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Sample records for a1 hnrnp a1

  1. Idiosyncrasies of hnRNP A1-RNA recognition: Can binding mode influence function.

    PubMed

    Levengood, Jeffrey D; Tolbert, Blanton S

    2018-04-09

    The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RNA binding proteins that function in most stages of RNA metabolism. The prototypical member, hnRNP A1, is composed of three major domains; tandem N-terminal RNA Recognition Motifs (RRMs) and a C-terminal mostly intrinsically disordered region. HnRNP A1 is broadly implicated in basic cellular RNA processing events such as splicing, stability, nuclear export and translation. Due to its ubiquity and abundance, hnRNP A1 is also frequently usurped to control viral gene expression. Deregulation of the RNA metabolism functions of hnRNP A1 in neuronal cells contributes to several neurodegenerative disorders. Because of these roles in human pathologies, the study of hnRNP A1 provides opportunities for the development of novel therapeutics, with disruption of its RNA binding capabilities being the most promising target. The functional diversity of hnRNP A1 is reflected in the complex nature by which it interacts with various RNA targets. Indeed, hnRNP A1 binds both structured and unstructured RNAs with binding affinities that span several magnitudes. Available structures of hnRNP A1-RNA complexes also suggest a degree of plasticity in molecular recognition. Given the reinvigoration in hnRNP A1, the goal of this review is to use the available structural biochemical developments as a framework to interpret its wide-range of RNA functions. Copyright © 2018. Published by Elsevier Ltd.

  2. The effect of O-GlcNAcylation on hnRNP A1 translocation and interaction with transportin1.

    PubMed

    Roth, Shira; Khalaila, Isam

    2017-01-01

    The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a major pre-mRNA binding protein involved in transcription and translation. Although predominantly nuclear, hnRNP A1 shuttles rapidly between the nucleus and the cytosol, delivering its anchored pre-mRNA for further processing. Translocation is important for hnRNP A1 to accomplish its transcriptional and translational roles. Transportin1 (Trn1), a translocation protein, facilitates the translocation of hnRNP A1 back to the nucleus. Moreover, phosphorylation of serine residues at hnRNP A1 C-terminal domain affects its translocation. In this study, we found that phosphorylation is not the only modification that hnRNP A1 undergoes, but also O-linked N-acetylglucosaminylation (O-GlcNAcylation) could occur. Several putative novel O-GlcNAcylation and phosphorylation sites in hnRNP A1 were mapped. Whereas enhanced O-GlcNAcylation increased hnRNP A1 interaction with Trn1, enhanced phosphorylation reduced the interaction between the proteins. In addition, elevated O-GlcNAcylation resulted in hnRNP A1 seclusion in the nucleus, whereas elevated phosphorylation resulted in its accumulation in the cytosol. These findings suggest that a new player, i.e., O-GlcNAcylation, regulates hnRNP A1 translocation and interaction with Trn1, possibly affecting its function. There is a need for further study, to elucidate the role of O-GlcNAcylation in the regulation of the specific activities of hnRNP A1 in transcription and translation. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1

    PubMed Central

    Gao, Guozhen; Dhar, Surbhi

    2017-01-01

    Abstract The type II arginine methyltransferase PRMT5 is responsible for the symmetric dimethylation of histone to generate the H3R8me2s and H4R3me2s marks, which correlate with the repression of transcription. However, the protein level of a number of genes (MEP50, CCND1, MYC, HIF1a, MTIF and CDKN1B) are reported to be downregulated by the loss of PRMT5, while their mRNA levels remain unchanged, which is counterintuitive for PRMT5's proposed role as a transcription repressor. We noticed that the majority of the genes regulated by PRMT5, at the posttranscriptional level, express mRNA containing an internal ribosome entry site (IRES). Using an IRES-dependent reporter system, we established that PRMT5 facilitates the translation of a subset of IRES-containing genes. The heterogeneous nuclear ribonucleoprotein, hnRNP A1, is an IRES transacting factor (ITAF) that regulates the IRES-dependent translation of Cyclin D1 and c-Myc. We showed that hnRNP A1 is methylated by PRMT5 on two residues, R218 and R225, and that this methylation facilitates the interaction of hnRNP A1 with IRES RNA to promote IRES-dependent translation. This study defines a new role for PRMT5 regulation of cellular protein levels, which goes beyond the known functions of PRMT5 as a transcription and splicing regulator. PMID:28115626

  4. Human hnRNP protein A1 gene expression. Structural and functional characterization of the promoter.

    PubMed

    Biamonti, G; Bassi, M T; Cartegni, L; Mechta, F; Buvoli, M; Cobianchi, F; Riva, S

    1993-03-05

    hnRNP protein A1 (34 kDa, pl 9.5) is a prominent member of the family of proteins (hnRNP proteins) that associate with the nascent transcripts of RNA polymerase II and that accompany the hnRNA through the maturation process and the export to the cytoplasm. New evidence suggests an active and specific role for some of these proteins, including protein A1, in splicing and transport. Contrary to the other hnRNP proteins, the intracellular level of protein A1 was reported to change as a function of proliferation state and cell type. In this work we analyse the A1 gene expression in different cells under different growth and differentiation conditions. Proliferation dependent expression was observed in lymphocytes and fibroblasts while purified neurons express high A1 mRNA levels both in the proliferative (before birth) and in the quiescent (after birth) state. Transformed cell lines exhibit very high (proliferation independent) A1 mRNA levels compared to differentiated tissues. A structural and functional characterization of the A1 gene promoter was carried out by means of DNase I footprinting and CAT assays. The observed promoter features can account for both elevated and regulated mRNA transcription. At least 12 control elements are contained in the 734 nucleotides upstream of the transcription start site. Assays with the deleted and/or mutated promoter indicate a co-operation of multiple transcriptional elements, distributed over the entire promoter, in determining the overall activity and the response to proliferative stimuli (serum).

  5. A Function for the hnRNP A1/A2 Proteins in Transcription Elongation.

    PubMed

    Lemieux, Bruno; Blanchette, Marco; Monette, Anne; Mouland, Andrew J; Wellinger, Raymund J; Chabot, Benoit

    2015-01-01

    The hnRNP A1 and A2 proteins regulate processes such as alternative pre-mRNA splicing and mRNA stability. Here, we report that a reduction in the levels of hnRNP A1 and A2 by RNA interference or their cytoplasmic retention by osmotic stress drastically increases the transcription of a reporter gene. Based on previous work, we propose that this effect may be linked to a decrease in the activity of the transcription elongation factor P-TEFb. Consistent with this hypothesis, the transcription of the reporter gene was stimulated when the catalytic component of P-TEFb, CDK9, was inhibited with DRB. While low levels of A1/A2 stimulated the association of RNA polymerase II with the reporter gene, they also increased the association of CDK9 with the repressor 7SK RNA, and compromised the recovery of promoter-distal transcription on the Kitlg gene after the release of pausing. Transcriptome analysis revealed that more than 50% of the genes whose expression was affected by the siRNA-mediated depletion of A1/A2 were also affected by DRB. RNA polymerase II-chromatin immunoprecipitation assays on DRB-treated and A1/A2-depleted cells identified a common set of repressed genes displaying increased occupancy of polymerases at promoter-proximal locations, consistent with pausing. Overall, our results suggest that lowering the levels of hnRNP A1/A2 elicits defective transcription elongation on a fraction of P-TEFb-dependent genes, hence favoring the transcription of P-TEFb-independent genes.

  6. Norovirus Genome Circularization and Efficient Replication Are Facilitated by Binding of PCBP2 and hnRNP A1

    PubMed Central

    López-Manríquez, Eduardo; Vashist, Surender; Ureña, Luis; Goodfellow, Ian; Chavez, Pedro; Mora-Heredia, José Eduardo; Cancio-Lonches, Clotilde; Garrido, Efraín

    2013-01-01

    Sequences and structures within the terminal genomic regions of plus-strand RNA viruses are targets for the binding of host proteins that modulate functions such as translation, RNA replication, and encapsidation. Using murine norovirus 1 (MNV-1), we describe the presence of long-range RNA-RNA interactions that were stabilized by cellular proteins. The proteins potentially responsible for the stabilization were selected based on their ability to bind the MNV-1 genome and/or having been reported to be involved in the stabilization of RNA-RNA interactions. Cell extracts were preincubated with antibodies against the selected proteins and used for coprecipitation reactions. Extracts treated with antibodies to poly(C) binding protein 2 (PCBP2) and heterogeneous nuclear ribonucleoprotein (hnRNP) A1 significantly reduced the 5′-3′ interaction. Both PCBP2 and hnRNP A1 recombinant proteins stabilized the 5′-3′ interactions and formed ribonucleoprotein complexes with the 5′ and 3′ ends of the MNV-1 genomic RNA. Mutations within the 3′ complementary sequences (CS) that disrupt the 5′-3′-end interactions resulted in a significant reduction of the viral titer, suggesting that the integrity of the 3′-end sequence and/or the lack of complementarity with the 5′ end is important for efficient virus replication. Small interfering RNA-mediated knockdown of PCBP2 or hnRNP A1 resulted in a reduction in virus yield, confirming a role for the observed interactions in efficient viral replication. PCBP2 and hnRNP A1 induced the circularization of MNV-1 RNA, as revealed by electron microscopy. This study provides evidence that PCBP2 and hnRNP A1 bind to the 5′ and 3′ ends of the MNV-1 viral RNA and contribute to RNA circularization, playing a role in the virus life cycle. PMID:23946460

  7. Up-regulation of hnRNP A1, Ezrin, tubulin β-2C and Annexin A1 in sentinel lymph nodes of colorectal cancer

    PubMed Central

    He, Zhen-Yu; Wen, Hao; Shi, Chuan-Bing; Wang, Jie

    2010-01-01

    AIM: To investigate the early metastasis-associated proteins in sentinel lymph node micrometastasis (SLNMM) of colorectal cancer (CRC) through comparative proteome. METHODS: Hydrophobic protein samples were extracted from individual-matched normal lymph nodes (NLN) and SLNMM of CRC. Differentially expressed protein spots were detected by two-dimensional electrophoresis and image analysis, and subsequently identified by matrix assisted laser desorption/ionization-time of flight mass spectrometry-mass spectrometry and Western blotting, respectively. RESULTS: Forty proteins were differentially expressed in NLN and SLNMM, and 4 metastasis-concerned proteins highly expressed in SLNMM were identified to be hnRNP A1, Ezrin, tubulin β-2C and Annexin A1. Further immunohistochemistry staining of these four proteins showed their clinicopathological characteristics in lymph node metastasis of CRC. CONCLUSION: Variations of hydrophobic protein expression in NLN and SLNMM of CRC and increased expression of hnRNP A1, Ezrin, tubulin β-2C and Annexin A1 in SLNMM suggest a significantly elevated early CRC metastasis. PMID:20872967

  8. Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7

    PubMed Central

    Beusch, Irene; Barraud, Pierre; Moursy, Ahmed; Cléry, Antoine; Allain, Frédéric Hai-Trieu

    2017-01-01

    HnRNP A1 regulates many alternative splicing events by the recognition of splicing silencer elements. Here, we provide the solution structures of its two RNA recognition motifs (RRMs) in complex with short RNA. In addition, we show by NMR that both RRMs of hnRNP A1 can bind simultaneously to a single bipartite motif of the human intronic splicing silencer ISS-N1, which controls survival of motor neuron exon 7 splicing. RRM2 binds to the upstream motif and RRM1 to the downstream motif. Combining the insights from the structure with in cell splicing assays we show that the architecture and organization of the two RRMs is essential to hnRNP A1 function. The disruption of the inter-RRM interaction or the loss of RNA binding capacity of either RRM impairs splicing repression by hnRNP A1. Furthermore, both binding sites within the ISS-N1 are important for splicing repression and their contributions are cumulative rather than synergistic. DOI: http://dx.doi.org/10.7554/eLife.25736.001 PMID:28650318

  9. Poly(ADP-Ribosyl)ation of hnRNP A1 Protein Controls Translational Repression in Drosophila.

    PubMed

    Ji, Yingbiao; Tulin, Alexei V

    2016-10-01

    Poly(ADP-ribosyl)ation of heterogeneous nuclear ribonucleoproteins (hnRNPs) regulates the posttranscriptional fate of RNA during development. Drosophila hnRNP A1, Hrp38, is required for germ line stem cell maintenance and oocyte localization. The mRNA targets regulated by Hrp38 are mostly unknown. We identified 428 Hrp38-associated gene transcripts in the fly ovary, including mRNA of the translational repressor Nanos. We found that Hrp38 binds to the 3' untranslated region (UTR) of Nanos mRNA, which contains a translation control element. We have demonstrated that translation of the luciferase reporter bearing the Nanos 3' UTR is enhanced by dsRNA-mediated Hrp38 knockdown as well as by mutating potential Hrp38-binding sites. Our data show that poly(ADP-ribosyl)ation inhibits Hrp38 binding to the Nanos 3' UTR, increasing the translation in vivo and in vitro hrp38 and Parg null mutants showed an increased ectopic Nanos translation early in the embryo. We conclude that Hrp38 represses Nanos translation, whereas its poly(ADP-ribosyl)ation relieves the repression effect, allowing restricted Nanos expression in the posterior germ plasm during oogenesis and early embryogenesis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  10. Poly(ADP-Ribosyl)ation of hnRNP A1 Protein Controls Translational Repression in Drosophila

    PubMed Central

    Ji, Yingbiao

    2016-01-01

    Poly(ADP-ribosyl)ation of heterogeneous nuclear ribonucleoproteins (hnRNPs) regulates the posttranscriptional fate of RNA during development. Drosophila hnRNP A1, Hrp38, is required for germ line stem cell maintenance and oocyte localization. The mRNA targets regulated by Hrp38 are mostly unknown. We identified 428 Hrp38-associated gene transcripts in the fly ovary, including mRNA of the translational repressor Nanos. We found that Hrp38 binds to the 3′ untranslated region (UTR) of Nanos mRNA, which contains a translation control element. We have demonstrated that translation of the luciferase reporter bearing the Nanos 3′ UTR is enhanced by dsRNA-mediated Hrp38 knockdown as well as by mutating potential Hrp38-binding sites. Our data show that poly(ADP-ribosyl)ation inhibits Hrp38 binding to the Nanos 3′ UTR, increasing the translation in vivo and in vitro. hrp38 and Parg null mutants showed an increased ectopic Nanos translation early in the embryo. We conclude that Hrp38 represses Nanos translation, whereas its poly(ADP-ribosyl)ation relieves the repression effect, allowing restricted Nanos expression in the posterior germ plasm during oogenesis and early embryogenesis. PMID:27402862

  11. sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism.

    PubMed

    Kunze, Michael M; Benz, Fabienne; Brauß, Thilo F; Lampe, Sebastian; Weigand, Julia E; Braun, Johannes; Richter, Florian M; Wittig, Ilka; Brüne, Bernhard; Schmid, Tobias

    2016-07-01

    Translation is an energy-intensive process and tightly regulated. Generally, translation is initiated in a cap-dependent manner. Under stress conditions, typically found within the tumor microenvironment in association with e.g. nutrient deprivation or hypoxia, cap-dependent translation decreases, and alternative modes of translation initiation become more important. Specifically, internal ribosome entry sites (IRES) facilitate translation of specific mRNAs under otherwise translation-inhibitory conditions. This mechanism is controlled by IRES trans-acting factors (ITAF), i.e. by RNA-binding proteins, which interact with and determine the activity of selected IRESs. We aimed at characterizing the translational regulation of the IL-33 decoy receptor sST2, which was enhanced by fibroblast growth factor 2 (FGF2). We identified and verified an IRES within the 5'UTR of sST2. Furthermore, we found that MEK/ERK signaling contributes to FGF2-induced, sST2-IRES activation and translation. Determination of the sST2-5'UTR structure by in-line probing followed by deletion analyses identified 23 nucleotides within the sST2-5'UTR to be required for optimal IRES activity. Finally, we show that the RNA-binding protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds to the sST2-5'UTR, acts as an ITAF, and thus controls the activity of the sST2-IRES and consequently sST2 translation. Specifically, FGF2 enhances nuclear-cytoplasmic translocation of hnRNP A1, which requires intact MEK/ERK activity. In summary, we provide evidence that the sST2-5'UTR contains an IRES element, which is activated by a MEK/ERK-dependent increase in cytoplasmic localization of hnRNP A1 in response to FGF2, enhancing the translation of sST2. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Antisense Masking of an hnRNP A1/A2 Intronic Splicing Silencer Corrects SMN2 Splicing in Transgenic Mice

    PubMed Central

    Hua, Yimin; Vickers, Timothy A.; Okunola, Hazeem L.; Bennett, C. Frank; Krainer, Adrian R.

    2008-01-01

    survival of motor neuron 2, centromeric (SMN2) is a gene that modifies the severity of spinal muscular atrophy (SMA), a motor-neuron disease that is the leading genetic cause of infant mortality. Increasing inclusion of SMN2 exon 7, which is predominantly skipped, holds promise to treat or possibly cure SMA; one practical strategy is the disruption of splicing silencers that impair exon 7 recognition. By using an antisense oligonucleotide (ASO)-tiling method, we systematically screened the proximal intronic regions flanking exon 7 and identified two intronic splicing silencers (ISSs): one in intron 6 and a recently described one in intron 7. We analyzed the intron 7 ISS by mutagenesis, coupled with splicing assays, RNA-affinity chromatography, and protein overexpression, and found two tandem hnRNP A1/A2 motifs within the ISS that are responsible for its inhibitory character. Mutations in these two motifs, or ASOs that block them, promote very efficient exon 7 inclusion. We screened 31 ASOs in this region and selected two optimal ones to test in human SMN2 transgenic mice. Both ASOs strongly increased hSMN2 exon 7 inclusion in the liver and kidney of the transgenic animals. Our results show that the high-resolution ASO-tiling approach can identify cis-elements that modulate splicing positively or negatively. Most importantly, our results highlight the therapeutic potential of some of these ASOs in the context of SMA. PMID:18371932

  13. Chemical Proteomics Identifies Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1 as the Molecular Target of Quercetin in Its Anti-cancer Effects in PC-3 Cells*

    PubMed Central

    Ko, Chia-Chen; Chen, Yun-Ju; Chen, Chih-Ta; Liu, Yu-Chih; Cheng, Fong-Chi; Hsu, Kai-Chao; Chow, Lu-Ping

    2014-01-01

    Quercetin, a flavonoid abundantly present in plants, is widely used as a phytotherapy in prostatitis and prostate cancer. Although quercetin has been reported to have a number of therapeutic effects, the cellular target(s) responsible for its anti-cancer action has not yet been clearly elucidated. Here, employing affinity chromatography and mass spectrometry, we identified heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) as a direct target of quercetin. A specific interaction between quercetin and hnRNPA1 was validated by immunoblotting and in vitro binding experiments. We found that quercetin bound the C-terminal region of hnRNPA1, impairing the ability of hnRNPA1 to shuttle between the nucleus and cytoplasm and ultimately resulting in its cytoplasmic retention. In addition, hnRNPA1 was recruited to stress granules after treatment of cells with quercetin for up to 48 h, and the levels of cIAP1 (cellular inhibitor of apoptosis), an internal ribosome entry site translation-dependent protein, were reduced by hnRNPA1 regulation. This is the first report that anti-cancer effects of quercetin are mediated, in part, by impairing functions of hnRNPA1, insights that were obtained using a chemical proteomics strategy. PMID:24962584

  14. A1C

    MedlinePlus

    A1C is a blood test for type 2 diabetes and prediabetes. It measures your average blood glucose, or blood sugar, level over the past 3 ... A1C alone or in combination with other diabetes tests to make a diagnosis. They also use the ...

  15. A1C test

    MedlinePlus

    ... every 3 or 6 months is recommended. Normal Results The following are the results when A1C is ... meaning of your specific test results. What Abnormal Results Mean An abnormal result means that you have ...

  16. A-1 Test Stand modifications

    NASA Image and Video Library

    2011-09-14

    Team members check the progress of a liquid nitrogen cold shock test on the A-1 Test Stand at Stennis Space Center on Sept. 15. The cold shock test is used to confirm the test stand's support system can withstand test conditions, when super-cold rocket engine propellant is piped. The A-1 Test Stand is preparing to conduct tests on the powerpack component of the J-2X rocket engine, beginning in early 2012.

  17. A-1 Test Stand work

    NASA Technical Reports Server (NTRS)

    2010-01-01

    A structural steel beam to support the new thrust measurement system on the A-1 Test Stand at NASA's John C. Stennis Space Center is lifted to waiting employees for installation. The beam is part of the thrust takeout structure needed to support the new measurement system. Four such beams have been installed at the stand in preparation for installation of the system in upcoming weeks. Operators are preparing the stand for testing the next generation of rocket engines for the U.S. space program.

  18. A-1 Test Stand work

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Employees at NASA's John C. Stennis Space Center work to maneuver a structural steam beam into place on the A-1 Test Stand on Jan. 13. The beam was one of several needed to form the thrust takeout structure that will support a new thrust measurement system being installed on the stand for future rocket engine testing. Once lifted onto the stand, the beams had to be hoisted into place through the center of the test stand, with only two inches of clearance on each side. The new thrust measurement system represents a state-of-the-art upgrade from the equipment installed more than 40 years ago when the test stand was first constructed.

  19. Hemoglobin A1c (HbA1c) Test: MedlinePlus Lab Test Information

    MedlinePlus

    ... medlineplus.gov/labtests/hemoglobina1chba1ctest.html Hemoglobin A1c (HbA1c) Test To use the sharing features on this page, ... enable JavaScript. What is a hemoglobin A1c (HbA1c) test? A hemoglobin A1c (HbA1c) test measures the amount ...

  20. 46 CFR 147A.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 5 2013-10-01 2013-10-01 false Purpose. 147A.1 Section 147A.1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.1 Purpose. The purpose of this part is to prescribe the requirements for shipboard...

  1. 46 CFR 147A.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 5 2012-10-01 2012-10-01 false Purpose. 147A.1 Section 147A.1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.1 Purpose. The purpose of this part is to prescribe the requirements for shipboard...

  2. 46 CFR 147A.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 5 2010-10-01 2010-10-01 false Purpose. 147A.1 Section 147A.1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.1 Purpose. The purpose of this part is to prescribe the requirements for shipboard...

  3. 46 CFR 147A.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 5 2014-10-01 2014-10-01 false Purpose. 147A.1 Section 147A.1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.1 Purpose. The purpose of this part is to prescribe the requirements for shipboard...

  4. 46 CFR 147A.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 5 2011-10-01 2011-10-01 false Purpose. 147A.1 Section 147A.1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.1 Purpose. The purpose of this part is to prescribe the requirements for shipboard...

  5. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Applicability. 2a.1 Section 2a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.1 Applicability. (a) Section 303(a) of the Public Health Service Act (42 U.S.C. 242a...

  6. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Applicability. 2a.1 Section 2a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.1 Applicability. (a) Section 303(a) of the Public Health Service Act (42 U.S.C. 242a...

  7. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Applicability. 2a.1 Section 2a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.1 Applicability. (a) Section 303(a) of the Public Health Service Act (42 U.S.C. 242a...

  8. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes the...

  9. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes the...

  10. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes the...

  11. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes the...

  12. 32 CFR 169a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Purpose. 169a.1 Section 169a.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... Department of Defense (DoD) to determine whether needed commercial activities (CAs) should be accomplished by...

  13. 32 CFR 169a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Purpose. 169a.1 Section 169a.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... Department of Defense (DoD) to determine whether needed commercial activities (CAs) should be accomplished by...

  14. 32 CFR 169a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Purpose. 169a.1 Section 169a.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... Department of Defense (DoD) to determine whether needed commercial activities (CAs) should be accomplished by...

  15. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Purpose. 168a.1 Section 168a.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND... National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191. (b...

  16. 32 CFR 169a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Purpose. 169a.1 Section 169a.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM... Department of Defense (DoD) to determine whether needed commercial activities (CAs) should be accomplished by...

  17. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Purpose. 168a.1 Section 168a.1 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND... National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191. (b...

  18. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2010-10-01 2010-10-01 false Scope. 54a.1 Section 54a.1 Public Health PUBLIC...

  19. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2014-10-01 2014-10-01 false Scope. 54a.1 Section 54a.1 Public Health PUBLIC...

  20. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2012-10-01 2012-10-01 false Scope. 54a.1 Section 54a.1 Public Health PUBLIC...

  1. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... research on mental health, including research on the use and effect of alcohol and other psychoactive drugs... engaged in research on mental health including research on the use and effect of alcohol and other... 42 Public Health 1 2011-10-01 2011-10-01 false Applicability. 2a.1 Section 2a.1 Public Health...

  2. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2011-10-01 2011-10-01 false Scope. 54a.1 Section 54a.1 Public Health PUBLIC...

  3. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2013-10-01 2013-10-01 false Scope. 54a.1 Section 54a.1 Public Health PUBLIC...

  4. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... research on mental health, including research on the use and effect of alcohol and other psychoactive drugs... engaged in research on mental health including research on the use and effect of alcohol and other... 42 Public Health 1 2010-10-01 2010-10-01 false Applicability. 2a.1 Section 2a.1 Public Health...

  5. 32 CFR 237a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Purpose. 237a.1 Section 237a.1 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC AFFAIRS... with industry on (1) public affairs matters in general, (2) industry-sponsored events, and (3...

  6. Blood Test: Hemoglobin A1C

    MedlinePlus

    ... levels can be high if diabetes is not well controlled. Why Are Hemoglobin A1c Tests Done? When a child has diabetes, hemoglobin A1c levels are followed to see how well medicines are working. If a child with diabetes ...

  7. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191. (b...

  8. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191. (b...

  9. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ENGINEERING GRADUATE FELLOWSHIPS § 168a.1 Purpose. This part: (a) Establishes guidelines for the award of National Defense Science and Engineering Graduate (NDSEG) Fellowships, as required by 10 U.S.C. 2191. (b...

  10. 32 CFR 352a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.1 Purpose. Pursuant to the authority vested in the... Finance and Accounting Service (DFAS) as an Agency of the Department of Defense with responsibilities...

  11. A-1 modification work under way

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Phil Schemanski of Pratt & Whitney Rocketdyne removes equipment inside the thrust drum on the A-1 Test Stand as part of a comprehensive modification project to prepare for testing the new J-2X engine.

  12. Last SSME test on A-1

    NASA Image and Video Library

    2006-09-29

    The Stennis Space Center conducted the final space shuttle main engine test on its A-1 Test Stand Friday. The A-1 Test Stand was the site of the first test on a shuttle main engine in 1975. Stennis will continue testing shuttle main engines on its A-2 Test Stand through the end of the Space Shuttle Program in 2010. The A-1 stand begins a new chapter in its operational history in October. It will be temporarily decommissioned to convert it for testing the J-2X engine, which will power the upper stage of NASA's new crew launch vehicle, the Ares I. Although this ends the stand's work on the Space Shuttle Program, it will soon be used for the rocket that will carry America's next generation human spacecraft, Orion.

  13. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C. 2106...

  14. 8 CFR 1274a.1 - Employer requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 1274a.1 Aliens and Nationality EXECUTIVE OFFICE FOR IMMIGRATION REVIEW, DEPARTMENT OF JUSTICE... proceedings. The procedures for hearings before an administrative law judge relating to civil penalties sought... administrative law judge and, to the extent relevant, to cases before an immigration judge or the Board of...

  15. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... Support Contract Between Sponsor and Household Member, on behalf of the sponsor and intending immigrants. The “household income” may not, however, include the income of an intending immigrant, unless the...

  16. A1C Test and Diabetes

    MedlinePlus

    ... per day (fasting or pre-breakfast, pre-lunch, pre-dinner, and bedtime). The straight black line shows an A1C measurement of 7.0 percent. The blue line shows an example of how blood glucose test results might look from self-monitoring four times ...

  17. Beyond HbA1c.

    PubMed

    Bloomgarden, Zachary

    2017-12-01

    It can scarcely be denied that the supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience. The diaTribe Foundation convened a meeting on the topic of glycemic outcomes beyond HbA1c on 21 July 2017, in Bethesda (MD, USA), focusing on potential uses of continuous glucose monitoring (CGM). Understanding patterns of glycemia in people with diabetes has long been a focus of approaches to improving treatment, and over the past few years this has become an available modality for clinical practice. Glucose levels are not the only biologic parameters affecting HbA1c levels; HbA1c changes with anemia or, more subtly, with changes in rates of erythrocyte turnover not reflected in hemoglobin levels outside the normal range. Renal disease often is associated with lower HbA1c than would be predicted based on an individual's glycemic levels. Furthermore, HbA1c levels tend to increase with age and are higher in some ethnic groups; for example, people of African ethnicity have higher HbA1c levels than people of Northern European descent. Indeed, we have argued that even as a measure of mean glycemia HbA1c is inherently imprecise. Overall, for some 20% of people with diabetes, HbA1c levels are substantially higher, or substantially lower, than those that would be predicted from mean blood glucose levels. If one recognizes that HbA1c is, at best, a partial measure of mean glycemic exposure, one must surely accept that HbA1c does not reflect variability within a day, from day to day, and from period to period. Many glucose-lowering medicines, particularly the sulfonylureas and insulin, cause hypoglycemia, with consequent negative effects on quality of life and patient-reported outcomes, as well as association with weight gain and adverse macrovascular outcome; hypoglycemia will, of course, not be captured by HbA1c measurement. Based on these

  18. TMS installation at A-1 Test Stand

    NASA Image and Video Library

    2010-03-03

    A new thrust measurement system is lifted onto the A-1 Test Stand deck at NASA's John C. Stennis Space Center in preparation for its installation. The new system is a state-of-the-art upgrade for the testing structure, which is being prepared for testing of next-generation rocket engines. The system was fabricated by Thrust Measurement Systems in Illinois at a cost of about $3.5 million.

  19. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function

    PubMed Central

    Kara, Firas M.; Chitu, Violeta; Sloane, Jennifer; Axelrod, Matthew; Fredholm, Bertil B.; Stanley, E. Richard; Cronstein, Bruce N.

    2010-01-01

    Adenosine regulates a wide variety of physiological processes via interaction with one or more G-protein-coupled receptors (A1R, A2AR, A2BR, and A3R). Because A1R occupancy promotes fusion of human monocytes to form giant cells in vitro, we determined whether A1R occupancy similarly promotes osteoclast function and formation. Bone marrow cells (BMCs) were harvested from C57Bl/6 female mice or A1R-knockout mice and their wild-type (WT) littermates and differentiated into osteoclasts in the presence of colony stimulating factor-1 and receptor activator of NF-κB ligand in the presence or absence of the A1R antagonist 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX). Osteoclast morphology was analyzed in tartrate-resistant acid phosphatase or F-actin-stained samples, and bone resorption was evaluated by toluidine blue staining of dentin. BMCs from A1R-knockout mice form fewer osteoclasts than BMCs from WT mice, and the A1R antagonist DPCPX inhibits osteoclast formation (IC50=1 nM), with altered morphology and reduced ability to resorb bone. A1R blockade increased ubiquitination and degradation of TRAF6 in RAW264.7 cells induced to differentiate into osteoclasts. These studies suggest a critical role for adenosine in bone homeostasis via interaction with adenosine A1R and further suggest that A1R may be a novel pharmacologic target to prevent the bone loss associated with inflammatory diseases and menopause.—Kara, F. M., Chitu, V., Sloane, J., Axelrod, M., Fredholm, B. B., Stanley, R., Cronstein, B. N. Adenosine A1 receptors (A1Rs) play a critical role in osteoclast formation and function. PMID:20181934

  20. TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor.

    PubMed

    Mohagheghi, Fatemeh; Prudencio, Mercedes; Stuani, Cristiana; Cook, Casey; Jansen-West, Karen; Dickson, Dennis W; Petrucelli, Leonard; Buratti, Emanuele

    2016-02-01

    The aggregation and mislocalization of RNA-binding proteins leads to the aberrant regulation of RNA metabolism and is a key feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. However, the pathological consequences of abnormal deposition of TDP-43 and other RNA-binding proteins remain unclear, as the specific molecular events that drive neurodegeneration have been difficult to identify and continue to be elusive. Here, we provide novel insight into the complexity of the RNA-binding protein network by demonstrating that the inclusion of exon 17b in the SORT1 mRNA, a pathologically relevant splicing event known to be regulated by TDP-43, is also considerably affected by additional RNA-binding proteins, such as hnRNP L, PTB/nPTB and hnRNP A1/A2. Most importantly, the expression of hnRNP A1/A2 and PTB/nPTB is significantly altered in patients with frontotemporal dementia with TDP-43-positive inclusions (FTLD-TDP), indicating that perturbations in RNA metabolism and processing in FTLD-TDP are not exclusively driven by a loss of TDP-43 function. These results also suggest that a comprehensive assessment of the RNA-binding protein network will dramatically advance our current understanding of the role of TDP-43 in disease pathogenesis, as well as enhance both diagnostic and therapeutic capabilities. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. J-2X installation on A-1

    NASA Image and Video Library

    2007-09-20

    Core components of the J-2X engine being designed for NASA's Constellation Program recently were installed on the A-1 Test Stand at NASA's Stennis Space Center near Bay St. Louis, Miss. Tests of the components, known as Powerpack 1A, will be conducted from November 2007 through February 2008. The Powerpack 1A test article consists of a gas generator and engine turbopumps originally developed for the Apollo Program that put Americans on the moon in the late 1960s and early 1970s. Engineers are testing these heritage components to obtain data that will help them modify the turbomachinery to meet the higher performance requirements of the Ares I and Ares V launch vehicles. The upcoming tests will simulate inlet and outlet conditions that would be present on the turbomachinery during a full-up engine hot-fire test.

  2. Architecture for a 1-GHz Digital RADAR

    NASA Technical Reports Server (NTRS)

    Mallik, Udayan

    2011-01-01

    An architecture for a Direct RF-digitization Type Digital Mode RADAR was developed at GSFC in 2008. Two variations of a basic architecture were developed for use on RADAR imaging missions using aircraft and spacecraft. Both systems can operate with a pulse repetition rate up to 10 MHz with 8 received RF samples per pulse repetition interval, or at up to 19 kHz with 4K received RF samples per pulse repetition interval. The first design describes a computer architecture for a Continuous Mode RADAR transceiver with a real-time signal processing and display architecture. The architecture can operate at a high pulse repetition rate without interruption for an infinite amount of time. The second design describes a smaller and less costly burst mode RADAR that can transceive high pulse repetition rate RF signals without interruption for up to 37 seconds. The burst-mode RADAR was designed to operate on an off-line signal processing paradigm. The temporal distribution of RF samples acquired and reported to the RADAR processor remains uniform and free of distortion in both proposed architectures. The majority of the RADAR's electronics is implemented in digital CMOS (complementary metal oxide semiconductor), and analog circuits are restricted to signal amplification operations and analog to digital conversion. An implementation of the proposed systems will create a 1-GHz, Direct RF-digitization Type, L-Band Digital RADAR--the highest band achievable for Nyquist Rate, Direct RF-digitization Systems that do not implement an electronic IF downsample stage (after the receiver signal amplification stage), using commercially available off-the-shelf integrated circuits.

  3. Treadmill desks: A 1-year prospective trial.

    PubMed

    Koepp, Gabriel A; Manohar, Chinmay U; McCrady-Spitzer, Shelly K; Ben-Ner, Avner; Hamann, Darla J; Runge, Carlisle F; Levine, James A

    2013-04-01

    Sedentariness is associated with weight gain and obesity. A treadmill desk is the combination of a standing desk and a treadmill that allow employees to work while walking at low speed. The hypothesis was that a 1-year intervention with treadmill desks is associated with an increase in employee daily physical activity (summation of all activity per minute) and a decrease in daily sedentary time (zero activity). Employees (n = 36; 25 women, 11 men) with sedentary jobs (87 ± 27 kg, BMI 29 ± 7 kg/m(2) , n = 10 Lean BMI < 25 kg/m(2) , n = 15 Overweight 25 < BMI < 30 kg/m(2) , n = 11 Obese BMI > 30 kg/m(2) ) volunteered to have their traditional desk replaced with a treadmill desk to promote physical activity for 1 year. Daily physical activity (using accelerometers), work performance, body composition, and blood variables were measured at Baseline and 6 and 12 months after the treadmill desk intervention. Subjects who used the treadmill desk increased daily physical activity from baseline 3,353 ± 1,802 activity units (AU)/day to, at 6 months, 4,460 ± 2,376 AU/day (P < 0.001), and at 12 months, 4,205 ± 2,238 AU/day (P < 0.001). Access to the treadmill desks was associated with significant decreases in daily sedentary time (zero activity) from at baseline 1,020 ± 75 min/day to, at 6 months, 929 ± 84 min/day (P < 0.001), and at 12 months, 978 ± 95 min/day (P < 0.001). For the whole group, weight loss averaged 1.4 ± 3.3 kg (P < 0.05). Weight loss for obese subjects was 2.3 ± 3.5 kg (P < 0.03). Access to the treadmill desks was associated with increased daily physical activity compared to traditional chair-based desks; their deployment was not associated with altered performance. For the 36 participants, fat mass did not change significantly, however, those who lost weight (n = 22) lost 3.4 ± 5.4 kg (P < 0.001) of fat mass. Weight loss was greatest in people with obesity. Access to treadmill desks may improve the health of office workers without affecting work

  4. Diagnostics for a 1.2 kA, 1 MeV, electron induction injector

    NASA Astrophysics Data System (ADS)

    Houck, T. L.; Anderson, D. E.; Eylon, S.; Henestroza, E.; Lidia, S. M.; Vanecek, D. L.; Westenskow, G. A.; Yu, S. S.

    1998-12-01

    We are constructing a 1.2 kA, 1 MeV, electron induction injector as part of the RTA program, a collaborative effort between LLNL and LBNL to develop relativistic klystrons for Two-Beam Accelerator applications. The RTA injector will also be used in the development of a high-gradient, low-emittance, electron source and beam diagnostics for the second axis of the Dual Axis Radiographic Hydrodynamic Test (DARHT) Facility. The electron source will be a 3.5″-diameter, thermionic, flat-surface, m-type cathode with a maximum shroud field stress of approximately 165 kV/cm. Additional design parameters for the injector include a pulse length of over 150 ns flat top (1% energy variation), and a normalized edge emittance of less than 200 π-mm-mr. Precise measurement of the beam parameters is required so that performance of the RTA injector can be confidently scaled to the 4 kA, 3 MeV, and 2-microsecond pulse parameters of the DARHT injector. Planned diagnostics include an isolated cathode with resistive divider for direct measurement of current emission, resistive wall and magnetic probe current monitors for measuring beam current and centroid position, capacitive probes for measuring A-K gap voltage, an energy spectrometer, and a pepperpot emittance diagnostic. Details of the injector, beam line, and diagnostics are presented.

  5. Crystallization and preliminary X-ray analysis of alginate lyases A1-II and A1-II′ from Sphingomonas sp. A1

    SciTech Connect

    Yamasaki, Masayuki; Ogura, Kohei; Moriwaki, Satoko

    The crystallization and preliminary characterization of the family PL-7 alginate lyases A1-II and A1-II′ from Sphingomonas sp. A1 are presented. Alginate lyases depolymerize alginate, a heteropolysaccharide consisting of α-l-guluronate and β-d-mannuronate, through a β-elimination reaction. The alginate lyases A1-II (25 kDa) and A1-II′ (25 kDa) from Sphingomonas sp. A1, which belong to polysaccharide lyase family PL-7, exhibit 68% homology in primary structure but have different substrate specificities. To determine clearly the structural basis for substrate recognition in the depolymerization mechanism by alginate lyases, both proteins were crystallized at 293 K using the vapour-diffusion method. A crystal of A1-II belonged tomore » space group P2{sub 1} and diffracted to 2.2 Å resolution, with unit-cell parameters a = 51.3, b = 30.1, c = 101.6 Å, β = 100.2°, while a crystal of A1-II′ belonged to space group P2{sub 1}2{sub 1}2{sub 1} and diffracted to 1.0 Å resolution, with unit-cell parameters a = 34.6, b = 68.5, c = 80.3 Å.« less

  6. Global standardisation of HbA1c.

    PubMed

    Lai, Leslie C

    2008-12-01

    HbA1c is used for assessing glycaemic control in patients with diabetes. It is also used for treatment goals and as a target for therapeutic intervention. The Direct Control and Complications Trial in the USA showed that HbA1c can be used to predict the risk of complications. Hence, it is important for HbA1c assays to be standardised. The National Glycohemoglobin Standardization Program (NGSP) in the USA was formed in 1996 so that HbA1c results from different laboratories would be comparable to those reported in the DCCT study. There were also HbA1c standardisation programmes in Sweden and Japan. These three standardisation programmes are, in fact, direct comparison methods (DCMs), and yield different HbA1c results. In 1994, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) established a Working Group on Standardisation of HbA1c. This working group has developed a global HbA1c reference system with very much improved intra-assay and inter-assay coefficients of variation. Recommendations have been made to report HbA1c results as IFCC-HbA1c values in SI units (mmol HbA1c/mol Hb) and NGSP-HbA1c (%) as well as estimated average glucose (eAG), once a tight relationship has been shown to exist between eAG and HbA1c.

  7. Evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins functionally interact with human and Drosophila TAR DNA-binding protein 43 (TDP-43).

    PubMed

    Romano, Maurizio; Buratti, Emanuele; Romano, Giulia; Klima, Raffaella; Del Bel Belluz, Lisa; Stuani, Cristiana; Baralle, Francisco; Feiguin, Fabian

    2014-03-07

    Human TDP-43 represents the main component of neuronal inclusions found in patients with neurodegenerative diseases, especially frontotemporal lobar degeneration and amyotrophic lateral sclerosis. In vitro and in vivo studies have shown that the TAR DNA-binding protein 43 (TDP-43) Drosophila ortholog (TBPH) can biochemically and functionally overlap the properties of the human factor. The recent direct implication of the human heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1, known TDP-43 partners, in the pathogenesis of multisystem proteinopathy and amyotrophic lateral sclerosis supports the hypothesis that the physical and functional interplay between TDP-43 and hnRNP A/B orthologs might play a crucial role in the pathogenesis of neurodegenerative diseases. To test this hypothesis and further validate the fly system as a useful model to study this type of diseases, we have now characterized human TDP-43 and Drosophila TBPH similarity in terms of protein-protein interaction pathways. In this work we show that TDP-43 and TBPH share the ability to associate in vitro with Hrp38/Hrb98DE/CG9983, the fruit fly ortholog of the human hnRNP A1/A2 factors. Interestingly, the protein regions of TDP-43 and Hrp38 responsible for reciprocal interactions are conserved through evolution. Functionally, experiments in HeLa cells demonstrate that TDP-43 is necessary for the inhibitory activity of Hrp38 on splicing. Finally, Drosophila in vivo studies show that Hrp38 deficiency produces locomotive defects and life span shortening in TDP-43 with and without animals. These results suggest that hnRNP protein levels can play a modulatory role on TDP-43 functions.

  8. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 9 2011-07-01 2011-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties. (1...

  9. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties. (1...

  10. 26 CFR 1.1311(a)-1 - Introduction.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Introduction. 1.1311(a)-1 Section 1.1311(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Readjustment of Tax Between Years and Special Limitations § 1.1311(a)-1 Introduction. (a...

  11. 26 CFR 1.501(a)-1 - Exemption from taxation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Exemption from taxation. 1.501(a)-1 Section 1.501(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(a)-1 Exemption from taxation. (a) In...

  12. 26 CFR 1.56A-1 - Imposition of tax.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Imposition of tax. 1.56A-1 Section 1.56A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-1 Imposition of tax. (a) In general...

  13. 26 CFR 1.501(a)-1 - Exemption from taxation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Exemption from taxation. 1.501(a)-1 Section 1.501(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(a)-1 Exemption from taxation. (a) In...

  14. 49 CFR 178.33a-1 - Compliance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Compliance. 178.33a-1 Section 178.33a-1 Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS SAFETY... Specifications for Inside Containers, and Linings § 178.33a-1 Compliance. (a) Required in all details. (b...

  15. 49 CFR 178.33a-1 - Compliance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Compliance. 178.33a-1 Section 178.33a-1 Transportation Other Regulations Relating to Transportation (Continued) PIPELINE AND HAZARDOUS MATERIALS SAFETY... Containers, and Linings § 178.33a-1 Compliance. (a) Required in all details. (b) [Reserved] [Order 71, 31 FR...

  16. Methods for Tumor Targeting with Salmonella typhimurium A1-R.

    PubMed

    Hoffman, Robert M; Zhao, Ming

    2016-01-01

    Salmonella typhimurium A1-R (S. typhimurium A1-R) has shown great preclinical promise as a broad-based anti-cancer therapeutic (please see Chapter 1 ). The present chapter describes materials and methods for the preclinical study of S. typhimurium A1-R in clinically-relevant mouse models. Establishment of orthotopic metastatic mouse models of the major cancer types is described, as well as other useful models, for efficacy studies of S. typhimurium A1-R or other tumor-targeting bacteria, as well. Imaging methods are described to visualize GFP-labeled S. typhimurium A1-R, as well as GFP- and/or RFP-labeled cancer cells in vitro and in vivo, which S. typhimurium A1-R targets. The mouse models include metastasis to major organs that are life-threatening to cancer patients including the liver, lung, bone, and brain and how to target these metastases with S. typhimurium A1-R. Various routes of administration of S. typhimurium A1-R are described with the advantages and disadvantages of each. Basic experiments to determine toxic effects of S. typhimurium A1-R are also described. Also described are methodologies for combining S. typhimurium A1-R and chemotherapy. The testing of S. typhimurium A1-R on patient tumors in patient-derived orthotopic xenograft (PDOX) mouse models is also described. The major methodologies described in this chapter should be translatable for clinical studies.

  17. SRD5A1 Genetic Variation and Prostate Cancer Epidemiology

    DTIC Science & Technology

    2006-05-01

    DAMD17-03-1-0136 TITLE: SRD5A1 Genetic Variation and Prostate Cancer Epidemiology PRINCIPAL INVESTIGATOR: Troy Phipps...DATES COVERED (From - To) 1 May 2003 – 30 Apr 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER SRD5A1 Genetic Variation and Prostate Cancer...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The human steroid 5-alpha reductase type I ( SRD5A1 ) gene was sequenced in 101

  18. 26 CFR 40.6011(a)-1 - Returns.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Returns. 40.6011(a)-1 Section 40.6011(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES EXCISE TAX PROCEDURAL REGULATIONS § 40.6011(a)-1 Returns. (a) In general—(1) Return required. The return of any tax to which this part 40 applies...

  19. 29 CFR 2550.403a-1 - Establishment of trust.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Establishment of trust. 2550.403a-1 Section 2550.403a-1... REGULATIONS FOR FIDUCIARY RESPONSIBILITY § 2550.403a-1 Establishment of trust. (a) In general. Except as otherwise provided in § 403b-1, all assets of an employee benefit plan shall be held in trust by one or more...

  20. Current aspects in hemoglobin A1c detection: a review.

    PubMed

    Ang, Shu Hwang; Thevarajah, M; Alias, Yatimah; Khor, Sook Mei

    2015-01-15

    Type 2 diabetes mellitus (T2DM) is a pressing health issue that threatens global health and the productivity of populations worldwide. Despite its long-recognized role in diabetes management, glycated hemoglobin (HbA1c) only received WHO endorsement as a T2DM diagnostic tool in 2011. Although conventional plasma-specific tests have long been utilized to diagnose T2DM, the public should be informed that plasma-specific tests are not markedly better than HbA1c tests, particularly in terms of variability and convenience for diagnosing diabetes. In the midst of the debates associated with establishing HbA1c as the preeminent diabetes diagnostic tool, unceasing efforts to standardize HbA1c tests have played an integral part in achieving more efficient communication from laboratory to clinical practice and thus better diabetes care. This review discusses the current status of HbA1c tests in the diagnosis, prevention, treatment and management of T2DM across the globe, focusing on increasing the recognition of glycated hemoglobin variants with effective utilization of different HbA1c methods, updating the current status of HbA1c standardization programs, tapping into the potential of POC analyzers to establish a cost-effective HbA1c test for diabetes care, and inspiring the advancement of HbA1c biosensors for future clinical usage. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. A1c Gear: Laboratory quality HbA1c measurement at the point of care.

    PubMed

    Ejilemele, Adetoun; Unabia, Jamie; Ju, Hyunsu; Petersen, John R

    2015-05-20

    HbA1c is an important part of assessing the diabetic control and since the use of point-of-care devices for monitoring HbA1c is increasing, it is important to determine how these devices compare to the central laboratory. One hundred and twenty patient samples were analyzed on the Bio-Rad Variant™II and one POC analyzer (Sakae A1c Gear). Three patient sample pools containing ~5%, ~7%, and ~10% HbA1c levels were run over 20 days. Three reagent lots and three instruments were evaluated for the A1c Gear. The 120 patient samples showed strong correlation (R(2)>0.989) when compared to the Variant™II with means=8.06% and 7.81%, for Variant IIand A1c Gear, respectively. Changing reagent lots or instruments had no impact for the A1c Gear. The ~5%, ~7%, and ~10% pools within-run and between-run imprecision was between 0.87-1.33% and 1.03-1.32%, and 1.41-2.35% and 1.24-1.89% with total imprecision of 1.67-2.35% and 1.61-2.31% for the A1c Gear and Variant II, respectively. The A1c Gear showed a small negative bias (0.25% HbA1c) across HbA1c measurement ranges of <11.5%. This bias was, however, acceptable and not considered to be clinically significant. The A1c Gear meets the criteria of total CV <3% leading us to the conclusion that the A1c Gear can give results as precise as the laboratory at the POC. Copyright © 2015. Published by Elsevier B.V.

  2. New a1(1420 ) state: Structure, mass, and width

    NASA Astrophysics Data System (ADS)

    Sundu, H.; Agaev, S. S.; Azizi, K.

    2018-03-01

    The structure, spectroscopic parameters and width of the resonance with quantum numbers JP C=1++ discovered by the COMPASS Collaboration and classified as the a1(1420 ) meson are examined in the context of QCD sum rule method. In the calculations the axial-vector meson a1(1420 ) is treated as a four-quark state with the diquark-antidiquark structure. The mass and current coupling of a1(1420 ) are evaluated using QCD two-point sum rule approach. Its observed decay mode a1(1420 )→f0(980 )π , and kinematically allowed ones, namely a1→K*±K∓ , a1→K*0K¯ 0 and a1→K¯ *0K0 channels are studied employing QCD sum rules on the light-cone. Our prediction for the mass of the a1(1420 ) state ma1=1416-79+81 MeV is in excellent agreement with the experimental result. Width of this state Γ =145.52 ±20.79 MeV within theoretical and experimental errors is also in accord with the COMPASS data.

  3. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Taxable transportation. 49.4262(a)-1 Section 49...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable transportation. (a) In general. Unless excluded under section 4262(b) (see § 49.4262(b)-1), taxable...

  4. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Taxable transportation. 49.4262(a)-1 Section 49...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable transportation. (a) In general. Unless excluded under section 4262(b) (see § 49.4262(b)-1), taxable...

  5. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Taxable transportation. 49.4262(a)-1 Section 49...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable transportation. (a) In general. Unless excluded under section 4262(b) (see § 49.4262(b)-1), taxable...

  6. 42 CFR 5a.1 - Statutory basis and purpose.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Statutory basis and purpose. 5a.1 Section 5a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL... the Public Health Service Act. These provisions define “underserved rural community” for purposes of...

  7. 42 CFR 5a.1 - Statutory basis and purpose.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Statutory basis and purpose. 5a.1 Section 5a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL... the Public Health Service Act. These provisions define “underserved rural community” for purposes of...

  8. 42 CFR 5a.1 - Statutory basis and purpose.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Statutory basis and purpose. 5a.1 Section 5a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL... the Public Health Service Act. These provisions define “underserved rural community” for purposes of...

  9. Retinoid regulation of the zebrafish cyp26a1 promoter.

    PubMed

    Hu, Ping; Tian, Miao; Bao, Jie; Xing, Guangdong; Gu, Xingxing; Gao, Xiang; Linney, Elwood; Zhao, Qingshun

    2008-12-01

    Cyp26A1 is a major enzyme that controls retinoic acid (RA) homeostasis by metabolizing RA into bio-inactive metabolites. Previous research revealed that the mouse Cyp26A1 promoter has two canonical RA response elements (RAREs) that underlie the regulation of the gene by RA. Analyzing the 2,533-base pairs (2.5 k) genomic sequence upstream of zebrafish cyp26a1 start codon, we report that the two RAREs are conserved in zebrafish cyp26a1 promoter. Mutagenesis demonstrated that the two RAREs work synergistically in RA inducibility of cyp26a1. Fusing the 2.5 k (kilobase pairs) fragment to the enhanced yellow fluorescent protein (eYFP) reporter gene, we have generated two transgenic lines of zebrafish [Tg(cyp26a1:eYFP)]. The transgenic zebrafish display expression patterns similar to that of cyp26a1 gene in vivo. Consistent with the in vitro results, the reporter activity is RA inducible in embryos. Taken together, our results demonstrate that the 2.5 k fragment underlies the regulation of the zebrafish cyp26a1 gene by RA. (c) 2008 Wiley-Liss, Inc.

  10. 26 CFR 1.666(a)-1 - Amount allocated.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...,000 in 1958, none in 1957, $1,000 in 1956. Example 3. A trust is created in 1952 under the laws of...) INCOME TAXES Treatment of Excess Distributions of Trusts Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(a)-1 Amount allocated. (a)(1) If a trust other than a foreign trust created by a U...

  11. An example of auto-anti-A1 agglutinins.

    PubMed

    Wright, J; Lim, F C; Freedman, J

    1980-10-01

    The serum of an elderly man, group A, Le(a+b-), contained an IgM antibody that agglutinated his own cells and the cells of random group A1 donors. Over a period of 5 months, the titre of these auto-anti-A1 agglutinins was 4 at 22 degrees C.

  12. Note on the photoproduction of the charged A1

    NASA Astrophysics Data System (ADS)

    Condo, G. T.; Handler, T.

    1987-05-01

    Arguments made nearly 15 years ago by Fox and Hey are updated in the light of recent experimental findings. These indicate that the charge-exchange photoproduction of the A1 should dominate that of the A2. Consistency with the experimental data demands an A1 mass of 1335+/-20 MeV and width of 180+/-55 MeV.

  13. 42 CFR 5a.1 - Statutory basis and purpose.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Statutory basis and purpose. 5a.1 Section 5a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL... the Public Health Service Act. These provisions define “underserved rural community” for purposes of...

  14. 42 CFR 5a.1 - Statutory basis and purpose.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Statutory basis and purpose. 5a.1 Section 5a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL... the Public Health Service Act. These provisions define “underserved rural community” for purposes of...

  15. Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress.

    PubMed

    Brocker, Chad; Lassen, Natalie; Estey, Tia; Pappa, Aglaia; Cantore, Miriam; Orlova, Valeria V; Chavakis, Triantafyllos; Kavanagh, Kathryn L; Oppermann, Udo; Vasiliou, Vasilis

    2010-06-11

    Mammalian ALDH7A1 is homologous to plant ALDH7B1, an enzyme that protects against various forms of stress, such as salinity, dehydration, and osmotic stress. It is known that mutations in the human ALDH7A1 gene cause pyridoxine-dependent and folic acid-responsive seizures. Herein, we show for the first time that human ALDH7A1 protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. Human ALDH7A1 expression in Chinese hamster ovary cells attenuated osmotic stress-induced apoptosis caused by increased extracellular concentrations of sucrose or sodium chloride. Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates, including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. The crystal structure for ALDH7A1 supports the enzyme's substrate specificities. Tissue distribution studies in mice showed the highest expression of ALDH7A1 protein in liver, kidney, and brain, followed by pancreas and testes. ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria, making it unique among the aldehyde dehydrogenase enzymes. Analysis of human and mouse cDNA sequences revealed mitochondrial and cytosolic transcripts that are differentially expressed in a tissue-specific manner in mice. In conclusion, ALDH7A1 is a novel aldehyde dehydrogenase expressed in multiple subcellular compartments that protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes.

  16. Aldehyde Dehydrogenase 7A1 (ALDH7A1) Is a Novel Enzyme Involved in Cellular Defense against Hyperosmotic Stress*

    PubMed Central

    Brocker, Chad; Lassen, Natalie; Estey, Tia; Pappa, Aglaia; Cantore, Miriam; Orlova, Valeria V.; Chavakis, Triantafyllos; Kavanagh, Kathryn L.; Oppermann, Udo; Vasiliou, Vasilis

    2010-01-01

    Mammalian ALDH7A1 is homologous to plant ALDH7B1, an enzyme that protects against various forms of stress, such as salinity, dehydration, and osmotic stress. It is known that mutations in the human ALDH7A1 gene cause pyridoxine-dependent and folic acid-responsive seizures. Herein, we show for the first time that human ALDH7A1 protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. Human ALDH7A1 expression in Chinese hamster ovary cells attenuated osmotic stress-induced apoptosis caused by increased extracellular concentrations of sucrose or sodium chloride. Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates, including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, α-aminoadipic semialdehyde. The crystal structure for ALDH7A1 supports the enzyme's substrate specificities. Tissue distribution studies in mice showed the highest expression of ALDH7A1 protein in liver, kidney, and brain, followed by pancreas and testes. ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria, making it unique among the aldehyde dehydrogenase enzymes. Analysis of human and mouse cDNA sequences revealed mitochondrial and cytosolic transcripts that are differentially expressed in a tissue-specific manner in mice. In conclusion, ALDH7A1 is a novel aldehyde dehydrogenase expressed in multiple subcellular compartments that protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. PMID:20207735

  17. In vivo cleavage of immunoglobulin A1 by immunoglobulin A1 proteases from Prevotella and Capnocytophaga species.

    PubMed

    Frandsen, E V; Reinholdt, J; Kjeldsen, M; Kilian, M

    1995-10-01

    Immunoglobulin A1 (IgA1) proteases secreted by oral Prevotella and Capnocytophaga species specifically cleave IgA1 at the same peptide bond in the hinge region, leaving intact monomeric Fab and Fc fragments. Assuming that Prevotella- and Capnocytophaga-induced Fab fragments of IgA1 expose a specific immunogenic neoepitope at the cleavage site, we established an enzyme-linked immunosorbent assay to measure human serum antibodies to this neoepitope as indirect evidence of in vivo activity of Prevotella and Capnocytophaga IgA1 proteases. The assay used a monoclonal antibody with specificity for the neoepitope, and the ability to block binding of the monoclonal antibody to the neoepitope was investigated. Absorption of sera with Prevotella melaninogenica-induced Fab fragments of IgA1 resulted in removal of antibodies blocking binding of the monoclonal antibody, whereas absorption with Fab fragments induced by bacterial IgA1 proteases of other cleavage specificities did not remove blocking antibodies. Consequently, we assume that the antibodies detected had been induced by a neoepitope an the Fab fragment of IgA1 exposed exclusively after cleavage with IgA1 proteases from Prevotella and Capnocytophaga, indicating in vivo activity of these IgA1 proteases. Evidence, though indirect, of in vivo activity of Prevotella and Capnocytophaga IgA1 proteases was present in 42 of 92 sera examined and in a significantly higher proportion of sera from adults with periodontal disease compared with control individuals. No correlation with disease was observed for the juvenile periodontitis groups.

  18. [About the HbA1c in the elderly].

    PubMed

    Farcet, Anaïs; Delalande, Géraldine; Oliver, Charles; Retornaz, Frédérique

    2016-03-01

    HbA1c product of non enzymatic glycation of HbA increases in relation with the mean blood glucose level during the former 2-3 months. HbA1c levels are correlated with the development of diabetic complications and HbA1c assessment is now the gold standard for evaluation of diabetes control. HbA1c level should not be higher than 7% to avoid these complications. However, in aged peoples, the objectives of diabetes control vary according to their health status. It must be good with HbA1c lower than 7-7.5% in healthy subjects and more relax in subjects with symptoms of frailty and risks of non perceived and self corrected hypoglycemia. Under these conditions, HbA1c values lower than 8 to 9% are advised. Nevertheless, hypoglycemia episodes may occur in patients with high HbA1c and capillary glucose follow-up is necessary for detection of such complications.

