velden, Yme; Bonnard, Damien; Orlov, Igor; van Bel, Nikki; Le Rouzic, Erwann; Miralles, Laia; Brias, Julie; Chevreuil, Francis; Spehner, Daniele; Chasset, Sophie; Ledoussal, Benoit; Mayr, Luzia; Moreau, François; García, Felipe; Gatell, José; Zamborlini, Alessia; Emiliani, Stéphane; Ruff, Marc; Klaholz, Bruno P.; Moog, Christiane; Berkhout, Ben; Plana, Montserrat; Benarous, Richard

2017-01-01

HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF

Safe genetic modification of cardiac stem cells using a site-specific integration technique.

Science.gov (United States)

Lan, Feng; Liu, Junwei; Narsinh, Kazim H; Hu, Shijun; Han, Leng; Lee, Andrew S; Karow, Marisa; Nguyen, Patricia K; Nag, Divya; Calos, Michele P; Robbins, Robert C; Wu, Joseph C

2012-09-11

Human cardiac progenitor cells (hCPCs) are a promising cell source for regenerative repair after myocardial infarction. Exploitation of their full therapeutic potential may require stable genetic modification of the cells ex vivo. Safe genetic engineering of stem cells, using facile methods for site-specific integration of transgenes into known genomic contexts, would significantly enhance the overall safety and efficacy of cellular therapy in a variety of clinical contexts. We used the phiC31 site-specific recombinase to achieve targeted integration of a triple fusion reporter gene into a known chromosomal context in hCPCs and human endothelial cells. Stable expression of the reporter gene from its unique chromosomal integration site resulted in no discernible genomic instability or adverse changes in cell phenotype. Namely, phiC31-modified hCPCs were unchanged in their differentiation propensity, cellular proliferative rate, and global gene expression profile when compared with unaltered control hCPCs. Expression of the triple fusion reporter gene enabled multimodal assessment of cell fate in vitro and in vivo using fluorescence microscopy, bioluminescence imaging, and positron emission tomography. Intramyocardial transplantation of genetically modified hCPCs resulted in significant improvement in myocardial function 2 weeks after cell delivery, as assessed by echocardiography (P=0.002) and MRI (P=0.001). We also demonstrated the feasibility and therapeutic efficacy of genetically modifying differentiated human endothelial cells, which enhanced hind limb perfusion (Pmodification system is a safe, efficient tool to enable site-specific integration of reporter transgenes in progenitor and differentiated cell types.

TÜRKİYE ÖZEL VE KAMU SAĞLIK SİGORTACILIĞI PRİM/HASAR SAĞLIK HARCAMASI DEĞERLENDİRMESİ

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Güvenç KOÇKAYA

2016-01-01

Full Text Available Reforms under Health Transformation Program was commenced in 2002 by Ministry of Health in Turkey brings significant improvements. These changes targeted at improving access to health services(HS and quality of HS. Social Security Institution(SSI is only government payer covering of population. In addition to public health insurance(HI there are also private HI companies(PHIC covering 3% of population. Aim of analysis is to understand difference between premium/claims of HI system in Turkey. With this aim the official data of premiums and claims of PHIC for years 2009-2013 was obtained from Turkish PHIC Association together with same data of government HI for the same years was obtained from SSI. Descriptive analysis were conducted with premiums and claims data of government and private health insurers. Total collected preimum of PHIC were 2.3 billion TL and claims were 1.7 billion TL on the year 2013. Premiums and claims of PHIC per capita were 822 TL and 631TL in 2013, respectively. Difference of premium/claims of all PHC was equal to 638 million TL or 26%. Same year, premiums and claims of SSI for HI were 53 billion and 49.9 billion TL. Premiums and claims of SSI per capita were 691 TL and 650 TL in 2013, respectively. Difference of premiums/claims of SSI HI was 4.1 billion and 6%. SSI has become monopsonic payer in health system with HI premium collection from all citizens. SSI determines its revenues and costs as it also determines the premium levels and reimbursement price of HS. This shows the success of SSI`s management while covering the whole population for a very comprehensive health care package. However, the SSI`s per capita premium is lower and its claims is higher than private sector averages. Question marks that come upon the productivity issue imply that the situation should be examined thoroughly.

An effective HIV-1 integrase inhibitor screening platform: Rationality validation of drug screening, conformational mobility and molecular recognition analysis for PFV integrase complex with viral DNA.

Science.gov (United States)

Du, Wenyi; Zuo, Ke; Sun, Xin; Liu, Wei; Yan, Xiao; Liang, Li; Wan, Hua; Chen, Fengzheng; Hu, Jianping

2017-11-01

As an important target for the development of novel anti-AIDS drugs, HIV-1 integrase (IN) has been widely concerned. However, the lack of a complete accurate crystal structure of HIV-1 IN greatly blocks the discovery of novel inhibitors. In this work, an effective HIV-1 IN inhibitor screening platform, namely PFV IN, was filtered from all species of INs. Next, the 40.8% similarity with HIV-1 IN, as well as the high efficiency of virtual screening and the good agreement between calculated binding free energies and experimental ones all proved PFV IN is a promising screening platform for HIV-1 IN inhibitors. Then, the molecular recognition mechanism of PFV IN by its substrate viral DNA and six naphthyridine derivatives (NRDs) inhibitors was investigated through molecular docking, molecular dynamics simulations and water-mediated interactions analyses. The functional partition of NRDs IN inhibitors could be divided into hydrophobic and hydrophilic ones, and the Mg 2+ ions, water molecules and conserved DDE motif residues all interacted with the hydrophilic partition, while the bases in viral DNA and residues like Tyr212, Pro214 interacted with the hydrophobic one. Finally, the free energy landscape (FEL) and cluster analyses were performed to explore the molecular motion of PFV IN-DNA system. It is found that the association with NRDs inhibitors would obviously decrease the motion amplitude of PFV IN-DNA, which may be one of the most potential mechanisms of IN inhibitors. This work will provide a theoretical basis for the inhibitor design based on the structure of HIV-1 IN. Copyright © 2017 Elsevier Inc. All rights reserved.

Adeno-associated virus Rep-mediated targeting of integrase-defective retroviral vector DNA circles into human chromosome 19

International Nuclear Information System (INIS)

Huang, Shuohao; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi

2012-01-01

Highlights: ► Adeno-associated virus (AAV) is capable of targeted integration in human cells. ► Integrase-defective retroviral vector (IDRV) enables a circular DNA delivery. ► A targeted integration system of IDRV DNA using the AAV integration mechanism. ► Targeted IDRV integration ameliorates the safety concerns for retroviral vectors. -- Abstract: Retroviral vectors have been employed in clinical trials for gene therapy owing to their relative large packaging capacity, alterable cell tropism, and chromosomal integration for stable transgene expression. However, uncontrollable integrations of transgenes are likely to cause safety issues, such as insertional mutagenesis. A targeted transgene integration system for retroviral vectors, therefore, is a straightforward way to address the insertional mutagenesis issue. Adeno-associated virus (AAV) is the only known virus capable of targeted integration in human cells. In the presence of AAV Rep proteins, plasmids possessing the p5 integration efficiency element (p5IEE) can be integrated into the AAV integration site (AAVS1) in the human genome. In this report, we describe a system that can target the circular DNA derived from non-integrating retroviral vectors to the AAVS1 site by utilizing the Rep/p5IEE integration mechanism. Our results showed that after G418 selection 30% of collected clones had retroviral DNA targeted at the AAVS1 site.

Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

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Neamati Nouri

2009-03-01

Full Text Available Abstract Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.

Ultrasensitive liquid chromatography-tandem mass spectrometric methodologies for quantification of five HIV-1 integrase inhibitors in plasma for a microdose clinical trial.

Science.gov (United States)

Sun, Li; Li, Hankun; Willson, Kenneth; Breidinger, Sheila; Rizk, Matthew L; Wenning, Larissa; Woolf, Eric J

2012-10-16

HIV-1 integrase strand transfer inhibitors are an important class of compounds targeted for the treatment of HIV-1 infection. Microdosing has emerged as an attractive tool to assist in drug candidate screening for clinical development, but necessitates extremely sensitive bioanalytical assays, typically in the pg/mL concentration range. Currently, accelerator mass spectrometry is the predominant tool for microdosing support, which requires a specialized facility and synthesis of radiolabeled compounds. There have been few studies attempted to comprehensively assess a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach in the context of microdosing applications. Herein, we describe the development of automated LC-MS/MS methods to quantify five integrase inhibitors in plasma with the limits of quantification at 1 pg/mL for raltegravir and 2 pg/mL for four proprietary compounds. The assays involved double extractions followed by UPLC coupled with negative ion electrospray MS/MS analysis. All methods were fully validated to the rigor of regulated bioanalysis requirements, with intraday precision between 1.20 and 14.1% and accuracy between 93.8 and 107% at the standard curve concentration range. These methods were successfully applied to a human microdose study and demonstrated to be accurate, reproducible, and cost-effective. Results of the study indicate that raltegravir displayed linear pharmacokinetics between a microdose and a pharmacologically active dose.

Anti-HIV-1 integrase activity of medicinal plants used as self medication by AIDS patients

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Sopa Kummee

2006-07-01

Full Text Available The extracts of selected medicinal plants used as self medication by AIDS patients were investigated for their inhibitory activities against HIV-1 integrase (HIV-1 IN using the multiplate integration assay (MIA. Of these, the water extract of Eclipta prostrata (whole plant exhibited the most potent inhibitory activity with an IC50 value of 4.8 μg/ml, followed by the methanol extract of Eclipta prostrata (whole plant, IC50 = 21.1 μg/ ml, the water extract of Barleria lupulina (stem, IC50 = 26.4 μg/ml, the chloroform extract of Barleria lupulina (stem, IC50 = 33.0 μg/ml, the methanol extract of Barleria lupulina (stem, IC50 = 38.2 μg/ml and the chloroform extract of Piper betle (leaf, IC50 = 39.3 μg/ml, respectively.

HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

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Cara Andrea

2007-03-01

Full Text Available Abstract Background The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN (IN inhibitors, IINs has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA derivatives active on the HIV-1 IN strand transfer (ST step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR reversing ability. Results The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells. Conclusion To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.

14 CFR 31.49 - Control systems.

Science.gov (United States)

2010-01-01

... minute when the balloon is at its maximum operating pressure. (d) Each hot air balloon must have a means to allow the controlled release of hot air during flight. (e) Each hot air balloon must have a means... STANDARDS: MANNED FREE BALLOONS Design Construction § 31.49 Control systems. (a) Each control must operate...

31 CFR 19.950 - Excluded Parties List System

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Excluded Parties List System 19.950 Section 19.950 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 19.950 Excluded Parties List System Excluded Parties...

45 CFR 1355.31 - Elements of the child and family services review system.

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2010-10-01

... GENERAL § 1355.31 Elements of the child and family services review system. Scope. Sections 1355.32 through... 45 Public Welfare 4 2010-10-01 2010-10-01 false Elements of the child and family services review system. 1355.31 Section 1355.31 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE...

The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome.

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Nikki van Bel

Full Text Available The viral integrase (IN is an essential protein for HIV-1 replication. IN inserts the viral dsDNA into the host chromosome, thereby aided by the cellular co-factor LEDGF/p75. Recently a new class of integrase inhibitors was described: allosteric IN inhibitors (ALLINIs. Although designed to interfere with the IN-LEDGF/p75 interaction to block HIV DNA integration during the early phase of HIV-1 replication, the major impact was surprisingly found on the process of virus maturation during the late phase, causing a reverse transcription defect upon infection of target cells. Virus particles produced in the presence of an ALLINI are misformed with the ribonucleoprotein located outside the virus core. Virus assembly and maturation are highly orchestrated and regulated processes in which several viral proteins and RNA molecules closely interact. It is therefore of interest to study whether ALLINIs have unpredicted pleiotropic effects on these RNA-related processes. We confirm that the ALLINI BI-D inhibits virus replication and that the produced virus is non-infectious. Furthermore, we show that the wild-type level of HIV-1 genomic RNA is packaged in virions and these genomes are in a dimeric state. The tRNAlys3 primer for reverse transcription was properly placed on this genomic RNA and could be extended ex vivo. In addition, the packaged reverse transcriptase enzyme was fully active when extracted from virions. As the RNA and enzyme components for reverse transcription are properly present in virions produced in the presence of BI-D, the inhibition of reverse transcription is likely to reflect the mislocalization of the components in the aberrant virus particle.

The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome.

Science.gov (United States)

van Bel, Nikki; van der Velden, Yme; Bonnard, Damien; Le Rouzic, Erwann; Das, Atze T; Benarous, Richard; Berkhout, Ben

2014-01-01

The viral integrase (IN) is an essential protein for HIV-1 replication. IN inserts the viral dsDNA into the host chromosome, thereby aided by the cellular co-factor LEDGF/p75. Recently a new class of integrase inhibitors was described: allosteric IN inhibitors (ALLINIs). Although designed to interfere with the IN-LEDGF/p75 interaction to block HIV DNA integration during the early phase of HIV-1 replication, the major impact was surprisingly found on the process of virus maturation during the late phase, causing a reverse transcription defect upon infection of target cells. Virus particles produced in the presence of an ALLINI are misformed with the ribonucleoprotein located outside the virus core. Virus assembly and maturation are highly orchestrated and regulated processes in which several viral proteins and RNA molecules closely interact. It is therefore of interest to study whether ALLINIs have unpredicted pleiotropic effects on these RNA-related processes. We confirm that the ALLINI BI-D inhibits virus replication and that the produced virus is non-infectious. Furthermore, we show that the wild-type level of HIV-1 genomic RNA is packaged in virions and these genomes are in a dimeric state. The tRNAlys3 primer for reverse transcription was properly placed on this genomic RNA and could be extended ex vivo. In addition, the packaged reverse transcriptase enzyme was fully active when extracted from virions. As the RNA and enzyme components for reverse transcription are properly present in virions produced in the presence of BI-D, the inhibition of reverse transcription is likely to reflect the mislocalization of the components in the aberrant virus particle.

Inorganic and organic fertilizers impact the abundance and proportion of antibiotic resistance and integron-integrase genes in agricultural grassland soil.

Science.gov (United States)

Nõlvak, Hiie; Truu, Marika; Kanger, Kärt; Tampere, Mailiis; Espenberg, Mikk; Loit, Evelin; Raave, Henn; Truu, Jaak

2016-08-15

Soil fertilization with animal manure or its digestate may facilitate an important antibiotic resistance dissemination route from anthropogenic sources to the environment. This study examines the effect of mineral fertilizer (NH4NO3), cattle slurry and cattle slurry digestate amendment on the abundance and proportion dynamics of five antibiotic resistance genes (ARGs) and two classes of integron-integrase genes (intI1 and intI2) in agricultural grassland soil. Fertilization was performed thrice throughout one vegetation period. The targeted ARGs (sul1, tetA, blaCTX-M, blaOXA2 and qnrS) encode resistance to several major antibiotic classes used in veterinary medicine such as sulfonamides, tetracycline, cephalosporins, penicillin and fluoroquinolones, respectively. The non-fertilized grassland soil contained a stable background of tetA, blaCTX-M and sul1 genes. The type of applied fertilizer significantly affected ARGs and integron-integrase genes abundances and proportions in the bacterial community (porganic fertilizer's application event, but this increase was followed by a stage of decrease, suggesting that microbes possessing these genes were predominantly entrained into soil via cattle slurry or its digestate application and had somewhat limited survival potential in a soil environment. However, the abundance of these three target genes did not decrease to a background level by the end of the study period. TetA was most abundant in mineral fertilizer treated soil and blaCTX-M in cattle slurry digestate amended soil. Despite significantly different abundances, the abundance dynamics of bacteria possessing these genes were similar (p<0.05 in all cases) in different treatments and resembled the dynamics of the whole bacterial community abundance in each soil treatment. Copyright © 2016. Published by Elsevier B.V.

Low latency control board for LLRF system: SIMCON 3.1

Science.gov (United States)

Giergusiewicz, Wojciech; Jalmuzna, Wojciech; Pozniak, Krzysztof; Ignashin, Nikolay; Grecki, Mariusz; Makowski, Dariusz; Jezynski, Tomasz; Perkuszewski, Karol; Czuba, Krzysztof; Simrock, Stefan; Romaniuk, Ryszard

2005-09-01

A new version of the SIMCON system is presented in this paper. The SIMCON stands for the microwave, resonant, superconductive accelerator cavity simulator and controller (embracing the hardware and software layers). The current version of the SIMCON is 3.1. which is a considerable step forward from the previous 8-channel version 3.0. which was released at the beginning of 2005 and was made operable in April. Many important upgrades were implemented in SIMCON 3.1. It is a stand-alone VME board (whereas SIMCON 3.0 was modular) based on the Virtex II Pro 30 chip with two embedded Power PCs and DSP blocks. It has Ethernet and multiple gigabit optical I/Os. The Simcon 3.1 board provides 10 ADC channels. The architecture idea and block diagrams of the PCB for SIMCON 3.1. are presented. Some of the applied novel technical solutions, Protel"R" views and schemes are shown. A number of initial conclusions were drawn from a few month experience with the development of this new board. The tables of predicted system parameters are quoted.

Mutations in the catalytic core or the C-terminus of murine leukemia virus (MLV) integrase disrupt virion infectivity and exert diverse effects on reverse transcription

International Nuclear Information System (INIS)

Steinrigl, Adolf; Nosek, Dagmara; Ertl, Reinhard; Guenzburg, Walter H.; Salmons, Brian; Klein, Dieter

2007-01-01

Understanding of the structures and functions of the retroviral integrase (IN), a key enzyme in the viral replication cycle, is essential for developing antiretroviral treatments and facilitating the development of safer gene therapy vehicles. Thus, four MLV IN-mutants were constructed in the context of a retroviral vector system, harbouring either a substitution in the catalytic centre, deletions in the C-terminus, or combinations of both modifications. IN-mutants were tested for their performance in different stages of the viral replication cycle: RNA-packaging; RT-activity; transient and stable infection efficiency; dynamics of reverse transcription and nuclear entry. All mutant vectors packaged viral RNA with wild-type efficiencies and displayed only slight reductions in RT-activity. Deletion of either the IN C-terminus alone, or in addition to part of the catalytic domain exerted contrasting effects on intracellular viral DNA levels, implying that IN influences reverse transcription in more than one direction

Molecular modeling study on the allosteric inhibition mechanism of HIV-1 integrase by LEDGF/p75 binding site inhibitors.

Directory of Open Access Journals (Sweden)

Weiwei Xue

Full Text Available HIV-1 integrase (IN is essential for the integration of viral DNA into the host genome and an attractive therapeutic target for developing antiretroviral inhibitors. LEDGINs are a class of allosteric inhibitors targeting LEDGF/p75 binding site of HIV-1 IN. Yet, the detailed binding mode and allosteric inhibition mechanism of LEDGINs to HIV-1 IN is only partially understood, which hinders the structure-based design of more potent anti-HIV agents. A molecular modeling study combining molecular docking, molecular dynamics simulation, and binding free energy calculation were performed to investigate the interaction details of HIV-1 IN catalytic core domain (CCD with two recently discovered LEDGINs BI-1001 and CX14442, as well as the LEDGF/p75 protein. Simulation results demonstrated the hydrophobic domain of BI-1001 and CX14442 engages one subunit of HIV-1 IN CCD dimer through hydrophobic interactions, and the hydrophilic group forms hydrogen bonds with HIV-1 IN CCD residues from other subunit. CX14442 has a larger tert-butyl group than the methyl of BI-1001, and forms better interactions with the highly hydrophobic binding pocket of HIV-1 IN CCD dimer interface, which can explain the stronger affinity of CX14442 than BI-1001. Analysis of the binding mode of LEDGF/p75 with HIV-1 IN CCD reveals that the LEDGF/p75 integrase binding domain residues Ile365, Asp366, Phe406 and Val408 have significant contributions to the binding of the LEDGF/p75 to HIV1-IN. Remarkably, we found that binding of BI-1001 and CX14442 to HIV-1 IN CCD induced the structural rearrangements of the 140 s loop and oration displacements of the side chains of the three conserved catalytic residues Asp64, Asp116, and Glu152 located at the active site. These results we obtained will be valuable not only for understanding the allosteric inhibition mechanism of LEDGINs but also for the rational design of allosteric inhibitors of HIV-1 IN targeting LEDGF/p75 binding site.

Architecture and Assembly of HIV Integrase Multimers in the Absence of DNA Substrates*

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Bojja, Ravi Shankar; Andrake, Mark D.; Merkel, George; Weigand, Steven; Dunbrack, Roland L.; Skalka, Anna Marie

2013-01-01

We have applied small angle x-ray scattering and protein cross-linking coupled with mass spectrometry to determine the architectures of full-length HIV integrase (IN) dimers in solution. By blocking interactions that stabilize either a core-core domain interface or N-terminal domain intermolecular contacts, we show that full-length HIV IN can form two dimer types. One is an expected dimer, characterized by interactions between two catalytic core domains. The other dimer is stabilized by interactions of the N-terminal domain of one monomer with the C-terminal domain and catalytic core domain of the second monomer as well as direct interactions between the two C-terminal domains. This organization is similar to the “reaching dimer” previously described for wild type ASV apoIN and resembles the inner, substrate binding dimer in the crystal structure of the PFV intasome. Results from our small angle x-ray scattering and modeling studies indicate that in the absence of its DNA substrate, the HIV IN tetramer assembles as two stacked reaching dimers that are stabilized by core-core interactions. These models of full-length HIV IN provide new insight into multimer assembly and suggest additional approaches for enzyme inhibition. PMID:23322775

A new activity of anti-HIV and anti-tumor protein GAP31: DNA adenosine glycosidase - Structural and modeling insight into its functions

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Li, Hui-Guang [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Huang, Philip L. [American Biosciences, Boston, MA 02114 (United States); Zhang, Dawei; Sun, Yongtao [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Chen, Hao-Chia [Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892 (United States); Zhang, John [Department of Chemistry, New York University, New York, NY 10003 (United States); Huang, Paul L. [Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114 (United States); Kong, Xiang-Peng, E-mail: xiangpeng.kong@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Lee-Huang, Sylvia, E-mail: sylvia.lee-huang@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States)

2010-01-01

We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

Versatile P(acman) BAC Libraries for Transgenesis Studies in Drosophila melanogaster

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Venken, Koen J.T.; Carlson, Joseph W.; Schulze, Karen L.; Pan, Hongling; He, Yuchun; Spokony, Rebecca; Wan, Kenneth H.; Koriabine, Maxim; de Jong, Pieter J.; White, Kevin P.; Bellen, Hugo J.; Hoskins, Roger A.

2009-04-21

We constructed Drosophila melanogaster BAC libraries with 21-kb and 83-kb inserts in the P(acman) system. Clones representing 12-fold coverage and encompassing more than 95percent of annotated genes were mapped onto the reference genome. These clones can be integrated into predetermined attP sites in the genome using Phi C31 integrase to rescue mutations. They can be modified through recombineering, for example to incorporate protein tags and assess expression patterns.

A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge.

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Andrews, Chasity D; Yueh, Yun Lan; Spreen, William R; St Bernard, Leslie; Boente-Carrera, Mar; Rodriguez, Kristina; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Ford, Susan; Mohri, Hiroshi; Cheng-Mayer, Cecilia; Hong, Zhi; Ho, David D; Markowitz, Martin

2015-01-14

Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP. Copyright © 2015, American Association for the Advancement of Science.

Resistance Analyses of Integrase Strand Transfer Inhibitors within Phase 3 Clinical Trials of Treatment-Naive Patients

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Kirsten L. White

2014-07-01

Full Text Available The integrase (IN strand transfer inhibitors (INSTIs, raltegravir (RAL, elvitegravir (EVG and dolutegravir (DTG, comprise the newest drug class approved for the treatment of HIV-1 infection, which joins the existing classes of reverse transcriptase, protease and binding/entry inhibitors. The efficacy of first-line regimens has attained remarkably high levels, reaching undetectable viral loads in 90% of patients by Week 48; however, there remain patients who require a change in regimen due to adverse events, virologic failure with emergent resistance or other issues of patient management. Large, randomized clinical trials conducted in antiretroviral treatment-naive individuals are required for drug approval in this population in the US, EU and other countries, with the primary endpoint for virologic success at Week 48. However, there are differences in the definition of virologic failure and the evaluation of drug resistance among the trials. This review focuses on the methodology and tabulation of resistance to INSTIs in phase 3 clinical trials of first-line regimens and discusses case studies of resistance.

Removal of bacterial cells, antibiotic resistance genes and integrase genes by on-site hospital wastewater treatment plants: surveillance of treated hospital effluent quality

KAUST Repository

Timraz, Kenda Hussain Hassan

2016-12-15

This study aims to evaluate the removal efficiency of microbial contaminants, including total cell counts, antibiotic-resistant bacteria (ARB), antibiotic resistance genes (ARGs, e.g. tetO, tetZ, sul1 and sul2) and integrase genes (e.g. intl1 and intl2), by wastewater treatment plants (WWTPs) operated on-site of two hospitals (i.e., SH WWTP and IH WWTP). Both SH and IH WWTPs utilize the conventional activated sludge process but differences in the removal efficiencies were observed. Over the 2 week sampling period, IH WWTP outperformed SH WWTP, and achieved an approximate 0.388 to 2.49-log log removal values (LRVs) for total cell counts compared to the 0.010 to 0.162-log removal in SH WWTP. Although ARB were present in the hospital influent, the treatment process of both hospitals effectively removed ARB from most of the effluent samples. In instances where ARB were recovered in the effluent, none of the viable isolates were identified to be opportunistic pathogenic species based on 16S rRNA gene sequencing. However, sul1 and intl1 genes remained detectable at up to 105 copies per mL or 8 x 10(-1) copies per 16S rRNA gene in the treated effluent, with an LRV of less than 1.2. When the treated effluent is discharged from hospital WWTPs into the public sewer for further treatment as per requirement in many countries, the detected amount of ARGs and integrase genes in the hospital effluent can become a potential source of horizontal gene dissemination in the municipal WWTP. Proper on-site wastewater treatment and surveillance of the effluent quality for emerging contaminants are therefore highly recommended.

Targeted transgene insertion into the CHO cell genome using Cre recombinase-incorporating integrase-defective retroviral vectors.

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Kawabe, Yoshinori; Shimomura, Takuya; Huang, Shuohao; Imanishi, Suguru; Ito, Akira; Kamihira, Masamichi

2016-07-01

Retroviral vectors have served as efficient gene delivery tools in various biotechnology fields. However, viral DNA is randomly inserted into the genome, which can cause problems, such as insertional mutagenesis and gene silencing. Previously, we reported a site-specific gene integration system, in which a transgene is integrated into a predetermined chromosomal locus of Chinese hamster ovary (CHO) cells using integrase-defective retroviral vectors (IDRVs) and Cre recombinase. In this system, a Cre expression plasmid is transfected into founder cells before retroviral transduction. In practical applications of site-specific gene modification such as for hard-to-transfect cells or for in vivo gene delivery, both the transgene and the Cre protein into retroviral virions should be encapsulate. Here, we generated novel hybrid IDRVs in which viral genome and enzymatically active Cre can be delivered (Cre-IDRVs). Cre-IDRVs encoding marker genes, neomycin resistance and enhanced green fluorescent protein (EGFP), flanked by wild-type and mutated loxP sites were produced using an expression plasmid for a chimeric protein of Cre and retroviral gag-pol. After analyzing the incorporation of the Cre protein into retroviral virions by Western blotting, the Cre-IDRV was infected into founder CHO cells, in which marker genes (hygromycin resistance and red fluorescent protein) flanked with corresponding loxP sites are introduced into the genome. G418-resistant colonies expressing GFP appeared and the site-specific integration of the transgene into the expected chromosomal site was confirmed by PCR and sequencing of amplicons. Moreover, when Cre-IDRV carried a gene expression unit for a recombinant antibody, the recombinant cells in which the antibody expression cassette was integrated in a site-specific manner were generated and the cells produced the recombinant antibody. This method may provide a promising tool to perform site-specific gene modification according to Cre

31 CFR 363.0 - What is the TreasuryDirect ® system?

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2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What is the TreasuryDirect ® system? 363.0 Section 363.0 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued... HELD IN TREASURYDIRECT General § 363.0 What is the TreasuryDirect ® system? The TreasuryDirect system...

40 CFR Table 31 to Subpart Uuu of... - Continuous Monitoring Systems for HAP Emissions From Sulfur Recovery Units

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2010-07-01

... 40 Protection of Environment 12 2010-07-01 2010-07-01 true Continuous Monitoring Systems for HAP Emissions From Sulfur Recovery Units 31 Table 31 to Subpart UUU of Part 63 Protection of Environment..., Subpt. UUU, Table 31 Table 31 to Subpart UUU of Part 63—Continuous Monitoring Systems for HAP Emissions...

New research resources at the Bloomington Drosophila Stock Center.

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Cook, Kevin R; Parks, Annette L; Jacobus, Luke M; Kaufman, Thomas C; Matthews, Kathleen A

2010-01-01

The Bloomington Drosophila Stock Center (BDSC) is a primary source of Drosophila stocks for researchers all over the world. It houses over 27,000 unique fly lines and distributed over 160,000 samples of these stocks this past year. This report provides a brief overview of significant recent events at the BDSC with a focus on new stock sets acquired in the past year, including stocks for phiC31 transformation, RNAi knockdown of gene expression, and SNP and quantitative trait loci discovery. We also describe additions to sets of insertions and molecularly defined chromosomal deficiencies, the creation of a new Deficiency Kit, and planned additions of X chromosome duplication sets.

78 FR 43258 - Privacy Act; System of Records: Human Resources Records, State-31

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2013-07-19

... DEPARTMENT OF STATE [Public Notice 8384] Privacy Act; System of Records: Human Resources Records... system of records, Human Resources Records, State- 31, pursuant to the provisions of the Privacy Act of... State proposes that the current system will retain the name ``Human Resources Records'' (previously...

Integrase inhibitors in late pregnancy and rapid HIV viral load reduction.

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Rahangdale, Lisa; Cates, Jordan; Potter, JoNell; Badell, Martina L; Seidman, Dominika; Miller, Emilly S; Coleman, Jenell S; Lazenby, Gweneth B; Levison, Judy; Short, William R; Yawetz, Sigal; Ciaranello, Andrea; Livingston, Elizabeth; Duthely, Lunthita; Rimawi, Bassam H; Anderson, Jean R; Stringer, Elizabeth M

2016-03-01

Minimizing time to HIV viral suppression is critical in pregnancy. Integrase strand transfer inhibitors (INSTIs), like raltegravir, are known to rapidly suppress plasma HIV RNA in nonpregnant adults. There are limited data in pregnant women. We describe time to clinically relevant reduction in HIV RNA in pregnant women using INSTI-containing and non-INSTI-containing antiretroviral therapy (ART) options. We conducted a retrospective cohort study of pregnant HIV-infected women in the United States from 2009 through 2015. We included women who initiated ART, intensified their regimen, or switched to a new regimen due to detectable viremia (HIV RNA >40 copies/mL) at ≥20 weeks gestation. Among women with a baseline HIV RNA permitting 1-log reduction, we estimated time to 1-log RNA reduction using the Kaplan-Meier estimator comparing women starting/adding an INSTI in their regimen vs other ART. To compare groups with similar follow-up time, we also conducted a subgroup analysis limited to women with ≤14 days between baseline and follow-up RNA data. This study describes 101 HIV-infected pregnant women from 11 US clinics. In all, 75% (76/101) of women were not taking ART at baseline; 24 were taking non-INSTI containing ART, and 1 received zidovudine monotherapy. In all, 39% (39/101) of women started an INSTI-containing regimen or added an INSTI to their ART regimen. Among 90 women with a baseline HIV RNA permitting 1-log reduction, the median time to 1-log RNA reduction was 8 days (interquartile range [IQR], 7-14) in the INSTI group vs 35 days (IQR, 20-53) in the non-INSTI ART group (P pregnancy. Inclusion of an INSTI may play a role in optimal reduction of HIV RNA for HIV-infected pregnant women presenting late to care or failing initial therapy. Larger studies are urgently needed to assess the safety and effectiveness of this approach. Copyright © 2016 Elsevier Inc. All rights reserved.

42 CFR 419.31 - Ambulatory payment classification (APC) system and payment weights.

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2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false Ambulatory payment classification (APC) system and... Outpatient Services § 419.31 Ambulatory payment classification (APC) system and payment weights. (a) APC... of resource use into APC groups. Except as specified in paragraph (a)(2) of this section, items and...

X-ray crystal structure of the N-terminal region of Moloney murine leukemia virus integrase and its implications for viral DNA recognition: N-Terminal Region of M-MuLV Integrase

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Guan, Rongjin [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Aiyer, Sriram [Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Cote, Marie L. [Department of Biochemistry, Robert Wood Johnson Medical School, UMDNJ, Piscataway New Jersey 08854; Xiao, Rong [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Jiang, Mei [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Acton, Thomas B. [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Roth, Monica J. [Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Montelione, Gaetano T. [Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854; Department of Biochemistry, Robert Wood Johnson Medical School, UMDNJ, Piscataway New Jersey 08854

2017-02-03

The retroviral integrase (IN) carries out the integration of a dsDNA copy of the viral genome into the host DNA, an essential step for viral replication. All IN proteins have three general domains, the N-terminal domain (NTD), the catalytic core domain, and the C-terminal domain. The NTD includes an HHCC zinc finger-like motif, which is conserved in all retroviral IN proteins. Two crystal structures of Moloney murine leukemia virus (M-MuLV) IN N-terminal region (NTR) constructs that both include an N-terminal extension domain (NED, residues 1–44) and an HHCC zinc-finger NTD (residues 45–105), in two crystal forms are reported. The structures of IN NTR constructs encoding residues 1–105 (NTR1–105) and 8–105 (NTR8–105) were determined at 2.7 and 2.15 Å resolution, respectively and belong to different space groups. While both crystal forms have similar protomer structures, NTR1–105 packs as a dimer and NTR8–105 packs as a tetramer in the asymmetric unit. The structure of the NED consists of three anti-parallel β-strands and an α-helix, similar to the NED of prototype foamy virus (PFV) IN. These three β-strands form an extended β-sheet with another β-strand in the HHCC Zn2+ binding domain, which is a unique structural feature for the M-MuLV IN. The HHCC Zn2+ binding domain structure is similar to that in HIV and PFV INs, with variations within the loop regions. Differences between the PFV and MLV IN NEDs localize at regions identified to interact with the PFV LTR and are compared with established biochemical and virological data for M-MuLV. Proteins 2017; 85:647–656.

A QSAR study of integrase strand transfer inhibitors based on a large set of pyrimidine, pyrimidone, and pyridopyrazine carboxamide derivatives

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de Campos, Luana Janaína; de Melo, Eduardo Borges

2017-08-01

In the present study, 199 compounds derived from pyrimidine, pyrimidone and pyridopyrazine carboxamides with inhibitory activity against HIV-1 integrase were modeled. Subsequently, a multivariate QSAR study was conducted with 54 molecules employed by Ordered Predictors Selection (OPS) and Partial Least Squares (PLS) for the selection of variables and model construction, respectively. Topological, electrotopological, geometric, and molecular descriptors were used. The selected real model was robust and free from chance correlation; in addition, it demonstrated favorable internal and external statistical quality. Once statistically validated, the training model was used to predict the activity of a second data set (n = 145). The root mean square deviation (RMSD) between observed and predicted values was 0.698. Although it is a value outside of the standards, only 15 (10.34%) of the samples exhibited higher residual values than 1 log unit, a result considered acceptable. Results of Williams and Euclidean applicability domains relative to the prediction showed that the predictions did not occur by extrapolation and that the model is representative of the chemical space of test compounds.

Probable secondary transmission of antimicrobial-resistant Escherichia coli between people living with and without pets.

