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Sample records for a1 hnrnp a1

  1. HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition

    PubMed Central

    Bonomi, Serena; di Matteo, Anna; Buratti, Emanuele; Cabianca, Daphne S.; Baralle, Francisco E.; Ghigna, Claudia; Biamonti, Giuseppe

    2013-01-01

    Epithelial-to-mesenchymal transition (EMT) is an embryonic program used by cancer cells to acquire invasive capabilities becoming metastatic. ΔRon, a constitutively active isoform of the Ron tyrosine kinase receptor, arises from skipping of Ron exon 11 and provided the first example of an alternative splicing variant causatively linked to the activation of tumor EMT. Splicing of exon 11 is controlled by two adjacent regulatory elements, a silencer and an enhancer of splicing located in exon 12. The alternative splicing factor and oncoprotein SRSF1 directly binds to the enhancer, induces the production of ΔRon and activates EMT leading to cell locomotion. Interestingly, we now find an important role for hnRNP A1 in controlling the activity of the Ron silencer. HnRNP A1 is able to antagonize the binding of SRSF1 and prevent exon skipping. Notably, hnRNP A1, by inhibiting the production of ΔRon, activates the reversal program, namely the mesenchymal-to-epithelial transition, which instead occurs at the final metastasis sites. Also, hnRNP A1 affects Ron splicing by regulating the expression level of hnRNP A2/B1, which similarly to SRSF1 can promote ΔRon production. These results shed light on how splicing regulation contributes to the tumor progression and provide potential targets to develop anticancer therapies. PMID:23863836

  2. hnRNP A1: the Swiss army knife of gene expression.

    PubMed

    Jean-Philippe, Jacques; Paz, Sean; Caputi, Massimo

    2013-09-16

    Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies.

  3. hnRNP A1: the Swiss army knife of gene expression.

    PubMed

    Jean-Philippe, Jacques; Paz, Sean; Caputi, Massimo

    2013-01-01

    Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies. PMID:24065100

  4. MNK1 expression increases during cellular senescence and modulates the subcellular localization of hnRNP A1

    SciTech Connect

    Ziaei, Samira; Shimada, Naoko; Kucharavy, Herman; Hubbard, Karen

    2012-03-10

    Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an RNA-binding protein that modulates splice site usage, polyadenylation, and cleavage efficiency. This protein has also been implicated in mRNA stability and transport from the nucleus. We have previously demonstrated that hnRNP A1 had diminished protein levels and showed cytoplasmic accumulation in senescent human diploid fibroblasts. Furthermore, we have shown that inhibition of p38 MAPK, a key regulator of cellular senescence, elevated hnRNP A1 protein levels and inhibited hnRNP A1 cytoplasmic localization. In this study, we have explored the possible involvement of MNK1, one of the downstream effector of p38 MAPK, in the regulation of hnRNP A1. We have demonstrated that pharmacological inhibition of MNK1 by CGP 57380 decreased the phosphorylation levels of hnRNP A1 in young and senescent fibroblast cells and blocked the cytoplasmic accumulation of hnRNP A1 in senescent cells. In addition, MNK1 formed a complex with hnRNP A1 in vivo. The expression levels of MNK1, phospho-MNK1, and phospho-eIF4E proteins were found to be elevated in senescent cells. These data suggest that MNK1 regulates the phosphorylation and the subcellular distribution of hnRNP A1 and that MNK1 may play a role in the induction of senescence. -- Highlights: Black-Right-Pointing-Pointer MNK1 and not MAPKAPK2 phosphorylates hnRNP A1. Black-Right-Pointing-Pointer MNK1 has elevated levels in senescent cells, this has not been reported previously. Black-Right-Pointing-Pointer MNK1 activity induces cytoplasmic accumulation of hnRNP A1 in senescent cells. Black-Right-Pointing-Pointer Altered cytoplasmic localization of hnRNP A1 may alter gene expression patterns. Black-Right-Pointing-Pointer Our studies may increase our understanding of RNA metabolism during cellular aging.

  5. TERRA, hnRNP A1, and DNA-PKcs Interactions at Human Telomeres.

    PubMed

    Le, Phuong N; Maranon, David G; Altina, Noelia H; Battaglia, Christine L R; Bailey, Susan M