  19. Effect of DNA methylation profile on OATP3A1 and OATP4A1 transcript levels in colorectal cancer.

    PubMed

    Rawłuszko-Wieczorek, Agnieszka Anna; Horst, Nikodem; Horbacka, Karolina; Bandura, Artur Szymon; Świderska, Monika; Krokowicz, Piotr; Jagodziński, Paweł Piotr

    2015-08-01

    Epidemiological studies indicate that 17β-estradiol (E2) prevents colorectal cancer (CRC). Organic anion transporting polypeptides (OATPs) are involved in the cellular uptake of various endogenous and exogenous substrates, including hormone conjugates. Because transfer of estrone sulfate (E1-S) can contribute to intra-tissue conversion of estrone to the biologically active form -E2, it is evident that the expression patterns of OATPs may be relevant to the analysis of CRC incidence and therapy. We therefore evaluated DNA methylation and transcript levels of two members of the OATP family, OATP3A1 and OATP4A1, that may be involved in E1-S transport in colorectal cancer patients. We detected a significant reduction in OATP3A1 and a significant increase in OATP4A1 mRNA levels in cancerous tissue, compared with histopathologically unchanged tissue (n=103). Moreover, we observed DNA hypermethylation in the OATP3A1 promoter region in a small subset of CRC patients and in HCT116 and Caco-2 colorectal cancer cell lines. We also observed increased OATP3A1 transcript following treatment with 5-aza-2-deoxycytidine and sodium butyrate. The OATP4A1 promoter region was hypomethylated in analyzed tissues and CRC cell lines and was not affected by these treatments. Our results suggest a potential mechanism for OATP3A1 downregulation that involves DNA methylation during colorectal carcinogenesis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  20. SRD5A1 Genetic Variation and Prostate Cancer Epidemiology

    DTIC Science & Technology

    2005-05-01

    DATES COVERED (Leave blank) May 2005 Annual Summary (1 May 2004 - 30 Apr 2005) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS SRD5A1 Genetic Variation and...secondary structure of the luciferase+ SRD5A1 3’-UTR mRNA was so different from the native SRD5Al message, that the 3’-UTR variants should be tested...in the context of a native mRNA. A eukaryotic expression vector containing 850bp of the human SRD5A1 promoter was seamlessly cloned onto the 5’ end of

  1. Selecting an A1C Point-of-Care Instrument

    PubMed Central

    Yong, Ee Vonn; Rasinen, Casey

    2015-01-01

    A1C point-of-care (POC) instruments benefit patients with diabetes by facilitating clinician decision making that results in significant glycemic improvements. Three National Glycohemoglobin Standardization Program (NGSP)–certified POC products are available in the United States: the handheld A1CNow (formerly manufactured by Bayer Diabetes Care but now made by Chek Diagnostics) and two bench-top models called the Axis-Shield Afinion Analyzer and the Siemens DCA Vantage. This article compares the three available NGSP-certified POC products in terms of accuracy, precision, ease of use, cost, and additional features. Its goal is to aid health care facilities in conveniently identifying the A1C POC product that best meets their needs. It additionally reviews evidence that supports the continued use of A1C POC instruments in the clinical arena. PMID:26300614

  2. Prevalence of normoglycemic, prediabetic and diabetic A1c levels

    PubMed Central

    Aponte, Judith

    2013-01-01

    AIM: To investigate normoglycemic, prediabetic and diabetic A1c levels in those with prediabetes; and prediabetic and diabetic A1c levels in those with non-prediabetes. METHODS: The National Health and Nutritional Examination Survey (NHANES) 2007-2008 and NHANES 2009-2010 were utilized to examine and compare trends and differences among five different ethnic groups (Mexican Americans, Other Hispanics, Non-Hispanic Whites, Non-Hispanic Blacks, Other/Multi-racials) with normoglycemic, prediabetic and diabetic A1c levels with self-reported prediabetes and prediabetic and diabetic A1c levels in those with self-reported non-prediabetes. Sample participants of the five ethnic groups were limited to those 20 years of age and older, who had completed the diabetes questionnaire and had A1c measured. Descriptive statistics were computed for all variables. χ2 were performed on all five ethnic groups to examine significant differences of normoglycemic, prediabetic and diabetic A1c levels in those with self-reported prediabetes, and prediabetic and diabetic A1c levels in those with self-reported non-prediabetes. RESULTS: This study demonstrates that of the five different ethnic groups from NHANES 2007-2008 to NHANES 2009-2010, Non-Hispanic Whites (6.5% increase) and Non-Hispanic Blacks (0.2% increase) were the only two groups with an increase in the number of self-reported prediabetes. Although the overall percentage of Mexican Americans who self-reported prediabetes had remained the same (5%) from NHANES 2007-2008 to NHANES 2009-2010, χ2 analysis showed significant differences when examining the different ranges of A1c levels (normoglycemic, prediabetic and diabetic). Among Mexican Americans who self-reported prediabetes, normoglycemic (P = 0.0001) and diabetic (P = 0.0001) A1c levels from NHANES 2007-2008 to NHANES 2009-2010. For Non-Hispanic Whites who self-reported prediabetes, prediabetic (P = 0.0222); and diabetic (P ≤ 0.0001) A1c levels from NHANES 2007-2008 to

  3. RNAi of COL1A1 in mesenchymal progenitor cells.

    PubMed

    Millington-Ward, Sophia; McMahon, Helena P; Allen, Danny; Tuohy, Gearóid; Kiang, Anna-Sophia; Palfi, Arpad; Kenna, Paul F; Humphries, Peter; Farrar, G Jane

    2004-10-01

    Given that mutant COL1A1 is known to cause Osteogenesis Imperfecta (OI), tools to modulate COL1A1 expression are likely to be of significant therapeutic value. In this context, we have evaluated RNA interference (RNAi) as a means to downregulate COL1A1 expression in Cos-7 cells and in human mesenchymal progenitor stem cells (MPCs), the latter cells giving rise to bone and therefore representing a target cell type for collagen-related disorders. In addition, allele-specificity, a key factor to the success of RNAi-based suppression, was explored with a view to developing a mutation-independent RNAi-based therapeutic for OI by targeting an intragenic SNP within transcripts derived from the COL1A1 gene. Preferential suppression of individual polymorphic alleles that differed by a single nucleotide was observed.

  4. ISS 7A.1 Flight Control Team Photo in BFCR

    NASA Image and Video Library

    2001-08-17

    JSC2001-02225 (17 August 2001) --- The members of the STS-105/ISS 7A.1 Orbit 2 team pose for a group portrait in the International Space Station (ISS) flight control room (BFCR) in Houston’s Mission Control Center (MCC). Orbit 2 flight director Rick LaBrode (front right) holds the STS-105 mission logo, and Astronaut Joan E. Higginbotham, ISS spacecraft communicator (CAPCOM), holds the ISS 7A.1 mission logo.

  5. Ephs and Ephrins in Cancer: Ephrin-A1 Signaling

    PubMed Central

    Beauchamp, Amanda; Debinski, Waldemar

    2011-01-01

    Ephrin-A1 and its primary receptor, EphA2, are involved in numerous physiological processes and have been intensely studied for their roles in malignancy. Ephrin-Eph signalling is complex on its own and is also cell-type dependent, making elucidation of the exact role of ephrin-A1 in neoplasia challenging. Multiple oncogenic signalling pathways, such as MAP/ERK and PI3K are affected by ephrin-A1, and in some cases evidence suggests the promotion of a specific pathway in one cell or cancer type and inhibition of the same pathway in another type of cell or cancer. EphrinA1 also plays an integral role in angiogenesis and tumor neovascularization. Until recently, studies investigating ephrins focused on the ligands as GPI-anchored proteins that required membrane anchoring or artificial clustering for Eph receptor activation. However, recent studies have demonstrated a functional role for soluble, monomeric ephrin-A1. This review will focus on various forms of ephrin-A1-specific signalling in human malignancy. PMID:22040911

  6. AMP is an adenosine A1 receptor agonist.

    PubMed

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  7. New phospholipase A1-producing bacteria from a marine fish.

    PubMed

    Nishihara, Masaaki; Kamata, Masazumi; Koyama, Tomoyuki; Yazawa, Kazunaga

    2008-01-01

    Phospholipase A1 is a hydrolytic enzyme that catalyzes the removal of the acyl group from position 1 of glycerophospholipids to form 2-acyl lysophospholipids. Lysophospholipids are used in foods, cosmetics, and pharmaceuticals as surfactants. Novel forms of phospholipase A1 that function at low temperatures are desirable for use in lipophilic systems in food processing. However, there is currently little variety in the available sources of phospholipase A1. Given this situation, we screened the intestinal contents of marine animals for phospholipase A1-producing bacteria. Colonies that formed a halo on K28CP screening medium and that grew in K28 medium were cultured in liquid K28 medium, and the supernatant was retrieved for analysis. Phosphatidylcholine was added to the culture supernatant, and the product of the reaction was analyzed by using TLC. For culture supernatants that were able to generate lysophosphatidylcholine, synthetic phosphatidylcholines were added, and the site of the reaction was determined by analyzing the fatty acid compositions of the lysophosphatidylcholines generated by GLC. A bacterial isolate from a flatfish, which we named HFKI0020, was found to have phospholipase A1 activity at low temperatures. We determined that the isolate HFKI0020 is closely related to Pseudomonas by using 16S rDNA sequence analysis and by characterizing the isolate with respect to its physiologic and biochemical properties. From the intestinal contents of a marine fish, we successfully isolated a bacterium that secretes phospholipase A1 that is active at low temperatures.

  8. Cooperative unfolding of apolipoprotein A-1 induced by chemical denaturation.

    PubMed

    Eckhardt, D; Li-Blatter, X; Schönfeld, H-J; Heerklotz, H; Seelig, J

    2018-05-25

    Apolipoprotein A-1 (Apo A-1) plays an important role in lipid transfer and obesity. Chemical unfolding of α-helical Apo A-1 is induced with guanidineHCl and monitored with differential scanning calorimetry (DSC) and CD spectroscopy. The unfolding enthalpy and the midpoint temperature of unfolding decrease linearly with increasing guanidineHCl concentration, caused by the weak binding of denaturant. At room temperature, binding of 50-60 molecules guanidineHCl leads to a complete Apo A-1 unfolding. The entropy of unfolding decreases to a lesser extent than the unfolding enthalpy. Apo A-1 chemical unfolding is a dynamic multi-state equilibrium that is analysed with the Zimm-Bragg theory modified for chemical unfolding. The chemical Zimm-Bragg theory predicts the denaturant binding constant K D and the protein cooperativity σ. Chemical unfolding of Apo A-1 is two orders of magnitude less cooperative than thermal unfolding. The free energy of thermal unfolding is ~0.2 kcal/mol per amino acid residue and ~1.0 kcal/mol for chemical unfolding at room temperature. The Zimm-Bragg theory calculates conformational probabilities and the chemical Zimm-Bragg theory predicts stretches of α-helical segments in dynamic equilibrium, unfolding and refolding independently and fast. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Efficient purification of Apolipoprotein A1 (ApoA1) from plasma by HEA HyperCel™: An alternative approach.

    PubMed

    G, Arun Govind; Kamalanathan, Agamudi Shivasankaran; Vijayalakshmi, Mookambeswaran Arunachalam; Venkataraman, Krishnan

    2018-01-15

    HDL-ApoA1 plays a pivotal role in the prevention of atherosclerosis and cardiovascular diseases. ApoA1 purification from blood plasma has always remained tedious, involving multiple steps, large volumes of plasma and substantial loss in the final yield of pure ApoA1. In this study, a two-step method has been developed and optimized for the purification of ApoA1 from plasma. Plasma was first subjected to 60% ammonium sulphate (NH 4 ) 2 SO 4 precipitation and subsequently, ApoA1 was recovered using mixed mode chromatographic sorbent, HEA HyperCel™. ApoA1 was found to be enriched in 60% (NH 4 ) 2 SO 4 supernatant that was dialyzed and injected onto HEA sorbent with 50 mM phosphate buffer pH 7.4. The bound proteins were eluted by decreasing the pH in step-gradient from pH 7.4 to pH 4.0 and subsequently to pH 3.5 using 50 mM sodium acetate buffer. Gel electrophoresis showed elution of homogeneous apoA1 at pH 3.5, with purity and yield of 63%. An interesting feature of this approach is that the purified ApoA1 was monomeric with a mass of 28,079.30 Da as confirmed by MS analysis. This simple and efficient method of purification of apoA1 serves as an alternative method which can be combined with traditional approaches and has a great potential for biochemical and clinical studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1.

    PubMed

    Kamo, Shunsuke; Nakanishi, Takeo; Aotani, Rika; Nakamura, Yoshinobu; Gose, Tomoka; Tamai, Ikumi

    2017-09-01

    To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty-one and 10 drugs were found to inhibit and enhance 6-CF uptake by more than 50%, respectively. Effect of the 51 drugs on 6-CF uptake was positively correlated with that on PGE 2 uptake (r = 0.64, p < 0.001). Among those, 5 drugs not structurally related to prostaglandins, suramin, pranlukast, zafirlukast, olmesartan medoxomil, and losartan potassium, exhibited more than 90% PGE 2 uptake inhibition. Inhibitory affinity of suramin to OATP2A1 was the highest (IC 50,2A1 of 0.17 μM), and its IC 50 values to MRP4-mediated PGE 2 transport (IC 50,MRP4 ) and PGE 2 synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC 50,Syn ) were 73.6 and 336.7 times higher than IC 50,2A1 , respectively. Moreover, structure-activity relationship study in 29 nonsteroidal anti-inflammatory drugs contained in the library displayed inhibitory activities of anthranilic acid derivatives, but enhancing effects of propionic acid derivatives. These results demonstrate that suramin is a potent selective inhibitor of OATP2A1, providing a comprehensive information about drugs in clinical use that interact with OATP2A1. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  11. Cellular RNA binding proteins NS1-BP and hnRNP K regulate influenza A virus RNA splicing.

    PubMed

    Tsai, Pei-Ling; Chiou, Ni-Ting; Kuss, Sharon; García-Sastre, Adolfo; Lynch, Kristen W; Fontoura, Beatriz M A

    2013-01-01

    Influenza A virus is a major human pathogen with a genome comprised of eight single-strand, negative-sense, RNA segments. Two viral RNA segments, NS1 and M, undergo alternative splicing and yield several proteins including NS1, NS2, M1 and M2 proteins. However, the mechanisms or players involved in splicing of these viral RNA segments have not been fully studied. Here, by investigating the interacting partners and function of the cellular protein NS1-binding protein (NS1-BP), we revealed novel players in the splicing of the M1 segment. Using a proteomics approach, we identified a complex of RNA binding proteins containing NS1-BP and heterogeneous nuclear ribonucleoproteins (hnRNPs), among which are hnRNPs involved in host pre-mRNA splicing. We found that low levels of NS1-BP specifically impaired proper alternative splicing of the viral M1 mRNA segment to yield the M2 mRNA without affecting splicing of mRNA3, M4, or the NS mRNA segments. Further biochemical analysis by formaldehyde and UV cross-linking demonstrated that NS1-BP did not interact directly with viral M1 mRNA but its interacting partners, hnRNPs A1, K, L, and M, directly bound M1 mRNA. Among these hnRNPs, we identified hnRNP K as a major mediator of M1 mRNA splicing. The M1 mRNA segment generates the matrix protein M1 and the M2 ion channel, which are essential proteins involved in viral trafficking, release into the cytoplasm, and budding. Thus, reduction of NS1-BP and/or hnRNP K levels altered M2/M1 mRNA and protein ratios, decreasing M2 levels and inhibiting virus replication. Thus, NS1-BP-hnRNPK complex is a key mediator of influenza A virus gene expression.

  12. Material Assessment of L97A1/L96A1 Grenades by Fourier Transform Infrared Spectroscopy and Thermogravimetric Analysis

    DTIC Science & Technology

    2010-12-01

    infrared (FTIR) spectroscopy Differential scanning calorimetry ( DSC ) L97A1/L96A1 grenades Thermogravimetric analysis (TGA) 16. SECURITY CLASSIFICATION OF...Spectroscopy The FTIR scan (fig. 3) shows two baseline materials • The blue spectra represent the Nylon 6 sample • The black spectra represent Nylon 6...The black spectra represent a sample taken from the body of the older grenade body • The relative size and location of all the peaks are identical

  13. Human SLC26A1 gene variants: a pilot study.

    PubMed

    Dawson, Paul A; Sim, Pearl; Mudge, David W; Cowley, David

    2013-01-01

    Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones.

  14. How does CKD affect HbA1c?

    PubMed

    Bloomgarden, Zachary; Handelsman, Yehuda

    2018-04-01

    HOW DOES CHRONIC KIDNEY DISEASE AFFECT HBA1C?: A number of factors determine HbA1c other than the level of glucose exposure alone. In an subset analysis of the Atherosclerosis Risk in Communities study of 941 diabetic people with varying degrees of chronic kidney disease (CKD), as well as 724 who did not have CKD, and mean age in the eighth decade, Jung et al. ask whether HbA1c is reliable as an indicator of glycemia in people with kidney disease (CKD) to the same degree as in those not having kidney disease, and, if not, whether measures of glycated serum proteins may be more useful. The only available measure of glycemia for comparison was a single fasting glucose level, and the authors acknowledge that this gives an incomplete measure, particularly in people with relatively mild diabetes, whose mean HbA1c was 6.4%, with most having levels of 7.5% or lower. In patients of this sort, postprandial glucose levels may better explain variations in mean HbA1c. Recognizing that the dataset may be limited, Jung et al. nevertheless give an intriguingly negative answer to the first question, of the reliability of HbA1c with kidney disease. Using Deming regression analysis, Jung et al. showed that the correlation between HbA1c and fasting glucose weakens as renal function worsens, and, moreover, that this appears particularly to be the case in people with anemia (hemoglobin <130 and <120 g/L for men and women, respectively), confirming earlier observations. Among those diabetic people with neither anemia nor CKD, the correlation coefficient between HbA1c and fasting glucose was r = 0.70, compared with r = 0.35 among those with both anemia and very severe CKD (estimated glomerular filtration rate [eGFR] <30 or <45 mL/min per 1.73 m 2 with at least microalbuminuria, or eGFR <60 mL/min per 1.73 m 2 with macroalbuminuria). As far as the second question, of whether the alternative measures, namely fructosamine and glycated albumin, may be more useful with CKD

  15. Current Status of HbA1c Biosensors

    PubMed Central

    Lin, Hua; Yi, Jun

    2017-01-01

    Glycated hemoglobin (HbA1c) is formed via non-enzymatic glycosylation reactions at the α–amino group of βVal1 residues in the tetrameric Hb, and it can reflect the ambient glycemic level over the past two to three months. A variety of HbA1c detection methods, including chromatography, immunoassay, enzymatic measurement, electrochemical sensor and capillary electrophoresis have been developed and used in research laboratories and in clinics as well. In this review, we summarize the current status of HbA1c biosensors based on the recognition of the sugar moiety on the protein and also their applications in the whole blood sample measurements. PMID:28777351

  16. AMP Is an Adenosine A1 Receptor Agonist*

    PubMed Central

    Rittiner, Joseph E.; Korboukh, Ilia; Hull-Ryde, Emily A.; Jin, Jian; Janzen, William P.; Frye, Stephen V.; Zylka, Mark J.

    2012-01-01

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5′-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5′-monophosphonate, ACP) directly activated the adenosine A1 receptor (A1R). In contrast, AMP only activated the adenosine A2B receptor (A2BR) after hydrolysis to adenosine by ecto-5′-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A1R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A1R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A1R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A1R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine. PMID:22215671

  17. [Microsurgical anatomy importance of A1-anterior communicating artery complex].

    PubMed

    Monroy-Sosa, Alejandro; Pérez-Cruz, Julio César; Reyes-Soto, Gervith; Delgado-Hernández, Carlos; Macías-Duvignau, Mario Alberto; Delgado-Reyes, Luis

    2013-01-01

    The anterior cerebral artery originates from the bifurcation of the internal carotid artery lateral to the optic chiasm, then joins with its contralateral counterpart via the anterior communicating artery. A1-anterior communicating artery complex is the most frequent anatomical variants and is the major site of aneurysms between 30 to 37%. Know the anatomy microsurgical, variants anatomical and importance of complex precommunicating segment-artery anterior communicating in surgery neurological of the pathology vascular, mainly aneurysms, in Mexican population. The study was performed in 30 brains injected. Microanatomy was studied (length and diameter) of A1-anterior communicating artery complex and its variants. 60 segments A1, the average length of left side was 11.35 mm and 11.84 mm was right. The average diameter of left was 1.67 mm and the right was 1.64 mm. The average number of perforators on the left side was 7.9 and the right side was 7.5. Anterior communicating artery was found in 29 brains of the optic chiasm, its course depended on the length of the A1 segment. The average length of the segment was 2.84 mm, the average diameter was 1.41 mm and the average number of perforators was 3.27. A1-anterior communicating artery complex variants were found in 18 (60%) and the presence of two blister-like aneurysms. It is necessary to understand the A1-anterior communicating artery complex microanatomy of its variants to have a three-dimensional vision during aneurysm surgery.

  18. Functional characterization of the human phosphodiesterase 7A1 promoter.

    PubMed Central

    Torras-Llort, Mònica; Azorín, Fernando

    2003-01-01

    In this paper, the human phosphodiesterase 7A1 (h PDE7A1 ) promoter region was identified and functionally characterized. Transient transfection experiments indicated that a 2.9 kb fragment of the h PDE7A1 5'-flanking region, to position -2907, has strong promoter activity in Jurkat T-cells. Deletion analysis showed that the proximal region, up to position -988, contains major cis -regulatory elements of the h PDE7A1 promoter. This minimal promoter region contains a regulatory CpG island which is essential for promoter activity. The CpG island contains three potential cAMP-response-element-binding protein (CREB)-binding sites that, as judged by in vivo dimethyl sulphate (DMS) footprinting, are occupied in Jurkat T-cells. Moreover, over-expression of CREB results in increased promoter activity, but, on the other hand, promoter activity decreases when a dominant-negative form of CREB (KCREB) is over-expressed. In vivo DMS footprinting strongly indicates that other transcription factors, such Ets-2, nuclear factor of activated T-cells 1 (NFAT-1) and nuclear factor kappaB (NF-kappaB), might also contribute to the regulation of h PDE7A1 promoter. Finally, h PDE7A1 promoter was found to be induced by treatment with PMA, but not by treatment with dibutyryl cAMP or forskolin. These results provide insights into the factors and mechanisms that regulate expression of the h PDE7A gene. PMID:12737631

  19. Characterization of SLCO5A1/OATP5A1, a Solute Carrier Transport Protein with Non-Classical Function

    PubMed Central

    Sebastian, Katrin; Detro-Dassen, Silvia; Rinis, Natalie; Fahrenkamp, Dirk; Müller-Newen, Gerhard; Merk, Hans F.; Schmalzing, Günther

    2013-01-01

    Organic anion transporting polypeptides (OATP/SLCO) have been identified to mediate the uptake of a broad range of mainly amphipathic molecules. Human OATP5A1 was found to be expressed in the epithelium of many cancerous and non-cancerous tissues throughout the body but protein characterization and functional analysis have not yet been performed. This study focused on the biochemical characterization of OATP5A1 using Xenopus laevis oocytes and Flp-In T-REx-HeLa cells providing evidence regarding a possible OATP5A1 function. SLCO5A1 is highly expressed in mature dendritic cells compared to immature dendritic cells (∼6.5-fold) and SLCO5A1 expression correlates with the differentiation status of primary blood cells. A core- and complex- N-glycosylated polypeptide monomer of ∼105 kDa and ∼130 kDa could be localized in intracellular membranes and on the plasma membrane, respectively. Inducible expression of SLCO5A1 in HeLa cells led to an inhibitory effect of ∼20% after 96 h on cell proliferation. Gene expression profiling with these cells identified immunologically relevant genes (e.g. CCL20) and genes implicated in developmental processes (e.g. TGM2). A single nucleotide polymorphism leading to the exchange of amino acid 33 (L→F) revealed no differences regarding protein expression and function. In conclusion, we provide evidence that OATP5A1 might be a non-classical OATP family member which is involved in biological processes that require the reorganization of the cell shape, such as differentiation and migration. PMID:24376674

  20. Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

    PubMed Central

    Squirewell, Edwin J.; Qin, Xiaoyan

    2014-01-01

    Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use has been limited by the low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1 (hSULT2A1) catalyzes the formation of an α-sulfooxy metabolite of tamoxifen that is reactive toward DNA, and this has been implicated in its carcinogenicity. Also, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA, with Ki values of 3.5 and 2.8 μM, respectively. In the hSULT2A1-catalyzed sulfation of PREG, 4-hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited Ki values of 12.7 and 9.8 μM, respectively, whereas corresponding Ki values of 19.4 and 17.2 μM were observed with DHEA as substrate. A Ki value of 9.1 μM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 μM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules. PMID:25157097

  1. PTSD and Sexual Orientation: An Examination of Criterion A1 and Non-Criterion A1 Events

    PubMed Central

    Alessi, Edward J.; Meyer, Ilan H.; Martin, James I.

    2015-01-01

    This large-scale cross-sectional study compared posttraumatic stress disorder (PTSD) prevalence among White, Black, and Latino lesbian, gay and bisexual individuals (LGBs; n = 382) and compared them with heterosexual individuals (n = 126). Building on previous research, we relaxed the criteria of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM–IV; American Psychiatric Association, 1994), allowing non-Criterion A1 events such as ending a relationship, unemployment, homelessness, and separation from parents to qualify, and we assessed differences in PTSD prevalence between standard DSM–IV criteria and the relaxed criteria. Findings revealed that participants reporting a non-Criterion A1 event were more likely than those reporting a Criterion A1 event to have symptoms diagnosable as PTSD. There was no significant difference in either DSM–IV or relaxed Criterion A1 PTSD prevalence between lesbian and gay, and heterosexual individuals or between bisexual and heterosexual individuals. Compared with White LGBs, Black and Latino LGBs had higher prevalence of PTSD with the relaxed Criterion A1 definition, but this was statistically significant only for Latinos. PMID:26113955

  2. Solution structure of the strawberry allergen Fra a 1

    PubMed Central

    Seutter von Loetzen, Christian; Schweimer, Kristian; Schwab, Wilfried; Rösch, Paul; Hartl-Spiegelhauer, Olivia

    2012-01-01

    The PR10 family protein Fra a 1E from strawberry (Fragaria x ananassa) is down-regulated in white strawberry mutants, and transient RNAi (RNA interference)-mediated silencing experiments confirmed that Fra a 1 is involved in fruit pigment synthesis. In the present study, we determined the solution structure of Fra a 1E. The protein fold is identical with that of other members of the PR10 protein family and consists of a seven-stranded antiparallel β-sheet, two short V-shaped α-helices and a long C-terminal α-helix that encompass a hydrophobic pocket. Whereas Fra a 1E contains the glycine-rich loop that is highly conserved throughout the protein family, the volume of the hydrophobic pocket and the size of its entrance are much larger than expected. The three-dimensional structure may shed some light on its physiological function and may help to further understand the role of PR10 proteins in plants. PMID:22913709

  3. 26 CFR 1.512(a)-1 - Definition.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.512(a)-1.... The unrelated business taxable income of a foreign organization exempt from taxation under section 501... taxation under section 501(a) consists of the organization's unrelated business taxable income which: (i...

  4. Passive smoking, Cyp1A1 gene polymorphism and dysmenorrhea

    PubMed Central

    Liu, Hong; Yang, Fan; Li, Zhiping; Chen, Changzhong; Fang, Zhian; Wang, Lihua; Hu, Yonghua; Chen, Dafang

    2007-01-01

    Objective This study investigated whether the association between passive smoking exposure and dysmenorrhea is modified by two susceptibility genes, CYP1A1MspI and CYP1A1HincII. Methods This report includes 1645 (1124 no dysmenorrhea, 521 dysmenorrhea) nonsmoking and nondrinking newly wed female workers at Anqing, China between June 1997 and June 2000. Multiple logistic regression models were used to estimate the associations of passive smoking exposure and genetic susceptibility with dysmenorrhea, adjusting for perceived stress. Results When stratified by women genotype, the adjusted OR of dysmenorrhea was 1.6 (95%CI=1.3-2.1) for passive smoking group with Ile/Ile462 genotype, and 1.5 (95%CI=1.1-2.1) with C/C6235 genotype, compared to non passive smoking group, respectively. The data further showed that there was a significant combined effect between passive smoking and the CYP1A1 Msp1 C/C6235 and HincII Ile/Ile462 genotype (OR=2.6, 95%CI=1.3-5.2). Conclusion CYP1A1 MspI and HincII genotypes modified the association between passive smoking and dysmenorrhea. PMID:17566695

  5. 26 CFR 31.3401(a)-1 - Wages.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Income Tax at Source § 31.3401(a)-1 Wages. (a) In general. (1) The term “wages” means all remuneration...(a) or excepted under section 3402(e). (2) The name by which the remuneration for services is... performed by the employee for his employer. (3) The basis upon which the remuneration is paid is immaterial...

  6. 26 CFR 31.3231(a)-1 - Who are employers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... insubstantial. (d) The term “employer” does not include any street, interurban, or suburban electric railway... Railroad Retirement Tax Act (Chapter 22, Internal Revenue Code of 1954) General Provisions § 31.3231(a)-1... connection with— (a) The transportation of passengers or property by railroad, or (b) The receipt, delivery...

  7. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable... which begins after November 15, 1962, only if such portion is not part of “uninterrupted international... transportation which begins after November 15, 1962, the tax, if applicable, applies only to the amount paid for...

  8. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.1 Purpose and scope. (a) Section 7(a) of the Williams-Steiger Occupational Safety and Health Act of 1970 establishes a National...

  9. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.1 Purpose and scope. (a) Section 7(a) of the Williams-Steiger Occupational Safety and Health Act of 1970 establishes a National...

  10. ISS 7A.1 Flight Control Team Photo in BFCR

    NASA Image and Video Library

    2001-08-16

    JSC2001-02227 (16 August 2001) --- The members of the STS-105/ISS 7A.1 Planning team pose for a group portrait in the International Space Station (ISS) flight control room (BFCR) in Houston’s Mission Control Center (MCC).

  11. Characterization of the COL2A1 VNTR polymorphism

    SciTech Connect

    Berg, E.S.; Olaisen, B.

    1993-05-01

    The variable number of tandem repeat (VNTR) region 3{prime} to the collagen type II gene (COL2A1) was amplified in vitro by the polymerase chain reaction. Subsequent high-resolution gel electrophoresis showed that the five earlier reported alleles could be further subtyped. A total of 17 allelic variants with a heterozygosity of 73.0% were found in 202 unrelated Norwegians. DNA sequencing of 19 COL2A1 alleles has been performed. The internal organization of the VNTR was common for all alleles, as previously shown for a few alleles. Moreover, the polymorphism in the COL2A1 locus is mainly due to variation in the numbers ofmore » copies of two repeat units, containing 34 and 31 bp, respectively, and/or to small deletions in either of the two units. DNA sequencing of alleles with the same electrophoretic size revealed no heterogeneity such as an alternating order of the different units, a feature that might have been expected to be the result of unequal crossing-over events. The observed ordered structure of the VNTR and the possibility of single-stranded DNA from the cores in the VNTR forming hairpins and loops suggest that the COL2A1 polymorphism may have evolved mainly by replication slippage mechanisms. 23 refs., 2 figs., 3 tabs.« less

  12. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.1 Purpose and scope. (a) Section 7(a) of the Williams-Steiger Occupational Safety and Health Act of 1970 establishes a National...

  13. 26 CFR 1.926(a)-1 - Distributions to shareholders.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... either of the administrative pricing methods of section 925(a)(1) or (2), (D) Out of earnings and profits... income and other exempt foreign trade income determined under either of the administrative pricing... earnings and profits attributable to other exempt foreign trade income determined under the transfer...

  14. 26 CFR 1.926(a)-1 - Distributions to shareholders.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... either of the administrative pricing methods of section 925(a)(1) or (2), (D) Out of earnings and profits... income and other exempt foreign trade income determined under either of the administrative pricing... earnings and profits attributable to other exempt foreign trade income determined under the transfer...

  15. Heterogeneous Nuclear Ribonucleoprotein (hnRNP) E1 Binds to hnRNP A2 and Inhibits Translation of A2 Response Element mRNAs

    PubMed Central

    Kosturko, Linda D.; Maggipinto, Michael J.; Korza, George; Lee, Joo Won; Carson, John H.

    2006-01-01

    Heterogeneous nuclear ribonucleoprotein (hnRNP) A2 is a trans-acting RNA-binding protein that mediates trafficking of RNAs containing the cis-acting A2 response element (A2RE). Previous work has shown that A2RE RNAs are transported to myelin in oligodendrocytes and to dendrites in neurons. hnRNP E1 is an RNA-binding protein that regulates translation of specific mRNAs. Here, we show by yeast two-hybrid analysis, in vivo and in vitro coimmunoprecipitation, in vitro cross-linking, and fluorescence correlation spectroscopy that hnRNP E1 binds to hnRNP A2 and is recruited to A2RE RNA in an hnRNP A2-dependent manner. hnRNP E1 is colocalized with hnRNP A2 and A2RE mRNA in granules in dendrites of oligodendrocytes. Overexpression of hnRNP E1 or microinjection of exogenous hnRNP E1 in neural cells inhibits translation of A2RE mRNA, but not of non-A2RE RNA. Excess hnRNP E1 added to an in vitro translation system reduces translation efficiency of A2RE mRNA, but not of nonA2RE RNA, in an hnRNP A2-dependent manner. These results are consistent with a model where hnRNP E1 recruited to A2RE RNA granules by binding to hnRNP A2 inhibits translation of A2RE RNA during granule transport. PMID:16775011

  16. Ultraviolet-A1 irradiation therapy for systemic lupus erythematosus.

    PubMed

    McGrath, H

    2017-10-01

    Systemic lupus erythematosus (lupus, SLE) is a chronic autoimmune disease characterized by the production of autoantibodies, which bind to antigens and are deposited within tissues to fix complement, resulting in widespread systemic inflammation. The studies presented herein are consistent with hyperpolarized, adenosine triphosphate (ATP)-deficient mitochondria being central to the disease process. These hyperpolarized mitochondria resist the depolarization required for activation-induced apoptosis. The mitochondrial ATP deficits add to this resistance to apoptosis and also reduce the macrophage energy that is needed to clear apoptotic bodies. In both cases, necrosis, the alternative pathway of cell death, results. Intracellular constituents spill into the blood and tissues, eliciting inflammatory responses directed at their removal. What results is "autoimmunity." Ultraviolet (UV)-A1 photons have the capacity to remediate this aberrancy. Exogenous exposure to low-dose, full-body, UV-A1 radiation generates singlet oxygen. Singlet oxygen has two major palliative actions in patients with lupus and the UV-A1 photons themselves have several more. Singlet oxygen depolarizes the hyperpolarized mitochondrion, triggering non-ATP-dependent apoptosis that deters necrosis. Next, singlet oxygen activates the gene encoding heme oxygenase (HO-1), a major governor of systemic homeostasis. HO-1 catalyzes the degradation of the oxidant heme into biliverdin (converted to bilirubin), Fe, and carbon monoxide (CO), the first three of these exerting powerful antioxidant effects, and in conjunction with a fourth, CO, protecting against injury to the coronary arteries, the central nervous system, and the lungs. The UV-A1 photons themselves directly attenuate disease in lupus by reducing B cell activity, preventing the suppression of cell-mediated immunity, slowing an epigenetic progression toward SLE, and ameliorating discoid and subacute cutaneous lupus. Finally, a combination of these

  17. Ultraviolet-A1 irradiation therapy for systemic lupus erythematosus

    PubMed Central

    2017-01-01

    Systemic lupus erythematosus (lupus, SLE) is a chronic autoimmune disease characterized by the production of autoantibodies, which bind to antigens and are deposited within tissues to fix complement, resulting in widespread systemic inflammation. The studies presented herein are consistent with hyperpolarized, adenosine triphosphate (ATP)-deficient mitochondria being central to the disease process. These hyperpolarized mitochondria resist the depolarization required for activation-induced apoptosis. The mitochondrial ATP deficits add to this resistance to apoptosis and also reduce the macrophage energy that is needed to clear apoptotic bodies. In both cases, necrosis, the alternative pathway of cell death, results. Intracellular constituents spill into the blood and tissues, eliciting inflammatory responses directed at their removal. What results is “autoimmunity.” Ultraviolet (UV)-A1 photons have the capacity to remediate this aberrancy. Exogenous exposure to low-dose, full-body, UV-A1 radiation generates singlet oxygen. Singlet oxygen has two major palliative actions in patients with lupus and the UV-A1 photons themselves have several more. Singlet oxygen depolarizes the hyperpolarized mitochondrion, triggering non-ATP-dependent apoptosis that deters necrosis. Next, singlet oxygen activates the gene encoding heme oxygenase (HO-1), a major governor of systemic homeostasis. HO-1 catalyzes the degradation of the oxidant heme into biliverdin (converted to bilirubin), Fe, and carbon monoxide (CO), the first three of these exerting powerful antioxidant effects, and in conjunction with a fourth, CO, protecting against injury to the coronary arteries, the central nervous system, and the lungs. The UV-A1 photons themselves directly attenuate disease in lupus by reducing B cell activity, preventing the suppression of cell-mediated immunity, slowing an epigenetic progression toward SLE, and ameliorating discoid and subacute cutaneous lupus. Finally, a combination of

  18. Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements.

    PubMed

    Ajiro, Masahiko; Tang, Shuang; Doorbar, John; Zheng, Zhi-Ming

    2016-10-15

    Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic pre-mRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. Expression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this

  19. Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

    PubMed Central

    Ajiro, Masahiko; Tang, Shuang; Doorbar, John

    2016-01-01

    ABSTRACT Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic pre-mRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCE Expression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been

  20. C/2013 A1 (Siding Spring vs. Mars)

    NASA Technical Reports Server (NTRS)

    Moorhead, Althea; Cooke, William

    2013-01-01

    Comet C/2013 A1 (Siding Spring): recently discovered long period comet. Will have close encounter with Mars on October 19, 2014. Collision is extremely unlikely. Passing through the coma and/or tail is likely. Increases risk to Martian spacecraft. Meteoroids (100 microns or larger): approx. or <20% chance of impact per square meter due to coma and tail. Gas may also a ect Martian atmosphere.

  1. Bafilomycin A1 and intracellular multiplication of Legionella pneumophila.

    PubMed Central

    Cattani, L; Goldoni, P; Pastoris, M C; Sinibaldi, L; Orsi, N

    1997-01-01

    Multiplication of Legionella pneumophila in HeLa cells was found to be inhibited by noncytotoxic concentrations of bafilomycin A1, with blockage of bacterial growth at a concentration 15.6 nM. The inhibiting action was evident only when the antibiotic was present during the initial phase of intracellular multiplication, i.e., during the formation of the phagosome, whereas the addition of the drug did not affect microorganisms already actively multiplying within the phagosome. PMID:8980784

  2. ISS 7A.1 Flight Control Team Photo in BFCR

    NASA Image and Video Library

    2001-08-16

    JSC2001-02229 (16 August 2001) --- The members of the STS-105/ISS 7A.1 Orbit 1 team pose for a group portrait in the International Space Station (ISS) flight control room (BFCR) in Houston’s Mission Control Center (MCC). Flight director Mark Ferring is kneeling as he holds the Expedition Three mission logo. Astronaut Stephanie D. Wilson, ISS spacecraft communicator (CAPCOM), is standing behind Ferring.

  3. Catechol-O-methyltransferase association with hemoglobin A1c

    PubMed Central

    Hall, Kathryn T.; Jablonski, Kathleen A.; Chen, Ling; Harden, Maegan; Tolkin, Benjamin R.; Kaptchuk, Ted J.; Bray, George A.; Ridker, Paul M.; Florez, Jose C.; Chasman, Daniel I.

    2016-01-01

    Aims Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes. Methods We tested whether COMT polymorphisms were associated with baseline HbA1c in the Women’s Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment. Results COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (β = −0.032% [0.012], p = 0.008) and borderline significant in MAGIC (β = −0.006% [0.003], p = 0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR = 0.98 [0.96–0.998], p = 0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR = 0.81 [0.65–1.00], p = 0.05). Conclusions COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD. PMID:27282867

  4. Analysis of M16A1 Basic Rifle Marksmanship Training

    DTIC Science & Technology

    1985-01-01

    preparatory marks- manship); A lecture is an oral explanation presented by a trainer to a group of trainees. Trainee participation is limited to...program employs two of.these* (the MIS Sighting Device and the Shot Group Analysis r;drd), while tri,. F-rt iHt -nning program emoloys only the Shot...stroi.’,. ti’, i:4 .’,, tlt i dlri’•.. . i•- iht hours. It is fol lowc-d 1ý ; .. ract !,ý i i Nit’oa ’ecord Firc oxcrc is.. Th I; practi(v tirint ir i a1

  5. Operating nanoliter scale NMR microcoils in a 1 tesla field.

    PubMed

    McDowell, Andrew F; Adolphi, Natalie L

    2007-09-01

    Microcoil probes enclosing sample volumes of 1.2, 3.3, 7.0, and 81 nanoliters are constructed as nuclear magnetic resonance (NMR) detectors for operation in a 1 tesla permanent magnet. The probes for the three smallest volumes utilize a novel auxiliary tuning inductor for which the design criteria are given. The signal-to-noise ratio (SNR) and line width of water samples are measured. Based on the measured DC resistance of the microcoils, together with the calculated radio frequency (RF) resistance of the tuning inductor, the SNR is calculated and shown to agree with the measured values. The details of the calculations indicate that the auxiliary inductor does not degrade the NMR probe performance. The diameter of the wire used to construct the microcoils is shown to affect the signal line widths.

  6. A 1.375-approximation algorithm for sorting by transpositions.

    PubMed

    Elias, Isaac; Hartman, Tzvika

    2006-01-01

    Sorting permutations by transpositions is an important problem in genome rearrangements. A transposition is a rearrangement operation in which a segment is cut out of the permutation and pasted in a different location. The complexity of this problem is still open and it has been a 10-year-old open problem to improve the best known 1.5-approximation algorithm. In this paper, we provide a 1.375-approximation algorithm for sorting by transpositions. The algorithm is based on a new upper bound on the diameter of 3-permutations. In addition, we present some new results regarding the transposition diameter: we improve the lower bound for the transposition diameter of the symmetric group and determine the exact transposition diameter of simple permutations.

  7. Optimizing the Construction of the A1 Collaboration Neutron Detector

    NASA Astrophysics Data System (ADS)

    Chinn, Edward; A1 Collaboration

    2016-09-01

    We report on the design and construction of a frame designed to optimize both the time efficiency and construction quality of the large scintillator elements These elements will be assembled to form a neutron detector for use by the A1 Collaboration at the Institute for Nuclear Physics in Mainz, Germany. The design had to provide adequate support for the 20 kg scintillator bars while gluing light guides and photomultiplier tubes to both sides of the bars using optical cement. The optical cement requires approximately 24 hours to dry and 100 bars have to be glued with this apparatus. To address each of these issues, several different prototypes were designed and reviewed. The selected apparatus minimized size to meet space constraints, with reduced material cost and provided the most time-efficient way to build the neutron detector. Once the schematic design was selected, we produced technical drawings in AutoDesk Inventor. Assembled the structure and completed gluing of the first batch of scintillators, in order to verify the performance. This apparatus was successful at producing high quality scintillators which were evaluated using cosmic rays. National Science Foundation Grant No. IIA-1358175.

  8. Bootstrapping the (A1, A2) Argyres-Douglas theory

    NASA Astrophysics Data System (ADS)

    Cornagliotto, Martina; Lemos, Madalena; Liendo, Pedro

    2018-03-01

    We apply bootstrap techniques in order to constrain the CFT data of the ( A 1 , A 2) Argyres-Douglas theory, which is arguably the simplest of the Argyres-Douglas models. We study the four-point function of its single Coulomb branch chiral ring generator and put numerical bounds on the low-lying spectrum of the theory. Of particular interest is an infinite family of semi-short multiplets labeled by the spin ℓ. Although the conformal dimensions of these multiplets are protected, their three-point functions are not. Using the numerical bootstrap we impose rigorous upper and lower bounds on their values for spins up to ℓ = 20. Through a recently obtained inversion formula, we also estimate them for sufficiently large ℓ, and the comparison of both approaches shows consistent results. We also give a rigorous numerical range for the OPE coefficient of the next operator in the chiral ring, and estimates for the dimension of the first R-symmetry neutral non-protected multiplet for small spin.

  9. Detection of alkaptonuria in a 1-week-old infant.

    PubMed

    Thalagahage, Krishan Nilantha Hewa; Jayaweera, Jayaweera Arachchige Asela Sampath; Kumbukgolla, Wikum Widuranga; Senavirathne, Indika

    2015-05-08

    Alkaptonuria is a rare disorder that results from an inherited deficiency of aromatic amino acid metabolism. Only 21% of the children under the age of 1 year having the disease are identified in clinics. We report a case of a 1-week-old child of a first-degree consanguineous couple with a symptom of frequent nappy staining. Analysis of urine showed a homogentisic acid concentration exceeding 200 mg/dL. The physical examination revealed that the child was healthy. The parents' watchfulness and the close attention paid to the child were the keys to the early detection of this rare disease. After identifying the disease, adequate follow-up of the patient is important to reduce further complications. Anti-inflammatory therapy and increasing the muscle strength by exercises such as swimming would be useful to restrict joint pains and immobilisation. A low protein diet also could be recommended; that fact is yet to be proven by clinical trials. 2015 BMJ Publishing Group Ltd.

  10. Detection of alkaptonuria in a 1-week-old infant

    PubMed Central

    Thalagahage, Krishan Nilantha Hewa; Jayaweera, Jayaweera Arachchige Asela Sampath; Kumbukgolla, Wikum Widuranga; Senavirathne, Indika

    2015-01-01

    Alkaptonuria is a rare disorder that results from an inherited deficiency of aromatic amino acid metabolism. Only 21% of the children under the age of 1 year having the disease are identified in clinics. We report a case of a 1-week-old child of a first-degree consanguineous couple with a symptom of frequent nappy staining. Analysis of urine showed a homogentisic acid concentration exceeding 200 mg/dL. The physical examination revealed that the child was healthy. The parents’ watchfulness and the close attention paid to the child were the keys to the early detection of this rare disease. After identifying the disease, adequate follow-up of the patient is important to reduce further complications. Anti-inflammatory therapy and increasing the muscle strength by exercises such as swimming would be useful to restrict joint pains and immobilisation. A low protein diet also could be recommended; that fact is yet to be proven by clinical trials. PMID:25956497

  11. A +1 ribosomal frameshifting motif prevalent among plant amalgaviruses.

    PubMed

    Nibert, Max L; Pyle, Jesse D; Firth, Andrew E

    2016-11-01

    Sequence accessions attributable to novel plant amalgaviruses have been found in the Transcriptome Shotgun Assembly database. Sixteen accessions, derived from 12 different plant species, appear to encompass the complete protein-coding regions of the proposed amalgaviruses, which would substantially expand the size of genus Amalgavirus from 4 current species. Other findings include evidence for UUU_CGN as a +1 ribosomal frameshifting motif prevalent among plant amalgaviruses; for a variant version of this motif found thus far in only two amalgaviruses from solanaceous plants; for a region of α-helical coiled coil propensity conserved in a central region of the ORF1 translation product of plant amalgaviruses; and for conserved sequences in a C-terminal region of the ORF2 translation product (RNA-dependent RNA polymerase) of plant amalgaviruses, seemingly beyond the region of conserved polymerase motifs. These results additionally illustrate the value of mining the TSA database and others for novel viral sequences for comparative analyses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Annexin A1: A new immunohistological marker of cholangiocarcinoma

    PubMed Central

    Hongsrichan, Nuttanan; Rucksaken, Rucksak; Chamgramol, Yaovalux; Pinlaor, Porntip; Techasen, Anchalee; Yongvanit, Puangrat; Khuntikeo, Narong; Pairojkul, Chawalit; Pinlaor, Somchai

    2013-01-01

    AIM: To evaluate a new immunohistological marker, annexin A1 (ANXA1), in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC). METHODS: Expression of ANXA1 protein was investigated in liver tissues from patients with CCA and HCC by immunohistochemistry. Its expression on differences stages of tumor development was investigated in hamster CCA tissues induced by Opisthorchis viverrini and N-nitrosodimethylamine. Moreover, mRNA expression of ANXA1 was assessed in CCA cell lines by quantitative real-time polymerase chain reaction and silencing of ANXA1 gene expression using small interfering RNA. RESULTS: In human CCA tissue arrays, immunohistochemical analysis revealed that the positive expression of ANXA1 was 94.1% (64/68 cases) consisting of a high expression (66.2%, 45/68 cases) and a low expression (33.8%, 23/68 cases). However, expression of ANXA1 protein was negative in all histologic patterns for HCC (46/46 cases) and healthy individuals (6/6 cases). In hamster with opisthorchiasis-associated CCA, the expression of ANXA1 was observed in the cytoplasm of inflammatory cells, bile duct epithelia and tumor cells. Grading scores of ANXA1 expression were significantly increased with tumor progression. In addition, mRNA expression of ANXA1 significantly increased in all of the various CCA cell lines tested compared to an immortalized human cholangiocyte cell line (MMNK1). Suppressing the ANXA1 gene significantly reduced the matrix metalloproteinase (MMP) 2 and MMP9, and transforming growth factor-β genes, but increased nuclear factor-κB gene expression. CONCLUSION: ANXA1 is highly expressed in CCA, but low in HCC, suggesting it may serve as a new immunohistochemical marker of CCA. ANXA1 may play a role in opisthorchiasis-associated cholangiocarcinogenesis. PMID:23674846

  13. Annexin A1 Complex Mediates Oxytocin Vesicle Transport

    PubMed Central

    Makani, Vishruti; Sultana, Rukhsana; Sie, Khin Sander; Orjiako, Doris; Tatangelo, Marco; Dowling, Abigail; Cai, Jian; Pierce, William; Butterfield, D. Allan; Hill, Jennifer; Park, Joshua

    2013-01-01

    Oxytocin is a major neuropeptide that modulates the brain functions involved in social behavior and interaction. Despite of the importance of oxytocin for neural control of social behavior, little is known about the molecular mechanism(s) by which oxytocin secretion in the brain is regulated. Pro-oxytocin is synthesized in the cell bodies of hypothalamic neurons in the supraoptic and paraventricular nuclei and processed to a 9-amino-acid mature form during post-Golgi transport to the secretion sites at the axon terminals and somatodendritic regions. Oxytocin secreted from the somatodendritic regions diffuses throughout the hypothalamus and its neighboring brain regions. Some oxytocin-positive axons innervate and secrete oxytocin to the brain regions distal to the hypothalamus. Brain oxytocin binds to its receptors in the brain regions involved in social behavior. Oxytocin is also secreted from the axon terminal at the posterior pituitary gland into the blood circulation. We have discovered a new molecular complex consisting of annexin A1 (ANXA1), A-kinase anchor protein 150 (AKAP150), and microtubule motor, that controls the distribution of oxytocin vesicles between the axon and the cell body in a protein kinase A (PKA)- and protein kinase C (PKC)-sensitive manner. ANXA1 showed significant co-localization with oxytocin vesicles. Activation of PKA enhanced the association of kinesin-2 with ANXA1, thus increasing the axon-localization of oxytocin vesicles. Conversely, activation of PKC decreased the binding of kinesin-2 to ANXA1, thus attenuating the axon-localization of oxytocin vesicles. Our study suggests that ANXA1 complex coordinates the actions of PKA and PKC to control the distribution of oxytocin vesicles between the axon and the cell body. PMID:24118254

  14. Monitoring of a 1 kWp Solar Photovoltaic System

    NASA Astrophysics Data System (ADS)

    Malek, M. F.; Zainuddin, H.; Rejab, S. N. M.; Shaari, S. N.; Shaari, S.; Omar, A. M.; Rusop, M.

    2009-06-01

    A 1 kWp `stand alone' PV system consists of 4 module (2 BP SX75U module and 2 BP 275F module), inverter, 2 thermocouple, 3 voltage sensor, 3 current sensor, 4 battery and data logger (Data Taker DT80) has been set up. This research involve nine parameters which are irradiance (Ia), ambient temperature (Tamb), module temperature (Tmod), module voltage (Vmod), battery voltage (Vbat), load voltage (Vload), module current (Imod), battery current (Ibat) and load current (Iload). All parameters were measured using the equipments and sensors that connected directly to data logger (Data Taker DT80) to interpret and show the data on computer using the Delogger sofware. The data then was transferred into the computer and analyzed using the Deview and Microsoft Excel software to determine the performance indices for the stand alone PV system. From the analysis a few performance indices were determined. The range of daily solar irradiation is between 2.20 kWhm-2 to 4.00 kWhm-2, while the range of total global irradiation is between 5.76 kWh to 10.48 kWh. For daily total energy yield, the range is between 0.23 kWh d-1 to 0.28 kWh d-1. The range for clearness index is between 0.49% to 0.89%. The range for final yield is between 0.77 kWh d-1 kWp-1 to 0.93 kWhd-1 kWp-1 while the range of array efficiency is between 2.53% to 4.65%. Lastly, the range of the performance ratio is between 22.08% to 40.58%.

  15. The cometary activity of Centaur P/2004 A1 (LONEOS)

    NASA Astrophysics Data System (ADS)

    Epifani, E. Mazzotta; Dall'Ora, M.; Perna, D.; Palumbo, P.; Colangeli, L.

    2011-08-01

    P/2004 A1 (LONEOS) is one of the few active objects in the dynamical class of Centaurs. It has been recently injected into an inner orbit with a perihelion distance q = 5.5 au. The aim of this paper is to characterize the dust coma of this peculiar object, 2.5 yr after its first 'new' perihelion passage inside the Solar system. Broad-band visible images taken at the TNG telescope in 2007 February were analysed in order to characterize the dust coma of the Centaur: it was still quite active at rh = 6.5 au post-perihelion, with a coma and a well-developed wide tail-like structure, with a measured R-Afρ= 162 ± 10 cm in an aperture radius ρ= 104 km. The (V - R) colour and the reddening values depict a scenario of a slightly red dust coma. A dust mass-loss rate of ? = 133 kg s-1 is derived from a photometric model, consistent with a scenario of a quite constant emission rate along the Centaur orbit. An upper limit for the Centaur radius of 3.5 km is derived by some realistic hypotheses on CO molecular production rate and on the mean grain scatterer size in the coma. Dynamical lifetime estimates compared to modelled loss rate result in a radius lower limit of 0.5 km, indicating therefore that the Centaur size is likely of the same order of magnitude of the short-period comets. Based on observations made at the Italian Telescopio Nazionale Galileo (TNG), operated on the island of La Palma by the Fundación Galileo Galilei of the INAF (Istituto Nazionale di Astrofisica) at the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofísica de Canarias.

  16. Experimental study of a 1 MW, 170 GHz gyrotron oscillator

    NASA Astrophysics Data System (ADS)

    Kimura, Takuji

    A detailed experimental study is presented of a 1 MW, 170 GHz gyrotron oscillator whose design is consistent with the ECH requirements of the International Thermonuclear Experimental Reactor (ITER) for bulk heating and current drive. This work is the first to demonstrate that megawatt power level at 170 GHz can be achieved in a gyrotron with high efficiency for plasma heating applications. Maximum output power of 1.5 MW is obtained at 170.1 GHz in 85 kV, 50A operation for an efficiency of 35%. Although the experiment at MIT is conducted with short pulses (3 μs), the gyrotron is designed to be suitable for development by industry for continuous wave operation. The peak ohmic loss on the cavity wall for 1 MW of output power is calculated to be 2.3 kW/cm2, which can be handled using present cooling technology. Mode competition problems in a highly over-moded cavity are studied to maximize the efficiency. Various aspects of electron gun design are examined to obtain high quality electron beams with very low velocity spread. A triode magnetron injection gun is designed using the EGUN simulation code. A total perpendicular velocity spread of less than 8% is realized by designing a low- sensitivity, non-adiabatic gun. The RF power is generated in a short tapered cavity with an iris step. The operating mode is the TE28,8,1 mode. A mode converter is designed to convert the RF output to a Gaussian beam. Power and efficiency are measured in the design TE28,8,1 mode at 170.1 GHz as well as the TE27,8,1 mode at 166.6 GHz and TE29,8,1 mode at 173.5 GHz. Efficiencies between 34%-36% are consistently obtained over a wide range of operating parameters. These efficiencies agree with the highest values predicted by the multimode simulations. The startup scenario is investigated and observed to agree with the linear theory. The measured beam velocity ratio is consistent with EGUN simulation. Interception of reflected beam by the mod-anode is measured as a function of velocity ratio

  17. HnRNP A3 genes and pseudogenes in the vertebrate genomes.

    PubMed

    Makeyev, Aleksandr V; Kim, Chang Bae; Ruddle, Frank H; Enkhmandakh, Badam; Erdenechimeg, Lkhamsuren; Bayarsaihan, Dashzeveg

    2005-04-01

    The hnRNP A/B type proteins are abundant nuclear factors that bind to Pol II transcripts and are involved in numerous RNA-related activities. To date most data on the hnRNP A/B family have been obtained with recombinant proteins and cell cultures. Further characterization can result from an examination of the impact of various modifications in intact functional loci; however, such characterization is hampered by the presence of numerous and widely dispersed hnRNP A/B-related sequences in the mammalian genome. We have found hnRNP A3, a poorly recognized member of the hnRNP A/B family, among candidate transcription factors that interact with the regulatory region of the Hoxc8 gene and screened the human and mouse genomes for genes that encode hnRNP A3. We demonstrate that the sequence reported previously as the human hnRNP A3 gene (Accession number S63912) and located on 10p11.1 belongs to a processed pseudogene of the functional intron-containing locus HNRPA3, which we have identified on 2q31.2. We have also identified its murine orthologs on mouse chromosome 2D and rat chromosome 3q23. Alternative splices were revealed at the N-terminus and in the middle of hnRNP A3. 14 and 28 additional loci in the human and mouse genome, respectively, were mapped and identified as hnRNP A3 processed pseudogenes. In addition, we have found and compared hnRNP A3 orthologous genes in Gallus gallus, Xenopus tropicalis, and Danio rerio. The present in silico analysis serves as a necessary step toward a further functional characterization of hnRNP A3. (c) 2005 Wiley-Liss, Inc.

  18. The Collection of Ice in Jet A-1 Fuel Pipes

    NASA Astrophysics Data System (ADS)

    Maloney, Thomas C.

    Ice collection and blockages in fuel systems have been of interest to the aerospace community since their discovery in the late 1950's when a B-52 crashed. A recent growth of interest was provoked by several incidents that occurred within the last few years. This study seeks to understand the underlying principles of ice growth in fuel flow systems. Tests were performed in a recirculated fuel system with a fuel tank that held approximately 115 gallons of Jet A-1 fuel and ice accumulation was observed in two removable test pipes. The setup was in an altitude chamber capable of -60 °F and the experiments involved full scale flow components. Initially, tests were done to better understand the system and variables that effected accumulation. First, initial conditions within the test pipes were varied. Next, pipe geometry, pipe surface properties, initial water content of the fuel and heat transfer from the fuel pipe were varied. As a result of the tests, observations were made about other effects involved in the study. The effects include: the result of sequentially run tests, the effect of the fuel on the freezing temperature of the entrained water, the effect of ice accumulation on pipe welds, and the effect of the test pipe entrance and exit flow conditions on ice accumulation. The results of initial tests were qualitative. Later quantitative tests were done to demonstrate the dependence of temperature, Reynolds number, and heat transfer on ice accumulation. Tests were quantified with a pressure increase across the pipe sections that was normalized by the expected theoretical initial pressure. As a result of these tests the effect of contamination in the fuel was revealed. For ease of reference, the initial tests were called "stage I" and the later tests were called "stage II". The results of stage I showed that accumulation of soft ice was greatest when a layer of hard ice had initially formed on the pipe surface. Stainless steel collected more ice than Teflon

  19. 17 CFR 240.11a1-1(T) - Transactions yielding priority, parity, and precedence.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., parity, and precedence. 240.11a1-1(T) Section 240.11a1-1(T) Commodity and Securities Exchanges SECURITIES... (rule 11a-1) § 240.11a1-1(T) Transactions yielding priority, parity, and precedence. (a) A transaction... section 11(a)(1) of the Act or specified in 17 CFR 240.11a1-4(T) shall be deemed to be revenue derived...