Science.gov (United States)

Chung, Yeon Soo; Park, Young Kyung; Park, Yong Ho; Park, Kun Taek

2017-03-18

Companion animals are considered as one of the reservoirs of antimicrobial-resistant (AR) bacteria that can be cross-transmitted to humans. However, limited information is available on the possibility of AR bacteria originating from companion animals being transmitted secondarily from owners to non-owners sharing the same space. To address this issue, the present study investigated clonal relatedness among AR E. coli isolated from dog owners and non-owners in the same college classroom or household. Anal samples (n=48) were obtained from 14 owners and 34 non-owners; 31 E. coli isolates were collected (nine from owners and 22 from non-owners). Of 31 E. coli, 20 isolates (64.5%) were resistant to at least one antimicrobial, and 16 isolates (51.6%) were determined as multi-drug resistant E. coli. Six isolates (19.4%) harbored integrase genes (five harbored class I integrase gene and one harbored class 2 integrase gene, respectively). Pulsed-field gel electrophoretic analysis identified three different E. coli clonal sets among isolates, indicating that cross-transmission of AR E. coli can easily occur between owners and non-owners. The findings emphasize a potential risk of spread of AR bacteria originating from pets within human communities, once they are transferred to humans. Further studies are needed to evaluate the exact risk and identify the risk factors of secondarily transmission by investigating larger numbers of isolates from pets, their owners and non-owners in a community.

Contribution of the C-terminal region within the catalytic core domain of HIV-1 integrase to yeast lethality, chromatin binding and viral replication

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Belhumeur Pierre

2008-11-01

Full Text Available Abstract Background HIV-1 integrase (IN is a key viral enzymatic molecule required for the integration of the viral cDNA into the genome. Additionally, HIV-1 IN has been shown to play important roles in several other steps during the viral life cycle, including reverse transcription, nuclear import and chromatin targeting. Interestingly, previous studies have demonstrated that the expression of HIV-1 IN induces the lethal phenotype in some strains of Saccharomyces cerevisiae. In this study, we performed mutagenic analyses of the C-terminal region of the catalytic core domain of HIV-1 IN in order to delineate the critical amino acid(s and/or motif(s required for the induction of the lethal phenotype in the yeast strain HP16, and to further elucidate the molecular mechanism which causes this phenotype. Results Our study identified three HIV-1 IN mutants, V165A, A179P and KR186,7AA, located in the C-terminal region of the catalytic core domain of IN that do not induce the lethal phenotype in yeast. Chromatin binding assays in yeast and mammalian cells demonstrated that these IN mutants were impaired for the ability to bind chromatin. Additionally, we determined that while these IN mutants failed to interact with LEDGF/p75, they retained the ability to bind Integrase interactor 1. Furthermore, we observed that VSV-G-pseudotyped HIV-1 containing these IN mutants was unable to replicate in the C8166 T cell line and this defect was partially rescued by complementation with the catalytically inactive D64E IN mutant. Conclusion Overall, this study demonstrates that three mutations located in the C-terminal region of the catalytic core domain of HIV-1 IN inhibit the IN-induced lethal phenotype in yeast by inhibiting the binding of IN to the host chromatin. These results demonstrate that the C-terminal region of the catalytic core domain of HIV-1 IN is important for binding to host chromatin and is crucial for both viral replication and the promotion of

MCNP4c JEFF-3.1 Based Libraries. Eccolib-Jeff-3.1 libraries; Les bibliotheques Eccolib-Jeff-3.1

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Sublet, J.Ch

2006-07-01

Continuous-energy and multi-temperatures MCNP Ace types libraries, derived from the Joint European Fusion-Fission JEFF-3.1 evaluations, have been generated using the NJOY-99.111 processing code system. They include the continuous-energy neutron JEFF-3.1/General Purpose, JEFF-3.1/Activation-Dosimetry and thermal S({alpha},{beta}) JEFF-3.1/Thermal libraries and data tables. The processing steps and features are explained together with the Quality Assurance processes and records linked to the generation of such multipurpose libraries. (author)

31 CFR 1.30 - Application to system of records maintained by Government contractors.

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2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Application to system of records maintained by Government contractors. 1.30 Section 1.30 Money and Finance: Treasury Office of the Secretary of the Treasury DISCLOSURE OF RECORDS Privacy Act § 1.30 Application to system of records maintained...

Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS

Directory of Open Access Journals (Sweden)

Ciervo Alessandra

2007-10-01

Full Text Available Abstract Background Treatment of feline immunodeficiency virus (FIV infection has been hampered by the absence of a specific combination antiretroviral treatment (ART. Integrase strand transfer inhibitors (INSTIs are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs. Methods Phylogenetic analysis of lentiviral integrase (IN sequences was carried out using the PAUP* software. A theoretical three-dimensional structure of the FIV IN catalytic core domain (CCD was obtained by homology modeling based on a crystal structure of HIV-1 IN CCD. The interaction of the transferred strand of viral DNA with the catalytic cavity of FIV IN was deduced from a crystal structure of a structurally similar transposase complexed with transposable DNA. Molecular docking simulations were conducted using a genetic algorithm (GOLD. Antiviral activity was tested in feline lymphoblastoid MBM cells acutely infected with the FIV Petaluma strain. Circular and total proviral DNA was quantified by real-time PCR. Results The calculated INSTI-binding sites were found to be nearly identical in FIV and HIV-1 IN CCDs. The close similarity of primate and feline lentivirus IN CCDs was also supported by phylogenetic analysis. In line with these bioinformatic analyses, FIV replication was efficiently inhibited in acutely infected cell cultures by three investigational INSTIs, designed for HIV-1 and belonging to different classes. Of note, the naphthyridine carboxamide INSTI, L-870,810 displayed an EC50 in the low nanomolar range. Inhibition of FIV integration in situ was shown by real-time PCR experiments that revealed accumulation of circular forms of FIV DNA within cells treated with L-870,810. Conclusion We report a drug class (other than nucleosidic reverse transcriptase inhibitors that is capable of inhibiting FIV replication in vitro. The present study helped establish L-870,810, a compound

Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS

Science.gov (United States)

Savarino, Andrea; Pistello, Mauro; D'Ostilio, Daniela; Zabogli, Elisa; Taglia, Fabiana; Mancini, Fabiola; Ferro, Stefania; Matteucci, Donatella; De Luca, Laura; Barreca, Maria Letizia; Ciervo, Alessandra; Chimirri, Alba; Ciccozzi, Massimo; Bendinelli, Mauro

2007-01-01

Background Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the absence of a specific combination antiretroviral treatment (ART). Integrase strand transfer inhibitors (INSTIs) are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs. Methods Phylogenetic analysis of lentiviral integrase (IN) sequences was carried out using the PAUP* software. A theoretical three-dimensional structure of the FIV IN catalytic core domain (CCD) was obtained by homology modeling based on a crystal structure of HIV-1 IN CCD. The interaction of the transferred strand of viral DNA with the catalytic cavity of FIV IN was deduced from a crystal structure of a structurally similar transposase complexed with transposable DNA. Molecular docking simulations were conducted using a genetic algorithm (GOLD). Antiviral activity was tested in feline lymphoblastoid MBM cells acutely infected with the FIV Petaluma strain. Circular and total proviral DNA was quantified by real-time PCR. Results The calculated INSTI-binding sites were found to be nearly identical in FIV and HIV-1 IN CCDs. The close similarity of primate and feline lentivirus IN CCDs was also supported by phylogenetic analysis. In line with these bioinformatic analyses, FIV replication was efficiently inhibited in acutely infected cell cultures by three investigational INSTIs, designed for HIV-1 and belonging to different classes. Of note, the naphthyridine carboxamide INSTI, L-870,810 displayed an EC50 in the low nanomolar range. Inhibition of FIV integration in situ was shown by real-time PCR experiments that revealed accumulation of circular forms of FIV DNA within cells treated with L-870,810. Conclusion We report a drug class (other than nucleosidic reverse transcriptase inhibitors) that is capable of inhibiting FIV replication in vitro. The present study helped establish L-870,810, a compound successfully tested in

Research Area 3: Mathematics (3.1 Modeling of Complex Systems)

Science.gov (United States)

2017-10-31

Title: RESEARCH AREA 3: MATHEMATICS (3.1 Modeling of Complex Systems). Proposal should be directed to Dr. John Lavery Report Term: 0-Other Email ...Paolo Rosso Email : prosso@dsic.upv.es values of the profile characteristics taken by the users), intersection (they represent the relationship between...accuracy, especially when adding fully connected layers at the end of the network. This work has resulted in the writing of a manuscript for the Journal

Comparison of Panasonic’s Dosimetric System with Gamma-31 Dosimeters

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Paweł Urban

2013-01-01

Full Text Available Equipment being used in medical or industrial institutions is often a source of ionizing radiation with different energies and types, which complicates the detection and assessment of doses. Up until now, for dosimetric measurements of ionizing radiation, Gamma-31 dosimeters have been used in the Central Mining Institute for many years. Now, this system will be expanded by a Panasonic system, for which measurement procedures were developed and comparisons with other dosimeters were held. The method is based on a four-element dosimeters UD-802 Panasonic equipped with CaSO and LiBO detectors additionally sheltered by filters of different surface mass. The use of UD-802 dosimeters, in contrast to Gamma-31 dosimeters, permits measuring radiation doses in a different range of photon energy. Consequently, it is possible to obtain a more accurate analysis of the hazards caused by gamma radiation in underground mines. The publication includes a description of the dosimetry system and presents the results of measurements conducted by means of both types of dosimeters. In order to verify the correctness of the indications of the new dosimetry system a series of measurements were carried out, which allowed examining the behaviour of the dosimeters under different environmental conditions. As a place of exposure, the selected laboratories in the Silesian Centre for Environmental Radiometry were chosen, where the work is connected with (TENORM and equipment producing ionizing radiation or containing sources of this type of radiation. Moreover, to observe the dosimeters behaviour in difficult environmental conditions, they were exposed in water treatment plants and an underground potassium salt mine.

28 CFR 700.31 - Exemption of the Office of Independent Counsel's systems of records-limited access.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Exemption of the Office of Independent Counsel's systems of records-limited access. 700.31 Section 700.31 Judicial Administration OFFICE OF INDEPENDENT COUNSEL PRODUCTION OR DISCLOSURE OF MATERIAL OR INFORMATION OF THE OFFICE OF INDEPENDENT COUNSEL Exemption of the Office of Independent...

Mechanism of inhibition of HIV-1 integrase by G-tetrad-forming oligonucleotides in Vitro.

Science.gov (United States)

Jing, N; Marchand, C; Liu, J; Mitra, R; Hogan, M E; Pommier, Y

2000-07-14

The G-tetrad-forming oligonucleotides and have been identified as potent inhibitors of human immunodeficiency virus type 1 integrase (HIV-1 IN) activity (Rando, R. F., Ojwang, J., Elbaggari, A., Reyes, G. R., Tinder, R., McGrath, M. S., and Hogan, M. E. (1995) J. Biol. Chem. 270, 1754-1760; Mazumder, A., Neamati, N., Ojwang, J. O., Sunder, S., Rando, R. F., and Pommier, Y. (1996) Biochemistry 35, 13762-13771; Jing, N., and Hogan, M. E. (1998) J. Biol. Chem. 273, 34992-34999). To understand the inhibition of HIV-1 IN activity by the G-quartet inhibitors, we have designed the oligonucleotides and, composed of three and four G-quartets with stem lengths of 19 and 24 A, respectively. The fact that increasing the G-quartet stem length from 15 to 24 A kept inhibition of HIV-1 IN activity unchanged suggests that the binding interaction occurs between a GTGT loop domain of the G-quartet inhibitors and a catalytic site of HIV-1 IN, referred to as a face-to-face interaction. Docking the NMR structure of (Jing and Hogan (1998)) into the x-ray structure of the core domain of HIV-1 IN, HIV-1 IN-(51-209) (Maignan, S., Guilloteau, J.-P. , Qing, Z.-L., Clement-Mella, C., and Mikol, V. (1998) J. Mol. Biol. 282, 359-368), was performed using the GRAMM program. The statistical distributions of hydrogen bonding between HIV-1 IN and were obtained from the analyses of 1000 random docking structures. The docking results show a high probability of interaction between the GTGT loop residues of the G-quartet inhibitors and the catalytic site of HIV-1 IN, in agreement with the experimental observation.

40 CFR 73.31 - Establishment of accounts.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 16 2010-07-01 2010-07-01 false Establishment of accounts. 73.31 Section 73.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) SULFUR DIOXIDE ALLOWANCE SYSTEM Allowance Tracking System § 73.31 Establishment of accounts. (a...

MCNP4c JEFF-3.1 Based Libraries. Eccolib-Jeff-3.1 libraries

International Nuclear Information System (INIS)

Sublet, J.Ch.

2006-01-01

Continuous-energy and multi-temperatures MCNP Ace types libraries, derived from the Joint European Fusion-Fission JEFF-3.1 evaluations, have been generated using the NJOY-99.111 processing code system. They include the continuous-energy neutron JEFF-3.1/General Purpose, JEFF-3.1/Activation-Dosimetry and thermal S(α,β) JEFF-3.1/Thermal libraries and data tables. The processing steps and features are explained together with the Quality Assurance processes and records linked to the generation of such multipurpose libraries. (author)

The S230R Integrase Substitution Associated with Viral Rebound during DTG Monotherapy Confers Low Levels INSTI Drug Resistance.

Science.gov (United States)

Pham, Hanh T; Labrie, Lydia; Wijting, Ingeborg E A; Hassounah, Said; Lok, Ka Yee; Portna, Inna; Goring, Mark; Han, Yingshan; Lungu, Cynthia; van der Ende, Marchina E; Brenner, Bluma G; Boucher, Charles A; Rijnders, Bart J A; van Kampen, Jeroen J A; Mesplède, Thibault; Wainberg, Mark A

2018-03-29

Dolutegravir (DTG) is an integrase strand-transfer inhibitor (INSTI) used for treatment of HIV-infected individuals. Due to its high genetic barrier to resistance, DTG has been clinically investigated as maintenance monotherapy to maintain viral suppression and to reduce complication and healthcare costs. Our study aims to explain the underlying mechanism related to the emergence of a S230R substitution in patients who experienced virological failure while using DTG monotherapy. We evaluated the effect of S230R substitution in regard to IN enzyme activity, viral infectivity, replicative capacity and susceptibility to different INSTIs by biochemical and cell-based assays. S230R substitution conferred 63% reduction in enzyme efficiency. The S230R virus was 1.29-fold less infectious than wildtype (WT), but could replicate in PM1 cells without significant delay. Resistance levels against DTG, CAB, RAL and EVG in tissue culture were 3.85-, 3.72-, 1.52-, and 1.21-fold, respectively. Our data indicate that the S230R substitution is comparable to the previously reported R263K in some respects. Virological failure under DTG monotherapy can occur through the development of such S230R or R263K mutations without the need for high levels DTG resistance.

Four-tiered π interaction at the dimeric interface of HIV-1 integrase critical for DNA integration and viral infectivity

International Nuclear Information System (INIS)

Al-Mawsawi, Laith Q.; Hombrouck, Anneleen; Dayam, Raveendra; Debyser, Zeger; Neamati, Nouri

2008-01-01

HIV-1 integrase (IN) is an essential enzyme for viral infection. Here, we report an extensive π electron orbital interaction between four amino acids, W132, M178, F181 and F185, located at the dimeric interface of IN that is critical for the strand transfer activity alone. Catalysis of nine different mutant IN proteins at these positions were evaluated. Whereas the 3'-processing activity is predominantly strong, the strand transfer activity of each enzyme was completely dependent on an intact π electron orbital interaction at the dimeric interface. Four representative IN mutants were constructed in the context of the infectious NL4.3 HIV-1 viral clone. Whereas viruses with an intact π electron orbital interaction at the IN dimeric interface replicated comparable to wild type, viruses containing an abolished π interaction were non-infectious. Q-PCR analysis of viral DNA forms during viral replication revealed pleiotropic effects of most mutations. We hypothesize that the π interaction is a critical contact point for the assembly of functional IN multimeric complexes, and that IN multimerization is required for a functional pre-integration complex. The rational design of small molecule inhibitors targeting the disruption of this π-π interaction should lead to powerful anti-retroviral drugs

Functional significance of SRJ domain mutations in CITED2.

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Chiann-mun Chen

Full Text Available CITED2 is a transcriptional co-activator with 3 conserved domains shared with other CITED family members and a unique Serine-Glycine Rich Junction (SRJ that is highly conserved in placental mammals. Loss of Cited2 in mice results in cardiac and aortic arch malformations, adrenal agenesis, neural tube and placental defects, and partially penetrant defects in left-right patterning. By screening 1126 sporadic congenital heart disease (CHD cases and 1227 controls, we identified 19 variants, including 5 unique non-synonymous sequence variations (N62S, R92G, T166N, G180-A187del and A187T in patients. Many of the CHD-specific variants identified in this and previous studies cluster in the SRJ domain. Transient transfection experiments show that T166N mutation impairs TFAP2 co-activation function and ES cell proliferation. We find that CITED2 is phosphorylated by MAPK1 in vitro at T166, and that MAPK1 activation enhances the coactivation function of CITED2 but not of CITED2-T166N. In order to investigate the functional significance in vivo, we generated a T166N mutation of mouse Cited2. We also used PhiC31 integrase-mediated cassette exchange to generate a Cited2 knock-in allele replacing the mouse Cited2 coding sequence with human CITED2 and with a mutant form deleting the entire SRJ domain. Mouse embryos expressing only CITED2-T166N or CITED2-SRJ-deleted alleles surprisingly show no morphological abnormalities, and mice are viable and fertile. These results indicate that the SRJ domain is dispensable for these functions of CITED2 in mice and that mutations clustering in the SRJ region are unlikely to be the sole cause of the malformations observed in patients with sporadic CHD. Our results also suggest that coding sequence mutations observed in case-control studies need validation using in vivo models and that predictions based on structural conservation and in vitro functional assays, or even in vivo global loss of function models, may be

A nuclear pulse amplitude acquisition system based on 80C31 single-chip microcomputer

International Nuclear Information System (INIS)

Zhao Xiuliang; Qu Guopu; Guo Lanying; Zhang Songbai

1999-01-01

A kind of multichannel nuclear pulse amplitude signal acquisition system is described, which is composed of pulse peak detector, integrated S/H circuit, A/D converter and 80C31 single-chip microcomputer

L-Chicoric acid inhibits human immunodeficiency virus type 1 integration in vivo and is a noncompetitive but reversible inhibitor of HIV-1 integrase in vitro

International Nuclear Information System (INIS)

Reinke, Ryan A.; Lee, Deborah J.; McDougall, Brenda R.; King, Peter J.; Victoria, Joseph; Mao Yingqun; Lei Xiangyang; Reinecke, Manfred G.; Robinson, W. Edward

2004-01-01

The human immunodeficiency virus (HIV) integrase (IN) must covalently join the viral cDNA into a host chromosome for productive HIV infection. L-Chicoric acid (L-CA) enters cells poorly but is a potent inhibitor of IN in vitro. Using quantitative real-time polymerase chain reaction (PCR), L-CA inhibits integration at concentrations from 500 nM to 10 μM but also inhibits entry at concentrations above 1 μM. Using recombinant HIV IN, steady-state kinetic analyses with L-CA were consistent with a noncompetitive or irreversible mechanism of inhibition. IN, in the presence or absence of L-CA, was successively washed. Inhibition of IN diminished, demonstrating that L-CA was reversibly bound to the protein. These data demonstrate that L-CA is a noncompetitive but reversible inhibitor of IN in vitro and of HIV integration in vivo. Thus, L-CA likely interacts with amino acids other than those which bind substrate

Metagenomic analysis of lysogeny in Tampa Bay: implications for prophage gene expression.

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Lauren McDaniel

Full Text Available Phage integrase genes often play a role in the establishment of lysogeny in temperate phage by catalyzing the integration of the phage into one of the host's replicons. To investigate temperate phage gene expression, an induced viral metagenome from Tampa Bay was sequenced by 454/Pyrosequencing. The sequencing yielded 294,068 reads with 6.6% identifiable. One hundred-three sequences had significant similarity to integrases by BLASTX analysis (e < or =0.001. Four sequences with strongest amino-acid level similarity to integrases were selected and real-time PCR primers and probes were designed. Initial testing with microbial fraction DNA from Tampa Bay revealed 1.9 x 10(7, and 1300 gene copies of Vibrio-like integrase and Oceanicola-like integrase L(-1 respectively. The other two integrases were not detected. The integrase assay was then tested on microbial fraction RNA extracted from 200 ml of Tampa Bay water sampled biweekly over a 12 month time series. Vibrio-like integrase gene expression was detected in three samples, with estimated copy numbers of 2.4-1280 L(-1. Clostridium-like integrase gene expression was detected in 6 samples, with estimated copy numbers of 37 to 265 L(-1. In all cases, detection of integrase gene expression corresponded to the occurrence of lysogeny as detected by prophage induction. Investigation of the environmental distribution of the two expressed integrases in the Global Ocean Survey Database found the Vibrio-like integrase was present in genome equivalents of 3.14% of microbial libraries and all four viral metagenomes. There were two similar genes in the library from British Columbia and one similar gene was detected in both the Gulf of Mexico and Sargasso Sea libraries. In contrast, in the Arctic library eleven similar genes were observed. The Clostridium-like integrase was less prevalent, being found in 0.58% of the microbial and none of the viral libraries. These results underscore the value of metagenomic data

31 CFR 19.500 - What is the purpose of the Excluded Parties List System (EPLS)?

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false What is the purpose of the Excluded Parties List System (EPLS)? 19.500 Section 19.500 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Excluded Parties List System...

48 CFR 31.205-8 - Contributions or donations.

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2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contributions or donations. 31.205-8 Section 31.205-8 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Organizations 31.205-8 Contributions or donations. Contributions or donations, including cash, property and...

30 CFR 27.31 - Testing methods.

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2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Testing methods. 27.31 Section 27.31 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR TESTING, EVALUATION, AND APPROVAL OF MINING PRODUCTS METHANE-MONITORING SYSTEMS Test Requirements § 27.31 Testing methods. A methane...

48 CFR 31.205-28 - Other business expenses.

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2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Other business expenses. 31.205-28 Section 31.205-28 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Organizations 31.205-28 Other business expenses. The following types of recurring costs are allowable (a...

CRISPR-Cas and Contact-Dependent Secretion Systems Present on Excisable Pathogenicity Islands with Conserved Recombination Modules.

Science.gov (United States)

Carpenter, Megan R; Kalburge, Sai S; Borowski, Joseph D; Peters, Molly C; Colwell, Rita R; Boyd, E Fidelma

2017-05-15

Pathogenicity islands (PAIs) are mobile integrated genetic elements that contain a diverse range of virulence factors. PAIs integrate into the host chromosome at a tRNA locus that contains their specific bacterial attachment site, attB , via integrase-mediated site-specific recombination generating attL and attR sites. We identified conserved recombination modules (integrases and att sites) previously described in choleragenic Vibrio cholerae PAIs but with novel cargo genes. Clustered regularly interspaced short palindromic repeat (CRISPR)-associated proteins (Cas proteins) and a type VI secretion system (T6SS) gene cluster were identified at the Vibrio pathogenicity island 1 (VPI-1) insertion site in 19 V. cholerae strains and contained the same recombination module. Two divergent type I-F CRISPR-Cas systems were identified, which differed in Cas protein homology and content. The CRISPR repeat sequence was identical among all V. cholerae strains, but the CRISPR spacer sequences and the number of spacers varied. In silico analysis suggests that the CRISPR-Cas systems were active against phages and plasmids. A type III secretion system (T3SS) was present in 12 V. cholerae strains on a 68-kb island inserted at the same tRNA-serine insertion site as VPI-2 and contained the same recombination module. Bioinformatics analysis showed that two divergent T3SSs exist among the strains examined. Both the CRISPR and T3SS islands excised site specifically from the bacterial chromosome as complete units, and the cognate integrases were essential for this excision. These data demonstrated that identical recombination modules that catalyze integration and excision from the chromosome can acquire diverse cargo genes, signifying a novel method of acquisition for both CRISPR-Cas systems and T3SSs. IMPORTANCE This work demonstrated the presence of CRISPR-Cas systems and T3SSs on PAIs. Our work showed that similar recombination modules can associate with different cargo genes and

Clinical Improvement by Switching to an Integrase Strand Transfer Inhibitor in Hemophiliac Patients with HIV: The Japan Cohort Study of HIV Patients Infected through Blood Products.

Science.gov (United States)

Kawado, Miyuki; Hashimoto, Shuji; Oka, Shin-Ichi; Fukutake, Katsuyuki; Higasa, Satoshi; Yatsuhashi, Hiroshi; Ogane, Miwa; Okamoto, Manabu; Shirasaka, Takuma

2017-01-01

This study aimed to determine improvement in HIV RNA levels and the CD4 cell count by switching to an antiretroviral regimen with an integrase strand transfer inhibitor (INSTI) in patients with HIV. This study was conducted on Japanese patients with HIV who were infected by blood products in the 1980s. Data were collected between 2007 and 2014. Data of 564 male hemophiliac patients with HIV from the Japan Cohort Study of HIV Patients Infected through Blood Products were available. Changes in antiretroviral regimen use, HIV RNA levels, and the CD4 cell count between 2007 and 2014 were examined. From 2007 to 2014, the proportion of use of a regimen with an INSTI increased from 0.0% to 41.0%. For patients with HIV who used a regimen, including an INSTI, the proportion of HIV RNA levels products. This suggests that performing this switch in clinical practice will lead to favorable effects.

Application of the cracked pipe element to creep crack growth prediction

Energy Technology Data Exchange (ETDEWEB)

Brochard, J.; Charras, T.

1997-04-01

The modification of a computer code for leak before break analysis is very briefly described. The CASTEM2000 code was developed for ductile fracture assessment of piping systems with postulated circumferential through-wall cracks under static or dynamic loading. The modification extends the capabilities of the cracked pipe element to the determination of fracture parameters under creep conditions (C*, {phi}c and {Delta}c). The model has the advantage of evaluating significant secondary effects, such as those from thermal loading.

48 CFR 31.205 - Selected costs.

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2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Selected costs. 31.205... REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205 Selected costs. ...

The Microbiota and Abundance of the Class 1 Integron-Integrase Gene in Tropical Sewage Treatment Plant Influent and Activated Sludge.

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Magna C Paiva

Full Text Available Bacteria are assumed to efficiently remove organic pollutants from sewage in sewage treatment plants, where antibiotic-resistance genes can move between species via mobile genetic elements known as integrons. Nevertheless, few studies have addressed bacterial diversity and class 1 integron abundance in tropical sewage. Here, we describe the extant microbiota, using V6 tag sequencing, and quantify the class 1 integron-integrase gene (intI1 in raw sewage (RS and activated sludge (AS. The analysis of 1,174,486 quality-filtered reads obtained from RS and AS samples revealed complex and distinct bacterial diversity in these samples. The RS sample, with 3,074 operational taxonomic units, exhibited the highest alpha-diversity indices. Among the 25 phyla, Proteobacteria, Bacteroidetes and Firmicutes represented 85% (AS and 92% (RS of all reads. Increased relative abundance of Micrococcales, Myxococcales, and Sphingobacteriales and reduced pathogen abundance were noted in AS. At the genus level, differences were observed for the dominant genera Simplicispira and Diaphorobacter (AS as well as for Enhydrobacter (RS. The activated sludge process decreased (55% the amount of bacteria harboring the intI1 gene in the RS sample. Altogether, our results emphasize the importance of biological treatment for diminishing pathogenic bacteria and those bearing the intI1 gene that arrive at a sewage treatment plant.

48 CFR 31.205-23 - Losses on other contracts.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Losses on other contracts. 31.205-23 Section 31.205-23 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION... Organizations 31.205-23 Losses on other contracts. An excess of costs over income under any other contract...

EVIDENCE FOR AN ACCRETION ORIGIN FOR THE OUTER HALO GLOBULAR CLUSTER SYSTEM OF M31

International Nuclear Information System (INIS)

Mackey, A. D.; Huxor, A. P.; Ferguson, A. M. N.; Irwin, M. J.; Chapman, S. C.; Tanvir, N. R.; McConnachie, A. W.; Ibata, R. A.; Lewis, G. F.

2010-01-01

We use a sample of newly discovered globular clusters from the Pan-Andromeda Archaeological Survey (PAndAS) in combination with previously cataloged objects to map the spatial distribution of globular clusters in the M31 halo. At projected radii beyond ∼30 kpc, where large coherent stellar streams are readily distinguished in the field, there is a striking correlation between these features and the positions of the globular clusters. Adopting a simple Monte Carlo approach, we test the significance of this association by computing the probability that it could be due to the chance alignment of globular clusters smoothly distributed in the M31 halo. We find that the likelihood of this possibility is low, below 1%, and conclude that the observed spatial coincidence between globular clusters and multiple tidal debris streams in the outer halo of M31 reflects a genuine physical association. Our results imply that the majority of the remote globular cluster system of M31 has been assembled as a consequence of the accretion of cluster-bearing satellite galaxies. This constitutes the most direct evidence to date that the outer halo globular cluster populations in some galaxies are largely accreted.

THE THREE-DIMENSIONAL STRUCTURE OF THE M31 SATELLITE SYSTEM; STRONG EVIDENCE FOR AN INHOMOGENEOUS DISTRIBUTION OF SATELLITES

International Nuclear Information System (INIS)

Conn, A. R.; Parker, Q. A.; Zucker, D. B.; Lewis, G. F.; Ibata, R. A.; Martin, N. F.; McConnachie, A. W.; Valls-Gabaud, D.; Tanvir, N.; Irwin, M. J.; Ferguson, A. M. N.; Chapman, S. C.

2013-01-01

We undertake an investigation into the spatial structure of the M31 satellite system utilizing the distance distributions presented in a previous publication. These distances make use of the unique combination of depth and spatial coverage of the Pan-Andromeda Archaeological Survey to provide a large, homogeneous sample consisting of 27 of M31's satellites, as well as M31 itself. We find that the satellite distribution, when viewed as a whole, is no more planar than one would expect from a random distribution of equal size. A disk consisting of 15 of the satellites is however found to be highly significant, and strikingly thin, with an rms thickness of just 12.34 +0.75 -0.43 kpc. This disk is oriented approximately edge-on with respect to the Milky Way and almost perpendicular to the Milky Way disk. It is also roughly orthogonal to the disk-like structure regularly reported for the Milky Way satellite system and in close alignment with M31's Giant Stellar Stream. A similar analysis of the asymmetry of the M31 satellite distribution finds that it is also significantly larger than one would expect from a random distribution. In particular, it is remarkable that 20 of the 27 satellites most likely lie on the Milky Way side of the galaxy, with the asymmetry being most pronounced within the satellite subset forming the aforementioned disk. This lopsidedness is all the more intriguing in light of the apparent orthogonality observed between the satellite disk structures of the Milky Way and M31.

31 CFR 31.218 - Enforcement.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Enforcement. 31.218 Section 31.218 Money and Finance: Treasury Office of the Secretary of the Treasury TROUBLED ASSET RELIEF PROGRAM... more of the following sanctions: (1) Rejection of work tainted by an organizational conflict of...

Gravitating SO (3,1) gauge field

International Nuclear Information System (INIS)

Aragone, C.; Restuccia, A.

1978-01-01

In this article, we postulate SO (3,1) as a local symmetry of any relativistic theory. This is equivalent to assuming the existence of a gauge field associated with this noncompact group. This SO (3,1) gauge field is the spinorial affinity which usually appears when we deal with weighting spinors, which, as is well known, cannot be coupled to the metric tensor field. Furthermore, according to the integral approach to gauge fields proposed by Yang, it is also recognized that in order to obtain models of gravity we have to introduce ordinary affinities as the gauge field associated with GL (4) (the local symmetry determined by the parallel transport). Thus if we assume both GL (4) and SO (3,1) as local independent symmetries we are led to analyze the dynamical gauge system constituted by the Einstein field interacting with the SO (3,1) Weyl--Yang gauge field. We think this system is a possible model of strong gravity. Once we give the first-order action for this Einstein--Weyl--Yang system we study whether the SO (3,1) gauge field could have a tetrad associated with it. It is also shown that both fields propagate along a unique characteristic cone. Algebraic and differential constraints are solved when the system evolves along a null coordinate. The unconstrained expression for the action of the system is found working in the Bondi gauge. That allows us to exhibit an explicit expression of the dynamical generator of the system. Its signature turns out to be nondefinite, due to the nondefinite contribution of the Weyl--Yang field, which has the typical spinorial behavior. A conjecture is made that such an unpleasant feature could be overcome in the quantized version of this model

31 CFR 31.201 - Definitions.

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2010-07-01

... agency agreement between a private sector entity and the Treasury for services under the TARP, other than... Stabilization Act of 2008. Key individual means an individual providing services to a private sector entity who... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Definitions. 31.201 Section 31.201...

Nuclear energy system department annual report. April 1, 2001 - March 31, 2002

International Nuclear Information System (INIS)

Nakajima, Hajime; Ohnuki, Akira; Kunii, Katsuhiko

2003-03-01

This report summarizes the research and development activities in the Department of Nuclear Energy System during the fiscal year of 2001 (April 1, 2001 - March 31, 2002). The Department has been organized from April 1998. The main research activity is aimed to build the basis of the development of future nuclear energy systems. The research activities of the Department cover basic nuclear data evaluation, conceptual design of a reduced-moderation water reactor, reactor physics experiments and development of the reactor analysis codes, experiment and analysis of thermal-hydrodynamics, energy system analysis and assessment, development of advanced materials for a reactor, lifetime reliability assessment on structural material, development of advanced nuclear fuel, design of a marine reactor and the research for a nuclear ship system. The maintenance and operation of reactor engineering facilities belonging to the Department are undertaken. The activities of the research committees to which the Department takes a role of secretariat are also summarized in this report. (author)

48 CFR 31.202 - Direct costs.

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2010-10-01

... REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.202 Direct... amount as an indirect cost if the accounting treatment— (1) Is consistently applied to all final cost... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Direct costs. 31.202...

31 CFR 357.31 - Certifying individuals.

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2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Certifying individuals. 357.31 Section 357.31 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL... institutions, corporate central credit unions, and institutions that are members of Treasury-recognized...

Nuclear energy system department annual report. April 1, 2000 - March 31, 2001

International Nuclear Information System (INIS)

Osugi, Toshitaka; Takase, Kazuyuki; Kunii, Katsuhiko

2002-03-01

This report summarizes the research and development activities in the Department of Nuclear Energy System during the fiscal year of 2000 (April 1, 2000 - March 31, 2001). The Department has been organized from April 1998. The main research activity is aimed to build the basis of the development of future nuclear energy systems. The research activities of the Department cover basic nuclear and atomic and molecular data evaluation, conceptual design of a reduced-moderation water reactor, reactor physics experiments and development of the reactor analysis codes, experiment and analysis of thermal-hydrodynamics, energy system analysis and assessment, development of advanced materials for a reactor, lifetime reliability assessment on structural material, development of advanced nuclear fuel, study of nuclear transmutation systems, design of a marine reactor and the research for a nuclear ship system. The maintenance and operation of reactor engineering facilities belonging to the Department are undertaken. The activities of the research committees to which the Department takes a role of secretariat are also summarized in this report. (author)

Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study.

Science.gov (United States)

Akil, Bisher; Blick, Gary; Hagins, Debbie P; Ramgopal, Moti N; Richmond, Gary J; Samuel, Rafik M; Givens, Naomi; Vavro, Cindy; Song, Ivy H; Wynne, Brian; Ait-Khaled, Mounir

2015-01-01

The Phase III VIKING-3 study demonstrated that dolutegravir (DTG) 50 mg twice daily was efficacious in antiretroviral therapy (ART)-experienced subjects harbouring raltegravir- and/or elvitegravir-resistant HIV-1. VIKING-4 (ING116529) included a placebo-controlled 7-day monotherapy phase to demonstrate that short-term antiviral activity was attributable to DTG. VIKING-4 is a Phase III randomized, double-blind study in therapy-experienced adults with integrase inhibitor (INI)-resistant virus randomized to DTG 50 mg twice daily or placebo while continuing their failing regimen (without raltegravir or elvitegravir) for 7 days (clinicaltrials.gov identifier NCT01568892). At day 8, all subjects switched to open-label DTG 50 mg twice daily and optimized background therapy including ≥1 fully active drug. The primary end point was change from baseline in plasma HIV-1 RNA at day 8. The study population (n=30) was highly ART-experienced with advanced HIV disease. Patients had extensive baseline resistance to all approved antiretroviral classes. Adjusted mean change in HIV-1 RNA at day 8 was 
-1.06 log10 copies/ml for the DTG arm and 0.10 log10 copies/ml for the placebo arm (treatment difference -1.16 log10 copies/ml [-1.52, -0.80]; PVIKING-3 study.