    2013-01-01

    Maintenance of telomeres, repetitive elements at eukaryotic chromosomal termini, and the end-capping structure and function they provide, are imperative for preserving genome integrity and stability. The discovery that telomeres are transcribed into telomere repeat containing RNA (TERRA) has revolutionized our view of this repetitive, rather unappreciated region of the genome. We have previously shown that the non-homologous end-joining, shelterin associated DNA dependent protein kinase catalytic subunit (DNA-PKcs) participates in mammalian telomeric end-capping, exclusively at telomeres created by leading-strand synthesis. Here, we explore potential roles of DNA-PKcs and its phosphorylation target heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) in the localization of TERRA at human telomeres. Evaluation of co-localized foci utilizing RNA-FISH and three-dimensional (3D) reconstruction strategies provided evidence that both inhibition of DNA-PKcs kinase activity and siRNA depletion of hnRNP A1 result in accumulation of TERRA at individual telomeres; depletion of hnRNP A1 also resulted in increased frequencies of fragile telomeres. These observations are consistent with previous demonstrations that decreased levels of the nonsense RNA-mediated decay factors SMG1 and UPF1 increase TERRA at telomeres and interfere with replication of leading-strand telomeres. We propose that hTR mediated stimulation of DNA-PKcs and subsequent phosphorylation of hnRNP A1 influences the cell cycle dependent distribution of TERRA at telomeres by contributing to the removal of TERRA from telomeres, an action important for progression of S-phase, and thereby facilitating efficient telomere replication and end-capping.

  6. Mechanistic Control of Carcinoembryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM1) Splice Isoforms by the Heterogeneous Nuclear Ribonuclear Proteins hnRNP L, hnRNP A1, and hnRNP M*

    PubMed Central

    Dery, Kenneth J.; Gaur, Shikha; Gencheva, Marieta; Yen, Yun; Shively, John E.; Gaur, Rajesh K.

    2011-01-01

    Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is expressed in a variety of cell types and is implicated in carcinogenesis. Alternative splicing of CEACAM1 pre-mRNA generates two cytoplasmic domain splice variants characterized by the inclusion (L-isoform) or exclusion (S-isoform) of exon 7. Here we show that the alternative splicing of CEACAM1 pre-mRNA is regulated by novel cis elements residing in exon 7. We report the presence of three exon regulatory elements that lead to the inclusion or exclusion of exon 7 CEACAM1 mRNA in ZR75 breast cancer cells. Heterologous splicing reporter assays demonstrated that the maintenance of authentic alternative splicing mechanisms were independent of the CEACAM1 intron sequence context. We show that forced expression of these exon regulatory elements could alter CEACAM1 splicing in HEK-293 cells. Using RNA affinity chromatography, three members of the heterogeneous nuclear ribonucleoprotein family (hnRNP L, hnRNP A1, and hnRNP M) were identified. RNA immunoprecipitation of hnRNP L and hnRNP A1 revealed a binding motif located central and 3′ to exon 7, respectively. Depletion of hnRNP A1 or L by RNAi in HEK-293 cells promoted exon 7 inclusion, whereas overexpression led to exclusion of the variable exon. By contrast, overexpression of hnRNP M showed exon 7 inclusion and production of CEACAM1-L mRNA. Finally, stress-induced cytoplasmic accumulation of hnRNP A1 in MDA-MB-468 cells dynamically alters the CEACAM1-S:CEACAM1:L ratio in favor of the l-isoform. Thus, we have elucidated the molecular factors that control the mechanism of splice-site recognition in the alternative splicing regulation of CEACAM1. PMID:21398516

  7. HnRNP A1 is Involved in Deep Vein Thrombosis Patients with Behçet's Disease

    PubMed Central

    Chen, Peng; Zhang, Chunyan; Liu, Chen; Zhang, Liyun; Yang, Chunhe; Chen, Guangyu; Ma, Dan; Tian, Yaping; Du, Hongwu

    2016-01-01

    Objective The aim of this study was to verify the hypothesis originated from bioinformatics and literature reviews that hnNRP A1 may be a new immune target of Behçet's disease (BD). Methods First, bioinformatics was used to show the correlation between hnRNP A1 and A2/B1 in amino acid sequences and three dimensional structures. Second, hnRNP A1 was expressed, purified, and immunologically confirmed by systematic immunology methods including: Western blotting, immunoprecipitation and Dot-ELISA. Then, ELISA was used to screen the anti-hnRNP A1 autoantibodies in newly confirmed clinical samples and the clinical significance was compared between anti-hnRNP A1 antibody positive and negative groups. Finally, the endothelial cells antigen profile of one anti-hnRNP A1 antibody positive BD patient was detected using immunoprecipitation with liquid chromatography tandem mass spectrometry (LC–TMS). Results In total 720 subjects enrolled and tested in this study. Our results demonstrated hnRNP A1 as a new immune target of BD. The reactivity of BD serum IgG antibodies against hnRNP A1 was significantly higher than healthy controls (P < 0.0001), and deep vein thrombosis (DVT) showed a significant higher in the anti-hnRNP A1 antibodies positive group (P < 0.05). PMID:27211563

  8. A truncated hnRNP A1 isoform, lacking the RGG-box RNA binding domain, can efficiently regulate HIV-1 splicing and replication.