  20. 17 CFR 240.11a1-1(T) - Transactions yielding priority, parity, and precedence.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., parity, and precedence. 240.11a1-1(T) Section 240.11a1-1(T) Commodity and Securities Exchanges SECURITIES... (rule 11a-1) § 240.11a1-1(T) Transactions yielding priority, parity, and precedence. (a) A transaction... section 11(a)(1) of the Act or specified in 17 CFR 240.11a1-4(T) shall be deemed to be revenue derived...

  1. Excess body weight affects HbA1c progression irrespective of baseline HbA1c levels in Japanese individuals: a longitudinal retrospective study.

    PubMed

    Nakajima, Kei; Suwa, Kaname

    2015-01-01

    Obese individuals with normal HbA1c levels and low-body-weight individuals with high-normal HbA1c levels are frequently encountered in clinical settings, but the effects of these phenotypes on the onset of diabetes are poorly understood. Therefore, we addressed this issue in a longitudinal study. We analyzed clinical parameters, including body mass index (BMI) and HbA1c levels, in 5325 non-diabetic Japanese people aged 20-75 years who underwent four medical checkups between 1999 (baseline) and 2007. The subjects were then classified into six baseline BMI categories, each of which was divided into two HbA1c groups, resulting in a total of 12 groups. In 405 obese subjects with a normal baseline HbA1c (BMI ≥ 27.0 kg/m(2), HbA1c 5.2-5.6%), the mean HbA1c level increased during the study period, and 50.9% developed prediabetes/diabetes. In contrast, in 77 low-body-weight subjects with a high-normal baseline HbA1c (BMI ≤ 18.9 kg/m(2), HbA1c 5.7-6.4%), the mean HbA1c level remained constant. Similar changes occurred in the other groups during the study, resulting in a linear increase in HbA1c levels with increasing BMI. Our results suggest that approximately half of the obese individuals with HbA1c in the normal range develop prediabetes or diabetes within 8 years, whereas low-body-weight individuals with high-normal HbA1c are less likely to exhibit worsening in glycemia. Thus, excess body weight may be the primary therapeutic target to prevent the early onset of diabetes, regardless of the individual's HbA1c.

  2. Isolation and characterization of cyp19a1a and cyp19a1b promoters in the protogynous hermaphrodite orange-spotted grouper (Epinephelus coioides).

    PubMed

    Zhang, Weimin; Lu, Huijie; Jiang, Haiyan; Li, Mu; Zhang, Shen; Liu, Qiongyou; Zhang, Lihong

    2012-02-01

    Aromatase (CYP19A1) catalyzes the conversion of androgens to estrogens. In teleosts, duplicated copies of cyp19a1 genes, namely cyp19a1a and cyp19a1b, were identified, however, the transcriptional regulation of these two genes remains poorly understood. In the present study, the 5'-flanking regions of the orange-spotted grouper cyp19a1a (gcyp19a1a) and cyp19a1b (gcyp19a1b) genes were isolated and characterized. The proximal promoter regions of both genes were relatively conserved when compared to those of the other teleosts. Notably, a conserved FOXO transcriptional factor binding site was firstly reported in the proximal promoter of gcyp19a1a, and deletion of the region (-112 to -60) containing this site significantly decreased the promoter activities. The deletion of the region (-246 to -112) containing the two conserved FTZ-F1 sites also dramatically decreased the transcriptional activities of gcyp19a1a promoter, and both two FTZ-F1 sites were shown to be stimulatory cis-acting elements. A FTZ-F1 homologue isolated from ricefield eel (eFTZ-F1) up-regulated gcyp19a1a promoter activities possibly via the FTZ-F1 sites, however, a previously identified orange-spotted grouper FTZ-F1 homologue (gFTZ-F1) did not activate the transcription of gcyp19a1a promoter unexpectedly. As to gcyp19a1b promoter, all the deletion constructs did not show good promoter activities in either TM4 or U251-MG cells. Estradiol (100nM) up-regulated gcyp19a1b promoter activities by about 13- and 36-fold in TM4 and U251-MG cells, respectively, via the conserved ERE motif, but did not stimulate gcyp19a1a promoter activities. These results are helpful to further elucidate the regulatory mechanisms of cyp19a1a and cyp19a1b expression in the orange-spotted grouper as well as other teleosts. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Suppression of HPV-16 late L1 5′-splice site SD3632 by binding of hnRNP D proteins and hnRNP A2/B1 to upstream AUAGUA RNA motifs

    PubMed Central

    Li, Xiaoze; Johansson, Cecilia; Glahder, Jacob; Mossberg, Ann-Kristin; Schwartz, Stefan

    2013-01-01

    Human papillomavirus type 16 (HPV-16) 5′-splice site SD3632 is used exclusively to produce late L1 mRNAs. We identified a 34-nt splicing inhibitory element located immediately upstream of HPV-16 late 5′-splice site SD3632. Two AUAGUA motifs located in these 34 nt inhibited SD3632. Two nucleotide substitutions in each of the HPV-16 specific AUAGUA motifs alleviated splicing inhibition and induced late L1 mRNA production from episomal forms of the HPV-16 genome in primary human keratinocytes. The AUAGUA motifs bind specifically not only to the heterogeneous nuclear RNP (hnRNP) D family of RNA-binding proteins including hnRNP D/AUF, hnRNP DL and hnRNP AB but also to hnRNP A2/B1. Knock-down of these proteins induced HPV-16 late L1 mRNA expression, and overexpression of hnRNP A2/B1, hnRNP AB, hnRNP DL and the two hnRNP D isoforms hnRNP D37 and hnRNP D40 further suppressed L1 mRNA expression. This inhibition may allow HPV-16 to hide from the immune system and establish long-term persistent infections with enhanced risk at progressing to cancer. There is an inverse correlation between expression of hnRNP D proteins and hnRNP A2/B1 and HPV-16 L1 production in the cervical epithelium, as well as in cervical cancer, supporting the conclusion that hnRNP D proteins and A2/B1 inhibit HPV-16 L1 mRNA production. PMID:24013563

  4. 26 CFR 1.381(a)-1 - General rule relating to carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... corporate acquisitions. 1.381(a)-1 Section 1.381(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Reorganizations § 1.381(a)-1 General rule relating to carryovers in certain corporate acquisitions. (a) Allowance... change in identity, form, or place of organization qualifying under section 368(a)(1)(F). (2) Acquiring...

  5. 26 CFR 1.381(a)-1 - General rule relating to carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... corporate acquisitions. 1.381(a)-1 Section 1.381(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Reorganizations § 1.381(a)-1 General rule relating to carryovers in certain corporate acquisitions. (a) Allowance... change in identity, form, or place of organization qualifying under section 368(a)(1)(F). (2) Acquiring...

  6. 26 CFR 1.381(a)-1 - General rule relating to carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... corporate acquisitions. 1.381(a)-1 Section 1.381(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Reorganizations § 1.381(a)-1 General rule relating to carryovers in certain corporate acquisitions. (a) Allowance... change in identity, form, or place of organization qualifying under section 368(a)(1)(F). (2) Acquiring...

  7. Physical interaction between the strawberry allergen Fra a 1 and an associated partner FaAP: Interaction of Fra a 1 proteins and FaAP.

    PubMed

    Franz-Oberdorf, Katrin; Langer, Andreas; Strasser, Ralf; Isono, Erika; Ranftl, Quirin L; Wunschel, Christian; Schwab, Wilfried

    2017-10-01

    The strawberry fruit allergens Fra a 1.01E, Fra a 1.02 and Fra a 1.03 belong to the group of pathogenesis-related 10 (PR-10) proteins and are homologs of the major birch pollen Bet v 1 and apple allergen Mal d 1. Bet v 1 related proteins are the most extensively studied allergens but their physiological function in planta remains elusive. Since Mal d 1-Associated Protein has been previously identified as interaction partner of Mal d 1 we studied the binding of the orthologous Fra a 1-Associated Protein (FaAP) to Fra a 1.01E/1.02/1.03. As the C-terminal sequence of FaAP showed strong auto-activation activity in yeast 2-hybrid analysis a novel time resolved DNA-switching system was successfully applied. Fra a 1.01E, Fra a 1.02, and Fra a 1.03 bind to FaAP with K D of 4.5 ± 1.1, 15 ± 3, and 11 ± 2 nM, respectively. Fra a 1.01E forms a dimer, whereas Fra a 1.02 and Fra a 1.03 bind as monomer. The results imply that PR-10 proteins might be integrated into a protein-interaction network and FaAP binding appears to be essential for the physiological function of the Fra a 1 proteins. © 2017 Wiley Periodicals, Inc.

  8. M825A1 White Phosphorous Malfunction Investigation Related to the M739/ M739A1 Safing and Arming Module

    DTIC Science & Technology

    1993-08-01

    AD-A269 205 AD AD-E402 378 Technical Report ARAED-TR-92031 M825A1 WHITE PHOSPHOROUS MALFUNCTION INVESTIGATION RELATED TO THE M739 /M739A1 SAFING AND...Aug 1993 - 4. TITLE AND SUBTITLE 5 FUNDING NUMBERS M825A1 WHITE PHOSPHOROUS MALFUNCTION INVESTIGATION RELATED TO THE M739 /M739AI SAFING AND ARMING...LT). An investigation of the data revealed changes in the burster and the M739 /M739A1 safing and arming (S&A) module. The Armaments Research

  9. A study assessing the association of glycated hemoglobin A1C (HbA1C) associated variants with HbA1C, chronic kidney disease and diabetic retinopathy in populations of Asian ancestry.

    PubMed

    Chen, Peng; Ong, Rick Twee-Hee; Tay, Wan-Ting; Sim, Xueling; Ali, Mohammad; Xu, Haiyan; Suo, Chen; Liu, Jianjun; Chia, Kee-Seng; Vithana, Eranga; Young, Terri L; Aung, Tin; Lim, Wei-Yen; Khor, Chiea-Chuen; Cheng, Ching-Yu; Wong, Tien-Yin; Teo, Yik-Ying; Tai, E-Shyong

    2013-01-01

    Glycated hemoglobin A1C (HbA1C) level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study.

  10. A Study Assessing the Association of Glycated Hemoglobin A1C (HbA1C) Associated Variants with HbA1C, Chronic Kidney Disease and Diabetic Retinopathy in Populations of Asian Ancestry

    PubMed Central

    Chen, Peng; Ong, Rick Twee-Hee; Tay, Wan-Ting; Sim, Xueling; Ali, Mohammad; Xu, Haiyan; Suo, Chen; Liu, Jianjun; Chia, Kee-Seng; Vithana, Eranga; Young, Terri L.; Aung, Tin; Lim, Wei-Yen; Khor, Chiea-Chuen; Cheng, Ching-Yu; Wong, Tien-Yin; Teo, Yik-Ying; Tai, E-Shyong

    2013-01-01

    Glycated hemoglobin A1C (HbA1C) level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study. PMID:24244560

  11. Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors.

    PubMed

    Liu, Jean; Reid, Allison R; Sawynok, Jana

    2013-03-01

    Acetaminophen (paracetamol) is a widely used analgesic, but its sites and mechanisms of action remain incompletely understood. Recent studies have separately implicated spinal adenosine A(1) receptors (A(1)Rs) and serotonin 5-HT(7) receptors (5-HT(7)Rs) in the antinociceptive effects of systemically administered acetaminophen. In the present study, we determined whether these two actions are linked by delivering a selective 5-HT(7)R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A(1)R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT(7)R antagonist SB269970 3μg. In mice lacking A(1)Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT(7)R and A(1)R mechanisms. We also explored potential roles of peripheral A(1)Rs in antinociception by acetaminophen administered both locally and systemically. In normal mice, intraplantar (i.pl.) acetaminophen 200μg produced antinociception in the formalin test, and this was blocked by co-administration of the selective A(1)R antagonist DPCPX 4.5μg. Acetaminophen administered into the contralateral hindpaw had no effect, indicating a local peripheral action. When acetaminophen was administered systemically, its antinociceptive effect was reversed by i.pl. DPCPX in normal mice; this was also observed in A(1)R wild type mice, but not in those lacking A(1)Rs. In summary, we demonstrate a link between spinal 5-HT(7)Rs and A(1)Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A(1)Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Critical early roles for col27a1a and col27a1b in zebrafish notochord morphogenesis, vertebral mineralization and post-embryonic axial growth.

    PubMed

    Christiansen, Helena E; Lang, Michael R; Pace, James M; Parichy, David M

    2009-12-29

    Fibrillar collagens are well known for their links to human diseases, with which all have been associated except for the two most recently identified fibrillar collagens, type XXIV collagen and type XXVII collagen. To assess functions and potential disease phenotypes of type XXVII collagen, we examined its roles in zebrafish embryonic and post-embryonic development. We identified two type XXVII collagen genes in zebrafish, col27a1a and col27a1b. Both col27a1a and col27a1b were expressed in notochord and cartilage in the embryo and early larva. To determine sites of type XXVII collagen function, col27a1a and col27a1b were knocked down using morpholino antisense oligonucleotides. Knockdown of col27a1a singly or in conjunction with col27a1b resulted in curvature of the notochord at early stages and formation of scoliotic curves as well as dysmorphic vertebrae at later stages. These defects were accompanied by abnormal distributions of cells and protein localization in the notochord, as visualized by transmission electron microscopy, as well as delayed vertebral mineralization as detected histologically. Together, our findings indicate a key role for type XXVII collagen in notochord morphogenesis and axial skeletogenesis and suggest a possible human disease phenotype.

  13. Forskolin stimulation promotes urea transporter UT-A1 ubiquitination, endocytosis, and degradation in MDCK cells

    PubMed Central

    Su, Hua; Carter, Conner B.; Laur, Oskar; Sands, Jeff M.

    2012-01-01

    The adenylyl cyclase stimulator forskolin (FSK) stimulates UT-A1 phosphorylation, membrane trafficking, and urea transport activity. Here, we found that FSK stimulation induces UT-A1 ubiquitination in UT-A1 Madin-Darby canine kidney (MDCK) cells. This suggests that phosphorylation by FSK also triggers the protein degradation machinery for UT-A1. UT-A1-MDCK cells were treated with 100 μg/ml cycloheximide to inhibit protein synthesis, with or without 10 μM FSK. Total UT-A1 protein abundance was significantly reduced after FSK treatment, concomitantly ubiquitinated UT-A1 was increased. We then specifically investigated the effect of FSK on UT-A1 expressed on the cell plasma membrane. FSK treatment accelerated UT-A1 removal from the cell plasma membrane by increasing UT-A1 endocytosis as judged by biotinylation/MesNa treatment and confocal microscopy. We further found that inhibition of the clathrin-mediated endocytic pathway, but not the caveolin-mediated endocytic pathway, significantly blocks FSK-stimulated UT-A1 endocytosis. The PKA inhibitor H89 and the proteasome inhibitors MG132 and lactacystin reduced FSK-induced membrane UT-A1 reduction. Our study shows that FSK activates the UT-A1 urea transporter and the activation/phosphorylation subsequently triggers the downregulation of UT-A1, which represents an important mechanism for the cell to return to the basal conditions after vasopressin stimulation. PMID:22914781

  14. UGT1A1*6 and UGT1A1*28 polymorphisms are correlated with irinotecan-induced toxicity: A meta-analysis.

    PubMed

    Yang, Yuwei; Zhou, MengMeng; Hu, Mingjun; Cui, Yanjie; Zhong, Qi; Liang, Ling; Huang, Fen

    2018-06-22

    Previous articles explored the role of UGT1A1 polymorphism on predicting irinotecan-induced toxicity, but the conclusions were still inconsistent and not comprehensive. We performed this meta-analysis to investigate the association between UGT1A1 polymorphism and irinotecan-induced toxicity. PubMed and Web of Science were searched for articles before July 2017. Inclusion and exclusion criteria were set to select eligible articles, and corresponding data were extracted from those articles. Subgroup analyses based on different cancer categories, doses and races were carried out to achieve comprehensive results. Statistical analyses were conducted using STATA 11.0. A total of 38 studies with 6742 cases were included after reading full text. Both UGT1A1*6 and UGT1A1*28 polymorphism are significantly associated with severe irinotecan-induced toxicity. Both Asian and Caucasian cancer patients with UGT1A1*28 variant had an increased risk. Compared with heterozygous variant, patients with homozygous variant suffered from a higher risk of toxicity. The effect of UGT1A1*28 polymorphism on diarrhea was less than on neutropenia. Subgroup analysis exhibited that for UGT1A1*6 polymorphism, patients treated with low-dose irinotecan were at a notable risk of toxicity. Moreover, the association between UGT1A1*6 polymorphism and irinotecan-induced toxicity was found in patients suffering from respiratory system cancers. Both UGT1A1*6 and UGT1A1*28 polymorphisms can be considered as predictors of irinotecan-induced toxicity, with effect varying by race, cancer type and irinotecan dose. © 2018 John Wiley & Sons Australia, Ltd.

  15. Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3.

    PubMed

    Gose, Tomoka; Nakanishi, Takeo; Kamo, Shunsuke; Shimada, Hiroaki; Otake, Katsumasa; Tamai, Ikumi

    2016-01-01

    Eicosapentaenoic acid (EPA)-derived prostaglandin E3 (PGE3) possesses an anti-inflammatory effect; however, information for transporters that regulate its peri-cellular concentration is limited. The present study, therefore, aimed to clarify transporters involved in local disposition of PGE3. PGE3 uptake was assessed in HEK293 cells transfected with OATP2A1/SLCO2A1, OATP1B1/SLCO1B1, OATP2B1/SLCO2B1, OAT1/SLC22A6, OCT1/SLC22A1 or OCT2/SLC22A2 genes, compared with HEK293 cells transfected with plasmid vector alone (Mock). PGE3 uptake by OATP2A1-expressing HEK293 cells (HEK/2A1) was the highest and followed by HEK/1B1, while no significantly higher uptake of PGE3 than Mock cells was detected by other transporters. Saturation kinetics in PGE3 uptake by HEK/2A1 estimated the Km as 7.202 ± 0.595 μM, which was 22 times higher than that of PGE2 (Km=0.331 ± 0.131 μM). Furthermore, tissue disposition of PGE3 was examined in wild-type (WT) and Slco2a1-deficient (Slco2a1(-/-)) mice after oral administration of EPA ethyl ester (EPA-E) when they underwent intraperitoneal injection of endotoxin (e.g., lipopolysaccharide). PGE3 concentration was significantly higher in the lung, and tended to increase in the colon, stomach, and kidney of Slco2a1(-/-), compared to WT mice. Ratio of PGE2 metabolite 15-keto PGE2 over PGE2 concentration was significantly lower in the lung and colon of Slco2a1(-/-) than that of WT mice, suggesting that PGE3 metabolism is downregulated in Slco2a1(-/-) mice. In conclusion, PGE3 was found to be a substrate of OATP2A1, and local disposition of PGE3 could be regulated by OATP2A1 at least in the lung. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Haemoglobin J-Baltimore can be detected by HbA1c electropherogram but with underestimated HbA1c value.

    PubMed

    Brunel, Valéry; Lahary, Agnčs; Chagraoui, Abdeslam; Thuillez, Christian

    2016-01-01

    Glycated haemoglobin (HbA(1c)) is considered the gold standard for assessing diabetes compensation and treatment. In addition, fortuitous detection of haemoglobin variants during HbA1c measurement is not rare. Recently, two publications reported different conclusions on accuracy of HbA(1c) value using capillary electrophoresis method in presence of haemoglobin J-Baltimore (HbJ).
Here we describe the fortuitous detection of unknown HbJ using capillary electrophoresis for measurement of HbA(1c). A patient followed for gestational diabetes in our laboratory presented unknown haemoglobin on Capillarys 2 Flex Piercing analyser which was identified as HbJ. HbJ is not associated with haematological abnormalities. High Performance Liquid Chromatography methods are known to possibly underestimate HbA(1c) value in the presence of this variant. This variant and its glycated form are clearly distinguished on electropherogram but HbJ was responsible for underestimating the true area of HbA(1c).
 Capillary electrophoresis is a good method for detecting HbJ but does not seem suitable for evaluation of HbA(1C) value in patients in presence of HbJ variant.

  17. The Long and Winding Road to Optimal HbA1c Measurement

    PubMed Central

    Little, Randie R.; Rohlfing, Curt

    2016-01-01

    The importance of hemoglobin A1c (HbA1c) as an indicator of mean glycemia and risks for complications in patients with diabetes mellitus was established by the results of long-term clinical trials, most notably the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), published in 1993 and 1998 respectively. However, clinical application of recommended HbA1c targets that were based on these studies was difficult due to lack of comparability of HbA1c results among assay methods and laboratories. Thus, the National Glycohemoglobin Standardization Program (NGSP) was initiated in 1996 with the goal of standardizing HbA1c results to those of the DCCT/UKPDS. HbA1c standardization efforts have been highly successful; however, a number of issues have emerged on the “long and winding road” to better HbA1c, including the development of a higher-order HbA1c reference method by the International Federation of Clinical Chemistry (IFCC), recommendations to use HbA1c to diagnose as well as monitor diabetes, and point-of-care (POC) HbA1c testing. Here, we review the past, present and future of HbA1c standardization and describe the current status of HbA1c testing, including limitations that healthcare providers need to be aware of when interpreting HbA1c results. PMID:23318564

  18. Point-of-Care Hemoglobin A1c Testing: An Evidence-Based Analysis

    PubMed Central

    2014-01-01

    Background The increasing prevalence of diabetes in Ontario means that there will be growing demand for hemoglobin A1c (HbA1c) testing to monitor glycemic control for the management of this chronic disease. Testing HbA1c where patients receive their diabetes care may improve system efficiency if the results from point-of-care HbA1c testing are comparable to those from laboratory HbA1c measurements. Objectives To review the correlation between point-of-care HbA1c testing and laboratory HbA1c measurement in patients with diabetes in clinical settings. Data Sources The literature search included studies published between January 2003 and June 2013. Search terms included glycohemoglobin, hemoglobin A1c, point of care, and diabetes. Review Methods Studies were included if participants had diabetes; if they compared point-of-care HbA1c devices (licensed by Health Canada and available in Canada) with laboratory HbA1c measurement (reference method); if they performed point-of-care HbA1c testing using capillary blood samples (finger pricks) and laboratory HbA1c measurement using venous blood samples within 7 days; and if they reported a correlation coefficient between point-of-care HbA1c and laboratory HbA1c results. Results Three point-of-care HbA1c devices were reviewed in this analysis: Bayer's A1cNow+, Bio-Rad's In2it, and Siemens’ DCA Vantage. Five observational studies met the inclusion criteria. The pooled results showed a positive correlation between point-of-care HbA1c testing and laboratory HbA1c measurement (correlation coefficient, 0.967; 95% confidence interval, 0.960–0.973). Limitations Outcomes were limited to the correlation coefficient, as this was a commonly reported measure of analytical performance in the literature. Results should be interpreted with caution due to risk of bias related to selection of participants, reference standards, and the multiple steps involved in POC HbA1c testing. Conclusions Moderate quality evidence showed a positive

  19. Immunoglobulins in Nasal Secretions of Healthy Humans: Structural Integrity of Secretory Immunoglobulin A1 (IgA1) and Occurrence of Neutralizing Antibodies to IgA1 Proteases of Nasal Bacteria

    PubMed Central

    Kirkeby, Line; Rasmussen, Trine Tang; Reinholdt, Jesper; Kilian, Mogens

    2000-01-01

    Certain bacteria, including overt pathogens as well as commensals, produce immunoglobulin A1 (IgA1) proteases. By cleaving IgA1, including secretory IgA1, in the hinge region, these enzymes may interfere with the barrier functions of mucosal IgA antibodies, as indicated by experiments in vitro. Previous studies have suggested that cleavage of IgA1 in nasal secretions may be associated with the development and perpetuation of atopic disease. To clarify the potential effect of IgA1 protease-producing bacteria in the nasal cavity, we have analyzed immunoglobulin isotypes in nasal secretions of 11 healthy humans, with a focus on IgA, and at the same time have characterized and quantified IgA1 protease-producing bacteria in the nasal flora of the subjects. Samples in the form of nasal wash were collected by using a washing liquid that contained lithium as an internal reference. Dilution factors and, subsequently, concentrations in undiluted secretions could thereby be calculated. IgA, mainly in the secretory form, was found by enzyme-linked immunosorbent assay to be the dominant isotype in all subjects, and the vast majority of IgA (median, 91%) was of the A1 subclass, corroborating results of previous analyses at the level of immunoglobulin-producing cells. Levels of serum-type immunoglobulins were low, except for four subjects in whom levels of IgG corresponded to 20 to 66% of total IgA. Cumulative levels of IgA, IgG, and IgM in undiluted secretions ranged from 260 to 2,494 (median, 777) μg ml−1. IgA1 protease-producing bacteria (Haemophilus influenzae, Streptococcus pneumoniae, or Streptococcus mitis biovar 1) were isolated from the nasal cavities of seven subjects at 2.1 × 103 to 7.2 × 106 CFU per ml of undiluted secretion, corresponding to 0.2 to 99.6% of the flora. Nevertheless, α-chain fragments characteristic of IgA1 protease activity were not detected in secretions from any subject by immunoblotting. Neutralizing antibodies to IgA1 proteases of autologous

  20. Depleted aldehyde dehydrogenase 1A1 (ALDH1A1) reverses cisplatin resistance of human lung adenocarcinoma cell A549/DDP.

    PubMed

    Wei, Yunyan; Wu, Shuangshuang; Xu, Wei; Liang, Yan; Li, Yue; Zhao, Weihong; Wu, Jianqing

    2017-01-01

    Cisplatin is the standard first-line chemotherapeutic agent for the treatment of non-small cell lung cancer (NSCLC). However, resistance to chemotherapy has been a major obstacle in the management of NSCLC. Aldehyde dehydrogenase 1A1 (ALDH1A1) overexpression has been observed in a variety of cancers, including lung cancer. The purpose of this study was to investigate the effect of ALDH1A1 expression on cisplatin resistance and explore the mechanism responsible. Reverse transcriptase-PCR was applied to measure the messenger RNA expression of ALDH1A1, while Western blot assay was employed to evaluate the protein expression of ALDH1A1, B-cell lymphoma 2, Bcl-2-like protein 4, phospho-protein kinase B (p-AKT) and AKT. A short hairpin RNA was used to knockdown ALDH1A1 expression. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine the effect of ALDH1A1 decrease on cell viability. The cell apoptotic rate was tested using flow cytometry assay. ALDH1A1 is overexpressed in cisplatin resistant cell line A549/DDP, compared with A549. ALDH1A1 depletion significantly decreased A549/DDP proliferation, increased apoptosis, and reduced cisplatin resistance. In addition, the phosphoinositide 3-kinase (PI3K) / AKT pathway is activated in A549/DDP, and ALDH1A1 knockdown reduced the phosphorylation level of AKT. Moreover, the combination of ALDH1A1-short hairpin RNA and PI3K/AKT pathway inhibitor LY294002 markedly inhibited cell viability, enhanced apoptotic cell death, and increased cisplatin sensitivity. These results suggest that ALDH1A1 depletion could reverse cisplatin resistance in human lung cancer cell line A549/DDP, and may act as a potential target for the treatment of lung cancers resistant to cisplatin. © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  1. High-accuracy calculations of the ground, 1 1A1', and the 2 1A1', 2 3A1', and 1 1E' excited states of H3+.

    PubMed

    Pavanello, Michele; Adamowicz, Ludwik

    2009-01-21

    Accurate variational Born-Oppenheimer calculations of the 1 (1)A(1) ('), 2 (1)A(1) ('), 2 (3)A(1) ('), and 1 (1)E(') states of the H(3) (+) ion at the ground-state equilibrium geometry are reported. The wave functions of the states are expanded in terms of explicitly correlated spherical Gaussian functions with shifted centers. In the variational optimization the analytical gradient of the energy with respect to the nonlinear exponential parameters of the Gaussians has been employed. The energies obtained in the calculations are the best variational estimates ever calculated for the four states. One-electron densities for the states, as well as a D(3h)-restricted potential energy surface of the ground state calculated around the equilibrium geometry, are also presented and discussed.

  2. 26 CFR 1.652(a)-1 - Simple trusts; inclusion of amounts in income of beneficiaries.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Simple trusts; inclusion of amounts in income of beneficiaries. 1.652(a)-1 Section 1.652(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Only § 1.652(a)-1 Simple trusts; inclusion of amounts in income of beneficiaries. Subject to the rules...

  3. 26 CFR 1.652(a)-1 - Simple trusts; inclusion of amounts in income of beneficiaries.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Simple trusts; inclusion of amounts in income of beneficiaries. 1.652(a)-1 Section 1.652(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Only § 1.652(a)-1 Simple trusts; inclusion of amounts in income of beneficiaries. Subject to the rules...

  4. 26 CFR 1.652(a)-1 - Simple trusts; inclusion of amounts in income of beneficiaries.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Simple trusts; inclusion of amounts in income of beneficiaries. 1.652(a)-1 Section 1.652(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Only § 1.652(a)-1 Simple trusts; inclusion of amounts in income of beneficiaries. Subject to the rules...

  5. 17 CFR 270.3a-1 - Certain prima facie investment companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Certain prima facie investment companies. 270.3a-1 Section 270.3a-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.3a-1 Certain prima facie investment...

  6. 17 CFR 240.15a-1 - Securities activities of OTC derivatives dealers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... options, forwards, futures, swap agreements, or collars involving currencies, interest or other rates... derivatives dealers. 240.15a-1 Section 240.15a-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... Under the Securities Exchange Act of 1934 Exemption of Certain Otc Derivatives Dealers § 240.15a-1...

  7. 17 CFR 240.15a-1 - Securities activities of OTC derivatives dealers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... derivatives dealers. 240.15a-1 Section 240.15a-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... Under the Securities Exchange Act of 1934 Exemption of Certain Otc Derivatives Dealers § 240.15a-1 Securities activities of OTC derivatives dealers. Preliminary Note: OTC derivatives dealers are a special...

  8. 17 CFR 240.36a1-2 - Exemption from SIPA for OTC derivatives dealers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... derivatives dealers. 240.36a1-2 Section 240.36a1-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... § 240.36a1-2 Exemption from SIPA for OTC derivatives dealers. Preliminary Note: OTC derivatives dealers... derivative dealers are subject to special requirements, including limitations on the scope of their...

  9. 26 CFR 1.652(a)-1 - Simple trusts; inclusion of amounts in income of beneficiaries.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Simple trusts; inclusion of amounts in income of beneficiaries. 1.652(a)-1 Section 1.652(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Only § 1.652(a)-1 Simple trusts; inclusion of amounts in income of beneficiaries. Subject to the rules...

  10. 26 CFR 1.642(a)(1)-1 - Partially tax-exempt interest.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Partially tax-exempt interest. 1.642(a)(1)-1 Section 1.642(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(a)(1)-1...

  11. 26 CFR 1.642(a)(1)-1 - Partially tax-exempt interest.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Partially tax-exempt interest. 1.642(a)(1)-1 Section 1.642(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.642(a)(1)-1 Partially tax...

  12. 17 CFR 240.11a1-4(T) - Bond transactions on national securities exchanges.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Bond transactions on national securities exchanges. 240.11a1-4(T) Section 240.11a1-4(T) Commodity and Securities Exchanges SECURITIES AND....11a1-4(T) Bond transactions on national securities exchanges. A transaction in a bond, note, debenture...

  13. 17 CFR 240.11a1-4(T) - Bond transactions on national securities exchanges.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Bond transactions on national securities exchanges. 240.11a1-4(T) Section 240.11a1-4(T) Commodity and Securities Exchanges SECURITIES AND....11a1-4(T) Bond transactions on national securities exchanges. A transaction in a bond, note, debenture...

  14. 26 CFR 1.652(a)-1 - Simple trusts; inclusion of amounts in income of beneficiaries.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Simple trusts; inclusion of amounts in income of beneficiaries. 1.652(a)-1 Section 1.652(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE....652(a)-1 Simple trusts; inclusion of amounts in income of beneficiaries. Subject to the rules in §§ 1...

  15. 26 CFR 1.860A-1 - Effective dates and transition rules.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 9 2011-04-01 2011-04-01 false Effective dates and transition rules. 1.860A-1 Section 1.860A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Real Estate Investment Trusts § 1.860A-1 Effective dates and...

  16. 26 CFR 1.860A-1 - Effective dates and transition rules.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 9 2014-04-01 2014-04-01 false Effective dates and transition rules. 1.860A-1 Section 1.860A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Real Estate Investment Trusts § 1.860A-1 Effective dates and...

  17. 26 CFR 1.860A-1 - Effective dates and transition rules.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 9 2013-04-01 2013-04-01 false Effective dates and transition rules. 1.860A-1 Section 1.860A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Real Estate Investment Trusts § 1.860A-1 Effective dates and...

  18. 26 CFR 1.860A-1 - Effective dates and transition rules.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 9 2012-04-01 2012-04-01 false Effective dates and transition rules. 1.860A-1 Section 1.860A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Real Estate Investment Trusts § 1.860A-1 Effective dates and...

  19. 42 CFR 59a.1 - Programs to which these regulations apply.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Programs to which these regulations apply. 59a.1 Section 59a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.1...

  20. 42 CFR 59a.1 - Programs to which these regulations apply.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Programs to which these regulations apply. 59a.1 Section 59a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.1...

  1. Genetics Home Reference: COL4A1-related brain small-vessel disease

    MedlinePlus

    ... COL4A1-related brain small-vessel disease COL4A1-related brain small-vessel disease Printable PDF Open All Close ... view the expand/collapse boxes. Description COL4A1 -related brain small-vessel disease is part of a group ...

  2. 26 CFR 1.642(a)(1)-1 - Partially tax-exempt interest.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Partially tax-exempt interest. 1.642(a)(1)-1 Section 1.642(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(a)(1)-1...

  3. 26 CFR 1.642(a)(1)-1 - Partially tax-exempt interest.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Partially tax-exempt interest. 1.642(a)(1)-1 Section 1.642(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(a)(1)-1...

  4. 26 CFR 1.642(a)(1)-1 - Partially tax-exempt interest.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Partially tax-exempt interest. 1.642(a)(1)-1 Section 1.642(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(a)(1)-1...

  5. 26 CFR 1.168(a)-1 - Modified accelerated cost recovery system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Modified accelerated cost recovery system. 1.168(a)-1 Section 1.168(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Corporations § 1.168(a)-1 Modified accelerated cost recovery system. (a) Section 168 determines the...

  6. 26 CFR 1.168(a)-1 - Modified accelerated cost recovery system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 2 2011-04-01 2011-04-01 false Modified accelerated cost recovery system. 1.168(a)-1 Section 1.168(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Corporations § 1.168(a)-1 Modified accelerated cost recovery system. (a) Section 168 determines the...

  7. 26 CFR 1.168(a)-1 - Modified accelerated cost recovery system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 2 2013-04-01 2013-04-01 false Modified accelerated cost recovery system. 1.168(a)-1 Section 1.168(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Corporations § 1.168(a)-1 Modified accelerated cost recovery system. (a) Section 168 determines the...

  8. 26 CFR 1.168(a)-1 - Modified accelerated cost recovery system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 2 2012-04-01 2012-04-01 false Modified accelerated cost recovery system. 1.168(a)-1 Section 1.168(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Corporations § 1.168(a)-1 Modified accelerated cost recovery system. (a) Section 168 determines the...

  9. 26 CFR 1.168(a)-1 - Modified accelerated cost recovery system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Modified accelerated cost recovery system. 1.168(a)-1 Section 1.168(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Corporations § 1.168(a)-1 Modified accelerated cost recovery system. (a) Section 168 determines the...

  10. Protective role of cytochrome P450 1A1 (CYP1A1) against benzo[a]pyrene-induced toxicity in mouse aorta.

    PubMed

    Uno, Shigeyuki; Sakurai, Kenichi; Nebert, Daniel W; Makishima, Makoto

    2014-02-28

    Benzo[a]pyrene (BaP) is an environmental pollutant produced by combustive processes, such as cigarette smoke and coke ovens, and is implicated in the pathogenesis of atherosclerosis. Cytochrome P450 1A1 (CYP1A1) plays a role in both metabolic activation and detoxication of BaP in a context-dependent manner. The role of CYP1A1 in BaP-induced toxicity in aorta remains unknown. First, we fed Apoe⁻/⁻ mice an atherogenic diet plus BaP and found that oral BaP-enhanced atherosclerosis is associated with increased reactive oxygen species (ROS) and inflammatory markers, such as plasma tumor necrosis factor levels and aortic mRNA expression of vascular endothelial growth factor A (Vegfa). We next examined the effect of an atherogenic diet plus BaP on ROS and inflammatory markers in Cyp1a1⁻/⁻ mice. Although this treatment was not sufficient to induce atherosclerotic lesions in Cyp1a1⁻/⁻ mice, plasma antioxidant levels were decreased in Cyp1a1⁻/⁻ mice even in the absence of BaP treatment. The atherogenic diet plus BaP effectively elevated plasma ROS levels and expression of atherosclerosis-related genes, specifically Vegfa, in Cyp1a1⁻/⁻ mice compared with wild-type mice. BaP treatment increased Vegfa mRNA levels in mouse embryonic fibroblasts from Cyp1a1⁻/⁻ mice but not from wild-type mice. BaP-induced DNA adduct formation was increased in the aorta of Cyp1a1⁻/⁻ mice, but not wild-type or Apoe⁻/⁻ mice, and the atherogenic diet decreased BaP-induced DNA adducts in Cyp1a1⁻/⁻ mice compared with mice on a control diet. These data suggest that ROS production contributes to BaP-exacerbated atherosclerosis and that CYP1A1 plays a protective role against oral BaP toxicity in aorta. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Hemoglobin A1c (HbA1c) changes over time among adolescent and young adult participants in the T1D exchange clinic registry.

    PubMed

    Clements, Mark A; Foster, Nicole C; Maahs, David M; Schatz, Desmond A; Olson, Beth A; Tsalikian, Eva; Lee, Joyce M; Burt-Solorzano, Christine M; Tamborlane, William V; Chen, Vincent; Miller, Kellee M; Beck, Roy W

    2016-08-01

    Hemoglobin A1c (HbA1c) levels among individuals with type 1 diabetes (T1D) influence the longitudinal risk for diabetes-related complications. Few studies have examined HbA1c trends across time in children, adolescents, and young adults with T1D. This study examines changes in glycemic control across the specific transition periods of pre-adolescence-to-adolescence and adolescence-to-young adulthood, and the demographic and clinical factors associated with these changes. Available HbA1c lab results for up to 10 yr were collected from medical records at 67 T1D Exchange clinics. Two retrospective cohorts were evaluated: the pre-adolescent-to-adolescent cohort consisting of 85 016 HbA1c measurements from 6574 participants collected when the participants were 8-18 yr old and the adolescent-to-young adult cohort, 2200 participants who were 16-26 yr old at the time of 17 279 HbA1c measurements. HbA1c in the 8-18 cohort increased over time after age 10 yr until ages 16-17; followed by a plateau. HbA1c levels in the 16-26 cohort remained steady from 16-18, and then gradually declined. For both cohorts, race/ethnicity, income, health insurance, and pump use were all significant in explaining individual variations in age-centered HbA1c (p < 0.001). For the 8-18 cohort, insulin pump use, age of onset, and health insurance were significant in predicting individual HbA1c trajectory. Glycemic control among patients 8-18 yr old worsens over time, through age 16. Elevated HbA1c levels observed in 18 yr-olds begin a steady improvement into early adulthood. Focused interventions to prevent deterioration in glucose control in pre-adolescence, adolescence, and early adulthood are needed. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Bis-Indole-Derived NR4A1 Ligands and Metformin Exhibit NR4A1-Dependent Glucose Metabolism and Uptake in C2C12 Cells.

    PubMed

    Mohankumar, Kumaravel; Lee, Jehoon; Wu, Chia Shan; Sun, Yuxiang; Safe, Stephen

    2018-05-01

    Treatment of C2C12 muscle cells with metformin or the NR4A1 ligand 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) induced NR4A1 and Glut4 messenger RNA and protein expression. Similar results were observed with buttressed (3- or 3,5-substituted) analogs of DIM-C-pPhOH, including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (DIM-C-pPhOH-3-Cl-5-OCH3), and the buttressed analogs were more potent than DIM-C-pPhOH NR4A1 agonists. Metformin and the bis-indole substituted analogs also induced expression of several glycolytic genes and Rab4, which has previously been linked to enhancing cell membrane accumulation of Glut4 and overall glucose uptake in C2C12 cells, and these responses were also observed after treatment with metformin and the NR4A1 ligands. The role of NR4A1 in mediating the responses induced by the bis-indoles and metformin was determined by knockdown of NR4A1, and this resulted in attenuating the gene and protein expression and enhanced glucose uptake responses induced by these compounds. Our results demonstrate that the bis-indole-derived NR4A1 ligands represent a class of drugs that enhance glucose uptake in C2C12 muscle cells, and we also show that the effects of metformin in this cell line are NR4A1-dependent.

  13. Physicochemical properties of hydroxylated polychlorinated biphenyls aid in predicting their interactions with rat sulfotransferase 1A1 (rSULT1A1)

    PubMed Central

    Liu, Yungang; Lehmler, Hans-Joachim; Robertson, Larry W.; Duffel, Michael W.

    2010-01-01

    Hydroxylated metabolites of polychlorinated biphenyls (OHPCBs) interact with rat sulfotransferase 1A1 (rSULT1A1) as substrates and inhibitors. Previous studies have shown that there are complex and incompletely understood structure-activity relationships governing the interaction of rSULT1A1 with these molecules. Furthermore, modification of the enzyme with glutathione disulfide (GSSG) results in the conversion of some OHPCBs from inhibitors to substrates. We have now examined estimated values for the acid-dissociation constant (Ka) and the octanol-water distribution coefficient (D), as well as experimentally determined dissociation constants for enzyme complexes, to assist in the prediction of interactions of OHPCBs with rSULT1A1. Under reducing conditions, initial velocities for rSULT1A1-catalyzed sulfation exhibited a positive correlation with pKa and a negative correlation with log D of the OHPCBs. IC50 values of inhibitory OHPCBs decreased with decreasing pKa values for both the glutathione (GSH)-pretreated and GSSG-pretreated forms of rSULT1A1. Comparison of GSH- and GSSG-pretreated forms of rSULT1A1 with respect to binding of OHPCB in the presence and absence of adenosine 3’,5’-diphosphate (PAP) revealed that the dissociation constants with the two redox states of the enzyme were similar for each OHPCB. Thus, pKa and log D values are useful in predicting the binding of OHPCBs to the two redox forms of rSULT1A1 as well as the rates of sulfation of those OHPCBs that are substrates. However, the differences in substrate specificity for OHPCBs that are seen with changes in redox status of the enzyme are not directly related to specific structural effects of individual OHPCBs within inhibitory enzyme-PAP-OHPCB complexes. PMID:21130751

  14. Retinal and Nonocular Abnormalities in Cyp27a1−/−Cyp46a1−/− Mice with Dysfunctional Metabolism of Cholesterol

    PubMed Central

    Saadane, Aicha; Mast, Natalia; Charvet, Casey D.; Omarova, Saida; Zheng, Wenchao; Huang, Suber S.; Kern, Timothy S.; Peachey, Neal S.; Pikuleva, Irina A.

    2015-01-01

    Cholesterol elimination from nonhepatic cells involves metabolism to side-chain oxysterols, which serve as transport forms of cholesterol and bioactive molecules modulating a variety of cellular processes. Cholesterol metabolism is tissue specific, and its significance has not yet been established for the retina, where cytochromes P450 (CYP27A1 and CYP46A1) are the major cholesterol-metabolizing enzymes. We generated Cyp27a1−/−Cyp46a1−/− mice, which were lean and had normal serum cholesterol and glucose levels. These animals, however, had changes in the retinal vasculature, retina, and several nonocular organs (lungs, liver, and spleen). Changes in the retinal vasculature included structural abnormalities (retinal-choroidal anastomoses, arteriovenous shunts, increased permeability, dilation, nonperfusion, and capillary degeneration) and cholesterol deposition and oxidation in the vascular wall, which also exhibited increased adhesion of leukocytes and activation of the complement pathway. Changes in the retina included increased content of cholesterol and its metabolite, cholestanol, which were focally deposited at the apical and basal sides of the retinal pigment epithelium. Retinal macrophages of Cyp27a1−/−Cyp46a1−/− mice were activated, and oxidative stress was noted in their photoreceptor inner segments. Our findings demonstrate the importance of retinal cholesterol metabolism for maintenance of the normal retina, and suggest new targets for diseases affecting the retinal vasculature. PMID:25065682

  15. Association of Hemoglobin A1c and Wound Healing in Diabetic Foot Ulcers.

    PubMed

    Fesseha, Betiel K; Abularrage, Christopher J; Hines, Kathryn F; Sherman, Ronald; Frost, Priscilla; Langan, Susan; Canner, Joseph; Likes, Kendall C; Hosseini, Sayed M; Jack, Gwendolyne; Hicks, Caitlin W; Yalamanchi, Swaytha; Mathioudakis, Nestoras

    2018-04-16

    This study evaluated the association between hemoglobin A 1c (A1C) and wound outcomes in patients with diabetic foot ulcers (DFUs). We conducted a retrospective analysis of an ongoing prospective, clinic-based study of patients with DFUs treated at an academic institution during a 4.7-year period. Data from 270 participants and 584 wounds were included in the analysis. Cox proportional hazards regression was used to assess the incidence of wound healing at any follow-up time in relation to categories of baseline A1C and the incidence of long-term (≥90 days) wound healing in relation to tertiles of nadir A1C change and mean A1C change from baseline, adjusted for potential confounders. Baseline A1C was not associated with wound healing in univariate or fully adjusted models. Compared with a nadir A1C change from baseline of -0.29 to 0.0 (tertile 2), a nadir A1C change of 0.09 to 2.4 (tertile 3) was positively associated with long-term wound healing in the subset of participants with baseline A1C <7.5% (hazard ratio [HR], 2.07; 95% CI, 1.08-4.00), but no association with wound healing was seen with the mean A1C change from baseline in this group. Neither nadir A1C change nor mean A1C change were associated with long-term wound healing in participants with baseline A1C ≥7.5%. There does not appear to be a clinically meaningful association between baseline or prospective A1C and wound healing in patients with DFUs. The paradoxical finding of accelerated wound healing and increase in A1C in participants with better baseline glycemic control requires confirmation in further studies. © 2018 by the American Diabetes Association.

  16. False positive fecal coliform in biosolid samples assayed using A-1 medium.

    PubMed

    Baker, Katherine H; Redmond, Brady; Herson, Diane S

    2005-01-01

    Two most probable number (MPN) methods-lauryl tryptose broth with Escherichia coli broth confirmation and direct A-1 broth incubation (A-1)--were compared for the enumeration of fecal coliform in lime-treated biosolid. Fecal coliform numbers were significantly higher using the A-1 method. Analysis of positive A-1 tubes, however, indicated that a high percentage of these were false positives. Therefore, the use of A-1 broth for 40 CFR Part 503 Pathogen Reduction (CFR, 1993) compliance testing is not recommended.

  17. Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders

    SciTech Connect

    Lemaire, Benjamin; Kubota, Akira; O'Meara, Conor M.

    Cytochrome P450 (CYP) enzymes for which there is no functional information are considered “orphan” CYPs. Previous studies showed that CYP20A1, an orphan, is expressed in human hippocampus and substantia nigra, and in zebrafish (Danio rerio) CYP20A1 maternal transcript occurs in eggs, suggesting involvement in brain and in early development. Moreover, hyperactivity is reported in humans with chromosome 2 microdeletions including CYP20A1. We examined CYP20A1 in zebrafish, including impacts of chemical exposure on expression. Zebrafish CYP20A1 cDNA was cloned, sequenced, and aligned with cloned human CYP20A1 and predicted vertebrate orthologs. CYP20A1s share a highly conserved N-terminal region and unusual sequences inmore » the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including the liver, heart, gonads, spleen and brain, as well as the eye and optic nerve. Putative binding sites in proximal promoter regions of CYP20A1s, and response of zebrafish CYP20A1 to selected nuclear and xenobiotic receptor agonists, point to up-regulation by agents involved in steroid hormone response, cholesterol and lipid metabolism. There also was a dose-dependent reduction of CYP20A1 expression in embryos exposed to environmentally relevant levels of methylmercury. Morpholino knockdown of CYP20A1 in developing zebrafish resulted in behavioral effects, including hyperactivity and a slowing of the optomotor response in larvae. The results suggest that altered expression of CYP20A1 might be part of a mechanism linking methylmercury exposure to neurobehavioral deficits. The expanded information on CYP20A1 brings us closer to “deorphanization”, that is, identifying CYP20A1 functions and its roles in health and disease. - Highlights: • The “orphan” CYP20A1 was cloned from zebrafish and its sequence analyzed. • Knockdown of CYP20A1 reduced an optomotor response and elicited bursts of activity. • Effects

  18. Flavor changing neutral current transition of B to a1 with light-cone sum rules

    NASA Astrophysics Data System (ADS)

    Momeni, S.; Khosravi, R.; Falahati, F.

    2017-01-01

    The B →a1ℓ+ℓ- decays occur by the electroweak penguin and box diagrams, which can be performed through the flavor changing neutral current (FCNC). We calculate the form factors of the FCNC B →a1 transitions in the light-cone sum rules approach, up to twist-4 distribution amplitudes of the axial vector meson a1. Forward-backward asymmetry, as well as branching ratios of B →a1ℓ+ℓ-, and B →a1γ decays are considered. A comparison is also made between our results and the predictions of other methods.

  19. Use of Fructosyl Peptide Oxidase for HbA1c Assay

    PubMed Central

    Yonehara, Satoshi; Inamura, Norio; Fukuda, Miho; Sugiyama, Koji

    2015-01-01

    ARKRAY, Inc developed the world’s first automatic glycohemoglobin analyzer based on HPLC (1981). After that, ARKRAY developed enzymatic HbA1c assay “CinQ HbA1c” with the spread and diversification of HbA1c measurement (2007). CinQ HbA1c is the kit of Clinical Chemistry Analyzer, which uses fructosyl peptide oxidase (FPOX) for a measurement reaction. This report mainly indicates the developmental background, measurement principle, and future of the enzymatic method HbA1c reagent. PMID:25633966

  20. Recovery sleep after extended wakefulness restores elevated A1 adenosine receptor availability in the human brain

    PubMed Central

    Elmenhorst, Eva-Maria; Hennecke, Eva; Kroll, Tina; Matusch, Andreas; Aeschbach, Daniel; Bauer, Andreas

    2017-01-01

    Adenosine and functional A1 adenosine receptor (A1AR) availability are supposed to mediate sleep–wake regulation and cognitive performance. We hypothesized that cerebral A1AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [18F]CPFPX positron emission tomography was used to quantify A1AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A1AR values after 8 h of baseline sleep from an earlier dataset. Polysomnography, cognitive performance, and sleepiness were monitored. Recovery from sleep deprivation was associated with a decrease in A1AR availability in several brain regions, ranging from 11% (insula) to 14% (striatum). A1AR availabilities after recovery did not differ from baseline sleep in the control group. The degree of performance impairment, sleepiness, and homeostatic sleep-pressure response to sleep deprivation correlated negatively with the decrease in A1AR availability. Sleep deprivation resulted in a higher A1AR availability in the human brain. The increase that was observed after 52 h of wakefulness was restored to control levels during a 14-h recovery sleep episode. Individuals with a large increase in A1AR availability were more resilient to sleep-loss effects than those with a subtle increase. This pattern implies that differences in endogenous adenosine and A1AR availability might be causal for individual responses to sleep loss. PMID:28373571

  1. hnRNP K Coordinates Transcriptional Silencing by SETDB1 in Embryonic Stem Cells

    PubMed Central

    Thompson, Peter J.; Dulberg, Vered; Moon, Kyung-Mee; Foster, Leonard J.; Chen, Carol; Karimi, Mohammad M.; Lorincz, Matthew C.

    2015-01-01

    Retrotransposition of endogenous retroviruses (ERVs) poses a substantial threat to genome stability. Transcriptional silencing of a subset of these parasitic elements in early mouse embryonic and germ cell development is dependent upon the lysine methyltransferase SETDB1, which deposits H3K9 trimethylation (H3K9me3) and the co-repressor KAP1, which binds SETDB1 when SUMOylated. Here we identified the transcription co-factor hnRNP K as a novel binding partner of the SETDB1/KAP1 complex in mouse embryonic stem cells (mESCs) and show that hnRNP K is required for ERV silencing. RNAi-mediated knockdown of hnRNP K led to depletion of H3K9me3 at ERVs, concomitant with de-repression of proviral reporter constructs and specific ERV subfamilies, as well as a cohort of germline-specific genes directly targeted by SETDB1. While hnRNP K recruitment to ERVs is dependent upon KAP1, SETDB1 binding at these elements requires hnRNP K. Furthermore, an intact SUMO conjugation pathway is necessary for SETDB1 recruitment to proviral chromatin and depletion of hnRNP K resulted in reduced SUMOylation at ERVs. Taken together, these findings reveal a novel regulatory hierarchy governing SETDB1 recruitment and in turn, transcriptional silencing in mESCs. PMID:25611934

  2. HnRNP C, YB-1 and hnRNP L coordinately enhance skipping of human MUSK exon 10 to generate a Wnt-insensitive MuSK isoform

    PubMed Central

    Nasrin, Farhana; Rahman, Mohammad Alinoor; Masuda, Akio; Ohe, Kenji; Takeda, Jun-ichi; Ohno, Kinji

    2014-01-01

    Muscle specific receptor tyrosine kinase (MuSK) is an essential postsynaptic transmembrane molecule that mediates clustering of acetylcholine receptors (AChR). MUSK exon 10 is alternatively skipped in human, but not in mouse. Skipping of this exon disrupts a cysteine-rich region (Fz-CRD), which is essential for Wnt-mediated AChR clustering. To investigate the underlying mechanisms of alternative splicing, we exploited block-scanning mutagenesis with human minigene and identified a 20-nucleotide block that contained exonic splicing silencers. Using RNA-affinity purification, mass spectrometry, and Western blotting, we identified that hnRNP C, YB-1 and hnRNP L are bound to MUSK exon 10. siRNA-mediated knockdown and cDNA overexpression confirmed the additive, as well as the independent, splicing suppressing effects of hnRNP C, YB-1 and hnRNP L. Antibody-mediated in vitro protein depletion and scanning mutagenesis additionally revealed that binding of hnRNP C to RNA subsequently promotes binding of YB-1 and hnRNP L to the immediate downstream sites and enhances exon skipping. Simultaneous tethering of two splicing trans-factors to the target confirmed the cooperative effect of YB-1 and hnRNP L on hnRNP C-mediated exon skipping. Search for a similar motif in the human genome revealed nine alternative exons that were individually or coordinately regulated by hnRNP C and YB-1. PMID:25354590

  3. Structured education using Dose Adjustment for Normal Eating (DAFNE) reduces long-term HbA1c and HbA1c variability.

    PubMed

    Walker, G S; Chen, J Y; Hopkinson, H; Sainsbury, C A R; Jones, G C

    2018-06-01

    Previous evidence has demonstrated that participation in the Dose Adjustment for Normal Eating (DAFNE) education programme can reduce HbA 1c and severe hypoglycaemia in people with Type 1 diabetes. In a number of studies, increased HbA 1c variability has been associated with higher diabetic morbidity and mortality. No studies have examined the impact of structured education on HbA 1c variability in Type 1 diabetes. People with Type 1 diabetes who had attended DAFNE were identified for inclusion from the Scottish Care Information-Diabetes dataset. HbA 1c median and variability, expressed as coefficient of variation (CV) before and after DAFNE was calculated. Some 1061 individuals participated in DAFNE education and 687 met the inclusion criteria. A significant median reduction in HbA 1c [-3.5 mmol/mol (-0.3%)] was seen at 12 months with a significant reduction [-1.5 mmol/mol (-0.1%)] still seen at 60 months of follow-up. HbA 1c variability as measured by CV was significantly lower during the post-DAFNE period: 0.08 (IQR 0.05-0.12) reduced to 0.07 (IQR 0.05-0.10); P = 0.002. The data confirm that DAFNE participation improves glycaemic control in Type 1 diabetes with benefits being sustained for 5 years. This study is the first to demonstrate reduced HbA 1c variability after completion of structured education. This is new evidence of the beneficial impact of DAFNE on glycaemic profile. © 2018 Diabetes UK.

  4. Apolipoprotein A-1 (apoA-1) deposition in, and release from, the enterocyte brush border: a possible role in transintestinal cholesterol efflux (TICE)?