Tripoli-4.4 Jeff-3.1 based libraries; Les bibliotheques Jeff-3.1 pour Tripoli-4.4

Energy Technology Data Exchange (ETDEWEB)

Jouanne, C. [CEA Saclay Dept. Modelisation de Systemes et Structures, 91 - Gif sur Yvette (France); Sublet, J.Ch. [CEA Cadarache, Dept. d' Etudes des Reacteurs, 13 - Saint Paul lez Durance (France)

2006-07-01

Continuous-energy and multi-temperatures TRIPOLI-4.4 libraries, derived from the Joint European Fusion-Fission JEFF-3.1 evaluations, have been generated using the NJOY-99.112 processing code system. They include the continuous-energy neutron JEFF-3.1/General Purpose and thermal S({alpha},{beta}) JEFF-3.1/Thermal libraries and data tables. The processing steps and features are explained together with the Quality Assurance processes and records linked to the generation of such multipurpose libraries. (authors)

STAR CLUSTERS IN M31. IV. A COMPARATIVE ANALYSIS OF ABSORPTION LINE INDICES IN OLD M31 AND MILKY WAY CLUSTERS

International Nuclear Information System (INIS)

Schiavon, Ricardo P.; Caldwell, Nelson; Morrison, Heather; Harding, Paul; Courteau, Stéphane; MacArthur, Lauren A.; Graves, Genevieve J.

2012-01-01

We present absorption line indices measured in the integrated spectra of globular clusters both from the Galaxy and from M31. Our samples include 41 Galactic globular clusters, and more than 300 clusters in M31. The conversion of instrumental equivalent widths into the Lick system is described, and zero-point uncertainties are provided. Comparison of line indices of old M31 clusters and Galactic globular clusters suggests an absence of important differences in chemical composition between the two cluster systems. In particular, CN indices in the spectra of M31 and Galactic clusters are essentially consistent with each other, in disagreement with several previous works. We reanalyze some of the previous data, and conclude that reported CN differences between M31 and Galactic clusters were mostly due to data calibration uncertainties. Our data support the conclusion that the chemical compositions of Milky Way and M31 globular clusters are not substantially different, and that there is no need to resort to enhanced nitrogen abundances to account for the optical spectra of M31 globular clusters.

STAR CLUSTERS IN M31. IV. A COMPARATIVE ANALYSIS OF ABSORPTION LINE INDICES IN OLD M31 AND MILKY WAY CLUSTERS

Energy Technology Data Exchange (ETDEWEB)

Schiavon, Ricardo P. [Gemini Observatory, Hilo, HI 96720 (United States); Caldwell, Nelson [Smithsonian Astrophysical Observatory, Cambridge, MA 02138 (United States); Morrison, Heather; Harding, Paul [Department of Astronomy, Case Western Reserve University, Cleveland, OH 44106-7215 (United States); Courteau, Stephane [Department of Physics, Engineering Physics and Astronomy, Queen' s University, Kingston, ON K7L 3N6 (Canada); MacArthur, Lauren A. [Herzberg Institute of Astrophysics, National Research Council of Canada/University of Victoria, Victoria, B.C. V9E 2E7 (Canada); Graves, Genevieve J., E-mail: rschiavon@gemini.edu, E-mail: caldwell@cfa.harvard.edu, E-mail: paul.harding@case.edu, E-mail: heather@vegemite.case.edu, E-mail: courteau@astro.queensu.ca, E-mail: Lauren.MacArthur@nrc-cnrc.gc.ca, E-mail: graves@astro.berkeley.edu [Department of Astronomy, University of California, Berkeley, CA 94720 (United States)

2012-01-15

We present absorption line indices measured in the integrated spectra of globular clusters both from the Galaxy and from M31. Our samples include 41 Galactic globular clusters, and more than 300 clusters in M31. The conversion of instrumental equivalent widths into the Lick system is described, and zero-point uncertainties are provided. Comparison of line indices of old M31 clusters and Galactic globular clusters suggests an absence of important differences in chemical composition between the two cluster systems. In particular, CN indices in the spectra of M31 and Galactic clusters are essentially consistent with each other, in disagreement with several previous works. We reanalyze some of the previous data, and conclude that reported CN differences between M31 and Galactic clusters were mostly due to data calibration uncertainties. Our data support the conclusion that the chemical compositions of Milky Way and M31 globular clusters are not substantially different, and that there is no need to resort to enhanced nitrogen abundances to account for the optical spectra of M31 globular clusters.

Light-controlled supramolecular helicity of a liquid crystalline phase using a helical polymer functionalized with a single chiroptical molecular switch

NARCIS (Netherlands)

Pijper, Dirk; Jongejan, Mahthild G. M.; Meetsma, Auke; Feringa, Ben L.

2008-01-01

Control over the preferred helical sense of a poly(n-hexyl isocyanate) (PHIC) by using a single light-driven molecular motor, covalently attached at the polymer's terminus, has been accomplished in solution via a combination of photochemical and thermal isomerizations. Here, we report that after

48 CFR 31.205-14 - Entertainment costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Entertainment costs. 31... CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-14 Entertainment costs. Costs of amusement, diversions, social activities, and any directly...

Mednarodni standardi - veličine in enote (ISO 31-0 do 31-13): International standards - quantities and units (ISO 31-0 to 31-13):

OpenAIRE

Glavič, Peter

2002-01-01

In this paper the international standards ISO 31 (Quantities and units) are presented with the following parts: ISO 31-0 (General principles), ISO 31-1 (Space and time), ISO 31-2 (Periodic and related phenomena), ISO 31-3 (Mechanics), ISO 31-4 (Heat), ISO 31-5 (Electricity and magnetism), ISO 31-8 (Physical chemistry and molecular physics), ISO 31-12 (Characteristic numbers)and others. The emphasis is given on the basic principles, which is important for writing of reports, presentations, art...

Nuclear Energy System Department annual report (April 1, 1998 - March 31, 1999)

Energy Technology Data Exchange (ETDEWEB)

NONE

2000-01-01

This report summarizes the research and development activities in the Department of Nuclear Energy System during the fiscal year of 1998 (April 1, 1998 - March 31, 1999). The Department has been organized from April 1998. The main research activity is aimed to build the basis of the development of future nuclear energy system. The research activities of the fiscal year cover basic nuclear and atomic and molecular data evaluation, conceptual design of reduced-moderation water reactor, development of reactor analysis code, reactor physics study on fast neutron system, control and sensing technology development for nuclear reactor, experiment and analysis of thermal-hydrodynamics, development of advanced material for reactor, lifetime reliability assessment on structural material for advanced reactor, development of advanced nuclear fuel, design of marine reactor and the research for nuclear ship system. The maintenance and operation of reactor engineering facilities belonging to the Department are undertaken. The activities of the research committee to which the Department takes a role of secretariat are also summarized in this report. The 98 papers are indexed individually. (J.P.N.)

Nuclear energy system department annual report. April 1, 1999 - March 31, 2000

International Nuclear Information System (INIS)

2001-03-01

This report summarizes the research and development activities in the Department of Nuclear Energy System during the fiscal year of 1999 (April 1, 1999 - March 31, 2000). The Department has been organized from April 1998. The main research activity is aimed to build the basis of the development of a future nuclear energy system. The research activities of the fiscal year cover basic nuclear and atomic and molecular data evaluation, conceptual design of a reduced-moderation water reactor, reactor physics experiments and development of the reactor analysis codes, experiment and analysis of thermal-hydrodynamics, development of advanced materials for a reactor, lifetime reliability assessment on structural material, development of advanced nuclear fuel, design of a marine reactor and the research for a nuclear ship system. The maintenance and operation of reactor engineering facilities belonging to the Department are undertaken. The activities of the research committee to which the Department takes a role of secretariat are also summarized in this report. (author)

48 CFR 31.201-7 - Construction and architect-engineer contracts.

Science.gov (United States)

2010-10-01

...-engineer contracts. 31.201-7 Section 31.201-7 Federal Acquisition Regulations System FEDERAL ACQUISITION... Organizations 31.201-7 Construction and architect-engineer contracts. Specific principles and procedures for... architect-engineer contracts related to construction projects, are in 31.105. The applicability of these...

The response of saprotrophic beetles to coast live oaks infected with Phytophthora ramorum

Science.gov (United States)

Brice A. McPherson; Nadir Ebilgin; David L. Wood; Pavel Svihra; Andrew J. Storer; Richard B. Standiford

2006-01-01

Saprotro phic ambrosia and bark beetles (Coleoptera: Scolytidae) tunnel into the bark overlying cankers caused by Phytophthora ramorum in coast live oaks, Quercus agrifolia. These insects are characteristically reported to colonize freshly dead or moribund trees (Furniss and Carolin, 1977). However, the initial attacks by these...

Genetics and mapping of a new leaf rust resistance gene in Triticum ...

Indian Academy of Sciences (India)

AMIT KUMAR SINGH

Selection G12 carries a new gene for leaf rust resistance, tentatively named as LrSelG12. [Singh A. K. ..... long arm of chromosome 3B were found to be polymor- phic between ... due to the evolution of new virulent races in India (Tomar et al.

14 CFR 31.55 - Deflation means.

Science.gov (United States)

2010-01-01

... emergency deflation of the envelope so as to allow a safe emergency landing. If a system other than a manual system is used, the reliability of the system used must be substantiated. [Amdt. 31-2, 30 FR 3377, Mar...

Nuclear Energy System Department annual report. (April 1, 2002 - March 31, 2003)

International Nuclear Information System (INIS)

Nakajima, Hajime; Shibata, Keiichi; Kugo, Teruhiko

2003-09-01

This report summarizes the research and development activities in the Department of Nuclear Energy System during the fiscal year of 2002 (April 1, 2002 - March 31, 2003). The Department has carried out researches and developments (R and Ds) of innovative nuclear energy system and their related fundamental technologies to ensure the long-term energy supply in Japan. The report deals with the R and Ds of an innovative water reactor, called Reduced-Moderation Water Reactor (RMWR), which has the capability of multiple recycling and breeding of plutonium using light water reactor technologies. In addition, as basic studies and fundamental researches of nuclear energy system in general, described are intensive researches in the fields of reactor physics, thermal-hydraulics, nuclear data, nuclear fuels, and materials. These activities are essential not only for the R and Ds of innovative nuclear energy systems but also for the improvement of safety and reliability of current nuclear energy systems. The maintenance and operation of reactor engineering facilities belonging to the Department support experimental activities. The activities of the research committees to which the Department takes a role of secretariat are also summarized. (author)

48 CFR 31.205-32 - Precontract costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Precontract costs. 31.205... CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-32 Precontract costs. Precontract costs means costs incurred before the effective date of the...

48 CFR 31.205-27 - Organization costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Organization costs. 31.205... CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-27 Organization costs. (a) Except as provided in paragraph (b) of this section, expenditures in...

RECURRENT NOVAE IN M31

Energy Technology Data Exchange (ETDEWEB)

Shafter, A. W. [Department of Astronomy, San Diego State University, San Diego, CA 92182 (United States); Henze, M. [European Space Astronomy Centre, P.O. Box 78, E-28692 Villanueva de la Cañada, Madrid (Spain); Rector, T. A. [Department of Physics and Astronomy, University of Alaska Anchorage, 3211 Providence Dr., Anchorage, AK 99508 (United States); Schweizer, F. [Carnegie Observatories, 813 Santa Barbara St., Pasadena, CA 91101 (United States); Hornoch, K. [Astronomical Institute, Academy of Sciences, CZ-251 65 Ondřejov (Czech Republic); Orio, M. [Astronomical Observatory of Padova (INAF), I-35122 Padova (Italy); Pietsch, W. [Max Planck Institute for Extraterrestrial Physics, P.O. Box 1312, Giessenbachstr., D-85741, Garching (Germany); Darnley, M. J.; Williams, S. C.; Bode, M. F. [Astrophysics Research Institute, Liverpool John Moores University, Liverpool L3 5RF (United Kingdom); Bryan, J., E-mail: aws@nova.sdsu.edu [McDonald Observatory, Austin, TX 78712 (United States)

2015-02-01

The reported positions of 964 suspected nova eruptions in M31 recorded through the end of calendar year 2013 have been compared in order to identify recurrent nova (RN) candidates. To pass the initial screen and qualify as a RN candidate, two or more eruptions were required to be coincident within 0.′1, although this criterion was relaxed to 0.′15 for novae discovered on early photographic patrols. A total of 118 eruptions from 51 potential RN systems satisfied the screening criterion. To determine what fraction of these novae are indeed recurrent, the original plates and published images of the relevant eruptions have been carefully compared. This procedure has resulted in the elimination of 27 of the 51 progenitor candidates (61 eruptions) from further consideration as RNe, with another 8 systems (17 eruptions) deemed unlikely to be recurrent. Of the remaining 16 systems, 12 candidates (32 eruptions) were judged to be RNe, with an additional 4 systems (8 eruptions) being possibly recurrent. It is estimated that ∼4% of the nova eruptions seen in M31 over the past century are associated with RNe. A Monte Carlo analysis shows that the discovery efficiency for RNe may be as low as 10% that for novae in general, suggesting that as many as one in three nova eruptions observed in M31 arise from progenitor systems having recurrence times ≲100 yr. For plausible system parameters, it appears unlikely that RNe can provide a significant channel for the production of Type Ia supernovae.

48 CFR 31.205-26 - Material costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Material costs. 31.205-26... CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-26 Material costs. (a) Material costs include the costs of such items as raw materials, parts...

48 CFR 31.205-4 - Bonding costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Bonding costs. 31.205-4... REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-4 Bonding costs. (a) Bonding costs arise when the Government requires assurance against financial loss to itself...

48 CFR 31.205-3 - Bad debts.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Bad debts. 31.205-3... REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-3 Bad debts. Bad debts, including actual or estimated losses arising from uncollectible accounts receivable due...

31 CFR 10.31 - Negotiation of taxpayer checks.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Negotiation of taxpayer checks. 10.31 Section 10.31 Money and Finance: Treasury Office of the Secretary of the Treasury PRACTICE BEFORE THE INTERNAL REVENUE SERVICE Duties and Restrictions Relating to Practice Before the Internal Revenue Service § 10.31 Negotiation of taxpayer checks. ...

Allele frequency present within the DYS635, DYS437, DYS448 ...

African Journals Online (AJOL)

Ejiro

2015-03-11

Mar 11, 2015 ... institute and courts of law. Key words: Allele ... individual identification and relatedness testing polymor- phic (Yamamoto et al. ... haplogroup an individual matches, STR analysis typically provides a person haplotype. Most tests on the Y chromosome examine between 12 and 67 STR markers. (Jobling et al.

48 CFR 31.205-36 - Rental costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Rental costs. 31.205-36... CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-36 Rental costs. (a) This subsection is applicable to the cost of renting or leasing real or...

26 CFR 31.3121(j)-1 - Covered transportation service.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Covered transportation service. 31.3121(j)-1... § 31.3121(j)-1 Covered transportation service. (a) Transportation systems acquired in whole or in part... operation of a public transportation system constitutes covered transportation service if any part of the...

31 CFR 31.217 - Confidentiality of information.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Confidentiality of information. 31.217 Section 31.217 Money and Finance: Treasury Office of the Secretary of the Treasury TROUBLED ASSET... from a source other than the retained entity. (b) Prohibitions. The retained entity shall not: (1...

Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations.

Directory of Open Access Journals (Sweden)

Mark A Winters

Full Text Available Failure of antiretroviral regimens containing elvitegravir (EVG and raltegravir (RAL can result in the appearance of integrase inhibitor (INI drug-resistance mutations (DRMs. While several INI DRMs have been identified, the evolution of EVG DRMs and the linkage of these DRMs with protease inhibitor (PI and reverse transcriptase inhibitor (RTI DRMs have not been studied at the clonal level. We examined the development of INI DRMs in 10 patients failing EVG-containing regimens over time, and the linkage of INI DRMs with PI and RTI DRMs in these patients plus 6 RAL-treated patients. A one-step RT-nested PCR protocol was used to generate a 2.7 kB amplicon that included the PR, RT, and IN coding region, and standard cloning and sequencing techniques were used to determine DRMs in 1,277 clones (mean 21 clones per time point. Results showed all patients had multiple PI, NRTI, and/or NNRTI DRMs at baseline, but no primary INI DRM. EVG-treated patients developed from 2 to 6 strains with different primary INI DRMs as early as 2 weeks after initiation of treatment, predominantly as single mutations. The prevalence of these strains fluctuated and new strains, and/or strains with new combinations of INI DRMs, developed over time. Final failure samples (weeks 14 to 48 typically showed a dominant strain with multiple mutations or N155H alone. Single N155H or multiple mutations were also observed in RAL-treated patients at virologic failure. All patient strains showed evidence of INI DRM co-located with single or multiple PI and/or RTI DRMs on the same viral strand. Our study shows that EVG treatment can select for a number of distinct INI-resistant strains whose prevalence fluctuates over time. Continued appearance of new INI DRMs after initial INI failure suggests a potent, highly dynamic selection of INI resistant strains that is unaffected by co-location with PI and RTI DRMs.

48 CFR 31.205-20 - Interest and other financial costs.

Science.gov (United States)

2010-10-01

... financial costs. 31.205-20 Section 31.205-20 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION GENERAL CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-20 Interest and other financial costs. Interest on borrowings (however represented), bond...

Effect of temperature on the fate of genes encoding tetracycline resistance and the integrase of class 1 integrons within anaerobic and aerobic digesters treating municipal wastewater solids.

Science.gov (United States)

Diehl, David L; LaPara, Timothy M

2010-12-01

The objective of this research was to investigate the ability of anaerobic and aerobic digesters to reduce the quantity of antibiotic resistant bacteria in wastewater solids. Lab-scale digesters were operated at different temperatures (22 °C, 37 °C, 46 °C, and 55 °C) under both anaerobic and aerobic conditions and fed wastewater solids collected from a full-scale treatment facility. Quantitative PCR was used to track five genes encoding tetracycline resistance (tet(A), tet(L), tet(O), tet(W), and tet(X)) and the gene encoding the integrase (intI1) of class 1 integrons. Statistically significant reductions in the quantities of these genes occurred in the anaerobic reactors at 37 °C, 46 °C, and 55 °C, with the removal rates and removal efficiencies increasing as a function of temperature. The aerobic digesters, in contrast, were generally incapable of significantly decreasing gene quantities, although these digesters were operated at much shorter mean hydraulic residence times. This research suggests that high temperature anaerobic digestion of wastewater solids would be a suitable technology for eliminating various antibiotic resistance genes, an emerging pollutant of concern.

46 CFR 252.31 - Wages of officers and crews.

Science.gov (United States)

2010-10-01

... 46 Shipping 8 2010-10-01 2010-10-01 false Wages of officers and crews. 252.31 Section 252.31... Subsidy Rates § 252.31 Wages of officers and crews. (a) Definitions. When used in this part: (1) Base period. The first base period under the wage index systems, as provided in section 603 of the Act, is the...

A Single-Center Retrospective Cohort Analysis of Maternal and Infant Outcomes in HIV-Infected Mothers Treated with Integrase Inhibitors During Pregnancy.

Science.gov (United States)

Mounce, Monique L; Pontiggia, Laura; Adams, Jessica L

2017-12-01

Integrase strand transfer inhibitors (INSTI) are currently being investigated for the treatment of HIV in pregnancy. The purpose of this study is to evaluate the differences in maternal and infant outcomes in HIV-positive mothers treated with INSTI-containing antiretroviral therapy (ART) during pregnancy compared to protease inhibitor (PI)-containing ART. A retrospective, cohort study of INSTI- and PI-based ART used in pregnancy between 2007 and 2015 was performed. The primary objective was to evaluate the differences in viral load (VL) suppression prior to delivery. Secondary endpoints included time to and duration of VL suppression and safety parameters in both mothers and infants. For the primary analysis, the two arms were matched 1:2 INSTI to PI based on the presence or absence of viremia at the time of pregnancy determination. Additional analysis was performed on the entire matched and unmatched dataset. Twenty-one patients were matched (7 INSTI and 14 PI). There were no significant differences between groups with respect to the proportion of patients with VL suppression prior to delivery (71.4% INSTI vs. 92.9% PI, p = 0.247), and there were no significant differences in any of the secondary endpoints. Patients with documented adherence issues were statistically more likely to not be virologically suppressed prior to delivery (p = 0.002). No differences in efficacy or safety were found between patients treated with INSTIs compared to PIs. This study supports the further investigation of the use of INSTIs during pregnancy to reduce HIV transmission.

Mutational analyses of the core domain of Avian Leukemia and Sarcoma Viruses integrase: critical residues for concerted integration and multimerization

International Nuclear Information System (INIS)

Moreau, Karen; Faure, Claudine; Violot, Sebastien; Gouet, Patrice; Verdier, Gerard; Ronfort, Corinne

2004-01-01

During replicative cycle of retroviruses, the reverse-transcribed viral DNA is integrated into the cell DNA by the viral integrase (IN) enzyme. The central core domain of IN contains the catalytic site of the enzyme and is involved in binding viral ends and cell DNA as well as dimerization. We previously performed single amino acid substitutions in the core domain of an Avian Leukemia and Sarcoma Virus (ALSV) IN [Arch. Virol. 147 (2002) 1761]. Here, we modeled the resulting IN mutants and analyzed the ability of these mutants to mediate concerted DNA integration in an in vitro assay, and to form dimers by protein-protein cross-linking and size exclusion chromatography. The N197C mutation resulted in the inability of the mutant to perform concerted integration that was concomitant with a loss of IN dimerization. Surprisingly, mutations Q102G and A106V at the dimer interface resulted in mutants with higher efficiencies than the wild-type IN in performing two-ended concerted integration of viral DNA ends. The G139D and A195V mutants had a trend to perform one-ended DNA integration of viral ends instead of two-ended integration. More drastically, the I88L and L135G mutants preferentially mediated nonconcerted DNA integration although the proteins form dimers. Therefore, these mutations may alter the formation of IN complexes of higher molecular size than a dimer that would be required for concerted integration. This study points to the important role of core domain residues in the concerted integration of viral DNA ends as well as in the oligomerization of the enzyme

A resolvase-like protein is requered for the site-specific integration of the temperate lactococcal bacteriophage TP901-1

DEFF Research Database (Denmark)

Christiansen, Bettina; Brøndsted, Lone; Vogensen, Finn K.

1996-01-01

upstream of attP. The N-terminal 150 to 1180 amino acids of Orf1 showed 38 to 44% similarity to the resolvase group of site-specific integrases, while no similarity to know proteins was found in the C-terminal end. Bacteriophage 'TP901-1 therefore contains a unique integration system that does not resemble...... the Int class of site-specific integrases usually found in temperate bacteriophages. The constructed integration vector, pBC170, integrates into the chromosomal attachment site very efficiently and forms stable transformants with a frequency corresponding to 20% of the transformation efficiency....

31 CFR 31.212 - Personal conflicts of interest.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Personal conflicts of interest. 31... RELIEF PROGRAM Conflicts of Interest § 31.212 Personal conflicts of interest. (a) Retained entity's... arrangement and key individuals have no personal conflicts of interest unless mitigation measures have...

10 CFR 1.31 - Office of the Chief Financial Officer.

Science.gov (United States)

2010-01-01

... management policy including accounting principles and standards for the agency and provides policy guidance... accounting and financial management system, including an accounting system, and financial reporting and... 10 Energy 1 2010-01-01 2010-01-01 false Office of the Chief Financial Officer. 1.31 Section 1.31...

Summaries of research and development activities by using JAEA computer system in FY2007. April 1, 2007 - March 31, 2008

International Nuclear Information System (INIS)

2008-11-01

Center for Computational Science and e-Systems (CCSE) of Japan Atomic Energy Agency (JAEA) installed large computer systems including super-computers in order to support research and development activities in JAEA. This report presents usage records of the JAEA computer system and the big users' research and development activities by using the computer system in FY2007 (April 1, 2007 - March 31, 2008). (author)

Summaries of research and development activities by using JAEA computer system in FY2009. April 1, 2009 - March 31, 2010

International Nuclear Information System (INIS)

2010-11-01

Center for Computational Science and e-Systems (CCSE) of Japan Atomic Energy Agency (JAEA) installed large computer systems including super-computers in order to support research and development activities in JAEA. This report presents usage records of the JAEA computer system and the big users' research and development activities by using the computer system in FY2009 (April 1, 2009 - March 31, 2010). (author)

Summaries of research and development activities by using JAERI computer system in FY2003. April 1, 2003 - March 31, 2004

International Nuclear Information System (INIS)

2005-03-01

Center for Promotion of Computational Science and Engineering (CCSE) of Japan Atomic Energy Research Institute (JAERI) installed large computer system included super-computers in order to support research and development activities in JAERI. CCSE operates and manages the computer system and network system. This report presents usage records of the JAERI computer system and big user's research and development activities by using the computer system in FY2003 (April 1, 2003 - March 31, 2004). (author)

Summaries of research and development activities by using JAEA computer system in FY2005. April 1, 2005 - March, 31, 2006

International Nuclear Information System (INIS)

2006-10-01

Center for Promotion of Computational Science and Engineering (CCSE) of Japan Atomic Energy Agency (JAEA) installed large computer systems including super-computers in order to support research and development activities in JAEA. CCSE operates and manages the computer system and network system. This report presents usage records of the JAERI computer system and the big users' research and development activities by using the computer system in FY2005 (April 1, 2005 - March 31, 2006). (author)

Summaries of research and development activities by using JAEA computer system in FY2006. April 1, 2006 - March 31, 2007

International Nuclear Information System (INIS)

2008-02-01

Center for Promotion of Computational Science and Engineering (CCSE) of Japan Atomic Energy Agency (JAEA) installed large computer systems including super-computers in order to support research and development activities in JAEA. CCSE operates and manages the computer system and network system. This report presents usage records of the JAEA computer system and the big users' research and development activities by using the computer system in FY2006 (April 1, 2006 - March 31, 2007). (author)

Mode of inhibition of HIV-1 Integrase by a C-terminal domain-specific monoclonal antibody*

Directory of Open Access Journals (Sweden)

Merkel George

2006-06-01

Full Text Available Abstract Background To further our understanding of the structure and function of HIV-1 integrase (IN we developed and characterized a library of monoclonal antibodies (mAbs directed against this protein. One of these antibodies, mAb33, which is specific for the C-terminal domain, was found to inhibit HIV-1 IN processing activity in vitro; a corresponding Fv fragment was able to inhibit HIV-1 integration in vivo. Our subsequent studies, using heteronuclear nuclear magnetic resonance spectroscopy, identified six solvent accessible residues on the surface of the C-terminal domain that were immobilized upon binding of the antibody, which were proposed to comprise the epitope. Here we test this hypothesis by measuring the affinity of mAb33 to HIV-1 proteins that contain Ala substitutions in each of these positions. To gain additional insight into the mode of inhibition we also measured the DNA binding capacity and enzymatic activities of the Ala substituted proteins. Results We found that Ala substitution of any one of five of the putative epitope residues, F223, R224, Y226, I267, and I268, caused a decrease in the affinity of the mAb33 for HIV-1 IN, confirming the prediction from NMR data. Although IN derivatives with Ala substitutions in or near the mAb33 epitope exhibited decreased enzymatic activity, none of the epitope substitutions compromised DNA binding to full length HIV-1 IN, as measured by surface plasmon resonance spectroscopy. Two of these derivatives, IN (I276A and IN (I267A/I268A, exhibited both increased DNA binding affinity and uncharacteristic dissociation kinetics; these proteins also exhibited non-specific nuclease activity. Results from these investigations are discussed in the context of current models for how the C-terminal domain interacts with substrate DNA. Conclusion It is unlikely that inhibition of HIV-1 IN activity by mAb33 is caused by direct interaction with residues that are essential for substrate binding. Rather

50 CFR 31.12 - Sale of wildlife specimens.

Science.gov (United States)

2010-10-01

... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Sale of wildlife specimens. 31.12 Section 31.12 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM WILDLIFE SPECIES MANAGEMENT Terms and Conditions of Wildlife...

48 CFR 52.232-31 - Invitation To Propose Financing Terms.

Science.gov (United States)

2010-10-01

... Financing Terms. 52.232-31 Section 52.232-31 Federal Acquisition Regulations System FEDERAL ACQUISITION... Clauses 52.232-31 Invitation To Propose Financing Terms. As prescribed in 32.205(b) and 32.206, insert the following provision: Invitation To Propose Financing Terms (OCT 1995) (a) The offeror is invited to propose...

Summaries of research and development activities by using JAERI computer system in FY2004 (April 1, 2004 - March 31, 2005)

International Nuclear Information System (INIS)

2005-08-01

Center for Promotion of Computational Science and Engineering (CCSE) of Japan Atomic Energy Research Institute (JAERI) installed large computer systems including super-computers in order to support research and development activities in JAERI. CCSE operates and manages the computer system and network system. This report presents usage records of the JAERI computer system and the big users' research and development activities by using the computer system in FY2004 (April 1, 2004 - March 31, 2005). (author)

48 CFR 31.205-11 - Depreciation.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Depreciation. 31.205-11....205-11 Depreciation. (a) Depreciation on a contractor's plant, equipment, and other capital facilities... method of depreciation or the class life asset depreciation range system is used, the residual value need...

Beta decay of 31,32Na and 31Mg

International Nuclear Information System (INIS)

Klotz, G.; Baumann, P.; Bounajma, M.; Huck, A.; Knipper, A.; Walter, G.; Poves, A.; Retamosa, J.

1993-01-01

31,32 Na and 31 Mg beta decays were studied at the CERN on-line mass separator ISOLDE by gamma, gamma-gamma and neutron-gamma measurements. In the 31 Na decay, the assignment of previously reported γ transitions and the observation of a new level at 3760 keV lead to a revised decay scheme. In the 31 Mg → 31 Al decay, a new decay scheme involves ten β branches and three states are reported for the first time. New spectroscopic results have been obtained in the 32 Na β - decay. A previously non-interpreted 1436 keV γ ray is now assigned in the 32 Mg scheme. (author) 33 refs., 16 figs., 12 tabs

31 CFR 356.31 - How does the STRIPS program work?

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false How does the STRIPS program work? 356.31 Section 356.31 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued...) Miscellaneous Provisions § 356.31 How does the STRIPS program work? (a) General. Notes or bonds may be “stripped...

A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75.

Directory of Open Access Journals (Sweden)

Stephen Hare

2009-01-01

Full Text Available Lens epithelium derived growth factor (LEDGF, also known as PC4 and SFRS1 interacting protein 1 (PSIP1 and transcriptional co-activator p75, is the cellular binding partner of lentiviral integrase (IN proteins. LEDGF accounts for the characteristic propensity of Lentivirus to integrate within active transcription units and is required for efficient viral replication. We now present a crystal structure containing the N-terminal and catalytic core domains (NTD and CCD of HIV-2 IN in complex with the IN binding domain (IBD of LEDGF. The structure extends the known IN-LEDGF interface, elucidating primarily charge-charge interactions between the NTD of IN and the IBD. A constellation of acidic residues on the NTD is characteristic of lentiviral INs, and mutations of the positively charged residues on the IBD severely affect interaction with all lentiviral INs tested. We show that the novel NTD-IBD contacts are critical for stimulation of concerted lentiviral DNA integration by LEDGF in vitro and for its function during the early steps of HIV-1 replication. Furthermore, the new structural details enabled us to engineer a mutant of HIV-1 IN that primarily functions only when presented with a complementary LEDGF mutant. These findings provide structural basis for the high affinity lentiviral IN-LEDGF interaction and pave the way for development of LEDGF-based targeting technologies for gene therapy.

Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing.

Science.gov (United States)

Hoyte, Ashley C; Jamin, Augusta V; Koneru, Pratibha C; Kobe, Matthew J; Larue, Ross C; Fuchs, James R; Engelman, Alan N; Kvaratskhelia, Mamuka

2017-12-01

The pyridine-based multimerization selective HIV-1 integrase (IN) inhibitors (MINIs) are a distinct subclass of allosteric IN inhibitors. MINIs potently inhibit HIV-1 replication during virion maturation by inducing hyper- or aberrant IN multimerization but are largely ineffective during the early steps of viral replication. Here, we investigated the mechanism for the evolution of a triple IN substitution (T124N/V165I/T174I) that emerges in cell culture with a representative MINI, KF116. We show that HIV-1 NL4-3(IN T124N/V165I/T174I) confers marked (>2000-fold) resistance to KF116. Two IN substitutions (T124N/T174I) directly weaken inhibitor binding at the dimer interface of the catalytic core domain but at the same time markedly impair HIV-1 replication capacity. Unexpectedly, T124N/T174I IN substitutions inhibited proteolytic processing of HIV-1 polyproteins Gag and Gag-Pol, resulting in immature virions. Strikingly, the addition of the third IN substitution (V165I) restored polyprotein processing, virus particle maturation, and significant levels of replication capacity. These results reveal an unanticipated role of IN for polyprotein proteolytic processing during virion morphogenesis. The complex evolutionary pathway for the emergence of resistant viruses, which includes the need for the compensatory V165I IN substitution, highlights a relatively high genetic barrier exerted by MINI KF116. Additionally, we have solved the X-ray structure of the drug-resistant catalytic core domain protein, which provides means for rational development of second-generation MINIs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Power systems development facility. Quarterly technical progress report, January 1, 1994--March 31, 1994

Energy Technology Data Exchange (ETDEWEB)

1994-07-01

This quarterly technical progress report summarizes work completed during the last quarter of the Second Budget Period, January 1 through March 31, 1994, entitled {open_quotes}Hot Gas Cleanup Test Facility for Gasification and Pressurized Combustion.{close_quotes} The objective of this project is to evaluate hot gas particulate control technologies using coal-derived gas streams. This will entail the design, construction, installation, and use of a flexible test facility which can operate under realistic gasification and combustion conditions. The major particulate control device issues to be addressed include the integration of the particulate control devices into coal utilization systems, on-line cleaning techniques, chemical and thermal degradation of components, fatigue or structural failures, blinding, collection efficiency as a function of particle size, and scale-up of particulate control systems to commercial size.

50 CFR 31.1 - Determination of surplus wildlife populations.

Science.gov (United States)

2010-10-01

... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Determination of surplus wildlife populations. 31.1 Section 31.1 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM WILDLIFE SPECIES MANAGEMENT Surplus...

SERF photovoltaic systems. Technical report on system performance for the period, August 1, 1994--July 31, 1995

Energy Technology Data Exchange (ETDEWEB)

Dyk, E.E. van; Strand, T.R.; Hansen, R.

1996-06-01

This report presents an analysis of performance data on the two identical, 6 kW{sub ac}, grid-connected photovoltaic systems located on the roof of the Solar Energy Research Facility building at the National Renewable Energy Laboratory in Golden, Colorado. The data cover the monitoring period August 1, 1994, to July 31, 1995, and the performance parameters analyzed include direct current and alternating current power, aperture-area efficiency, energy, capacity factor, and performance index. These parameters are compared to plane-of-array irradiance, ambient temperature, and back-of-module temperature as a function of time, either daily or monthly. We also obtained power ratings of the systems for data corresponding to different test conditions. This study has shown, in addition to expected seasonal trends, that system monitoring is a valuable tool in assessing performance and detecting faulty equipment. Furthermore, methods applied for this analysis may be used to evaluate and compare systems using cells of different technologies. The systems were both found to be operating at approximately 7% below their estimated rating, which was based on Photovoltaics for Utility-Scale Applications test conditions. This may be attributed to the design inverter efficiency being estimated at 95% compared to measured values of approximately 88%, as well as the fact that aperture-area efficiency that was overestimated at 12.8% compared to a measured value of 11.0%. The continuous monitoring also revealed faulty peak-power point tracking equipment.