    PubMed

    Danielsen, E Michael; Hansen, Gert H; Rasmussen, Karina; Niels-Christiansen, Lise-Lotte; Frenzel, Franz

    2012-03-01

    Transintestinal cholesterol efflux (TICE) has been proposed to represent a non-hepatobiliary route of cholesterol secretion directly "from blood to gut" and to play a physiologically significant role in excretion of neutral sterols, but so far little is known about the proteins involved in the process. We have previously observed that apolipoprotein A-1 (apoA-1) synthesized by enterocytes of the small intestine is mainly secreted apically into the gut lumen during fasting where its assembly into chylomicrons and basolateral discharge is at a minimal level. In the present work we showed, both by immunomicroscopy and subcellular fractionation, that a fraction of the apically secreted apoA-1 in porcine small intestine was not released from the cell surface but instead deposited in the brush border. Cholesterol was detected in immunoisolated microvillar apoA-1, and it was partially associated with detergent resistant membranes (DRMs), indicative of localization in lipid raft microdomains. The apolipoprotein was not readily released from microvillar vesicles by high salt or by incubation with phosphatidylcholine-specific phospholipase C or trypsin, indicating a relatively firm attachment to the membrane bilayer. However, whole bile or taurocholate efficiently released apoA-1 at low concentrations that did not solubilize the transmembrane microvillar protein aminopeptidase N. Based on these findings and the well known role played by apoA-1 in extrahepatic cellular cholesterol removal and reverse cholesterol transport (RCT), we propose that brush border-deposited apoA-1 in the small intestine acts in TICE by mediating cholesterol efflux into the gut lumen. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Expression and Functional Significance of HtrA1 Loss in Endometrial Cancer

    PubMed Central

    Mullany, Sally A.; Moslemi-Kebria, Mehdi; Rattan, Ramandeep; Khurana, Ashwani; Clayton, Amy; Ota, Takayo; Mariani, Andrea; Podratz, Karl C.; Chien, Jeremy; Shridhar, Viji

    2010-01-01

    Purpose The purpose of this study was to determine if loss of serine protease HtrA1 in endometrial cancer will promote the invasive potential of EC cell lines. Experimental design Western blot analysis and immunohistochemistry methods were used to determine HtrA1 expression in EC cell lines and primary tumors, respectively. Migration, invasion assays and in vivo xenograft experiment were performed to compare the extent of metastasis between HtrA1 expressing and HtrA-1 knocked down clones. Results Western blot analysis of HtrA1 in 13 EC cell lines revealed complete loss of HtrA1 expression in all 7 papillary serous EC cell lines. Downregulation of HtrA1 in Hec1A and Hec1B cell lines resulted in a 3-4 fold increase in the invasive potential. Exogenous expression of HtrA1 in Ark 1 and Ark 2 cells resulted in 3-4 fold decrease in both invasive and migration potential of these cells. There was an increased rate of metastasis to the lungs associated with HtrA1 downregulation in Hec1B cells compared to control cells with endogenous HtrA1 expression. Enhanced expression of HtrA1 in Ark 2 cells resulted in significantly less tumor nodules metastasizing to the lungs compared to parental or protease deficient (SA mutant) Ark 2 cells. Immunohistochemical (IHC) analysis showed 57% (105/184) of primary EC tumors had low HtrA1 expression. The association of low HtrA1 expression with high-grade endometrioid tumors was statistically significant (p=0.016). Conclusions Collectively, these data indicate loss of HtrA1 may contribute to the aggressiveness and metastatic ability of endometrial tumors. PMID:21098697

  6. Experimental murine myopia induces collagen type Iα1 (COL1A1) DNA methylation and altered COL1A1 messenger RNA expression in sclera

    PubMed Central

    Zhou, Xiangtian; Ji, Fengtao; An, Jianhong; Zhao, Fuxin; Shi, Fanjun; Huang, Furong; Li, Yuan; Jiao, Shiming; Yan, Dongsheng; Chen, Xiaoyan; Chen, JiangFan

    2012-01-01

    Purpose To investigate whether myopia development is associated with changes of scleral DNA methylation in cytosine-phosphate-guanine (CpG) sites in the collagen 1A1 (COL1A1) promoter and messenger RNA (mRNA) levels following murine form deprivation myopia. Methods Fifty-seven C57BL/6 mice (postnatal day 23) were randomly assigned to four groups: (1) monocular form deprivation (MD) in which a diffuser lens was placed over one eye for 28 days; (2) normal controls without MD; (3) MD recovery in which the diffuser lens was removed for seven days; and (4) MD recovery normal controls. The DNA methylation pattern in COL1A1 promoter and exon 1 was determined by bisulfite DNA sequencing, and the COL1A1 mRNA level in sclera was determined by quantitative PCR. Results MD was found to induce myopia in the treated eyes. Six CpG sites in the promoter and exon 1 region of COL1A1 were methylated with significantly higher frequency in the treated eyes than normal control eyes (p<0.05), with CpG island methylation in MD-contralateral eyes being intermediate. Consistent with the CpG methylation, scleral COL1A1 mRNA was reduced by 57% in the MD-treated eyes compared to normal controls (p<0.05). After seven days of MD recovery, CpG methylation was significantly reduced (p=0.01). The methylation patterns returned to near normal level in five CpG sites, but the sixth was hypomethylated compared to normal controls. Conclusions In parallel with the development of myopia and the reduced COL1A1 mRNA, the frequency of methylation in CpG sites of the COL1A1 promoter/exon 1 increased during MD and returned to near normal during recovery. Thus, hypermethylation of CpG sites in the promoter/exon 1 of COL1A1 may underlie reduced collagen synthesis at the transcriptional level in myopic scleras. PMID:22690110

  7. Bilirubin UDP-Glucuronosyltransferase 1A1 (UGT1A1) Gene Promoter Polymorphisms and HPRT, Glycophorin A, and Micronuclei Mutant Frequencies in Human Blood

    SciTech Connect

    Grant, D; Hall, I J; Eastmond, D

    2004-10-06

    A dinucleotide repeat polymorphism (5-, 6-, 7-, or 8-TA units) has been identified within the promoter region of UDP-glucuronosyltransferase 1A1 gene (UGT1A1). The 7-TA repeat allele has been associated with elevated serum bilirubin levels that cause a mild hyperbilirubinemia (Gilbert's syndrome). Studies suggest that promoter transcriptional activity of UGT1A1 is inversely related to the number of TA repeats and that unconjugated bilirubin concentration increases directly with the number of TA repeat elements. Because bilirubin is a known antioxidant, we hypothesized that UGT1A1 repeats associated with higher bilirubin may be protective against oxidative damage. We examined the effect of UGT1A1 genotypemore » on somatic mutant frequency in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) gene in human lymphocytes and the glycophorin A (GPA) gene of red blood cells (both N0, NN mutants), and the frequency of lymphocyte micronuclei (both kinetochore (K) positive or micronuclei K negative) in 101 healthy smoking and nonsmoking individuals. As hypothesized, genotypes containing 7-TA and 8-TA displayed marginally lower GPA{_}NN mutant frequency relative to 5/5, 5/6, 6/6 genotypes (p<0.05). In contrast, our analysis showed that lower expressing UGT1A1 alleles (7-TA and 8-TA) were associated with modestly increased HPRT mutation frequency (p<0.05) while the same low expression genotypes were not significantly associated with micronuclei frequencies (K-positive or K-negative) when compared to high expression genotypes (5-TA and 6-TA). We found weak evidence that UGT1A1 genotypes containing 7-TA and 8-TA were associated with increased GPA{_}N0 mutant frequency relative to 5/5, 5/6, 6/6 genotypes (p<0.05). These data suggest that UGT1A1 genotype may modulate somatic mutation of some types, in some cell lineages, by a mechanism not involving bilirubin antioxidant activity. More detailed studies examining UGT1A1 promoter variation, oxidant/antioxidant balance and

  8. Successful ABO-Incompatible Renal Transplantation:  Blood Group A1B Donor Into A2B Recipient With Anti-A1 Isoagglutinins.

    PubMed

    Fadeyi, Emmanuel A; Stratta, Robert J; Farney, Alan C; Pomper, Gregory J

    2016-08-01

    Transplantation of the blood group A2B in a recipient was successfully performed in the setting of receiving a deceased donor kidney from an "incompatible" A1B donor. The donor and recipient were both typed for ABO blood group, including ABO genotyping. The donor and recipient were tested for ABO, non-ABO, and human leukocyte antigen (HLA) antibodies. The donor and recipient were typed for HLA antigens, including T- and B-flow cytometry crossmatch tests. The recipient's RBCs were negative with A1 lectin, and immunoglobulin G anti-A1 was demonstrated in the recipient's plasma. The donor-recipient pair was a four-antigen HLA mismatch, but final T- and B-flow cytometry crossmatch tests were compatible. The transplant procedure was uneventful; the patient experienced immediate graft function with no episodes of rejection or readmissions more than 2 years later. It may be safe to transplant across the A1/A2 blood group AB mismatch barrier in the setting of low titer anti-A1 isoagglutinins without the need for pretransplant desensitization even if the antibody produced reacts with anti-human globulin. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport.

    PubMed

    Kim, Hye In; Raffler, Johannes; Lu, Wenyun; Lee, Jung-Jin; Abbey, Deepti; Saleheen, Danish; Rabinowitz, Joshua D; Bennett, Michael J; Hand, Nicholas J; Brown, Christopher; Rader, Daniel J

    2017-10-05

    Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. SLC22A1 encodes a hepatic plasma membrane transporter whose role in acylcarnitine physiology has not been described. By targeted metabolomics and isotope tracing experiments in loss- and gain-of-function cell and mouse models of Slc22a1, we uncovered a role of SLC22A1 in the efflux of acylcarnitines from the liver to the circulation. We further validated the impacts of human variants on SLC22A1-mediated acylcarnitine efflux in vitro, explaining their association with serum acylcarnitine levels. Our findings provide the detailed molecular mechanisms of the GWAS association for serum acylcarnitines at the SLC22A1 locus by functionally validating the impact of SLC22A1 and its variants on acylcarnitine transport. Copyright © 2017. Published by Elsevier Inc.

  10. Interaction of atorvastatin with the human glial transporter SLC16A1.

    PubMed

    Sasaki, Shotaro; Futagi, Yuya; Ideno, Masaya; Kobayashi, Masaki; Narumi, Katsuya; Furugen, Ayako; Iseki, Ken

    2016-10-05

    Solute carrier (SLC) 16A1 is a pH-dependent carrier of 5-oxoproline, a derivative of the amino acid. SLC16A1 interacts with carboxylate group-containing substrates, which are also present in atorvastatin, and might be the reason for its ability to interact with atorvastatin. Does atorvastatin interact with the carrier? Does it also interact with the carrier via the substrate recognition site? This study was carried out to answer these questions. Polymerase chain reaction was used to determine the expression of SLC16A1 in normal human astrocytes. We induced SLC16A1 expression in a mammalian cell line and in Xenopus laevis oocytes. We used [(3)H] 5-oxoproline for direct measurement of SLC16A1-specific transport activity. SLC16A1 was clearly observed in normal human astrocytes. 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors inhibited the SLC16A1-specific transport of 5-oxoproline. Atorvastatin was the most potent inhibitor, with an inhibition constant of 40μM. The drug was a non-competitive inhibitor of SLC16A1. In the present study, we showed non-competitive inhibition of SLC16A1-specific transport activity by atorvastatin. However, the affinity between the drug and the carrier was extremely low. Therefore, the interaction of atorvastatin with SLC16A1 is unlikely to be a problem in clinical practice. Copyright © 2016. Published by Elsevier B.V.

  11. Phylogenetic relationships among Perissodactyla: secretoglobin 1A1 gene duplication and triplication in the Equidae family.

    PubMed

    Côté, Olivier; Viel, Laurent; Bienzle, Dorothee

    2013-12-01

    Secretoglobin family 1A member 1 (SCGB 1A1) is a small anti-inflammatory and immunomodulatory protein that is abundantly secreted in airway surface fluids. We recently reported the existence of three distinct SCGB1A1 genes in the domestic horse genome as opposed to the single gene copy consensus present in other mammals. The origin of SCGB1A1 gene triplication and the evolutionary relationship of the three genes amongst Equidae family members are unknown. For this study, SCGB1A1 genomic data were collected from various Equus individuals including E. caballus, E. przewalskii, E. asinus, E. grevyi, and E. quagga. Three SCGB1A1 genes in E. przewalskii, two SCGB1A1 genes in E. asinus, and a single SCGB1A1 gene in E. grevyi and E. quagga were identified. Sequence analysis revealed that the non-synonymous nucleotide substitutions between the different equid genes coded for 17 amino acid changes. Most of these changes localized to the SCGB 1A1 central cavity that binds hydrophobic ligands, suggesting that this area of SCGB 1A1 evolved to accommodate diverse molecular interactions. Three-dimensional modeling of the proteins revealed that the size of the SCGB 1A1 central cavity is larger than that of SCGB 1A1A. Altogether, these findings suggest that evolution of the SCGB1A1 gene may parallel the separation of caballine and non-caballine species amongst Equidae, and may indicate an expansion of function for SCGB1A1 gene products. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. HsfA1a upregulates melatonin biosynthesis to confer cadmium tolerance in tomato plants.

    PubMed

    Cai, Shu-Yu; Zhang, Yun; Xu, You-Ping; Qi, Zhen-Yu; Li, Meng-Qi; Ahammed, Golam Jalal; Xia, Xiao-Jian; Shi, Kai; Zhou, Yan-Hong; Reiter, Russel J; Yu, Jing-Quan; Zhou, Jie

    2017-03-01

    Melatonin regulates broad aspects of plant responses to various biotic and abiotic stresses, but the upstream regulation of melatonin biosynthesis by these stresses remains largely unknown. Herein, we demonstrate that transcription factor heat-shock factor A1a (HsfA1a) conferred cadmium (Cd) tolerance to tomato plants, in part through its positive role in inducing melatonin biosynthesis under Cd stress. Analysis of leaf phenotype, chlorophyll content, and photosynthetic efficiency revealed that silencing of the HsfA1a gene decreased Cd tolerance, whereas its overexpression enhanced plant tolerance to Cd. HsfA1a-silenced plants exhibited reduced melatonin levels, and HsfA1a overexpression stimulated melatonin accumulation and the expression of the melatonin biosynthetic gene caffeic acid O-methyltransferase 1 (COMT1) under Cd stress. Both an in vitro electrophoretic mobility shift assay and in vivo chromatin immunoprecipitation coupled with qPCR analysis revealed that HsfA1a binds to the COMT1 gene promoter. Meanwhile, Cd stress induced the expression of heat-shock proteins (HSPs), which was compromised in HsfA1a-silenced plants and more robustly induced in HsfA1a-overexpressing plants under Cd stress. COMT1 silencing reduced HsfA1a-induced Cd tolerance and melatonin accumulation in HsfA1a-overexpressing plants. Additionally, the HsfA1a-induced expression of HSPs was partially compromised in COMT1-silenced wild-type or HsfA1a-overexpressing plants under Cd stress. These results demonstrate that HsfA1a confers Cd tolerance by activating transcription of the COMT1 gene and inducing accumulation of melatonin that partially upregulates expression of HSPs. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Should Studies of Diabetes Treatment Stratification Correct for Baseline HbA1c?

    PubMed Central

    Jones, Angus G.; Lonergan, Mike; Henley, William E.; Pearson, Ewan R.; Hattersley, Andrew T.; Shields, Beverley M.

    2016-01-01

    Aims Baseline HbA1c is a major predictor of response to glucose lowering therapy and therefore a potential confounder in studies aiming to identify other predictors. However, baseline adjustment may introduce error if the association between baseline HbA1c and response is substantially due to measurement error and regression to the mean. We aimed to determine whether studies of predictors of response should adjust for baseline HbA1c. Methods We assessed the relationship between baseline HbA1c and glycaemic response in 257 participants treated with GLP-1R agonists and assessed whether it reflected measurement error and regression to the mean using duplicate ‘pre-baseline’ HbA1c measurements not included in the response variable. In this cohort and an additional 2659 participants treated with sulfonylureas we assessed the relationship between covariates associated with baseline HbA1c and treatment response with and without baseline adjustment, and with a bias correction using pre-baseline HbA1c to adjust for the effects of error in baseline HbA1c. Results Baseline HbA1c was a major predictor of response (R2 = 0.19,β = -0.44,p<0.001).The association between pre-baseline and response was similar suggesting the greater response at higher baseline HbA1cs is not mainly due to measurement error and subsequent regression to the mean. In unadjusted analysis in both cohorts, factors associated with baseline HbA1c were associated with response, however these associations were weak or absent after adjustment for baseline HbA1c. Bias correction did not substantially alter associations. Conclusions Adjustment for the baseline HbA1c measurement is a simple and effective way to reduce bias in studies of predictors of response to glucose lowering therapy. PMID:27050911

  14. Phase transition in a tetragonal In90Pb10 alloy under high pressure: a switch from c/a > 1 to c/a < 1

    NASA Astrophysics Data System (ADS)

    Degtyareva, V. F.; Bdikin, I. K.; Porsch, F.; Novokhatskaya, N. I.

    2003-03-01

    The effect of pressure on tetragonal In-Pb alloys with 10, 15, and 22 at.% Pb has been studied up to pressure 30 GPa with diamond anvil cells using synchrotron radiation. The In-type face-centred tetragonal phase of the In alloy with 10 at.% Pb undergoes under pressure a phase transition with a discontinuous jump of the axial ratio from c/a > 1 to c/a < 1 via a two-phase region from 7 to 20 GPa. The tetragonal phases of the In alloys with 15 and 22 at.% Pb with c/a < 1 at ambient pressure show only a slight decrease in c/a with pressure increase. The correlation of the axial ratio with the alloy content and its change with pressure in In alloys and In itself are attributed to Brillouin-zone-Fermi-sphere interactions.

  15. S1(1A1)<--S0(1A1) transition of benzo[g,h,i]perylene in supersonic jets and rare gas matrices.

    PubMed

    Rouillé, G; Arold, M; Staicu, A; Krasnokutski, S; Huisken, F; Henning, Th; Tan, X; Salama, F

    2007-05-07

    The study of the S1(1A1)<--S0(1A1) transition of benzo[g,h,i]perylene (BghiP, C22H12) in supersonic jets and solid rare gas matrices is reported. In the jet-cooled spectrum, the origin band position is located at 25,027.1+/-0.2 cm-1, the assignment being supported by the analysis of vibrational shifts and rotational band contours. Except for the origin band, which is weak, all bands are attributed to the fundamental excitation of nontotally symmetric b1 vibrational modes of S1. The intensity pattern is interpreted as a consequence of the weak oscillator strength of the electronic transition combined with intensity-borrowing through vibronic interaction between the S1(1A1) and S2(1B1) states. The spectra of the S1(1A1)<--S0(1A1) and S2(1B1)<--S0(1A1) transitions have also been measured for BghiP in solid neon and argon matrices. The comparison of the redshifts determined for either transition reveals that the polarizability of BghiP is larger in its S2 than in its S1 state. Bandwidths of 2.7 cm-1 measured in supersonic jets, which provide conditions relevant for astrophysics, are similar to those of most diffuse interstellar bands. The electronic transitions of BghiP are found to lie outside the ranges covered by present databases. From the comparison between experimental spectra and theoretical computations, it is concluded that the accuracy of empirical and ab initio approaches in predicting electronic energies is still not sufficient to identify astrophysically interesting candidates for spectroscopic laboratory studies.

  16. Correlation Between Expression of High Temperature Requirement Serine Protease A1 (HtrA1) in Nucleus Pulposus and T2 Value of Magnetic Resonance Imaging.

    PubMed

    Li, Dapeng; Yue, Jiawei; Jiang, Lu; Huang, Yonghui; Sun, Jifu; Wu, Yan

    2017-04-22

    BACKGROUND Degrading enzymes play an important role in the process of disc degeneration. The objective of this study was to investigate the correlation between the expression of high temperature requirement serine protease A1 (HtrA1) in the nucleus pulposus and the T2 value of the nucleus pulposus region in magnetic resonance imaging (MRI). MATERIAL AND METHODS Thirty-six patients who had undergone surgical excision of the nucleus pulposus were examined by MRI before surgery. Pfirrmann grading of the target intervertebral disc was performed according to the sagittal T2-weighted imaging, and the T2 value of the target nucleus pulposus was measured according to the median sagittal T2 mapping. The correlation between the Pfirrmann grade and the T2 value was analyzed. The expression of HtrA1 in the nucleus pulposus was analyzed by RT-PCR and Western blot. The correlation between the expression of HtrA1 and the T2 value was analyzed. RESULTS The T2 value of the nucleus pulposus region was 33.11-167.91 ms, with an average of 86.64±38.73 ms. According to Spearman correlation analysis, there was a rank correlation between T2 value and Pfirrmann grade (P<0.0001), and the correlation coefficient (rs)=-0.93617. There was a linear correlation between the mRNA level of HtrA1 and T2 value in nucleus pulposus tissues (a=3.88, b=-0.019, F=112.63, P<0.0001), normalized regression coefficient=-0.88. There was a linear correlation between the expression level of HtrA1 protein and the T2 value in the nucleus pulposus tissues (a=3.30, b=-0.016, F=93.15, P<0.0001) and normalized regression coefficient=-0.86. CONCLUSIONS The expression of HtrA1 was strongly related to the T2 value, suggesting that HtrA1 plays an important role in the pathological process of intervertebral disc degeneration.

  17. Serological Analysis of Immunogenic Properties of Recombinant Meningococcus IgA1 Protease-Based Proteins.

    PubMed

    Kotelnikova, O V; Zinchenko, A A; Vikhrov, A A; Alliluev, A P; Serova, O V; Gordeeva, E A; Zhigis, L S; Zueva, V S; Razgulyaeva, O A; Melikhova, T D; Nokel, E A; Drozhzhina, E Yu; Rumsh, L D

    2016-07-01

    Using the genome sequence of IgA1 protease of N. meningitidis of serogroup B, four recombinant proteins of different structure and molecular weight were constructed. These proteins were equal in inducing the formation of specific antibodies to IgA1 protease and had protective properties against meningococci. In the sera of immunized mice, anti-IgA1 protease antibodies were detected by whole-cell ELISA, which indicated the presence of IgA1 protease on the surface of these bacteria. We hypothesized that the protective properties of IgA1 protease-based antigens and IgA1 protease analogs could be realized not only via impairment of bacterium adhesion to the mucosa, but also via suppression of this pathogen in the organism. The presented findings seem promising for using these proteins as the basis for anti-meningococcus vaccine.

  18. 26 CFR 1.667(a)-1A - Denial of refund to trusts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Denial of refund to trusts. 1.667(a)-1A Section 1.667(a)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME... Taxable Years Beginning Before January 1, 1969 § 1.667(a)-1A Denial of refund to trusts. If an amount is...

  19. 26 CFR 1.667(a)-1A - Denial of refund to trusts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Denial of refund to trusts. 1.667(a)-1A Section 1.667(a)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME... Beginning Before January 1, 1969 § 1.667(a)-1A Denial of refund to trusts. If an amount is deemed under...

  20. Systemic effects of arctic pollutants in beluga whales indicated by CYP1A1 expression.

    PubMed

    Wilson, Joanna Y; Cooke, Suzy R; Moore, Michael J; Martineau, Daniel; Mikaelian, Igor; Metner, Donald A; Lockhart, W Lyle; Stegeman, John J

    2005-11-01

    Cytochrome P450 1A1 (CYP1A1) is induced by exposure to polycyclic aromatic hydrocarbons (PAHs) and planar halogenated aromatic hydrocarbons (PHAHs) such as non-ortho polychlorinated biphenyls (PCBs). In this study, we examined CYP1A1 protein expression immunohistochemically in multiple organs of beluga whales from two locations in the Arctic and from the St. Lawrence estuary. These beluga populations have some of the lowest (Arctic sites) and highest (St. Lawrence estuary) concentrations of PCBs in blubber of all cetaceans. Samples from these populations might be expected to have different contaminant-induced responses, reflecting their different exposure histories. The pattern and extent of CYP1A1 staining in whales from all three locations were similar to those seen in animal models in which CYP1A has been highly induced, indicating a high-level expression in these whales. CYP1A1 induction has been related to toxic effects of PHAHs or PAHs in some species. In St. Lawrence beluga, the high level of CYP1A1 expression coupled with high levels of contaminants (including CYP1A1 substrates, e.g., PAH procarcinogens potentially activated by CYP1A1) indicates that CYP1A1 could be involved in the development of neoplastic lesions seen in the St. Lawrence beluga population. The systemic high-level expression of CYP1A1 in Arctic beluga suggests that effects of PAHs or PHAHs may be expected in Arctic populations, as well. The high-level expression of CYP1A1 in the Arctic beluga suggests that this species is highly sensitive to CYP1A1 induction by aryl hydrocarbon receptor agonists.

  1. Longitudinal trends in HbA1c patterns and association with outcomes: A systematic review.

    PubMed

    Luo, Miyang; Tan, Kristin Hui Xian; Tan, Chuen Seng; Lim, Wei Yen; Tai, E-Shyong; Venkataraman, Kavita

    2018-04-17

    This study aimed to review studies that identified patterns of longitudinal HbA 1c trends in patients with diabetes and to summarize factors and outcomes associated with distinct trajectory patterns. PubMed and Web of Science were systematically searched for studies examining HbA 1c trends among patients with diabetes from database inception through September 2017. Articles were included if they met the following inclusion criteria: (a) longitudinal study of subjects with diabetes only, (b) use of serial measurements of HbA 1c , and (c) analysis of the trend of HbA 1c using group-based trajectory approaches. Twenty studies were included, 11 on type 1 diabetes and 9 on type 2 diabetes. These studies identified 2 to 6 HbA 1c trajectory patterns. The most commonly identified patterns included stable HbA 1c around 7.0% and at levels between 8.0% and 9.9%, which usually captured the HbA 1c pattern among the majority of subjects in the study population. Unstable patterns identified included increasing HbA 1c trend, decreasing HbA 1c trend, and non-linear patterns. These patterns were associated with differential risk of disease outcomes, over and beyond single-point HbA 1c measures. Age, gender, ethnicity, diabetes duration, disease management frequency, cardiovascular risk factors, insulin treatment, family environment, and psychosocial factors were the most frequently reported factors associated with membership of specific HbA 1c pattern groups. Common patterns of longitudinal HbA 1c trends were identified despite heterogeneity among the studies. A better understanding of what underlies these different patterns may provide opportunities to tailor therapies and care for these patients to reduce adverse outcomes. © 2018 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.

  2. Systemic Effects of Arctic Pollutants in Beluga Whales Indicated by CYP1A1 Expression

    PubMed Central

    Wilson, Joanna Y.; Cooke, Suzy R.; Moore, Michael J.; Martineau, Daniel; Mikaelian, Igor; Metner, Donald A.; Lockhart, W. Lyle; Stegeman, John J.

    2005-01-01

    Cytochrome P450 1A1 (CYP1A1) is induced by exposure to polycyclic aromatic hydrocarbons (PAHs) and planar halogenated aromatic hydrocarbons (PHAHs) such as non-ortho polychlorinated biphenyls (PCBs). In this study, we examined CYP1A1 protein expression immunohistochemically in multiple organs of beluga whales from two locations in the Arctic and from the St. Lawrence estuary. These beluga populations have some of the lowest (Arctic sites) and highest (St. Lawrence estuary) concentrations of PCBs in blubber of all cetaceans. Samples from these populations might be expected to have different contaminant-induced responses, reflecting their different exposure histories. The pattern and extent of CYP1A1 staining in whales from all three locations were similar to those seen in animal models in which CYP1A has been highly induced, indicating a high-level expression in these whales. CYP1A1 induction has been related to toxic effects of PHAHs or PAHs in some species. In St. Lawrence beluga, the high level of CYP1A1 expression coupled with high levels of contaminants (including CYP1A1 substrates, e.g., PAH procarcinogens potentially activated by CYP1A1) indicates that CYP1A1 could be involved in the development of neoplastic lesions seen in the St. Lawrence beluga population. The systemic high-level expression of CYP1A1 in Arctic beluga suggests that effects of PAHs or PHAHs may be expected in Arctic populations, as well. The high-level expression of CYP1A1 in the Arctic beluga suggests that this species is highly sensitive to CYP1A1 induction by aryl hydrocarbon receptor agonists. PMID:16263517

  3. Tyrosine Phosphorylation of the Pioneer Transcription Factor FoxA1 Promotes Activation of Estrogen Signaling.

    PubMed

    Yamaguchi, Noritaka; Shibazaki, Misato; Yamada, Chiaki; Anzai, Erina; Morii, Mariko; Nakayama, Yuji; Kuga, Takahisa; Hashimoto, Yuuki; Tomonaga, Takeshi; Yamaguchi, Naoto

    2017-06-01

    The pioneer transcription factor FoxA1 plays an important role in estrogen signaling by opening closed chromatin and promoting recruitment of the estrogen receptor to its target regions in DNA. In this study, we analyzed tyrosine phosphorylation of FoxA1 by the non-receptor-type tyrosine kinase c-Abl. c-Abl was shown to phosphorylate FoxA1 at multiple sites, especially in the N- and C-terminal regions. Tyr429 and Tyr464 were identified as the major phosphorylation sites in the FoxA1 C-terminal region. The phosphomimetic and nonphosphorylatable FoxA1 mutants were generated by glutamic acid and phenylalanine substitutions at these tyrosine residues, respectively. The phosphomimetic FoxA1 promoted the activation of estrogen signaling, whereas the nonphosphorylatable FoxA1 suppressed its activation. Stimulation with the epidermal growth factor, which activates c-Abl, enhanced the activation of estrogen signaling. In contrast, the c-Abl inhibitor imatinib reduced its activation. The phosphomimetic FoxA1 mutant showed a higher affinity toward histone H3 than the wild-type. These results suggest that c-Abl-mediated phosphorylation of FoxA1 promotes the activation of estrogen signaling by inducing its binding to histones. J. Cell. Biochem. 118: 1453-1461, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. The biosynthesis of human hemoglobin A1c. Slow glycosylation of hemoglobin in vivo.

    PubMed Central

    Bunn, H F; Haney, D N; Kamin, S; Gabbay, K H; Gallop, P M

    1976-01-01

    Hemoglobin A1c, the most abundant minor hemoglobin component in human erythrocytes, is formed by the condensation of glucose with the N-terminal amino groups of the beta-chains of Hb A. The biosynthesis of this glycosylated hemoglobin was studied in vitro by incubating suspensions of reticulocytes and bone marrow cells with [3H]leucine or 59Fe-bound transferrin. In all experiments, the specific activity of Hb A1c was significantly lower than that of Hb A, suggesting that the formation of Hb A1c is a posttranslational modification. The formation of Hb A1c in vivo was determined in two individuals who were given an infusion of 59Fe-labeled transferrin. As expected, the specific activity of Hb A rose promptly to a maximum during the 1st week and remained nearly constant thereafter. In contrast, the specific activity of Hb A1c and also of Hbs A1a and A1b rose slowly, reaching that of Hb A by about day 60. These results indicate that Hb A1c is slowly formed during the 120-day life-span of the erythrocyte, probably by a nonenzymatic process. Patients with shortened erythrocyte life-span due to hemolysis had markedly decreased levels of Hb A1c. PMID:932199

  5. The impact of the UGT1A1*60 allele on bilirubin serum concentrations.

    PubMed

    Pasternak, Amy L; Crews, Kristine R; Caudle, Kelly E; Smith, Colton; Pei, Deqing; Cheng, Cheng; Broeckel, Ulrich; Gaur, Aditya H; Hankins, Jane; Relling, Mary V; Haidar, Cyrine E

    2017-01-01

    Identify the functional status of the uridine-diphosphate glucuronyl transferase 1A1 (UGT1A1) -3279T>G (*60) variant. Retrospective review of clinically obtained serum bilirubin concentrations in pediatric patients to evaluate the association of the UGT1A1 -3279T>G (*60) variant with bilirubin concentrations and assessed linkage disequilibrium of the UGT1A1 -3279T>G (*60) and A(TA)7TAA (*28) variants. Total bilirubin concentration did not differ between patients who had a UGT1A1*1/*1 diplotype and patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant. Total bilirubin concentration was lower in patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant than in patients homozygous for the UGT1A1 A(TA)7TAA (*28/*28) variant (p < 0.01). The -3279T>G (*60) and A(TA)7TAA (*28) variants were in strong incomplete linkage disequilibrium in both black and white patients. The presence of the UGT1A1 -3279T>G (*60) variant is not associated with increased bilirubin concentrations.

  6. EF1A1/HSC70 Cooperatively Suppress Brain Endothelial Cell Apoptosis via Regulating JNK Activity.

    PubMed

    Liu, Ying; Jiang, Shu; Yang, Peng-Yuan; Zhang, Yue-Fan; Li, Tie-Jun; Rui, Yao-Cheng

    2016-10-01

    In our previous study, eEF1A1 was identified to be a new target for protecting brain ischemia injury, but the mechanism remains largely unknown. In this study, we screened the downstream cellular protein molecules interacted with eEF1A1 and found mechanism of eEF1A1 in brain ischemia protection. Through co-immunoprecipitation and mass spectrometry for searching the interaction of proteins with eEF1A1 in bEnd3 cells, HSC70 was identified to be a binding protein of eEF1A1, which was further validated by Western blot and immunofluorescence. eEF1A1 or HSC70 knockdown, respectively, increased OGD-induced apoptosis of brain vascular endothelial cells, which was detected by Annexin V-FITC/PI staining. HSC70 or eEF1A1 knockdown enhances phosphorylated JNK, phosphorylation of c-JUN (Ser63, Ser73), cleaved caspase-9, and cleaved caspase-3 expression, which could be rescued by JNK inhibitor. In summary, our data suggest that the presence of chaperone forms of interaction between eEF1A1 and HSC70 in brain vascular endothelial cells, eEF1A1 and HSC70 can play a protective role in the process of ischemic stroke by inhibiting the JNK signaling pathway activation. © 2016 John Wiley & Sons Ltd.

  7. Can overt diabetes mellitus be predicted by an early A1C value in gestational diabetics?

    PubMed

    Granada, Catalina; Forbes, Joanna; Sangi-Haghpeykar, Haleh; Davidson, Christina

    2014-01-01

    To test the hypothesis that a hemoglobin A1C value (A1C) in early pregnancy is predictive of overt diabetes mellitus (DM) postpartum in women with gestational diabetes (GDM). In this case-control analysis of women with an early pregnancy diagnosis of GDM, we estimated the association between an early pregnancy A1C and subsequent diagnosis of DM. Women with a normal postpartum diabetic screen (controls) were compared against those with confirmed postpartum DM (cases). Ability of A1C levels to predict DM was examined via logistic regression analysis and corresponding receiver operating characteristic values. During the 10-year study period 166 women met the inclusion criteria: 140 (84%) had normal postpartum testing (controls), and 26 (16%) were diagnosed with DM (cases). The mean A1C value was significantly higher among cases than controls (6.7 vs. 5.6, p < 0.0001, SD 1.3-5). Cases had A1Cs ranging from 5.5- 11.7%, while controls had A1Cs ranging from 4.3-7.8%. The best discriminatory cut point for postpartum DM was an A1C > 5.9% (sensitivity 81%, specificity 83%, positive predictive value 47%, negative predictive value Our findings suggest that an elevated early pregnancy A1C may be predictive of overt DM. Larger studies are needed to further validate this association.

  8. Analytical performances of a new enzymatic assay for hemoglobin A1c.

    PubMed

    Jaisson, Stéphane; Desmons, Aurore; Renard, Benoît; Chevelle, Benjamin; Leroy, Nathalie; Gillery, Philippe

    2014-07-01

    HbA1c is considered the gold standard for the follow-up of diabetic patients and a new diagnostic tool for diabetes mellitus, which implies the availability of reliable assay methods. We have evaluated a new assay developed by Abbott Laboratories, based on the enzymatic quantification of HbA1c by a fructosyl dipeptide oxidase using Architect analyzers. Precision, linearity, correlation with a HPLC method, accuracy and potential impact interferences on HbA1c measurement have been evaluated. Intra-day and between-day CVs were lower than 1.2% and linearity was excellent from 19 mmol/mol (3.9%) to 163 mmol/mol (17.1%). The results were well correlated with those obtained by the HPLC (Variant II device, kit NU - BioRad): HbA1c [Architect, mmol/mol]=0.986×HbA1c [Variant II, mmol/mol]+0.713 (r=0.998, n=109). This method provided consistent results with IFCC titrated quality control samples. Classical interferences in HbA1c assays (i.e. labile HbA1c, carbamylated hemoglobin, triglycerides or bilirubin) did not have an impact on HbA1c quantification by this method. This new enzymatic assay proved to be a robust and reliable method for HbA1c measurement suitable for routine practice in clinical chemistry laboratories. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Relationship of hemoglobin A1c to mortality in nonsmoking insurance applicants.

    PubMed

    Stout, Robert L; Fulks, Michael; Dolan, Vera F; Magee, Mark E; Suarez, Luis

    2007-01-01

    Determine the relationship between hemoglobin A1c value and 5-year, all-cause mortality in nonsmoking life insurance applicants. By use of the Social Security Master Death Index, mortality was examined in 286,443 non-smoking insurance applicants aged 40 and up for whom blood samples for hemoglobin A1c were submitted to the Clinical Reference Laboratory. Results were stratified by hemoglobin A1c value, gender and age bands 40 to 59, 60 to 69 and 70 and up. Increased mortality is apparent at hemoglobin A1c values of 6% and above, is linear, and on a percentage basis decreases with age. Hemoglobin A1c values less than 5% also are associated with increased mortality. Absolute mortality rates for females with elevated hemoglobin A1c are generally lower than rates for males, although mortality relative to the gender-specific reference group with hemoglobin A1c of 5% to 5.9% is generally the same for both. The importance of even small elevations of hemoglobin A1c above 5.9% is apparent. For screening, it is the degree of blood sugar elevation as measured by hemoglobin A1c rather than any diagnostic label that is critical in risk assessment.

  10. Analysis of HbA1c on an automated multicapillary zone electrophoresis system.

    PubMed

    Rollborn, Niclas; Åkerfeldt, Torbjörn; Nordin, Gunnar; Xu, Xiao Yan; Mandic-Havelka, Aleksandra; Hansson, Lars-Olof; Larsson, Anders

    2017-02-01

    Hemoglobin A1c (HbA1c) is a frequently requested laboratory test and there is thus a need for high throughput instruments for this assay. We evaluated a new automated multicapillary zone electrophoresis instrument (Capillarys 3 Tera, Sebia, Lisses, France) for analysis of HbA1c in venous samples. Routine requested HbA1c samples were analyzed immunologically on a Roche c6000 instrument (n = 142) and then with the Capillarys 3 Tera instrument. The Capillarys 3 Tera instrument performed approximately 70 HbA1c tests/hour. There was a strong linear correlation between Capillarys 3 Tera and Roche Tina-Quant HbA1c Gen 3 assay (y = 1.003x - 0.3246 R 2  = .996). The total CV for the 12 capillaries varied between 0.8 and 2.2% and there was a good agreement between duplicate samples (R 2  = .997). In conclusion, the Capillarys 3 Tera instrument has a high assay capacity for HbA1c. It has a good precision and agreement with the Roche Tina-Quant HbA1c method and is well suited for high volume testing of HbA1c.

  11. The Analysis of A1 Level Speaking Exam in Terms of Syntax: The Effect of General Competence on Syntax in A1 Level Speaking

    ERIC Educational Resources Information Center

    Misir, Hülya

    2017-01-01

    This study aims at discovering the relevance of general competence of Turkish and Arab learners who have an A1 level of English proficiency in preparatory school of University of Turkish Aeronautical Association (UTAA) to their speaking skill in terms of syntax by analyzing the recordings of speaking exams in the first semester. One can ask why…

  12. Proteomic analysis reveals the enhancement of human serum apolipoprotein A-1(APO A-1) in individuals infected with multiple dengue virus serotypes.

    PubMed

    Manchala, Nageswar Reddy; Dungdung, Ranjeet; Pilankatta, Rajendra

    2017-10-01

    Human serum protein profiling of the individual infected with multiple dengue virus serotypes for identifying the potential biomarkers and to investigate the cause for the severity of dengue virus infection. Dengue virus NS1-positive serum samples were pooled into two groups (S2 and S3) based on the molecular serotyping and number of heterotypic infections. The pooled serum samples were subjected to two-dimensional gel electrophoresis (2DGE) to identify the differentially expressed proteins. The peptide masses of upregulated protein were detected by matrix-assisted laser desorption-ionisation time-of-flight MALDI-TOF mass spectrometry and analysed by MASCOT search engine. The results were compared with the control group (S1). The commonly upregulated protein was validated by quantitative ELISA and compared with control as well as single serotypic infected samples. Based on 2DGE, total thirteen proteins were differentially upregulated in S2 and S3 groups as compared to control. Some of the upregulated proteins were involved in mediating the complement activation of immune response. The apolipoprotein A-1 (APO A-1) was upregulated in S2 and S3 groups. Upon validation, APO A-1 levels were increased in line with the number of heterotypic infection of dengue viruses. Heterotypic infection of dengue viruses upregulate the serum proteins involved in the complement pathway in the early phase of infection. There was a significant increase in the level of APO A-1 in three different serotypic infections of dengue virus as compared to control. Further, the role of APO-A1 can be explored in elucidating the mechanism of dengue pathogenesis. © 2017 John Wiley & Sons Ltd.

  13. Deletions at SLC18A1 increased the risk of CRC and lower SLC18A1 expression associated with poor CRC outcome.

    PubMed

    Zhang, Dandan; Li, Zhenli; Xu, Xiaohong; Zhou, Dan; Tang, Shunli; Yin, Xiaoyang; Xu, Fangying; Li, Hui; Zhou, Yuan; Zhu, Tao; Deng, Hong; Zhang, Shuai; Huang, Qiong; Wang, Jing; Yin, Wei; Zhu, Yimin; Lai, Maode

    2017-10-26

    Copy number variations (CNVs) contribute to the development of colorectal cancer (CRC). We conducted a two-stage association study to identify CNV risk loci for CRC. We performed a gene-based rare CNV study on 694 sporadic CRC and 1641 controls using Illumina Human-OmniExpress-12v1.0 BeadChips, and further replicated in 934 CRC cases and 2680 controls for risk CNVs by using TaqMan Copy Number Assay. Tumor buddings, cancer cells in the center of primary tumor and normal intestinal epithelial cells were captured using laser capture microdissection (LCM) and were assayed using AffymetrixGeneChip® Human Genome U133 Plus 2.0 Array. In addition, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus data were assessed for the effects of risk CNVs. We found that germline deletions affecting the last six exons of SLC18A1 significantly associated with CRC with a combined P value of 6.4 × 10-5 by a two-stage analysis. Both in TCGA CRC RNA seq dataset and GDS4382, SLC18A1 was significantly down regulated in CRC tissues than in paired normal tissues (N = 32 and 17 pairs, P = 0.004 and 0.009, respectively). In LCM samples, similar observations were obtained that the expression levels of SLC18A1 in the tumor buddings, cancer cells in the center of primary tumor, and stroma of both tumor budding and cancer cells were lower than normal intestinal epithelial and stromal cells (fold change = 0.17-0.62, 0.12-0.57 and 0.37-0.68, respectively). In summary, the germline deletions at SLC18A1 contributed to the development of CRC. The role of SLC18A1 required further exploration. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. HUMAN HtrA1 IN THE ARCHIVED EYES WITH AGE-RELATED MACULAR DEGENERATION

    PubMed Central

    Chan, Chi-Chao; Shen, Defen; Zhou, Min; Ross, Robert J.; Ding, Xiaoyan; Zhang, Kang; Green, W. Richard; Tuo, Jingsheng

    2007-01-01

    Purpose HtrA1 belongs to the high temperature requirement factor A family of serine proteases, which are involved in protein quality control and cell fate. A single-nucleotide polymorphism (SNP), rs11200638, in the promoter of HtrA1 at chromosome 10q26 is reported as a likely causal variant for age-related macular degeneration (AMD). The SNP is located in the regulatory region and increases production of HtrA1 protein. This study investigates HtrA1 expression and SNP genotypes in archived ocular slides with AMD. Methods Macular, nonretinal, and peripheral retinal cells were microdissected from archived slides from 57 eyes with AMD and 16 age-matched, non-AMD controls. HtrA1 rs11200638 SNP genotyping was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. HtrA1 transcripts were measured using real-time reverse transcriptase–PCR. HtrA1 protein expression was evaluated using avidin-biotin complex immunohistochemistry. Results HtrA1 (G/A) SNP was successfully genotyped in 52 AMD cases and 13 non-AMD subjects. The frequencies of the risk allele (A) were 55 of 104 (52.9%) and 8 of 26 (30.8%) in AMD and control groups, respectively. HtrA1 mRNA was detected in normal peripheral and macular retinas, higher in the periphery than maculae. HtrA1 mRNA was much higher in the macula and a lot lower in the periphery of the AMD eyes as compared to control eyes. HtrA1 protein was expressed in normal retinal vascular endothelia and retinal pigment epithelia. Intense immunoreaction against HtrA1 was found in AMD lesions, slightly more in wet than dry AMD lesions. Conclusion This study successfully analyzes HtrA1 SNP and transcript expression in microdissected cells from archived paraffin fixed slides. Up-regulation of HtrA1 is detected in the macular lesions of AMD eyes. The data further suggest that rs11200638 in HtrA1 promoter is associated with AMD development. PMID:18427598

  15. Organic Anion Transporting Polypeptide 1a1 Null Mice Are Sensitive to Cholestatic Liver Injury

    PubMed Central

    Zhang, Youcai; Csanaky, Iván L.; Cheng, Xingguo; Lehman-McKeeman, Lois D.; Klaassen, Curtis D.

    2012-01-01

    Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in livers of mice and is thought to transport bile acids (BAs) from blood into liver. Because Oatp1a1 expression is markedly decreased in mice after bile duct ligation (BDL). We hypothesized that Oatp1a1-null mice would be protected against liver injury during BDL-induced cholestasis due largely to reduced hepatic uptake of BAs. To evaluate this hypothesis, BDL surgeries were performed in both male wild-type (WT) and Oatp1a1-null mice. At 24 h after BDL, Oatp1a1-null mice showed higher serum alanine aminotransferase levels and more severe liver injury than WT mice, and all Oatp1a1-null mice died within 4 days after BDL, whereas all WT mice survived. At 24 h after BDL, surprisingly Oatp1a1-null mice had higher total BA concentrations in livers than WT mice, suggesting that loss of Oatp1a1 did not prevent BA accumulation in the liver. In addition, secondary BAs dramatically increased in serum of Oatp1a1-null BDL mice but not in WT BDL mice. Oatp1a1-null BDL mice had similar basolateral BA uptake (Na+-taurocholate cotransporting polypeptide and Oatp1b2) and BA-efflux (multidrug resistance–associated protein [Mrp]-3, Mrp4, and organic solute transporter α/β) transporters, as well as BA-synthetic enzyme (Cyp7a1) in livers as WT BDL mice. Hepatic expression of small heterodimer partner Cyp3a11, Cyp4a14, and Nqo1, which are target genes of farnesoid X receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor 2, respectively, were increased in WT BDL mice but not in Oatp1a1-null BDL mice. These results demonstrate that loss of Oatp1a1 function exacerbates cholestatic liver injury in mice and suggest that Oatp1a1 plays a unique role in liver adaptive responses to obstructive cholestasis. PMID:22461449

  16. Effects of COL8A1 on the proliferation of muscle-derived satellite cells.

    PubMed

    Li, Xiaofan; Wang, Zhao; Tong, Huili; Yan, Yunqin; Li, Shufeng

    2018-04-25

    Collagen type VIII alpha 1 chain (COL8A1) is a component of the extracellular matrix. Our previous studies suggested that COL8A1 is associated with the proliferation of muscle-derived satellite cells (MDSCs). Additionally, it has been demonstrated that COL8A1 promotes the proliferation of smooth muscle cells and liver cancer cells. Therefore, we predicted that COL8A1 is associated with the proliferation of bovine MDSCs, which have potential applications in research. In this study, we constructed vectors to activate and repress COL8A1 in bovine MDSCs using the CRISPR/Cas9 technique and determined the effects of COL8A1 modulation by EdU labeling, western blotting, and dual-luciferase reporter assays. The results showed that activation of COL8A1 increased the number of EdU-positive cells and expression of the proliferation markers cyclin B1 (CCNB1) and P-AKT. The expression of P-Akt was unchanged after addition of LY294002 (a protein kinase inhibitor capable of blocking the signal transduction pathway of the phosphoinositide 3-kinase). In contrast, repression of COL8A1 reduced the number of EdU-positive cells and expression of CCNB1 and P-AKT. We also observed upregulation and downregulation of COL8A1 following the overexpression and repression of EGR1, respectively. The dual-luciferase reporter assay revealed that EGR1 regulates the promoter activity of COL8A1. To our knowledge, this is the first study demonstrating that EGR1 positively regulates the expression of COL8A1, which in turn promotes the proliferation of bovine MDSCs via the PI3K/AKT signaling pathway. This article is protected by copyright. All rights reserved.

  17. Adenosine A1 receptors contribute to immune regulation after neonatal hypoxic ischemic brain injury.

    PubMed

    Winerdal, Max; Winerdal, Malin E; Wang, Ying-Qing; Fredholm, Bertil B; Winqvist, Ola; Ådén, Ulrika

    2016-03-01

    Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A1 receptor deficiency (A1R(-/-)) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A1R(-/-) mice displayed larger infarctions (+33%, p < 0.05) and performed worse in beam walking tests (44% more mistakes, p < 0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A1R(-/-) versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A1R(-/-). Also, A1R(-/-) B lymphocytes expressed less IL-10 than their WT counterparts, the A1R antagonist DPCPX decreased IL-10 expression whereas the A1R agonist CPA increased it. CD4(+) T lymphocytes including FoxP3(+) T regulatory cells, were unaffected by genotype, whereas CD8(+) T lymphocyte responses were smaller in A1R(-/-) mice. Using PCA to characterize the immune profile, we could discriminate the A1R(-/-) and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI.

  18. MAGE-A1 promotes melanoma proliferation and migration through C-JUN activation

    SciTech Connect

    Wang, Dong; The 309th Hospital of China People's Liberation Army, Beijing 100091; Wang, Junyun

    2016-05-13

    MAGE-A1 belongs to the chromosome X-clustered genes of cancer-testis antigen family and is normally expressed in the human germ line but is also overexpressed in various tumors. Previous studies of MAGE-A1 in melanoma mainly focused on methylation changes or its role in immunotherapy, however, its biological functions in melanoma have remained unknown. In order to determine the role of MAGE-A1 in melanoma growth and metastasis, we manipulated melanoma cell lines with overexpression and knockdown of MAGE-A1. Integration of cell proliferation assays, transwell migration and invasion assays, and RNA-Seq analysis revealed that up-regulation of MAGE-A1 dramatically promoted proliferation, migration, and invasionmore » of human melanoma cell lines in vitro, while down-regulation of MAGE-A1 inhibited those characteristics associated with tumor cells. Furthermore, transcriptome sequencing revealed that MAGE-A1 exerts its tumor promoting activity by activating p-C-JUN directly or through ERK-MAPK signaling pathways. Based on our findings, we propose that MAGE-A1 may be a potential therapeutic target for melanoma patients. - Highlights: • MAGE-A1 promotes proliferation and clone formation in melanoma cell lines. • MAGE-A1 enhances tumor cell migration and invasion in melanoma cell lines. • Network including C-JUN, IL8, and ARHGAP29 play critical role in malignant melanoma. • Oncogenic MAGE-A1 increases p-C-JUN levels, possibly via ERK-MAPK signaling pathway.« less

  19. Epigenetic Regulation of Vitamin D 24-Hydroxylase/CYP24A1 in Human Prostate Cancer

    PubMed Central

    Luo, Wei; Karpf, Adam R.; Deeb, Kristin K.; Muindi, Josephia R.; Morrison, Carl D.; Johnson, Candace S.; Trump, Donald L.

    2010-01-01

    Calcitriol, a regulator of calcium homeostasis with antitumor properties, is degraded by the product of the CYP24A1 gene which is downregulated in human prostate cancer by unknown mechanisms. We found that CYP24A1 expression is inversely correlated with promoter DNA methylation in prostate cancer cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) activates CYP24A1 expression in prostate cancer cells. In vitro methylation of the CYP24A1 promoter represses its promoter activity. Furthermore, inhibition of histone deacetylases by trichostatin A (TSA) enhances the expression of CYP24A1 in prostate cancer cells. ChIP-qPCR reveals that specific histone modifications are associated with the CYP24A1 promoter region. Treatment with TSA increases H3K9ac and H3K4me2 and simultaneously decreases H3K9me2 at the CYP24A1 promoter. ChIP-qPCR assay reveals that treatment with DAC and TSA increases the recruitment of VDR to the CYP24A1 promoter. RT-PCR analysis of paired human prostate samples reveals that CYP24A1 expression is down-regulated in prostate malignant lesions compared to adjacent histologically benign lesions. Bisulfite pyrosequencing shows that CYP24A1 gene is hypermethylated in malignant lesions compared to matched benign lesions. Our findings indicate that repression of CYP24A1 gene expression in human prostate cancer cells is mediated in part by promoter DNA methylation and repressive histone modifications. PMID:20587525

  20. 17 CFR 240.11a-1 - Regulation of floor trading.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Regulation of floor trading... Securities Exchange Act of 1934 Adoption of Floor Trading Regulation (rule 11a-1) § 240.11a-1 Regulation of floor trading. (a) No member of a national securities exchange, while on the floor of such exchange...

  1. COL1A1 promotes metastasis in colorectal cancer by regulating the WNT/PCP pathway

    PubMed Central

    Zhang, Zheying; Wang, Yongxia; Zhang, Jinghang; Zhong, Jiateng; Yang, Rui

    2018-01-01

    Colorectal cancer (CRC) is the third leading cause of cancer-associated mortality, and is a major health problem. Collagen type I α 1 (COL1A1) is a major component of collagen type I. Recently, it was reported to be overexpressed in a variety of tumor tissues and cells. However, the function of COL1A1 in CRC remains unclear. Herein, the present study demonstrated that COL1A1 was upregulated in CRC tissues and the paired lymph node tissues. Transwell assays showed that COL1A1 promoted CRC cell migration in vitro. Moreover, it was revealed that COL1A1 levels were correlated with those of WNT/planar cell polarity (PCP) signaling pathway genes; inhibition of COL1A1 decreased the expression levels of Ras-related C3 botulinum toxin substrate 1-GTP, phosphorylated-c-Jun N-terminal kinase, and RhoA-GTP, all of which are key genes in the WNT/PCP signaling pathway. These results may indicate the mechanisms underlying the oncogenic role of COL1A1 in CRC. In summary, the present data indicated that COL1A1 may serve as an oncoprotein, and that it may be used as a potential therapeutic target in CRC. PMID:29393423

  2. Novel structural features of xylanase A1 from Paenibacillus sp. JDR-2

    Treesearch

    Franz J. St John; James F. Preston; Edwin Pozharski

    2012-01-01

    The Gram-positive bacterium Paenibacillus sp. JDR-2 (PbJDR2) has been shown to have novel properties in the utilization of the abundant but chemically complex hemicellulosic sugar glucuronoxylan. Xylanase A1 of PbJDR2 (PbXynA1) has been implicated in an efficient process in which extracellular...

  3. 26 CFR 25.2523(a)-1 - Gift to spouse; in general.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Gift to spouse; in general. 25.2523(a)-1...) ESTATE AND GIFT TAXES GIFT TAX; GIFTS MADE AFTER DECEMBER 31, 1954 Deductions § 25.2523(a)-1 Gift to spouse; in general. (a) In general. In determining the amount of taxable gifts for the calendar quarter...

  4. 17 CFR 275.204A-1 - Investment adviser codes of ethics.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... ethics. 275.204A-1 Section 275.204A-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... codes of ethics. (a) Adoption of code of ethics. If you are an investment adviser registered or required... enforce a written code of ethics that, at a minimum, includes: (1) A standard (or standards) of business...

  5. 40 CFR Table A-1 to Subpart A of... - Global Warming Potentials

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 22 2013-07-01 2013-07-01 false Global Warming Potentials A Table A-1... A-1 to Subpart A of Part 98—Global Warming Potentials Global Warming Potentials [100-Year Time Horizon] Name CAS No. Chemical formula Global warming potential(100 yr.) Carbon dioxide 124-38-9 CO2 1...

  6. 40 CFR Table A-1 to Subpart A of... - Global Warming Potentials

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 21 2014-07-01 2014-07-01 false Global Warming Potentials A Table A-1... A-1 to Subpart A of Part 98—Global Warming Potentials Global Warming Potentials [100-Year Time Horizon] Name CAS No. Chemical formula Global warming potential(100 yr.) Carbon dioxide 124-38-9 CO2 1...

  7. Comparison of Technology Use between Biology and Physics Teachers in a 1:1 Laptop Environment

    ERIC Educational Resources Information Center

    Crook, Simon J.; Sharma, Manjula D.; Wilson, Rachel

    2015-01-01

    Using a mixed-methods approach the authors compared the associated practices of senior physics teachers (n = 7) and students (n = 53) in a 1:1 laptop environment with those of senior biology teachers (n = 10) and students (n = 125) also in a 1:1 laptop environment, in seven high schools in Sydney, NSW, Australia. They found that the physics…

  8. Association of CYP1A1 gene polymorphism with chronic kidney disease: a case control study.

    PubMed

    Siddarth, Manushi; Datta, Sudip K; Ahmed, Rafat S; Banerjee, Basu D; Kalra, Om P; Tripathi, Ashok K

    2013-07-01

    CYP1A1 is an important xenobiotic metabolizing enzyme, present in liver and kidney. Expression of CYP1A1 enzyme increases manifold when kidney cells are exposed to nephrotoxins/chemicals leading to oxidative stress-induced cell damage. To study the association of CYP1A1 gene polymorphism in patients of chronic kidney disease with unknown etiology (CKDU), we recruited 334 CKDU patients and 334 age and sex matched healthy controls. CYP1A1*2A and *2C polymorphisms were studied by PCR-RFLP and allele specific-PCR respectively. Subjects carrying at least one mutant allele of CYP1A1*2A (TC, CC) and *2C (AG, GG) were shown to be associated with 1.4-2-fold increased risk of CKDU. Also, genotypic combinations of hetero-/homozygous mutants of CYP1A1*2A (TC, CC) with hetero-/homozygous mutant genotypes of CYP1A1*2C (AG, GG) i.e. TC/AG (p<0.01), TC/GG (p<0.05), CC/AG (p<0.05) and CC/GG (p<0.01) were associated with CKDU with an odd ratio ranging 1.8-3.3 times approximately. This study demonstrates association of CYP1A1 polymorphisms with CKDU. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Characterization of Two Distinct Structural Classes of Selective Aldehyde Dehydrogenase 1A1 Inhibitors

    DOE PAGES

    Morgan, Cynthia A.; Hurley, Thomas D.

    2015-01-29

    Aldehyde dehydrogenases (ALDH) catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid. Alterations in ALDH1A1 activity are associated with such diverse diseases as cancer, Parkinson’s disease, obesity, and cataracts. Inhibitors of ALDH1A1 could aid in illuminating the role of this enzyme in disease processes. However, there are no commercially available selective inhibitors for ALDH1A1. Here we characterize two distinct chemical classes of inhibitors that are selective for human ALDH1A1 compared to eight other ALDH isoenzymes. The prototypical members of each structural class, CM026 and CM037, exhibit sub-micromolar inhibition constants, but have different mechanisms of inhibition. The crystal structuresmore » of these compounds bound to ALDH1A1 demonstrate that they bind within the aldehyde binding pocket of ALDH1A1 and exploit the presence of a unique Glycine residue to achieve their selectivity. Lastly, these two novel and selective ALDH1A1 inhibitors may serve as chemical tools to better understand the contributions of ALDH1A1 to normal biology and to disease states.« less

  10. 17 CFR 275.204A-1 - Investment adviser codes of ethics.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ethics. 275.204A-1 Section 275.204A-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... codes of ethics. (a) Adoption of code of ethics. If you are an investment adviser registered or required... enforce a written code of ethics that, at a minimum, includes: (1) A standard (or standards) of business...

  11. 40 CFR Appendix A1 to Subpart F of... - Generic Maximum Contaminant Levels

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 18 2012-07-01 2012-07-01 false Generic Maximum Contaminant Levels A1 Appendix A1 to Subpart F of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Recycling and Emissions Reduction Pt. 82...

  12. 40 CFR Appendix A1 to Subpart F of... - Generic Maximum Contaminant Levels

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 17 2010-07-01 2010-07-01 false Generic Maximum Contaminant Levels A1 Appendix A1 to Subpart F of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Recycling and Emissions Reduction Pt. 82...

  13. 40 CFR Appendix A1 to Subpart F of... - Generic Maximum Contaminant Levels

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 18 2013-07-01 2013-07-01 false Generic Maximum Contaminant Levels A1 Appendix A1 to Subpart F of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Recycling and Emissions Reduction Pt. 82...

  14. 40 CFR Appendix A1 to Subpart F of... - Generic Maximum Contaminant Levels

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 17 2011-07-01 2011-07-01 false Generic Maximum Contaminant Levels A1 Appendix A1 to Subpart F of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Recycling and Emissions Reduction Pt. 82...

  15. 40 CFR Appendix A1 to Subpart F of... - Generic Maximum Contaminant Levels

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 18 2014-07-01 2014-07-01 false Generic Maximum Contaminant Levels A1 Appendix A1 to Subpart F of Part 82 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Recycling and Emissions Reduction Pt. 82...

  16. 17 CFR 275.204A-1 - Investment adviser codes of ethics.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... ethics. 275.204A-1 Section 275.204A-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... codes of ethics. (a) Adoption of code of ethics. If you are an investment adviser registered or required... enforce a written code of ethics that, at a minimum, includes: (1) A standard (or standards) of business...

  17. 17 CFR 275.204A-1 - Investment adviser codes of ethics.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... ethics. 275.204A-1 Section 275.204A-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... codes of ethics. (a) Adoption of code of ethics. If you are an investment adviser registered or required... enforce a written code of ethics that, at a minimum, includes: (1) A standard (or standards) of business...

  18. 17 CFR 275.204A-1 - Investment adviser codes of ethics.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... ethics. 275.204A-1 Section 275.204A-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... codes of ethics. (a) Adoption of code of ethics. If you are an investment adviser registered or required... enforce a written code of ethics that, at a minimum, includes: (1) A standard (or standards) of business...