X-31 Kiel Probe Side View

Science.gov (United States)

1993-01-01

A photograph of the noseboom on the X-31 shows the Kiel air data probe angled at 10 degrees to better align the tip with the airflow at very high angles of attack. The devices were mounted on the nose of the X-31s to measure air pressure. Icing in the unheated Kiel probe on the first X-31 (Bu. No. 164584), caused that aircraft to crash on January 19, 1995. The aircraft obtained data that may apply to the design and development of highly-maneuverable aircraft of the future. Each had a three-axis thrust-vectoring system, coupled with advanced flight controls, to allow it to maneuver tightly at very high angles of attack. The X-31 Enhanced Fighter Maneuverability (EFM) demonstrator flew at the Ames- Dryden Flight Research Facility, Edwards, California (redesignated the Dryden Flight Research Center in 1994) from February 1992 until 1995 and before that at the Air Force's Plant 42 in Palmdale, California. The goal of the project was to provide design information for the next generation of highly maneuverable fighter aircraft. This program demonstrated the value of using thrust vectoring (directing engine exhaust flow) coupled with an advanced flight control system to provide controlled flight to very high angles of attack. The result was a significant advantage over most conventional fighters in close-in combat situations. The X-31 flight program focused on agile flight within the post-stall regime, producing technical data to give aircraft designers a better understanding of aerodynamics, effectiveness of flight controls and thrust vectoring, and airflow phenomena at high angles of attack. Stall is a condition of an airplane or an airfoil in which lift decreases and drag increases due to the separation of airflow. Thrust vectoring compensates for the loss of control through normal aerodynamic surfaces that occurs during a stall. Post-stall refers to flying beyond the normal stall angle of attack, which in the X-31 was at a 30-degree angle of attack. During Dryden

Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV.

Directory of Open Access Journals (Sweden)

Anneleen Hombrouck

2007-03-01

Full Text Available Retroviruses by definition insert their viral genome into the host cell chromosome. Although the key player of retroviral integration is viral integrase, a role for cellular cofactors has been proposed. Lentiviral integrases use the cellular protein LEDGF/p75 to tether the preintegration complex to the chromosome, although the existence of alternative host proteins substituting for the function of LEDGF/p75 in integration has been proposed. Truncation mutants of LEDGF/p75 lacking the chromosome attachment site strongly inhibit HIV replication by competition for the interaction with integrase. In an attempt to select HIV strains that can overcome the inhibition, we now have used T-cell lines that stably express a C-terminal fragment of LEDGF/p75. Despite resistance development, the affinity of integrase for LEDGF/p75 is reduced and replication kinetics in human primary T cells is impaired. Detection of the integrase mutations A128T and E170G at key positions in the LEDGF/p75-integrase interface provides in vivo evidence for previously reported crystallographic data. Moreover, the complementary inhibition by LEDGF/p75 knockdown and mutagenesis at the integrase-LEDGF/p75 interface points to the incapability of HIV to circumvent LEDGF/p75 function during proviral integration. Altogether, the data provide a striking example of the power of viral molecular evolution. The results underline the importance of the LEDGF/p75 HIV-1 interplay as target for innovative antiviral therapy. Moreover, the role of LEDGF/p75 in targeting integration will stimulate research on strategies to direct gene therapy vectors into safe landing sites.

31 CFR 357.27 - Reinvestment.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Reinvestment. 357.27 Section 357.27 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE... AND BILLS HELD IN LEGACY TREASURY DIRECT Legacy Treasury Direct Book-Entry Securities System (Legacy...

Remaining Sites Verification Package for the 100-F-31, 144-F Sanitary Sewer System, Waste Site Reclassification Form 2006-033

Energy Technology Data Exchange (ETDEWEB)

L. M. Dittmer

2006-08-24

The 100-F-31 waste site is a former septic system that supported the inhalation laboratories, also referred to as the 144-F Particle Exposure Laboratory (132-F-2 waste site), which housed animals exposed to particulate material. The 100-F-31 waste site has been remediated to achieve the remedial action objectives specified in the Remaining Sites ROD. The results of verification sampling show that residual contaminant concentrations do not preclude any future uses and allow for unrestricted use of shallow zone soils. The results also demonstrate that residual contaminant concentrations are protective of groundwater and the Columbia River.

Development of pharmacophore similarity-based quantitative activity hypothesis and its applicability domain: applied on a diverse data-set of HIV-1 integrase inhibitors.

Science.gov (United States)

Kumar, Sivakumar Prasanth; Jasrai, Yogesh T; Mehta, Vijay P; Pandya, Himanshu A

2015-01-01

Quantitative pharmacophore hypothesis combines the 3D spatial arrangement of pharmacophore features with biological activities of the ligand data-set and predicts the activities of geometrically and/or pharmacophoric similar ligands. Most pharmacophore discovery programs face difficulties in conformational flexibility, molecular alignment, pharmacophore features sampling, and feature selection to score models if the data-set constitutes diverse ligands. Towards this focus, we describe a ligand-based computational procedure to introduce flexibility in aligning the small molecules and generating a pharmacophore hypothesis without geometrical constraints to define pharmacophore space, enriched with chemical features necessary to elucidate common pharmacophore hypotheses (CPHs). Maximal common substructure (MCS)-based alignment method was adopted to guide the alignment of carbon molecules, deciphered the MCS atom connectivity to cluster molecules in bins and subsequently, calculated the pharmacophore similarity matrix with the bin-specific reference molecules. After alignment, the carbon molecules were enriched with original atoms in their respective positions and conventional pharmacophore features were perceived. Distance-based pharmacophoric descriptors were enumerated by computing the interdistance between perceived features and MCS-aligned 'centroid' position. The descriptor set and biological activities were used to develop support vector machine models to predict the activities of the external test set. Finally, fitness score was estimated based on pharmacophore similarity with its bin-specific reference molecules to recognize the best and poor alignments and, also with each reference molecule to predict outliers of the quantitative hypothesis model. We applied this procedure to a diverse data-set of 40 HIV-1 integrase inhibitors and discussed its effectiveness with the reported CPH model.

Inducing indel mutation in the SOX6 gene by zinc finger nuclease for gamma reactivation: An approach towards gene therapy of beta thalassemia.

Science.gov (United States)

Modares Sadeghi, Mehran; Shariati, Laleh; Hejazi, Zahra; Shahbazi, Mansoureh; Tabatabaiefar, Mohammad Amin; Khanahmad, Hossein

2018-03-01

β-thalassemia is a common autosomal recessive disorder characterized by a deficiency in the synthesis of β-chains. Evidences show that increased HbF levels improve the symptoms in patients with β-thalassemia or sickle cell anemia. In this study, ZFN technology was applied to induce a mutation in the binding domain region of SOX6 to reactivate γ-globin expression. The sequences coding for ZFP arrays were designed and sub cloned in TDH plus as a transfer vector. The ZFN expression was confirmed using Western blot analysis. In the next step, using the site-directed mutagenesis strategy through the overlap PCR, a missense mutation (D64V) was induced in the catalytic domain of the integrase gene in the packaging plasmid and verified using DNA sequencing. Then, the integrase minus lentivirus containing ZFN cassette was packaged. Transduction of K562 cells with this virus was performed. Mutation detection assay was performed. The indel percentage of the cells transducted with lenti virus containing ZFN was 31%. After 5 days of erythroid differentiation with 15 μg/mL cisplatin, the levels of γ-globin mRNA were sixfold in the cells treated with ZFN compared to untreated cells. In the meantime, the measurement of HbF expression levels was carried out using hemoglobin electrophoresis and showed the same results. Integrase minus lentivirus can provide a useful tool for efficient transient gene expression and helps avoid disadvantages of gene targeting using the native virus. The ZFN strategy applied here to induce indel on SOX6 gene in adult erythroid progenitors may provide a method to activate fetal hemoglobin expression in individuals with β-thalassemia. © 2017 Wiley Periodicals, Inc.

Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor-based regimen: week 24 phase 3 results from VIKING-3

Science.gov (United States)

Nichols, G; Mills, A; Grossberg, R; Lazzarin, A; Maggiolo, F; Molina, J; Pialoux, G; Wright, D; Ait-Khaled, M; Huang, J; Vavro, C; Wynne, B; Yeo, J

2012-01-01

Background VIKING-3 aimed to examine efficacy and safety of dolutegravir (DTG) 50 mg twice daily in patients with resistance to multiple ARV classes, including integrase inhibitors (INI). Methods RAL and/or EVG-resistant (current or historical) adult subjects with screening plasma HIV-1 RNA ≥500 c/mL and resistance to ≥2 other ART classes received open-label DTG 50 mg BID while continuing their failing regimen (without RAL/EVG). At Day 8 the background regimen was optimised and DTG continued. Activity of the optimized background regimen (OBR) was determined by Monogram Net Assessment. Primary endpoints were antiviral efficacy at Day 8 and Week 24. Results 183 subjects enrolled, 124 with INI-resistance at screening and 59 with historical (but no screening) resistance. Population was advanced: at BL, median CD4 140, prior ART 13 yrs, 56% CDC Class C; 79% had >2 NRTI, 75% >1 NNRTI, and 70% >2 PI resistance-associated mutations, and 61% had non-R5 HIV detected. Of the 114 subjects who had the opportunity to complete 24 weeks on study before data cutoff, 72 (63%) had 1 log HIV RNA decline of 2, respectively. Discontinuations due to adverse events were uncommon (6/183, 3%); the most common drug-related AEs were diarrhoea, nausea and headache, each reported in only 5% of subjects. Conclusion A majority of the highly treatment-experienced subjects in VIKING-3 achieved suppression with DTG-based therapy. Responses were associated with Baseline IN genotype but not OSS, highlighting the importance and independence of DTG antiviral activity. DTG had a low rate of discontinuation due to adverse events at 50 mg BID in this advanced patient population.

Potential benefit of dolutegravir once daily: efficacy and safety

Directory of Open Access Journals (Sweden)

Fantauzzi A

2013-02-01

Full Text Available Alessandra Fantauzzi,1 Ombretta Turriziani,2 Ivano Mezzaroma11Department of Clinical Medicine, 2Department of Molecular Medicine, Sapienza, University of Rome, Rome, ItalyAbstract: The viral integrase enzyme has recently emerged as a primary alternative target to block HIV-1 replication, and integrase inhibitors are considered a pivotal new class of antiretroviral drugs. Dolutegravir is an investigational next-generation integrase inhibitor showing some novel and intriguing characteristics, ie, it has a favorable pharmacokinetic profile with a prolonged intracellular half-life, rendering feasible once-daily dosing without the need for ritonavir boosting and without regard to meals. Moreover, dolutegravir is primarily metabolized via uridine diphosphate glucuronosyltranferase 1A1, with a minor component of the cytochrome P450 3A4 isoform, thereby limiting drug–drug interactions. Furthermore, its metabolic profile enables coadministration with most of the other available antiretroviral agents without dose adjustment. Recent findings also demonstrate that dolutegravir has significant activity against HIV-1 isolates with resistance mutations associated with raltegravir and/or elvitegravir. The attributes of once-daily administration and the potential to treat integrase inhibitor-resistant viruses make dolutegravir an interesting and promising investigational drug. In this review, the main concerns about the efficacy and safety of dolutegravir as well as its resistance profile are explored by analysis of currently available data from preclinical and clinical studies.Keywords: antiretroviral drugs, HIV-1 integrase, integrase inhibitors, dolutegravir, once daily

SWAT3.1 - the integrated burnup code system driving continuous energy Monte Carlo codes MVP and MCNP

International Nuclear Information System (INIS)

Suyama, Kenya; Mochizuki, Hiroki; Takada, Tomoyuki; Ryufuku, Susumu; Okuno, Hiroshi; Murazaki, Minoru; Ohkubo, Kiyoshi

2009-05-01

Integrated burnup calculation code system SWAT is a system that combines neutronics calculation code SRAC,which is widely used in Japan, and point burnup calculation code ORIGEN2. It has been used to evaluate the composition of the uranium, plutonium, minor actinides and the fission products in the spent nuclear fuel. Based on this idea, the integrated burnup calculation code system SWAT3.1 was developed by combining the continuous energy Monte Carlo code MVP and MCNP, and ORIGEN2. This enables us to treat the arbitrary fuel geometry and to generate the effective cross section data to be used in the burnup calculation with few approximations. This report describes the outline, input data instruction and several examples of the calculation. (author)

31 CFR 31.211 - Organizational conflicts of interest.

Science.gov (United States)

2010-07-01

... conflict may depend on a variety of factors, including the type of conflict, the scope of work under the... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Organizational conflicts of interest... ASSET RELIEF PROGRAM Conflicts of Interest § 31.211 Organizational conflicts of interest. (a) Retained...

48 CFR 31.002 - Availability of accounting guide.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Availability of accounting... GENERAL CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES 31.002 Availability of accounting guide. Contractors needing assistance in developing or improving their accounting systems and procedures...

Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

International Nuclear Information System (INIS)

Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet; Quistgaard, Esben M.; Nordlund, Par; Thanabalu, Thirumaran; Torres, Jaume

2015-01-01

The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target

Interaction between human BAP31 and respiratory syncytial virus small hydrophobic (SH) protein

Energy Technology Data Exchange (ETDEWEB)

Li, Yan; Jain, Neeraj; Limpanawat, Suweeraya; To, Janet [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Quistgaard, Esben M. [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm (Sweden); Nordlund, Par [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm (Sweden); Thanabalu, Thirumaran [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore); Torres, Jaume, E-mail: jtorres@ntu.edu.sg [School of Biological Sciences, Nanyang Technological University, 637551 (Singapore)

2015-08-15

The small hydrophobic (SH) protein is a short channel-forming polypeptide encoded by the human respiratory syncytial virus (hRSV). Deletion of SH protein leads to the viral attenuation in mice and primates, and delayed apoptosis in infected cells. We have used a membrane-based yeast two-hybrid system (MbY2H) and a library from human lung cDNA to detect proteins that bind SH protein. This led to the identification of a membrane protein, B-cell associated protein 31 (BAP31). Transfected SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. Titration of purified C-terminal endodomain of BAP31 against isotopically labeled SH protein in detergent micelles suggests direct interaction between the two proteins. Given the key role of BAP31 in protein trafficking and its critical involvement in pro- and anti-apoptotic pathways, this novel interaction may constitute a potential drug target. - Highlights: • A yeast two-hybrid system (MbY2H) detected BAP31 as a binder of RSV SH protein. • Transfected SH and BAP31 co-localize in lung epithelial cells. • Endogenous BAP31 is pulled down by RSV SH protein. • BAP31 endodomain interacts with the N-terminal α-helix of SH protein in micelles. • This interaction is proposed to be a potential drug target.

31 CFR 357.28 - Transaction requests.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Transaction requests. 357.28 Section 357.28 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL... System (Legacy Treasury Direct) § 357.28 Transaction requests. (a) General. Unless otherwise authorized...

31 CFR 357.25 - Security interests.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Security interests. 357.25 Section 357.25 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL... System (Legacy Treasury Direct) § 357.25 Security interests. (a) General. The Department will not...

Improvement of FK506 Production in Streptomyces tsukubaensis by Genetic Enhancement of the Supply of Unusual Polyketide Extender Units via Utilization of Two Distinct Site-Specific Recombination Systems

Science.gov (United States)

Chen, Dandan; Zhang, Qi; Zhang, Qinglin; Cen, Peilin

2012-01-01

FK506 is a potent immunosuppressant that has a wide range of clinical applications. Its 23-member macrocyclic scaffold, mainly with a polyketide origin, features two methoxy groups at C-13 and C-15 and one allyl side chain at C-21, due to the region-specific incorporation of two unusual extender units derived from methoxymalonyl-acyl carrier protein (ACP) and allylmalonyl-coenzyme A (CoA), respectively. Whether their intracellular formations can be a bottleneck for FK506 production remains elusive. In this study, we report the improvement of FK506 yield in the producing strain Streptomyces tsukubaensis by the duplication of two sets of pathway-specific genes individually encoding the biosyntheses of these two extender units, thereby providing a promising approach to generate high-FK506-producing strains via genetic manipulation. Taking advantage of the fact that S. tsukubaensis is amenable to two actinophage (ΦC31 and VWB) integrase-mediated recombination systems, we genetically enhanced the biosyntheses of methoxymalonyl-ACP and allylmalonyl-CoA, as indicated by transcriptional analysis. Together with the optimization of glucose supplementation, the maximal FK506 titer eventually increased by approximately 150% in comparison with that of the original strain. The strategy of engineering the biosynthesis of unusual extender units described here may be applicable to improving the production of other polyketide or nonribosomal peptide natural products that contain pathway-specific building blocks. PMID:22582065

31 CFR 357.26 - Direct Deposit.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Direct Deposit. 357.26 Section 357.26 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE... AND BILLS HELD IN LEGACY TREASURY DIRECT Legacy Treasury Direct Book-Entry Securities System (Legacy...

31 CFR 800.208 - Critical infrastructure.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Critical infrastructure. 800.208 Section 800.208 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... infrastructure means, in the context of a particular covered transaction, a system or asset, whether physical or...

31 CFR 337.7 - Servicing transactions.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Servicing transactions. 337.7 Section 337.7 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE...-entry debenture system, to be announced in advance by separate public notice, any transfer or...

5-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integrase.

Science.gov (United States)

Sun, Lin; Gao, Ping; Dong, Guanyu; Zhang, Xujie; Cheng, Xiqiang; Ding, Xiao; Wang, Xueshun; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Menéndez-Arias, Luis; Zhan, Peng; Liu, Xinyong

2018-06-18

We reported herein the design, synthesis and biological evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as HIV-1 reverse transcriptase (RT) ribonuclease H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, we also performed IN inhibition assays. Notably, the majority of these derivatives inhibited RNase H and IN at micromolar concentrations. Among them, compound 7a exhibited similar inhibitory activity against RNase H and IN (IC 50 RNase H  = 1.77 μM, IC 50 IN  = 1.18 μM, ratio = 1.50). To the best of our knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Molecular modeling has been used to predict the binding mode of 7a in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compounds appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 molecules with suitable drug profiles. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Decontamination systems information and research program. Quarterly report, January 1--March 31, 1997

Energy Technology Data Exchange (ETDEWEB)

NONE

1997-12-31

Progress reports are given on the following projects: (A) Subsurface contaminants, containment and remediation: 1.1 Characteristic evaluation of grout barriers in grout testing chamber; 1.2 Development of standard test protocols and barrier design models for desiccation barriers; 1.3 Development of standard test protocols and barrier design models for in-situ formed barriers -- technical support; 1.4 Laboratory studies and field testing at the DOE/RMI Extrusion Plant (Ashtabula, Ohio); 1.5 Use of drained enhanced soil flushing for contaminants removal; (B) Mixed waste characterization, treatment and disposal: Analysis of the Vortec cyclone melting system for remediation of PCB contaminated soils using computational fluid dynamics; (C) Decontamination and decommissioning: 3.1 Production and evaluation of biosorbents and cleaning solutions for use in D and D; 3.2 Use of Spintek centrifugal membrane technology and sorbents/cleaning solutions in the D and D of DOE facilities; (D) Cross-cutting innovative technologies: 4.1 Use of centrifugal membrane technology with novel membranes to treat hazardous/radioactive wastes; 4.2 Environmental pollution control devices based on novel forms of carbon; 4.3 Design of rotating membrane filtration system for remediation technologies; and (E) Outreach: Small business technical based support.

[Isolation and identification of the temperate bacteriophage from isolated strains of Streptococcus suis serotype 2].

Science.gov (United States)

Ma, Yuling; Lu, Chengping; Fan, Hongjie

2008-04-01

A PCR assay was developed to study the distributional characteristics of phage integrase gene in Streptococcus suis serotype 2 (SS2). A 323bp distinct DNA target can be amplified in 25 strains of virulent SS2, while can not be amplified in avirulent strain T15, 5 strains of other serotypes (SS1, SS7, SS9) and strains of group C Streptococcus strains from pigs, which suggested that the phage integrase gene may be related to the pathogenicity of SS2 and can be consider as a detection factor of the virulent gene of SS2. The sequencing and restriction endonuclease analysis of the PCR products were also done. Comparisons between the sequences of phage integrase gene with that of SS2 strain, showed a high homology with SS2 China strains 98HAH33, 05ZYH33 and North American strain 89-1591. Complete cell lysis was observed with SS2 virulent strains but not with avirulent strain T15 after the induction by mitomycin C. Electron microscopy analysis of the lysate from SS2 virulent strains HA9801 and ZY05719 revealed the presence of phage particles. The induced phage, named SS2-HA and SS2-ZY, both have a small isometric nucleocapsid approximately 50 nm in diameter and have no tail and is therefore a member of the Tectiviridae family. The phage integrase gene sequence of phage SS2-HA and SS2-ZY shared high homologue identities with virulent SS2 strains, which suggested that the phage integrase gene of SS2 has high specify. The temperate phage and phage integrase gene can only detected from SS2 virulent strains but not from avirulent strain, and the detection of phage integrase gene was related to the virulence-associate factors of SS2, such as the muramidase-released protein gene (mrp), which suggested that the temperate phage of SS2 may be related to the pathogenicity of SS2.

Labeling of multiple HIV-1 proteins with the biarsenical-tetracysteine system.

Directory of Open Access Journals (Sweden)

Cândida F Pereira

Full Text Available Due to its small size and versatility, the biarsenical-tetracysteine system is an attractive way to label viral proteins for live cell imaging. This study describes the genetic labeling of the human immunodeficiency virus type 1 (HIV-1 structural proteins (matrix, capsid and nucleocapsid, enzymes (protease, reverse transcriptase, RNAse H and integrase and envelope glycoprotein 120 with a tetracysteine tag in the context of a full-length virus. We measure the impact of these modifications on the natural virus infection and, most importantly, present the first infectious HIV-1 construct containing a fluorescently-labeled nucleocapsid protein. Furthermore, due to the high background levels normally associated with the labeling of tetracysteine-tagged proteins we have also optimized a metabolic labeling system that produces infectious virus containing the natural envelope glycoproteins and specifically labeled tetracysteine-tagged proteins that can easily be detected after virus infection of T-lymphocytes. This approach can be adapted to other viral systems for the visualization of the interplay between virus and host cell during infection.

Evaluation of the effect of short-term treatment with the integrase inhibitor raltegravir (Isentress) on the course of progressive feline leukemia virus infection.

Science.gov (United States)

Boesch, Andrea; Cattori, Valentino; Riond, Barbara; Willi, Barbara; Meli, Marina L; Rentsch, Katharina M; Hosie, Margaret J; Hofmann-Lehmann, Regina; Lutz, Hans

2015-02-25

Cats persistently infected with the gammaretrovirus feline leukemia virus (FeLV) are at risk to die within months to years from FeLV-associated disease, such as immunosuppression, anemia or lymphoma/leukemia. The integrase inhibitor raltegravir has been demonstrated to reduce FeLV replication in vitro. The aim of the present study was to investigate raltegravir in vivo for its safety and efficacy to suppress FeLV replication. The safety was tested in three naïve specified pathogen-free (SPF) cats during a 15 weeks treatment period (initially 20mg then 40mg orally b.i.d.). No adverse effects were noted. The efficacy was tested in seven persistently FeLV-infected SPF cats attained from 18 cats experimentally exposed to FeLV-A/Glasgow-1. The seven cats were treated during nine weeks (40mg then 80mg b.i.d.). Raltegravir was well tolerated even at the higher dose. A significant decrease in plasma viral RNA loads (∼5×) was found; however, after treatment termination a rebound effect was observed. Only one cat developed anti-FeLV antibodies and viral RNA loads remained decreased after treatment termination. Of note, one of the untreated FeLV-A infected cats developed fatal FeLV-C associated anemia within 5 weeks of FeLV-A infection. Moreover, progressive FeLV infection was associated with significantly lower enFeLV loads prior to infection supporting that FeLV susceptibility may be related to the genetic background of the cat. Overall, our data demonstrate the ability of raltegravir to reduce viral replication also in vivo. However, no complete control of viremia was achieved. Further investigations are needed to find an optimized treatment against FeLV. (250 words). Copyright © 2014 Elsevier B.V. All rights reserved.

The Himalayas revisited

Digital Repository Service at National Institute of Oceanography (India)

Iyer, S.D.; Mukhopadhyay, R.

- crystallization and grain boun d ary migration occurring simultaneously in different minerals from several regions in the Hi malayas; the process appears to be repeated in cyclic order during progre s- sive deformation. R. Islam and others found ophiolitic... may have fine - tuned the geomagnetic inversion of the metamorphic sequence, advo cating the theory of post - metamor - phic tectonic modification. Considering the large - scale tecto nic activities and associated metamorphism...

31 CFR 0.216 - Privacy Act.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Privacy Act. 0.216 Section 0.216... RULES OF CONDUCT Rules of Conduct § 0.216 Privacy Act. Employees involved in the design, development, operation, or maintenance of any system of records or in maintaining records subject to the Privacy Act of...

Metrological 2iOF fibre-optic system for position and displacement measurement with 31 pm resolution

Science.gov (United States)

Orłowska, Karolina; Świåtkowski, Michał; Kunicki, Piotr; Gotszalk, Teodor

2018-04-01

In the present paper, we describe a high sensitivity intensity fibre-optic displacement sensor with tens of picometre resolution combined with a sub-picometre resolution interferometric calibration system. Both integrated components form the so-called "2 in one ferrule" system 2iOF. The design and construction of the presented device depend on integrating two sensors' systems within one fibre-optic measuring head, which allows performing in situ calibration process with no additional time-consuming adjustment procedure. The resolution of the 2iOF system is 31 pm/Hz1/2 obtained with an interferometric Fabry-Perot based calibration system—providing accuracy better than tens of fm/Hz1/2 within 1 MHz bandwidth in the measurement range of up to 100 μm. The direct response from the intensity sensor is then the 2iOF output one. It is faster and more convenient to analyze in comparison, with much better resolution (3 orders of magnitude higher) but on the other hand also more time consuming and dependent on the absolute sample position interferometer. The proposed system is flexible and open to various applications. We will present the results of the piezoelectrical actuator displacement measurements, which were performed using the developed system.

Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling.

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Artico, M; Di Santo, R; Costi, R; Novellino, E; Greco, G; Massa, S; Tramontano, E; Marongiu, M E; De Montis, A; La Colla, P

1998-10-08

Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the

Ab Initio Calculations of 31P NMR Chemical Shielding Anisotropy Tensors in Phosphates: Variations Due to Ring Formation

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Todd M. Alam

2002-08-01

Full Text Available Abstract: Ring formation in phosphate systems is expected to influence both the magnitude and orientation of the phosphorus (31P nuclear magnetic resonance (NMR chemical shielding anisotropy (CSA tensor. Ab initio calculations of the 31P CSA tensor in both cyclic and acyclic phosphate clusters were performed as a function of the number of phosphate tetrahedral in the system. The calculation of the 31P CSA tensors employed the GAUSSIAN 98 implementation of the gauge-including atomic orbital (GIAO method at the Hartree-Fock (HF level. It is shown that both the 31P CSA tensor anisotropy, and the isotropic chemical shielding can be used for the identification of cyclic phosphates. The differences between the 31P CSA tensor in acyclic and cyclic phosphate systems become less pronounced with increasing number of phosphate groups within the ring. The orientation of the principal components for the 31P CSA tensor shows some variation due to cyclization, most notably with the smaller, highly strained ring systems.

Measuring the total and baryonic mass profiles of the very massive CASSOWARY 31 strong lens

DEFF Research Database (Denmark)

Grillo, Claudio; Christensen, L.; Gallazzi, A.

2013-01-01

We investigate the total and baryonic mass distributions in deflector number 31 (CSWA 31) of the Cambridge And Sloan Survey Of Wide ARcs in the skY (CASSOWARY). We confirm spectroscopically a four-image lensing system at redshift 1.4870 with Very Large Telescope/X-shooter observations. The lensed...... find that the CSWA 31 deflector has properties suggesting it to be among the most distant and massive fossil systems studied so far. The unusually strong central dark matter dominance and the possible fossil nature of this system render it an interesting target for detailed tests of cosmological models...

Incorporation of aptamers in the terminal loop of shRNAs yields an effective and novel combinatorial targeting strategy.

Science.gov (United States)

Pang, Ka Ming; Castanotto, Daniela; Li, Haitang; Scherer, Lisa; Rossi, John J

2018-01-09

Gene therapy by engineering patient's own blood cells to confer HIV resistance can potentially lead to a functional cure for AIDS. Toward this goal, we have previously developed an anti-HIV lentivirus vector that deploys a combination of shRNA, ribozyme and RNA decoy. To further improve this therapeutic vector against viral escape, we sought an additional reagent to target HIV integrase. Here, we report the development of a new strategy for selection and expression of aptamer for gene therapy. We developed a SELEX protocol (multi-tag SELEX) for selecting RNA aptamers against proteins with low solubility or stability, such as integrase. More importantly, we expressed these aptamers in vivo by incorporating them in the terminal loop of shRNAs. This novel strategy allowed efficient expression of the shRNA-aptamer fusions that targeted RNAs and proteins simultaneously. Expressed shRNA-aptamer fusions targeting HIV integrase or reverse transcriptase inhibited HIV replication in cell cultures. Viral inhibition was further enhanced by combining an anti-integrase aptamer with an anti-HIV Tat-Rev shRNA. This construct exhibited efficacy comparable to that of integrase inhibitor Raltegravir. Our strategy for the selection and expression of RNA aptamers can potentially extend to other gene therapy applications. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Gene Expression in Class 2 Integrons Is SOS-Independent and Involves Two Pc Promoters.

Science.gov (United States)

Jové, Thomas; Da Re, Sandra; Tabesse, Aurore; Gassama-Sow, Amy; Ploy, Marie-Cécile

2017-01-01

Integrons are powerful bacterial genetic elements that permit the expression and dissemination of antibiotic-resistance gene cassettes. They contain a promoter Pc that allows the expression of gene cassettes captured through site-specific recombination catalyzed by IntI, the integron-encoded integrase. Class 1 and 2 integrons are found in both clinical and environmental settings. The regulation of intI and of Pc promoters has been extensively studied in class 1 integrons and the regulatory role of the SOS response on intI expression has been shown. Here we investigated class 2 integrons. We characterized the P intI2 promoter and showed that intI2 expression is not regulated via the SOS response. We also showed that, unlike class 1 integrons, class 2 integrons possess not one but two active Pc promoters that are located within the attI2 region that seem to contribute equally to gene cassette expression. Class 2 integrons mostly encode an inactive truncated integrase, but the rare class 2 integrons that encode an active integrase are associated with less efficient Pc2 promoter variants. We propose an evolutionary model for class 2 integrons in which the absence of repression of the integrase gene expression led to mutations resulting in either inactive integrase or Pc variants of weaker activity, thereby reducing the potential fitness cost of these integrons.

Comparison of (31)P saturation and inversion magnetization transfer in human liver and skeletal muscle using a clinical MR system and surface coils.

Science.gov (United States)

Buehler, Tania; Kreis, Roland; Boesch, Chris

2015-02-01

(31)P MRS magnetization transfer ((31)P-MT) experiments allow the estimation of exchange rates of biochemical reactions, such as the creatine kinase equilibrium and adenosine triphosphate (ATP) synthesis. Although various (31)P-MT methods have been successfully used on isolated organs or animals, their application on humans in clinical scanners poses specific challenges. This study compared two major (31)P-MT methods on a clinical MR system using heteronuclear surface coils. Although saturation transfer (ST) is the most commonly used (31)P-MT method, sequences such as inversion transfer (IT) with short pulses might be better suited for the specific hardware and software limitations of a clinical scanner. In addition, small NMR-undetectable metabolite pools can transfer MT to NMR-visible pools during long saturation pulses, which is prevented with short pulses. (31)P-MT sequences were adapted for limited pulse length, for heteronuclear transmit-receive surface coils with inhomogeneous B1 , for the need for volume selection and for the inherently low signal-to-noise ratio (SNR) on a clinical 3-T MR system. The ST and IT sequences were applied to skeletal muscle and liver in 10 healthy volunteers. Monte-Carlo simulations were used to evaluate the behavior of the IT measurements with increasing imperfections. In skeletal muscle of the thigh, ATP synthesis resulted in forward reaction constants (k) of 0.074 ± 0.022 s(-1) (ST) and 0.137 ± 0.042 s(-1) (IT), whereas the creatine kinase reaction yielded 0.459 ± 0.089 s(-1) (IT). In the liver, ATP synthesis resulted in k = 0.267 ± 0.106 s(-1) (ST), whereas the IT experiment yielded no consistent results. ST results were close to literature values; however, the IT results were either much larger than the corresponding ST values and/or were widely scattered. To summarize, ST and IT experiments can both be implemented on a clinical body scanner with heteronuclear transmit-receive surface coils; however, ST results are

Contribution of the C-terminal tri-lysine regions of human immunodeficiency virus type 1 integrase for efficient reverse transcription and viral DNA nuclear import

Directory of Open Access Journals (Sweden)

Fowke Keith R

2005-10-01

Full Text Available Abstract Background In addition to mediating the integration process, HIV-1 integrase (IN has also been implicated in different steps during viral life cycle including reverse transcription and viral DNA nuclear import. Although the karyophilic property of HIV-1 IN has been well demonstrated using a variety of experimental approaches, the definition of domain(s and/or motif(s within the protein that mediate viral DNA nuclear import and its mechanism are still disputed and controversial. In this study, we performed mutagenic analyses to investigate the contribution of different regions in the C-terminal domain of HIV-1 IN to protein nuclear localization as well as their effects on virus infection. Results Our analysis showed that replacing lysine residues in two highly conserved tri-lysine regions, which are located within previously described Region C (235WKGPAKLLWKGEGAVV and sequence Q (211KELQKQITK in the C-terminal domain of HIV-1 IN, impaired protein nuclear accumulation, while mutations for RK263,4 had no significant effect. Analysis of their effects on viral infection in a VSV-G pseudotyped RT/IN trans-complemented HIV-1 single cycle replication system revealed that all three C-terminal mutant viruses (KK215,9AA, KK240,4AE and RK263,4AA exhibited more severe defect of induction of β-Gal positive cells and luciferase activity than an IN class 1 mutant D64E in HeLa-CD4-CCR5-β-Gal cells, and in dividing as well as non-dividing C8166 T cells, suggesting that some viral defects are occurring prior to viral integration. Furthermore, by analyzing viral DNA synthesis and the nucleus-associated viral DNA level, the results clearly showed that, although all three C-terminal mutants inhibited viral reverse transcription to different extents, the KK240,4AE mutant exhibited most profound effect on this step, whereas KK215,9AA significantly impaired viral DNA nuclear import. In addition, our analysis could not detect viral DNA integration in each C

1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor.

Science.gov (United States)

Gu, Wan-gang; Ip, Denis Tsz-Ming; Liu, Si-jie; Chan, Joseph H; Wang, Yan; Zhang, Xuan; Zheng, Yong-tang; Wan, David Chi-Cheong

2014-04-25

Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1 μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19 μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery. Copyright © 2014. Published by Elsevier Ireland Ltd.

40 CFR 260.31 - Standards and criteria for variances from classification as a solid waste.

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2010-07-01

... from classification as a solid waste. 260.31 Section 260.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) HAZARDOUS WASTE MANAGEMENT SYSTEM: GENERAL Rulemaking Petitions § 260.31 Standards and criteria for variances from classification as a solid waste. (a) The...