  19. 17 CFR 270.19a-1 - Written statement to accompany dividend payments by management companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... that an open-end company may treat as a separate source its net profits from such sales during its... specify the sources from which the remainder was paid. Every company which in any fiscal year elects to... dividend payments by management companies. 270.19a-1 Section 270.19a-1 Commodity and Securities Exchanges...

  20. 26 CFR 1.514(a)-1 - Unrelated debt-financed income and deductions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., and salary of $15,000 to the manager of the building. The debt/basis percentage for 1974 with respect....514(a)-1 Section 1.514(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... section 514 and § 1.514(b)-1) as an item of gross income derived from an unrelated trade or business the...

  1. 26 CFR 1.514(a)-1 - Unrelated debt-financed income and deductions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., and salary of $15,000 to the manager of the building. The debt/basis percentage for 1974 with respect....514(a)-1 Section 1.514(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... section 514 and § 1.514(b)-1) as an item of gross income derived from an unrelated trade or business the...

  2. 26 CFR 1.514(a)-1 - Unrelated debt-financed income and deductions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., and salary of $15,000 to the manager of the building. The debt/basis percentage for 1974 with respect....514(a)-1 Section 1.514(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... section 514 and § 1.514(b)-1) as an item of gross income derived from an unrelated trade or business the...

  3. 76 FR 56637 - Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-14

    ... Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines AGENCY: Federal Aviation... directive (AD) for certain model IO-720-A1B Lycoming Engines reciprocating engines. This AD requires a... crankshaft due to incorrect parts installed. We are issuing this AD to prevent engine crankshaft failure and...

  4. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy

    PubMed Central

    Alavi, Marcel V.; Mao, Mao; Pawlikowski, Bradley T.; Kvezereli, Manana; Duncan, Jacque L.; Libby, Richard T.; John, Simon W. M.; Gould, Douglas B.

    2016-01-01

    Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1+/Δex41mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes. PMID:26813606

  5. Cytochrome P450, CYP93A1, as a defense marker in soybean

    USDA-ARS?s Scientific Manuscript database

    CYP93A1 is a cytochrome P450 that is involved in the synthesis of the phytoalexin glyceollin in soybean (Glycine max L. Merr). The gene encoding CYP93A1 has been used as a defense marker in soybean cell cultures, however, little is known regarding how this gene is expressed in the intact plant. To f...

  6. Metrics Beyond Hemoglobin A1C in Diabetes Management: Time in Range, Hypoglycemia, and Other Parameters.

    PubMed

    Wright, Lorena Alarcon-Casas; Hirsch, Irl B

    2017-05-01

    We review clinical instances in which A1C should not be used and reflect on the use of other glucose metrics that can be used, in substitution of or in combination with A1C and SMBG, to tailor an individualized approach that will result in better outcomes and patient empowerment.

  7. 26 CFR 1.381(a)-1 - General rule relating to carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... corporate acquisitions. 1.381(a)-1 Section 1.381(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT...)-1 General rule relating to carryovers in certain corporate acquisitions. (a) Allowance of carryovers... requirements of section 354(b)(1)(A) and (B) are satisfied; and (v) A mere change in identity, form, or place...

  8. 26 CFR 1.381(a)-1 - General rule relating to carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... corporate acquisitions. 1.381(a)-1 Section 1.381(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT...)-1 General rule relating to carryovers in certain corporate acquisitions. (a) Allowance of carryovers... requirements of section 354(b)(1)(A) and (B) are satisfied; and (v) A mere change in identity, form, or place...

  9. 26 CFR 31.3121(a)(1)-1 - Annual wage limitation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Annual wage limitation. 31.3121(a)(1)-1 Section... § 31.3121(a)(1)-1 Annual wage limitation. (a) In general. (1) The term “wages” does not include that... for such calendar year (exclusive of remuneration excepted from wages in accordance with paragraph (j...

  10. 17 CFR 240.11a-1 - Regulation of floor trading.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Regulation of floor trading... Securities Exchange Act of 1934 Adoption of Floor Trading Regulation (rule 11a-1) § 240.11a-1 Regulation of floor trading. (a) No member of a national securities exchange, while on the floor of such exchange...

  11. 17 CFR 240.11a-1 - Regulation of floor trading.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Regulation of floor trading... Securities Exchange Act of 1934 Adoption of Floor Trading Regulation (rule 11a-1) § 240.11a-1 Regulation of floor trading. (a) No member of a national securities exchange, while on the floor of such exchange...

  12. 17 CFR 240.11a-1 - Regulation of floor trading.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Regulation of floor trading... Securities Exchange Act of 1934 Adoption of Floor Trading Regulation (rule 11a-1) § 240.11a-1 Regulation of floor trading. (a) No member of a national securities exchange, while on the floor of such exchange...

  13. A Chemical and Structural Study of the A1N-Si Interface

    NASA Technical Reports Server (NTRS)

    George, T.; Beye, R.

    1997-01-01

    Samples of A1N grown on silicon [111] subtrates were examined using electron enery loss spectroscopy (EELS) and selected area diffraction (SAD) with high-resolution transmission electron microscopy (TEM) to determine the source of out-of-place tilts and in-plane rotations of the A1N crystallites at the Si interface.

  14. 17 CFR 240.36a1-2 - Exemption from SIPA for OTC derivatives dealers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Exemption from SIPA for OTC derivatives dealers. 240.36a1-2 Section 240.36a1-2 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations...

  15. 42 CFR 65a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false To what programs do these regulations apply? 65a.1..., INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.1 To what programs do these regulations apply? (a) The regulations of this...

  16. 42 CFR 65a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false To what programs do these regulations apply? 65a.1..., INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.1 To what programs do these regulations apply? (a) The regulations of this...

  17. 42 CFR 65a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false To what programs do these regulations apply? 65a.1..., INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.1 To what programs do these regulations apply? (a) The regulations of this...

  18. Dynamic Regulation of FoxA1 by Steroid Receptors | Center for Cancer Research

    Cancer.gov

    The estrogen receptor (ER) is a key regulator in breast cancer initiation and progression. A widely discussed model proposes that forkhead box protein A1 (FoxA1) acts as a pioneer factor in cancer by binding and penetrating closed chromatin to allow access by transcription factors (TFs), including ER.

  19. 17 CFR 240.11a-1 - Regulation of floor trading.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Regulation of floor trading... Securities Exchange Act of 1934 Adoption of Floor Trading Regulation (rule 11a-1) § 240.11a-1 Regulation of floor trading. (a) No member of a national securities exchange, while on the floor of such exchange...

  20. 17 CFR 270.2a-1 - Valuation of portfolio securities in special cases.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Valuation of portfolio securities in special cases. 270.2a-1 Section 270.2a-1 Commodity and Securities Exchanges SECURITIES AND... of portfolio securities in special cases. (a) Any investment company whose securities are qualified...

  1. Enhanced tubuloglomerular feedback in mice with vascular overexpression of A1 adenosine receptors

    PubMed Central

    Oppermann, Mona; Qin, Yan; Lai, En Yin; Eisner, Christoph; Li, Lingli; Huang, Yuning; Mizel, Diane; Fryc, Justyna; Wilcox, Christopher S.; Briggs, Josephine; Schnermann, Jurgen

    2009-01-01

    Adenosine 1 receptors (A1AR) in the kidney are expressed in the vasculature and the tubular system. Pharmacological inhibition or global genetic deletion of A1AR causes marked reductions or abolishment of tubuloglomerular feedback (TGF) responses. To assess the function of vascular A1AR in TGF, we generated transgenic mouse lines in which A1AR expression in smooth muscle was augmented by placing A1AR under the control of a 5.38-kb fragment of the rat smooth muscle α-actin promoter and first intron (12). Two founder lines with highest expression in the kidney [353 ± 42 and 575 ± 43% compared with the wild type (WT)] were used in the experiments. Enhanced expression of A1AR at the expected site in these lines was confirmed by augmented constrictor responses of isolated afferent arterioles to administration of the A1AR agonist N6-cyclohexyladenosine. Maximum TGF responses (0–30 nl/min flow step) were increased from 8.4 ± 0.9 mmHg in WT (n = 21) to 14.2 ± 0.7 mmHg in A1AR-transgene (tg) 4 (n = 22; P < 0.0001), and to 12.6 ± 1.2 mmHg in A1AR-tg7 (n = 12; P < 0.02). Stepwise changes in perfusion flow caused greater numerical TGF responses in A1AR-tg than WT in all flow ranges with differences reaching levels of significance in the intermediate flow ranges of 7.5–10 and 10–15 nl/min. Proximal-distal single-nephron glomerular filtration rate (SNGFR) differences (free-flow micropuncture) were also increased in A1AR-tg, averaging 6.25 ± 1.5 nl/min compared with 2.6 ± 0.51 nl/min in WT (P = 0.034). Basal plasma renin concentrations as well as the suppression of renin secretion after volume expansion were similar in A1AR-tg and WT mice, suggesting lack of transgene expression in juxtaglomerular cells. These data indicate that A1AR expression in vascular smooth muscle cells is a critical component for TGF signaling and that changes in renal vascular A1AR expression may determine the magnitude of TGF responses. PMID:19741017

  2. Test of the multiquark structure of a1(1420 ) in strong two-body decays

    NASA Astrophysics Data System (ADS)

    Gutsche, Thomas; Ivanov, Mikhail A.; Körner, Jürgen G.; Lyubovitskij, Valery E.; Xu, Kai

    2017-12-01

    We present an analysis of strong two-body decays of the a1(1420 ) with JP C=1++ recently reported by the COMPASS Collaboration at CERN. Following the interpretation of the COMPASS Collaboration that the a1 is an unusual state with a four-quark q q ¯s s ¯ structure we consider two possible configurations for this state—hadronic molecular and color diquark-antidiquark structures. We find that the dominant decay mode of the a1 is the decay into K and K*. In particular, we calculate that the four decay modes a1→V P with V P =K*±K∓, K*0K¯0, K¯*0K0 together give a dominant contribution to the measured total width of about 150 MeV. The observational mode a1→f0(980 )+π0 is significantly suppressed by one order of magnitude.

  3. Unanticipated error in HbA(1c) measurement on the HLC-723 G7 analyzer.

    PubMed

    van den Ouweland, Johannes M W; de Keijzer, Marinus H; van Daal, Henny

    2010-04-01

    Investigation of falsely elevated HbA(1c) measurements on the HLC-723 G7 analyser. Comparison of HbA(1c) in blood samples that were diluted either in hemolysis reagent or water. HbA(1c) results became falsely elevated when samples were diluted in hemolysis reagent, but not in water. QC-procedures failed to detect this error as calibrator and QC samples were manually diluted in water, according to manufacturer's instructions, whereas patient samples were automatically diluted using hemolysing reagent. After replacement of the instruments' sample-loop and rotor seal comparable HbA(1c) results were obtained, irrespective of dilution with hemolysing reagent or water. This case illustrates the importance of treating calibrator and QC materials similar to routine patient samples in order to prevent unnoticed drift in patient HbA(1c) results. Copyright 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  4. Study on the DNA-protein crosslinks induced by chromium (VI) in SPC-A1

    NASA Astrophysics Data System (ADS)

    Liu, Yanqun; Ding, Jianjun; Lu, Xiongbing; You, Hao

    2018-01-01

    Objective: This study was designed to investigate the effect of chromium (VI) on DNA-protein crosslinks (DPC) of SPC-A1 cells. Methods: We exposed SPC-A1 cells were cultured in 1640 medium and treated with the SPC-A1 cells in vitro to different concentrations of Hexavalent chromium Cr(VI) for 2h, the KC1-SDS precipitation assay were used to measure the DNA-protein cross-linking effect. Results: All the different concentrations of Cr(VI) could cause the increase of DPC coefficient in SPC-A1 cells. But this effect was not significant (P>0.05) at low concentrations; while in high concentration Cr(VI) induced SPC-A1 cells could produce DNA-protein cross-linking effect significantly (P<0.05). Conclusions: chromium (VI) could induce DNA-protein crosslink.

  5. Apolipoprotein A-1-related amyloidosis 2 case reports and review of the literature.

    PubMed

    Lu, Chunlei; Zuo, Ke; Lu, Yinghui; Liang, Shaoshan; Huang, Xianghua; Zeng, Caihong; Zhang, Jiong; An, Yu; Wang, Jinquan

    2017-09-01

    Apolipoprotein A-1 (ApoA-1)-related amyloidosis is characterized by the deposition of ApoA-1 in various organs and can be either hereditary or nonhereditary. It is rare and easily misdiagnosed. Renal involvement is common in hereditary ApoA-1 amyloidosis, but rare in the nonhereditary form. We reported two cases with ApoA-1 amyloidosis, a 64-year-old man suffering from nephrotic syndrome and a 40-year-old man with nephrotic syndrome and splenomegaly. Renal biopsies revealed glomerular, interstitial and vascular amyloid deposits and positive phospholipase A2 receptor staining in the glomerular capillary loop in case 1, and mesangial amyloid deposits in case 2. After immunostaining failed to determine the specific amyloid protein, proteomic analysis of amyloid deposits by mass spectrometry was performed and demonstrated the ApoA-1 origin of the amyloid. Genetic testing revealed no mutation of the APOA1 gene in case 1 but a heterozygous mutation, Trp74Arg, in case 2. Case 1 was thus diagnosed as nonhereditary ApoA-1 associated renal amyloidosis with membranous nephropathy, and case 2 as hereditary ApoA-1 amyloidosis with multiorgan injuries (kidney and spleen) and a positive family history. Case 1 was treated with glucocorticoid combined with cyclosporine. Case 2 was treated with calcitriol and angiotensin converting enzyme inhibitors. Two cases were followed up for 5 months and 2 years, respectively; and case 1 was found to have attenuated proteinuria while case 2 had an elevation of cholestasis indices along with renal insufficiency. Proteomic analysis by mass spectrometry of the amyloid deposits combined with genetic analysis can provide accurate diagnosis of ApoA-1 amyloidosis. Besides, these 2 cases expand our knowledge of ApoA-1-related renal amyloidosis.

  6. Hypoglycemia Reduction and Changes in Hemoglobin A1c in the ASPIRE In-Home Study.

    PubMed

    Weiss, Ram; Garg, Satish K; Bode, Bruce W; Bailey, Timothy S; Ahmann, Andrew J; Schultz, Kenneth A; Welsh, John B; Shin, John J

    2015-08-01

    ASPIRE In-Home randomized 247 subjects with type 1 diabetes to sensor-augmented pump therapy with or without the Threshold Suspend (TS) feature, which interrupts insulin delivery at a preset sensor glucose value. We studied the effects of TS on nocturnal hypoglycemia (NH) in relation to baseline hemoglobin A1c (A1C) and change in A1C during the study. NH event rates and mean area under curve (AUC) of NH events were evaluated at different levels of baseline A1C (<7%, 7-8%, and >8%) and at different levels of changes in A1C (less than -0.3% [decreased], -0.3% to 0.3% [stable], and >0.3% [increased]), in the TS Group compared with the Control Group (sensor-augmented pump only). In the TS Group, 27.9% of the NH events were accompanied by a confirmatory blood glucose value, compared with 39.3% in the Control Group. Among subjects with baseline A1C levels of <7% or 7-8%, those in the TS Group had significantly lower NH event rates than those in the Control Group (P=0.001 and P=0.004, respectively). Among subjects with decreased or stable A1C levels, those in the TS Group had significantly lower NH event rates, and the events had lower AUCs (P≤0.001 for each). Among subjects with increased A1C levels, those in the TS Group had NH events with significantly lower AUCs (P<0.001). Use of the TS feature was associated with decreases in the rate and severity (as measured by AUC) of NH events in many subjects, including those with low baseline A1C levels and those whose A1C values decreased during the study period. Use of the TS feature can help protect against hypoglycemia in those wishing to intensify diabetes management to achieve target glucose levels.

  7. Structural and Functional Modifications of Corneal Crystallin ALDH3A1 by UVB Light

    PubMed Central

    Estey, Tia; Chen, Ying; Carpenter, John F.; Vasiliou, Vasilis

    2010-01-01

    As one of the most abundantly expressed proteins in the mammalian corneal epithelium, aldehyde dehydrogenase 3A1 (ALDH3A1) plays critical and multifaceted roles in protecting the cornea from oxidative stress. Recent studies have demonstrated that one protective mechanism of ALDH3A1 is the direct absorption of UV-energy, which reduces damage to other corneal proteins such as glucose-6-phosphate dehydrogenase through a competition mechanism. UV-exposure, however, leads to the inactivation of ALDH3A1 in such cases. In the current study, we demonstrate that UV-light caused soluble, non-native aggregation of ALDH3A1 due to both covalent and non-covalent interactions, and that the formation of the aggregates was responsible for the loss of ALDH3A1 enzymatic activity. Spectroscopic studies revealed that as a result of aggregation, the secondary and tertiary structure of ALDH3A1 were perturbed. LysC peptide mapping using MALDI-TOF mass spectrometry shows that UV-induced damage to ALDH3A1 also includes chemical modifications to Trp, Met, and Cys residues. Surprisingly, the conserved active site Cys of ALDH3A1 does not appear to be affected by UV-exposure; this residue remained intact after exposure to UV-light that rendered the enzyme completely inactive. Collectively, our data suggest that the UV-induced inactivation of ALDH3A1 is a result of non-native aggregation and associated structural changes rather than specific damage to the active site Cys. PMID:21203538

  8. Harman induces CYP1A1 enzyme through an aryl hydrocarbon receptor mechanism

    SciTech Connect

    El Gendy, Mohamed A.M.; El-Kadi, Ayman O.S., E-mail: aelkadi@pharmacy.ualberta.c

    Harman is a common compound in several foods, plants and beverages. Numerous studies have demonstrated its mutagenic, co-mutagenic and carcinogenic effects; however, the exact mechanism has not been fully identified. Aryl hydrocarbon receptor (AhR) is a transcription factor regulating the expression of the carcinogen-activating enzyme; cytochrome P450 1A1 (CYP1A1). In the present study, we examined the ability of harman to induce AhR-mediated signal transduction in human and rat hepatoma cells; HepG2 and H4IIE cells. Our results showed that harman significantly induced CYP1A1 mRNA in a time- and concentration-dependent manner. Similarly, harman significantly induced CYP1A1 at protein and activity levels inmore » a concentration-dependent manner. Moreover, the AhR antagonist, resveratrol, inhibited the increase in CYP1A1 activity by harman. The RNA polymerase inhibitor, actinomycin D, completely abolished the CYP1A1 mRNA induction by harman, indicating a transcriptional activation. The role of AhR in CYP1A1 induction by harman was confirmed by using siRNA specific for human AhR. The ability of harman to induce CYP1A1 was strongly correlated with its ability to stimulate AhR-dependent luciferase activity and electrophoretic mobility shift assay. At post-transcriptional and post-translational levels, harman did not affect the stability of CYP1A1 at the mRNA and the protein levels, excluding other mechanisms participating in the obtained effects. We concluded that harman can directly induce CYP1A1 gene expression in an AhR-dependent manner and may represent a novel mechanism by which harman promotes mutagenicity, co-mutagenicity and carcinogenicity.« less

  9. The changing relationship between HbA1c and FPG according to different FPG ranges.

    PubMed

    Guan, X; Zheng, L; Sun, G; Guo, X; Li, Y; Song, H; Tian, F; Sun, Y

    2016-05-01

    Since the American Diabetes Association included hemoglobin A1c (HbA1c) in the diagnostic criteria for diabetes in 2010, the clinical use of HbA1c has remained controversial. We explored the use of HbA1c for diagnosing diabetes and intermediate hyperglycemia in comparison with fasting plasma glucose (FPG). We screened 3710 adult subjects (mean age = 55.24 years) comprising 1704 males and 2006 females. We drew an receiver operating characteristic (ROC) curve to evaluate the ability of HbA1c to diagnose diabetes and intermediate hyperglycemia according to FPG. We used Kappa coefficient and Pearson's correlation coefficient to evaluate the relationship between HbA1c and FPG in different FPG ranges. The areas under ROC curve to diagnose diabetes and intermediate hyperglycemia were 0.859 (95 % CI 0.827-0.892) and 0.633 (95 % CI 0.615-0.651). The kappa coefficients between FPG and HbA1c for diagnosis of diabetes and intermediate hyperglycemia were 0.601 (P < 0.001) and 0.104 (P < 0.001). The Pearson's correlation coefficient of FPG and HbA1c was 0.640 (P < 0.001), but when we classified FPG as normal, intermediate hyperglycemia and diabetes, the coefficients became 0.07 (P = 0.002), 0.185 (P < 0.001) and 0.760 (P < 0.001), respectively. The relationship between HbA1c and FPG changed according to the different FPG ranges. When FPG was higher, the relationship was stronger. HbA1c and FPG were highly consistent in diagnosing diabetes, but they were not in predicting intermediate hyperglycemia.

  10. Trajectories of HbA1c Levels in Children and Youth with Type 1 Diabetes

    PubMed Central

    Pinhas-Hamiel, Orit; Hamiel, Uri; Boyko, Valentina; Graph-Barel, Chana; Reichman, Brian; Lerner-Geva, Liat

    2014-01-01

    Purpose To illustrate the distribution of Hemoglobin A1c (HbA1c) levels according to age and gender among children, adolescents and youth with type 1 diabetes (T1DM). Methods Consecutive HbA1c measurements of 349 patients, aged 2 to 30 years with T1DM were obtained from 1995 through 2010. Measurement from patients diagnosed with celiac disease (n = 20), eating disorders (n = 41) and hemoglobinopathy (n = 1) were excluded. The study sample comprised 4815 measurements of HbA1c from 287 patients. Regression percentiles of HbA1c were calculated as a function of age and gender by the quantile regression method using the SAS procedure QUANTREG. Results Crude percentiles of HbA1c as a function of age and gender, and the modeled curves produced using quantile regression showed good concordance. The curves show a decline in HbA1c levels from age 2 to 4 years at each percentile. Thereafter, there is a gradual increase during the prepubertal years with a peak at ages 12 to 14 years. HbA1c levels subsequently decline to the lowest values in the third decade. Curves of females and males followed closely, with females having HbA1c levels about 0.1% (1.1 mmol/mol) higher in the 25th 50th and 75th percentiles. Conclusion We constructed age-specific distribution curves for HbA1c levels for patients with T1DM. These percentiles may be used to demonstrate the individual patient's measurements longitudinally compared with age-matched patients. PMID:25275650

  11. hnRNP L regulates differences in expression of mouse integrin alpha2beta1.

    PubMed

    Cheli, Yann; Kunicki, Thomas J

    2006-06-01

    There is a 2-fold variation in platelet integrin alpha2beta1 levels among inbred mouse strains. Decreased alpha2beta1 in 4 strains carrying Itga2 haplotype 2 results from decreased affinity of heterogeneous ribonucleoprotein L (hnRNP L) for a 6 CA repeat sequence (CA6) within intron 1. Seven strains bearing haplotype 1 and a 21 CA repeat sequence at this position (CA21) express twice the level of platelet alpha2beta1 and exhibit an equivalent gain of platelet function in vitro. By UV crosslinking and immunoprecipitation, hnRNP L binds more avidly to CA21, relative to CA6. By cell-free, in vitro mRNA splicing, decreased binding of hnRNP L results in decreased splicing efficiency and an increased proportion of alternatively spliced product. The splicing enhancer activity of CA21 in vivo is abolished by prior treatment with hnRNP L-specific siRNA. Thus, decreased surface alpha2beta1 results from decreased Itga2 pre-mRNA splicing regulated by hnRNP L and depends on CA repeat length at a specific site in intron 1.

  12. hnRNP L regulates differences in expression of mouse integrin α2β1

    PubMed Central

    Cheli, Yann; Kunicki, Thomas J.

    2006-01-01

    There is a 2-fold variation in platelet integrin α2β1 levels among inbred mouse strains. Decreased α2β1 in 4 strains carrying Itga2 haplotype 2 results from decreased affinity of heterogeneous ribonucleoprotein L (hnRNP L) for a 6 CA repeat sequence (CA6) within intron 1. Seven strains bearing haplotype 1 and a 21 CA repeat sequence at this position (CA21) express twice the level of platelet α2β1 and exhibit an equivalent gain of platelet function in vitro. By UV crosslinking and immunoprecipitation, hnRNP L binds more avidly to CA21, relative to CA6. By cell-free, in vitro mRNA splicing, decreased binding of hnRNP L results in decreased splicing efficiency and an increased proportion of alternatively spliced product. The splicing enhancer activity of CA21 in vivo is abolished by prior treatment with hnRNP L–specific siRNA. Thus, decreased surface α2β1 results from decreased Itga2 pre-mRNA splicing regulated by hnRNP L and depends on CA repeat length at a specific site in intron 1. PMID:16455949

  13. Association of Intact dupA (dupA1) rather than dupA1 cluster with duodenal ulcer in Indian population.

    PubMed

    Alam, Jawed; Ghosh, Prachetash; Ganguly, Mou; Sarkar, Avijit; De, Ronita; Mukhopadhyay, Asish K

    2015-01-01

    The duodenal ulcer promoting gene (dupA) and dupA cluster in Helicobacter pylori have been described as a risk factor for duodenal ulcer development in some populations. Polymorphic gene dupA can be divided into two groups, intact dupA1 (long or short type based on the presence or absence of 615-bp extra sequences at the 5' region) having complete reading frame and other truncated dupA2 having frame-shift mutation. This study was aimed to elucidate the role of dupA of H. pylori and their clusters in the disease manifestation of Indian population. A total of 170 H. pylori strains were screened for the presence of dupA, dupA alleles and dupA cluster by PCR and sequencing. Pro-inflammatory cytokine (IL-8) with different dupA variant H. pylori stimulated gastric epithelial cells (AGS cells) was measured by ELISA. A total of 50 strains (29.4%) were positive for dupA among the tested 170 strains. The prevalence of dupA1 in duodenal ulcer (DU) and non-ulcer dyspepsia (NUD) populations was found to be 25.5% (25/98) and 11.1% (8/72), respectively and 16.4% (28/170) of the tested strains had dupA1, cagA and vacAs1m1 positive. The distribution of long and short type dupA1 has not been significantly associated with the disease outcome. The dupA cluster analysis showed that 10.2% (10/98) and 8.3% (6/72) strains were positive among DU and NUD, respectively. IL-8 production was significantly higher in dupA1(+) , cagA (+), vacA (+) (902.5 ± 79.01 pg/mL) than dupA2 (+) , cagA (+) , vacA (+) (536.0 ± 100.4 pg/mL, P = 0.008) and dupA (-), cagA (+), vacA (+) (549.7 ± 104.1 pg/mL, P = 0.009). Phylogenetic analysis of dupA indicated that the Indian H. pylori strains clustered with East Asian strains but distinct from Western strains. This is the first known genetic element of Indian H. pylori that is genetically closer to the East Asian strains but differed from the Western strains. The intact dupA1 was significantly associated with DU than NUD (P = 0

  14. Eukaryotic initiation factor 5A-1 (eIF5A-1) as a diagnostic marker for aberrant proliferation in intraepithelial neoplasia of the vulva.

    PubMed

    Cracchiolo, Bernadette M; Heller, Debra S; Clement, Paul M J; Wolff, Edith C; Park, Myung-Hee; Hanauske-Abel, Hartmut M

    2004-07-01

    The mature eukaryotic translation initiation factor 5A contains the unusual amino acid hypusine, formed post-translationally from a specific lysine residue and essential for proliferation of eukaryotic cells. We hypothesized that the major eIF5A isoform, eIF5A-1, is an in situ biomarker for proliferation. NIH-353, a polyclonal immunoreagent specific for hypusine-containing eIF5A-1, was used to test this proposal in biopsies of vulvar high-grade intraepithelial neoplasia (VIN), characterized by the presence of proliferating cells throughout the thickness of the epithelium. Methods. Formalin-fixed and paraffin-embedded archival samples with an independently established diagnosis of VIN 3 were stained immunohistochemically after antigen retrieval, employing NIH-353 and, for comparison, the standard Ki-67 antibody. NIH-353 labeled neoplastic keratinocytes throughout the thickness of the epithelium in all VIN 3 samples. Malignant cells in a case of focally invasive squamous cell carcinoma also stained strongly for mature, hypusine-containing eIF5A-1. Epithelium adjacent to these lesions, though still of apparently normal morphology, was immunoreactive throughout its full thickness. At inflammatory foci of lesional sites, solitary reactive lymphocytes were positive, as were individual proliferating cells within dermal appendages. The submucosal stroma lacked reactive cells. NIH-353 identifies mature eIF5A-1 as an in situ biomarker for proliferation. Like Ki-67, this immunoreagent promises broad applicability in histopathological diagnosis and may be helpful in outcome prediction. In contrast to Ki-67, NIH-353 visualizes a molecular target for antineoplastic therapy, and thus may guide the development and clinical testing of drugs that, like the fungicide ciclopirox, inhibit hypusine formation and cell proliferation.

  15. Is insulin the preferred treatment for HbA1c >9%?

    PubMed

    Bloomgarden, Zachary

    2017-09-01

    The algorithms and guidelines of the American Association of Clinical Endocrinologists and the American Diabetes Association recommend that insulin administration be strongly considered for people with type 2 diabetes (T2D) with HbA1c levels exceeding 9.0% and 10%, respectively. Although the caveat is given in both sets of recommendations that this is particularly appropriate when patients are "symptomatic," referring to urinary frequency with increased thirst and appetite, weight loss, and ketosis, the clinical definition of such presentations may be ill-defined, and it is noteworthy that both documents consider insulin to offer particular benefit under such circumstances. However, with multiple options for glycemic treatment, it is of interest to reconsider this argument for insulin use. It should be recalled that in the UK Prospective Diabetes Study, diet alone was associated with a reduction in HbA1c from 9% to 7%. Drug-naïve people with T2D do often show surprisingly strong reductions in HbA1c with metformin-based dual-agent oral treatment approaches; a recent report showed that even with baseline HbA1c >11%, the combination of metformin with a sulfonylurea, pioglitazone, or sitagliptin was associated with reduction in HbA1c from 11.6% to 6.0%. A 32-week study of the combination of rosiglitazone with metformin in patients with mean baseline HbA1c 8.9% showed a mean HbA1c reduction of 2.3%, and an open-label cohort with baseline HbA1c 11.8% had a reduction in HbA1c to 7.8%. With metformin plus sitagliptin, a mean placebo-adjusted HbA1c reduction of 2.1% from a baseline of 8.8% was reported, with those patients with baseline HbA1c >9% having a 2.6% reduction in HbA1c, and an open-label cohort with baseline HbA1c 11.2% having a 2.9% reduction in HbA1c. Similar 2% HbA1c reductions from baseline levels of 9.1% were seen with metformin in initial combination with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin. Although such dual oral agent

  16. Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains

    PubMed Central

    Rungaldier, Stefanie; Oberwagner, Walter; Salzer, Ulrich; Csaszar, Edina; Prohaska, Rainer

    2013-01-01

    The widely expressed, homo-oligomeric, lipid raft-associated, monotopic integral membrane protein stomatin and its homologues are known to interact with and modulate various ion channels and transporters. Stomatin is a major protein of the human erythrocyte membrane, where it associates with and modifies the glucose transporter GLUT1; however, previous attempts to purify hetero-oligomeric stomatin complexes for biochemical analysis have failed. Because lateral interactions of membrane proteins may be short-lived and unstable, we have used in situ chemical cross-linking of erythrocyte membranes to fix the stomatin complexes for subsequent purification by immunoaffinity chromatography. To further enrich stomatin, we prepared detergent-resistant membranes either before or after cross-linking. Mass spectrometry of the isolated, high molecular, cross-linked stomatin complexes revealed the major interaction partners as glucose transporter-1 (GLUT1), anion exchanger (band 3), and water channel (aquaporin-1). Moreover, ferroportin-1 (SLC40A1), urea transporter-1 (SLC14A1), nucleoside transporter (SLC29A1), the calcium-pump (Ca-ATPase-4), CD47, and flotillins were identified as stomatin-interacting proteins. These findings are in line with the hypothesis that stomatin plays a role as membrane-bound scaffolding protein modulating transport proteins. PMID:23219802

  17. Response of ELA-A1 horses immunized with lipopeptide containing an equine infectious anemia virus ELA-A1-restricted CTL epitope to virus challenge.

    PubMed

    Ridgely, Sherritta L; Zhang, Baoshan; McGuire, Travis C

    2003-01-17

    Lipopeptide containing an ELA-A1-restricted cytotoxic T lymphocyte (CTL) epitope from the envelope surface unit (SU) protein of the EIAV(WSU5) strain was used to immunize three horses having the ELA-A1 haplotype. Peptide-specific ELA-A1-restricted CTL were induced in all three horses, although these were present transiently in PBMC. These horses were further immunized with lipopeptide containing the corresponding CTL epitope from the EIAV(PV) strain. Then, the three immunized horses and three non-immunized horses were challenged by intravenous inoculation with 300 TCID(50) EIAV(PV). All horses developed cell free viremia, fever and thrombocytopenia. However, there was a statistically lower fever and thrombocytopenia severity score in the immunized group. Shorter duration of plasma viral load in two of the three immunized horses likely explains the less severe clinical disease in this group. Results indicate that lipopeptide immunization had a protective effect against development of clinical disease following virus challenge.

  18. Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains.

    PubMed

    Rungaldier, Stefanie; Oberwagner, Walter; Salzer, Ulrich; Csaszar, Edina; Prohaska, Rainer

    2013-03-01

    The widely expressed, homo-oligomeric, lipid raft-associated, monotopic integral membrane protein stomatin and its homologues are known to interact with and modulate various ion channels and transporters. Stomatin is a major protein of the human erythrocyte membrane, where it associates with and modifies the glucose transporter GLUT1; however, previous attempts to purify hetero-oligomeric stomatin complexes for biochemical analysis have failed. Because lateral interactions of membrane proteins may be short-lived and unstable, we have used in situ chemical cross-linking of erythrocyte membranes to fix the stomatin complexes for subsequent purification by immunoaffinity chromatography. To further enrich stomatin, we prepared detergent-resistant membranes either before or after cross-linking. Mass spectrometry of the isolated, high molecular, cross-linked stomatin complexes revealed the major interaction partners as glucose transporter-1 (GLUT1), anion exchanger (band 3), and water channel (aquaporin-1). Moreover, ferroportin-1 (SLC40A1), urea transporter-1 (SLC14A1), nucleoside transporter (SLC29A1), the calcium-pump (Ca-ATPase-4), CD47, and flotillins were identified as stomatin-interacting proteins. These findings are in line with the hypothesis that stomatin plays a role as membrane-bound scaffolding protein modulating transport proteins. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. [Detection of UGT1A1*28 Polymorphism Using Fragment Analysis].

    PubMed

    Huang, Ying; Su, Jian; Huang, Xiaosui; Lu, Danxia; Xie, Zhi; Yang, Suqing; Guo, Weibang; Lv, Zhiyi; Wu, Hongsui; Zhang, Xuchao

    2017-12-20

    Uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1), UGT1A1*28 polymorphism can reduce UGT1A1 enzymatic activity, which may lead to severe toxicities in patients who receive irinotecan. This study tries to build a fragment analysis method to detect UGT1A1*28 polymorphism. A total of 286 blood specimens from the lung cancer patients who were hospitalized in Guangdong General Hospital between April 2014 to May 2015 were detected UGT1A1*28 polymorphism by fragment analysis method. Comparing with Sanger sequencing, precision and accuracy of the fragment analysis method were 100%. Of the 286 patients, 236 (82.5% harbored TA6/6 genotype, 48 (16.8%) TA 6/7 genotype and 2 (0.7%) TA7/7 genotype. Our data suggest hat the fragment analysis method is robust for detecting UGT1A1*28 polymorphism in clinical practice. It's simple, time-saving, and easy-to-carry.

  20. Downregulation of Col1a1 induces differentiation in mouse spermatogonia

    PubMed Central

    Chen, Sun-Hong; Li, Ding; Xu, Chen

    2012-01-01

    Col1a1 (one of the subunit of collagen type I) is a collagen, which belongs to a family of extracellular matrix (ECM) proteins that play an important role in cellular proliferation and differentiation. However, the role of Col1a1 in spermatogenesis, especially in the control of proliferation and differentiation of spermatogonial stem cells (SSCs), remains unknown. In this study, we explored effects of downregulation of Col1a1 on differentiation and proliferation of mouse spermatogonia. Loss-of-function study revealed that Oct4 and Plzf, markers of SSC self-renewal, were significantly decreased, whereas the expression of c-kit and haprin, hallmarks of SSC differentiation, was enhanced after Col1a1 knockdown. Cell cycle analyses indicated that two-thirds of spermatogonia were arrested in S phase after Col1a1 knockdown. In vivo experiments, DNA injection and electroporation of the testes showed that spermatogonia self-renewal ability was impaired remarkably with the loss-of-function of Col1a1. Our data suggest that silencing of Col1a1 can suppress spermatogonia self-renewal and promote spermatogonia differentiation. PMID:23064687

  1. A Test in Context: Hemoglobin A1c and Cardiovascular Disease.

    PubMed

    Gore, M Odette; McGuire, Darren K

    2016-12-06

    Measurement of glycated hemoglobin (HbA 1c ), the most widely accepted indicator of long-term glycemic exposure, is central for the diagnosis and management of diabetes mellitus. Levels of HbA 1c track epidemiologically with diabetic complications, and glycemic control, as reflected by HbA 1c reduction, results in decreased risk of microvascular complications, including diabetic kidney disease, neuropathy, and retinopathy. The relationship between HbA 1c reduction and cardiovascular disease prevention in patients with diabetes is more complex, with data from large randomized trials published over the past decade providing clear evidence that lowering of HbA 1c per se is an inadequate marker for a therapeutic regimen's impact on cardiovascular outcomes and patient survival. Recent revisions in professional society guidelines moved away from uniform recommendations and toward a more nuanced, patient-centered approach to HbA 1c therapeutic targets. The context and key evidence underpinning these recent changes are discussed in this paper, alongside a brief overview of HbA 1c contemporary assays and their limitations. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  2. HbA1c is outcome predictor in diabetic patients with sepsis.

    PubMed

    Gornik, Ivan; Gornik, Olga; Gasparović, Vladimir

    2007-07-01

    We have investigated predictive value of HbA1c for hospital mortality and length of stay (LOS) in patients with type 2 diabetes admitted because of sepsis. A prospective observational study was implemented in a university hospital, 286 patients with type 2 diabetes admitted with sepsis were included. Leukocyte count, CRP, admission plasma glucose, APACHE II and SOFA score were noted at admission, HbA1c was measured on the first day following admission. Hospital mortality and hospital length of stay (LOS) were the outcome measures. Admission HbA1c was significantly lower in surviving patients than in non-survivors (median 8.2% versus 9.75%, respectively; P<0.001). There was a significant correlation between admission HbA1c and hospital LOS of surviving patients (r=0.29; P<0.001). Logistic regression showed that HbA1c is an independent predictor of hospital mortality (odds ratio 1.36), together with female sex (OR 2.24), APACHE II score (OR 1.08) and SOFA score (OR 1.28). Multiple regression showed that HbA1c and APACHE II score are independently related to hospital LOS. According to our results, HbA1c is an independent predictive factor for hospital mortality and hospital LOS of diabetic patients with sepsis.

  3. Hemoglobin A1c can be helpful in predicting progression to diabetes after Whipple procedure.

    PubMed

    Hamilton, Lisa; Jeyarajah, D Rohan

    2007-01-01

    Normoglycemic patients undergoing pancreaticoduodenectomy (Whipple procedure) often inquire whether they will be diabetic postoperatively. There is limited information on this issue. We therefore looked at a more subtle measurement of long-term glycemic control, hemoglobin A1c (HgbA1c), as a prognostic tool in predicting progression to diabetes post Whipple. A retrospective review over a 6-year period of all patients undergoing Whipple procedures at a single institution was conducted. In all, 27 patients had no prior history of diabetes, complete follow-up, and measured preoperative HgbA1c values. Postoperative diabetes was defined as the need for oral hypoglycemic agents or insulin. These charts were analyzed for progression to diabetes after Whipple. Of the 27 patients, 10 were considered to have postoperative diabetes. The average preoperative HgbA1c value for these patients was 6.3+/-0.66. This was statistically different from the 17 patients without postoperative diabetes (average HgbA1c 5.2+/-0.39, p<0.001). The positive predictive value, negative predictive value, sensitivity, and specificity were 82%, 94%, 90%, and 88%, respectively. This study demonstrates that progression to diabetes is very unlikely after Whipple operation if the preoperative HgbA1c value is in the normal range. The apparent utility of HgbA1c in predicting postoperative diabetes in this small study suggests that this laboratory test may be very helpful in counseling patients for Whipple operation.

  4. Functional Characterization of 5-Oxoproline Transport via SLC16A1/MCT1*

    PubMed Central

    Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

    2015-01-01

    Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H+) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na+-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H+-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. PMID:25371203

  5. Characterisation of a flavonoid ligand of the fungal protein Alt a 1

    PubMed Central

    Garrido-Arandia, María; Silva-Navas, Javier; Ramírez-Castillejo, Carmen; Cubells-Baeza, Nuria; Gómez-Casado, Cristina; Barber, Domingo; Pozo, Juan C.; Melendi, Pablo G.; Pacios, Luis F.; Díaz-Perales, Araceli

    2016-01-01

    Spores of pathogenic fungi are virtually ubiquitous and cause human disease and severe losses in crops. The endophytic fungi Alternaria species produce host-selective phytotoxins. Alt a 1 is a strongly allergenic protein found in A. alternata that causes severe asthma. Despite the well-established pathogenicity of Alt a 1, the molecular mechanisms underlying its action and physiological function remain largely unknown. To gain insight into the role played by this protein in the pathogenicity of the fungus, we studied production of Alt a 1 and its activity in spores. We found that Alt a 1 accumulates inside spores and that its release with a ligand is pH-dependent, with optimum production in the 5.0–6.5 interval. The Alt a 1 ligand was identified as a methylated flavonoid that inhibits plant root growth and detoxifies reactive oxygen species. We also found that Alt a 1 changes its oligomerization state depending on the pH of the surrounding medium and that these changes facilitate the release of the ligand. Based on these results, we propose that release of Alt a 1 should be a pathogenic target in approaches used to block plant defenses and consequently to favor fungal entry into the plant. PMID:27633190

  6. Characterisation of a flavonoid ligand of the fungal protein Alt a 1.

    PubMed

    Garrido-Arandia, María; Silva-Navas, Javier; Ramírez-Castillejo, Carmen; Cubells-Baeza, Nuria; Gómez-Casado, Cristina; Barber, Domingo; Pozo, Juan C; Melendi, Pablo G; Pacios, Luis F; Díaz-Perales, Araceli

    2016-09-16

    Spores of pathogenic fungi are virtually ubiquitous and cause human disease and severe losses in crops. The endophytic fungi Alternaria species produce host-selective phytotoxins. Alt a 1 is a strongly allergenic protein found in A. alternata that causes severe asthma. Despite the well-established pathogenicity of Alt a 1, the molecular mechanisms underlying its action and physiological function remain largely unknown. To gain insight into the role played by this protein in the pathogenicity of the fungus, we studied production of Alt a 1 and its activity in spores. We found that Alt a 1 accumulates inside spores and that its release with a ligand is pH-dependent, with optimum production in the 5.0-6.5 interval. The Alt a 1 ligand was identified as a methylated flavonoid that inhibits plant root growth and detoxifies reactive oxygen species. We also found that Alt a 1 changes its oligomerization state depending on the pH of the surrounding medium and that these changes facilitate the release of the ligand. Based on these results, we propose that release of Alt a 1 should be a pathogenic target in approaches used to block plant defenses and consequently to favor fungal entry into the plant.

  7. Functional characterization of 5-oxoproline transport via SLC16A1/MCT1.

    PubMed

    Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

    2015-01-23

    Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H (+)) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na(+)-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H(+)-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. 9-cis Retinoic Acid is the ALDH1A1 Product that Stimulates Melanogenesis

    PubMed Central

    Paterson, Elyse K.; Ho, Hsiang; Kapadia, Rubina; Ganesan, Anand K.

    2013-01-01

    Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyzes the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis, and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1A1 product all-trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9-cis retinal and its corresponding product 9-cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA, and melanin. ALDH1A1 depletion inhibited the ability of 9-cis retinal but not 9-cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalyzing the conversion of 9-cis retinal to 9-cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli’s salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9-cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9-cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo. PMID:23489423

  9. Effects of α-Thalassemia on HbA1c Measurement.

    PubMed

    Xu, Anping; Ji, Ling; Chen, Weidong; Xia, Yong; Zhou, Yu

    2016-11-01

    α-Thalassemia is a benign condition that is often present in patients with diabetes mellitus. Here, we evaluated the effects of different genotypes α-thalassemia on HbA 1c measurement. A total of 189 samples from nondiabetic patients were analyzed. HbA 1c analysis was performed by ion-exchange high-performance liquid chromatography, boronate affinity HPLC, immunoassay, and capillary electrophoresis. Fasting glucose, fructosamin, and HbA 2 were also performed. All samples were confirmed by genotyping for thalassemia. In patients with two or three functional α-genes, HbA 1c values were not significantly different from those of controls (P > 0.05); however, in individuals with α-thalassemia with one functional α-gene (i.e., HbH disease), HbA 1c levels were significantly different from those of controls (P < 0.01). HbA 1c values were significantly lower in individuals with HbH disease than in control individuals and patients in the other two α-thalassemia groups. For patients with HbH disease, there were no significant differences in the four HbA 1c measurement systems (P > 0.05). In this study, HbA 1c values in samples from individuals with two or three functional α-genes basically reflected the normal mean blood glucose level, while those in samples from individuals with one functional α-gene did not. © 2016 Wiley Periodicals, Inc.

  10. SULT1A1 copy number variation: ethnic distribution analysis in an Indian population.

    PubMed

    Almal, Suhani; Padh, Harish

    2017-11-01

    Cytosolic sulfotransferases (SULTs) are phase II detoxification enzymes involved in metabolism of numerous xenobiotics, drugs and endogenous compounds. Interindividual variation in sulfonation capacity is important for determining an individual's response to xenobiotics. SNPs in SULTs, mainly SULT1A1 have been associated with cancer risk and also with response to therapeutic agents. Copy number variation (CNVs) in SULT1A1 is found to be correlated with altered enzyme activity. This short report primarily focuses on CNV in SULT1A1 and its distribution among different ethnic populations around the globe. Frequency distribution of SULT1A1 copy number (CN) in 157 healthy Indian individuals was assessed using florescent-based quantitative PCR assay. A range of 1 to >4 copies, with a frequency of SULT1A1 CN =2 (64.9%) the highest, was observed in our (Indian) population. Upon comparative analysis of frequency distribution of SULT1A1 CN among diverse population groups, a statistically significant difference was observed between Indians (our data) and African-American (AA) (p = 0.0001) and South African (Tswana) (p < 0.0001) populations. Distribution of CNV in the Indian population was found to be similar to that in European-derived populations of American and Japanese. CNV of SULT1A1 varies significantly among world populations and may be one of the determinants of health and diseases.

  11. Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death.

    PubMed

    Almeida, Ana S; Soares, Nuno L; Vieira, Melissa; Gramsbergen, Jan Bert; Vieira, Helena L A

    2016-01-01

    Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO's improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO

  12. Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death

    PubMed Central

    Almeida, Ana S.; Soares, Nuno L.; Vieira, Melissa; Gramsbergen, Jan Bert

    2016-01-01

    Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO’s improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO

  13. Axial resonances a$$_{1}$$(1260), b$$_{1}$$(1235) and their decays from the lattice

    DOE PAGES

    Lang, C. B.; Leskovec, Luka; Mohler, Daniel; ...

    2014-04-28

    The light axial-vector resonancesmore » $$a_1(1260)$$ and $$b_1(1235)$$ are explored in Nf=2 lattice QCD by simulating the corresponding scattering channels $$\\rho\\pi$$ and $$\\omega\\pi$$. Interpolating fields $$\\bar{q} q$$ and $$\\rho\\pi$$ or $$\\omega\\pi$$ are used to extract the s-wave phase shifts for the first time. The $$\\rho$$ and $$\\omega$$ are treated as stable and we argue that this is justified in the considered energy range and for our parameters $$m_\\pi\\simeq 266~$$MeV and $$L\\simeq 2~$$fm. We neglect other channels that would be open when using physical masses in continuum. Assuming a resonance interpretation a Breit-Wigner fit to the phase shift gives the $$a_1(1260)$$ resonance mass $$m_{a1}^{res}=1.435(53)(^{+0}_{-109})$$ GeV compared to $$m_{a1}^{exp}=1.230(40)$$ GeV. The $$a_1$$ width $$\\Gamma_{a1}(s)=g^2 p/s$$ is parametrized in terms of the coupling and we obtain $$g_{a_1\\rho\\pi}=1.71(39)$$ GeV compared to $$g_{a_1\\rho\\pi}^{exp}=1.35(30)$$ GeV derived from $$\\Gamma_{a1}^{exp}=425(175)$$ MeV. In the $$b_1$$ channel, we find energy levels related to $$\\pi(0)\\omega(0)$$ and $$b_1(1235)$$, and the lowest level is found at $$E_1 \\gtrsim m_\\omega+m_\\pi$$ but is within uncertainty also compatible with an attractive interaction. Lastly, assuming the coupling $$g_{b_1\\omega\\pi}$$ extracted from the experimental width we estimate $$m_{b_1}^{res}=1.414(36)(^{+0}_{-83})$$.« less

  14. Inhibition of Prevotella and Capnocytophaga immunoglobulin A1 proteases by human serum.

    PubMed

    Frandsen, E V; Kjeldsen, M; Kilian, M

    1997-07-01

    Oral Prevotella and Capnocytophaga species, regularly isolated from periodontal pockets and associated with extraoral infections, secret specific immunoglobulin A1 (IgA1) proteases cleaving human IgA1 in the hinge region into intact Fab and Fc fragments. To investigate whether these enzymes are subject to inhibition in vivo in humans, we tested 34 sera from periodontally diseased and healthy individuals in an enzyme-linked immunosorbent assay for the presence and titers of inhibition of seven Prevotella and Capnocytophaga proteases. All or nearly all of the sera inhibited the IgA1 protease activity of Prevotella buccae, Prevotella oris, and Prevotella loescheii. A minor proportion of the sera inhibited Prevotella buccalis, Prevotella denticola, and Prevotella melaninogenica IgA1 proteases, while no sera inhibited Capnocytophaga ochracea IgA1 protease. All inhibition titers were low, ranging from 5 to 55, with titer being defined as the reciprocal of the dilution of serum causing 50% inhibition of one defined unit of protease activity. No correlation between periodontal disease status and the presence, absence, or titer of inhibition was observed. The nature of the low titers of inhibition in all sera of the IgA1 proteases of P. buccae, P. oris, and P. loescheii was further examined. In size exclusion chromatography, inhibitory activity corresponded to the peak volume of IgA. Additional inhibition of the P. oris IgA1 protease was found in fractions containing both IgA and IgG. Purification of the IgG fractions of five sera by passage of the sera on a protein G column resulted in recovery of inhibitory IgG antibodies against all three IgA1 proteases, with the highest titer being for the P. oris enzyme. These finding indicate that inhibitory activity is associated with enzyme-neutralizing antibodies.

  15. Inhibition of Prevotella and Capnocytophaga immunoglobulin A1 proteases by human serum.

    PubMed Central

    Frandsen, E V; Kjeldsen, M; Kilian, M

    1997-01-01

    Oral Prevotella and Capnocytophaga species, regularly isolated from periodontal pockets and associated with extraoral infections, secret specific immunoglobulin A1 (IgA1) proteases cleaving human IgA1 in the hinge region into intact Fab and Fc fragments. To investigate whether these enzymes are subject to inhibition in vivo in humans, we tested 34 sera from periodontally diseased and healthy individuals in an enzyme-linked immunosorbent assay for the presence and titers of inhibition of seven Prevotella and Capnocytophaga proteases. All or nearly all of the sera inhibited the IgA1 protease activity of Prevotella buccae, Prevotella oris, and Prevotella loescheii. A minor proportion of the sera inhibited Prevotella buccalis, Prevotella denticola, and Prevotella melaninogenica IgA1 proteases, while no sera inhibited Capnocytophaga ochracea IgA1 protease. All inhibition titers were low, ranging from 5 to 55, with titer being defined as the reciprocal of the dilution of serum causing 50% inhibition of one defined unit of protease activity. No correlation between periodontal disease status and the presence, absence, or titer of inhibition was observed. The nature of the low titers of inhibition in all sera of the IgA1 proteases of P. buccae, P. oris, and P. loescheii was further examined. In size exclusion chromatography, inhibitory activity corresponded to the peak volume of IgA. Additional inhibition of the P. oris IgA1 protease was found in fractions containing both IgA and IgG. Purification of the IgG fractions of five sera by passage of the sera on a protein G column resulted in recovery of inhibitory IgG antibodies against all three IgA1 proteases, with the highest titer being for the P. oris enzyme. These finding indicate that inhibitory activity is associated with enzyme-neutralizing antibodies. PMID:9220164

  16. The membrane-permeabilizing effect of avenacin A-1 involves the reorganization of bilayer cholesterol.

    PubMed Central

    Armah, C N; Mackie, A R; Roy, C; Price, K; Osbourn, A E; Bowyer, P; Ladha, S

    1999-01-01

    Avenacin A-1 is a member of a group of naturally occurring compounds called saponins. It is found in oat plants, where it protects against fungal pathogens. A combined electrical and optical chamber was used to determine the interaction of avenacin A-1 with Montal-Mueller planar lipid bilayers. This system allowed simultaneous measurement of the effect of avenacin A-1 on the fluorescence and lateral diffusion of a fluorescent lipid probe and permeability of the planar lipid bilayer. As expected, cholesterol was required for avenacin A-1-induced bilayer permeabilization. The planar lipid bilayers were also challenged with monodeglucosyl, bis-deglucosyl, and aglycone derivatives of avenacin A-1. The results show that the permeabilizing activity of the native avenacin A-1 was completely abolished after one, two, or all three sugar residues are hydrolyzed (monodeglucosyl, bis-deglucosyl, and aglycone derivatives, respectively). Fluorescence recovery after photobleaching (FRAP) measurements on cholesterol-containing planar lipid bilayers revealed that avenacin A-1 caused a small but significant reduction in the lateral diffusion of the phospholipid probe N-(7-nitrobenzoyl-2-oxa-1,3-diazol-4-yl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-PE). Similarly, with the sterol probe (22-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3beta-ol (NBD-Chol), avenacin A-1, but not its derivatives, caused a more pronounced reduction in the lateral diffusion than that observed with the phospholipid probe. The data indicate that an intact sugar moiety of avenacin A-1 is required to reorganize membrane cholesterol into pores. PMID:9876141

  17. Diagnostic accuracy of HbA1c in diabetes between Eastern and Western.

    PubMed

    Yan, Shuang; Liu, Siying; Zhao, Yashuang; Zhang, Wencui; Sun, Xiaohui; Li, Jianing; Jiang, Fuli; Ju, Jiaming; Lang, Ning; Zhang, Yingqi; Zhou, Weiyu; Li, Qiang

    2013-07-01

    In 2010, the American Diabetes Association recommended the use of HbA1c as a diagnostic criterion for diabetes. However, HbA1c is not an accepted diagnostic tool for diabetes in Eastern Asia, because genetic differences compromise the standardization of the diagnostic cut-off point. This study evaluated differences in the use of HbA1c for diagnosing diabetes in Eastern and Western populations and investigated whether HbA1c cut-off point of ≥ 6.5% is diagnostic of diabetes in patients from Eastern Asia. Literature was obtained from MEDLINE, EMBASE and Cochrane databases. The pooled sensitivity and specificity of each HbA1c cut-off point were extracted and compared between Western and Eastern populations. Differences in the cut-off point for diagnosing diabetes in each region were compared by examining differences in the area under summary receiver operating characteristic (SROC) curves. Twelve publications from Eastern countries (n = 59,735) and 13 from Western countries (n = 22,954) were included in the analysis. Areas under SROC curves in the Eastern and Western groups were 0.9331 and 0.9120, respectively (P = 0.98). The cut-off point of the highest Youden index was 6.0%. At the HbA1c cut-off point of 6.5%, the pooled sensitivity and specificity were 58.7% and 98.4% for Eastern countries and 65.5% and 98.1% for Western countries, respectively. HbA1c exhibits the same diagnostic value for diabetes in Eastern and Western populations. In both populations, HbA1c levels > 6.0% identify the population at high risk of diabetes, and HbA1c > 6.5% is diagnostic of clinically established diabetes. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

  18. Optimal Hemoglobin A1c Levels for Screening of Diabetes and Prediabetes in the Japanese Population.

    PubMed

    Shimodaira, Masanori; Okaniwa, Shinji; Hanyu, Norinao; Nakayama, Tomohiro

    2015-01-01

    The aim of this study was to evaluate the utility of hemoglobin A1c (HbA1c) to identify individuals with diabetes and prediabetes in the Japanese population. A total of 1372 individuals without known diabetes were selected for this study. A 75 g oral glucose tolerance test (OGTT) was used to diagnose diabetes and prediabetes. The ability of HbA1c to detect diabetes and prediabetes was investigated using receiver operating characteristic (ROC) analysis. The kappa (κ) coefficient was used to test the agreement between HbA1c categorization and OGTT-based diagnosis. ROC analysis demonstrated that HbA1c was a good test to identify diabetes and prediabetes, with areas under the curve of 0.918 and 0.714, respectively. Optimal HbA1c cutoffs for diagnosing diabetes and prediabetes were 6.0% (sensitivity 83.7%, specificity 87.6%) and 5.7% (sensitivity 60.6%, specificity 72.1%), respectively, although the cutoff for prediabetes showed low accuracy (67.6%) and a high false-negative rate (39.4%). Agreement between HbA1c categorization and OGTT-based diagnosis was low in diabetes (κ = 0.399) and prediabetes (κ = 0.324). In Japanese subjects, the HbA1c cutoff of 6.0% had appropriate sensitivity and specificity for diabetes screening, whereas the cutoff of 5.7% had modest sensitivity and specificity in identifying prediabetes. Thus, HbA1c may be inadequate as a screening tool for prediabetes.

  19. The transcription factor Lc-Maf participates in Col27a1 regulation during chondrocyte maturation

    SciTech Connect

    Mayo, Jaime L.; Holden, Devin N.; Barrow, Jeffery R.

    2009-08-01

    The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage undergoing endochondral ossification and participates in the regulation of type II collagen through a cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS) cells were transiently transfected with anmore » Lc-Maf expression plasmid, and quantitative RT-PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes. Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2 was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process of endochondral ossification by participating in the regulation of Col27a1 expression.« less

  20. The novel role of HtrA1 in gingivitis, chronic and aggressive periodontitis.

    PubMed

    Lorenzi, Teresa; Niţulescu, Elena Annabel; Zizzi, Antonio; Lorenzi, Maria; Paolinelli, Francesca; Aspriello, Simone Domenico; Baniţă, Monica; Crăiţoiu, Stefania; Goteri, Gaia; Barbatelli, Giorgio; Lombardi, Tommaso; Di Felice, Roberto; Marzioni, Daniela; Rubini, Corrado; Castellucci, Mario

    2014-01-01

    Proteolytic tissue degradation is a typical phenomenon in inflammatory periodontal diseases. HtrA1 (High temperature requirement A 1) has a serine protease activity and is able to degrade fibronectin whose fragments induce the expression and secretion of several matrix metalloproteinases (MMPs). The aim of this study was to investigate for the first time if HtrA1 has a role in gingivitis and in generalized forms of chronic and aggressive periodontitis. Expression of HtrA1 was investigated in 16 clinically healthy gingiva, 16 gingivitis, 14 generalized chronic periodontitis and 10 generalized aggressive periodontitis by immunohistochemistry and real-time PCR. Statistical comparisons were performed by the Kruskall-Wallis test. Significantly higher levels of HtrA1 mRNA and protein expression were observed in pathological respect to healthy tissues. In particular, we detected an increase of plasma cell HtrA1 immunostaining from gingivitis to chronic and aggressive periodontitis, with the higher intensity in aggressive disease. In addition, we observed the presence of HtrA1 in normal and pathological epithelium, with an increased expression, particularly in its superficial layer, associated with increasingly severe forms of periodontal disease. We can affirm that HtrA1 expression in plasma cells could be correlated with the destruction of pathological periodontal tissue, probably due to its ability to trigger the overproduction of MMPs and to increase the inflammatory mediators TNF-α and IL-1β by inhibition of TGF-β. Moreover, epithelial HtrA1 immunostaining suggests a participation of the molecule in the host inflammatory immune responses necessary for the control of periodontal infection.

  1. The Novel Role of HtrA1 in Gingivitis, Chronic and Aggressive Periodontitis

    PubMed Central

    Zizzi, Antonio; Lorenzi, Maria; Paolinelli, Francesca; Aspriello, Simone Domenico; Baniţă, Monica; Crăiţoiu, Ştefania; Goteri, Gaia; Barbatelli, Giorgio; Lombardi, Tommaso; Di Felice, Roberto; Marzioni, Daniela; Rubini, Corrado; Castellucci, Mario

    2014-01-01

    Proteolytic tissue degradation is a typical phenomenon in inflammatory periodontal diseases. HtrA1 (High temperature requirement A 1) has a serine protease activity and is able to degrade fibronectin whose fragments induce the expression and secretion of several matrix metalloproteinases (MMPs). The aim of this study was to investigate for the first time if HtrA1 has a role in gingivitis and in generalized forms of chronic and aggressive periodontitis. Expression of HtrA1 was investigated in 16 clinically healthy gingiva, 16 gingivitis, 14 generalized chronic periodontitis and 10 generalized aggressive periodontitis by immunohistochemistry and real-time PCR. Statistical comparisons were performed by the Kruskall-Wallis test. Significantly higher levels of HtrA1 mRNA and protein expression were observed in pathological respect to healthy tissues. In particular, we detected an increase of plasma cell HtrA1 immunostaining from gingivitis to chronic and aggressive periodontitis, with the higher intensity in aggressive disease. In addition, we observed the presence of HtrA1 in normal and pathological epithelium, with an increased expression, particularly in its superficial layer, associated with increasingly severe forms of periodontal disease. We can affirm that HtrA1 expression in plasma cells could be correlated with the destruction of pathological periodontal tissue, probably due to its ability to trigger the overproduction of MMPs and to increase the inflammatory mediators TNF-α and IL-1β by inhibition of TGF-β. Moreover, epithelial HtrA1 immunostaining suggests a participation of the molecule in the host inflammatory immune responses necessary for the control of periodontal infection. PMID:24979214

  2. Predictors of HbA1c levels in patients initiating metformin.

    PubMed

    Martono, Doti P; Hak, Eelko; Lambers Heerspink, Hiddo; Wilffert, Bob; Denig, Petra

    2016-12-01

    The aim was to assess demographic and clinical factors as predictors of short (6 months) and long term (18 months) HbA1c levels in diabetes patients initiating metformin treatment. We conducted a cohort study including type 2 diabetes patients who received their first metformin prescription between 2007 and 2013 in the Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) database. The primary outcome was HbA1c level at follow-up adjusted for baseline HbA1c; the secondary outcome was failing to achieve the target HbA1c level of 53 mmol/mol. Associations were analyzed by linear and logistic regression. Multiple imputation was used for missing data. Additional analyses stratified by dose and adherence level were conducted. The cohort included 6050 patients initiating metformin. Baseline HbA1c at target consistently predicted better HbA1c outcomes. Longer diabetes duration and lower total cholesterol level at baseline were predictors for higher HbA1c levels at 6 months. At 18 months, cholesterol level was not a predictor. Longer diabetes duration was also associated with not achieving the target HbA1c at follow-up. The association for longer diabetes duration was especially seen in patients starting on low dose treatment. No consistent associations were found for comorbidity and comedication. Diabetes duration was a relevant predictor of HbA1c levels after 6 and 18 months of follow-up in patients initiating metformin treatment. Given the study design, no causal inference can be made. Our study suggests that prompt treatment intensification may be needed in patients who have a longer diabetes duration at treatment initiation.

  3. Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer.

    PubMed

    Hiraki, Masayuki; Maeda, Takahiro; Mehrotra, Neha; Jin, Caining; Alam, Maroof; Bouillez, Audrey; Hata, Tsuyoshi; Tagde, Ashujit; Keating, Amy; Kharbanda, Surender; Singh, Harpal; Kufe, Donald

    2018-01-01

    B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial-mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1-C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti-apoptotic members of the BCL-2 family.

  4. Design, synthesis and biological evaluation of a bivalent micro opiate and adenosine A1 receptor antagonist.

    PubMed

    Mathew, Smitha C; Ghosh, Nandita; By, Youlet; Berthault, Aurélie; Virolleaud, Marie-Alice; Carrega, Louis; Chouraqui, Gaëlle; Commeiras, Laurent; Condo, Jocelyne; Attolini, Mireille; Gaudel-Siri, Anouk; Ruf, Jean; Parrain, Jean-Luc; Rodriguez, Jean; Guieu, Régis

    2009-12-01

    The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A(1) adenosine and mu opiate receptors with a K(i) of 0.8+/-0.05 and 0.7+/-0.03 microM, respectively. This hybrid molecule increases cAMP production in cells that over express the mu receptor as well as those over expressing the A(1) adenosine receptor and reverses the antalgic effects of mu and A(1) adenosine receptor agonists in animals.

  5. Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.

    PubMed

    Gale, Daniel P; Molyneux, Karen; Wimbury, David; Higgins, Patricia; Levine, Adam P; Caplin, Ben; Ferlin, Anna; Yin, Peiran; Nelson, Christopher P; Stanescu, Horia; Samani, Nilesh J; Kleta, Robert; Yu, Xueqing; Barratt, Jonathan

    2017-07-01

    IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O -glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in white and Chinese populations. Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. White patients with IgAN exhibited significantly higher Gd-IgA1 levels than did Chinese patients. Among individuals without IgAN, Gd-IgA1 levels did not correlate with kidney function. Gd-IgA1 level heritability (h 2 ), estimated by comparing midparental and offspring Gd-IgA1 levels, was 0.39. Genome-wide association analysis by linear regression identified alleles at a single locus spanning the C1GALT1 gene that strongly associated with Gd-IgA1 level ( β =0.26; P =2.35×10 -9 ). This association was replicated in a genome-wide association study of separate cohorts comprising 308 patients with membranous GN from the UK ( P <1.00×10 -6 ) and 622 controls with normal kidney function from the UK ( P <1.00×10 -10 ), and in a candidate gene study of 704 Chinese patients with IgAN ( P <1.00×10 -5 ). The same extended haplotype associated with elevated Gd-IgA1 levels in all cohorts studied. C1GALT1 encodes a galactosyltransferase enzyme that is important in O -galactosylation of glycoproteins. These findings demonstrate that common variation at C1GALT1 influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1 O -glycosylation may vary between white and Chinese patients with IgAN. Copyright © 2017 by the American Society of Nephrology.

  6. Mung bean decreases plasma cholesterol by up-regulation of CYP7A1.

    PubMed

    Yao, Yang; Hao, Liu; Shi, Zhenxing; Wang, Lixia; Cheng, Xuzhen; Wang, Suhua; Ren, Guixing

    2014-06-01

    Our results affirmed that supplementation of 1 or 2% mung bean could decrease plasma total cholesterol and triacylglycerol level. Mung bean increased mRNA 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. Most importantly, mung bean increased not only the protein level of cholesterol-7α-hydroxylase (CYP7A1) but also mRNA CYP7A1. It was concluded that the hypocholesterolemic activity of mung bean was most probable mediated by enhancement of bile acid excretion and up-regulation of CYP7A1.

  7. Impact of HbA1c Testing at Point of Care on Diabetes Management

    PubMed Central

    Schnell, Oliver; Crocker, J. Benjamin; Weng, Jianping

    2016-01-01

    Diabetes is a highly prevalent disease also implicated in the development of several other serious complications like cardiovascular or renal disease. HbA1c testing is a vital step for effective diabetes management, however, given the low compliance to testing frequency and, commonly, a subsequent delay in the corresponding treatment modification, HbA1c at the point of care (POC) offers an opportunity for improvement of diabetes care. In this review, based on data from 1999 to 2016, we summarize the evidence supporting a further implementation of HbA1c testing at POC, discuss its limitations and propose recommendations for further development. PMID:27898388

  8. 18. Yards & Docks Drawing 112,447 (463A1) (1931), 'Battery Overhaul ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. Yards & Docks Drawing 112,447 (463-A-1) (1931), 'Battery Overhaul Bldg., Acid Mixing Plant & Misc. Details' - Mare Island Naval Shipyard, Acid Mixing Facility, California Avenue & E Street, Vallejo, Solano County, CA

  9. 226. Early construction on section 2A1. This was the site ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    226. Early construction on section 2-A-1. This was the site of the first construction on the Blue Ride Parkway. - Blue Ridge Parkway, Between Shenandoah National Park & Great Smoky Mountains, Asheville, Buncombe County, NC

  10. Association of fibrinogen with HbA1C in diabetic foot ulcer

    NASA Astrophysics Data System (ADS)

    Pase, M. A.; Gatot, D.; Lindarto, D.

    2018-03-01

    Fibrinogen is one of the inflammatory markers of vascular changes and endothelial dysfunction in diabetic patients. The aim of this study to associate serum fibrinogen levels with HbA1C in diabetic foot ulcer (DFU). This study was cross-sectional and retrospective in DFU patients from January to July 2017 in Haji Adam Malik Central General Hospital. The patients enrolled in the study were T2DM with DFU as a complication. The grading of DFU was evaluated according to the Wagner’s Classification. Serum fibrinogen level, HbA1C and ankle-brachial index (ABI) were carried out directly in the patients. Fibrinogen serum levels were found significantly with HbA1C (P=0.001, r=0.387) and ABI (P=0.008, r=-0.454). Fibrinogen serum levels in DFU patients were positively correlated with HbA1C and significantly higher in patients with poor glycemic control.

  11. Annexin A1 influences in breast cancer: Controversies on contributions to tumour, host and immunoediting processes.

    PubMed

    Tu, Yan; Johnstone, Cameron N; Stewart, Alastair G

    2017-05-01

    Annexin A1 is a multifunctional protein characterised by its actions in modulating the innate and adaptive immune response. Accumulating evidence of altered annexin A1 expression in many human tumours raises interest in its functional role in cancer biology. In breast cancer, altered annexin A1 expression levels suggest a potential influence on tumorigenic and metastatic processes. However, reports of conflicting results reveal a relationship that is much more complex than first conceptualised. In this review, we explore the diverse actions of annexin A1 on breast tumour cells and various host cell types, including stromal immune and structural cells, particularly in the context of cancer immunoediting. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. 26 CFR 48.4062(a)-1 - Specific parts or accessories.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., and Taxable Fuel Automotive and Related Items § 48.4062(a)-1 Specific parts or accessories. Spark plugs, storage batteries, leaf springs, coils, timers, and tire chains, which are suitable for use on or...

  13. Draft Genome Sequence of Magnesium-Dissolving Lactococcus garvieae A1, Isolated from Soil

    PubMed Central

    Altın, Gonca; Şahin, Fikrettin

    2017-01-01

    ABSTRACT The probiotic bacterium Lactococcus garvieae A1, isolated from soil, is interesting for biomining applications. Here, we report the draft genome sequence and annotation of this strain, with a focus on metal transporter enzymes. PMID:28546485

  14. 29. OUTLET WORKS: GENERAL PLAN AND SECTIONS. Sheet A1, date ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    29. OUTLET WORKS: GENERAL PLAN AND SECTIONS. Sheet A-1, date stamped January, 1939. File no. SA 949/80. - Prado Dam, Outlet Works, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

  15. 17 CFR 240.17a-1 - Recordkeeping rule for national securities exchanges, national securities associations...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... national securities exchanges, national securities associations, registered clearing agencies and the... Certain Stabilizing Activities § 240.17a-1 Recordkeeping rule for national securities exchanges, national...) Every national securities exchange, national securities association, registered clearing agency and the...

  16. O2(a1Δ) vibrational kinetics in oxygen-iodine laser

    NASA Astrophysics Data System (ADS)

    Torbin, A. P.; Pershin, A. A.; Heaven, M. C.; Azyazov, V. N.; Mebel, A. M.

    2018-04-01

    Kinetics of vibrationally-excited singlet oxygen O2(a1Δ,ν) in gas mixture O3/N2/CO2 was studied using a pulse laser technique. Molecules O2(a1Δ,ν) were produced by laser photolysis of ozone at 266 nm. The O3 molecules number density was followed using time-resolved absorption spectroscopy. It was found that an upper bound for the rate constant of chemical reaction O2(a1Δ,ν)+ O3 is about 10-15 cm3/s. The rate constants of O2(a1Δ,ν= 1, 2 and 3) quenching by CO2 are presented.

  17. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals.

    PubMed

    Domenice, Sorahia; Machado, Aline Zamboni; Ferreira, Frederico Moraes; Ferraz-de-Souza, Bruno; Lerario, Antonio Marcondes; Lin, Lin; Nishi, Mirian Yumie; Gomes, Nathalia Lisboa; da Silva, Thatiana Evelin; Silva, Rosana Barbosa; Correa, Rafaela Vieira; Montenegro, Luciana Ribeiro; Narciso, Amanda; Costa, Elaine Maria Frade; Achermann, John C; Mendonca, Berenice Bilharinho

    2016-12-01

    Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction

  18. HbA1c Identifies Subjects With Prediabetes and Subclinical Left Ventricular Diastolic Dysfunction.

    PubMed

    Di Pino, Antonino; Mangiafico, Sarah; Urbano, Francesca; Scicali, Roberto; Scandura, Salvatore; D'Agate, Veronica; Piro, Salvatore; Tamburino, Corrado; Purrello, Francesco; Rabuazzo, Agata Maria

    2017-10-01

    Prediabetes is associated with subclinical cardiac changes associated with heart failure development. We investigated diastolic function and its association with markers of glycation and inflammation related to cardiovascular disease in patients with prediabetes. We focused on individuals with prediabetes identified only by glycated hemoglobin A1c [HbA1c; 5.7% to 6.4% and normal fasting glucose (NFG) and normal glucose tolerance (NGT) after an oral glucose tolerance test (OGTT)]. Cross-sectional study. Departments of Clinical and Experimental Medicine and Cardiology, University of Catania, Catania, Italy. HbA1c, OGTT, Doppler echocardiography, soluble receptor for advanced glycation end products (sRAGEs), and endogenous secretory RAGE (esRAGE) were evaluated. We recruited 167 subjects with NFG/NGT who were stratified according to HbA1c level: controls (HbA1c <5.7%) and HbA1c prediabetes (HbA1c 5.7% to 6.4%). Patients with HbA1c prediabetes (n = 106) showed a lower peak mitral inflow in early diastole (E wave) to late diastolic atrial filling velocity (A wave) ratio (E/A ratio) than controls (n = 61) (1.10 ± 0.24 vs 1.18 ± 0.23; P < 0.05). They showed a higher left atrium volume (LAV) (28.4 ± 5 vs 22.1 ± 3; P < 0.05) and sphericity index (SI) (0.6 ± 0.06 vs 0.5 ± 0.05; P < 0.05). After multiple regression analyses, HbA1c, sRAGE, and esRAGE were the major determinants of E/A ratio, LAV, and SI. Subjects with HbA1c prediabetes exhibited subclinical cardiac alterations associated with sRAGE, esRAGE, and HbA1c. These subjects would not have been classified as having prediabetes on the basis of fasting glycemia or post-OGTT values. Copyright © 2017 Endocrine Society

  19. Maternal obesity alters feto-placental Cytochrome P4501A1 activity

    PubMed Central

    DuBois, Barent N.; O’Tierney, Perrie; Pearson, Jacob; Friedman, Jacob E.; Thornburg, Kent; Cherala, Ganesh

    2012-01-01

    Cytochrome P4501A1 (CYP1A1), an important drug metabolizing enzyme, is expressed in human placenta throughout gestation as well as in fetal liver. Obesity, a chronic inflammatory condition, is known to alter CYP enzyme expression in non-placental tissues. In the present study, we test the hypothesis that maternal obesity alters the distribution of CYP1A1 activity in feto-placental unit. Placentas were collected from non-obese (BMI<30) and obese (BMI>30) women at term. Livers were collected from gestation day 130 fetuses of non-human primates fed either control diet or high-fat diet (HFD). Cytosol and microsomes were collected using differential centrifugation, and incubated with 7-Ethoxyresorufin. The CYP1A1 specific activity (pmoles of resorufin formed/min/mg of protein) was measured at excitation/emission wavelength of 530/590nm. Placentas of obese women had significantly reduced microsomal CYP1A1 activity compared to non-obese women (0.046 vs. 0.082; p<0.05); however no such effect was observed on cytosolic activity. Similarly, fetal liver from HFD fed mothers had significantly reduced microsomal CYP1A1 activity (0.44±0.04 vs. 0.20±0.10; p<0.05), with no significant difference in cytosolic CYP1A1 activity (control, 1.23±0.20; HFD, 0.80±0.40). Interestingly, multiple linear regression analyses of placental efficiency indicates cytosolic CYP1A1 activity is a main effect (5.67±2.32 (β±SEM); p=0.022) along with BMI (−0.57±0.26; p=0.037), fetal gender (1.07±0.26; p<0.001), and maternal age (0.07±0.03; p=0.011). In summary, while maternal obesity affects microsomal CYP1A1 activity alone, cytosolic activity along with maternal BMI is an important determinant of placental efficiency. Together, these data suggest that maternal lifestyle could have a significant impact on CYP1A1 activity, and hints at a possible role for CYP1A1 in feto-placental growth and thereby well-being of fetus. PMID:23046808

  20. Control of alternative splicing by forskolin through hnRNP K during neuronal differentiation.

    PubMed

    Cao, Wenguang; Razanau, Aleh; Feng, Dairong; Lobo, Vincent G; Xie, Jiuyong

    2012-09-01

    The molecular basis of cell signal-regulated alternative splicing at the 3' splice site remains largely unknown. We isolated a protein kinase A-responsive ribonucleic acid (RNA) element from a 3' splice site of the synaptosomal-associated protein 25 (Snap25) gene for forskolin-inhibited splicing during neuronal differentiation of rat pheochromocytoma PC12 cells. The element binds specifically to heterogeneous nuclear ribonucleo protein (hnRNP) K in a phosphatase-sensitive way, which directly competes with the U2 auxiliary factor U2AF65, an essential component of early spliceosomes. Transcripts with similarly localized hnRNP K target motifs upstream of alternative exons are enriched in genes often associated with neurological diseases. We show that such motifs upstream of the Runx1 exon 6 also bind hnRNP K, and importantly, hnRNP K is required for forskolin-induced repression of the exon. Interestingly, this exon encodes the peptide domain that determines the switch of the transcriptional repressor/activator activity of Runx1, a change known to be critical in specifying neuron lineages. Consistent with an important role of the target genes in neurons, knocking down hnRNP K severely disrupts forskolin-induced neurite growth. Thus, through hnRNP K, the neuronal differentiation stimulus forskolin targets a critical 3' splice site component of the splicing machinery to control alternative splicing of crucial genes. This also provides a regulated direct competitor of U2AF65 for cell signal control of 3' splice site usage.

  1. Control of alternative splicing by forskolin through hnRNP K during neuronal differentiation

    PubMed Central

    Cao, Wenguang; Razanau, Aleh; Feng, Dairong; Lobo, Vincent G.; Xie, Jiuyong

    2012-01-01

    The molecular basis of cell signal-regulated alternative splicing at the 3′ splice site remains largely unknown. We isolated a protein kinase A-responsive ribonucleic acid (RNA) element from a 3′ splice site of the synaptosomal-associated protein 25 (Snap25) gene for forskolin-inhibited splicing during neuronal differentiation of rat pheochromocytoma PC12 cells. The element binds specifically to heterogeneous nuclear ribonucleo protein (hnRNP) K in a phosphatase-sensitive way, which directly competes with the U2 auxiliary factor U2AF65, an essential component of early spliceosomes. Transcripts with similarly localized hnRNP K target motifs upstream of alternative exons are enriched in genes often associated with neurological diseases. We show that such motifs upstream of the Runx1 exon 6 also bind hnRNP K, and importantly, hnRNP K is required for forskolin-induced repression of the exon. Interestingly, this exon encodes the peptide domain that determines the switch of the transcriptional repressor/activator activity of Runx1, a change known to be critical in specifying neuron lineages. Consistent with an important role of the target genes in neurons, knocking down hnRNP K severely disrupts forskolin-induced neurite growth. Thus, through hnRNP K, the neuronal differentiation stimulus forskolin targets a critical 3′ splice site component of the splicing machinery to control alternative splicing of crucial genes. This also provides a regulated direct competitor of U2AF65 for cell signal control of 3′ splice site usage. PMID:22684629

  2. Renner-Teller quantum dynamics of NH(a(1)Delta) + H reactions on the NH(2) A(2)A(1) and X(2)B(1) coupled surfaces.

    PubMed

    Defazio, P; Gamallo, P; González, M; Petrongolo, C

    2010-09-16

    Four reactions NH(a1Delta) + H′(2S) are investigated by the quantum mechanical real wavepacket method, taking into account nonadiabatic Renner-Teller (RT) and rovibronic Coriolis couplings between the involved states. We consider depletion (d) to N(2D) + H2(X1Sigmag+), exchange (e) to NH′(a1Delta) + H(2S), quenching (q) to NH(X3Sigma-) + H′(2S), and exchange-quenching (eq) to NH′(X3Sigma-) + H(2S). We extend our RT theory to a general AB + C collision using a geometry-dependent but very simple and empirical RT matrix element. Reaction probabilities, cross sections, and rate constants are presented, and RT results are compared with Born-Oppenheimer (BO), experimental, and semiclassical data. The nonadiabatic couplings open two new channels, (q) and (eq), and increase the (d) and (e) reactivity with respect to the BO one, when NH(a1Delta) is rotationally excited. In this case, the quantum cross sections are larger than the semiclassical ones at low collision energies. The calculated rate constants at 300 K are k(d) = 3.06, k(e) = 3.32, k(q) = 1.44, and k(eq) = 1.70 in 10(-11) cm3 s(-1) compared with the measured values k(d) = (3.2 =/- 1.7), k(q + eq) = (1.7 +/- 0.3), and k(total) = (4.8 +/- 1.7). The theoretical depletion rate is thus in good agreement with the experimental value, but the quenching and total rates are overestimated, because the present RT couplings are too large. This discrepancy is probably due to our simple and empirical RT matrix element.

  3. Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR.

    PubMed

    Manzella, Christopher; Singhal, Megha; Alrefai, Waddah A; Saksena, Seema; Dudeja, Pradeep K; Gill, Ravinder K

    2018-04-17

    Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We tested the hypothesis that serotonin (5-HT) is an endogenous activator of AhR in intestinal epithelial cells. Treatment of Caco-2 monolayers with 5-HT induced CYP1A1 mRNA in a time- and concentration-dependent manner and also stimulated CYP1A1 activity. CYP1A1 induction by 5-HT was dependent upon uptake via serotonin transporter (SERT). Antagonism of AhR and knockdown of AhR and its binding partner aryl hydrocarbon receptor nuclear translocator (ARNT) attenuated CYP1A1 induction by 5-HT. Activation of AhR was evident by its nuclear translocation after 5-HT treatment and by induction of an AhR-responsive luciferase reporter. In vivo studies showed a dramatic decrease in CYP1A1 expression and other AhR target genes in SERT KO ileal mucosa by microarray analysis. These results suggest that intracellular accumulation of 5-HT via SERT induces CYP1A1 expression via AhR in intestinal epithelial cells, and SERT deficiency in vivo impairs activation of AhR. Our studies provide a novel link between the serotonergic and AhR pathways which has implications in xenobiotic metabolism and intestinal inflammation.

  4. 40 CFR Table A-1 to Subpart A of... - Global Warming Potentials

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 22 2012-07-01 2012-07-01 false Global Warming Potentials A Table A-1... A-1 to Subpart A of Part 98—Global Warming Potentials [100-Year Time Horizon] Name CAS No. Chemical formula Global warming potential(100 yr.) Carbon dioxide 124-38-9 CO2 1 Methane 74-82-8 CH4 21 Nitrous...

  5. Is the COL5A1 rs12722 gene polymorphism associated with running economy?

    PubMed

    Bertuzzi, Rômulo; Pasqua, Leonardo A; Bueno, Salomão; Lima-Silva, Adriano Eduardo; Matsuda, Monique; Marquezini, Monica; Saldiva, Paulo H

    2014-01-01

    The COL5A1 rs12722 polymorphism is considered to be a novel genetic marker for endurance running performance. It has been postulated that COL5A1 rs12722 may influence the elasticity of tendons and the energetic cost of running. To date, there are no experimental data in the literature supporting the relationship between range of motion, running economy, and the COL5A1 rs12722 gene polymorphism. Therefore, the main purpose of the current study was to analyze the influence of the COL5A1rs12722 polymorphism on running economy and range of motion. One hundred and fifty (n = 150) physically active young men performed the following tests: a) a maximal incremental treadmill test, b) two constant-speed running tests (10 km · h(-1)) and 12 km · h(-1)) to determine the running economy, and c) a sit-and-reach test to determine the range of motion. All of the subjects were genotyped for the COL5A1 rs12722 single-nucleotide polymorphism. The genotype frequencies were TT = 27.9%, CT = 55.8%, and CC = 16.3%. There were no significant differences between COL5A1 genotypes for running economy measured at 10 km · h(-1) (p = 0.232) and 12 km · h(-1) (p = 0.259). Similarly, there were no significant differences between COL5A1 genotypes for range of motion (p = 0.337). These findings suggest that the previous relationship reported between COL5A1 rs12722 genotypes and running endurance performance might not be mediated by the energetic cost of running.

  6. A novel research model for evaluating sunscreen protection in the UV-A1.

    PubMed

    Figueiredo, Sônia Aparecida; de Moraes, Dayane Cristina; Vilela, Fernanda Maria Pinto; de Faria, Amanda Natalina; Dos Santos, Marcelo Henrique; Fonseca, Maria José Vieira

    2018-01-01

    The use of a broad spectrum sunscreen is considered one of the main and most popular measures for preventing the damaging effects of ultraviolet radiation (UVR) on the skin. In this study we have developed a novel in vitro method to assess sunscreens efficacy to protect calcineurin enzyme activity, a skin cell marker. The photoprotective efficacy of sunscreen products was assessed by measuring the UV-A1 radiation-induced depletion of calcineurin (Cn) enzyme activity in primary neonatal human dermal fibroblast (HDFn) cell lysates. After exposure to 24J/cm 2 UV-A1 radiation, the sunscreens containing larger amounts of UV-A1 filters (brand B), the astaxanthin (UV-A1 absorber) and the Tinosorb® M (UV-A1 absorber) were capable of preventing loss of Cn activity when compared to the sunscreens formulations of brand A (low concentration of UV-A1 filters), with the Garcinia brasiliensis extract (UV-B absorber) and with the unprotected cell lysate and exposed to irradiation (Irradiated Control - IC). The Cn activity assay is a reproducible, accurate and selective technique for evaluating the effectiveness of sunscreens against the effects of UV-A1 radiation. The developed method showed that calcineurin activity have the potential to act as a biological indicator of UV-A1 radiation-induced damages in skin and the assay might be used to assess the efficacy of sunscreens agents and plant extracts prior to in vivo tests. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Role of the modulation of CYP1A1 expression and activity in chemoprevention.

    PubMed

    Badal, S; Delgoda, R

    2014-07-01

    As one of the main extra-hepatic cytochrome P450 (CYP) enzymes, CYP1A1 has been comprehensively investigated for its ability to metabolize both exogenous and endogenous compounds into their carcinogenic derivatives. These derivatives are linked to cancer initiation and progression. The compound benzo-a-pyrene (BaP), a copious and noxious compound present in coal tar, automobile exhaust fumes, cigarette smoke and charbroiled food, is metabolised by CYP1A1 and has been studied in great detail. Other compounds reliant on the same enzyme for their activation include 7,12 dimethylbenz(a)anthracene (DMBA) and heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). This review takes an in-depth look at a number of phytochemicals, plant extracts and a few synthetic compounds that have been researched and deemed potential chemopreventives via their interaction with the activity and expression of CYP1A1. It will also review a useful active site model of CYP1A1. Based on inhibitors of CYP1A1 that have demonstrated in vivo use as chemopreventors, CYP1A1 is a useful initial target for screening compounds with such potential, with the use of rapid in vitro and/or in silico assessments. Chemoprevention is a means by which healthy tissues are protected via the prevention, inhibition or reversal of carcinogenesis. This review focuses on one important pathway of carcinogenesis and identifies the important role that CYP1A1 plays in that pathway. It is hoped that highlighting the importance of such a key target, will help revive further research into and application of inhibitors of CYP1A1 towards generating improved chemopreventors. Copyright © 2014 John Wiley & Sons, Ltd.

  8. Telemetry Standards, RCC Standard 106-17, Annex A.1, Pulse Amplitude Modulation Standards

    DTIC Science & Technology

    2017-07-01

    conform to either Figure Error! No text of specified style in document.-1 or Figure Error! No text of specified style in document.-2. Figure Error...No text of specified style in document.-1. 50 percent duty cycle PAM with amplitude synchronization A 20-25 percent deviation reserved for pulse...synchronization is recommended. Telemetry Standards, RCC Standard 106-17 Annex A.1, July 2017 A.1.2 Figure Error! No text of specified style

  9. Red cell distribution width is associated with hemoglobin A1C elevation, but not glucose elevation.

    PubMed

    Bao, Xue; Wan, Min; Gu, Yeqing; Song, Yanqi; Zhang, Qing; Liu, Li; Meng, Ge; Wu, Hongmei; Xia, Yang; Shi, HongBin; Su, Qian; Fang, Liyun; Yang, Huijun; Yu, Fei; Sun, Shaomei; Wang, Xing; Zhou, Ming; Jia, Qiyu; Song, Kun; Wang, Guolin; Yu, Ming; Niu, Kaijun

    2017-10-01

    To investigate the association between red cell distribution width (RDW) and elevation of glucose/glycated hemoglobin (HbA1c). An analysis was conducted using data from a prospective cohort study of adults. People without prediabetes or diabetes (n=7,795) were followed for a mean of 2.90years (range: 1-7years, 95% confidence interval: 2.86-2.94years). Glucose elevation is defined as fasting glucose levels exceeding 5.6mmol/l, or 2-hour glucose values in the oral glucose tolerance test exceeding 7.8mmol/l. HbA1c elevation is defined as a HbA1c value exceeding a normal limit of 39mmol/mol (5.7%). Adjusted Cox proportional hazards regression models were used to assess the association between RDW quartiles and elevation of HbA1c/glucose. The multiple-adjusted hazard ratios (95% confidence interval) of HbA1c elevation for increased quartiles of RDW were 1.00 (reference), 1.08 (0.89, 1.30), 1.28 (1.07, 1.54), and 1.54 (1.29, 1.85) (P for trend<0.0001). However, no significant association was observed between RDW and blood glucose (fasting and postprandial). Elevated RDW is independently related to future HbA1c elevation, but not to glucose elevation. This suggests that RDW may associate with HbA1c through a non-glycemic way, which should be taken into consideration when using HbA1c as a diagnostic criterion of prediabetes or diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Regulation of translation by upstream translation initiation codons of surfactant protein A1 splice variants

    PubMed Central

    Tsotakos, Nikolaos; Silveyra, Patricia; Lin, Zhenwu; Thomas, Neal; Vaid, Mudit

    2014-01-01

    Surfactant protein A (SP-A), a molecule with roles in lung innate immunity and surfactant-related functions, is encoded by two genes in humans: SFTPA1 (SP-A1) and SFTPA2 (SP-A2). The mRNAs from these genes differ in their 5′-untranslated regions (5′-UTR) due to differential splicing. The 5′-UTR variant ACD′ is exclusively found in transcripts of SP-A1, but not in those of SP-A2. Its unique exon C contains two upstream AUG codons (uAUGs) that may affect SP-A1 translation efficiency. The first uAUG (u1) is in frame with the primary start codon (p), but the second one (u2) is not. The purpose of this study was to assess the impact of uAUGs on SP-A1 expression. We employed RT-qPCR to determine the presence of exon C-containing SP-A1 transcripts in human RNA samples. We also used in vitro techniques including mutagenesis, reporter assays, and toeprinting analysis, as well as in silico analyses to determine the role of uAUGs. Exon C-containing mRNA is present in most human lung tissue samples and its expression can, under certain conditions, be regulated by factors such as dexamethasone or endotoxin. Mutating uAUGs resulted in increased luciferase activity. The mature protein size was not affected by the uAUGs, as shown by a combination of toeprint and in silico analysis for Kozak sequence, secondary structure, and signal peptide and in vitro translation in the presence of microsomes. In conclusion, alternative splicing may introduce uAUGs in SP-A1 transcripts, which in turn negatively affect SP-A1 translation, possibly affecting SP-A1/SP-A2 ratio, with potential for clinical implication. PMID:25326576

  11. 40 CFR Table A-1 to Subpart A of... - Global Warming Potentials

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Global Warming Potentials A Table A-1... A-1 to Subpart A of Part 98—Global Warming Potentials [100-Year Time Horizon] Name CAS No. Chemical formula Global warming potential(100 yr.) Carbon dioxide 124-38-9 CO2 1 Methane 74-82-8 CH4 21 Nitrous...

  12. 40 CFR Table A-1 to Subpart A of... - Global Warming Potentials

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 21 2011-07-01 2011-07-01 false Global Warming Potentials A Table A-1... A-1 to Subpart A of Part 98—Global Warming Potentials [100-Year Time Horizon] Name CAS No. Chemical formula Global warming potential(100 yr.) Carbon dioxide 124-38-9 CO2 1 Methane 74-82-8 CH4 21 Nitrous...

  13. A Combinatorial Geometry Computer Description of the M577A1 Light Tracked Command Post Carrier

    DTIC Science & Technology

    1979-12-01

    REPORT DATE DECEMBER 1979 13. NUMBER OF PAGES 107 1 «. MONITORING AGENCY NAME ft ADDRESS(lf dlHermt Irom Controlling OUIce) 15...DISTRIBUTION LIST 103 LIST OF FIGURES Figure Page 1 . The M577A1 Command Post Carrier 10 2. Intersection (+), Subtraction (-), Union (OR) of Solids...with a computer- ized description of the M577A1. A photograph of the vehicle is shown in Figure 1 . Presently, the BRL employs a technique known as

  14. Intrinsic A(1) adenosine receptor activation during ischemia or reperfusion improves recovery in mouse hearts.

    PubMed

    Peart, J; Headrick, J P

    2000-11-01

    We assessed the role of A(1) adenosine receptor (A(1)AR) activation by endogenous adenosine in the modulation of ischemic contracture and postischemic recovery in Langendorff-perfused mouse hearts subjected to 20 min of total ischemia and 30 min of reperfusion. In control hearts, the rate-pressure product (RPP) and first derivative of pressure development over time (+dP/dt) recovered to 57 +/- 3 and 58 +/- 3% of preischemia, respectively. Diastolic pressure remained elevated at 20 +/- 2 mmHg (compared with 3 +/- 1 mmHg preischemia). Interstitial adenosine, assessed by microdialysis, rose from approximately 0.3 to 1.9 microM during ischemia compared with approximately 15 microM in rat heart. Nonetheless, these levels will near maximally activate A(1)ARs on the basis of effects of exogenous adenosine and 2-chloroadenosine. Neither A(1)AR blockade with 200 nM 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) during the ischemic period alone nor A(1)AR activation with 50 nM N(6)-cyclopentyladenosine altered rapidity or extent of ischemic contracture. However, ischemic DPCPX treatment significantly depressed postischemic recovery of RPP and +dP/dt (44 +/- 3 and 40 +/- 4% of preischemia, respectively). DPCPX treatment during the reperfusion period alone also reduced recovery of RPP and +dP/dt (to 44 +/- 2 and 47 +/- 2% of preischemia, respectively). These data indicate that 1) interstitial adenosine is lower in mouse versus rat myocardium during ischemia, 2) A(1)AR activation by endogenous adenosine or exogenous agonists does not modify ischemic contracture in murine myocardium, 3) A(1)AR activation by endogenous adenosine during ischemia attenuates postischemic stunning, and 4) A(1)AR activation by endogenous adenosine during the reperfusion period also improves postischemic contractile recovery.

  15. 26 CFR 1.925(a)-1 - Transfer pricing rules for FSCs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 10 2010-04-01 2010-04-01 false Transfer pricing rules for FSCs. 1.925(a)-1... pricing rules for FSCs. (a)-(c)(7) [Reserved]. For further guidance, see § 1.925(a)-1T(a) through (c)(7... administrative pricing methods are used, some or all of these determinations may be made on the basis of groups...

  16. Oral care practices and A1c among youth with type 1 and type 2 diabetes.

    PubMed

    Merchant, Anwar T; Oranbandid, Supatra; Jethwani, Monica; Choi, Youn-Hee; Morrato, Elaine H; Pitiphat, Waranuch; Mayer-Davis, Elizabeth J

    2012-07-01

    Periodontal treatment is associated with lower hemoglobin A1c in individuals with diabetes, but the relationship between oral hygiene practices and A1c among youth with diabetes is understudied. This study evaluates the cross-sectional relationships among oral health habits, reported oral conditions, and A1c and control of diabetes among a subset of youth with diabetes enrolled in the SEARCH for Diabetes in Youth study in South Carolina. Oral hygiene practices were determined by questionnaire, and periodontal bone loss was defined as alveolar bone loss ≥3 mm on ≥1 permanent tooth site on preexisting bitewing radiographs. A1c was considered controlled if individuals were aged ≤6 years with A1c <8.5%; aged 7 to 11 years with A1c <8.0%; aged 12 to 18 years with A1c <7.5%; and aged ≥19 years with A1c <7.0%. Among 155 participants, 68% brushed their teeth no less than once daily, 84% flossed, and 70% rinsed, respectively, less than once a week. Diabetes control was associated with toothbrushing (≥1 time daily [odds ratio (OR) = 3.10; 95% confidence interval (CI) = 1.26 to 7.62] and using mouthrinse at least once weekly (OR = 3.33; 95% CI = 1.30 to 8.54) after multivariate adjustment. Periodontal bone loss was three times more common among those with dry mouth (OR = 3.05; 95% CI = 1.07 to 8.70). Clinicians should be aware that children with diabetes tend to have poor oral hygiene practices. Dry mouth may indicate periodontal bone loss in children with diabetes.

  17. Is the COL5A1 rs12722 Gene Polymorphism Associated with Running Economy?

    PubMed Central

    Bertuzzi, Rômulo; Pasqua, Leonardo A.; Bueno, Salomão; Lima-Silva, Adriano Eduardo; Matsuda, Monique; Marquezini, Monica; Saldiva, Paulo H.

    2014-01-01

    The COL5A1 rs12722 polymorphism is considered to be a novel genetic marker for endurance running performance. It has been postulated that COL5A1 rs12722 may influence the elasticity of tendons and the energetic cost of running. To date, there are no experimental data in the literature supporting the relationship between range of motion, running economy, and the COL5A1 rs12722 gene polymorphism. Therefore, the main purpose of the current study was to analyze the influence of the COL5A1rs12722 polymorphism on running economy and range of motion. One hundred and fifty (n = 150) physically active young men performed the following tests: a) a maximal incremental treadmill test, b) two constant-speed running tests (10 km•h−1 and 12 km•h−1) to determine the running economy, and c) a sit-and-reach test to determine the range of motion. All of the subjects were genotyped for the COL5A1 rs12722 single-nucleotide polymorphism. The genotype frequencies were TT = 27.9%, CT = 55.8%, and CC = 16.3%. There were no significant differences between COL5A1 genotypes for running economy measured at 10 km•h−1 (p = 0.232) and 12 km•h−1 (p = 0.259). Similarly, there were no significant differences between COL5A1 genotypes for range of motion (p = 0.337). These findings suggest that the previous relationship reported between COL5A1 rs12722 genotypes and running endurance performance might not be mediated by the energetic cost of running. PMID:25188268

  18. Whole Blood Donation Affects the Interpretation of Hemoglobin A1c

    PubMed Central

    Lenters-Westra, Erna; de Kort, Wim; Bokhorst, Arlinke G.; Bilo, Henk J. G.; Slingerland, Robbert J.; Vos, Michel J.

    2017-01-01

    Introduction Several factors, including changed dynamics of erythrocyte formation and degradation, can influence the degree of hemoglobin A1c (HbA1c) formation thereby affecting its use in monitoring diabetes. This study determines the influence of whole blood donation on HbA1c in both non-diabetic blood donors and blood donors with type 2 diabetes. Methods In this observational study, 23 non-diabetic blood donors and 21 blood donors with type 2 diabetes donated 475 mL whole blood and were followed prospectively for nine weeks. Each week blood samples were collected and analyzed for changes in HbA1c using three secondary reference measurement procedures. Results Twelve non-diabetic blood donors (52.2%) and 10 (58.8%) blood donors with type 2 diabetes had a significant reduction in HbA1c following blood donation (reduction >-4.28%, P < 0.05). All non-diabetic blood donors with a normal ferritin concentration predonation had a significant reduction in HbA1c. In the non-diabetic group the maximum reduction was -11.9%, in the type 2 diabetes group -12.0%. When eligible to donate again, 52.2% of the non-diabetic blood donors and 41.2% of the blood donors with type 2 diabetes had HbA1c concentrations significantly lower compared to their predonation concentration (reduction >-4.28%, P < 0.05). Conclusion Patients with type 2 diabetes contributing to whole blood donation programs can be at risk of falsely lowered HbA1c. This could lead to a wrong interpretation of their glycemic control by their general practitioner or internist. PMID:28118412

  19. Glycated haemoglobin (HbA1c), diabetes and trajectories of change in episodic memory performance.

    PubMed

    Pappas, Colleen; Andel, Ross; Infurna, Frank J; Seetharaman, Shyam

    2017-02-01

    As the ageing population grows, it is important to identify strategies to moderate cognitive ageing. We examined glycated haemoglobin (HbA1c) and diabetes in relation to level and change in episodic memory in older adults with and without diabetes. Data from 4419 older adults with (n=950) and without (n=3469) diabetes participating in a nationally representative longitudinal panel study (the Health and Retirement Study) were examined. Average baseline age was 72.66 years and 58% were women. HbA1c was measured in 2006 and episodic memory was measured using immediate and delayed list recall over 4 biennial waves between 2006 and 2012. Growth curve models were used to assess trajectories of episodic memory change. In growth curve models adjusted for age, sex, education, race, depressive symptoms and waist circumference, higher HbA1c levels and having diabetes were associated with poorer baseline episodic memory (p=0.036 and <0.001, respectively) and greater episodic memory decline (p=0.006 and 0.004, respectively). The effect of HbA1c on episodic memory decline was smaller than the effect of age. The results were stronger for women than men and were not modified by age or race. When the main analyses were estimated for those with and without diabetes separately, HbA1c was significantly linked to change in episodic memory only among those with diabetes. Higher HbA1c and diabetes were both associated with declines in episodic memory, with this relationship further exacerbated by having diabetes and elevated HbA1c. HbA1c appeared more important for episodic memory performance among women than men. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Ephrin-A1/EphA4-mediated adhesion of monocytes to endothelial cells.

    PubMed

    Jellinghaus, Stefanie; Poitz, David M; Ende, Georg; Augstein, Antje; Weinert, Sönke; Stütz, Beryl; Braun-Dullaeus, Rüdiger C; Pasquale, Elena B; Strasser, Ruth H

    2013-10-01

    The Eph receptors represent the largest family of receptor tyrosine kinases. Both Eph receptors and their ephrin ligands are cell-surface proteins, and they typically mediate cell-to-cell communication by interacting at sites of intercellular contact. The major aim of the present study was to investigate the involvement of EphA4-ephrin-A1 interaction in monocyte adhesion to endothelial cells, as this process is a crucial step during the initiation and progression of the atherosclerotic plaque. Immunohistochemical analysis of human atherosclerotic plaques revealed expression of EphA4 receptor and ephrin-A1 ligand in major cell types within the plaque. Short-time stimulation of endothelial cells with the soluble ligand ephrin-A1 leads to a fourfold increase in adhesion of human monocytes to endothelial cells. In addition, ephrin-A1 further increases monocyte adhesion to already inflamed endothelial cells. EphrinA1 mediates its effect on monocyte adhesion via the activated receptor EphA4. This ephrinA1/EphA4 induced process involves the activation of the Rho signaling pathway and does not require active transcription. Rho activation downstream of EphA4 leads to increased polymerization of actin filaments in endothelial cells. This process was shown to be crucial for the proadhesive effect of ephrin-A1. The results of the present study show that ephrin-A1-induced EphA4 forward signaling promotes monocyte adhesion to endothelial cells via activation of RhoA and subsequent stress-fiber formation by a non-transcriptional mechanism. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Barriers to A1C testing among a managed care population.

    PubMed

    Delaronde, Steven

    2005-01-01

    The purpose of this study is to explore reasons adults with diabetes do not receive at least 2 A1C tests per year as recommended by the American Diabetes Association (ADA). ConnectiCare, a regional managed care company based in Farmington, Connecticut, identified adult members with diabetes who did not have a medical claim for an A1C laboratory test from their physician. A questionnaire was sent to 740 randomly selected members asking them to report the number of A1C tests they received in the past 12 months and reasons for not receiving the number of tests recommended by the ADA. After sending an automated telephone reminder to nonrespondents, a 26% (n = 192) response rate was achieved. Thirty-three percent of respondents (n = 63) reported having diabetes and receiving fewer than 2 A1C tests in the past year. Respondents were equally divided between men and women, with a mean age of 58 years. The primary reasons given for not obtaining at least 2 A1C tests as recommended by the ADA were that respondents were unaware that the test is recommended (49%), not informed of the need for the test by their physician (38%), never heard of the A1C test (33%), and not seen regularly by their physician (19%). Diabetes self-management education remains an important means of encouraging adherence to important ADA recommendations such as regular A1C testing. Barriers to A1C testing can be addressed in multiple settings, including individual and group education, disease management programs, and physician education.

  2. 26 CFR 1.925(a)-1 - Transfer pricing rules for FSCs.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 10 2011-04-01 2011-04-01 false Transfer pricing rules for FSCs. 1.925(a)-1... Transfer pricing rules for FSCs. (a)-(c)(7) [Reserved]. For further guidance, see § 1.925(a)-1T(a) through... administrative pricing methods are used, some or all of these determinations may be made on the basis of groups...

  3. Modifying murine von Willebrand factor A1 domain for in vivo assessment of human platelet therapies.

    PubMed

    Chen, Jianchun; Tan, Kui; Zhou, Hairu; Lo, Hsuan-Fu; Tronik-Le Roux, Diana; Liddington, Robert C; Diacovo, Thomas G

    2008-01-01

    The A1 domain of von Willebrand factor (VWF-A1) plays a crucial role in hemostasis and thrombosis by initiating platelet adhesion at sites of arterial injury through interactions with the platelet receptor glycoprotein Ib alpha (GPIbalpha). Here we report that murine VWF-A1 supports limited binding of human platelets. However, atomic models of GPIbalpha-VWF-A1 complexes identified an electrostatic 'hot-spot' that, when mutated in murine VWF-A1, switches its binding specificity from mouse to human GPIbalpha. Furthermore, mice expressing this mutant VWF-A1 display a bleeding phenotype that can be corrected by infusion of human platelets. Mechanistically, human platelets correct the phenotype by forming occlusive thrombi, an event that can be abrogated by blockade of GPIbalpha or by the preadministration of inhibitors of platelet activation or adhesion (clopidogrel (Plavix) and abciximab (ReoPro), respectively). Thus, by modifying a protein interface, we have generated a potential biological platform for preclinical screening of antithrombotics that specifically target human platelets.

  4. Association of plasma PCB levels and HbA1c concentration in Iran.

    PubMed

    Eftekhari, Sahar; Aminian, Omid; Moinfar, Zeinab; Schettgen, Thomas; Kaifie, Andrea; Felten, Michael; Kraus, Thomas; Esser, André

    2018-01-01

    The rapid increase in prevalence of diabetes mellitus over the last decades warrants more attention to the effects of environmental and occupational exposures on glucose metabolism. Our study aimed to assess the association between the plasma levels of various congeners of polychlorinated biphenyls (PCBs) and the serum concentration of glycated haemoglobin (HbA1c). Our study population consisted of 140 Iranian adults from seven different occupational groups and a group of non-occupationally exposed female participants. The plasma concentration of PCBs were determined at the laboratory of occupational toxicology at RWTH Aachen University, Germany. We considered an HbA1c concentration of 5.7% and more as indicating a disturbed glucose metabolism. Logistic regression was used to assess the association between quartiles of concentrations of PCB congeners and serum HbA1c. Participants with an increased HbA1c value had higher plasma levels of PCB 138, 153, 180 and the PCB sum, although this association was statistically not significant. There was no significant difference between the levels of PCB 138, 153, 180, the sum of these congeners, and PCB 118 in their quartiles when comparing with HbA1c concentrations. For our cohort, we could not demonstrate a significant association between PCB and HbA1c concentrations indicating a disturbance of glucose metabolism.

  5. Understanding the new HbA1c units for the diagnosis of Type 2 diabetes.

    PubMed

    Braatvedt, Geoff D; Cundy, Tim; Crooke, Michael; Florkowski, Chris; Mann, Jim I; Lunt, Helen; Jackson, Rod; Orr-Walker, Brandon; Kenealy, Timothy; Drury, Paul L

    2012-09-21

    In New Zealand laboratories the measurement of glycated haemoglobin (HbA1c) for diagnosis of diabetes is now only reported in SI units of mmol/mol. HbA1c is now recommended as the preferred test to diagnose diabetes in most circumstances. The requirement for a second positive test in asymptomatic individuals is retained. An HbA1c greater than and equal to 50 mmol/mol (repeated on a second occasion in asymptomatic patients) is diagnostic of diabetes and a value less than and equal to 40 mmol/mol represents normal glucose tolerance. For patients with an initial HbA1c result of 41-49 mmol/mol, cardiovascular risk assessment and lifestyle interventions are recommended with repeat HbA1c screening in 6-12 months. For patients whose HbA1c is less than and equal to 40 mmol/mol, repeat screening (including for CVD risk) at intermittent intervals is recommended as per published guidelines.

  6. Evaluation of the DCA Vantage analyzer for HbA 1c assay.

    PubMed

    Szymezak, Jean; Leroy, Nathalie; Lavalard, Emmanuelle; Gillery, Philippe

    2008-01-01

    Measurement of HbA 1c is key in monitoring diabetic patients in both laboratories and clinical units, where HbA 1c results are used as part of patient education. We have evaluated the DCA Vantage, a new device for immunological assay of HbA 1c. HbA 1c results obtained were evaluated in terms of precision, linearity, specificity and practicability, and were compared with results obtained by a Variant II HPLC method. The method exhibited intra- and inter-assay coefficients of variation lower than 2.6% and 4.0%, respectively, and good correlation with the comparison HPLC method (r2=0.9776). No interference was noted in the presence of labile HbA 1c or carbamylated hemoglobin. The new device exhibited improved practicability characteristics and allowed better sample identification, better management of quality control routines and greater connectivity possibilities compared to the previous DCA 2000 analyzer. This new analyzer exhibited analytical and practical characteristics very suitable for HbA 1c assay for laboratory or point-of-care use according to good laboratory practice.

  7. SLC11A1 polymorphisms and host susceptibility to cutaneous leishmaniasis in Pakistan.

    PubMed

    Sophie, Mariam; Hameed, Abdul; Muneer, Akhtar; Samdani, Azam J; Saleem, Saima; Azhar, Abid

    2017-01-07

    The vector-borne cutaneous leishmaniasis (CL) is endemic in several regions of Pakistan mainly affecting poor populations. Host genetic factors, particularly SLC11A1 (solute carrier transmembrane protein) within macrophages, play a crucial role in disease pathology and susceptibility. Association of SLC11A1 with cutaneous leishmaniasis, a neglected tropical disease, is not well established. Inconsistencies have been observed within different populations worldwide with respect to genetic susceptibility. This study was designed to investigate genetic variation(s) in SLC11A1 and to assess possible association with cutaneous leishmaniasis in Pakistan. Eight polymorphisms (rs2276631, rs3731864, rs2290708, rs2695342, rs201565523, rs17215556, rs17235409, rs17235416) were genotyped across SLC11A1 in 274 patients and 119 healthy controls. Six polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Two single nucleotide polymorphisms were analyzed with newly designed semi-nested PCR assays. Case-control analysis showed no association between selected polymorphisms in SLC11A1 and cutaneous leishmaniasis. No significant difference was observed in the distribution of alleles between leishmaniasis patients and healthy individuals. Strong pairwise linkage disequilibrium was observed between rs2276631 and rs2290708 (r 2  = 64); and rs17235409 and rs17235416 (r 2  = 78). This study shows that genetic variations in the candidate gene SLC11A1 do not affect susceptibility to cutaneous leishmaniasis in the sample population from Pakistan.

  8. Endophilin-A1 BAR domain interaction with arachidonyl CoA.

    PubMed

    Petoukhov, Maxim V; Weissenhorn, Winfried; Svergun, Dmitri I

    2014-01-01

    Endophilin-A1 belongs to the family of BAR domain containing proteins that catalyze membrane remodeling processes via sensing, inducing and stabilizing membrane curvature. We show that the BAR domain of endophilin-A1 binds arachidonic acid and molds its coenzyme A (CoA) activated form, arachidonyl-CoA into a defined structure. We studied low resolution structures of endophilin-A1-BAR and its complex with arachidonyl-CoA in solution using synchrotron small-angle X-ray scattering (SAXS). The free endophilin-A1-BAR domain is shown to be dimeric at lower concentrations but builds tetramers and higher order complexes with increasing concentrations. Extensive titration SAXS studies revealed that the BAR domain produces a homogenous complex with the lipid micelles. The structural model of the complexes revealed two arachidonyl-CoA micelles bound to the distal arms of an endophilin-A1-BAR dimer. Intriguingly, the radius of the bound micelles significantly decreases compared to that of the free micelles, and this structural result may provide hints on the potential biological relevance of the endophilin-A1-BAR interaction with arachidonyl CoA.

  9. The implications of using Hemoglobin A1C for diagnosing Diabetes Mellitus

    PubMed Central

    Malkani, Samir; Mordes, John P

    2011-01-01

    Until 2010 the diagnosis of diabetes mellitus was based solely on glucose concentration, but American Diabetes Association (ADA) recommendations now include a new criterion: hemoglobin A1C ≥6.5%. Because this change may have significant implications for diabetes diagnosis, we conducted a comprehensive literature review including peer-reviewed articles not referenced in the ADA report. We conclude that A1C and plasma glucose tests are frequently discordant for diagnosing diabetes. A1C ≥6.5% identifies fewer individuals as having diabetes than glucose-based criteria. Convenience of A1C test might increase the number of patients diagnosed, but this is unproven. Diagnostic cut-points for both glucose and A1C are based on consensus judgments regarding optimal sensitivity and specificity for the complications of hyperglycemia. A1C may not accurately reflect levels of glycemia in some situations, but in comparison with glucose measurements, it has greater analytic stability and less temporal variability. When choosing a diagnostic test for diabetes, the limitations of each choice must be understood. Clinical judgment and consideration of patient preference are required to appropriately select among the diagnostic alternatives. PMID:21531226

  10. [Hepatotoxicity of emodin based on UGT1A1 enzyme-mediated bilirubin in liver microsomes].

    PubMed

    Wang, Qi; Dai, Zhong; Zhang, Yu-Jie; Ma, Shuang-Cheng

    2016-12-01

    To study the hepatotoxicity of emodin based on bilirubin metabolism mediated by glucuronidation of UGT1A1 enzyme. In this study, three different incubation systems were established by using RLM, HLM, and rUGT1A1, with bilirubin as the substrate. Different concentrations of bilirubin and emodin were added in the incubation systems. The double reciprocal Michaelis equation was drawn based on the total amount of bilirubin glucuronidation. The apparent inhibition constant Ki was then calculated with the slope curve to predict the hepatotoxicity. The results indicated that emodin had a significant inhibition to the UGT1A1 enzyme in all of the three systems, with Ki=5.400±0.956(P<0.05) in HLM system, Ki =10.020±0.611(P<0.05) in RLM system, Ki=4.850±0.528(P<0.05) in rUGT1A1 system. Meanwhile, emodin had no significant difference between rat and human in terms of inhibition of UGT1A1 enzyme. Emodin had a potential risk of the hepatotoxicity by inhibiting the UGT1A1 enzyme activity. And the method established in this study provides a new thought and new method to evaluate hepatotoxicity and safety of traditional Chinese medicines. Copyright© by the Chinese Pharmaceutical Association.

  11. O2(a1Δ) Quenching In The O/O2/O3 System

    NASA Astrophysics Data System (ADS)

    Azyazov, V. N.; Mikheyev, P. A.; Postell, D.; Heaven, M. C.

    2010-10-01

    The development of discharge singlet oxygen generators (DSOG's) that can operate at high pressures is required for the power scaling of the discharge oxygen iodine laser. In order to achieve efficient high-pressure DSOG operation it is important to understand the mechanisms by which singlet oxygen (O2(a1Δ)) is quenched in these devices. It has been proposed that three-body deactivation processes of the type O2(a1Δ)+O+M→2O2+M provide significant energy loss channels. To further explore these reactions the physical and reactive quenching of O2(a1Δ) in O(3P)/O2/O3/CO2/He/Ar mixtures has been investigated. Oxygen atoms and singlet oxygen molecules were produced by the 248 nm laser photolysis of ozone. The kinetics of O2(a1Δ) quenching were followed by observing the 1268 nm fluorescence of the O2a1Δ-X3∑ transition. Fast quenching of O2(a1Δ) in the presence of oxygen atoms and molecules was observed. The mechanism of the process has been examined using kinetic models, which indicate that quenching by vibrationally excited ozone is the dominant reaction.

  12. The heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a host factor required for dengue virus and Junín virus multiplication.

    PubMed

    Brunetti, Jesús E; Scolaro, Luis A; Castilla, Viviana

    2015-05-04

    Heterogeneous nuclear ribonucleoproteins (hnRNPs) are cellular factors involved in the replication of several viruses. In this study we analyzed the expression and intracellular localization of hnRNP A2 and hnRNP K in cell cultures infected with two viruses that cause human hemorrhagic fevers: dengue virus type 2 (DENV-2) and Junín virus (JUNV). We determined that DENV-2 promoted the cytoplasmic translocation of hnRNP K and to a lesser extent of hnRNP A2, meanwhile, JUNV infection induced an increase in hnRNP K cytoplasmic localization whereas hnRNP A2 remained mainly in the nucleus of infected cells. Both hnRNP K and hnRNP A2 were localized predominantly in the nucleus of JUNV persistently-infected cells even after superinfection with JUNV indicating that persistent infection does not alter nucleo-cytoplasmic transport of these hnRNPs. Total levels of hnRNP K expression were unaffected by DENV-2 or JUNV infection. In addition we determined, using small interfering RNAs, that hnRNP K knockout inhibits DENV-2 and JUNV multiplication. Our results indicate that DENV-2 and JUNV induce hnRNP K cytoplasmic translocation to favor viral multiplication. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Association of Sickle Cell Trait With Hemoglobin A1c in African Americans.