X-31 Kiel Probe Close-up Showing Inside

Science.gov (United States)

1993-01-01

A close-up photograph of the Kiel air data probe on the noseboom on the X-31 aircraft shows the orifices used to collect air pressure measurements. Icing in the unheated Kiel probe on the first X-31 (Bu. No. 164584) caused that aircraft to crash. The aircraft obtained data that may apply to the design and development of highly-maneuverable aircraft of the future. Each has a three-axis thrust-vectoring system, coupled with advanced flight controls, to allow it to maneuver tightly at very high angles of attack. The X-31 Enhanced Fighter Maneuverability (EFM) demonstrator flew at the Ames- Dryden Flight Research Facility, Edwards, California (redesignated the Dryden Flight Research Center in 1994) from February 1992 until 1995 and before that at the Air Force's Plant 42 in Palmdale, California. The goal of the project was to provide design information for the next generation of highly maneuverable fighter aircraft. This program demonstrated the value of using thrust vectoring (directing engine exhaust flow) coupled with an advanced flight control system to provide controlled flight to very high angles of attack. The result was a significant advantage over most conventional fighters in close-in combat situations. The X-31 flight program focused on agile flight within the post-stall regime, producing technical data to give aircraft designers a better understanding of aerodynamics, effectiveness of flight controls and thrust vectoring, and airflow phenomena at high angles of attack. Stall is a condition of an airplane or an airfoil in which lift decreases and drag increases due to the separation of airflow. Thrust vectoring compensates for the loss of control through normal aerodynamic surfaces that occurs during a stall. Post-stall refers to flying beyond the normal stall angle of attack, which in the X-31 was at a 30-degree angle of attack. During Dryden flight testing, the X-31 aircraft established several milestones. On November 6, 1992, the X-31 achieved controlled

Reflections on the use of the World Health Organization’s (WHO OneHealth Tool: Implications for health planning in low and middle income countries (LMICs [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

John Q. Wong

2018-02-01

Full Text Available The World Health Organization (WHO launched the OneHealth Tool (OHT to help low and middle income countries to develop their capacities for sector-wide priority setting. In 2016, we sought to use the OHT to aid the Philippine Health Insurance Corporation (PHIC, the national health insurer of the Philippines, in decisions to expand benefit packages using cost-effectiveness analyses. With technical support from the WHO, we convened health planning officers from the Philippine Department of Health (DOH and the Philippine Health Insurance Corporation (PHIC conduct generalized cost-effective analyses (GCEA of selected un-financed noncommunicable disease interventions using OHT. We collected epidemiological and cost data through health facility surveys, review of literature such as cost libraries and clinical practice guidelines, and expert consultations. Although we were unable to use GCEA results directly to set policy, we learnt important policy lessons which we outline here that might help inform other countries looking to inform service coverage decisions. Additionally, the entire process and GCEA visualizations helped high-level policymakers in the health sector, who have traditionally relied on ad hoc decision making, to realize the need for a systematic and transparent priority-setting process that can continuously provide the evidence needed to inform service coverage decisions.

TMS320C31

International Nuclear Information System (INIS)

Park, Gwi Tae; Lee, Sang Rak

1998-01-01

This book is divided into four parts, which introduces TMS320C31 with C language. The first part deals with digital signal processor on what is DPS?, types of DPS and structure of TMS320C31. The second part introduces program development by C language, cstartup cord and C compiler. The third part describes OS30, Emile 30 and BIOS. The last part is for application board design of T31 and test examples of T31 board : external flag test, ram test, external read port test and communication test.

Unusual Structure of the attB Site of the Site-Specific Recombination System of Lactobacillus delbrueckii Bacteriophage mv4

Science.gov (United States)

Auvray, Frédéric; Coddeville, Michèle; Ordonez, Romy Catoira; Ritzenthaler, Paul

1999-01-01

The temperate phage mv4 integrates its genome into the chromosome of Lactobacillus delbrueckii subsp. bulgaricus by site-specific recombination within the 3′ end of a tRNASer gene. Recombination is catalyzed by the phage-encoded integrase and occurs between the phage attP site and the bacterial attB site. In this study, we show that the mv4 integrase functions in vivo in Escherichia coli and we characterize the bacterial attB site with a site-specific recombination test involving compatible plasmids carrying the recombination sites. The importance of particular nucleotides within the attB sequence was determined by site-directed mutagenesis. The structure of the attB site was found to be simple but rather unusual. A 16-bp DNA fragment was sufficient for function. Unlike most genetic elements that integrate their DNA into tRNA genes, none of the dyad symmetry elements of the tRNASer gene were present within the minimal attB site. No inverted repeats were detected within this site either, in contrast to the lambda site-specific recombination model. PMID:10572145

31 CFR 281.8 - Reporting and accounting.

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2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Reporting and accounting. 281.8 Section 281.8 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL... Reporting and accounting. The Treasury Department will maintain a system of central accounting and reporting...

48 CFR 31.205-34 - Recruitment costs.

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2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Recruitment costs. 31.205....205-34 Recruitment costs. (a) Subject to paragraph (b) of this subsection, the following costs are... positions; or (2) Includes material that is not relevant for recruitment purposes, such as extensive...

48 CFR 31.205-46 - Travel costs.

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2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Travel costs. 31.205-46....205-46 Travel costs. (a) Costs for transportation, lodging, meals, and incidental expenses. (1) Costs... at the time of travel as set forth in the— (i) Federal Travel Regulation, prescribed by the General...

31 CFR 337.0 - Scope of regulations.

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2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Scope of regulations. 337.0 Section 337.0 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE... Public Debt Accounting operates the FHA debenture computer system and performs the day-to-day operations...

48 CFR 31.205-42 - Termination costs.

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2010-10-01

... nonrecurring labor, material, and related overhead costs incurred in the early part of production and result... the settlement proposal as a direct charge, such costs shall not also be included in overhead. Initial... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Termination costs. 31.205...

31 CFR 1.25 - Accounting of disclosures.

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2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Accounting of disclosures. 1.25... Privacy Act § 1.25 Accounting of disclosures. (a) Accounting of certain disclosures. Each component, with respect to each system of records under its control, shall: (1) Keep an accurate accounting of: (i) The...

48 CFR 31.205-30 - Patent costs.

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2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Patent costs. 31.205-30....205-30 Patent costs. (a) The following patent costs are allowable to the extent that they are incurred... patent application where title or royalty-free license is to be conveyed to the Government. (b) General...

Detection of Integrase Gene in E. coli Isolated from Pigs at Different Stages of Production System

Directory of Open Access Journals (Sweden)

Eulalia de la Torre

2014-01-01

Full Text Available Integrons are one of the genetic elements involved in the acquisition of antibiotic resistance. The aim of the present research is to investigate the presence of integrons in commensal Escherichia coli (E. coli strains, isolated from pigs at different stages of production system and from the environment in an Argentinian farm. Five sows postpartum and five randomly chosen piglets from each litter were sampled by rectal swabs. They were sampled again at day 21 and at day 70. Environmental samples from the farm were also obtained. E. coli containing any integron class or combination of both integrons was detected by polymerase chain reaction in 100% of sows and in piglets at different stages of production: farrowing pen stage 68.1%;, weaning 60%, and growing/finishing 85.8%, showing an increase along the production system. From environmental samples 78.4% of E. coli containing any integron class was detected. We conclude that animals and farm environment can act as reservoirs for potential spread of resistant bacteria by means of mobile genetic elements as integrons, which has a major impact on production of food animals and that can reach man through the food chain, constituting a problem for public health.

[Mechanisms of action, pharmacology and interactions of dolutegravir].

Science.gov (United States)

Ribera, Esteban; Podzamczer, Daniel

2015-03-01

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI), whose potential and binding half-life in the integrase are far superior to those of raltegravir and elvitegravir, conferring it with unique characteristics in terms of its genetic barrier to resistance and activity against viruses with one or more mutations in the integrase. The pharmacokinetic properties of dolutegravir allow once-daily dosing (50 mg), with or without food, maintaining concentrations far above those effective against wild-type viruses. If integrase resistance mutations are present, the recommended dosing regimen is 50 mg/12 h. The distribution of dolutegravir in cerebrospinal fluid is good and effective concentrations are also reached in the male and female genital tracts. Dolutegravir is metabolized by UGT1A1 and, to a lesser extent, by CYP3A4, without being an inducer or inhibitor of the usual metabolic systems. It has a very low potential for drug interactions and can be administered in routine doses with most drugs. Dose adjustment is not required, even in patients with renal insufficiency or mild or moderate liver failure. Increasing the dose of dolutegravir (50 mg/12 h) is only recommended when administered with efavirenz, nevirapine, fosamprenavir/r, tipranavir/r, rifampicin, carbamazepine, phenytoin and phenobarbital. Coadministration of dolutegravir with etravirine is not recommended without a protease inhibitor or with Hypericum perforatum. Dolutegravir should be administered 2 h before or 6 h after antacids or products with polyvalent cations. Dolutegravir can reduce renal tubule secretion of substances excreted via OCT2, with a slight initial increase in creatinine, with no risk of renal toxicity. The drug can also increase metformin concentrations and consequently monitoring is recommended in case dose adjustment is required. In summary, dolutegravir has excellent pharmacokinetic and drug interaction profiles. Copyright © 2015 Elsevier España, S

48 CFR 31.205-13 - Employee morale, health, welfare, food service, and dormitory costs and credits.

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2010-10-01

... AND PROCEDURES Contracts With Commercial Organizations 31.205-13 Employee morale, health, welfare... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Employee morale, health, welfare, food service, and dormitory costs and credits. 31.205-13 Section 31.205-13 Federal Acquisition...

48 CFR 31.205-12 - Economic planning costs.

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2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Economic planning costs... GENERAL CONTRACTING REQUIREMENTS CONTRACT COST PRINCIPLES AND PROCEDURES Contracts With Commercial Organizations 31.205-12 Economic planning costs. Economic planning costs are the costs of general long-range...

Retroviral DNA Integration

Science.gov (United States)

2016-01-01

The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications. PMID:27198982

31 CFR 357.23 - Judicial proceedings-sovereign immunity.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Judicial proceedings-sovereign immunity. 357.23 Section 357.23 Money and Finance: Treasury Regulations Relating to Money and Finance... Securities System (Legacy Treasury Direct) § 357.23 Judicial proceedings—sovereign immunity. (a) Department...

28 CFR 345.31 - Recruitment.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Recruitment. 345.31 Section 345.31 Judicial Administration FEDERAL PRISON INDUSTRIES, INC., DEPARTMENT OF JUSTICE FEDERAL PRISON INDUSTRIES (FPI) INMATE WORK PROGRAMS Recruitment and Hiring Practices § 345.31 Recruitment. Inmate workers for...

49 CFR 31.2 - Definitions.

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Definitions. 31.2 Section 31.2 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.2 Definitions. ALJ means an... means any representation, certification, affirmation, document, record, or accounting or bookkeeping...

ENEA-Bologna production and testing of Jeff-3.1 multi-group cross section libraries for nuclear fission applications

International Nuclear Information System (INIS)

Pescarini, M.; Orsi, R.; Sinitsa, V.

2008-01-01

The ENEA-Bologna Nuclear Data Group produced the JEFF-3.1 VITJEFF31.BOLIB and MATJEFF31. BOLIB fine-group coupled neutron and photon (199 n + 42 γ) cross section libraries for nuclear fission applications, respectively in AMPX and MATXS format, with the same specifications and energy group structure of the Endf/B-VI-3 VITAMIN-B6 American library. Each library, containing 181 nuclide cross section files, was generated from the same set of cross section data files in GENDF format, obtained through the Bondarenko (f-factor) method, with an ENEA-Bologna revised version of the GROUPR module of the NJOY-99.160 system. Collapsed working libraries of self-shielded cross sections in FIDO-ANISN format, used by the deterministic transport codes of the DANTSYS and DOORS systems, can be generated from VITJEFF31.BOLIB and MATJEFF31.BOLIB through, respectively, further data processing with an ENEA-Bologna revised version of the SCAMPI system and with the TRANSX code. This paper describes the methodology and specifications of the data processing performed and presents some results of the VITJEFF31.BOLIB validation. (authors)

50 CFR 12.31 - Accountability.

Science.gov (United States)

2010-10-01

... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Accountability. 12.31 Section 12.31 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR TAKING... SEIZURE AND FORFEITURE PROCEDURES Disposal of Forfeited or Abandoned Property § 12.31 Accountability. All...

14 CFR 31.39 - Protection.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Protection. 31.39 Section 31.39 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: MANNED FREE BALLOONS Design Construction § 31.39 Protection. Each part of the balloon must be...

28 CFR 527.31 - Procedures.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Procedures. 527.31 Section 527.31 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE INMATE ADMISSION, CLASSIFICATION, AND TRANSFER TRANSFERS Transfer of Inmates to State Agents for Production on State Writs § 527.31 Procedures...

The ways of solving modern demogra phic pro blem

Directory of Open Access Journals (Sweden)

S. Buslaev

2015-01-01

Full Text Available This article discusses one of the major global challenges of our time – the demographic one. The paper analyzes the history of the problem ofrefugees and forced migrants for the purpose of its decision, cites statistics data and the main trends of global migration, the main regions of emigration and immigration. The paper makes conclusions on the further development of the situation, gives the recommendations on possible ways to solve the refugee problem.

14 CFR 211.31 - Application.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Application. 211.31 Section 211.31... REGULATIONS APPLICATIONS FOR PERMITS TO FOREIGN AIR CARRIERS Freely Associated State Air Carriers § 211.31 Application. The application shall include, in addition to other requirements of this part, documentation...

49 CFR 31.21 - Discovery.

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Discovery. 31.21 Section 31.21 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.21 Discovery. (a) The following types of discovery are authorized: (1) Requests for production of documents for inspection and...

45 CFR 85.31 - Employment.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Employment. 85.31 Section 85.31 Public Welfare....31 Employment. No qualified individuals with handicaps shall, on the basis of handicap, be subjected to discrimination in employment under any program or activity conducted by the agency. The...

24 CFR 320.31 - Default.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Default. 320.31 Section 320.31 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) GOVERNMENT... SECURITIES Bond-Type Securities § 320.31 Default. Upon default of the issuer, the Association has the right...

10 CFR 905.31 - Term.

Science.gov (United States)

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Term. 905.31 Section 905.31 Energy DEPARTMENT OF ENERGY ENERGY PLANNING AND MANAGEMENT PROGRAM Power Marketing Initiative § 905.31 Term. Western will extend resource commitments for 20 years from the date existing contracts expire to existing customers with long...

28 CFR 31.201 - Audit.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Audit. 31.201 Section 31.201 Judicial Administration DEPARTMENT OF JUSTICE OJJDP GRANT PROGRAMS Formula Grants General Requirements § 31.201 Audit. The State must assure that it adheres to the audit requirements enumerated in the “Financial and...

28 CFR 550.31 - Procedures.

Science.gov (United States)

2010-07-01

... the allotted time period. An inmate may rebut this presumption during the disciplinary process. (b... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Procedures. 550.31 Section 550.31... Urine Surveillance § 550.31 Procedures. (a) Staff of the same sex as the inmate tested shall directly...

10 CFR 712.31 - Purpose.

Science.gov (United States)

2010-01-01

... 10 Energy 4 2010-01-01 2010-01-01 false Purpose. 712.31 Section 712.31 Energy DEPARTMENT OF ENERGY HUMAN RELIABILITY PROGRAM Medical Standards § 712.31 Purpose. The standards and procedures set forth in... impairment in reliability; (b) Facilitate the early diagnosis and treatment of disease or impairment and...

X-ray Binaries in the Central Region of M31

Science.gov (United States)

Trudolyubov, Sergey P.; Priedhorsky, W. C.; Cordova, F. A.

2006-09-01

We present the results of the systematic survey of X-ray sources in the central region of M31 using the data of XMM-Newton observations. The spectral properties and variability of 124 bright X-ray sources were studied in detail. We found that more than 80% of sources observed in two or more observations show significant variability on the time scales of days to years. At least 50% of the sources in our sample are spectrally variable. The fraction of variable sources in our survey is much higher than previously reported from Chandra survey of M31, and is remarkably close to the fraction of variable sources found in M31 globular cluster X-ray source population. We present spectral distribution of M31 X-ray sources, based on the spectral fitting with a power law model. The distribution of spectral photon index has two main peaks at 1.8 and 2.3, and shows clear evolution with source luminosity. Based on the similarity of the properties of M31 X-ray sources and their Galactic counterparts, we expect most of X-ray sources in our sample to be accreting binary systems with neutron star and black hole primaries. Combining the results of X-ray analysis (X-ray spectra, hardness-luminosity diagrams and variability) with available data at other wavelengths, we explore the possibility of distinguishing between bright neutron star and black hole binary systems, and identify 7% and 25% of sources in our sample as a probable black hole and neutron star candidates. Finally, we compare the M31 X-ray source population to the source populations of normal galaxies of different morphological type. Support for this work was provided through NASA Grant NAG5-12390. Part of this work was done during a summer workshop ``Revealing Black Holes'' at the Aspen Center for Physics, S. T. is grateful to the Center for their hospitality.

21 CFR 601.31 - Definition.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Definition. 601.31 Section 601.31 Food and Drugs... Diagnostic Radiopharmaceuticals § 601.31 Definition. For purposes of this part,diagnostic radiopharmaceutical means: (a) An article that is intended for use in the diagnosis or monitoring of a disease or a...

40 CFR 31.33 - Supplies.

Science.gov (United States)

2010-07-01

...) Disposition. If there is a residual inventory of unused supplies exceeding $5,000 in total aggregate fair... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Supplies. 31.33 Section 31.33... Requirements Changes, Property, and Subawards § 31.33 Supplies. (a) Title. Title to supplies acquired under a...

31 CFR 337.6 - Conversions to book-entry.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Conversions to book-entry. 337.6... HOUSING ADMINISTRATION DEBENTURES Certificated Debentures § 337.6 Conversions to book-entry. Upon implementation of the book-entry debenture system, to be announced in advance by separate public notice, all new...

31st IMAC Conference on Structural Dynamics

CERN Document Server

Adams, Douglas; Carrella, Alex; Mayes, Randy; Rixen, Daniel; Allen, Matt; Cunha, Alvaro; Catbas, Fikret; Pakzad, Shamim; Racic, Vitomir; Pavic, Aleksandar; Reynolds, Paul; Simmermacher, Todd; Cogan, Scott; Moaveni, Babak; Papadimitriou, Costas; Allemang, Randall; Clerck, James; Niezrecki, Christopher; Wicks, Alfred

2013-01-01

Topics in Nonlinear Dynamics, Volume 1: Proceedings of the 31st IMAC, A Conference and Exposition on Structural Dynamics, 2013, the first volume of seven from the Conference, brings together contributions to this important area of research and engineering. The collection presents early findings and case studies on fundamental and applied aspects of Structural Dynamics, including papers on:   Nonlinear Oscillations Nonlinearities In Practice Nonlinear System Identification: Methods Nonlinear System Identification: Friction & Contact Nonlinear Modal Analysis Nonlinear Modeling & Simulation Nonlinear Vibration Absorbers Constructive Utilization of Nonlinearity.

Swift observations of SDSS J141118.31+481257.6 during its first detected outburst

Science.gov (United States)

Sandoval, L. E. Rivera; Maccarone, T.

2018-05-01

We report Swift observations of the AM CVn-type system SDSS J141118.31+481257.6 (RA=14:11:18.31, Dec=+48:12:57.6) during its first ever recorded outburst. The system was detected by Tadashi Kojima on 2018-May-20 with a V magnitude of 12.6 +- 0.2 (http://ooruri.kusastro.kyoto-u.ac.jp/mailarchive/vsnet-alert/22176), an increase of 7 mags compared to any previous measurement in the same filter.

A tailing genome walking method suitable for genomes with high local GC content.

Science.gov (United States)

Liu, Taian; Fang, Yongxiang; Yao, Wenjuan; Guan, Qisai; Bai, Gang; Jing, Zhizhong

2013-10-15

The tailing genome walking strategies are simple and efficient. However, they sometimes can be restricted due to the low stringency of homo-oligomeric primers. Here we modified their conventional tailing step by adding polythymidine and polyguanine to the target single-stranded DNA (ssDNA). The tailed ssDNA was then amplified exponentially with a specific primer in the known region and a primer comprising 5' polycytosine and 3' polyadenosine. The successful application of this novel method for identifying integration sites mediated by φC31 integrase in goat genome indicates that the method is more suitable for genomes with high complexity and local GC content. Copyright © 2013 Elsevier Inc. All rights reserved.

32 CFR 634.31 - Parking.

Science.gov (United States)

2010-07-01

... 32 National Defense 4 2010-07-01 2010-07-01 true Parking. 634.31 Section 634.31 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Traffic Supervision § 634.31 Parking. (a) The most efficient use of existing on- and off-street parking...

27 CFR 31.82 - Hotels.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Hotels. 31.82 Section 31... Same Premises § 31.82 Hotels. The proprietor of a hotel who conducts the sale of liquors throughout the hotel premises is only required to register under this part for one place. For example, different areas...

12 CFR 3.1 - Authority.

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Authority. 3.1 Section 3.1 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY MINIMUM CAPITAL RATIOS; ISSUANCE OF DIRECTIVES Authority and Definitions § 3.1 Authority. This part is issued under the authority of 12 U.S.C. 1 et seq...

12 CFR 31.1 - Authority.

Science.gov (United States)

2010-01-01

... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Authority. 31.1 Section 31.1 Banks and Banking COMPTROLLER OF THE CURRENCY, DEPARTMENT OF THE TREASURY EXTENSIONS OF CREDIT TO INSIDERS AND TRANSACTIONS WITH AFFILIATES § 31.1 Authority. This part is issued by the Comptroller of the Currency pursuant to 12 U.S.C. 93a...

Clinical evaluation of neoplasms with localized P-31 spectroscopy

International Nuclear Information System (INIS)

Charles, H.C.; Sostman, H.D.; Dewhirst, M.W.; Leopold, K.A.; Oleson, J.; Harrelson, J.

1988-01-01

Forty integrated P-31 MR spectroscopy and H-1 MR imaging studies were accomplished in eight humans and four dogs with soft-tissue sarcomas on a 1.5-T Signa MR system (General Electric) with the H-1 body coil and a 6-cm diameter P-31 surface coil. Proton MR imaging studies (T1-weighted, T2-weighted, and GRASS) were performed prior to the spectroscopic study. Phosphorus studies (repetition time = 1,500 msec) were acquired with both simple B1 localization and 1D-chemical shift imaging (FOV = 128 cm, no. of views = 128, TX = 12.8 min). Patients were treated with fractionated radiation therapy and radio-frequency hyperthermia over 1 month. Patients underwent definitive resection 3 weeks after completion of radiation therapy, while canines were followed clinically. Of note was significant variation in PCr, PME, Pi, and PDE with spatial location in the tissue. The metabolic profile of these tumors as measured by P-31 spectroscopy altered significantly during therapy

40 CFR 122.31 - As a Tribe, what is my role under the NPDES storm water program?

Science.gov (United States)

2010-07-01

... ELIMINATION SYSTEM Permit Application and Special NPDES Program Requirements § 122.31 As a Tribe, what is my... 40 Protection of Environment 21 2010-07-01 2010-07-01 false As a Tribe, what is my role under the NPDES storm water program? 122.31 Section 122.31 Protection of Environment ENVIRONMENTAL PROTECTION...

Expression of Caenorhabditis elegans antimicrobial peptide NLP-31 in Escherichia coli

Science.gov (United States)

Lim, Mei-Perng; Nathan, Sheila

2014-09-01

Burkholderia pseudomallei is the causative agent of melioidosis, a fulminant disease endemic in Southeast Asia and Northern Australia. The standardized form of therapy is antibiotics treatment; however, the bacterium has become increasingly resistant to these antibiotics. This has spurred the need to search for alternative therapeutic agents. Antimicrobial peptides (AMPs) are small proteins that possess broad-spectrum antimicrobial activity. In a previous study, the nematode Caenorhabditis elegans was infected by B. pseudomallei and a whole animal transcriptome analysis identified a number of AMP-encoded genes which were induced significantly in the infected worms. One of the AMPs identified is NLP-31 and to date, there are no reports of anti-B. pseudomallei activity demonstrated by NLP-31. To produce NLP-31 protein for future studies, the gene encoding for NLP-31 was cloned into the pET32b expression vector and transformed into Escherichia coli BL21(DE3). Protein expression was induced with 1 mM IPTG for 20 hours at 20°C and recombinant NLP-31 was detected in the soluble fraction. Taken together, a simple optimized heterologous production of AMPs in an E. coli expression system has been successfully developed.

48 CFR 31.205-48 - Research and development costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Research and development... Organizations 31.205-48 Research and development costs. Research and development, as used in this subsection... grant for research and development effort, the excess is unallowable under any other Government contract...

Topological features of the Sokolov integrable case on the Lie algebra so(3,1)

International Nuclear Information System (INIS)

Novikov, D V

2014-01-01

The integrable Sokolov case on so(3,1) ⋆ is investigated. This is a Hamiltonian system with two degrees of freedom, in which the Hamiltonian and the additional integral are homogeneous polynomials of degrees 2 and 4, respectively. It is an interesting feature of this system that connected components of common level surfaces of the Hamiltonian and the additional integral turn out to be noncompact. The critical points of the moment map and their indices are found, the bifurcation diagram is constructed, and the topology of noncompact level surfaces is determined, that is, the closures of solutions of the Sokolov system on so(3,1) are described. Bibliography: 24 titles

40 CFR 455.31 - Specialized definitions.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 29 2010-07-01 2010-07-01 false Specialized definitions. 455.31 Section 455.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES....31 Specialized definitions. (a) “Metallo-organic active ingredients” means carbon containing active...

7 CFR 1212.31 - United States.

Science.gov (United States)

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false United States. 1212.31 Section 1212.31 Agriculture..., Consumer Education, and Industry Information Order Definitions § 1212.31 United States. “United States... territories and possessions of the United States. ...

Ethiop. J. Sci. & Technol. 9(1) 31-44, 2016 31 Investigation of 1, 10 ...

African Journals Online (AJOL)

9(1) 31-44, 2016. 31. Investigation of 1, 10-Phenanthroline based Ionic Liquids using X-ray photoelectron spectroscopy ... 1, 10-Phenanthrolinium based ionic liquids are among the new compounds ..... Chemical Reviews 102(10):3667-. 3692.

[Efficacy of dolutegravir in treatment-experienced patients: the SAILING and VIKING trials].

Science.gov (United States)

Moreno, Santiago; Berenguer, Juan

2015-03-01

Dolutegravir is an HIV integrase inhibitor with a high genetic barrier to resistance and is active against raltegravir- and/or elvitegravir-resistant strains. The clinical development of dolutegravir for HIV infection rescue therapy is based on 3 clinical trials. In the SAILING trial, dolutegravir (5 mg once daily) in combination with 2 other antiretroviral agents was well tolerated and showed greater virological effect than raltegravir (400 mg twice daily) in the treatment of integrase inhibitor-naïve adults with virological failure infected with HIV strains with at least two-class drug resistance. The VIKING studies were designed to evaluate the efficacy of dolutegravir as rescue therapy in treatment-experienced patients infected with HIV strains with resistance mutations to raltegravir and/or elvitegravir. VIKING-1-2 was a dose-ranging phase IIb trial. VIKING-3 was a phase III trial in which dolutegravir (50 mg twice daily) formed part of an optimized regimen and proved safe and effective in this difficult-to-treat group of patients. Dolutegravir is the integrase inhibitor of choice for rescue therapy in multiresistant HIV infection, both in integrase inhibitor-naïve patients and in those previously treated with raltegravir or elvitegravir. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Certified Reference Material for Use in 1H, 31P, and 19F Quantitative NMR, Ensuring Traceability to the International System of Units.

Science.gov (United States)

Rigger, Romana; Rück, Alexander; Hellriegel, Christine; Sauermoser, Robert; Morf, Fabienne; Breitruck, KathrinBreitruck; Obkircher, Markus

2017-09-01

In recent years, quantitative NMR (qNMR) spectroscopy has become one of the most important tools for content determination of organic substances and quantitative evaluation of impurities. Using Certified Reference Materials (CRMs) as internal or external standards, the extensively used qNMR method can be applied for purity determination, including unbroken traceability to the International System of Units (SI). The implementation of qNMR toward new application fields, e.g., metabolomics, environmental analysis, and physiological pathway studies, brings along more complex molecules and systems, thus making use of 1H qNMR challenging. A smart workaround is possible by the use of other NMR active nuclei, namely 31P and 19F. This article presents the development of three classes of qNMR CRMs based on different NMR active nuclei (1H, 31P, and 19F), and the corresponding approaches to establish traceability to the SI through primary CRMs from the National Institute of Standards and Technology and the National Metrology Institute of Japan. These TraceCERT® qNMR CRMs are produced under ISO/IEC 17025 and ISO Guide 34 using high-performance qNMR.

40 CFR 233.31 - Coordination requirements.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Coordination requirements. 233.31 Section 233.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) OCEAN DUMPING 404 STATE PROGRAM REGULATIONS Program Operation § 233.31 Coordination requirements. (a) If a proposed...

7 CFR 3430.31 - Guiding principles.

Science.gov (United States)

2010-01-01

... 7 Agriculture 15 2010-01-01 2010-01-01 false Guiding principles. 3430.31 Section 3430.31 Agriculture Regulations of the Department of Agriculture (Continued) COOPERATIVE STATE RESEARCH, EDUCATION... § 3430.31 Guiding principles. The guiding principle for Federal assistance application review and...

40 CFR 31.45 - Quality assurance.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Quality assurance. 31.45 Section 31.45... Requirements Reports, Records, Retention, and Enforcement § 31.45 Quality assurance. If the grantee's project... quality assurance practices consisting of policies, procedures, specifications, standards, and...

22 CFR 226.31 - Insurance coverage.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Insurance coverage. 226.31 Section 226.31 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ADMINISTRATION OF ASSISTANCE AWARDS TO U.S. NON-GOVERNMENTAL ORGANIZATIONS Post-award Requirements Property Standards § 226.31 Insurance coverage. Recipients...

40 CFR 406.31 - Specialized definitions.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 28 2010-07-01 2010-07-01 true Specialized definitions. 406.31 Section 406.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GRAIN MILLS POINT SOURCE CATEGORY Normal Wheat Flour Milling Subcategory § 406.31 Specialized...

10 CFR 21.31 - Procurement documents.

Science.gov (United States)

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Procurement documents. 21.31 Section 21.31 Energy NUCLEAR REGULATORY COMMISSION REPORTING OF DEFECTS AND NONCOMPLIANCE Procurement Documents § 21.31 Procurement documents. Each individual, corporation, partnership, dedicating entity, or other entity subject to the...

40 CFR 145.31 - Approval process.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 22 2010-07-01 2010-07-01 false Approval process. 145.31 Section 145.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE UIC PROGRAM REQUIREMENTS Program Approval, Revision and Withdrawal § 145.31 Approval process. (a...

14 CFR 31.35 - Fabrication methods.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Fabrication methods. 31.35 Section 31.35 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: MANNED FREE BALLOONS Design Construction § 31.35 Fabrication methods. The methods of fabrication...

Structure-based virtual screening toward the discovery of novel inhibitors for impeding the protein-protein interaction between HIV-1 integrase and human lens epithelium-derived growth factor (LEDGF/p75).

Science.gov (United States)

Panwar, Umesh; Singh, Sanjeev Kumar

2017-10-23

HIV-1 integrase is a unique promising component of the viral replication cycle, catalyzing the integration of reverse transcribed viral cDNA into the host cell genome. Generally, IN activity requires both viral as well as a cellular co-factor in the processing replication cycle. Among them, the human lens epithelium-derived growth factor (LEDGF/p75) represented as promising cellular co-factor which supports the viral replication by tethering IN to the chromatin. Due to its major importance in the early steps of HIV replication, the interaction between IN and LEDGF/p75 has become a pleasing target for anti-HIV drug discovery. The present study involves the finding of novel inhibitor based on the information of dimeric CCD of IN in complex with known inhibitor, which were carried out by applying a structure-based virtual screening concept with molecular docking. Additionally, Free binding energy, ADME properties, PAINS analysis, Density Functional Theory, and Enrichment Calculations were performed on selected compounds for getting a best lead molecule. On the basis of these analyses, the current study proposes top 3 compounds: Enamine-Z742267384, Maybridge-HTS02400, and Specs-AE-848/37125099 with acceptable pharmacological properties and enhanced binding affinity to inhibit the interaction between IN and LEDGF/p75. Furthermore, Simulation studies were carried out on these molecules to expose their dynamics behavior and stability. We expect that the findings obtained here could be future therapeutic agents and may provide an outline for the experimental studies to stimulate the innovative strategy for research community.

49 CFR 8.31 - Industrial security.

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Industrial security. 8.31 Section 8.31.../ACCESS Access to Information § 8.31 Industrial security. (a) Background. The National Industrial Security... industrial security services for the Department of Transportation. Regulations prescribed by the Secretary of...

45 CFR 99.31 - Posthearing briefs.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Posthearing briefs. 99.31 Section 99.31 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROCEDURE FOR HEARINGS FOR THE CHILD CARE AND DEVELOPMENT FUND Posthearing Procedures, Decisions § 99.31 Posthearing briefs. The...

45 CFR 1170.31 - Discrimination prohibited.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 3 2010-10-01 2010-10-01 false Discrimination prohibited. 1170.31 Section 1170.31... ASSISTED PROGRAMS OR ACTIVITIES Accessibility § 1170.31 Discrimination prohibited. No qualified handicapped... denied the benefits of, be excluded from participation in, or otherwise be subjected to discrimination...

45 CFR 1151.31 - Discrimination prohibited.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 3 2010-10-01 2010-10-01 false Discrimination prohibited. 1151.31 Section 1151.31... HUMANITIES NATIONAL ENDOWMENT FOR THE ARTS NONDISCRIMINATION ON THE BASIS OF HANDICAP Discrimination Prohibited Employment § 1151.31 Discrimination prohibited. (a) No qualified handicapped person shall, on the...

22 CFR 192.31 - Applicable benefits.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Applicable benefits. 192.31 Section 192.31 Foreign Relations DEPARTMENT OF STATE HOSTAGE RELIEF VICTIMS OF TERRORISM COMPENSATION Medical Benefits for Captive Situations § 192.31 Applicable benefits. A person eligible for benefits under this part...

30 CFR 281.31 - Overriding royalties.

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false Overriding royalties. 281.31 Section 281.31 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR OFFSHORE LEASING OF MINERALS OTHER THAN OIL, GAS, AND SULPHUR IN THE OUTER CONTINENTAL SHELF Financial Considerations § 281.31...

32 CFR 989.31 - Pollution prevention.

Science.gov (United States)

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Pollution prevention. 989.31 Section 989.31... ENVIRONMENTAL IMPACT ANALYSIS PROCESS (EIAP) § 989.31 Pollution prevention. The Pollution Prevention Act of 1990..., whenever feasible. Pollution prevention approaches should be applied to all pollution-generating activities...

31 CFR 363.9 - What does this subpart cover?

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What does this subpart cover? 363.9 Section 363.9 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL... cover? This subpart provides general rules governing securities held within the TreasuryDirect ® system...

48 CFR 31.205-10 - Cost of money.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Cost of money. 31.205-10....205-10 Cost of money. (a) General. Cost of money— (1) Is an imputed cost that is not a form of...) Refers to— (i) Facilities capital cost of money (48 CFR 9904.414); and (ii) Cost of money as an element...

45 CFR 98.31 - Parental access.

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2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Parental access. 98.31 Section 98.31 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION CHILD CARE AND DEVELOPMENT FUND Program Operations (Child Care Services)-Parental Rights and Responsibilities § 98.31 Parental access. The...

14 CFR 31.63 - Safety belts.

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2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Safety belts. 31.63 Section 31.63 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: MANNED FREE BALLOONS Design Construction § 31.63 Safety belts. (a) There must be a safety belt...

22 CFR 96.31 - Corporate structure.

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2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Corporate structure. 96.31 Section 96.31 Foreign Relations DEPARTMENT OF STATE LEGAL AND RELATED SERVICES ACCREDITATION OF AGENCIES AND APPROVAL OF... Approval Licensing and Corporate Governance § 96.31 Corporate structure. (a) The agency qualifies for...

50 CFR 3.1 - Discrimination prohibited.

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2010-10-01

... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Discrimination prohibited. 3.1 Section 3.1... PROVISIONS NONDISCRIMINATION-CONTRACTS, PERMITS, AND USE OF FACILITIES § 3.1 Discrimination prohibited. No..., be denied the benefits of, or be otherwise subjected to any form of discrimination or segregation...

40 CFR 31.41 - Financial reporting.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Financial reporting. 31.41 Section 31... Post-Award Requirements Reports, Records, Retention, and Enforcement § 31.41 Financial reporting. (a... may from time to time be authorized by OMB, for: (i) Submitting financial reports to Federal agencies...

14 CFR 1260.31 - National security.

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2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false National security. 1260.31 Section 1260.31... Provisions § 1260.31 National security. National Security October 2000 Normally, NASA grants do not involve... who will have access to the information must obtain the appropriate security clearance in advance of...

40 CFR 31.25 - Program income.

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2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Program income. 31.25 Section 31.25... Requirements Financial Administration § 31.25 Program income. (a) General. Grantees are encouraged to earn income to defray program costs. Program income includes income from fees for services performed, from the...

7 CFR 1773.31 - Auditor's report.

Science.gov (United States)

2010-01-01

... 7 Agriculture 12 2010-01-01 2010-01-01 false Auditor's report. 1773.31 Section 1773.31 Agriculture... (CONTINUED) POLICY ON AUDITS OF RUS BORROWERS RUS Reporting Requirements § 1773.31 Auditor's report. The CPA... the auditor's report. The auditor's report should also state that the report on compliance and on...

19 CFR 12.31 - Plant pests.

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2010-04-01

... 19 Customs Duties 1 2010-04-01 2010-04-01 false Plant pests. 12.31 Section 12.31 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY SPECIAL CLASSES OF MERCHANDISE Wild Animals, Birds, and Insects § 12.31 Plant pests. The importation in a...

14 CFR 120.31 - Prohibited drugs.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Prohibited drugs. 120.31 Section 120.31... AND OPERATORS FOR COMPENSATION OR HIRE: CERTIFICATION AND OPERATIONS DRUG AND ALCOHOL TESTING PROGRAM... Under § 91.147 of This Chapter and Safety-Sensitive Employees § 120.31 Prohibited drugs. (a) Each...

21 CFR 332.31 - Professional labeling.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Professional labeling. 332.31 Section 332.31 Food... HUMAN USE ANTIFLATULENT PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Labeling § 332.31 Professional labeling. (a) The labeling of the product provided to health professionals (but not to the general public) may...

12 CFR 1703.31 - General purposes.

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2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false General purposes. 1703.31 Section 1703.31 Banks and Banking OFFICE OF FEDERAL HOUSING ENTERPRISE OVERSIGHT, DEPARTMENT OF HOUSING AND URBAN... Legal Proceedings in Which OFHEO Is Not a Named Party § 1703.31 General purposes. The purposes of this...

34 CFR 31.11 - Offset process.

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2010-07-01

... 34 Education 1 2010-07-01 2010-07-01 false Offset process. 31.11 Section 31.11 Education Office of the Secretary, Department of Education SALARY OFFSET FOR FEDERAL EMPLOYEES WHO ARE INDEBTED TO THE UNITED STATES UNDER PROGRAMS ADMINISTERED BY THE SECRETARY OF EDUCATION § 31.11 Offset process. (a) The...

7 CFR 1006.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1006.31 Section 1006.31 Agriculture... Handling Handler Reports § 1006.31 Payroll reports. (a) On or before the 20th day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in detail...

7 CFR 1005.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1005.31 Section 1005.31 Agriculture... Handling Handler Reports § 1005.31 Payroll reports. (a) On or before the 20th day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in detail...

7 CFR 1001.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1001.31 Section 1001.31 Agriculture... Handling Handler Reports § 1001.31 Payroll reports. (a) On or before the 22nd day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in detail...

7 CFR 1007.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1007.31 Section 1007.31 Agriculture... Handling Handler Reports § 1007.31 Payroll reports. (a) On or before the 20th day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in detail...

14 CFR 31.45 - Fuel cells.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Fuel cells. 31.45 Section 31.45 Aeronautics... STANDARDS: MANNED FREE BALLOONS Design Construction § 31.45 Fuel cells. If fuel cells are used, the fuel cells, their attachments, and related supporting structure must be shown by tests to be capable of...

49 CFR 391.31 - Road test.

Science.gov (United States)

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false Road test. 391.31 Section 391.31 Transportation... COMBINATION VEHICLE (LCV) DRIVER INSTRUCTORS Tests § 391.31 Road test. (a) Except as provided in subpart G, a person shall not drive a commercial motor vehicle unless he/she has first successfully completed a road...

Introduction to 3+1 numerical relativity

CERN Document Server

Alcubierre, Miguel

2008-01-01

This book introduces the modern field of 3+1 numerical relativity. The book has been written in a way as to be as self-contained as possible, and only assumes a basic knowledge of special relativity. Starting from a brief introduction to general relativity, it discusses the different concepts and tools necessary for the fully consistent numerical simulation of relativistic astrophysical systems, with strong and dynamical gravitational fields. Among the topics discussed in detail arethe following: the initial data problem, hyperbolic reductions of the field equations, gauge conditions, the evol

7 CFR 1030.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1030.31 Section 1030.31 Agriculture... Handling Handler Reports § 1030.31 Payroll reports. (a) On or before the 22nd day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in the detail...

7 CFR 1126.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1126.31 Section 1126.31 Agriculture... Handling Handler Reports § 1126.31 Payroll reports. (a) On or before the 20th day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in the detail...

7 CFR 1032.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1032.31 Section 1032.31 Agriculture... Handling Handler Reports § 1032.31 Payroll reports. (a) On or before the 20th day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in the detail...

7 CFR 1124.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1124.31 Section 1124.31 Agriculture... Regulating Handling Handler Reports § 1124.31 Payroll reports. (a) On or before the 20th day after the end of... § 1000.9(c) shall report to the market administrator its producer payroll for the month, in the detail...

7 CFR 1033.31 - Payroll reports.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Payroll reports. 1033.31 Section 1033.31 Agriculture... Handling Handler Reports § 1033.31 Payroll reports. (a) On or before the 22nd day after the end of each....9(c) shall report to the market administrator its producer payroll for the month, in the detail...

26 CFR 31.0-1 - Introduction.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Introduction. 31.0-1 Section 31.0-1 Internal... OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Introduction § 31.0-1 Introduction. (a) In general. The regulations in this part relate to the employment taxes imposed by subtitle C...

30 CFR 33.31 - Test space.

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Test space. 33.31 Section 33.31 Mineral... § 33.31 Test space. (a) Drilling tests shall be conducted in a test space formed by two curtains suspended across a mine opening in such a manner that the volume of the test space shall be approximately 2...

14 CFR 21.31 - Type design.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Type design. 21.31 Section 21.31... PROCEDURES FOR PRODUCTS AND PARTS Type Certificates § 21.31 Type design. The type design consists of— (a) The... configuration and the design features of the product shown to comply with the requirements of that part of this...

14 CFR 31.43 - Fitting factor.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Fitting factor. 31.43 Section 31.43... STANDARDS: MANNED FREE BALLOONS Design Construction § 31.43 Fitting factor. (a) A fitting factor of at least... structure. This factor applies to all parts of the fitting, the means of attachment, and the bearing on the...

Cellular and molecular mechanisms of HIV-1 integration targeting.

Science.gov (United States)

Engelman, Alan N; Singh, Parmit K

2018-07-01

Integration is central to HIV-1 replication and helps mold the reservoir of cells that persists in AIDS patients. HIV-1 interacts with specific cellular factors to target integration to interior regions of transcriptionally active genes within gene-dense regions of chromatin. The viral capsid interacts with several proteins that are additionally implicated in virus nuclear import, including cleavage and polyadenylation specificity factor 6, to suppress integration into heterochromatin. The viral integrase protein interacts with transcriptional co-activator lens epithelium-derived growth factor p75 to principally position integration within gene bodies. The integrase additionally senses target DNA distortion and nucleotide sequence to help fine-tune the specific phosphodiester bonds that are cleaved at integration sites. Research into virus-host interactions that underlie HIV-1 integration targeting has aided the development of a novel class of integrase inhibitors and may help to improve the safety of viral-based gene therapy vectors.

Gauge stability of 3+1 formulations of general relativity

International Nuclear Information System (INIS)

Khokhlov, A M; Novikov, I D

2002-01-01

We present a general approach to the analysis of gauge stability of 3+1 formulations of general relativity (GR). Evolution of coordinate perturbations and the corresponding perturbations of lapse and shift can be described by a system of eight quasi-linear partial differential equations. Stability with respect to gauge perturbations depends on the choice of gauge and a background metric, but it does not depend on a particular form of a 3+1 system if its constrained solutions are equivalent to those of the Einstein equations. Stability of a number of known gauges is investigated in the limit of short-wavelength perturbations. All fixed gauges except a synchronous gauge are found to be ill posed. A maximal slicing gauge and its parabolic extension are shown to be ill posed as well. A necessary condition is derived for well-posedness of metric-dependent algebraic gauges. Well-posed metric-dependent gauges are found, however, to be generally unstable. Both instability and ill-posedness are associated with the existence of growing modes of coordinate perturbations related to perturbations of physical accelerations of reference frames

31 CFR 391.1 - General.

Science.gov (United States)

2010-07-01

... Justice; (6) Where the late charges pertain to claims involving savings bonds and notes arising under 31 U.S.C. 3105 and 3106 which are replaced pursuant to 31 U.S.C. 3126; (7) For reasons of equity or good...

Inverse correlation between promoter strength and excision activity in class 1 integrons.

Directory of Open Access Journals (Sweden)

Thomas Jové

2010-01-01

Full Text Available Class 1 integrons are widespread genetic elements that allow bacteria to capture and express gene cassettes that are usually promoterless. These integrons play a major role in the dissemination of antibiotic resistance among Gram-negative bacteria. They typically consist of a gene (intI encoding an integrase (that catalyzes the gene cassette movement by site-specific recombination, a recombination site (attI1, and a promoter (Pc responsible for the expression of inserted gene cassettes. The Pc promoter can occasionally be combined with a second promoter designated P2, and several Pc variants with different strengths have been described, although their relative distribution is not known. The Pc promoter in class 1 integrons is located within the intI1 coding sequence. The Pc polymorphism affects the amino acid sequence of IntI1 and the effect of this feature on the integrase recombination activity has not previously been investigated. We therefore conducted an extensive in silico study of class 1 integron sequences in order to assess the distribution of Pc variants. We also measured these promoters' strength by means of transcriptional reporter gene fusion experiments and estimated the excision and integration activities of the different IntI1 variants. We found that there are currently 13 Pc variants, leading to 10 IntI1 variants, that have a highly uneven distribution. There are five main Pc-P2 combinations, corresponding to five promoter strengths, and three main integrases displaying similar integration activity but very different excision efficiency. Promoter strength correlates with integrase excision activity: the weaker the promoter, the stronger the integrase. The tight relationship between the aptitude of class 1 integrons to recombine cassettes and express gene cassettes may be a key to understanding the short-term evolution of integrons. Dissemination of integron-driven drug resistance is therefore more complex than previously thought.

48 CFR 31.205-1 - Public relations and advertising costs.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Public relations and... Organizations 31.205-1 Public relations and advertising costs. (a) Public relations means all functions and...; or (2) Maintaining or promoting reciprocal understanding and favorable relations with the public at...

28 CFR 552.31 - Negotiations.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Negotiations. 552.31 Section 552.31 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE INSTITUTIONAL MANAGEMENT CUSTODY Hostage... negotiation process. Instead, this responsibility is ordinarily assigned to a team of individuals specifically...

More on equations of motion for interacting massless field of all spins in 3+1 dimensions

Energy Technology Data Exchange (ETDEWEB)

Vasiliev, M A [Inst. of Theoretical Physics, Goteborg (Sweden)

1992-07-09

We establish the simple link between the recently proposed equations of motion for interacting massless fields of all spins 0{<=}s<{infinity} in 3+1 dimensions and conventional formulations of free higher-spin dynamics. In addition, we discuss various types of formal generalizations of the system of equations of Vasiliev which may give rise to interesting relativistic systems in 2+1 and 3+1 dimensions. In particular, it is shown that there exists a class of equations generalizing Vasiliev's system, parametrized by an arbitrary function of one variable. Self-dual higher-spin equations are discussed briefly. (orig.).

Control of the Water Transport Activity of Barley HvTIP3;1 Specifically Expressed in Seeds.

Science.gov (United States)

Utsugi, Shigeko; Shibasaka, Mineo; Maekawa, Masahiko; Katsuhara, Maki

2015-09-01

Tonoplast intrinsic proteins (TIPs) are involved in the transport and storage of water, and control intracellular osmotic pressure by transporting material related to the water potential of cells. In the present study, we focused on HvTIP3;1 during the periods of seed development and desiccation in barley. HvTIP3;1 was specifically expressed in seeds. An immunochemical analysis showed that HvTIP3;1 strongly accumulated in the aleurone layers and outer layers of barley seeds. The water transport activities of HvTIP3;1 and HvTIP1;2, which also accumulated in seeds, were measured in the heterologous expression system of Xenopus oocytes. When they were expressed individually, HvTIP1;2 transported water, whereas HvTIP3;1 did not. However, HvTIP3;1 exhibited water transport activity when co-expressed with HvTIP1;2 in oocytes, and this activity was higher than when HvTIP1;2 was expressed alone. This is the first report to demonstrate that the water permeability of a TIP aquaporin was activated when co-expressed with another TIP. The split-yellow fluorescent protein (YFP) system in onion cells revealed that HvTIP3;1 interacted with HvTIP1;2 to form a heterotetramer in plants. These results suggest that HvTIP3;1 functions as an active water channel to regulate water movement through tissues during the periods of seed development and desiccation. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Phosphorus-31 spectroscopic imaging of the human liver

International Nuclear Information System (INIS)

Biran, M.; Raffard, G.; Canioni, P.; Kien, P.

1993-01-01

During the last decade, progresses in the field of nuclear magnetic resonance spectroscopy (M.R.S.), have allowed the metabolic studies of complex biological systems. Since the coming out of whole body magnets, clinical applications are possible; they utilize magnetic field gradients coupled with selective pulse sequences. Study of the phosphorylated metabolism of human liver can be performed with sequences as ISIS, FROGS or 1D-CSI. But they present some disadvantages (for instance contamination by phosphocreatine from muscle). In the present work, we have studied the human liver in vivo by 31 P spectroscopic imaging. Several spectra could be acquired with only one acquisition. This study has needed the building of radiofrequency coils (surface coils), specially designed for liver observation (15 cm diameter 31 P coil and 19 cm diameter proton coil, both transmitter and receiver coils). Preliminary studies have been done on a phantom followed by in vivo measurements on healthy subject livers. We have obtained localized 31 P N.M.R. spectra corresponding to different voxels within the hepatic tissue. The conditions of acquisition of spectra and the problems related to the saturation of phosphorylated metabolite signals (in particular phosphodiesters) are discussed. (author). 5 figs., 15 refs

40 CFR 31.32 - Equipment.

Science.gov (United States)

2010-07-01

... awarding agency. (d) Management requirements. Procedures for managing equipment (including replacement... return. (e) Disposition. When original or replacement equipment acquired under a grant or subgrant is no... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Equipment. 31.32 Section 31.32...

7 CFR 1794.31 - Classification.

Science.gov (United States)

2010-01-01

... 7 Agriculture 12 2010-01-01 2010-01-01 false Classification. 1794.31 Section 1794.31 Agriculture... Classification. (a) Electric and telecommunications programs. RUS will normally determine the proper environmental classification of projects based on its evaluation of the project description set forth in the...

Molecular study on some antibiotic resistant genes in Salmonella spp. isolates

Science.gov (United States)

Nabi, Ari Q.

2017-09-01

Studying the genes related with antimicrobial resistance in Salmonella spp. is a crucial step toward a correct and faster treatment of infections caused by the pathogen. In this work Integron mediated antibiotic resistant gene IntI1 (Class I Integrase IntI1) and some plasmid mediated antibiotic resistance genes (Qnr) were scanned among the isolated non-Typhoid Salmonellae strains with known resistance to some important antimicrobial drugs using Sybr Green real time PCR. The aim of the study was to correlate the multiple antibiotics and antimicrobial resistance of Salmonella spp. with the presence of integrase (IntI1) gene and plasmid mediated quinolone resistant genes. Results revealed the presence of Class I Integrase gene in 76% of the isolates with confirmed multiple antibiotic resistances. Moreover, about 32% of the multiple antibiotic resistant serotypes showed a positive R-PCR for plasmid mediated qnrA gene encoding for nalidixic acid and ciprofloxacin resistance. No positive results could be revealed form R-PCRs targeting qnrB or qnrS. In light of these results we can conclude that the presence of at least one of the qnr genes and/or the presence of Integrase Class I gene were responsible for the multiple antibiotic resistance to for nalidixic acid and ciprofloxacin from the studied Salmonella spp. and further studies required to identify the genes related with multiple antibiotic resistance of the pathogen.

28 CFR 513.31 - Limitations.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Limitations. 513.31 Section 513.31 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE GENERAL MANAGEMENT AND ADMINISTRATION... published in 5 CFR part 297 and by Department of Justice regulations published in 28 CFR part 16. ...

44 CFR 206.31 - Purpose.

Science.gov (United States)

2010-10-01

... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Purpose. 206.31 Section 206.31 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND... purpose of this subpart is to describe the process leading to a Presidential declaration of a major...

22 CFR 171.31 - Definitions.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Definitions. 171.31 Section 171.31 Foreign Relations DEPARTMENT OF STATE ACCESS TO INFORMATION AVAILABILITY OF INFORMATION AND RECORDS TO THE PUBLIC... Department, including, but not limited to education, financial transactions, medical history, and criminal or...

31 CFR 103.135 - Anti-money laundering programs for operators of credit card systems.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Anti-money laundering programs for...-Money Laundering Programs Anti-Money Laundering Programs § 103.135 Anti-money laundering programs for.... Virgin Islands. (b) Anti-money laundering program requirement. Effective July 24, 2002, each operator of...

31 CFR 357.0 - Book-entry systems.

Science.gov (United States)

2010-07-01

... AND BILLS HELD IN LEGACY TREASURY DIRECT General Information § 357.0 Book-entry systems. (a) Treasury... securities are held in a tiered system through securities intermediaries such as financial institutions or... securities are held directly by the Department of the Treasury in accounts maintained in the investor's name...

27 CFR 5.31 - General.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false General. 5.31 Section 5.31 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS LABELING AND ADVERTISING OF DISTILLED SPIRITS Labeling Requirements for Distilled Spirits...

Structural and biochemical characterization of novel bacterial α-galactosidases belonging to glycoside hydrolase family 31.

Science.gov (United States)

Miyazaki, Takatsugu; Ishizaki, Yuichi; Ichikawa, Megumi; Nishikawa, Atsushi; Tonozuka, Takashi

2015-07-01

Glycoside hydrolase family 31 (GH31) proteins have been reportedly identified as exo-α-glycosidases with activity for α-glucosides and α-xylosides. We focused on a GH31 subfamily, which contains proteins with low sequence identity (Pedobacter heparinus and Pedobacter saltans. The enzymes unexpectedly exhibited α-galactosidase activity, but were not active on α-glucosides and α-xylosides. The crystal structures of one of the enzymes, PsGal31A, in unliganded form and in complexes with D-galactose or L-fucose and the catalytic nucleophile mutant in unliganded form and in complex with p-nitrophenyl-α-D-galactopyranoside, were determined at 1.85-2.30 Å (1 Å=0.1 nm) resolution. The overall structure of PsGal31A contains four domains and the catalytic domain adopts a (β/α)8-barrel fold that resembles the structures of other GH31 enzymes. Two catalytic aspartic acid residues are structurally conserved in the enzymes, whereas most residues forming the active site differ from those of GH31 α-glucosidases and α-xylosidases. PsGal31A forms a dimer via a unique loop that is not conserved in other reported GH31 enzymes; this loop is involved in its aglycone specificity and in binding L-fucose. Considering potential genes for α-L-fucosidases and carbohydrate-related proteins within the vicinity of Pedobacter Gal31, the identified Gal31 enzymes are likely to function in a novel sugar degradation system. This is the first report of α-galactosidases which belong to GH31 family. © 2015 Authors; published by Portland Press Limited.

Prediction of the binding mode and resistance profile for a dual-target pyrrolyl diketo acid scaffold against HIV-1 integrase and reverse-transcriptase-associated ribonuclease H.

Science.gov (United States)

Yang, Fengyuan; Zheng, Guoxun; Fu, Tingting; Li, Xiaofeng; Tu, Gao; Li, Ying Hong; Yao, Xiaojun; Xue, Weiwei; Zhu, Feng

2018-06-27

The rapid emergence of drug-resistant variants is one of the most common causes of highly active antiretroviral therapeutic (HAART) failure in patients infected with HIV-1. Compared with the existing HAART, the recently developed pyrrolyl diketo acid scaffold targeting both HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) is an efficient approach to counteract the failure of anti-HIV treatment due to drug resistance. However, the binding mode and potential resistance profile of these inhibitors with important mechanistic principles remain poorly understood. To address this issue, an integrated computational method was employed to investigate the binding mode of inhibitor JMC6F with HIV-1 IN and RNase H. By using per-residue binding free energy decomposition analysis, the following residues: Asp64, Thr66, Leu68, Asp116, Tyr143, Gln148 and Glu152 in IN, Asp443, Glu478, Trp536, Lys541 and Asp549 in RNase H were identified as key residues for JMC6F binding. And then computational alanine scanning was carried to further verify the key residues. Moreover, the resistance profile of the currently known major mutations in HIV-1 IN and 2 mutations in RNase H against JMC6F was predicted by in silico mutagenesis studies. The results demonstrated that only three mutations in HIV-1 IN (Y143C, Q148R and N155H) and two mutations in HIV-1 RNase H (Y501R and Y501W) resulted in a reduction of JMC6F potency, thus indicating their potential role in providing resistance to JMC6F. These data provided important insights into the binding mode and resistance profile of the inhibitors with a pyrrolyl diketo acid scaffold in HIV-1 IN and RNase H, which would be helpful for the development of more effective dual HIV-1 IN and RNase H inhibitors.

Eccolib-Jeff-3.1 libraries; Les bibliotheques Eccolib-Jeff-3.1

Energy Technology Data Exchange (ETDEWEB)

Sublet, J Ch; Dean, Ch; Plisson-Rieunier, D

2006-07-01

The multi-group, multi-temperature libraries ECCOLIB-JEFF-3.1, derived from the JEFF-3.1 evaluations, have been produced using the NJOY-99 and CALENDF-2005 processing codes and the MERGE-3.8 and GECCO-1.4 interface tools. The processing steps are explained along side the Quality Assurance processes linked to such libraries. Final results encompass five main libraries; two fine 1968 group with probability tables for 104 major isotopes allowing detailed criticality studies, another in the same groups structure for the thermal compounds, and two others in coarser 172 XMAS and 175 Vitamin-J group structures for other criticality and shielding, transport studies. (authors)

22 CFR 42.31 - Family-sponsored immigrants.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Family-sponsored immigrants. 42.31 Section 42.31 Foreign Relations DEPARTMENT OF STATE VISAS VISAS: DOCUMENTATION OF IMMIGRANTS UNDER THE IMMIGRATION AND NATIONALITY ACT, AS AMENDED Immigrants Subject to Numerical Limitations § 42.31 Family...

14 CFR 31.23 - Flight load factor.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Flight load factor. 31.23 Section 31.23... STANDARDS: MANNED FREE BALLOONS Strength Requirements § 31.23 Flight load factor. In determining limit load, the limit flight load factor must be at least 1.4. ...

19 CFR 210.31 - Requests for admission.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Requests for admission. 210.31 Section 210.31 Customs Duties UNITED STATES INTERNATIONAL TRADE COMMISSION INVESTIGATIONS OF UNFAIR PRACTICES IN IMPORT TRADE ADJUDICATION AND ENFORCEMENT Discovery and Compulsory Process § 210.31 Requests for admission. (a...

28 CFR 32.31 - Scope of subpart.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Scope of subpart. 32.31 Section 32.31 Judicial Administration DEPARTMENT OF JUSTICE PUBLIC SAFETY OFFICERS' DEATH, DISABILITY, AND EDUCATIONAL ASSISTANCE BENEFIT CLAIMS Educational Assistance Benefit Claims § 32.31 Scope of subpart. Consistent with...

27 CFR 31.95 - Caterers.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Caterers. 31.95 Section 31....95 Caterers. (a) General. When a contract to furnish liquors is made by a caterer at a place of business for which the caterer has registered under this part, no additional registration is required by...

49 CFR 31.41 - Stay pending appeal.

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Stay pending appeal. 31.41 Section 31.41 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.41 Stay pending appeal. (a) An initial decision is stayed automatically pending disposition of a motion for reconsideration...

The vast thin plane of M31 corotating dwarfs: an additional fossil signature of the M31 merger and of its considerable impact in the whole Local Group

Science.gov (United States)

Hammer, François; Yang, Yanbin; Fouquet, Sylvain; Pawlowski, Marcel S.; Kroupa, Pavel; Puech, Mathieu; Flores, Hector; Wang, Jianling

2013-06-01

The recent discovery by Ibata et al. of a vast thin disc of satellites (VTDS) around M31 offers a new challenge for the understanding of the Local Group properties. This comes in addition to the unexpected proximity of the Magellanic Clouds (MCs) to the Milky Way (MW), and to another vast polar structure (VPOS), which is almost perpendicular to our Galaxy disc. We find that the VTDS plane is coinciding with several stellar, tidally induced streams in the outskirts of M31, and, that its velocity distribution is consistent with that of the giant stream (GS). This is suggestive of a common physical mechanism, likely linked to merger tidal interactions, knowing that a similar argument may apply to the VPOS at the MW location. Furthermore, the VTDS is pointing towards the MW, being almost perpendicular to the MW disc, as the VPOS is. We compare these properties to the modelling of M31 as an ancient, gas-rich major merger, which has been successfully used to predict the M31 substructures and the GS origin. We find that without fine tuning, the induced tidal tails are lying in the VTDS plane, providing a single and common origin for many stellar streams and for the vast stellar structures surrounding both the MW and M31. The model also reproduces quite accurately positions and velocities of the VTDS spheroidal dwarfs. Our conjecture leads to a novel interpretation of the Local Group past history, as a gigantic tidal tail due to the M31 ancient merger is expected to send material towards the MW, including the MCs. Such a link between M31 and the MW is expected to be quite exceptional, though it may be in qualitative agreement with the reported rareness of MW-MCs systems in nearby galaxies.

DOES M31 RESULT FROM AN ANCIENT MAJOR MERGER?

International Nuclear Information System (INIS)

Hammer, F.; Wang, J. L.; Puech, M.; Flores, H.; Fouquet, S.; Yang, Y. B.

2010-01-01

The M31 haunted halo is likely associated with a rich merger history, currently assumed to be caused by multiple minor mergers. Here we use the GADGET2 simulation code to test whether M31 could have experienced a major merger in its past history. Our results indicate that a (3 ± 0.5):1 gaseous-rich merger with r pericenter = 25 ± 5 kpc and a polar orbit can explain many properties of M31 and of its halo. The interaction and fusion may have begun 8.75 ± 0.35 and 5.5 ± 0.5 Gyr ago, respectively. Observed fractions of the bulge and the thin and thick disks can be retrieved for a star formation history that is almost quiescent before the fusion. This also accords well with the observed relative fractions of intermediate age and old stars in both the thick disk and the Giant Stream. In this model, the Giant Stream is caused by returning stars from a tidal tail which contains material previously stripped from the satellite prior to the fusion. These returning stars are trapped into elliptical orbits or loops for long periods of time which can reach a Hubble time, and belong to a plane that is 45 0 offset from the M31 disk position angle. Because these streams of stars are permanently fed by new infalling stars with high energy from the tidal tail, we predict large loops which scale rather well with the features recently discovered in the M31 outskirts. We demonstrate that a single merger could explain first-order (intensity and size), morphological, and kinematical properties of the disk, thick disk, bulge, and streams in the halo of M31, as well as the observed distribution of stellar ages, and perhaps metallicities. This challenges the current scenarios assuming that each feature in the disk (the 10 kpc ring) or in its outskirts (thick disk, the Giant Stream, and the numerous streams) is associated with an equivalent number of minor mergers. Given the large number of parameters, further constraints are certainly required to better render the complexity of M31 and

14 CFR 99.19-99.31 - [Reserved

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false [Reserved] 99.19-99.31 Section 99.19-99.31 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIR TRAFFIC AND GENERAL OPERATING RULES SECURITY CONTROL OF AIR TRAFFIC General §§ 99.19-99.31 [Reserved] ...

40 CFR 31.44 - Termination for convenience.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Termination for convenience. 31.44 Section 31.44 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL... convenience. Except as provided in § 31.43 awards may be terminated in whole or in part only as follows: (a...

49 CFR 659.31 - Hazard management process.

Science.gov (United States)

2010-10-01

... 49 Transportation 7 2010-10-01 2010-10-01 false Hazard management process. 659.31 Section 659.31... Agency § 659.31 Hazard management process. (a) The oversight agency must require the rail transit agency..., operational changes, or other changes within the rail transit environment. (b) The hazard management process...

19 CFR 111.31 - Conflict of interest.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 1 2010-04-01 2010-04-01 false Conflict of interest. 111.31 Section 111.31 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY CUSTOMS BROKERS Duties and Responsibilities of Customs Brokers § 111.31 Conflict of interest. (a...

39 CFR 955.31 - Dismissal without prejudice.

Science.gov (United States)

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Dismissal without prejudice. 955.31 Section 955.31... OF CONTRACT APPEALS § 955.31 Dismissal without prejudice. In certain cases, appeals docketed before... discretion, dismiss such appeals from its docket without prejudice to their restoration when the cause of...

The rarely reported tet(31) tetracycline resistance determinant is common in Gallibacterium anatis

DEFF Research Database (Denmark)

Bojesen, Anders M.; Bager, Ragnhild J.; Ifrah, Dan

2011-01-01

The present investigation was undertaken to identify and characterize the tetracycline resistance determinant in 22 Gallibacterium anatis strains for which no determinant was identified using primers specific for tet(A, B, C, D, E, G, H, K, L, M, O). A recent study found tet(B) to be the most pre...... from very different production systems and localities. In addition, tet(31) was identified in strains isolated over a 30-year period. This is the first report on tet(31) since its original identification in Aeromonas salmonicida....

STAR CLUSTERS IN M31. II. OLD CLUSTER METALLICITIES AND AGES FROM HECTOSPEC DATA

International Nuclear Information System (INIS)

Caldwell, Nelson; Schiavon, Ricardo; Morrison, Heather; Harding, Paul; Rose, James A.

2011-01-01

We present new high signal-to-noise spectroscopic data on the M31 globular cluster (GC) system, obtained with the Hectospec multifiber spectrograph on the 6.5 m MMT. More than 300 clusters have been observed at a resolution of 5 A and with a median S/N of 75 per A, providing velocities with a median uncertainty of 6 km s -1 . The primary focus of this paper is the determination of mean cluster metallicities, ages, and reddenings. Metallicities were estimated using a calibration of Lick indices with [Fe/H] provided by Galactic GCs. These match well the metallicities of 24 M31 clusters determined from Hubble Space Telescope color-magnitude diagrams, the differences having an rms of 0.2 dex. The metallicity distribution is not generally bimodal, in strong distinction with the bimodal Galactic globular distribution. Rather, the M31 distribution shows a broad peak, centered at [Fe/H] = -1, possibly with minor peaks at [Fe/H] = -1.4, -0.7, and -0.2, suggesting that the cluster systems of M31 and the Milky Way had different formation histories. Ages for clusters with [Fe/H] > - 1 were determined using the automatic stellar population analysis program EZ A ges. We find no evidence for massive clusters in M31 with intermediate ages, those between 2 and 6 Gyr. Moreover, we find that the mean ages of the old GCs are remarkably constant over about a decade in metallicity (-0.95∼< [Fe/H] ∼<0.0).

29 CFR 1960.31 - Inspections by OSHA.

Science.gov (United States)

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Inspections by OSHA. 1960.31 Section 1960.31 Labor... MATTERS Inspection and Abatement § 1960.31 Inspections by OSHA. (a) The Secretary or the Secretary's... scheduled inspections as an integral part of OSHA's evaluation of an agency's safety and health program in...

29 CFR 1620.31 - Issuance of subpoenas.

Science.gov (United States)

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Issuance of subpoenas. 1620.31 Section 1620.31 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION THE EQUAL PAY ACT § 1620.31 Issuance of subpoenas. (a) With respect to the enforcement of the Equal Pay Act, any member of the...

40 CFR 31.26 - Non-Federal audit.

Science.gov (United States)

2010-07-01

... awards in a fiscal year, shall: (1) Determine whether State or local subgrantees have met the audit... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Non-Federal audit. 31.26 Section 31.26... Requirements Financial Administration § 31.26 Non-Federal audit. (a) Basic rule. Grantees and subgrantees are...

19 CFR 123.31 - Merchandise in transit.

Science.gov (United States)

2010-04-01

... 19 Customs Duties 1 2010-04-01 2010-04-01 false Merchandise in transit. 123.31 Section 123.31... TREASURY CUSTOMS RELATIONS WITH CANADA AND MEXICO Shipments in Transit Through the United States § 123.31 Merchandise in transit. (a) From one contiguous country to another. Merchandise may be transported in transit...

38 CFR 17.31 - Duty periods defined.

Science.gov (United States)

2010-07-01

... Definitions and Active Duty § 17.31 Duty periods defined. Full-time duty as a member of the Women's Army Auxiliary Corps, Women's Reserve of the Navy and Marine Corps and Women's Reserve of the Coast Guard. [34 FR..., 1996, § 17.31(b)(5) was redesignated as § 17.31. Protection of Patient Rights ...

26 CFR 31.3306(b)-1 - Wages.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Wages. 31.3306(b)-1 Section 31.3306(b)-1... Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3306(b)-1 Wages. (a) Applicable law and... after 1938 constitutes wages is determined under section 3306(b). Accordingly, only remuneration paid...

Hypersociability in the behavioral phenotype of 17q21.31 microdeletion syndrome

NARCIS (Netherlands)

Egger, J.I.M.; Wingbermühle, P.A.M.; Verhoeven, W.M.A.; Dijkman, M.W.; Radke, S.; Bruijn, E.R.A. de; Vries, B. de; Kessels, R.P.C.; Koolen, D.A.

2013-01-01

The 17q21.31 microdeletion syndrome with its characteristic features including developmental delay, moderate intellectual disability, facial dysmorphisms, and anomalies of the brain and multiple organ systems was recently described. As to its behavioral profile, scarce data from clinical

25 CFR 89.31 - Negotiation of contract.

Science.gov (United States)

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Negotiation of contract. 89.31 Section 89.31 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR TRIBAL GOVERNMENT ATTORNEY CONTRACTS WITH INDIAN TRIBES Five Civilized Tribes § 89.31 Negotiation of contract. That person or governing entity recognized as having authority to act for and in behalf o...

26 CFR 31.3231(e)-1 - Compensation.

Science.gov (United States)

2010-04-01

.... (a) Definition—(1) The term compensation has the same meaning as the term wages in section 3121(a... regarding the inclusion of fringe benefits in compensation, see § 31.3121(a)-1T. (6) Split-dollar life... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Compensation. 31.3231(e)-1 Section 31.3231(e)-1...