    PubMed

    Lacy, Mary E; Wellenius, Gregory A; Sumner, Anne E; Correa, Adolfo; Carnethon, Mercedes R; Liem, Robert I; Wilson, James G; Sacks, David B; Jacobs, David R; Carson, April P; Luo, Xi; Gjelsvik, Annie; Reiner, Alexander P; Naik, Rakhi P; Liu, Simin; Musani, Solomon K; Eaton, Charles B; Wu, Wen-Chih

    2017-02-07

    Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it. To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans. Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures. Presence of SCT. Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure. The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose

  14. BMP-2, Hypoxia, and COL1A1/HtrA1 siRNAs Favor Neo-Cartilage Hyaline Matrix Formation in Chondrocytes

    PubMed Central

    Ollitrault, David; Legendre, Florence; Drougard, Carole; Briand, Mélanie; Benateau, Hervé; Goux, Didier; Chajra, Hanane; Poulain, Laurent; Hartmann, Daniel; Vivien, Denis; Shridhar, Vijayalakshmi; Baldi, Alfonso; Mallein-Gerin, Frédéric; Boumediene, Karim; Demoor, Magali

    2015-01-01

    Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets. PMID:24957638

  15. Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish.

    PubMed

    Pott, Alexander; Bock, Sarah; Berger, Ina M; Frese, Karen; Dahme, Tillman; Keßler, Mirjam; Rinné, Susanne; Decher, Niels; Just, Steffen; Rottbauer, Wolfgang

    2018-05-08

    The genetic underpinnings that orchestrate the vertebrate heart rate are not fully understood yet, but of high clinical importance, since diseases of cardiac impulse formation and propagation are common and severe human arrhythmias. To identify novel regulators of the vertebrate heart rate, we deciphered the pathogenesis of the bradycardia in the homozygous zebrafish mutant hiphop (hip) and identified a missense-mutation (N851K) in Na + /K + -ATPase α1-subunit (atp1a1a.1). N851K affects zebrafish Na + /K + -ATPase ion transport capacity, as revealed by in vitro pump current measurements. Inhibition of the Na + /K + -ATPase in vivo indicates that hip rather acts as a hypomorph than being a null allele. Consequently, reduced Na + /K + -ATPase function leads to prolonged QT interval and refractoriness in the hip mutant heart, as shown by electrocardiogram and in vivo electrical stimulation experiments. We here demonstrate for the first time that Na + /K + -ATPase plays an essential role in heart rate regulation by prolonging myocardial repolarization. Copyright © 2018. Published by Elsevier Ltd.

  16. BMP-2, hypoxia, and COL1A1/HtrA1 siRNAs favor neo-cartilage hyaline matrix formation in chondrocytes.

    PubMed

    Ollitrault, David; Legendre, Florence; Drougard, Carole; Briand, Mélanie; Benateau, Hervé; Goux, Didier; Chajra, Hanane; Poulain, Laurent; Hartmann, Daniel; Vivien, Denis; Shridhar, Vijayalakshmi; Baldi, Alfonso; Mallein-Gerin, Frédéric; Boumediene, Karim; Demoor, Magali; Galera, Philippe

    2015-02-01

    Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets.

  17. HbA1c measurement and relationship to incident stroke.

    PubMed

    Robson, R; Lacey, A S; Luzio, S D; Van Woerden, H; Heaven, M L; Wani, M; Halcox, J P J; Castilla-Guerra, L; Dawson, J; Hewitt, J

    2016-04-01

    To determine the proportion of people with diabetes who have HbA1c measured, what proportion achieve an HbA1c level of < 58 mmol/mol (7.5%), the frequency of testing and if there was any change in HbA1c level in the year before and the year after an incident stroke. This study used the Secure Anonymised Information Linkage (SAIL) databank, which stores hospital data for the whole of Wales and ~ 65% of Welsh general practice records, to identify cases of stroke in patients with diabetes between 2000 and 2010. These were matched against patients with diabetes but without stroke disease. We assessed the frequency of HbA1c testing and change in HbA1c in the first year after stroke. Estimation was made of the proportion of patients achieving an HbA1c measurement ≤ 58 mmol/mol (7.5%). There were 1741 patients with diabetes and stroke. Of these, 1173 (67.4%) had their HbA1c checked before their stroke and 1137 (65.3%) after their stroke. In the control group of 16 838 patients with diabetes but no stroke, 8413 (49.9%) and 9288 (55.1%) had their HbA1c checked before and after the case-matched stroke date, respectively. In patients with diabetes and stroke, HbA1c fell from 61-56 mmol/mol (7.7-7.3%) after their stroke (P < 0.001). Before the study, 55.0% of patients with stroke had an HbA1c ≥ 58 mmol/mol compared with 65.2% of control patients, these figures were 62.5% and 65.3% after the stroke. The frequency of diabetes testing was higher in patients who had experienced a stroke before and after their incident stroke compared with control patients but did not increase after their stroke. Glucose control improved significantly in the year after a stroke. © 2015 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

  18. Hemoglobin A1c levels and aortic arterial stiffness: the Cardiometabolic Risk in Chinese (CRC) study.

    PubMed

    Liang, Jun; Zhou, Na; Teng, Fei; Zou, Caiyan; Xue, Ying; Yang, Manqing; Song, Huaidong; Qi, Lu

    2012-01-01

    The American Diabetes Association (ADA) recently published new clinical guidelines in which hemoglobin A1c (HbA1c) was recommended as a diagnostic test for diabetes. The present study was to investigate the association between HbA1c and cardiovascular risk, and compare the associations with fasting glucose and 2-hour oral glucose tolerance test (2 h OGTT). The study samples are from a community-based health examination survey in central China. Carotid-to-femoral pulse wave velocity (cfPWV) and HbA1c were measured in 5,098 men and women. After adjustment for age, sex, and BMI, the levels of HbA1c were significantly associated with an increasing trend of cfPWV in a dose-dependent fashion (P for trend <0.0001). The associations remained significant after further adjustment for blood pressure, heart rate, and lipids (P = 0.004), and the difference in cfPWV between the highest and the lowest quintiles of HbA1c was 0.31 m/s. Fasting glucose and 2 h OGTT were not associated with cfPWV in the multivariate analyses. HbA1c showed additive effects with fasting glucose or 2 h OGTT on cfPWV. In addition, age and blood pressure significantly modified the associations between HbA1c and cfPWV (P for interactions <0.0001 for age; and  = 0.019 for blood pressure). The associations were stronger in subjects who were older (≥60 y; P for trend = 0.004) and had higher blood pressure (≥120 [systolic blood pressure]/80 mmHg [diastolic blood pressure]; P for trend = 0.028) than those who were younger and had lower blood pressure (P for trend >0.05). HbA1c was related to high cfPWV, independent of conventional cardiovascular risk factors. Senior age and high blood pressure might amplify the adverse effects of HbA1c on cardiovascular risk.

  19. Hemorheological alterations in adults with prediabetes identified by hemoglobin A1c levels.

    PubMed

    Marini, M A; Fiorentino, T V; Andreozzi, F; Mannino, G C; Succurro, E; Sciacqua, A; Perticone, F; Sesti, G

    2017-07-01

    A link between increased blood viscosity and type 2 diabetes has been previously reported. Herein, we investigated the association of blood viscosity with prediabetes, identified by glycated hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria, and subclinical atherosclerosis. The study cohort includes 1136 non-diabetic adults submitted to anthropometrical evaluation, an oral glucose tolerance test and ultrasound measurement of carotid intima-media thickness (IMT). Whole blood viscosity was estimated using a validated formula based on hematocrit and total plasma proteins. After adjusting for age, and gender, individuals with HbA1c-defined prediabetes (HbA1c 5.7-6.4% [39-47 mmol/mol]) exhibited significantly higher values of hematocrit, and predicted blood viscosity as compared with controls. Increased levels of IMT were observed in subjects with HbA1c-defined prediabetes in comparison to controls. Predicted blood viscosity was positively correlated with age, waist circumference, blood pressure, cholesterol, triglycerides, fibrinogen, white blood cell, HbA1c, fasting and 2-h post-load glucose levels, fasting insulin, IMT and inversely correlated with HDL and Matsuda index of insulin sensitivity. Of the three glycemic parameters, i.e. HbA1c, fasting and 2-h post-load glucose, only HbA1c showed a significant correlation with predicted blood viscosity (β = 0.054, P = 0.04) in a multivariate regression analysis model including multiple atherosclerosis risk factors. The study shows that individuals with HbA1c-defined prediabetes have increased predicted blood viscosity and IMT. The HbA1c criterion may be helpful to capture individuals with an increased risk of diabetes and cardiovascular disease who may benefit from an intensive lifestyle intervention. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical

  20. Association between hypoglycemia risk and hemoglobin A1C in patients with type 2 diabetes mellitus.

    PubMed

    Yu, Shengsheng; Fu, Alex Z; Engel, Samuel S; Shankar, R Ravi; Radican, Larry

    2016-08-01

    To better manage type 2 diabetes mellitus (T2DM), the tradeoff between improved glycemic control and hypoglycemia should be evaluated. The purpose of this study was to assess the relationship between hypoglycemia and hemoglobin A1c (HbA1c) in a real-world population. Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) was a multi-center, observational study. Patients ≥30 years old using any oral anti-hyperglycemic agent were recruited from seven European and five Asian countries between 2006 and 2007. Hypoglycemia events were collected through patient-reported questionnaires. HbA1c data was collected through chart review. Logistic regression was performed to assess the relationship between hypoglycemia and the most proximate HbA1c levels adjusting for potential confounders (demographics, clinical variables, other medication use, and comorbid conditions). A total of 4399 patients were recruited and analyzed. Mean age was 60 years, 52% were male, and 75% were on sulfonylureas (S.U.s). Respectively, 37% or 42% of patients reported hypoglycemia in the past 6 (Asia) or 12 months (Europe) before recruitment. Prevalence of hypoglycemia increased significantly (33% to 40%) as HbA1c decreased (p = 0.035). The same trend was also observed among S.U.-treated patients (p < 0.01). After adjusting for confounders, hypoglycemia prevalence was significantly higher for HbA1c <7.0% (odds ratio [O.R.] = 1.66 [95% C.I. 1.21, 2.28]; p = 0.002) vs. HbA1c ≥10.0%. Our analyses pooled data from Asia and Europe, which differed in terms of the recall period for ascertaining hypoglycemia symptoms and the timing of latest HbA1c measure. Lower HbA1c level was associated with higher hypoglycemia prevalence among S.U.-treated patients. HbA1c level should be taken into consideration when reporting hypoglycemia prevalence.

  1. Hypoglycemia Reduction and Changes in Hemoglobin A1c in the ASPIRE In-Home Study

    PubMed Central

    Weiss, Ram; Garg, Satish K.; Bode, Bruce W.; Bailey, Timothy S.; Ahmann, Andrew J.; Schultz, Kenneth A.; Welsh, John B.

    2015-01-01

    Abstract Background: ASPIRE In-Home randomized 247 subjects with type 1 diabetes to sensor-augmented pump therapy with or without the Threshold Suspend (TS) feature, which interrupts insulin delivery at a preset sensor glucose value. We studied the effects of TS on nocturnal hypoglycemia (NH) in relation to baseline hemoglobin A1c (A1C) and change in A1C during the study. Materials and Methods: NH event rates and mean area under curve (AUC) of NH events were evaluated at different levels of baseline A1C (<7%, 7–8%, and >8%) and at different levels of changes in A1C (less than −0.3% [decreased], −0.3% to 0.3% [stable], and >0.3% [increased]), in the TS Group compared with the Control Group (sensor-augmented pump only). Results: In the TS Group, 27.9% of the NH events were accompanied by a confirmatory blood glucose value, compared with 39.3% in the Control Group. Among subjects with baseline A1C levels of <7% or 7–8%, those in the TS Group had significantly lower NH event rates than those in the Control Group (P=0.001 and P=0.004, respectively). Among subjects with decreased or stable A1C levels, those in the TS Group had significantly lower NH event rates, and the events had lower AUCs (P≤0.001 for each). Among subjects with increased A1C levels, those in the TS Group had NH events with significantly lower AUCs (P<0.001). Conclusions: Use of the TS feature was associated with decreases in the rate and severity (as measured by AUC) of NH events in many subjects, including those with low baseline A1C levels and those whose A1C values decreased during the study period. Use of the TS feature can help protect against hypoglycemia in those wishing to intensify diabetes management to achieve target glucose levels. PMID:26237308

  2. HbA1c for diagnosis and prognosis of gestational diabetes mellitus.

    PubMed

    Kwon, Soon Sung; Kwon, Ja-Young; Park, Yong-Won; Kim, Young-Han; Lim, Jong-Baeck

    2015-10-01

    HbA1c is a widely used marker in diagnosing type 2 diabetes mellitus (DM), but its clinical utility in diagnosing gestational diabetes mellitus (GDM) is not established. Here, we evaluated the clinical usefulness of HbA1c in diagnosing GDM and predicting the risk of future type 2 DM development among GDM patients. This retrospective, cross-sectional study included 321 subjects who underwent 100-g oral glucose tolerance tests (OGTT) during pregnancy. HbA1c and other variables were analyzed to evaluate their diagnostic performance for GDM. To evaluate the clinical usefulness of HbA1c in predicting future type 2 DM development, we classified GDM subjects who had more than 3 months of follow-up data into two subgroups: those who developed postpartum type 2 DM (PDM) and those who did not. HbA1c was significantly higher in the GDM group than in the normal control group. With the 100-g OGTT as reference, HbA1c showed 91.3% sensitivity and 62% specificity at a cut-off value of 5.05% (32 mmol/mol) for GDM diagnosis. At a cut-off value of 5.25% (34 mmol/mol), sensitivity was 73.6% and specificity was 77.2%. HbA1c levels during pregnancy were higher in those with PDM than in those without PDM (5.91 [41 mmol/mol] vs. 5.44% [36 mmol/mol], p<0.001). The prognostic value of HbA1c for PDM was evaluated by ROC curve analysis, with sensitivity of 78.6% and specificity of 72.5% at a cut-off value of 5.55% (37 mmol/mol). HbA1c showed high sensitivity with relatively low specificity for diagnosis of GDM in pregnant women and was a potential predictor of PDM. HbA1c may be able to be used as a simple and less invasive alternative screening test for OGTT in GDM patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Fibromyalgia, mood disorders, and intense creative energy: A1AT polymorphisms are not always silent.

    PubMed

    Schmechel, Donald E; Edwards, Christopher L

    2012-12-01

    Persons with single copies of common alpha-1-antitrypsin polymorphisms such as S and Z are often considered "silent carriers". Published evidence however supports a complex behavioral phenotype or trait - intense creative energy ("ICE")-associated with A1AT polymorphisms. We now confirm that phenotype and present an association of fibromyalgia syndrome (FMS) and A1AT in a consecutive series of neurological patients. This is a retrospective case control series of 3176 consecutive patients presenting to Duke University Memory Clinic (747 patients) and to regional community-based Caldwell Hospital Neurology and Memory center (2429 patients). Work-up included medical history and examination, psychological evaluation, and genetic analysis. Chronic widespread pain (CWP) or FMS were diagnosed according to clinical guidelines, mostly as secondary diagnoses. Neurological patients carrying A1AT polymorphisms were common (ca 16% prevalence) and carriers had significantly higher use of inhaler and anxiolytic medications. Patients with ICE phenotype had a significantly higher proportion of A1AT polymorphisms (42%) compared to non-ICE patients (13%). Presence of CWP or FMS was common (14-22%) with average age at presentation of 56 years old and mostly female gender (82%). Patients with CWP/FMS had again significantly higher proportion of A1AT polymorphisms (38%) compared to other neurological patients (13%). Patients with anxiety disorders, bipolar I or bipolar II disorders or PTSD also had increased proportion of A1AT polymorphisms and significant overlap with ICE and FMS phenotype. Significant reductions in CWP/FMS prevalence are seen in apolipoprotein E4 carriers and methylene tetrahydrofolate reductase (MTHFR) mutation homozygotes. Since ICE phenotype is reported as a lifelong behavioral attribute, the presumption is that A1AT carriers have fundamental differences in brain development and inflammatory response. In support of this concept is finding those persons reporting a

  4. Entry of Botulinum Neurotoxin Subtypes A1 and A2 into Neurons.

    PubMed

    Kroken, Abby R; Blum, Faith C; Zuverink, Madison; Barbieri, Joseph T

    2017-01-01

    Botulinum neurotoxins (BoNTs) are the most toxic proteins for humans but also are common therapies for neurological diseases. BoNTs are dichain toxins, comprising an N-terminal catalytic domain (LC) disulfide bond linked to a C-terminal heavy chain (HC) which includes a translocation domain (H N ) and a receptor binding domain (H C ). Recently, the BoNT serotype A (BoNT/A) subtypes A1 and A2 were reported to possess similar potencies but different rates of cellular intoxication and pathology in a mouse model of botulism. The current study measured H C A1 and H C A2 entry into rat primary neurons and cultured Neuro2A cells. We found that there were two sequential steps during the association of BoNT/A with neurons. The initial step was ganglioside dependent, while the subsequent step involved association with synaptic vesicles. H C A1 and H C A2 entered the same population of synaptic vesicles and entered cells at similar rates. The primary difference was that H C A2 had a higher degree of receptor occupancy for cells and neurons than HcA1. Thus, H C A2 and H C A1 share receptors and entry pathway but differ in their affinity for receptor. The initial interaction of H C A1 and H C A2 with neurons may contribute to the unique pathologies of BoNT/A1 and BoNT/A2 in mouse models. Copyright © 2016 American Society for Microbiology.

  5. Naturally Occurring Structural Isomers in Serum IgA1 O-Glycosylation

    PubMed Central

    Takahashi, Kazuo; Smith, Archer D.; Poulsen, Knud; Kilian, Mogens; Julian, Bruce A.; Mestecky, Jiri; Novak, Jan; Renfrow, Matthew B.

    2013-01-01

    IgA is the most abundantly produced antibody and plays an important role in the mucosal immune system. Human IgA is represented by two isotypes, IgA1 and IgA2. The major structural difference between these two subclasses is the presence of nine potential sites of O-glycosylation in the hinge region between the first and second constant region domains of the heavy chain. Thr225, Thr228, Ser230, Ser232 and Thr236 have been identified as the predominant sites of O-glycan attachment. The range and distribution of O-glycan chains at each site within the context of adjacent sites in this clustered region create a complex heterogeneity of surface epitopes that is incompletely defined. We previously described the analysis of IgA1 O-glycan heterogeneity by use of high resolution LC/MS and electron capture dissociation tandem MS to unambiguously localize all amino acid attachment sites in IgA1 (Ale) myeloma protein. Here, we report the identification and elucidation of IgA1 O-glycopeptide structural isomers that occur based on amino acid position of the attached glycans (positional isomers) and the structure of the O-glycan chains at individual sites (glycan isomers). These isomers are present in a model IgA1 (Mce1) myeloma protein and occur naturally in normal human serum IgA1. Variable O-glycan chains attached to Ser230, Thr233 or Thr236 produce the predominant positional isomers, including O-glycans composed of a single GalNAc residue. These findings represent the first definitive identification of structural isomeric IgA1 O-glycoforms, define the single-site heterogeneity for all O-glycan sites in a single sample, and have implications for defining epitopes based on clustered O-glycan variability. PMID:22067045

  6. Fast Dissemination of New HIV-1 CRF02/A1 Recombinants in Pakistan

    PubMed Central

    Chen, Yue; Hora, Bhavna; DeMarco, Todd; Shah, Sharaf Ali; Ahmed, Manzoor; Sanchez, Ana M.; Su, Chang; Carter, Meredith; Stone, Mars; Hasan, Rumina; Hasan, Zahra; Busch, Michael P.; Denny, Thomas N.; Gao, Feng

    2016-01-01

    A number of HIV-1 subtypes are identified in Pakistan by characterization of partial viral gene sequences. Little is known whether new recombinants are generated and how they disseminate since whole genome sequences for these viruses have not been characterized. Near full-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes or next generation sequencing from 34 HIV-1-infected individuals in Pakistan. Phylogenetic tree analysis showed that the newly characterized sequences were 16 subtype As, one subtype C, and 17 A/G recombinants. Further analysis showed that all 16 subtype A1 sequences (47%), together with the vast majority of sequences from Pakistan from other studies, formed a tight subcluster (A1a) within the subtype A1 clade, suggesting that they were derived from a single introduction. More in-depth analysis of 17 A/G NFLG sequences showed that five shared similar recombination breakpoints as in CRF02 (15%) but were phylogenetically distinct from the prototype CRF02 by forming a tight subcluster (CRF02a) while 12 (38%) were new recombinants between CRF02a and A1a or a divergent A1b viruses. Unique recombination patterns among the majority of the newly characterized recombinants indicated ongoing recombination. Interestingly, recombination breakpoints in these CRF02/A1 recombinants were similar to those in prototype CRF02 viruses, indicating that recombination at these sites more likely generate variable recombinant viruses. The dominance and fast dissemination of new CRF02a/A1 recombinants over prototype CRF02 suggest that these recombinant have more adapted and may become major epidemic strains in Pakistan. PMID:27973597

  7. HbA1c as a predictor of diabetes after gestational diabetes mellitus.

    PubMed

    Claesson, Rickard; Ignell, Claes; Shaat, Nael; Berntorp, Kerstin

    2017-02-01

    We wanted to investigate third-trimester HbA1c as a predictor of diabetes after gestational diabetes mellitus (GDM). Women with GDM were followed up prospectively for five years from pregnancy to detect the development of diabetes. The ability of HbA1c to predict diabetes was evaluated with receiver-operating characteristic (ROC) curves and logistic regression analysis. By five years, 73 of 196 women had been diagnosed with diabetes. An optimal cut-off point for HbA1c of 36mmol/mol (5.4%) could predict diabetes with 45% sensitivity and 92% specificity. For HbA1c ≥39mmol/mol (≥5.7%), sensitivity, specificity, and positive predictive value were 30%, 97%, and 91%, respectively. In logistic regression analysis, adjusting for the diagnostic glucose concentration during pregnancy, HbA1c levels in the upper quartile (≥36mmol/mol) were associated with a 5.5-fold increased risk of diabetes. Third-trimester HbA1c levels in the pre-diabetes range revealed women with post-partum diabetes with high specificity and high positive predictive value. HbA1c testing could be used as a strategy to select high-risk women for lifestyle interventions aimed at prevention of diabetes starting during pregnancy. The results should encourage further validation in other populations using new diagnostic criteria for GDM. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  8. Misregulated progesterone secretion and impaired pregnancy in Cyp11a1 transgenic mice.

    PubMed

    Chien, Yu; Cheng, Wei-Cheng; Wu, Menq-Rong; Jiang, Si-Tse; Shen, Che-Kun James; Chung, Bon-chu

    2013-10-01

    Normal pregnancy is supported by increased levels of progesterone (P4), which is secreted from ovarian luteal cells via enzymatic steps catalyzed by P450scc (CYP11A1) and HSD3B. The development and maintenance of corpora lutea during pregnancy, however, are less well understood. Here we used Cyp11a1 transgenic mice to delineate the steps of luteal cell differentiation during pregnancy. Cyp11a1 in a bacterial artificial chromosome was injected into mouse embryos to generate transgenic mice with transgene expression that recapitulated endogenous Cyp11a1 expression. Cyp11a1 transgenic females displayed reduced pregnancy rate, impaired implantation and placentation, and decreased litter size in utero, although they produced comparable numbers of blastocysts. The differentiation of transgenic luteal cells was delayed during early pregnancy as shown by the delayed activation of genes involved in steroidogenesis and cholesterol availability. Luteal cell mitochondria were elongated, and their numbers were reduced, with morphology and numbers similar to those observed in granulosa cells. Transgenic luteal cells accumulated lipid droplets and secreted less progesterone during early pregnancy. The progesterone level returned to normal on gestation day 9 but was not properly withdrawn at term, leading to delayed stillbirth. P4 supplementation rescued the implantation rates but not the ovarian defects. Thus, overexpression of Cyp11a1 disrupts normal development of the corpus luteum, leading to progesterone insufficiency during early pregnancy. Misregulation of the progesterone production in Cyp11a1 transgenic mice during pregnancy resulted in aberrant implantation, anomalous placentation, and delayed parturition.

  9. Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia.

    PubMed

    Mistry, Hiten D; Kurlak, Lesia O; Mansour, Yosef T; Zurkinden, Line; Mohaupt, Markus G; Escher, Geneviève

    2017-06-01

    Preeclampsia is a pregnancy-specific condition that leads to increased cardiovascular risk in later life. A decrease in cholesterol efflux capacity is linked to CVD. We hypothesized that in preeclampsia there would be a disruption of maternal/fetal plasma to efflux cholesterol, as well as differences in the concentrations of both placental sterol 27-hydroxylase (CYP27A1) and apoA1 binding protein (AIBP). Total, HDL-, and ABCA1-mediated cholesterol effluxes were performed with maternal and fetal plasma from women with preeclampsia and normotensive controls (both n = 17). apoA1 and apoE were quantified by chemiluminescence, and 27-hydroxycholesterol (27-OHC) by GC-MS. Immunohistochemistry was used to determine placental expression/localization of CYP27A1, AIBP, apoA1, apoE, and SRB1. Maternal and fetal total and HDL-mediated cholesterol efflux capacities were increased in preeclampsia (by 10-20%), but ABCA1-mediated efflux was decreased (by 20-35%; P < 0.05). Maternal and fetal apoE concentrations were higher in preeclampsia. Fetal plasma 27-OHC levels were decreased in preeclamptic samples ( P < 0.05). Placental protein expression of both CYP27A1 and AIBP were localized around fetal vessels and significantly increased in preeclampsia ( P = 0.04). Placental 27-OHC concentrations were also raised in preeclampsia ( P < 0.05). Increased HDL-mediated cholesterol efflux capacity and placental CYP27A1/27-OHC could be a rescue mechanism in preeclampsia, to remove cholesterol from cells to limit lipid peroxidation and increase placental angiogenesis. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  10. Neue biosensorische Prinzipien für die Hämoglobin-A1c Bestimmung

    NASA Astrophysics Data System (ADS)

    Stöllner, Daniela

    2002-06-01

    Hämoglobin-A1c (HbA1c) ist ein Hämoglobin (Hb)-Subtypus, der durch nicht-enzymatische Glykierung des N-terminalen Valinrestes der Hämoglobin-beta-Kette entsteht. Das gemessene Verhältnis von HbA1c zum Gesamt-Hämoglobin (5-20 % bei Diabetikern) repräsentiert den Mittelwert der Blutglucosekonzentration über einen zweimonatigen Zeitraum und stellt zur Beurteilung der diabetischen Stoffwechsellage eine Ergänzung zur Akutkontrolle der Glukosekonzentration dar. Ziel der vorliegenden Arbeit war es, einen amperometrischen Biosensor für die Bestimmung des medizinisch relevanten Parameters HbA1c zu entwickeln. Durch Selektion geeigneter Bioerkennungselemente und deren Immobilisierung unter Erhalt der Bindungsfunktion für die Zielmoleküle Hämoglobin bzw. HbA1c wurden spezifische, hochaffine und regenerationsstabile Sensoroberflächen geschaffen. Für die Entwicklung des HbA1c-Biosensors wurden zwei Konzepte - Enzymsensor und Immunosensor - miteinander verglichen. Die enzymatische Umsetzung von HbA1c erfolgte mit der Fructosylamin Oxidase (FAO) aus Pichia pastoris N 1-1 unter Freisetzung von H2O2, welches sowohl optisch über eine Indikatorreaktion als auch elektrochemisch nach Einschluss der FAO in PVA-SbQ und Fixierung des Immobilisats vor einer H2O2-Elektrode nachgewiesen wurde. Die Kalibration des Enzymsensors mit der HbA1c-Modellsubstanz Fructosyl-Valin ergab Nachweisgrenzen, die ausserhalb des physiologisch relevanten HbA1c-Konzentrationsbereich lagen. Aus der Umsetzung von glykierten Peptiden mit einer nicht HbA1c analogen Aminosäurensequenz, z.B. Fructosyl-Valin-Glycin wurde zudem eine geringe HbA1c-Spezifität abgeleitet. Für den Immunosensor wurden zwei heterogene Immunoassay-Formate unter Verwendung von hochaffinen und spezifischen Antikörpern in Kombination mit Glucose Oxidase (GOD) als Markerenzym zum Nachweis von HbA1c untersucht. Beim indirekt-kompetitiven Immunoassay wurde anstelle des kompletten HbA1c-Moleküls das glykierte Pentapeptid

  11. Association Between Preoperative Hemoglobin A1c Levels, Postoperative Hyperglycemia, and Readmissions Following Gastrointestinal Surgery.

    PubMed

    Jones, Caroline E; Graham, Laura A; Morris, Melanie S; Richman, Joshua S; Hollis, Robert H; Wahl, Tyler S; Copeland, Laurel A; Burns, Edith A; Itani, Kamal M F; Hawn, Mary T

    2017-11-01

    Preoperative hyperglycemia is associated with adverse postoperative outcomes among patients who undergo surgery. Whether preoperative hemoglobin A1c (HbA1c) or postoperative glucose levels are more useful in predicting adverse events following surgery is uncertain in the current literature. To examine the use of preoperative HbA1c and early postoperative glucose levels for predicting postoperative complications and readmission. In this observational cohort study, inpatient gastrointestinal surgical procedures performed at 117 Veterans Affairs hospitals from 2007 to 2014 were identified, and cases of known infection within 3 days before surgery were excluded. Preoperative HbA1c levels were examined as a continuous and categorical variable (<5.7%, 5.7%-6.5%, and >6.5%). A logistic regression modeled postoperative complications and readmissions with the closest preoperative HbA1c within 90 days and the highest postoperative glucose levels within 48 hours of undergoing surgery. Postoperative complications and 30-day unplanned readmission following discharge. Of 21 541 participants, 1193 (5.5%) were women, and the mean (SD) age was 63.7 (10.6) years. The cohort included 23 094 operations with measurements of preoperative HbA1c levels and postoperative glucose levels. The complication and 30-day readmission rates were 27.2% and 14.7%, respectively. In logistic regression models adjusting for HbA1c, postoperative glucose levels, postoperative insulin use, diabetes, body mass index (calculated as weight in kilograms divided by height in meters squared), and other patient and procedural factors, peak postoperative glucose levels of more than 250 mg/dL were associated with increased 30-day readmissions (odds ratio, 1.18; 95% CI, 0.99-1.41; P = .07). By contrast, a preoperative HbA1c of more than 6.5% was associated with decreased 30-day readmissions (odds ratio, 0.85; 95% CI, 0.74-0.96; P = .01). As preoperative HbA1c increased, the frequency of 48-hour

  12. Identification of an evolutionarily conserved regulatory element of the zebrafish col2a1a gene.

    PubMed

    Dale, Rodney M; Topczewski, Jacek

    2011-09-15

    Zebrafish (Danio rerio) is an excellent model organism for the study of vertebrate development including skeletogenesis. Studies of mammalian cartilage formation were greatly advanced through the use of a cartilage specific regulatory element of the Collagen type II alpha 1 (Col2a1) gene. In an effort to isolate such an element in zebrafish, we compared the expression of two col2a1 homologues and found that expression of col2a1b, a previously uncharacterized zebrafish homologue, only partially overlaps with col2a1a. We focused our analysis on col2a1a, as it is expressed in both the stacked chondrocytes and the perichondrium. By comparing the genomic sequence surrounding the predicted transcriptional start site of col2a1a among several species of teleosts we identified a small highly conserved sequence (R2) located 1.7 kb upstream of the presumptive transcriptional initiation site. Interestingly, neither the sequence nor location of this element is conserved between teleost and mammalian Col2a1. We generated transient and stable transgenic lines with just the R2 element or the entire 1.7 kb fragment 5' of the transcriptional initiation site. The identified regulatory elements enable the tracking of cellular development in various tissues by driving robust reporter expression in craniofacial cartilage, ear, notochord, floor plate, hypochord and fins in a pattern similar to the expression of endogenous col2a1a. Using a reporter gene driven by the R2 regulatory element, we analyzed the morphogenesis of the notochord sheath cells as they withdraw from the stack of initially uniform cells and encase the inflating vacuolated notochord cells. Finally, we show that like endogenous col2a1a, craniofacial expression of these reporter constructs depends on Sox9a transcription factor activity. At the same time, notochord expression is maintained after Sox9a knockdown, suggesting that other factors can activate expression through the identified regulatory element in this tissue

  13. Identification of an evolutionarily conserved regulatory element of the zebrafish col2a1a gene

    PubMed Central

    Dale, Rodney M.; Topczewski, Jacek

    2011-01-01

    Zebrafish (Danio rerio) is an excellent model organism for the study of vertebrate development including skeletogenesis. Studies of mammalian cartilage formation were greatly advanced through the use of a cartilage specific regulatory element of the Collagen type II alpha 1 (Col2a1) gene. In an effort to isolate such an element in zebrafish, we compared the expression of two col2a1 homologues and found that expression of col2a1b, a previously uncharacterized zebrafish homologue, only partially overlaps with col2a1a. We focused our analysis on col2a1a, as it is expressed in both the stacked chondrocytes and the perichondrium. By comparing the genomic sequence surrounding the predicted transcriptional start site of col2a1a among several species of teleosts we identified a small highly conserved sequence (R2) located 1.7 kb upstream of the presumptive transcriptional initiation site. Interestingly, neither the sequence nor location of this element is conserved between teleost and mammalian Col2a1. We generated transient and stable transgenic lines with just the R2 element or the entire 1.7 kb fragment 5’ of the transcriptional initiation site. The identified regulatory elements enable the tracking of cellular development in various tissues by driving robust reporter expression in craniofacial cartilage, ear, notochord, floor plate, hypochord and fins in a pattern similar to the expression of endogenous col2a1a. Using a reporter gene driven by the R2 regulatory element, we analyzed the morphogenesis of the notochord sheath cells as they withdraw from the stack of initially uniform cells and encase the inflating vacuolated notochord cells. Finally, we show that like endogenous col2a1a, craniofacial expression of these reporter constructs depends on Sox9a transcription factor activity. At the same time, notochord expression is maintained after Sox9a knockdown, suggesting that other factors can activate expression through the identified regulatory element in this tissue

  14. Performance evaluation of the Arkray Adams HA-8160 HbA1c analyser.

    PubMed

    Thevarajah, T Malathi; Nani, Nordin; Chew, Y Y

    2008-12-01

    HbA1c measurement is currently routinely used to predict long term outcome of diabetes, thus playing a fundamental role in the management of diabetes. The relationship between HbA1c value and long term diabetic complications has been established by a randomised control Diabetes Control and Complications Trial (DCCT) which used high performance liquid chromatography (HPLC) as a reference method for HbA1c assay. To ensure that HbA1c results from a variety HbA1c assay methods are similar to the DCCT values, the American Diabetes Association (ADA) recommended that all laboratories should use methods certified by the National Glycohemoglobin Standardization Programme (NGSP) with interassay coefficient variation (CV) of < 5% (ideally < 3%). The International Federation of Clinical Chemistry (IFCC) working group on HbA1c standardisation has set a CV < 2.5% as a criteria for its reference laboratories. To evaluate the performance of Arkray Adams HA-8160 HbA1c analyser which uses a cation exchange HPLC method and its correlation to HbA1c assay on Cobas Integra 800 which is an immunoturbidimetric method. For the imprecision study, patient samples and control material of two levels were analysed on HA-8160 analyser 20 times in a single run (within-run imprecision) and twice a day on five consecutive days (between-run imprecision). For the recovery study, two samples each with high and low values were selected and mixed in ratios of 1:3, 1:1 and 3:1, and were analysed by HA-8160. Sixty samples were analysed by both Cobas Integra 800 and HA-8160 for method comparison study. Ten uraemic samples and ten thalassaemic samples were assayed on Cobas Integra 800 and HA 8160 for interference study. Within-run CVs were 0.6% and 0.7% for medium and high value samples respectively, 0.6% and 0.7% for low and high level controls respectively. Between-run CVs were 0.5% and 0.4% for medium and high value samples respectively, 0.5% and 0.6% for low and high level controls respectively. The

  15. HbA1c and the Prediction of Type 2 Diabetes in Children and Adults

    PubMed Central

    Vijayakumar, Pavithra; Nelson, Robert G.; Hanson, Robert L.; Knowler, William C.

    2017-01-01

    OBJECTIVE Long-term data validating glycated hemoglobin (HbA1c) in assessing the risk of type 2 diabetes in children are limited. HbA1c, fasting plasma glucose (FPG), and 2-h postload plasma glucose (2hPG) concentrations were measured in a longitudinal study of American Indians to determine their utility in predicting incident diabetes, all of which is thought to be type 2 in this population. RESEARCH DESIGN AND METHODS Incident diabetes (FPG ≥126 mg/dL [7.0 mmol/L], 2hPG ≥200 mg/dL [11.1 mmol/L], HbA1c ≥6.5% [8 mmol/mol], or clinical diagnosis) was determined in 2,095 children without diabetes ages 10–19 years monitored through age 39, and in 2,005 adults ages 20–39 monitored through age 59. Areas under the receiver operating characteristic (ROC) curve for HbA1c, FPG, and 2hPG in predicting diabetes within 10 years were compared. RESULTS During long-term follow-up of children and adolescents who did not initially have diabetes, the incidence rate of subsequent diabetes was fourfold (in boys) as high and more than sevenfold (in girls) as high in those with HbA1c ≥5.7% as in those with HbA1c ≤5.3%—greater rate ratios than experienced by adults in the same HbA1c categories. Analyses of ROCs revealed no significant differences between HbA1c, FPG, and 2hPG in sensitivity and specificity for identifying children and adolescents who later developed diabetes. CONCLUSIONS HbA1c is a useful predictor of diabetes risk in children and can be used to identify prediabetes in children with other type 2 diabetes risk factors with the same predictive value as FPG and 2hPG. PMID:27810987

  16. HbA1c and the Prediction of Type 2 Diabetes in Children and Adults.

    PubMed

    Vijayakumar, Pavithra; Nelson, Robert G; Hanson, Robert L; Knowler, William C; Sinha, Madhumita

    2017-01-01

    Long-term data validating glycated hemoglobin (HbA 1c ) in assessing the risk of type 2 diabetes in children are limited. HbA 1c , fasting plasma glucose (FPG), and 2-h postload plasma glucose (2hPG) concentrations were measured in a longitudinal study of American Indians to determine their utility in predicting incident diabetes, all of which is thought to be type 2 in this population. Incident diabetes (FPG ≥126 mg/dL [7.0 mmol/L], 2hPG ≥200 mg/dL [11.1 mmol/L], HbA 1c ≥6.5% [8 mmol/mol], or clinical diagnosis) was determined in 2,095 children without diabetes ages 10-19 years monitored through age 39, and in 2,005 adults ages 20-39 monitored through age 59. Areas under the receiver operating characteristic (ROC) curve for HbA 1c , FPG, and 2hPG in predicting diabetes within 10 years were compared. During long-term follow-up of children and adolescents who did not initially have diabetes, the incidence rate of subsequent diabetes was fourfold (in boys) as high and more than sevenfold (in girls) as high in those with HbA 1c ≥5.7% as in those with HbA 1c ≤5.3%-greater rate ratios than experienced by adults in the same HbA 1c categories. Analyses of ROCs revealed no significant differences between HbA 1c , FPG, and 2hPG in sensitivity and specificity for identifying children and adolescents who later developed diabetes. HbA 1c is a useful predictor of diabetes risk in children and can be used to identify prediabetes in children with other type 2 diabetes risk factors with the same predictive value as FPG and 2hPG. © 2017 by the American Diabetes Association.

  17. Polymorphisms of CYP1A1 and GSTM1 Genes and Susceptibility to Oral Cancer

    PubMed Central

    Cha, In-Ho; Park, Jong Yun; Chung, Won-Yoon; Choi, Min-Ah; Kim, Hyung-Jun

    2007-01-01

    Purpose Oral cancer is the fifth most common form of cancer in the world and comprises 6.5% of all cancer deaths. Since one of the major risk factors for oral cancer is tobacco use, we hypothesized that polymorphic genes coding for tobacco carcinogen-metabolizing enzymes may play a role in oral cancer susceptibility. Materials and Methods To investigate the association between polymorphisms of the CYP1A1 and GSTM1 genes and risks for oral squamous cell carcinoma (OSCC) in the Korean population, the prevalence of the CYP1A1 Mspl and GSTM1 null polymorphisms were examined in 72 patients with histologically confirmed primary OSCC, as well as in 221 healthy control subjects. Results A significant risk increase for oral cancer was observed among subjects with the homozygous CYP1A1 (m2/m2) genotype (OR = 3.8, 95% CI = 1.9-7.7), but not the GSTM1 null genotype (OR = 0.7, 95% CI = 0.4-1.3). Risk for oral cancer was significantly increased in subjects with the homozygous CYP1A1 (m2/m2) genotype, regardless of smoking history (smokers; OR = 4.4; 95% CI = 1.2-16.3; non-smokers OR = 4.9; 95% CI=1.9-12.5). Using the potentially most protective genotype GSTM1 (+)/CYP1A1 [(m1/m1)+(m1/m2)] as the reference group, an increased risk for oral cancer was observed among subjects with the GSTM1 (+)/ CYP1A1 (m2/m2) (OR = 2.0, 95% CI = 0.8-5.2), and GSTM1 (-)/ CYP1A1 (m2/m2) (OR=4.9, 95% CI = 1.5-15.5) genotypes (p < 0.009, (χ2 trend test). Conclusion Our results suggest that individuals with a genotype of CYP1A1 (m2/m2) and GSTM1 (-) are highly susceptible for OSCC and that the CYP1A1 (m2/m2) genotype is closely associated with increased risk of OSCC in Koreans. PMID:17461521

  18. In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion.

    PubMed

    Thangavelu, Pulari U; Krenács, Tibor; Dray, Eloise; Duijf, Pascal H G

    2016-01-01

    Metastasis is a leading cause of death among cancer patients. In the tumor microenvironment, altered levels of extracellular matrix proteins, such as collagens, can facilitate the first steps of cancer cell metastasis, including invasion into surrounding tissue and intravasation into the blood stream. However, the degree of misexpression of collagen genes in tumors remains understudied, even though this knowledge could greatly facilitate the development of cancer treatment options aimed at preventing metastasis. We systematically evaluate the expression of all 44 collagen genes in breast cancer and assess whether their misexpression provides clinical prognostic significance. We use immunohistochemistry on 150 ductal breast cancers and 361 cervical cancers and study DNA methylation in various epithelial cancers. In breast cancer, various tests show that COL4A1 and COL4A2 overexpression and COL17A1 ( BP180 , BPAG2 ) underexpression provide independent prognostic strength (HR = 1.25, 95% CI = 1.17-1.34, p  = 3.03 × 10 -10 ; HR = 1.18, 95% CI = 1.11-1.25, p  = 8.11 × 10 -10 ; HR = 0.86, 95% CI = 0.81-0.92, p  = 4.57 × 10 -6 ; respectively). Immunohistochemistry on ductal breast cancers confirmed that the COL17A1 protein product, collagen XVII, is underexpressed. This strongly correlates with advanced stage, increased invasion, and postmenopausal status. In contrast, immunohistochemistry on cervical tumors showed that collagen XVII is overexpressed in cervical cancer and this is associated with increased local dissemination. Interestingly, consistent with the opposed direction of misexpression in these cancers, the COL17A1 promoter is hypermethylated in breast cancer and hypomethylated in cervical cancer. We also find that the COL17A1 promoter is hypomethylated in head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma, in all of which collagen XVII overexpression has previously been

  19. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution

    PubMed Central

    König, Julian; Zarnack, Kathi; Rot, Gregor; Curk, Tomaž; Kayikci, Melis; Zupan, Blaž; Turner, Daniel J.; Luscombe, Nicholas M.; Ule, Jernej

    2010-01-01

    In the nucleus of eukaryotic cells, nascent transcripts are associated with heterogeneous nuclear ribonucleoprotein (hnRNP) particles that are nucleated by hnRNP C. Despite their abundance however, it remained unclear whether these particles control pre-mRNA processing. Here, we developed individual-nucleotide resolution UV-cross-linking and immunoprecipitation (iCLIP) to study the role of hnRNP C in splicing regulation. iCLIP data demonstrate that hnRNP C recognizes uridine tracts with a defined long-range spacing consistent with hnRNP particle organization. hnRNP particles assemble on both introns and exons, but remain generally excluded from splice sites. Integration of transcriptome-wide iCLIP data and alternative splicing profiles into an ‘RNA map’ indicates how the positioning of hnRNP particles determines their effect on inclusion of alternative exons. The ability of high-resolution iCLIP data to provide insights into the mechanism of this regulation holds promise for studies of other higher-order ribonucleoprotein complexes. PMID:20601959

  20. Association of COL1A1 polymorphism with high myopia: a Meta-analysis

    PubMed Central

    Jin, Guang-Ming; Zhao, Xiao-Jing; Chen, Ai-Ming; Chen, Yong-Xing; Li, Qin

    2016-01-01

    AIM To investigate the association between collagen type I alpha 1 (COL1A1) gene and high myopia. METHODS In this Meta-analysis, we examined 5 published case-control studies that involved 1942 high myopia cases and 2929 healthy controls to assess the association between the COL1A1 rs2075555 polymorphism and high myopia risk. We calculated the pooled odds ratios (ORs) of COL1A1 rs2075555 polymorphism in high myopia cases vs healthy controls to evaluate the strength of the association. RESULTS Overall, there was no significant difference both in the genotype and allele distributions of COL1A1 rs2075555 polymorphism between high myopia cases and healthy controls: CC vs AA OR=1.10, 95% confidence interval (CI)=0.76-1.58; AC vs AA OR=0.98, 95%CI 0.80-1.20; CC/AC vs AA/OR=1.01, 95%CI 0.84-1.22; CC vs AC/AA OR=1.06, 95%CI=0.93-1.20; C vs A OR=1.06, 95%CI 0.91-1.23). In addition, in the stratified analyses by ethnicity, no significant associations were found in any genetic model both in European and Asia cohorts. CONCLUSION Our results indicate that the COL1A1 rs2075555 polymorphism may not affect susceptibility to high myopia. PMID:27162737

  1. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer's disease.

    PubMed

    Kobayashi, Yodai; Sugahara, Hirosuke; Shimada, Kousuke; Mitsuyama, Eri; Kuhara, Tetsuya; Yasuoka, Akihito; Kondo, Takashi; Abe, Keiko; Xiao, Jin-Zhong

    2017-10-18

    It has previously been shown that the consumption of probiotics may have beneficial effects not only on peripheral tissues but also on the central nervous system and behavior via the microbiota-gut-brain axis, raising the possibility that treatment with probiotics could be an effective therapeutic strategy for managing neurodegenerative disorders. In this study, we investigated the effects of oral administration of Bifidobacterium breve strain A1 (B. breve A1) on behavior and physiological processes in Alzheimer's disease (AD) model mice. We found that administration of B. breve A1 to AD mice reversed the impairment of alternation behavior in a Y maze test and the reduced latency time in a passive avoidance test, indicating that it prevented cognitive dysfunction. We also demonstrated that non-viable components of the bacterium or its metabolite acetate partially ameliorated the cognitive decline observed in AD mice. Gene profiling analysis revealed that the consumption of B. breve A1 suppressed the hippocampal expressions of inflammation and immune-reactive genes that are induced by amyloid-β. Together, these findings suggest that B. breve A1 has therapeutic potential for preventing cognitive impairment in AD.

  2. Variation in the CYP19A1 gene and risk of colon and rectal cancer

    PubMed Central

    Slattery, Martha L.; Lundgreen, Abbie; Herrick, Jennifer S.; Kadlubar, Susan; Caan, Bette J.; Potter, John D.; Wolff, Roger K.

    2011-01-01

    CYP19A1, or aromatase, influences estrogen-metabolizing enzymes and may influence cancer risk. We examine variation in the CYP19A1 gene and risk of colorectal cancer using data from population-based case–control studies (colon n = 1,574 cases, 1,970 controls; rectal n = 791 cases, 999 controls). Four SNPs were statistically significantly associated with colon cancer and four were associated with rectal cancer. After adjustment for multiple comparisons, the AA genotype of rs12591359 was associated with an increased risk of colon cancer (OR 1.44 95% CI 1.16–1.80) and the AA genotype of rs2470144 was associated with a reduced risk of rectal cancer (OR 0.65 95% CI 0.50–0.84). Variants of CYP19A1 were associated with CIMP+ and CIMP+/KRAS2-mutated tumors. CT/TT genotypes of rs1961177 were significantly associated with an increased likelihood of a MSI+ colon tumor (OR 1.77 95% CI 1.26–2.37). We observed statistically significant interactions between genetic variation in NFκB1 and CYP19A1 for both colon and rectal cancer. Our data suggest the importance of CYP19A1 in the development of colon and rectal cancer and that estrogen may influence risk through an inflammation-related mechanism. PMID:21479914

  3. Anticonvulsant effect of AMP by direct activation of adenosine A1 receptor.

    PubMed

    Muzzi, Mirko; Coppi, Elisabetta; Pugliese, Anna Maria; Chiarugi, Alberto

    2013-12-01

    Purinergic neurotransmission mediated by adenosine (Ado) type 1 receptors (A1Rs) plays pivotal roles in negative modulation of epileptic seizures, and Ado is thought to be a key endogenous anticonvulsant. Recent evidence, however, indicates that AMP, the metabolic precursor of Ado, also activate A1Rs. Here, we evaluated the antiepileptic effects of AMP adopting in vitro and in vivo models of epilepsy. We report that AMP reversed the increase in population spike (PS) amplitude and the decrease in PS latency induced by a Mg(2+)-free extracellular solution in CA1 neurons of mouse hippocampal slices. The AMP effects were inhibited by the A1R antagonist DPCPX, but not prevented by inhibiting conversion of AMP into Ado, indicating that AMP inhibited per se sustained hippocampal excitatory neurotransmission by directly activating A1Rs. AMP also reduced seizure severity and mortality in a model of audiogenic convulsion. Of note, the anticonvulsant effects of AMP were potentiated by preventing its conversion into Ado and inhibited by DPCPX. When tested in a model of kainate-induced seizure, AMP prolonged latency of convulsions but had no effects on seizure severity and mortality. Data provide the first evidence that AMP is an endogenous anticonvulsant acting at A1Rs. © 2013.

  4. Potentiation of adenosine A1 receptor agonist CPA-induced antinociception by paeoniflorin in mice.

    PubMed

    Liu, Da-Zhi; Zhao, Fei-Li; Liu, Jing; Ji, Xin-Quan; Ye, Yang; Zhu, Xing-Zu

    2006-08-01

    The effect of paeoniflorin (PF), a major constituent isolated from Paeony radix, on N6-Cyclopentyladenosine (CPA), a selective adenosine A1 receptor (A1 receptor) agonist, induced antinociception was examined in mice. In the tail-pressure test, CPA (0.05, 0.1, 0.2 mg/kg, s.c.) could induce antinociception in a dose-dependent manner. PF (5, 10, 20 mg/kg, s.c.) alone failed to exhibit any antinociceptive effect in mice; however, pretreatment of PF (20 mg/kg, s.c.) could significantly enhance CPA-induced antinociception. Additionally, pretreatment of 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.25 mg/kg, s.c.), a selective A1 receptor antagonist, could antagonize the antinociceptive effect of combining CPA with PF. Furthermore, in the competitive binding experiments, PF did not displace the binding of [3H]-8-Cyclopentyl-1,3-dipropylxanthine ([3H]-DPCPX) but displaced that of [3H]-2-Chloro-N6-cyclopentyladenosine ([3H]-CCPA, a selective A1 receptor agonist) to the membrane preparation of rat cerebral cortex. These results suggested that PF might selectively increase the binding and antinociceptive effect of CPA by binding with A1 receptor.

  5. Molecular characterization of subgenotype A1 (subgroup Aa) of hepatitis B virus.

    PubMed

    Kramvis, Anna; Kew, Michael C

    2007-07-01

    Subgenotypes of hepatitis B virus (HBV) were first recognized after a unique segment of genotype A was identified when sequencing the preS2/S region of southern African HBV isolates. Originally named subgroup A', subsequently called subgroup Aa (for Africa) or subgenotype A1, this subgenotype is found in South Africa, Malawi, Uganda, Tanzania, Somalia, Yemen, India, Nepal, the Philippines and Brazil. The relatively higher mean nucleotide divergence of subgenotype A1 suggests that it has been endemic and has a long evolutionary history in the populations where it prevails. Distinctive sequence characteristics could account for the high hepatitis B e-antigen (HBeAg) negativity and low HBV DNA levels in carriers of this subgenotype. Substitutions or mutations can reduce HBeAg expression at three levels: (i) 1762T1764A atthe transcriptional level; (ii) substitutions at nt 1809-1812 at the translational level; and (iii) 1862T at the post-translational level. Co-existence of 1762T1764A and nt 1809-1812 mutations reduces HBeAg expression in an additive manner. In addition, subgenotype A1 has unique sequence alterations in the transcriptional regulatory elements and the polymerase coding region. The distinct sequence characteristics of subgenotype A1 may contribute to the 4.5-fold increased risk of heptocellular carcinoma in HBV carriers infected with genotype A, which is entirely attributable to subgenotype A1.

  6. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption.

    PubMed

    Posavec Marjanović, Melanija; Hurtado-Bagès, Sarah; Lassi, Maximilian; Valero, Vanesa; Malinverni, Roberto; Delage, Hélène; Navarro, Miriam; Corujo, David; Guberovic, Iva; Douet, Julien; Gama-Perez, Pau; Garcia-Roves, Pablo M; Ahel, Ivan; Ladurner, Andreas G; Yanes, Oscar; Bouvet, Philippe; Suelves, Mònica; Teperino, Raffaele; Pospisilik, J Andrew; Buschbeck, Marcus

    2017-11-01

    Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD + -derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD + consumption. The resultant accumulation of the NAD + precursor NMN allows for maintenance of mitochondrial NAD + pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD + consumption and establishing a buffer of NAD + precursors in differentiated cells.

  7. The targetable A1 Huntington disease haplotype has distinct Amerindian and European origins in Latin America

    PubMed Central

    Kay, Chris; Tirado-Hurtado, Indira; Cornejo-Olivas, Mario; Collins, Jennifer A; Wright, Galen; Inca-Martinez, Miguel; Veliz-Otani, Diego; Ketelaar, Maria E; Slama, Ramy A; Ross, Colin J; Mazzetti, Pilar; Hayden, Michael R

    2017-01-01

    Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. HD occurs worldwide, but the causative mutation is found on different HTT haplotypes in distinct ethnic groups. In Latin America, HD is thought to have European origins, but indigenous Amerindian ancestry has not been investigated. Here, we report dense HTT haplotypes in 62 mestizo Peruvian HD families, 17 HD families from across Latin America, and 42 controls of defined Peruvian Amerindian ethnicity to determine the origin of HD in populations of admixed Amerindian and European descent. HD in Peru occurs most frequently on the A1 HTT haplotype (73%), as in Europe, but on an unexpected indigenous variant also found in Amerindian controls. This Amerindian A1 HTT haplotype predominates over the European A1 variant among geographically disparate Latin American controls and in HD families from across Latin America, supporting an indigenous origin of the HD mutation in mestizo American populations. We also show that a proportion of HD mutations in Peru occur on a C1 HTT haplotype of putative Amerindian origin (14%). The majority of HD mutations in Latin America may therefore occur on haplotypes of Amerindian ancestry rather than on haplotypes resulting from European admixture. Despite the distinct ethnic ancestry of Amerindian and European A1 HTT, alleles on the parent A1 HTT haplotype allow for development of identical antisense molecules to selectively silence the HD mutation in the greatest proportion of patients in both Latin American and European populations. PMID:28000697

  8. Enhanced UGT1A1 Gene and Protein Expression in Endometriotic Lesions.

    PubMed

    Piccinato, Carla A; Neme, Rosa M; Torres, Natália; da Silva Victor, Elivane; Brudniewski, Heloísa F; Rosa E Silva, Júlio C; Ferriani, Rui A

    2018-01-01

    The cellular function in endometriosis lesions depends on a highly estrogenic milieu. Lately, it is becoming evident that, besides the circulating levels of estrogens, the balance of synthesis versus inactivation (metabolism) of estrogens by intralesion steroid-metabolizing enzymes also determines the local net estrogen availability. In order to extend the knowledge of the role of estrogen-metabolizing enzymes in endometriosis, we investigated the gene and protein expression of a key uridine diphospho-glucuronosyltransferase (UGT) for estrogen glucuronidation, UGT1A1, in eutopic endometrial samples obtained from nonaffected and endometriosis-affected women and also from endometriotic lesions. Although UGT1A1 messenger RNA (mRNA) expression was detected at similar frequencies in endometriotic lesions and in eutopic endometrial samples, the levels of mRNA expression were greater in deep-infiltrating endometriotic lesions and in non-deep-infiltrating lesions when compared with either control endometrium or eutopic endometrium from women with endometriosis. Overall, we observed that protein expression of UGT1A1 was significantly more frequent in samples from endometriotic lesions in comparison with endometria. In addition, expression of UGT1A1 protein was greater in deep-infiltrating than in non-deep-infiltrating endometriotic lesions. We suggest that the finding of increased expression of UGT1A1 in lesions versus endometria might be related to impairment of regulatory mechanisms, in response to a highly estrogenic milieu, and that this enzyme may be a new target for therapy.

  9. Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

    PubMed Central

    Holcomb, John B.; Tilley, Barbara C.; Baraniuk, Sarah; Fox, Erin E.; Wade, Charles E.; Podbielski, Jeanette M.; del Junco, Deborah J.; Brasel, Karen J.; Bulger, Eileen M.; Callcut, Rachael A.; Cohen, Mitchell Jay; Cotton, Bryan A.; Fabian, Timothy C.; Inaba, Kenji; Kerby, Jeffrey D.; Muskat, Peter; O’Keeffe, Terence; Rizoli, Sandro; Robinson, Bryce R. H.; Scalea, Thomas M.; Schreiber, Martin A.; Stein, Deborah M.; Weinberg, Jordan A.; Callum, Jeannie L.; Hess, John R.; Matijevic, Nena; Miller, Christopher N.; Pittet, Jean-Francois; Hoyt, David B.; Pearson, Gail D.; Leroux, Brian; van Belle, Gerald

    2015-01-01

    IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% [95% CI, −9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% [95% CI, −10.4% to −0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and

  10. Mechanism of Inhibition of Hsp90 Dimerization by Gyrase B Inhibitor Coumermycin A1 (C-A1) Revealed by Molecular Dynamics Simulations and Thermodynamic Calculations.

    PubMed

    Cele, Favourite N; Kumalo, Hezekiel; Soliman, Mahmoud E S

    2016-09-01

    Heat shock protein (Hsp) 90 an emerging and attracting target in the anti-HIV drug discovery process due to the key role it plays in the pathogenicity of HIV-1 virus. In this research study, long-range all-atom molecular dynamics simulations were engaged for the bound and the unbound proteins to enhance the understanding of the molecular mechanisms of the Hsp90 dimerization and inhibition. Results evidently showed that coumermycin A1 (C-A1), a recently discovered Hsp90 inhibitor, binds at the dimer's active site of the Hsp90 protein and leads to a substantial parting between dimeric opposed residues, which include Arg591.B, Lys594.A, Ser663.A, Thr653.B, Ala665.A, Thr649.B, Leu646.B and Asn669.A. Significant differences in magnitudes were observed in radius of gyration, root-mean-square deviation and root-mean-square fluctuation, which confirms a reasonably more flexible state in the apo conformation associated with it dimerization. In contrast, the bound conformer of Hsp90 showed less flexibility. This visibly highpoints the inhibition process resulting from the binding of the ligand. These findings were further validated by principal component analysis. We believe that the detailed dynamic analyses of Hsp90 presented in this study, would give an imperative insight and better understanding to the function and mechanisms of inhibition. Furthermore, information obtained from the binding mode of the inhibitor would be of great assistance in the design of more potent inhibitors against the HIV target Hsp90.

  11. Collisional relaxation of O2(a1Δ, υ = 1, 2, 3) by CO2

    NASA Astrophysics Data System (ADS)

    Torbin, A. P.; Pershin, A. A.; Mebel, A. M.; Zagidullin, M. V.; Heaven, M. C.; Azyazov, V. N.