3+1 Pariisis

Index Scriptorium Estoniae

2000-01-01

Pariisis Arhitektuurigaleriis La Galerie d'Architecture näitus "4 Architectures", kuhu on valitud arhitektuuribürood neljast riigist: 3+1 arhitektid Eestist, Archis Lätist, Private Ideology Leedust, White arkitekter Rootsist.

40 CFR 427.31 - Specialized definitions.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 29 2010-07-01 2010-07-01 false Specialized definitions. 427.31 Section 427.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS ASBESTOS MANUFACTURING POINT SOURCE CATEGORY Asbestos Paper (Starch Binder) Subcategory...

26 CFR 31.3401(a)-1 - Wages.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Wages. 31.3401(a)-1 Section 31.3401(a)-1... Income Tax at Source § 31.3401(a)-1 Wages. (a) In general. (1) The term “wages” means all remuneration..., pensions, and retired pay are wages within the meaning of the statute if paid as compensation for services...

14 CFR 31.25 - Factor of safety.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Factor of safety. 31.25 Section 31.25... STANDARDS: MANNED FREE BALLOONS Strength Requirements § 31.25 Factor of safety. (a) Except as specified in paragraphs (b) and (c) of this section, the factor of safety is 1.5. (b) A factor of safety of at least five...

Development of a Chemically Defined Medium for Better Yield and Purification of Enterocin Y31 from Enterococcus faecium Y31

Directory of Open Access Journals (Sweden)

Wenli Liu

2017-01-01

Full Text Available The macro- and micronutrients in traditional medium, such as MRS, used for cultivating lactic acid bacteria, especially for bacteriocin production, have not been defined, preventing the quantitative monitoring of metabolic flux during bacteriocin biosynthesis. To enhance Enterocin Y31 production and simplify steps of separation and purification, we developed a simplified chemically defined medium (SDM for the growth of Enterococcus faecium Y31 and production of its bacteriocin, Enterocin Y31. We found that the bacterial growth was unrelated to Enterocin Y31 production in MRS; therefore, both the growth rate and the Enterocin Y31 production were set as the index for investigation. Single omission experiments revealed that 5 g/L NaCl, five vitamins, two nucleic acid bases, MgSO4·7H2O, MnSO4·4H2O, KH2PO4, K2HPO4, CH3COONa, fourteen amino acids, and glucose were essential for the strain’s growth and Enterocin Y31 production. Thus, a novel simplified and defined medium (SDM was formulated with 30 components in total. Consequently, Enterocin Y31 production yield was higher in SDM as compared to either MRS or CDM. SDM improved the Enterocin Y31 production and simplified the steps of purification (only two steps, which has broad potential applications.

A novel genetic tool for metabolic optimization of Corynebacterium glutamicum: efficient and repetitive chromosomal integration of synthetic promoter-driven expression libraries

DEFF Research Database (Denmark)

Shen, Jing; Chen, Jun; Jensen, Peter Ruhdal

2017-01-01

readily could integrate into the attB site in this strain providing expression of the corresponding integrase. Subsequent expression of the Cre recombinase promoted recombination between the modified loxP sites, resulting in a strain only retaining the target insertions and an attB site. To simplify...... the procedure, non-replicating circular expression units for the phage integrase and the Cre recombinase were used. As a showcase, we used the tool to construct a battery of strains simultaneously expressing the two reporter genes, lacZ (encoding β-galactosidase) and gusA (encoding β...

Emerging contaminants and nutrients synergistically affect the spread of class 1 integron-integrase (intI1) and sul1 genes within stable streambed bacterial communities.

Science.gov (United States)

Subirats, Jèssica; Timoner, Xisca; Sànchez-Melsió, Alexandre; Balcázar, José Luis; Acuña, Vicenç; Sabater, Sergi; Borrego, Carles M

2018-07-01

Wastewater effluents increase the nutrient load of receiving streams while introducing a myriad of anthropogenic chemical pollutants that challenge the resident aquatic (micro)biota. Disentangling the effects of both kind of stressors and their potential interaction on the dissemination of antibiotic resistance genes in bacterial communities requires highly controlled manipulative experiments. In this work, we investigated the effects of a combined regime of nutrients (at low, medium and high concentrations) and a mixture of emerging contaminants (ciprofloxacin, erythromycin, sulfamethoxazole, diclofenac, and methylparaben) on the bacterial composition, abundance and antibiotic resistance profile of biofilms grown in artificial streams. In particular, we investigated the effect of this combined stress on genes encoding resistance to ciprofloxacin (qnrS), erythromycin (ermB), sulfamethoxazole (sul1 and sul2) as well as the class 1 integron-integrase gene (intI1). Only genes conferring resistance to sulfonamides (sul1 and sul2) and intI1 gene were detected in all treatments during the study period. Besides, bacterial communities exposed to emerging contaminants showed higher copy numbers of sul1 and intI1 genes than those not exposed, whereas nutrient amendments did not affect their abundance. However, bacterial communities exposed to both emerging contaminants and a high nutrient concentration (1, 25 and 1 mg L -1 of phosphate, nitrate and ammonium, respectively) showed the highest increase on the abundance of sul1 and intI1 genes thus suggesting a factors synergistic effect of both stressors. Since none of the treatments caused a significant change on the composition of bacterial communities, the enrichment of sul1 and intI1 genes within the community was caused by their dissemination under the combined pressure exerted by nutrients and emerging contaminants. To the best of our knowledge, this is the first study demonstrating the contribution of nutrients on

MicroRNA-31 Regulates Chemosensitivity in Malignant Pleural Mesothelioma

Directory of Open Access Journals (Sweden)

Hannah L. Moody

2017-09-01

Full Text Available Malignant pleural mesothelioma (MPM is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31 is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Although miR-31 re-expression increased chemoresistance, paradoxically, a higher relative intracellular accumulation of platinum was detected. This was coupled to a significantly decreased intranuclear concentration of platinum. Linked with a downregulation of OCT1, a bipotential transcriptional regulator with multiple miR-31 target binding sites, we subsequently identified an indirect miR-31-mediated upregulation of ABCB9, a transporter associated with drug accumulation in lysosomes, and increased uptake of platinum to lysosomes. However, when overexpressed directly, ABCB9 promoted cellular chemosensitivity, suggesting that miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, our data suggest that miR-31 loss from MPM tumors promotes chemosensitivity and may be prognostically beneficial in the context of therapeutic sensitivity. Keywords: malignant pleural mesothelioma, microRNA-31, chemoresistance, cisplatin, ABCB9

40 CFR 407.31 - Specialized definitions.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 28 2010-07-01 2010-07-01 true Specialized definitions. 407.31 Section 407.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS CANNED AND PRESERVED FRUITS AND VEGETABLES PROCESSING POINT SOURCE CATEGORY Citrus Products...

Medium-energy physics program. Progress report, November 1, 1976--January 31, 1977

Energy Technology Data Exchange (ETDEWEB)

Dunn, E. (comp.)

1977-06-01

Operations and research programs at the LAMPF Linac are reported for the period from November 1, 1976 through January 31, 1977. The contents include: (1) a summary and a list of recent publications; (2) engineering support; (3) accelerator support; (4) accelerator systems development; (5) injector systems; (6) electronic instrumentation and computer systems; (7) accelerator operations; (8) experimental areas; (9) beam line development; (10) large-spectrometer systems; (11) research; (12) nuclear chemistry; (13) practical applications of LAMPF; (14) the PIGMI program (Pion Generator for Medical Irradiations); and (15) management. (PMA)

Medium-energy physics program. Progress report, November 1, 1976--January 31, 1977

International Nuclear Information System (INIS)

Dunn, E.

1977-06-01

Operations and research programs at the LAMPF Linac are reported for the period from November 1, 1976 through January 31, 1977. The contents include: (1) a summary and a list of recent publications; (2) engineering support; (3) accelerator support; (4) accelerator systems development; (5) injector systems; (6) electronic instrumentation and computer systems; (7) accelerator operations; (8) experimental areas; (9) beam line development; (10) large-spectrometer systems; (11) research; (12) nuclear chemistry; (13) practical applications of LAMPF; (14) the PIGMI program (Pion Generator for Medical Irradiations); and (15) management

Enterprise JavaBeans 31

CERN Document Server

Rubinger, Andrew

2010-01-01

Learn how to code, package, deploy, and test functional Enterprise JavaBeans with the latest edition of this bestselling guide. Written by the developers of JBoss EJB 3.1, this book not only brings you up to speed on each component type and container service in this implementation, it also provides a workbook with several hands-on examples to help you gain immediate experience with these components. With version 3.1, EJB's server-side component model for building distributed business applications is simpler than ever. But it's still a complex technology that requires study and lots of practi

40 CFR 432.31 - Special definitions.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 29 2010-07-01 2010-07-01 false Special definitions. 432.31 Section 432.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND... definitions. For the purpose of this subpart: Low-processing packinghouse means a packinghouse that processes...

31. maini on Narvas Hermanni kindluses...

Index Scriptorium Estoniae

2002-01-01

Tallinna Kunstikooli õpetajate Lilian Mosolaineni maalide (31. maini), Urmas Orgussaare joonistuste ja nahkehistöö ning Anna Litvinova maalide näitus (juuni lõpuni). Narva Kunstikoolis Tallinna Kunstikooli õpilaste tööde näitus 31. maini (kujundajad Peeter Kuutma, Riste Laasberg).

15 CFR 700.31 - Metalworking machines.

Science.gov (United States)

2010-01-01

... 15 Commerce and Foreign Trade 2 2010-01-01 2010-01-01 false Metalworking machines. 700.31 Section 700.31 Commerce and Foreign Trade Regulations Relating to Commerce and Foreign Trade (Continued) BUREAU OF INDUSTRY AND SECURITY, DEPARTMENT OF COMMERCE NATIONAL SECURITY INDUSTRIAL BASE REGULATIONS...

31 CFR 357.20 - Securities account in Legacy Treasury Direct ®.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Securities account in Legacy Treasury Direct ®. 357.20 Section 357.20 Money and Finance: Treasury Regulations Relating to Money and Finance... Securities System (Legacy Treasury Direct) § 357.20 Securities account in Legacy Treasury Direct ®. (a...

31 CFR 357.30 - Cases of delay or suspension of payment.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Cases of delay or suspension of payment. 357.30 Section 357.30 Money and Finance: Treasury Regulations Relating to Money and Finance... Securities System (Legacy Treasury Direct) § 357.30 Cases of delay or suspension of payment. If evidence...

7 CFR 3016.31 - Real property.

Science.gov (United States)

2010-01-01

... 7 Agriculture 15 2010-01-01 2010-01-01 false Real property. 3016.31 Section 3016.31 Agriculture Regulations of the Department of Agriculture (Continued) OFFICE OF THE CHIEF FINANCIAL OFFICER, DEPARTMENT OF AGRICULTURE UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND COOPERATIVE AGREEMENTS TO STATE AND LOCAL...

7 CFR 982.31 - Grower districts.

Science.gov (United States)

2010-01-01

... 7 Agriculture 8 2010-01-01 2010-01-01 false Grower districts. 982.31 Section 982.31 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... importance of production in each district and the number of growers in each district; (2) the geographic...

17 CFR 31.15 - Reporting to leverage customers.

Science.gov (United States)

2010-04-01

... customers. 31.15 Section 31.15 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION LEVERAGE TRANSACTIONS § 31.15 Reporting to leverage customers. Each leverage transaction merchant shall furnish in writing directly to each leverage customer: (a) Promptly upon the repurchase, resale...

In vivo 31P MR spectroscopy of breast tumors: preliminary results

International Nuclear Information System (INIS)

Choe, Bo Young; Kim, Hak Hee; Suh, Tae Suk; Shinn, Kyung Sub; Jung, Sang Seol

1995-01-01

To evaluate the various phosphorus metabolism of breast tumors with use of in vivo phosphorus-31 ( 31 P) MR spectroscopy (MRS). Five patients with breast tumor (benign in two, malignant in three) and three normal healthy volunteers participated in this study. All in vivo 31 P MRS examinations were performed on 1.5T whole-body MRI/MRS system by using a Free Induction Decay (FID) pulse sequence. T1-weighted MR images were used for localization of tumors. Peak areas for each phosphorus metabolite were measured using a Marquart algorithm. Breast carcinoma had a substantially larger phosphomonoester (PME) and a smaller phosphocreatine (PCr) peak intensity than normal breast tissue. This was reflected in the relatively higher PME/PCr ratio of breast carcinomas as well as phosphodiester (PDE)/PCr, inorganic phosphate (Pi)/PCr, and adenosine triphosphate (ATP)/PCr ratios, compared with normal controls. The mean pH value of breast tumor demonstrating the alkaline nature was higher than that of normal controls. Spectral patterns between benign breast disease and normal breast tissue were quite similar, and differentiation was not established. Our preliminary study suggests that in vivo 31 P MRS is a noninvasive examination which may be useful in the early differentiation of malignant breast tumors from normal and benign conditions. However, normal control and benign conditions could not be characterized on the basis of the phosphorus metabolite ratios

32 CFR 1900.31 - Procedures for business information.

Science.gov (United States)

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Procedures for business information. 1900.31 Section 1900.31 National Defense Other Regulations Relating to National Defense CENTRAL INTELLIGENCE... Matters § 1900.31 Procedures for business information. (a) In general. Business information obtained by...

27 CFR 25.31 - Brewery buildings.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Brewery buildings. 25.31... OF THE TREASURY LIQUORS BEER Construction and Equipment Construction § 25.31 Brewery buildings. Brewery buildings shall be arranged and constructed to afford adequate protection to the revenue and to...

30 CFR 7.31 - New technology.

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false New technology. 7.31 Section 7.31 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR TESTING, EVALUATION, AND APPROVAL OF... technology. MSHA may approve brattice cloth and ventilation tubing that incorporates technology for which the...

SENSITIVE 21 cm OBSERVATIONS OF NEUTRAL HYDROGEN IN THE LOCAL GROUP NEAR M31

Energy Technology Data Exchange (ETDEWEB)

Wolfe, Spencer A.; Pisano, D. J. [Dept. of Physics and Astronomy, West Virginia University, Morgantown, WV 26506 (United States); Lockman, Felix J., E-mail: swolfe4@mix.wvu.edu, E-mail: DJPisano@mail.wvu.edu, E-mail: jlockman@nrao.edu [National Radio Astronomy Observatory, Green Bank, WV 24944 (United States)

2016-01-10

Very sensitive 21 cm H i measurements have been made at several locations around the Local Group galaxy M31 using the Green Bank Telescope at an angular resolution of 9.′1, with a 5σ detection level of N{sub H} {sub i} = 3.9 × 10{sup 17} cm{sup −2} for a 30 km s{sup −1} line. Most of the H i in a 12 square-degree area almost equidistant between M31 and M33 is contained in nine discrete clouds that have a typical size of a few kpc and a H i mass of 10{sup 5}M{sub ⊙}. Their velocities in the Local Group Standard of Rest lie between −100 and +40 km s{sup −1}, comparable to the systemic velocities of M31 and M33. The clouds appear to be isolated kinematically and spatially from each other. The total H i mass of all nine clouds is 1.4 × 10{sup 6}M{sub ⊙} for an adopted distance of 800 kpc, with perhaps another 0.2 × 10{sup 6}M{sub ⊙} in smaller clouds or more diffuse emission. The H i mass of each cloud is typically three orders of magnitude less than the dynamical (virial) mass needed to bind the cloud gravitationally. Although they have the size and H i mass of dwarf galaxies, the clouds are unlikely to be part of the satellite system of the Local Group, as they lack stars. To the north of M31, sensitive H i measurements on a coarse grid find emission that may be associated with an extension of the M31 high-velocity cloud (HVC) population to projected distances of ∼100 kpc. An extension of the M31 HVC population at a similar distance to the southeast, toward M33, is not observed.

Patterns of primary production in the Red Sea

Digital Repository Service at National Institute of Oceanography (India)

Qurban, M.A.; Wafar, M.; Jyothibabu, R.; Manikandan, K.P.

for bio- phic stations occupied in e Indian Ocean (source - et al., 1995), remotely-sensed (CZCS) chlorophyll data were used to make deductions on rates of primary production at basin-scale. The conclusion consistently arrived at from all earlier studies... acquired along the axis of the basin in the 2013 cruise, Wafar et al. (2016a) identified alternating zonal currents at six locations – 18–18.5°N, 19–20.5°N, 22°N, 24°N, 24.5°N and 26°N - and concluded that they represent three successive anticyclonic cells...

Social cognition and the behavioural phenotype of 17q21.31 microdeletion syndrome

NARCIS (Netherlands)

Egger, J.I.M.; Wingbermühle, P.A.M.; Verhoeven, W.M.A.; Dijkman, M.W.; Kessels, R.P.C.; Koolen, D.A.

2012-01-01

Introduction Recently, the 17q21.31 microdeletion syndrome was described with characteristic features including developmental delay, moderate intellectual disability, facial dysmorphisms, and anomalies of the brain and multiple organ systems. With respect to behaviour, scarce data from clinical

Metagenomic exploration reveals a marked change in the river resistome and mobilome after treated wastewater discharges.

Science.gov (United States)

Lekunberri, Itziar; Balcázar, José Luis; Borrego, Carles M

2018-03-01

Mobile genetic elements (MGEs) are key agents in the spread of antibiotic resistance genes (ARGs) across environments. Here we used metagenomics to compare the river resistome (collection of all ARGs) and mobilome (e.g., integrases, transposases, integron integrases and insertion sequence common region "ISCR" elements) between samples collected upstream (n = 6) and downstream (n = 6) of an urban wastewater treatment plant (UWWTP). In comparison to upstream metagenomes, downstream metagenomes showed a drastic increase in the abundance of ARGs, as well as markers of MGEs, particularly integron integrases and ISCR elements. These changes were accompanied by a concomitant prevalence of 16S rRNA gene signatures of bacteria affiliated to families encompassing well-known human and animal pathogens. Our results confirm that chronic discharges of treated wastewater severely impact the river resistome affecting not only the abundance and diversity of ARGs but also their potential spread by enriching the river mobilome in a wide variety of MGEs. Copyright © 2017 Elsevier Ltd. All rights reserved.

47 CFR 0.31 - Functions of the Office.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Functions of the Office. 0.31 Section 0.31 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL COMMISSION ORGANIZATION Organization Office of Engineering and Technology § 0.31 Functions of the Office. The Office of Engineering and Technology has the...

40 CFR 255.31 - Integration with other acts.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Integration with other acts. 255.31 Section 255.31 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES... Relationship to Other Programs § 255.31 Integration with other acts. The Governor shall integrate the...

31 CFR 205.18 - Are administrative costs subject to this part?

Science.gov (United States)

2010-07-01

... or other system under an approved cost allocation plan, the State will draw down funds to meet cash... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Are administrative costs subject to... Treasury-State Agreement § 205.18 Are administrative costs subject to this part? (a) A State and FMS may...

Simulated hatchery system to assess bacteriophage efficacy against Vibrio harveyi.

Science.gov (United States)

Raghu Patil, J; Desai, Srividya Narayanamurthy; Roy, Panchali; Durgaiah, Murali; Saravanan, R Sanjeev; Vipra, Aradhana

2014-12-02

Vibriosis caused by luminous Vibrio harveyi commonly contributes to poor survival in shrimp hatcheries and aquaculture ponds. Lytic bacteriophages pathogenic for V. harveyi are currently being investigated as an alternative to antibiotics to prevent vibriosis. Here, 8 bacteriophages were isolated from oysters and clams using V. harveyi strains as baiting hosts. Among these bacteriophages, 1 strain (VHP6b) identified as broadly pathogenic for 27 V. harveyi strains examined was further characterized by electron microscopy and genome sequence analysis. Phage VHP6b possessed a tail and morphology consistent with it being a member of the family Siphoviridae, and its genome and proteome were most closely related to the Vibrio phages SSP02 and MAR10. An integrase gene essential for lysogeny was not evident. The ability of bacteriophage VHP6b to protect shrimp postlarvae against vibriosis caused by V. harveyi strain VH6 was demonstrated in a model system designed to simulate typical hatchery conditions. Bacteriophage treatment improved survival of postlarvae by 40 to 60% under these conditions, so therapies based on this or other bacteriophages may be useful in shrimp hatcheries.

28 CFR 31.202 - Civil rights.

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Civil rights. 31.202 Section 31.202....202 Civil rights. (a) To carry out the State's Federal civil rights responsibilities the plan must: (1) Designate a civil rights contact person who has lead responsibility in insuring that all applicable civil...

24 CFR 970.31 - Replacement units.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Replacement units. 970.31 Section... PUBLIC HOUSING PROGRAM-DEMOLITION OR DISPOSITION OF PUBLIC HOUSING PROJECTS § 970.31 Replacement units. Notwithstanding any other provision of law, replacement public housing units may be built on the original public...

14 CFR 142.31 - Advertising limitations.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Advertising limitations. 142.31 Section 142...) SCHOOLS AND OTHER CERTIFICATED AGENCIES TRAINING CENTERS General § 142.31 Advertising limitations. (a) A certificate holder may not conduct, and may not advertise to conduct, any training, testing, and checking that...

27 CFR 31.232 - Wine bottling.

Science.gov (United States)

2010-04-01

.... The decanting of wine by caterers or other retail dealers for table or room service, banquets, and... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Wine bottling. 31.232... OF THE TREASURY LIQUORS ALCOHOL BEVERAGE DEALERS Miscellaneous § 31.232 Wine bottling. Each person...

Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

Directory of Open Access Journals (Sweden)

Aylin Yilmaz

2009-09-01

Full Text Available Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF and plasma in subjects receiving antiretroviral treatment regimens containing this drug.Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma.Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0. The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180. CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations.Approximately 50% of the CSF specimens exceeded the IC(95 levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

Science.gov (United States)

Yilmaz, Aylin; Gisslén, Magnus; Spudich, Serena; Lee, Evelyn; Jayewardene, Anura; Aweeka, Francesca; Price, Richard W

2009-09-01

Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug. Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma. Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations. Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

10 CFR 36.31 - Control of source movement.

Science.gov (United States)

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Control of source movement. 36.31 Section 36.31 Energy NUCLEAR REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR IRRADIATORS Design and Performance Requirements for Irradiators § 36.31 Control of source movement. (a) The mechanism that moves the...

40 CFR 31.5 - Effect on other issuances.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Effect on other issuances. 31.5 Section 31.5 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE... General § 31.5 Effect on other issuances. All other grants administration provisions of codified program...

Structural, magnetic and transport properties of Mn3.1Sn0.9 and Mn3.1Sn0.9N compounds

International Nuclear Information System (INIS)

Feng, W.J.; Li, D.; Ren, W.J.; Li, Y.B.; Li, W.F.; Li, J.; Zhang, Y.Q.; Zhang, Z.D.

2007-01-01

The cubic anti-perovskite Mn 3.1 Sn 0.9 N compound is prepared via nitrogenation of the hexagonal Mn 3.1 Sn 0.9 compound. A magnetic phase diagram of Mn 3.1 Sn 0.9 compound is constructed by analysis of data of its magnetic properties. For Mn 3.1 Sn 0.9 N compound, parasitic ferromagnetism exists in the temperature range of 5-370 K, besides a spin-reorientation at about 280 K. Mn 3.1 Sn 0.9 compound exhibits a metallic conducting behavior, while Mn 3.1 Sn 0.9 N displays a metal-nonmetal transition due to the electron localization caused by the static disorder. The differences of the physical properties between the both compounds, are discussed, in terms of the correlation of the hexagonal DO 19 and the cubic anti-perovskite structures, the reduction of the distances between Mn atoms, and the spin-pairing or charge transfer effect due to the electron donation by N 2p to Mn 3d states after introduction of N atoms into the interstitial sites of Mn 3.1 Sn 0.9 compound

TMS320C31 master

International Nuclear Information System (INIS)

Yun, Deok Yong

1999-06-01

The contents of this book are explanation of basic conception for DSP, perfect a complete master of TMS320C31, I/O interface design and memory, practice with PC print port, basic programing skill, assembly and C programing technique, timer and interrupt application skill, serial communication programing technique, application of digital conditioning and application of digital servo control. This book is divided into two parts, which is about TMS320C31 master of theory and application.

49 CFR 31.10 - Default upon failure to answer.

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Default upon failure to answer. 31.10 Section 31.10 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.10 Default upon failure to answer. (a) If the defendant does not answer within the time prescribed in § 31.9...

Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs

DEFF Research Database (Denmark)

Damkjaer, Mads; Nielsen, Gorm; Bodendiek, Silke

2012-01-01

Background and purpose.  In rodents, the endothelial KCa-channels, KCa3.1 and KCa2.3, have been shown to play a crucial role in initiating endothelium-derived hyperpolarising factor(EDHF) vasodilator responses. However, it is not known to which extent these channels are involved in blood pressure...... regulation in large mammals which also allow addressing safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect on blood pressure and heart rate of the KCa3.1/KCa2.3-activator SKA-31 in dogs. Experimental approach.  Canine endothelial KCa3.1/KCa2.......3 functions were studied by patch-clamp electrophysiology and wire-myography in mesenteric arteries. The systemic cardiovascular actions of acute SKA-31 administration were monitored in conscious, unstressed beagle dogs. Key results.  Mesenteric endothelial cells expressed functional KCa3.1 and KCa2...

14 CFR 31.65 - Position lights.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Position lights. 31.65 Section 31.65 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS...; and z is not greater than 0.002. (2) Aviation white— x is not less than 0.300 and not greater than 0...

7 CFR 30.31 - Classification of leaf tobacco.

Science.gov (United States)

2010-01-01

... 7 Agriculture 2 2010-01-01 2010-01-01 false Classification of leaf tobacco. 30.31 Section 30.31... REGULATIONS TOBACCO STOCKS AND STANDARDS Classification of Leaf Tobacco Covering Classes, Types and Groups of Grades § 30.31 Classification of leaf tobacco. For the purpose of this classification leaf tobacco shall...

7 CFR 550.31 - Questionnaires and survey plans.

Science.gov (United States)

2010-01-01

... 7 Agriculture 6 2010-01-01 2010-01-01 false Questionnaires and survey plans. 550.31 Section 550.31... Agreements Program Management § 550.31 Questionnaires and survey plans. The Cooperator is required to submit to the REE Agency copies of questionnaires and other forms for clearance in accordance with the...

42 CFR 31.2 - Persons entitled to treatment.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Persons entitled to treatment. 31.2 Section 31.2... Public Health Service § 31.2 Persons entitled to treatment. To the extent and under the circumstances... treatment and hospitalization by the Service: (a) Coast Guard. (1) Commissioned officers, chief warrant...

42 CFR 31.11 - Persons entitled to treatment.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Persons entitled to treatment. 31.11 Section 31.11... § 31.11 Persons entitled to treatment. To the extent and under the circumstances prescribed in this part, the following persons shall be entitled to medical, surgical, and dental treatment and...

14 CFR 294.31 - Use of business name.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Use of business name. 294.31 Section 294.31 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS CANADIAN CHARTER AIR TAXI OPERATORS General Rules for Registrants § 294.31 Use of business name...

29 CFR 1919.31 - Proof tests-loose gear.

Science.gov (United States)

2010-07-01

... 29 Labor 7 2010-07-01 2010-07-01 false Proof tests-loose gear. 1919.31 Section 1919.31 Labor... (CONTINUED) GEAR CERTIFICATION Certification of Vessels: Tests and Proof Loads; Heat Treatment; Competent Persons § 1919.31 Proof tests—loose gear. (a) Chains, rings, shackles and other loose gear (whether...

21 CFR 25.31 - Human drugs and biologics.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

27 CFR 71.31 - Attorneys and other representatives.

Science.gov (United States)

2010-04-01

... representatives. 71.31 Section 71.31 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... applicant may be represented by an attorney, certified public accountant, or other person enrolled to practice before the Alcohol and Tobacco Tax and Trade Bureau under 31 CFR part 8—Practice before the...

Genetics Home Reference: 5q31.3 microdeletion syndrome

Science.gov (United States)

... up of a patient with 5q31.3 microdeletion syndrome and the smallest de novo 5q31.2q31.3 deletion involving PURA. Mol Cytogenet. 2015 Nov 14;8:89. doi: 10.1186/s13039-015-0193-9. eCollection 2015. ... 5q31.3 Microdeletion syndrome: clinical and molecular characterization of two further cases. ...

31 CFR 16.42 - Judicial review.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Judicial review. 16.42 Section 16.42... FRAUD CIVIL REMEDIES ACT OF 1986 § 16.42 Judicial review. Section 3805 of title 31, United States Code, authorizes judicial review by an appropriate United States District Court of a final decision of the...

27 CFR 31.123 - New corporation.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false New corporation. 31.123... Requiring Registration As A New Business § 31.123 New corporation. Where a new corporation is formed to take over and conduct the business of one or more corporations that have registered under this part, the new...

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

Directory of Open Access Journals (Sweden)

Sergio Serrano-Villar

2016-01-01

Full Text Available Whether initiation of antiretroviral therapy (ART regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6, lipoteichoic acid (LTA, soluble CD14 (sCD14 and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively, with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease

Construction of initial data for 3+1 numerical relativity

Energy Technology Data Exchange (ETDEWEB)

Gourgoulhon, Eric [Laboratoire Univers et Theories, UMR 8102 du C.N.R.S., Observatoire de Paris, Universite Paris 7 - Denis Diderot, F-92195 Meudon Cedex (France)

2007-11-15

This lecture is devoted to the problem of computing initial data for the Cauchy problem of 3+1 general relativity. The main task is to solve the constraint equations. The conformal technique, introduced by Lichnerowicz and enhanced by York, is presented. Two standard methods, the conformal transverse-traceless one and the conformal thin sandwich, are discussed and illustrated by some simple examples. Finally a short review regarding initial data for binary systems (black holes and neutron stars) is given.

46 CFR 31.20-1 - Waters-TB/ALL.

Science.gov (United States)

2010-10-01

... 46 Shipping 1 2010-10-01 2010-10-01 false Waters-TB/ALL. 31.20-1 Section 31.20-1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS INSPECTION AND CERTIFICATION Waters Operated Over § 31.20-1 Waters—TB/ALL. The certificate of inspection shall show the waters over which the tank vessel...

49 CFR 31.39 - Appeal to authority head.

Science.gov (United States)

2010-10-01

... shall forward two copies of the notice of appeal to the authority head, and shall forward or make... 49 Transportation 1 2010-10-01 2010-10-01 false Appeal to authority head. 31.39 Section 31.39 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.39 Appeal to authority...

49 CFR 173.31 - Use of tank cars.

Science.gov (United States)

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Use of tank cars. 173.31 Section 173.31... SHIPMENTS AND PACKAGINGS Preparation of Hazardous Materials for Transportation § 173.31 Use of tank cars. (a) General. (1) No person may offer a hazardous material for transportation in a tank car unless the tank car...

7 CFR 1738.31 - Full faith and credit.

Science.gov (United States)

2010-01-01

... 7 Agriculture 11 2010-01-01 2010-01-01 false Full faith and credit. 1738.31 Section 1738.31... AGRICULTURE RURAL BROADBAND ACCESS LOANS AND LOAN GUARANTEES Types of Loans § 1738.31 Full faith and credit. Loan guarantees made under this part are supported by the full faith and credit of the United States. ...

Validation of 31 of the most commonly used immunohistochemical antibodies in cytology prepared using the Cellient(®) automated cell block system.

Science.gov (United States)

Montgomery, Eric; Gao, Chen; de Luca, Julie; Bower, Jessie; Attwood, Kristropher; Ylagan, Lourdes

2014-12-01

The Cellient(®) cell block system has become available as an alternative, partially automated method to create cell blocks in cytology. We sought to show a validation method for immunohistochemical (IHC) staining on the Cellient cell block system (CCB) in comparison with the formalin fixed paraffin embedded traditional cell block (TCB). Immunohistochemical staining was performed using 31 antibodies on 38 patient samples for a total of 326 slides. Split samples were processed using both methods by following the Cellient(®) manufacturer's recommendations for the Cellient cell block (CCB) and the Histogel method for preparing the traditional cell block (TCB). Interpretation was performed by three pathologists and two cytotechnologists. Immunohistochemical stains were scored as: 0/1+ (negative) and 2/3+ (positive). Inter-rater agreement for each antibody was evaluated for CCB and TCB, as well as the intra-rater agreement between TCB and CCB between observers. Interobserver staining concordance for the TCB was obtained with statistical significance (P Cellient system are reliable and concordant with stains performed on the same split samples processed via a formalin fixed-paraffin embedded (FFPE) block. The Cellient system is a welcome adjunct to cytology work-flow by producing cell block material of sufficient quality to allow the use of routine IHC. © 2014 Wiley Periodicals, Inc.

19 CFR 159.31 - Rates to be used.

Science.gov (United States)

2010-04-01

... (CONTINUED) LIQUIDATION OF DUTIES Conversion of Foreign Currency § 159.31 Rates to be used. Except as otherwise specified in this subpart, no rate or rates of exchange shall be used to convert foreign currency... 19 Customs Duties 2 2010-04-01 2010-04-01 false Rates to be used. 159.31 Section 159.31 Customs...

Investigating CFTR and KCa3.1 Protein/Protein Interactions.

Directory of Open Access Journals (Sweden)

Hélène Klein

Full Text Available In epithelia, Cl- channels play a prominent role in fluid and electrolyte transport. Of particular importance is the cAMP-dependent cystic fibrosis transmembrane conductance regulator Cl- channel (CFTR with mutations of the CFTR encoding gene causing cystic fibrosis. The bulk transepithelial transport of Cl- ions and electrolytes needs however to be coupled to an increase in K+ conductance in order to recycle K+ and maintain an electrical driving force for anion exit across the apical membrane. In several epithelia, this K+ efflux is ensured by K+ channels, including KCa3.1, which is expressed at both the apical and basolateral membranes. We show here for the first time that CFTR and KCa3.1 can physically interact. We first performed a two-hybrid screen to identify which KCa3.1 cytosolic domains might mediate an interaction with CFTR. Our results showed that both the N-terminal fragment M1-M40 of KCa3.1 and part of the KCa3.1 calmodulin binding domain (residues L345-A400 interact with the NBD2 segment (G1237-Y1420 and C- region of CFTR (residues T1387-L1480, respectively. An association of CFTR and F508del-CFTR with KCa3.1 was further confirmed in co-immunoprecipitation experiments demonstrating the formation of immunoprecipitable CFTR/KCa3.1 complexes in CFBE cells. Co-expression of KCa3.1 and CFTR in HEK cells did not impact CFTR expression at the cell surface, and KCa3.1 trafficking appeared independent of CFTR stimulation. Finally, evidence is presented through cross-correlation spectroscopy measurements that KCa3.1 and CFTR colocalize at the plasma membrane and that KCa3.1 channels tend to aggregate consequent to an enhanced interaction with CFTR channels at the plasma membrane following an increase in intracellular Ca2+ concentration. Altogether, these results suggest 1 that the physical interaction KCa3.1/CFTR can occur early during the biogenesis of both proteins and 2 that KCa3.1 and CFTR form a dynamic complex, the formation of which

Development of a Chemically Defined Medium for Better Yield and Purification of Enterocin Y31 from Enterococcus faecium Y31

OpenAIRE

Liu, Wenli; Zhang, Lanwei; Yi, Huaxi

2017-01-01

The macro- and micronutrients in traditional medium, such as MRS, used for cultivating lactic acid bacteria, especially for bacteriocin production, have not been defined, preventing the quantitative monitoring of metabolic flux during bacteriocin biosynthesis. To enhance Enterocin Y31 production and simplify steps of separation and purification, we developed a simplified chemically defined medium (SDM) for the growth of Enterococcus faecium Y31 and production of its bacteriocin, Enterocin Y31...

Development of Rolling Schedules for AZ31 Magnesium Alloy Sheets

Science.gov (United States)

2015-06-01

Materials 2 2.2 Hot Rolling 3 2.2 Sample Characterization: Microstructure and Tensile Properties 3 3. Rolling Experiments 5 3.1 High-Temperature...material systems for protective and structural applications, especially in ground vehicles. Magnesium (Mg), due to its low density (~25% that of steel ...applications, wrought Mg is difficult to produce in thin sheets because of its inherently low ductility . As a result, Mg sheet is often produced at

Monitoring of the insecticide trichlorfon by phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy

International Nuclear Information System (INIS)

Talebpour, Zahra; Ghassempour, Alireza; Zendehzaban, Mehdi; Bijanzadeh, Hamid Reza; Mirjalili, Mohammad Hossein

2006-01-01

Trichlorfon is an organophosphorus insecticide, which is extensively being used for protection of fruit crops. Trichlorfon is a thermal labile compound, which cannot be easily determined by gas chromatography (GC) and has no suitable group for sensitive detection by high performance liquid chromatography (HPLC). In this study, a 31 P nuclear magnetic resonance ( 31 P NMR) has been described for monitoring of trichlorfon without any separation step. The quantitative works of 31 P NMR spectroscopy has been performed in the presence of an internal standard (hexamethylphosphoramide). Limit of detection (LOD) for this method has been found to be 55 mg L -1 , without any sample preparation, and the linear working range was 150-5500 mg L -1 . Relative standard deviation (R.S.D.%) of the method for three replicates within and between days was obtained ≤9%. The average recovery efficiency was approximately 99-112%. This method was applied for monitoring trichlorfon in a commercial insecticide sample and tomato sample

26 CFR 31.3401(b)-1 - Payroll period.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Payroll period. 31.3401(b)-1 Section 31.3401(b... Collection of Income Tax at Source § 31.3401(b)-1 Payroll period. (a) The term payroll period means the... elapsed and receives the remainder at the end of the week, the payroll period is still the calendar week...

Basicity determination for neutral phosphorus organic extragents by NMR 31P-method in two-phase systems, and quantitative interrelations of acido-basic extractive properties

International Nuclear Information System (INIS)

Laskorin, B.N.; Yakshin, V.V.; Meshcheryakov, N.M.; Yagodin, V.G.

1988-01-01

Consideration is given to the method for determination of basicity of neutral organophosphorus compounds of XGZP=0 type (X, G, Z=C 4 H 9 , C 8 H 17 , C 6 H 5 ). The method is based on change of chemical shift of phosphorus-31 nuclei in two-phase extraction system depending on acidity function H O , H A , H PO . It is shown that the method can be used for evaluation and forecasting of phosphine oxide ability in the processes of UO 2 SO 4 solvent extraction from aqueous solutions of sulfuric acid

Contemporary zebrafish transgenesis with Tol2 and application for Cre/lox recombination experiments.

Science.gov (United States)

Felker, A; Mosimann, C

2016-01-01

Spatiotemporal transgene regulation by transgenic DNA recombinases is a central tool for reverse genetics in multicellular organisms, with excellent applications for misexpression and lineage tracing experiments. One of the most widespread technologies for this purpose is Cre recombinase-controlled lox site recombination that is attracting increasing interest in the zebrafish field. Tol2-mediated zebrafish transgenesis provides a stable platform to integrate lox cassette transgenes, while the amenability of the zebrafish embryo to drug treatments makes the model an ideal candidate for tamoxifen-inducible CreERT2 experiments. In addition, advanced transgenesis technologies such as phiC31 or CRISPR-Cas9-based knock-ins are even further promoting zebrafish transgenesis for Cre/lox applications. In this chapter, we will first introduce the basics of Cre/lox methodology, CreERT2 regulation by tamoxifen, as well as the utility of Tol2 and other contemporary transgenesis techniques for Cre/lox experiments. We will then outline in detail practical experimental steps for efficient transgenesis toward the creation of single-insertion transgenes and will introduce protocols for 4-hydroxytamoxifen-mediated CreERT2 induction to perform spatiotemporal lox transgene regulation experiments in zebrafish embryos. Last, we will discuss advanced experimental applications of Cre/lox beyond traditional lineage tracing approaches. Copyright © 2016 Elsevier Inc. All rights reserved.

Fast and efficient Drosophila melanogaster gene knock-ins using MiMIC transposons.

Science.gov (United States)

Vilain, Sven; Vanhauwaert, Roeland; Maes, Ine; Schoovaerts, Nils; Zhou, Lujia; Soukup, Sandra; da Cunha, Raquel; Lauwers, Elsa; Fiers, Mark; Verstreken, Patrik

2014-10-08

Modern molecular genetics studies necessitate the manipulation of genes in their endogenous locus, but most of the current methodologies require an inefficient donor-dependent homologous recombination step to locally modify the genome. Here we describe a methodology to efficiently generate Drosophila knock-in alleles by capitalizing on the availability of numerous genomic MiMIC transposon insertions carrying recombinogenic attP sites. Our methodology entails the efficient PhiC31-mediated integration of a recombination cassette flanked by unique I-SceI and/or I-CreI restriction enzyme sites into an attP-site. These restriction enzyme sites allow for double-strand break-mediated removal of unwanted flanking transposon sequences, while leaving the desired genomic modifications or recombination cassettes. As a proof-of-principle, we mutated LRRK, tau, and sky by using different MiMIC elements. We replaced 6 kb of genomic DNA encompassing the tau locus and 35 kb encompassing the sky locus with a recombination cassette that permits easy integration of DNA at these loci and we also generated a functional LRRK(HA) knock in allele. Given that ~92% of the Drosophila genes are located within the vicinity (MiMIC element, our methodology enables the efficient manipulation of nearly every locus in the fruit fly genome without the need for inefficient donor-dependent homologous recombination events. Copyright © 2014 Vilain et al.

secHsp70 as a tool to approach amyloid-β42 and other extracellular amyloids.

Science.gov (United States)

De Mena, Lorena; Chhangani, Deepak; Fernandez-Funez, Pedro; Rincon-Limas, Diego E

2017-07-03

Self-association of amyloidogenic proteins is the main pathological trigger in a wide variety of neurodegenerative disorders. These aggregates are deposited inside or outside the cell due to hereditary mutations, environmental exposures or even normal aging. Cumulative evidence indicates that the heat shock chaperone Hsp70 possesses robust neuroprotection against various intracellular amyloids in Drosophila and mouse models. However, its protective role against extracellular amyloids was largely unknown as its presence outside the cells is very limited. Our recent manuscript in PNAS revealed that an engineered form of secreted Hsp70 (secHsp70) is highly protective against toxicity induced by extracellular deposition of the amyloid-β42 (Aβ42) peptide. In this Extra View article, we extend our analysis to other members of the heat shock protein family. We created PhiC31-based transgenic lines for human Hsp27, Hsp40, Hsp60 and Hsp70 and compared their activities in parallel against extracellular Aβ42. Strikingly, only secreted Hsp70 exhibits robust protection against Aβ42-triggered toxicity in the extracellular milieu. These observations indicate that the ability of secHsp70 to suppress Aβ42 insults is quite unique and suggest that targeted secretion of Hsp70 may represent a new therapeutic approach against Aβ42 and other extracellular amyloids. The potential applications of this engineered chaperone are discussed.

3:1 compression to ventilation ratio versus continuous chest compression with asynchronous ventilation in a porcine model of neonatal resuscitation.

Science.gov (United States)

Schmölzer, Georg M; O'Reilly, Megan; Labossiere, Joseph; Lee, Tze-Fun; Cowan, Shaun; Nicoll, Jessica; Bigam, David L; Cheung, Po-Yin

2014-02-01

In contrast to the resuscitation guidelines of children and adults, guidelines on neonatal resuscitation recommend synchronized 90 chest compressions with 30 manual inflations (3:1) per minute in newborn infants. The study aimed to determine if chest compression with asynchronous ventilation improves the recovery of bradycardic asphyxiated newborn piglets compared to 3:1 Compression:Ventilation cardiopulmonary resuscitation (CPR). Term newborn piglets (n=8/group) were anesthetized, intubated, instrumented and exposed to 45-min normocapnic hypoxia followed by asphyxia. Protocolized resuscitation was initiated when heart rate decreased to 25% of baseline. Piglets were randomized to receive resuscitation with either 3:1 compressions to ventilations (3:1C:V CPR group) or chest compressions with asynchronous ventilations (CCaV) or sham. Continuous respiratory parameters (Respironics NM3(®)), cardiac output, mean systemic and pulmonary artery pressures, and regional blood flows were measured. Piglets in 3:1C:V CPR and CCaV CPR groups had similar time to return of spontaneous circulation, survival rates, hemodynamic and respiratory parameters during CPR. The systemic and regional hemodynamic recovery in the subsequent 4h was similar in both groups and significantly lower compared to sham-operated piglets. Newborn piglets resuscitated by CCaV had similar return of spontaneous circulation, survival, and hemodynamic recovery compared to those piglets resuscitated by 3:1 Compression:Ventilation ratio. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

47 CFR 11.31 - EAS protocol.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false EAS protocol. 11.31 Section 11.31... characters. FM or TV call signs must use a slash ASCII character number 47 (/) in lieu of a dash. (c) The EAS... the State EAS Mapbook. FIPS# State: AL 01 AK 02 AZ 04 AR 05 CA 06 CO 08 CT 09 DE 10 DC 11 FL 12 GA 13...

31 CFR 357.14 - What authority does a Federal Reserve Bank have?

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What authority does a Federal Reserve Bank have? 357.14 Section 357.14 Money and Finance: Treasury Regulations Relating to Money and Finance... Entry System (TRADES) § 357.14 What authority does a Federal Reserve Bank have? (a) Each Federal Reserve...

Areva as of December 31, 2011; Areva au 31 decembre 2011

Energy Technology Data Exchange (ETDEWEB)

Marie, Patricia; Briand, Pauline; Michaut, Maxime; Scorbiac, Marie de; Repaire, Philippine du

2012-01-26

In 2011, AREVA's consolidated revenue came to 8.872 billion euros, down slightly (-2.6%) compared with 2010 (-1.2% like for like). The decrease in revenue in nuclear operations was partially offset by significant growth in the renewable energies business. Foreign exchange and changes in the scope of consolidation had respectively a negative impact of 113 million euros and 16 million euros over the period. Revenue totaled 2.922 billion euros in the fourth quarter of 2011, stable compared with the fourth quarter of 2010 (-0.5% on a reported basis and -0.5% like for like). Foreign exchange had a negligible impact during the period. Led by nuclear operations, the group's backlog was 45.6 billion euros at December 31, 2011, up 3.1% year on year and 6.7% in relation to September 30, 2011. Order cancellations since Fukushima were limited to 464 million euros as of December 31, 2011. In accordance with the requirements of IFRS 8, AREVA's business segment information is presented for each operating Business Group (BG), which is the level of information examined by the group's governance bodies. Subsequent to the establishment of a subsidiary combining all of the group's mining operations, data for the Mining Business Group are now reported separately from those of the Front End Business Group. Data used for comparisons with 2010 were restated to reflect this new organization. The business segment information therefore corresponds to AREVA's five operating Business Groups: Mining, Front End, Reactors and Services, Back End and Renewable Energies

9 CFR 355.31 - Supervision by inspector.

Science.gov (United States)

2010-01-01

... INSPECTION AND CERTIFICATION CERTIFIED PRODUCTS FOR DOGS, CATS, AND OTHER CARNIVORA; INSPECTION... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Supervision by inspector. 355.31 Section 355.31 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE...

9 CFR 78.31 - Brucellosis reactor swine.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Brucellosis reactor swine. 78.31... AGRICULTURE INTERSTATE TRANSPORTATION OF ANIMALS (INCLUDING POULTRY) AND ANIMAL PRODUCTS BRUCELLOSIS Restrictions on Interstate Movement of Swine Because of Brucellosis § 78.31 Brucellosis reactor swine. (a...

Automated identification of OB associations in M31

Science.gov (United States)

Magnier, Eugene A.; Battinelli, Paolo; Lewin, Walter H. G.; Haiman, Zoltan; Paradijs, Jan Van; Hasinger, Guenther; Pietsch, Wolfgang; Supper, Rodrigo; Truemper, Joachim

1993-01-01

A new identification of OB associations in M31 has been performed using the Path Linkage Criterion (PLC) technique of Battinelli (1991). We found 174 associations with a very small contamination (less than 5%) by random clumps of stars. The expected total number and average size of OB associations in the region of M 31 covered by our data set (Magnier et al. 1992) are approximately 280 and approximately 90 pc, respectively. M31 associations therefore have sizes similar to those of OB associations observed in nearby galaxies, so that we can consider them to be classical OB associations. This list of OB associations will be used for the study of the spatial distribution of OB associations and their correlation with other objects. Taking into account the fact that we do not cover the entire disk of M31, we extrapolate a total number of association in M31 of approximately 420.

40 CFR 792.31 - Testing facility management.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 31 2010-07-01 2010-07-01 true Testing facility management. 792.31... facility management. For each study, testing facility management shall: (a) Designate a study director as... appropriately tested for identity, strength, purity, stability, and uniformity, as applicable. (e) Assure that...

Production data from a Leica ZBA31H+ shaped e-beam mask writer located at the Photronics facility, Manchester, England

Science.gov (United States)

Johnson, Stephen; Loughran, Dominic; Osborne, Peter; Sixt, Pierre; Doering, Hans-Joachim

1999-06-01

The ZBA31H+) is a variable shaped spot, vector scan e- beam lithography system operating at 20 keV. The specified performance is designed to produce reticles to 250 nanometer design rules, and beyond. In November 98 the acceptance results of a newly installed Leica ZBA31H+), at Photonic Manchester, were presented in a paper at the VDE/VDI 15th European Conference on Mask Technology. This paper is a continuation of that work and presents data from a capability study carried out, on 4000 angstrom EBR9 HS31 resist. Analysis of: mean to target, uniformity, X/Y bias, isolated vs. dense linewidths, linearity, and registration performance of the tool is presented, and the effects of re- iterative develop on process capability compared. Theoretically, a shaped beam system has advantages over raster scan in terms of write time and edge definition capabilities. In this paper, comparative write times against an Etec Mebes 4500 system are included. The ZBA31H+) has to write very small polygons in order to image non-axial or non-45 degree features. The resulting effect on image quality and write time is investigated. In order to improve the fidelity of small OPC structures, Leica have investigated alternative writing strategies, and their results to data are presented here.

Cloning, expression, purification, crystallization and preliminary X-ray analysis of the 31 kDa Vibrio cholerae heat-shock protein VcHsp31

International Nuclear Information System (INIS)

Das, Samir; Dey, Sanjay; Roy, Trina; Sen, Udayaditya

2011-01-01

A heat-shock protein from V. cholerae (VcHsp31) has been cloned, expressed, purified and crystallized. Crystals of VcHsp31 belonged to a monoclinic space group and diffracted to 1.9 Å resolution. The Gram-negative bacterium Vibrio cholerae, which is responsible for the diarrhoeal disease cholera in humans, induces the expression of numerous heat-shock genes. VcHsp31 is a 31 kDa putative heat-shock protein that belongs to the DJ-1/PfpI superfamily, functioning as both a chaperone and a protease. VcHsp31 has been cloned, overexpressed and purified by Ni 2+ –NTA affinity chromatography followed by gel filtration. Crystals of VcHsp31 were grown in the presence of PEG 6000 and MPD; they belonged to space group P2 1 and diffracted to 1.9 Å resolution. Assuming the presence of six molecules in the asymmetric unit, the Matthews coefficient was estimated to be 1.97 Å 3 Da −1 , corresponding to a solvent content of 37.4%

28 CFR 523.31 - Who is eligible for DCEGT?

Science.gov (United States)

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Who is eligible for DCEGT? 523.31 Section 523.31 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE INMATE ADMISSION, CLASSIFICATION, AND TRANSFER COMPUTATION OF SENTENCE District of Columbia Educational Good Time Credit § 523.31...

31st International Colloquium in Group Theoretical Methods in Physics

CERN Document Server

Gazeau, Jean-Pierre; Faci, Sofiane; Micklitz, Tobias; Scherer, Ricardo; Toppan, Francesco

2017-01-01

This proceedings records the 31st International Colloquium on Group Theoretical Methods in Physics (“Group 31”). Plenary-invited articles propose new approaches to the moduli spaces in gauge theories (V. Pestun, 2016 Weyl Prize Awardee), the phenomenology of neutrinos in non-commutative space-time, the use of Hardy spaces in quantum physics, contradictions in the use of statistical methods on complex systems, and alternative models of supersymmetry. This volume’s survey articles broaden the colloquia’s scope out into Majorana neutrino behavior, the dynamics of radiating charges, statistical pattern recognition of amino acids, and a variety of applications of gauge theory, among others. This year’s proceedings further honors Bertram Kostant (2016 Wigner Medalist), as well as S.T. Ali and L. Boyle, for their life-long contributions to the math and physics communities. The aim of the ICGTMP is to provide a forum for physicists, mathematicians, and scientists of related disciplines who develop or apply ...

Pathogenicity Island Cross Talk Mediated by Recombination Directionality Factors Facilitates Excision from the Chromosome.

Science.gov (United States)

Carpenter, Megan R; Rozovsky, Sharon; Boyd, E Fidelma

2015-12-14

Pathogenicity islands (PAIs) are mobile integrated genetic elements (MIGEs) that contain a diverse range of virulence factors and are essential in the evolution of pathogenic bacteria. PAIs are widespread among bacteria and integrate into the host genome, commonly at a tRNA locus, via integrase-mediated site-specific recombination. The excision of PAIs is the first step in the horizontal transfer of these elements and is not well understood. In this study, we examined the role of recombination directionality factors (RDFs) and their relationship with integrases in the excision of two PAIs essential for Vibrio cholerae host colonization: Vibrio pathogenicity island 1 (VPI-1) and VPI-2. VPI-1 does not contain an RDF, which allowed us to answer the question of whether RDFs are an absolute requirement for excision. We found that an RDF was required for efficient excision of VPI-2 but not VPI-1 and that RDFs can induce excision of both islands. Expression data revealed that the RDFs act as transcriptional repressors to both VPI-1- and VPI-2-encoded integrases. We demonstrated that the RDFs Vibrio excision factor A (VefA) and VefB bind at the attachment sites (overlapping the int promoter region) of VPI-1 and VPI-2, thus supporting this mode of integrase repression. In addition, V. cholerae RDFs are promiscuous due to their dual functions of promoting excision of both VPI-1 and VPI-2 and acting as negative transcriptional regulators of the integrases. This is the first demonstration of cross talk between PAIs mediated via RDFs which reveals the complex interactions that occur between separately acquired MIGEs. Deciphering the mechanisms of pathogenicity island excision is necessary for understanding the evolution and spread of these elements to their nonpathogenic counterparts. Such mechanistic insight would assist in predicting the mobility of uncharacterized genetic elements. This study identified extensive RDF-mediated cross talk between two nonhomologous VPIs and

40 CFR 160.31 - Testing facility management.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Testing facility management. 160.31... GOOD LABORATORY PRACTICE STANDARDS Organization and Personnel § 160.31 Testing facility management. For each study, testing facility management shall: (a) Designate a study director as described in § 160.33...

21 CFR 58.31 - Testing facility management.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Testing facility management. 58.31 Section 58.31... management. For each nonclinical laboratory study, testing facility management shall: (a) Designate a study... appropriately tested for identity, strength, purity, stability, and uniformity, as applicable. (e) Assure that...

26 CFR 31.3221-3 - Supplemental tax.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Supplemental tax. 31.3221-3 Section 31.3221-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Railroad...

40 CFR 60.31d - Emissions guidelines.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 6 2010-07-01 2010-07-01 false Emissions guidelines. 60.31d Section 60...) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES Emissions Guidelines and Compliance Times for Sulfuric Acid Production Units § 60.31d Emissions guidelines. Sulfuric acid production units. The emission...

26 CFR 31.3406(d)-2 - Payee certification failure.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Payee certification failure. 31.3406(d)-2 Section 31.3406(d)-2 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SOURCE Collection of Income Tax at Source § 31.3406(d)-2 Payee certification failure. (a) Requirement to...

Annual report of R and D activities in Center for Computational Science and e-Systems from April 1, 2006 to March 31, 2007

International Nuclear Information System (INIS)

2008-03-01

This report provides an overview of the research and development activities of the Center for Computational Science and e-Systems (CCSE), JAEA in fiscal year 2006 (April 1, 2006 - March 31, 2007). These research and development activities have been performed by the Simulation Technology Research and Development Office and the Computer Science Research and Development Office. The primary results of the research and development activities are the development of simulation techniques for a virtual earthquake testbed, an intelligent infrastructure for atomic energy research, computational biological disciplines to predict DNA repair function of protein, and material models for a neutron detection device, crack propagation, and gas bubble formation in nuclear fuel. (author)

18 CFR 1308.31 - Filing and service.

Science.gov (United States)

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Filing and service. 1308.31 Section 1308.31 Conservation of Power and Water Resources TENNESSEE VALLEY AUTHORITY CONTRACT... opposing party may be made personally or by mail. The copy presented for filing shall bear an appropriate...

32 CFR 1907.31 - Right of appeal.

Science.gov (United States)

2010-07-01

... 32 National Defense 6 2010-07-01 2010-07-01 false Right of appeal. 1907.31 Section 1907.31 National Defense Other Regulations Relating to National Defense CENTRAL INTELLIGENCE AGENCY CHALLENGES TO... this Order. Action by that body will be the subject of rules to be promulgated by the Information...

31 CFR 352.0 - Offering of bonds.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Offering of bonds. 352.0 Section 352.0 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE... terminate at the close of business on August 31, 2004. [69 FR 40318, July 2, 2004] ...

27 CFR 31.160 - Monthly summary report.

Science.gov (United States)

2010-04-01

... documents regarding the receipt and disposition of distilled spirits that have a direct role in determining... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Monthly summary report. 31.160 Section 31.160 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU...

27 CFR 31.133 - Change in management.

Science.gov (United States)

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Change in management. 31..., DEPARTMENT OF THE TREASURY LIQUORS ALCOHOL BEVERAGE DEALERS Changes in Registration Information Other Changes § 31.133 Change in management. A change in management that involves no change in ownership of the...

SciDAC's Earth System Grid Center for Enabling Technologies Semi-Annual Progress Report for the Period October 1, 2009 through March 31, 2010

Energy Technology Data Exchange (ETDEWEB)

Williams, Dean N. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Foster, I. T. [Argonne National Lab. (ANL), Argonne, IL (United States); Middleton, D. E. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Ananthakrishnan, R. [Argonne National Lab. (ANL), Argonne, IL (United States); Siebenlist, F. [Argonne National Lab. (ANL), Argonne, IL (United States); Shoshani, A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Sim, A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Bell, G. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Drach, R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Ahrens, J. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Jones, P. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Brown, D. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Chastang, J. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Cinquini, L. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Fox, P. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Harper, D. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Hook, N. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Nienhouse, E. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Strand, G. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); West, P. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Wilcox, H. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Wilhelmi, N. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Zednik, S. [National Center for Atmospheric Research (NCAR), Boulder, CO (United States); Hankin, S. [National Oceanic and Atmospheric Administration (NOAA), Washington, DC (United States); Schweitzer, R. [National Oceanic and Atmospheric Administration (NOAA), Washington, DC (United States); Bernholdt, D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Chen, M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Miller, R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Shipman, G. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Wang, F. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bharathi, S. [Univ. of Southern California, Marina Del Rey, CA (United States). Information Sciences Institute; Chervenak, A. [Univ. of Southern California, Marina Del Rey, CA (United States). Information Sciences Institute; Schuler, R. [Univ. of Southern California, Marina Del Rey, CA (United States). Information Sciences Institute; Su, M. [Univ. of Southern California, Marina Del Rey, CA (United States). Information Sciences Institute

2010-04-21

This report summarizes work carried out by the ESG-CET during the period October 1, 2009 through March 31, 2009. It includes discussion of highlights, overall progress, period goals, collaborations, papers, and presentations. To learn more about our project, and to find previous reports, please visit the Earth System Grid Center for Enabling Technologies (ESG-CET) website. This report will be forwarded to the DOE SciDAC program management, the Office of Biological and Environmental Research (OBER) program management, national and international collaborators and stakeholders (e.g., the Community Climate System Model (CCSM), the Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report (AR5), the Climate Science Computational End Station (CCES), the SciDAC II: A Scalable and Extensible Earth System Model for Climate Change Science, the North American Regional Climate Change Assessment Program (NARCCAP), and other wide-ranging climate model evaluation activities).

32 CFR 635.31 - Lost, abandoned, or unclaimed property.

Science.gov (United States)

2010-07-01

... 32 National Defense 4 2010-07-01 2010-07-01 true Lost, abandoned, or unclaimed property. 635.31 Section 635.31 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL INVESTIGATIONS LAW ENFORCEMENT REPORTING Offense Reporting § 635.31 Lost, abandoned, or unclaimed property. This is...

The Integron: Adaptation On Demand.

Science.gov (United States)

Escudero, José Antonio; Loot, Céline; Nivina, Aleksandra; Mazel, Didier

2015-04-01

The integron is a powerful system which, by capturing, stockpiling, and rearranging new functions carried by gene encoding cassettes, confers upon bacteria a rapid adaptation capability in changing environments. Chromosomally located integrons (CI) have been identified in a large number of environmental Gram-negative bacteria. Integron evolutionary history suggests that these sedentary CIs acquired mobility among bacterial species through their association with transposable elements and conjugative plasmids. As a result of massive antibiotic use, these so-called mobile integrons are now widespread in clinically relevant bacteria and are considered to be the principal agent in the emergence and rise of antibiotic multiresistance in Gram-negative bacteria. Cassette rearrangements are catalyzed by the integron integrase, a site-specific tyrosine recombinase. Central to these reactions is the single-stranded DNA nature of one of the recombination partners, the attC site. This makes the integron a unique recombination system. This review describes the current knowledge on this atypical recombination mechanism, its implications in the reactions involving the different types of sites, attC and attI, and focuses on the tight regulation exerted by the host on integron activity through the control of attC site folding. Furthermore, cassette and integrase expression are also highly controlled by host regulatory networks and the bacterial stress (SOS) response. These intimate connections to the host make the integron a genetically stable and efficient system, granting the bacteria a low cost, highly adaptive evolution potential "on demand".

42 CFR 86.31 - Eligibility; minimum requirements.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Eligibility; minimum requirements. 86.31 Section 86.31 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH AND RELATED ACTIVITIES GRANTS FOR EDUCATION PROGRAMS IN OCCUPATIONAL SAFETY AND HEALTH Occupational Safety and Health Direct...

31 CFR 321.15 - Liability for losses.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Liability for losses. 321.15 Section... INSTITUTIONS OF UNITED STATES SAVINGS BONDS AND UNITED STATES SAVINGS NOTES (FREEDOM SHARES) Losses Resulting From Erroneous Payments § 321.15 Liability for losses. Under the governing statute, as amended (31 U.S...

41 CFR 60-2.31 - Program summary.

Science.gov (United States)

2010-07-01

... 41 Public Contracts and Property Management 1 2010-07-01 2010-07-01 true Program summary. 60-2.31...-AFFIRMATIVE ACTION PROGRAMS Miscellaneous § 60-2.31 Program summary. The affirmative action program must be summarized and updated annually. The program summary must be prepared in a format which will be prescribed by...

Molecular clouds in M31 and M33

International Nuclear Information System (INIS)

Blitz, L.

1985-01-01

In order to determine the properties of the molecular clouds in nearby spiral galaxies, 49 H II regions in M31 and 6 H II regions in M33 were observed using the J = 1→0 transition of CO. Of these, 17 were detected in M31 and two in M33. For the CO detection in M31, = 0.14 K, = 12.5 km s -1 , and = 2.1 K km s -1 . The two detections in M33, which are toward the giant H II regions NGC 604 and NGC 595, are somewhat weaker than the mean values for clouds in M31, neither T(/sub R/ nor ΔV shows any gradient with galactic radius, but is a decreasing function of radius. The mean values of and are considerably larger than the values that would be obtained by extrapolating local giant molecular clouds to the distance of M31. It is suggested that most of the CO emission is from small clouds in the beam which overwhelm the emission from the giant molecular clouds. Some observational tests of this suggestion are proposed. Like the molecular clouds in the Milky Way, the giant molecular clouds in M31 appear to be tidally limited. In M33 the larger inclination angle would make the observed contribution from small molecular clouds less significant, which is consistent with the observations

26 CFR 31.3221-1 - Measure of employer tax.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Measure of employer tax. 31.3221-1 Section 31... TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Railroad Retirement Tax Act (Chapter 22, Internal Revenue Code of 1954) Tax on Employers § 31.3221-1...

26 CFR 31.3201-1 - Measure of employee tax.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Measure of employee tax. 31.3201-1 Section 31... TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Railroad Retirement Tax Act (Chapter 22, Internal Revenue Code of 1954) Tax on Employees § 31.3201-1...

26 CFR 31.3301-1 - Persons liable for tax.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Persons liable for tax. 31.3301-1 Section 31... TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3301-1 Persons liable for...

26 CFR 31.3111-1 - Measure of employer tax.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Measure of employer tax. 31.3111-1 Section 31... TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Federal Insurance Contributions Act (Chapter 21, Internal Revenue Code of 1954) Tax on Employers § 31.3111...

26 CFR 31.3101-1 - Measure of employee tax.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Measure of employee tax. 31.3101-1 Section 31... TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Federal Insurance Contributions Act (Chapter 21, Internal Revenue Code of 1954) Tax on Employees § 31.3101...

Pectin methylesterase31 positively regulates salt stress tolerance in Arabidopsis.

Science.gov (United States)

Yan, Jingwei; He, Huan; Fang, Lin; Zhang, Aying

2018-02-05

The alteration of cell wall component and structure is an important adaption to saline environment. Pectins, a major cell wall component, are often present in a highly methylesterified form. The level of methyl esterification determined by pectin methylesterases (PMEs) influences many important wall properties that are believed to relate to the adaption to saline stress. However, little is known about the function of PMEs in response to salt stress. Here, we established a link between pectin methylesterase31 (PME31) and salt stress tolerance. Salt stress significantly increases PME31 expression. PME31 is located in the plasma membrane and the expression level of PME31 was high in dry seeds. Knock-down mutants in PME31 conferred hypersensitive phenotypes to salt stress in seed germination and post-germination growth. Real-time PCR analysis revealed that the transcript levels of several stress genes (DREB2A, RD29A and RD29B) are lower in pme31-2 mutant than that in the wild type in response to salt stress. These results suggested that PME31 could positively modulate salt stress tolerance. Copyright © 2018 Elsevier Inc. All rights reserved.

27 CFR 479.31 - Liability for tax.

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2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 3 2010-04-01 2010-04-01 false Liability for tax. 479.31... OTHER FIREARMS Special (Occupational) Taxes § 479.31 Liability for tax. (a) General. Every person who... United States shall pay a special (occupational) tax at a rate specified by § 479.32. The tax shall be...

26 CFR 31.3301-4 - When wages are paid.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false When wages are paid. 31.3301-4 Section 31.3301... Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3301-4 When wages are paid. Wages are paid when actually or constructively paid. Wages are constructively paid when they are credited to the...

26 CFR 31.3401(a)-2 - Exclusions from wages.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Exclusions from wages. 31.3401(a)-2 Section 31... Collection of Income Tax at Source § 31.3401(a)-2 Exclusions from wages. (a) In general. (1) The term “wages... specifically excepted from wages under section 3401(a). (2) The exception attaches to the remuneration for...

26 CFR 31.3402(h)(4)-1 - Other methods.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Other methods. 31.3402(h)(4)-1 Section 31.3402... Collection of Income Tax at Source § 31.3402(h)(4)-1 Other methods. (a) Maximum permissible deviations. An employer may use any other method of withholding under which the employer will deduct and withhold upon...

26 CFR 31.3401(a)(2)-1 - Agricultural labor.

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2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Agricultural labor. 31.3401(a)(2)-1 Section 31... SOURCE Collection of Income Tax at Source § 31.3401(a)(2)-1 Agricultural labor. The term “wages” does not include remuneration for services which constitute agricultural labor as defined in section 3121(g). For...

The ellipticities of a sample of globular clusters in M31

International Nuclear Information System (INIS)

Lupton, R.H.

1989-01-01

Images for a sample of 18 globular clusters in M31 have been obtained. The mean ellipticity on the sky in the range 7-14 pc (2-4 arcsec) is 0.08 + or - 0.02 and 0.12 + or - 0.01 in the range 14-21 pc (4-6 arcsec), with corresponding true ellipticities of 0.12 and 0.18. The difference between the inner and outer parts is significant at a 99 percent level. The flattening of the inner parts is statistically indistinguishable from that of the Galactic globular clusters, while the outer parts are flatter than the Galactic clusters at a 99.8 percent confidence level. There is a significant anticorrelation of ellipticity with line strength; such a correlation may in retrospect also be seen in the Galactic globular cluster system. For the M31 data, this anticorrelation is stronger in the inner parts of the galaxy. 30 refs

Bone Mineral 31P and Matrix-Bound Water Densities Measured by Solid-State 1H and 31P MRI

Science.gov (United States)

Seifert, Alan C.; Li, Cheng; Rajapakse, Chamith S.; Bashoor- Zadeh, Mahdieh; Bhagat, Yusuf A.; Wright, Alexander C.; Zemel, Babette S.; Zavaliangos, Antonios; Wehrli, Felix W.

2014-01-01

Bone is a composite material consisting of mineral and hydrated collagen fractions. MRI of bone is challenging due to extremely short transverse relaxation times, but solid-state imaging sequences exist that can acquire the short-lived signal from bone tissue. Previous work to quantify bone density via MRI used powerful experimental scanners. This work seeks to establish the feasibility of MRI-based measurement on clinical scanners of bone mineral and collagen-bound water densities, the latter as a surrogate of matrix density, and to examine the associations of these parameters with porosity and donors’ age. Mineral and matrix-bound water images of reference phantoms and cortical bone from 16 human donors, ages 27-97 years, were acquired by zero-echo-time 31P and 1H MRI on whole body 7T and 3T scanners, respectively. Images were corrected for relaxation and RF inhomogeneity to obtain density maps. Cortical porosity was measured by micro-CT, and apparent mineral density by pQCT. MRI-derived densities were compared to x-ray-based measurements by least-squares regression. Mean bone mineral 31P density was 6.74±1.22 mol/L (corresponding to 1129±204 mg/cc mineral), and mean bound water 1H density was 31.3±4.2 mol/L (corresponding to 28.3±3.7 %v/v). Both 31P and bound water (BW) densities were correlated negatively with porosity (31P: R2 = 0.32, p bone mineralization ratio (expressed here as the ratio of 31P density to bound water density), which is proportional to true bone mineralization, was found to be uncorrelated with porosity, age, or pQCT density. This work establishes the feasibility of image-based quantification of bone mineral and bound water densities using clinical hardware. PMID:24846186

Distribution and activity of a Dippu DH31-like peptide in the large milkweed bug Oncopeltus fasciatus.

Science.gov (United States)

Te Brugge, V A; Orchard, I

2008-02-01

The milkweed bug, Oncopeltus fasciatus, is a plant feeding hemipteran. While there has been much research done on the neurohormonal control of the post-feeding diuresis in the blood-feeding hemipteran, Rhodnius prolixus, little is known about the control of the post-feeding diuresis in O. fasciatus. One of the neurohormones that may play a role in this rapid diuresis belongs to the calcitonin-like diuretic hormone (DH31) family of insect peptides. In this study we demonstrate the presence of DH31-like immunoreactivity in the central nervous system (CNS) and gut of O. fasciatus 5th instars. As well, DH31-like material was quantified and partially purified from the CNS of 5th instar O. fasciatus using reversed-phase liquid chromatography (RPLC) and monitored with an enzyme-linked immunosorbent assay (ELISA). When tested on O. fasciatus 5th instar Malpighian tubules, DH31-like peptides significantly increased the rate of secretion over saline controls. The results suggest that there is a DH31-like peptide(s) present in the CNS of O. fasciatus and that this peptide may play a role in the control of Malpighian tubule secretion.