    2018-01-01

    Rate coefficients for the vibrational relaxation of O2(a1Δ, υ) by CO2 have been determined from the decay of fluorescence of the a1Δg → X3 Σg- (υ-υ‧) transitions with υ = υ‧ = 1, 2 and 3. O2(a1Δ, υ) molecules were produced by pulsed laser photolysis of ozone at a wavelength of 266 nm. The rate coefficients were measured to be (1.9 ± 0.2) × 10-14 cm3/s, (2.4 ± 0.2) × 10-14 cm3/s and (2.7 ± 0.3) × 10-14 cm3/s for υ = 1, 2 and 3 respectively.

  12. Association Between the Presence of Iron Deficiency Anemia and Hemoglobin A1c in Korean Adults

    PubMed Central

    Hong, Jae W.; Ku, Cheol R.; Noh, Jung H.; Ko, Kyung S.; Rhee, Byoung D.; Kim, Dong-Jun

    2015-01-01

    Abstract Few studies have investigated the clinical effect of iron deficiency anemia (IDA) on the use of the Hemoglobin A1c (HbA1c) as a screening parameter for diabetes or prediabetes. We investigated the association between IDA and HbA1c levels in Korean adults. Among the 11,472 adults (≥19 years of age) who participated in the 2011–2012 Korea National Health and Nutrition Examination Survey (a cross-sectional and nationally representative survey conducted by the Korean Center for Disease Control for Health Statistics), 807 patients with diabetes currently taking anti-diabetes medications were excluded from this study. We compared the weighted HbA1c levels and weighted proportion (%) of HbA1c levels of ≥5.7%, ≥6.1%, and ≥6.5% according to the range of fasting plasma glucose (FPG) levels and the presence of IDA. Among 10,665 participants (weighted n = 35,229,108), the prevalence of anemia and IDA was 7.3% and 4.3%, respectively. The HbA1c levels were higher in participants with IDA (5.70% ± 0.02%) than in normal participants (5.59% ± 0.01%; P < 0.001), whereas there was no significant difference in FPG levels. In participants with an FPG level of <100 mg/dL and 100 to 125 mg/dL, the weighted HbA1c level was higher in those with IDA (5.59% ± 0.02% and 6.00% ± 0.05%) than in normal participants (5.44% ± 0.01% and 5.82% ± 0.01%) after adjusting for confounders such as age, sex, FPG level, heavy alcohol drinking, waist circumference, and smoking status as well as after exclusion of an estimated glomerular filtration rate of <60 mL/min/1.73 m2 (P < 0.001, <0.01). The weighted proportions (%) of an HbA1c level of ≥5.7% and ≥6.1% were also higher in participants with IDA than in normal participants (P < 0.001, <0.05). However, the weighted HbA1c levels in individuals with an FPG level ≥126 mg/dL and a weighted proportion (%) of an HbA1c level of ≥6.5% showed no significant differences according to

  13. Fracture mechanics in fiber reinforced composite materials, taking as examples B/A1 and CRFP

    NASA Technical Reports Server (NTRS)

    Peters, P. W. M.

    1982-01-01

    The validity of linear elastic fracture mechanics and other fracture criteria was investigated with laminates of boron fiber reinforced aluminum (R/A1) and of carbon fiber reinforced epoxide (CFRP). Cracks are assessed by fracture strength Kc or Kmax (critical or maximum value of the stress intensity factor). The Whitney and Nuismer point stress criterion and average stress criterion often show that Kmax of fiber composite materials increases with increasing crack length; however, for R/A1 and CFRP the curve showing fracture strength as a function of crack length is only applicable in a small domain. For R/A1, the reason is clearly the extension of the plastic zone (or the damage zone n the case of CFRP) which cannot be described with a stress intensity factor.

  14. A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome.

    PubMed

    Kohmoto, Tomohiro; Tsuji, Atsumi; Morita, Kei-Ichi; Naruto, Takuya; Masuda, Kiyoshi; Kashimada, Kenichi; Enomoto, Keisuke; Morio, Tomohiro; Harada, Hiroyuki; Imoto, Issei

    2016-01-01

    Stickler syndrome (STL) is an autosomal, dominantly inherited, clinically variable and genetically heterogeneous connective tissue disorder characterized by ocular, auditory, orofacial and skeletal abnormalities. We conducted targeted resequencing using a next-generation sequencer for molecular diagnosis of a 2-year-old girl who was clinically suspected of having STL with Pierre Robin sequence. We detected a novel heterozygous missense mutation, NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A], in COL11A1, resulting in a Gly to Asp substitution at position 1507 [NM_001854.3(COL11A1_i001)] within one of the collagen-like domains of the triple helical region. The same mutation was detected in her 4-year-old brother with cleft palate and high-frequency sensorineural hearing loss.

  15. A novel COL11A1 missense mutation in siblings with non-ocular Stickler syndrome

    PubMed Central

    Kohmoto, Tomohiro; Tsuji, Atsumi; Morita, Kei-ichi; Naruto, Takuya; Masuda, Kiyoshi; Kashimada, Kenichi; Enomoto, Keisuke; Morio, Tomohiro; Harada, Hiroyuki; Imoto, Issei

    2016-01-01

    Stickler syndrome (STL) is an autosomal, dominantly inherited, clinically variable and genetically heterogeneous connective tissue disorder characterized by ocular, auditory, orofacial and skeletal abnormalities. We conducted targeted resequencing using a next-generation sequencer for molecular diagnosis of a 2-year-old girl who was clinically suspected of having STL with Pierre Robin sequence. We detected a novel heterozygous missense mutation, NM_001854.3:n.4838G>A [NM_001854.3 (COL11A1_v001):c.4520G>A], in COL11A1, resulting in a Gly to Asp substitution at position 1507 [NM_001854.3(COL11A1_i001)] within one of the collagen-like domains of the triple helical region. The same mutation was detected in her 4-year-old brother with cleft palate and high-frequency sensorineural hearing loss. PMID:27081569

  16. C 1Σ+ , A 1Σ+ , and b 3Π0+ states of LiRb

    NASA Astrophysics Data System (ADS)

    Stevenson, I. C.; Blasing, D. B.; Chen, Y. P.; Elliott, D. S.

    2016-12-01

    We present the first spectroscopic studies of the C 1Σ+ electronic state and the A 1Σ+ -b 3Π0+ complex in 7Li-85Rb. Using resonantly enhanced, two-photon ionization, we observed v =7 , 9, 12, 13, and 26-45 of the C 1Σ+ state. We augment the REMPI data with a form of depletion spectra in regions of dense spectral lines. The A 1Σ+ -b 3Π0+ complex was observed with depletion spectroscopy, depleting to vibrational levels v =0 →29 of the A 1Σ+ state and v =8 →18 of the b 3Π0+ state. For all three series, we determine the term energy and vibrational constants. Finally, we outline several possible future projects based on the data presented here.

  17. Identification of the Coumermycin A1 Biosynthetic Gene Cluster of Streptomyces rishiriensis DSM 40489

    PubMed Central

    Wang, Zhao-Xin; Li, Shu-Ming; Heide, Lutz

    2000-01-01

    The biosynthetic gene cluster of the aminocoumarin antibiotic coumermycin A1 was cloned by screening of a cosmid library of Streptomyces rishiriensis DSM 40489 with heterologous probes from a dTDP-glucose 4,6-dehydratase gene, involved in deoxysugar biosynthesis, and from the aminocoumarin resistance gyrase gene gyrBr. Sequence analysis of a 30.8-kb region upstream of gyrBr revealed the presence of 28 complete open reading frames (ORFs). Fifteen of the identified ORFs showed, on average, 84% identity to corresponding ORFs in the biosynthetic gene cluster of novobiocin, another aminocoumarin antibiotic. Possible functions of 17 ORFs in the biosynthesis of coumermycin A1 could be assigned by comparison with sequences in GenBank. Experimental proof for the function of the identified gene cluster was provided by an insertional gene inactivation experiment, which resulted in an abolishment of coumermycin A1 production. PMID:11036020

  18. Hepatitis B Virus Subgenotype A1: Evolutionary Relationships between Brazilian, African and Asian Isolates

    PubMed Central

    Lago, Bárbara V.; Mello, Francisco C.; Kramvis, Anna; Niel, Christian; Gomes, Selma A.

    2014-01-01

    Brazil is a country of low hepatitis B virus (HBV) endemicity in which the genotype A of HBV (HBV/A) is the most prevalent. The complete nucleotide sequences of 26 HBV/A isolates, originating from eight Brazilian states, were determined. All were adw2. Twenty-three belonged to subgenotype A1 and three to A2. By phylogenetic analysis, it was shown that all the 23 HBV/A1 isolates clustered together with isolates from Bangladesh, India, Japan, Nepal, the Philippines and United Arab Emirates, but not with those of Congo, Kenya, Malawi, Rwanda, South Africa, Tanzania, Uganda and Zimbabwe. Four amino acid residues in the polymerase (His138 in the terminal protein domain, Pro18 and His90 in the spacer, and Ser109 in the reverse transcriptase), and one (Phe17) in the precore region, predominated in Latin American and Asian HBV/A1 isolates, but were rarely encountered in African isolates, with the exception of those from Somalia. Specific variations of two adjacent amino acids in the C-terminal domain of the HBx protein, namely Ala146 and Pro147, were found in all the Brazilian, but rarely in the other HBV/A1 isolates. By Bayesian analysis, the existence of an ‘Asian-American’ clade within subgenotype A1 was supported by a posterior probability value of 0.996. The close relatedness of the Brazilian, Asian and Somalian isolates suggests that the HBV/A1 strains predominant in Brazil did not originate from the five million slaves who were imported from Central and Western Africa from 1551 to 1840, but rather from the 300–400,000 captives forcibly removed from southeast Africa at the middle of the 19th century. PMID:25122004

  19. HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease

    PubMed Central

    Chen, Zhiyong; Migeon, Tiffany; Verpont, Marie-Christine; Zaidan, Mohamad; Sado, Yoshikazu; Kerjaschki, Dontscho; Ronco, Pierre

    2016-01-01

    Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman’s capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44, α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman’s capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders. PMID:26260163

  20. Association of a polymorphism of BTN2A1 with dyslipidemia in East Asian populations

    PubMed Central

    FUJIMAKI, TETSUO; KATO, KIMIHIKO; OGURI, MITSUTOSHI; YOHIDA, TETSURO; HORIBE, HIDEKI; YOKOI, KIYOSHI; WATANABE, SACHIRO; SATOH, KEI; AOYAGI, YUKITOSHI; TANAKA, MASASHI; YOSHIDA, HIROTO; SHINKAI, SHOJI; NOZAWA, YOSHINORI; SHIN, DONG-JIK; LEE, JONG HO; JANG, YANGSOO; YAMADA, YOSHIJI

    2011-01-01

    We previously identified rs6929846 of the butyrophilin, subfamily 2, member A1 gene (BTN2A1) as a susceptibility locus for myocardial infarction in Japanese individuals by a genome-wide association study. The aim of the present study was to examine the relation of the rs6929846 polymorphism of BTN2A1 to dyslipidemia in Japanese and Korean populations, given that dyslipidemia is an important risk factor for myocardial infarction. A total of 10,953 individuals from three independent subject panels were examined. The relations of the rs6929846 polymorphism of BTN2A1 to serum concentrations of triglycerides, high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol were examined in each subject panel. The C→T polymorphism (rs6929846) of BTN2A1 was significantly associated with serum concentrations of triglycerides in Japanese subject panels A (P=0.0004) and B (P=0.0010), and in the Korean population (P=0.0095), with the minor T allele being related to an increased serum concentration of triglycerides. The rs6929846 was associated with serum concentrations of HDL-cholesterol in Japanese subject panels A (P=0.0047) and B (P=0.0015), with the T allele being related to a decreased serum concentration of HDL-cholesterol, but not in the Korean population. This polymorphism was associated with the serum concentration of LDL-cholesterol only in Japanese subject panel B (P=0.0059), with the T allele being related to an increased serum concentration of LDL-cholesterol. The results suggest that BTN2A1 may be a susceptibility gene for hypertriglyceridemia in East Asian populations and for low serum HDL-cholesterol in the Japanese population. PMID:22977569

  1. CYTOCHROME P450 17A1 STRUCTURES WITH PROSTATE CANCER DRUGS ABIRATERONE AND TOK-001

    PubMed Central

    DeVore, Natasha M.; Scott, Emily E.

    2011-01-01

    Cytochrome P450 17A1 (P450c17) catalyzes the biosynthesis of androgens in humans1. Since prostate cancer cells proliferate in response to androgen steroids2,3, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer4, but drug development has been hampered by the lack of a CYP17A1 structure. Here we report the only known structures of CYP17A1, which contain either abiraterone, a first-in-class steroidal inhibitor recently approved by the FDA for late-stage prostate cancer5, or TOK-001, another inhibitor in clinical trials4,6. Both bind the heme iron forming a 60° angle above the heme plane, packing against the central I helix with the 3β-OH interacting with N202 in the F helix. Importantly, this binding mode differs substantially from those predicted by homology models or from steroids in other cytochrome P450 enzymes with known structures, with some features more similar to steroid receptors. While the overall CYP17A1 structure provides a rationale for understanding many mutations found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate better understanding of the enzyme’s dual hydroxylase and lyase catalytic capabilities and assist in rational drug design. Specifically, structure-based design is expected to aid development of inhibitors that bind only CYP17A1 and solely inhibit its androgen-generating lyase activity to improve treatment of prostate and other hormone-responsive cancers. PMID:22266943

  2. Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder.

    PubMed

    Abraham, Shaji; Knapp, Deborah W; Cheng, Liang; Snyder, Paul W; Mittal, Suresh K; Bangari, Dinesh S; Kinch, Michael; Wu, Lan; Dhariwal, Jay; Mohammed, Sulma I

    2006-01-15

    The EphA2 receptor tyrosine kinase is believed to play a role in tumor growth and metastasis. The clinical significance of the expression of EphA2 was observed in breast, prostate, colon, skin, cervical, ovarian, and lung cancers. The purpose of this work was to determine the expression of EphA2 and its ligand, Ephrin A-1, and E-cadherin in carcinoma of the urinary bladder, and determine EphA2 as a new target for therapy in bladder cancer. EphA2 mRNA and protein expression was investigated by reverse transcription-PCR and Western blot, respectively, in bladder cancer cell lines. In addition, the expression of EphA2, Ephrin A-1, and E-cadherin in tissues from patients with different stages of urinary bladder cancer was determined by immunohistochemistry. Furthermore, the ability of Ephrin A-1 to inhibit growth of bladder cancer cells was also investigated using an adenoviral delivery system. Western blot analysis showed high EphA2 expression in TCCSUP, T24, and UMUC-3 cell lines. In tissues, the staining intensity of EphA2 was less in normal urothelium but increased greatly in advancing stages of urothelial carcinoma (P < 0.05). Similarly, the staining intensity of Ephrin A-1 was low in normal tissues and high in cancerous tissues, but it was similar across the various stages of urothelial carcinoma (T(a)-T(4)). E-cadherin immunoreactivity decreased in urothelial cancer. Association of EphA2 and Ephrin A-1 expression was found to be significant between T(a) stage and T(1)-T(2) (P < 0.04) and T(a) and T(3)-T(4) stages (P < 0.0001). Adenovirus delivery of Ephrin A-1 inhibited proliferation of TCCSUP cells. EphA2 may serve as a novel target for bladder cancer therapy.

  3. K2-EDTA and K3-EDTA Greiner Tubes for HbA1c Measurement.

    PubMed

    Vrtaric, Alen; Filipi, Petra; Hemar, Marina; Nikolac, Nora; Simundic, Ana-Maria

    2016-02-01

    To determine whether K2-ethylenediaminetetraacetic acid (EDTA) and K3-EDTA Greiner tubes could be used interchangeably for glycosylated hemoglobin, type A1C (HbA1c) measurement via the Abbott Laboratories ARCHITECT chemiluminescent microparticle HbA1c assay on the ARCHITECT i2000SR immunoanalyzer at our university hospital. We drew blood from a total of 45 outpatients into plastic Greiner Vacuette tubes, some of which were lined with K2-EDTA and others with K3-EDTA anticoagulant. Data are presented as median and interquartile range values. We used the Wilcoxon test and Passing-Bablok regression for tube comparison. For K2-EDTA tubes median HbA1c concentration was 54 mmol/mol (41 to 71 mmol/mol) and for K3-EDTA tubes 56 mmol/mol (43 to 69 mmol/mol). There was no statistically significant difference between K2-EDTA and K3-EDTA (bias= -1.29 mmol/mol; P = 0.24). Passing-Bablok regression showed that there is no constant and proportional error: y = -0.23 (95% CI[-3.52 to 0.69]) + 1.00( 95% CI[0.98 to 1.06]) x. In this study, we provide evidence for the lack of any clinically and statistically significant bias between K2-EDTA and K3-EDTA HbA1c measurements. Thus, Greiner tubes lined with K2-EDTA and those lined with K3-EDTA can safely be used interchangeably to measure HbA1c via the Abbott Laboratories ARCHITECT assay. © American Society for Clinical Pathology, 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

    PubMed

    Chen, Zhiyong; Migeon, Tiffany; Verpont, Marie-Christine; Zaidan, Mohamad; Sado, Yoshikazu; Kerjaschki, Dontscho; Ronco, Pierre; Plaisier, Emmanuelle

    2016-04-01

    Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders. Copyright © 2016 by the American Society of Nephrology.

  5. Noninvasive type 2 diabetes screening: superior sensitivity to fasting plasma glucose and A1C.

    PubMed

    Maynard, John D; Rohrscheib, Mark; Way, Jeffrey F; Nguyen, Catriona M; Ediger, Marwood N

    2007-05-01

    This study compared the performance of a novel noninvasive technology to fasting plasma glucose (FPG) and A1C tests for detecting undiagnosed diabetes and impaired glucose tolerance. The design was a head-to-head evaluation in a naïve population. Consented subjects received FPG and A1C tests and an oral glucose tolerance test (OGTT). Subjects were also measured by a noninvasive device that detects the fluorescence of skin advanced glycation end products. A total of 351 subjects participated. Subjects with 2-h OGTT values > or = 140 mg/dl defined the positive screening class. A total of 84 subjects (23.9% prevalence) screened positive. The performances of the noninvasive device, FPG, and A1C were evaluated for sensitivity and specificity against this classification. At the impaired fasting glucose threshold (FPG = 100 mg/dl), the FPG testing sensitivity was 58% and the specificity was 77.4%. At that same specificity, the sensitivity for A1C testing was 63.8%, while the noninvasive testing sensitivity was 74.7%. The sensitivity advantage of the noninvasive device over both blood tests for detecting diabetes and precursors was statistically significant (P < 0.05). The noninvasive technology showed clinical performance advantages over both FPG and A1C testing. The sensitivity differential indicated that the noninvasive device is capable of identifying 28.8% more individuals in the OGTT-defined positive screening class than FPG testing and 17.1% more than A1C testing. The combination of higher sensitivity and greater convenience--rapid results with no fasting or blood draws--makes the device well suited for opportunistic screening.

  6. EphrinA1-Fc attenuates myocardial ischemia/reperfusion injury in mice

    PubMed Central

    DuSablon, Augustin; Parks, Justin; Whitehurst, K’Shylah; Estes, Heather; Chase, Robert; Vlahos, Eleftherios; Sharma, Uma; Wert, David

    2017-01-01

    EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy cardiomyocytes, is lost in injured cells following myocardial infarction. Previously, we have reported that a single intramyocardial injection of chimeric ephrinA1-Fc at the time of ischemia reduced injury in the nonreperfused myocardium by 50% at 4 days post-MI by reducing apoptosis and inflammatory cell infiltration. In a clinically relevant model of acute ischemia (30min)/reperfusion (24hr or 4 days) injury, we now demonstrate that ephrinA1-Fc reduces infarct size by 46% and completely preserves cardiac function (ejection fraction, fractional shortening, and chamber dimensions) in the short-term (24hrs post-MI) as well as long-term (4 days). At 24 hours post-MI, diminished serum inflammatory cell chemoattractants in ephrinA1-Fc-treated mice reduces recruitment of neutrophils and leukocytes into the myocardium. Differences in relative expression levels of EphA-Rs are described in the context of their putative role in mediating cardioprotection. Validation by Western blotting of selected targets from mass spectrometry analyses of pooled samples of left ventricular tissue homogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenuate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased glycolysis to optimize anaerobic ATP production. Taken together, reduced injury is due a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult. PMID:29236774

  7. EphrinA1-Fc attenuates myocardial ischemia/reperfusion injury in mice.

    PubMed

    DuSablon, Augustin; Parks, Justin; Whitehurst, K'Shylah; Estes, Heather; Chase, Robert; Vlahos, Eleftherios; Sharma, Uma; Wert, David; Virag, Jitka

    2017-01-01

    EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy cardiomyocytes, is lost in injured cells following myocardial infarction. Previously, we have reported that a single intramyocardial injection of chimeric ephrinA1-Fc at the time of ischemia reduced injury in the nonreperfused myocardium by 50% at 4 days post-MI by reducing apoptosis and inflammatory cell infiltration. In a clinically relevant model of acute ischemia (30min)/reperfusion (24hr or 4 days) injury, we now demonstrate that ephrinA1-Fc reduces infarct size by 46% and completely preserves cardiac function (ejection fraction, fractional shortening, and chamber dimensions) in the short-term (24hrs post-MI) as well as long-term (4 days). At 24 hours post-MI, diminished serum inflammatory cell chemoattractants in ephrinA1-Fc-treated mice reduces recruitment of neutrophils and leukocytes into the myocardium. Differences in relative expression levels of EphA-Rs are described in the context of their putative role in mediating cardioprotection. Validation by Western blotting of selected targets from mass spectrometry analyses of pooled samples of left ventricular tissue homogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenuate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased glycolysis to optimize anaerobic ATP production. Taken together, reduced injury is due a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult.

  8. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy.

    PubMed

    Zhang, Lei; Liu, Wen; Wang, Qun; Li, Qinpei; Wang, Huijuan; Wang, Jun; Teng, Tieshan; Chen, Mingliang; Ji, Ailing; Li, Yanzhang

    2018-03-02

    Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K), which is the key enzyme in the mammalian target of rapamycin (mTOR) pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53)-sestrins-AMPK-mTOR signaling pathway.

  9. Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments.

    PubMed

    Barratt, Daniel T; Coller, Janet K; Somogyi, Andrew A

    2006-06-05

    The TaqI A polymorphism (A(1)) of the dopamine D(2) receptor gene (DRD2), although not a specific predictor of opioid dependence, has been strongly associated with high levels of prior heroin use and poor treatment outcomes among methadone maintenance patients. The aims of this study were to confirm these findings via a retrospective analysis of A(1) allele frequency in methadone (n = 46) and buprenorphine (n = 25) patients, and non-opioid-dependent controls (n = 95). Subjects were genotyped at the DRD2 TaqI A locus using PCR amplification followed by TaqI restriction enzyme digestion and gel electrophoresis. For methadone and buprenorphine subjects, heroin use (prior to treatment), treatment outcomes, and withdrawal occurrence were determined from comprehensive case notes. No significant differences in A(1) allele frequency (%) were observed between: methadone (19.6%), buprenorphine (18.0%), and control (17.9%) groups (P > 0.7); successful and poor treatment outcome groups, methadone: 20.0% and 19.2%, respectively (P = 1.0); buprenorphine: 18.4% and 20.0%, respectively (P = 1.0). Also, there were no significant relationships between TaqI A genotype and prior heroin use (P = 0.47). However, among the successful methadone subjects, significantly fewer A(1) allele carriers experienced withdrawal than non-A(1) carriers (P = 0.04). In conclusion, the DRD2 genotype effects did not affect opioid maintenance treatment outcomes. This suggests the need for a further prospective investigation into the role of the DRD2 A(1) allele in heroin use and response to maintenance pharmacotherapies for opioid dependence.

  10. HbA1c levels in individuals heterozygous for hemoglobin variants.

    PubMed

    Tavares, Ricardo Silva; Souza, Fábio Oliveira de; Francescantonio, Isabel Cristina Carvalho Medeiros; Soares, Weslley Carvalho; Mesquita, Mauro Meira

    2017-04-01

    To evaluate the levels of glycated hemoglobin (HbA1c) in patients heterozygous for hemoglobin variants and compare the results of this test with those of a control group. This was an experimental study based on the comparison of HbA1c tests in two different populations, with a test group represented by individuals heterozygous for hemoglobin variants (AS and AC) and a control group consisting of people with electrophoretic profile AA. The two populations were required to meet the following inclusion criteria: Normal levels of fasting glucose, hemoglobin, urea and triglycerides, bilirubin > 20 mg/dL and non-use of acetylsalicylic acid. 50 heterozygous subjects and 50 controls were evaluated between August 2013 and May 2014. The comparison of HbA1c levels between heterozygous individuals and control subjects was performed based on standard deviation, mean and G-Test. The study assessed a test group and a control group, both with 39 adults and 11 children. The mean among heterozygous adults for HbA1c was 5.0%, while the control group showed a rate of 5.74%. Heterozygous children presented mean HbA1c at 5.11%, while the controls were at 5.78%. G-Test yielded p=0.93 for children and p=0.89 for adults. Our study evaluated HbA1c using ion exchange chromatography resins, and the patients heterozygous for hemoglobin variants showed no significant difference from the control group.

  11. The CYP17 MspA1 Polymorphism and the Gender Dysphoria.

    PubMed

    Fernández, Rosa; Cortés-Cortés, Joselyn; Esteva, Isabel; Gómez-Gil, Esther; Almaraz, Mari Cruz; Lema, Estefanía; Rumbo, Teresa; Haro-Mora, Juan-Jesús; Roda, Ester; Guillamón, Antonio; Pásaro, Eduardo

    2015-06-01

    The A2 allele of the CYP17 MspA1 polymorphism has been linked to higher levels of serum testosterone, progesterone, and estradiol. To determine whether the CYP17 MspA1 polymorphism is associated with transsexualism. We analyzed 151 male-to-female (MtF), 142 female-to-male (FtM), 167 control male, and 168 control female individuals. Fragments that included the mutation were amplified by PCR and digested with MspA1. Our data were compared with the allele/genotype frequencies provided by the 1000 Genomes Data Base, and contrasted with a MEDLINE search of the CYP17 MspA1 polymorphism in the literature. We investigated the association between transsexualism and the CYP17 MspA1 polymorphism. A2 frequency was higher in the FtM (0.45) than the female control (0.38) and male control (0.39) groups, or the MtF group (0.36). This FtM > MtF pattern reached statistical significance (P = 0.041), although allele frequencies were not gender specific in the general population (P = 0.887). This observation concurred with the 1000 Genomes Data Base and the MEDLINE search. Our data confirm a sex-dependent allele distribution of the CYP17 MspA1 polymorphism in the transsexual population, FtM > MtF, suggestive of a hypothetical A2 involvement in transsexualism since the allele frequencies in the general population seem to be clearly related to geographic origin and ethnic background, but not sex. © 2015 International Society for Sexual Medicine.

  12. Spin Diffusion Coefficient of A1-PHASE of Superfluid 3He at Low Temperatures

    NASA Astrophysics Data System (ADS)

    Afzali, R.; Pashaee, F.

    The spin diffusion coefficient tensor of the A1-phase of superfluid 3He at low temperatures and melting pressure is calculated using the Boltzmann equation approach and Pfitzner procedure. Then considering Bogoliubov-normal interaction, we show that the total spin diffusion is proportional to 1/T2, the spin diffusion coefficient of superfluid component D\\uparrowxzxz is proportional to T-2, and the spin diffusion coefficient of super-fluid component D\\uparrowxxxx (=D\\uarrowxyxy) is independent of temperature. Furthermore, it is seen that superfluid components play an important role in spin diffusion of the A1-phase.

  13. Association of frailty with the serine protease HtrA1 in older adults.

    PubMed

    Lorenzi, Maria; Lorenzi, Teresa; Marzetti, Emanuele; Landi, Francesco; Vetrano, Davide L; Settanni, Silvana; Antocicco, Manuela; Bonassi, Stefano; Valdiglesias, Vanessa; Bernabei, Roberto; Onder, Graziano

    2016-08-01

    Frailty is a geriatric syndrome characterized by multi system dysregulation. It has been suggested that chronic inflammation may be involved in the pathogenesis of frailty. No study so far has identified accurate, specific and sensitive molecular biomarkers for frailty. High-temperature requirement serine protease A1 (HtrA1) is a secreted multidomain serine protease implicated in the inhibition of signaling of active transforming growth factor-β (TGF-β)1, a cytokine which has an important anti-inflammation role. The aim of the present study was to investigate the association of circulating levels of HtrA1 with frailty in a sample of older adults. The study was performed in 120 older adults aged >65years and admitted to a geriatric outpatient clinic. The frailty status of participants was assessed by both the Fried's criteria (physical frailty, PF) and a modified Rockwood's frailty index (FI). Plasma HtrA1 concentration was measured using commercial ELISA kit. Frailty was identified in 61/120 participants (50.8%) using PF, and in 60/118 subjects (50.8%) using FI. Plasma levels of HtrA1 were significantly higher in individuals classified as frail according to PF (75.9ng/mL, 95% CI 67.4-85.6) as compared with non-frail participants (48.4ng/mL, 95% CI 42.5-54.6, p<0.001). A significant association was also observed between frailty, assessed by FI, and HtrA1 levels (72.2ng/mL, 95% CI 63.4-82.3, vs. 50.4ng/mL, 95% CI 44.3-58.0, p<0.001). These associations were confirmed after adjusting for potential confounders. This study demonstrates for the first time the association of plasma levels of HtrA1 with frailty status. Future investigations are needed to validate the potential value of HtrA1 as possible biomarker for frailty. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. SLC6A1 Mutation and Ketogenic Diet in Epilepsy With Myoclonic-Atonic Seizures.

    PubMed

    Palmer, Samantha; Towne, Meghan C; Pearl, Phillip L; Pelletier, Renee C; Genetti, Casie A; Shi, Jiahai; Beggs, Alan H; Agrawal, Pankaj B; Brownstein, Catherine A

    2016-11-01

    Epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy or Doose syndrome, has been recently linked to variants in the SLC6A1 gene. Epilepsy with myoclonic-atonic seizures is often refractory to antiepileptic drugs, and the ketogenic diet is known for treating medically intractable seizures, although the mechanism of action is largely unknown. We report a novel SLC6A1 variant in a patient with epilepsy with myoclonic-atonic seizures, analyze its effects, and suggest a mechanism of action for the ketogenic diet. We describe a ten-year-old girl with epilepsy with myoclonic-atonic seizures and a de novo SLC6A1 mutation who responded well to the ketogenic diet. She carried a c.491G>A mutation predicted to cause p.Cys164Tyr amino acid change, which was identified using whole exome sequencing and confirmed by Sanger sequencing. High-resolution structural modeling was used to analyze the likely effects of the mutation. The SLC6A1 gene encodes a transporter that removes gamma-aminobutyric acid from the synaptic cleft. Mutations in SLC6A1 are known to disrupt the gamma-aminobutyric acid transporter protein 1, affecting gamma-aminobutyric acid levels and causing seizures. The p.Cys164Tyr variant found in our study has not been previously reported, expanding on the variants linked to epilepsy with myoclonic-atonic seizures. A 10-year-old girl with a novel SLC6A1 mutation and epilepsy with myoclonic-atonic seizures had an excellent clinical response to the ketogenic diet. An effect of the diet on gamma-aminobutyric acid reuptake mediated by gamma-aminobutyric acid transporter protein 1 is suggested. A personalized approach to epilepsy with myoclonic-atonic seizures patients carrying SLC6A1 mutation and a relationship between epilepsy with myoclonic-atonic seizures due to SLC6A1 mutations, GABAergic drugs, and the ketogenic diet warrants further exploration. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Altitude Decompression Sickness between 6858 and 9144 m Following a 1-h Prebreathe

    DTIC Science & Technology

    2005-01-01

    benefit of a 1-h prebreathe in comparison to no 6858 m after 1 h of prebreathe. However, during 6858-m and 7620-m exposures, a 1-h prebreathe is highly...first 90 min of exposure. Use of 4-h vs. 8-h exposures METHODS does not appear to underestimate DCS risk at or above 7620 m. Keywords: DCS, hypobaric ...exposure. This allowed their endpoint criteria for defining a symptom as DCS comparison of these results with the majority of Air were more severe than

  16. Lipid and liver abnormalities in haemoglobin A1c-defined prediabetes and type 2 diabetes.

    PubMed

    Calanna, S; Scicali, R; Di Pino, A; Knop, F K; Piro, S; Rabuazzo, A M; Purrello, F

    2014-06-01

    We aimed to investigate lipid abnormalities and liver steatosis in patients with HbA1c-defined prediabetes and type 2 diabetes compared to individuals with HbA1c-defined normoglycaemia. Ninety-one subjects with prediabetes according to HbA1c, i.e. from 5.7 to 6.4% (39-46 mmol/mol), 50 newly diagnosed patients with HbA1c-defined type 2 diabetes (HbA1c ≥6.5% [≥48 mmol/mol]), and 67 controls with HbA1c lower than 5.7% (<39 mmol/mol), were studied. Fasting blood samples for lipid profiles, fatty liver index (FLI), bioimpedance analysis, ultrasound scan of the liver, and BARD (body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes) score for evaluation of liver fibrosis, were performed in all subjects. In comparison to controls, subjects with prediabetes were characterised by: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure, triglycerides levels and apolipoprotein B/apolipoprotein AI ratio, higher FLI, increased prevalence of and more severe hepatic steatosis, similar BARD score, and higher total body fat mass. In comparison to subjects with diabetes, subjects with prediabetes exhibited: similar blood pressure and apolipoprotein B/apolipoprotein AI ratio, similar FLI, reduced prevalence of and less severe hepatic steatosis, lower BARD score, increased percent fat and lower total body muscle mass. In comparison to controls, subjects with diabetes showed: lower apolipoprotein AI and HDL cholesterol levels, higher blood pressure and triglycerides levels, higher FLI, increased prevalence of and more severe hepatic steatosis, higher BARD score, and higher total body muscle mass. Moreover, HbA1c was correlated with BMI, HOMA-IR, triglycerides, HDL cholesterol, AST, and ALT. Subjects with HbA1c-defined prediabetes and type 2 diabetes, respectively, are characterised by abnormalities in lipid profile and liver steatosis, thus exhibiting a severe risk profile for cardiovascular and liver diseases. Copyright © 2014

  17. The Thermal Flash Protection System, low pass filter JN175666A1

    SciTech Connect

    Washington, L.A.

    1987-06-01

    This report discusses the development of the JN175666A1 Low Pass Filter used in the B1-B Thermal Flash Protection System. It also discusses problems encountered during development of the ceramic capacitors and how they were resolved. Included in this report is a description of the filter, the electrical and environmental tests, why they were performed and data accumulated during the development testing. After completing the evaluation of this device, it is concluded that the JN175666A1 filter is a usable component for the B1-B system.

  18. Hb variants in Korea: effect on HbA1c using five routine methods.

    PubMed

    Yun, Yeo-Min; Ji, Misuk; Ko, Dae-Hyun; Chun, Sail; Kwon, Gye Cheol; Lee, Kyunghoon; Song, Sang Hoon; Seong, Moon Woo; Park, Sung Sup; Song, Junghan

    2017-07-26

    Quantification of glycated hemoglobin (HbA1c) is a challenge in patients with hemoglobin (Hb) variants. We evaluated the impact of various Hb variants on five routine HbA1c assays by comparing with the IFCC reference measurement procedure (RMP). Whole blood samples showing warning flags or no results on routine HPLC HbA1c assays were confirmed for Hb variants and were submitted to HbA1c quantification using Sebia Capillarys 2 Flex Piercing, Roche Tina-quant HbA1c Gen. 2, Bio-Rad Variant II Turbo 2.0, ADAMS HA-8180, Tosoh G8 standard mode, and IFCC RMP using LC-MS. Among 114 samples, the most common variants were Hb G-Coushatta (n=47), Queens (n=41), Ube-4 (n=11), Chad (n=4), Yamagata (n=4), G-His-Tsou (n=2), G-Taipei (n=1), Fort de France (n=1), Hoshida (n=1), and two novel variants (Hb α-globin, HBA 52 Gly>Cys and Hb β-globin, HBB 146 His>Asn). In terms of control samples, all the result of HbA1c were "acceptable", within the criteria of ±7% compared to IFCC RMP target values. However, percentage of "unacceptable" results of samples with Hb variants were 16% for Capillarys 2, 7% for Tina-quant, 51% for Variant II Turbo 2.0, 95% for G8 standard mode, and 89% for HA-8180. The Capillarys 2 and HA-8180 assay did not provide the results in 5 and 40 samples with Hb variants, respectively. HbA1c results from five routine assays in patients with relatively common Hb variants in Korea showed various degrees of bias compared to those of IFCC RMP. Therefore, laboratories should be aware of the limitation of their methods with respect to interference from Hb variants found commonly in their local population and suggest an alternative HbA1c quantification method.

  19. Nuclear matrix and hnRNP share a common structural constituent associated with premessenger RNA.

    PubMed Central

    Gallinaro, H; Puvion, E; Kister, L; Jacob, M

    1983-01-01

    Nuclear matrix and heterogeneous nuclear ribonucleoprotein (hnRNP) were compared to establish whether premessenger RNA (premRNA) was associated with a same constituent in both structures. The isolation of nuclear matrix included the removal of chromatin and of 0.4 M KCl-soluble material. HnRNP, isolated by a standard method was also treated by 0.4 M KCl. Both isolation procedures caused the removal of DNA, histones, a fraction of small nuclear RNA and of nonhistone proteins including the hnRNP proteins in the 30 000-40 000 mol. wt. range. High resolution autoradiography showed that hnRNA remained associated with the residual fibrils in both structures. They both contained the same premRNA and maturation products as shown by the analysis of the transcripts of the early region 3 of adenovirus 2. In addition, the small nuclear RNA and protein of the salt-resistant complexes were also present in the matrix. The results are compatible with the idea that the salt-resistant complexes from hnRNP constitute the fibrils associated with premRNA in the nucleoplasmic matrix. The fibrils may be the basic unit of splicing and their organization in matrix might provide the spatial configuration necessary for regulation. Images Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 7. PMID:6557026

  20. 78 FR 36440 - Approval and Promulgation of Implementation Plans; Tennessee; 110(a)(1) and (2) Infrastructure...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-18

    ... Lead National Ambient Air Quality Standards AGENCY: Environmental Protection Agency (EPA). ACTION... the requirements of sections 110(a)(1) and (2) of the Clean Air Act (CAA or Act) for the 2008 Lead... that ensure the 2008 Lead NAAQS are implemented, enforced, and maintained in Tennessee. With the...

  1. 26 CFR 53.4941(a)-1 - Imposition of initial taxes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...(d)(1)(B) and § 53.4941(d)-2 (c)(1). The tax imposed by section 4941(a)(1) is at the rate of 5... transaction in which he is participating is an act of self-dealing. (5) Due to reasonable cause. A foundation... act shall not, by itself, give rise to any inference that a person participated in such act knowingly...

  2. 26 CFR 53.4941(a)-1 - Imposition of initial taxes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...(d)(1)(B) and § 53.4941(d)-2 (c)(1). The tax imposed by section 4941(a)(1) is at the rate of 5... transaction in which he is participating is an act of self-dealing. (5) Due to reasonable cause. A foundation... act shall not, by itself, give rise to any inference that a person participated in such act knowingly...

  3. Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues.

    PubMed

    Igarashi, Maki; Takasawa, Kei; Hakoda, Akiko; Kanno, Junko; Takada, Shuji; Miyado, Mami; Baba, Takashi; Morohashi, Ken-Ichirou; Tajima, Toshihiro; Hata, Kenichiro; Nakabayashi, Kazuhiko; Matsubara, Yoichi; Sekido, Ryohei; Ogata, Tsutomu; Kashimada, Kenichi; Fukami, Maki

    2017-01-01

    The role of monogenic mutations in the development of 46,XX testicular/ovotesticular disorders of sex development (DSD) remains speculative. Although mutations in NR5A1 are known to cause 46,XY gonadal dysgenesis and 46,XX ovarian insufficiency, such mutations have not been implicated in testicular development of 46,XX gonads. Here, we identified identical NR5A1 mutations in two unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The p.Arg92Trp mutation was absent from the clinically normal mothers and from 200 unaffected Japanese individuals. In silico analyses scored p.Arg92Trp as probably pathogenic. In vitro assays demonstrated that compared with wild-type NR5A1, the mutant protein was less sensitive to NR0B1-induced suppression on the SOX9 enhancer element. Other sequence variants found in the patients were unlikely to be associated with the phenotype. The results raise the possibility that specific mutations in NR5A1 underlie testicular development in genetic females. © 2016 WILEY PERIODICALS, INC.

  4. 26 CFR 25.2522(a)-1 - Charitable and similar gifts; citizens or residents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Charitable and similar gifts; citizens or... TREASURY (CONTINUED) ESTATE AND GIFT TAXES GIFT TAX; GIFTS MADE AFTER DECEMBER 31, 1954 Deductions § 25.2522(a)-1 Charitable and similar gifts; citizens or residents. (a) In determining the amount of taxable...

  5. 77 FR 5703 - Approval and Promulgation of Implementation Plans; North Carolina; 110(a)(1) and (2...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-06

    ... and Promulgation of Implementation Plans; North Carolina; 110(a)(1) and (2) Infrastructure... Carolina, through the Department of Environment and Natural Resources (NC DENR), Division of Air Quality... is commonly referred to as an ``infrastructure'' SIP. North Carolina certified that the North...

  6. 11 CFR 111.4 - Complaints (2 U.S.C. 437g(a)(1)).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 11 Federal Elections 1 2012-01-01 2012-01-01 false Complaints (2 U.S.C. 437g(a)(1)). 111.4 Section... knowledge and statements based upon information and belief. (d) The complaint should conform to the... accompanied by an identification of the source of information which gives rise to the complainants belief in...

  7. 11 CFR 111.4 - Complaints (2 U.S.C. 437g(a)(1)).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 11 Federal Elections 1 2010-01-01 2010-01-01 false Complaints (2 U.S.C. 437g(a)(1)). 111.4 Section... knowledge and statements based upon information and belief. (d) The complaint should conform to the... accompanied by an identification of the source of information which gives rise to the complainants belief in...

  8. 11 CFR 111.4 - Complaints (2 U.S.C. 437g(a)(1)).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 11 Federal Elections 1 2011-01-01 2011-01-01 false Complaints (2 U.S.C. 437g(a)(1)). 111.4 Section... knowledge and statements based upon information and belief. (d) The complaint should conform to the... accompanied by an identification of the source of information which gives rise to the complainants belief in...

  9. 11 CFR 111.4 - Complaints (2 U.S.C. 437g(a)(1)).

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 11 Federal Elections 1 2014-01-01 2014-01-01 false Complaints (2 U.S.C. 437g(a)(1)). 111.4 Section... knowledge and statements based upon information and belief. (d) The complaint should conform to the... accompanied by an identification of the source of information which gives rise to the complainants belief in...

  10. Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.

    PubMed

    Lammel Lindemann, Jan A; Angajala, Anusha; Engler, David A; Webb, Paul; Ayers, Stephen D

    2014-05-05

    Thyroid hormone (TH) modulates serum cholesterol by acting on TH receptor β1 (TRβ1) in liver to regulate metabolic gene sets. In rodents, one important TH regulated step involves induction of Cyp7a1, an enzyme in the cytochrome P450 family, which enhances cholesterol to bile acid conversion and plays a crucial role in regulation of serum cholesterol levels. Current models suggest, however, that Cyp7a1 has lost the capacity to respond to THs in humans. We were prompted to re-examine TH effects on cholesterol metabolic genes in human liver cells by a recent study of a synthetic TH mimetic which showed that serum cholesterol reductions were accompanied by increases in a marker for bile acid synthesis in humans. Here, we show that TH effects upon cholesterol metabolic genes are almost identical in mouse liver, mouse and human liver primary cells and human hepatocyte cell lines. Moreover, Cyp7a1 is a direct TR target gene that responds to physiologic TR levels through a set of distinct response elements in its promoter. These findings suggest that THs regulate cholesterol to bile acid conversion in similar ways in humans and rodent experimental models and that manipulation of hormone signaling pathways could provide a strategy to enhance Cyp7a1 activity in human patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. 47 CFR 80.1087 - Ship radio equipment-Sea area A1.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... which the ship is normally navigated, operating either: (1) On VHF using DSC; or (2) Through the polar...; or (4) On HF using DSC; or (5) Through the INMARSAT geostationary satellite service if within... communication. (b) The VHF radio installation, required by § 80.1085(a)(1), must also be capable of transmitting...

  12. 47 CFR 80.1087 - Ship radio equipment-Sea area A1.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... which the ship is normally navigated, operating either: (1) On VHF using DSC; or (2) Through the polar...; or (4) On HF using DSC; or (5) Through the INMARSAT geostationary satellite service if within... communication. (b) The VHF radio installation, required by § 80.1085(a)(1), must also be capable of transmitting...

  13. Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

    PubMed Central

    2009-01-01

    CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism. PMID:19531241

  14. AMP-guided tumour-specific nanoparticle delivery via adenosine A1 receptor.

    PubMed

    Dai, Tongcheng; Li, Na; Han, Fajun; Zhang, Hua; Zhang, Yuanxing; Liu, Qin

    2016-03-01

    Active targeting-ligands have been increasingly used to functionalize nanoparticles for tumour-specific clinical applications. Here we utilize nucleotide adenosine 5'-monophosphate (AMP) as a novel ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for tumour-targeted imaging. We demonstrate that AMP-conjugated NPs (NPs-AMP) efficiently bind to and are following internalized into colon cancer cell CW-2 and breast cancer cell MDA-MB-468 in vitro. RNA interference and inhibitor assays reveal that the targeting effects mainly rely on the specific binding of AMP to adenosine A1 receptor (A1R), which is greatly up-regulated in cancer cells than in matched normal cells. More importantly, NPs-AMP specifically accumulate in the tumour site of colon and breast tumour xenografts and are further internalized into the tumour cells in vivo via tail vein injection, confirming that the high in vitro specificity of AMP can be successfully translated into the in vivo efficacy. Furthermore, NPs-AMP exhibit an active tumour-targeting behaviour in various colon and breast cancer cells, which is positively related to the up-regulation level of A1R in cancer cells, suggesting that AMP potentially suits for more extensive A1R-overexpressing cancer models. This work establishes AMP to be a novel tumour-targeting ligand and provides a promising strategy for future diagnostic or therapeutic applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. The renal urate transporter SLC17A1 locus: confirmation of association with gout.

    PubMed

    Hollis-Moffatt, Jade E; Phipps-Green, Amanda J; Chapman, Brett; Jones, Gregory T; van Rij, Andre; Gow, Peter J; Harrison, Andrew A; Highton, John; Jones, Peter B; Montgomery, Grant W; Stamp, Lisa K; Dalbeth, Nicola; Merriman, Tony R

    2012-04-27

    Two major gout-causing genes have been identified, the urate transport genes SLC2A9 and ABCG2. Variation within the SLC17A1 locus, which encodes sodium-dependent phosphate transporter 1, a renal transporter of uric acid, has also been associated with serum urate concentration. However, evidence for association with gout is equivocal. We investigated the association of the SLC17A1 locus with gout in New Zealand sample sets. Five variants (rs1165196, rs1183201, rs9358890, rs3799344, rs12664474) were genotyped across a New Zealand sample set totaling 971 cases and 1,742 controls. Cases were ascertained according to American Rheumatism Association criteria. Two population groups were studied: Caucasian and Polynesian. At rs1183201 (SLC17A1), evidence for association with gout was observed in both the Caucasian (odds ratio (OR) = 0.67, P = 3.0 × 10-6) and Polynesian (OR = 0.74, P = 3.0 × 10-3) groups. Meta-analysis confirmed association of rs1183201 with gout at a genome-wide level of significance (OR = 0.70, P = 3.0 × 10-8). Haplotype analysis suggested the presence of a common protective haplotype. We confirm the SLC17A1 locus as the third associated with gout at a genome-wide level of significance.

  16. Severe Hemolytic Jaundice in a Neonate with a Novel COL4A1 Mutation.

    PubMed

    Tomotaki, Seiichi; Mizumoto, Hiroshi; Hamabata, Takayuki; Kumakura, Akira; Shiota, Mitsutaka; Arai, Hiroshi; Haginoya, Kazuhiro; Hata, Daisuke

    2016-12-01

    We report our experience with a preterm infant with severe hemolytic jaundice who required exchange transfusion just after birth. The patient was negative for alloimmune hemolysis as a result of maternal-fetal blood type incompatibility, and tests for inherited defects in erythrocyte metabolism, membrane function, and hemoglobin synthesis were normal. We also performed a bone marrow examination, but could not identify the cause of hemolysis. The patient had several other complications, including porencephaly, epilepsy, elevated serum levels of creatine kinase, and persistent microscopic hematuria. Later, we detected a genetic mutation in COL4A1, which was recently found to be associated with hemolytic anemia. We therefore believe that all of the patient's clinical features, including hemolytic anemia, were due to the mutation in COL4A1. Genetic testing for COL4A1 mutations is recommended in neonates who exhibit hemolytic disease of unknown etiology, especially when other complications compatible with COL4A1-related disorders are present. Copyright © 2014. Published by Elsevier B.V.

  17. 42 CFR 65a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Section 65a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS... understanding, assessing, and attenuating the adverse effects on human health resulting from exposure to...-biomedical research project in the fields of ecology, hydrogeology, and/or engineering, and including the...

  18. 42 CFR 65a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Section 65a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS... understanding, assessing, and attenuating the adverse effects on human health resulting from exposure to...-biomedical research project in the fields of ecology, hydrogeology, and/or engineering, and including the...

  19. 26 CFR 41.4482(a)-1 - Definition of highway motor vehicle.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Definition of highway motor vehicle. 41.4482(a... (CONTINUED) MISCELLANEOUS EXCISE TAXES EXCISE TAX ON USE OF CERTAIN HIGHWAY MOTOR VEHICLES Tax on Use of Certain Highway Motor Vehicles § 41.4482(a)-1 Definition of highway motor vehicle. (a) Highway motor...

  20. 26 CFR 41.4482(a)-1 - Definition of highway motor vehicle.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Definition of highway motor vehicle. 41.4482(a... (CONTINUED) MISCELLANEOUS EXCISE TAXES EXCISE TAX ON USE OF CERTAIN HIGHWAY MOTOR VEHICLES Tax on Use of Certain Highway Motor Vehicles § 41.4482(a)-1 Definition of highway motor vehicle. (a) Highway motor...

  1. 26 CFR 48.4161(a)-1 - Imposition and rate of tax; fishing equipment.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Imposition and rate of tax; fishing equipment... § 48.4161(a)-1 Imposition and rate of tax; fishing equipment. (a) Imposition of tax. Section 4161(a) imposes a tax on the sale of the following articles of fishing equipment (including in each case parts or...

  2. 26 CFR 48.4161(a)-1 - Imposition and rate of tax; fishing equipment.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Imposition and rate of tax; fishing equipment... § 48.4161(a)-1 Imposition and rate of tax; fishing equipment. (a) Imposition of tax. Section 4161(a) imposes a tax on the sale of the following articles of fishing equipment (including in each case parts or...

  3. Metrics for glycaemic control - from HbA1c to continuous glucose monitoring.

    PubMed

    Kovatchev, Boris P

    2017-07-01

    As intensive treatment to lower levels of HbA 1c characteristically results in an increased risk of hypoglycaemia, patients with diabetes mellitus face a life-long optimization problem to reduce average levels of glycaemia and postprandial hyperglycaemia while simultaneously avoiding hypoglycaemia. This optimization can only be achieved in the context of lowering glucose variability. In this Review, I discuss topics that are related to the assessment, quantification and optimal control of glucose fluctuations in diabetes mellitus. I focus on markers of average glycaemia and the utility and/or shortcomings of HbA 1c as a 'gold-standard' metric of glycaemic control; the notion that glucose variability is characterized by two principal dimensions, amplitude and time; measures of glucose variability that are based on either self-monitoring of blood glucose data or continuous glucose monitoring (CGM); and the control of average glycaemia and glucose variability through the use of pharmacological agents or closed-loop control systems commonly referred to as the 'artificial pancreas'. I conclude that HbA 1c and the various available metrics of glucose variability reflect the management of diabetes mellitus on different timescales, ranging from months (for HbA 1c ) to minutes (for CGM). Comprehensive assessment of the dynamics of glycaemic fluctuations is therefore crucial for providing accurate and complete information to the patient, physician, automated decision-support or artificial-pancreas system.

  4. 77 FR 5706 - Approval and Promulgation of Implementation Plans; Georgia; 110(a)(1) and (2) Infrastructure...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-06

    ... the 1997 8-Hour Ozone National Ambient Air Quality Standards AGENCY: Environmental Protection Agency... the 1997 8-hour ozone national ambient air quality standards (NAAQS). Section 110(a) of the CAA... 110(a)(1) and (2) for the 1997 8-Hour Ozone and PM 2.5 National Ambient Air Quality Standards.'' \\1...

  5. Supporting a 1:1 Program with a Student Technology Team

    ERIC Educational Resources Information Center

    Peterson, Lana; Scharber, Cassandra

    2017-01-01

    Purpose: The purpose of this paper is to describe the practice of using student technology teams (STTs) offered at a high school within a 1:1 district. Design/methodology/approach: This qualitative case study (Merriam, 1998, 2009) documents how an STT program functioned in 2015-2016 academic year. Findings: Findings show the STT provided a rich…

  6. A Rare Encounter with Very Massive Stars in NGC~3125-A1

    NASA Astrophysics Data System (ADS)

    Wofford, A.; Leitherer, C.; Chandar, R.; Bouret, J. C.

    2014-09-01

    Super star cluster A1 in the nearby starburst galaxy NGC~3125 shows broad He II λ1640 emission (FWHM ~ 1200 km/s) of unprecedented strength (equivalent width, EW = 7.1+/-0.4 angstroms). Previous attempts to characterize A1's massive star content were hampered by the low resolution of the UV spectrum and the lack of co-spatial panchromatic data. We obtained far-UV to near-IR spectroscopy of the two principal emitting regions in the galaxy with the Space Telescope Imaging Spectrograph and the Cosmic Origins Spectrograph on board the Hubble Space Telescope. We use these data to derive the ages, reddenings, masses, and Wolf-Rayet (WR) to O star ratios of three compact clusters in the galaxy. We rule out that the extraordinary HeII lambda 1640 emission and OV lambda 1371 absorption in A1 are due to an extremely flat upper Initial Mass Function (IMF), and suggest that they originate in the winds of Very Massive Stars ( > 120 Msun, VMS). In order to reproduce the properties of peculiar clusters such as A1, the stellar evolution tracks implemented in Starburst99 need to be extended to masses >120 Msun.

  7. 26 CFR 48.4216(a)-1 - Charges to be included in sale price.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Charges to be included in sale price. 48.4216(a... to Manufacturers Taxes § 48.4216(a)-1 Charges to be included in sale price. (a) In general. The... the taxes imposed under Chapter 32 certain collateral charges made in connection with the sale of a...

  8. 26 CFR 48.4216(a)-1 - Charges to be included in sale price.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Charges to be included in sale price. 48.4216(a... to Manufacturers Taxes § 48.4216(a)-1 Charges to be included in sale price. (a) In general. The... the taxes imposed under Chapter 32 certain collateral charges made in connection with the sale of a...

  9. 26 CFR 48.4216(a)-1 - Charges to be included in sale price.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Charges to be included in sale price. 48.4216(a... to Manufacturers Taxes § 48.4216(a)-1 Charges to be included in sale price. (a) In general. The... the taxes imposed under Chapter 32 certain collateral charges made in connection with the sale of a...

  10. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... (CISS) projects for the development and expansion of: maternal and infant health home visiting; projects... GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.1 To which programs does this regulation apply? The regulation... Child Health (MCH) Federal Set-Aside project grant programs. Section 502(a) authorizes funding for...

  11. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... (CISS) projects for the development and expansion of: maternal and infant health home visiting; projects... GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.1 To which programs does this regulation apply? The regulation... Child Health (MCH) Federal Set-Aside project grant programs. Section 502(a) authorizes funding for...

  12. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... (CISS) projects for the development and expansion of: maternal and infant health home visiting; projects... GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.1 To which programs does this regulation apply? The regulation... Child Health (MCH) Federal Set-Aside project grant programs. Section 502(a) authorizes funding for...

  13. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... (CISS) projects for the development and expansion of: maternal and infant health home visiting; projects... GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.1 To which programs does this regulation apply? The regulation... Child Health (MCH) Federal Set-Aside project grant programs. Section 502(a) authorizes funding for...

  14. 42 CFR 51a.1 - To which programs does this regulation apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... (CISS) projects for the development and expansion of: maternal and infant health home visiting; projects... GRANTS FOR MATERNAL AND CHILD HEALTH § 51a.1 To which programs does this regulation apply? The regulation... Child Health (MCH) Federal Set-Aside project grant programs. Section 502(a) authorizes funding for...

  15. Draft Genome Sequence of Magnesium-Dissolving Lactococcus garvieae A1, Isolated from Soil.

    PubMed

    Altın, Gonca; Nikerel, Emrah; Şahin, Fikrettin

    2017-05-25

    The probiotic bacterium Lactococcus garvieae A1, isolated from soil, is interesting for biomining applications. Here, we report the draft genome sequence and annotation of this strain, with a focus on metal transporter enzymes. Copyright © 2017 Altın et al.

  16. Regulation of renal adenosine A(1) receptors: effect of dietary sodium chloride.

    PubMed

    Smith, J A; Whitaker, E M; Yaktubay, N; Morton, M J; Bowmer, C J; Yates, M S

    1999-11-12

    The influence of dietary NaCl on the regulation of renal adenosine A(1) receptors was investigated in the rat. Renal membranes from rats fed on a diet low (0.04%) in NaCl showed a 46% increase in B(max) for the binding of [3H]-1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX), a selective adenosine A(1) receptor antagonist, compared to membranes from rats fed on a normal diet (0.4% NaCl). Conversely, a high NaCl diet (4.0%) resulted in a 37% decrease in B(max). Levels of renal adenosine A(1) receptor mRNA were 65% lower in rats on a high salt diet. Autoradiographic studies showed that, for the inner medullary collecting ducts, a low NaCl diet resulted in a 30% increase in [3H]DPCPX binding with a 39% decrease noted in rats maintained on a high salt diet. The results indicate that changes in adenosine A(1) receptor density may represent a novel mechanism whereby the kidneys adapt to changes in salt load.

  17. 77 FR 33372 - Approval and Promulgation of Implementation Plans; South Carolina; 110(a)(1) and (2...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-06

    ... analysis of how South Carolina addressed the elements of sections 110(a)(1) and (2) ``Infrastructure... failed to submit a complete SIP that provided the basic program elements of section 110(a)(2) necessary... elements identified in section 110(a)(2) are not governed by the three year submission deadline of section...

  18. Mannheimia haemolytica A1-induced fibrinosuppurative meningoencephalitis in a naturally-infected Holstein-Friesian calf

    USDA-ARS?s Scientific Manuscript database

    Mannheimia haemolytica is an opportunistic bacterium that is widely recognized among the bovine respiratory disease complex as the predominant pathogen associated with pleuropneumonia in cattle. Among the characterized M. haemolytica serotypes, A1 is the major cause of severe pulmonary lesions in ca...

  19. 26 CFR 1.672(a)-1 - Definition of adverse party.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... TAX (CONTINUED) INCOME TAXES Grantors and Others Treated As Substantial Owners § 1.672(a)-1 Definition... a power which he possesses respecting the trust. A trustee is not an adverse party merely because of his interest as trustee. A person having a general power of appointment over the trust property is...

  20. 26 CFR 41.4482(a)-1 - Definition of highway motor vehicle.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Definition of highway motor vehicle. 41.4482(a... (CONTINUED) MISCELLANEOUS EXCISE TAXES EXCISE TAX ON USE OF CERTAIN HIGHWAY MOTOR VEHICLES Tax on Use of Certain Highway Motor Vehicles § 41.4482(a)-1 Definition of highway motor vehicle. (a) Highway motor...