    PubMed

    Jean-Philippe, Jacques; Paz, Sean; Lu, Michael L; Caputi, Massimo

    2014-01-01

    Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is one of the most abundant RNA binding proteins. hnRNP A1 is localized prevalently in the nucleus but it can relocate to the cytoplasm in response to specific stimuli shuttling between nuclear and cytoplasmic compartments. The cellular localization of this protein is regulated by a short C-terminus motif (M9) and other less defined sequences. The RNA binding specificity of this protein is dependent on multiple RNA binding domains (RBDs), which regulate its role in RNA processing and expression. hnRNP A1 plays multiple roles in gene expression by regulating the biogenesis and translation of messengers RNAs, the processing of miRNAs, affecting transcription and controlling telomere maintenance. The multiple functions of this protein correlate with diverse roles in genetic disease, cancer and the replication of viral pathogens. Utilizing a tagged hnRNP A1 deletion library we have shown that the three hnRNP A1 RBDs contribute to the prevalent nuclear distribution of the protein. Our data also indicate that a truncated form of the protein, lacking one of the RBDs, the RGG-box, can regulate splicing of a splicing reporter minigene and down-regulate replication of the HIV-1 virus with efficiency comparable to the wild-type protein. This functional hnRNP A1 deletion mutant is similar to a predicted hnRNP A1 isoform, which had not been previously experimentally characterized. PMID:24530421

  9. hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA linked to tumor progression

    PubMed Central

    Pierredon, Sandra; Le Bras, Morgane; Iacovoni, Jason S.; Teulade-Fichou, Marie-Paule; Favre, Gilles; Roché, Henri; Filleron, Thomas; Millevoi, Stefania; Vagner, Stéphan

    2016-01-01

    The expression and role of RNA binding proteins (RBPs) controlling mRNA translation during tumor progression remains largely uncharacterized. Analysis by immunohistochemistry of the expression of hnRNP A1, hnRNPH, RBM9/FOX2, SRSF1/ASF/SF2, SRSF2/SC35, SRSF3/SRp20, SRSF7/9G8 in breast tumors shows that the expression of hnRNP A1, but not the other tested RBPs, is associated with metastatic relapse. Strikingly, hnRNP A1, a nuclear splicing regulator, is also present in the cytoplasm of tumor cells of a subset of patients displaying exceedingly worse prognosis. Expression of a cytoplasmic mutant of hnRNP A1 leads to increased translation of the mRNA encoding the tyrosine kinase receptor RON/MTS1R, known for its function in tumor dissemination, and increases cell migration in vitro. hnRNP A1 directly binds to the 5′ untranslated region of the RON mRNA and activates its translation through G-quadruplex RNA secondary structures. The correlation between hnRNP A1 and RON tumoral expression suggests that these findings hold clinical relevance. PMID:26930004

  10. Separable roles in vivo for the two RNA binding domains of Drosophila A1-hnRNP homolog.

    PubMed Central

    Zu, K; Sikes, M L; Beyer, A L

    1998-01-01

    We analyzed the roles of the three domains of a Drosophila hnRNP A1 homolog by expression of wild-type and mutant versions of HRB87F/hrp36 in Drosophila melanogaster. HRB87F/hrp36 is one of two Drosophila proteins that is most similar to mammalian A1 hnRNP, and like A1, consists of two copies of the RNA-binding domain (RBD) motif followed by a glycine-rich domain (GRD). The role of the domains in nuclear localization and RNA binding to polytene chromosomal sites was determined. RBD-1 and the GRD were largely responsible for both the cellular location of the protein and for the typical chromosomal distribution pattern of the protein at sites of PolII transcription. RBD-1 also provided a role in the exon-skipping activity of the protein that was not provided by RBD-2. On the other hand, RBD-2 and the GRD were responsible for the very limited chromosomal distribution pattern seen upon heat shock, when HRB87F/hrp36 is sequestered at heat-shock puff 93D, which encodes a long nucleus-restricted RNA. Thus, these studies indicate that the two RBDs function independently of each other but in concert with the GRD. In addition, the self-association property of the GRD was strikingly evident in these overexpressed proteins. PMID:9848655

  11. HnRNP A1 tethers KSRP to an exon splicing silencer that inhibits an erythroid-specific splicing event in PU.1-induced erythroleukemia

    PubMed Central

    Douablin, Alexandre; Deguillien, Mireille; Breig, Osman; Baklouti, Faouzi

    2015-01-01

    Exon 16 inclusion is a critical splicing event that triggers the production of a functional protein 4.1R in mature normal erythroblasts, and is obviated in PU.1-induced erythroleukemia cells. Exon 16 contains an exonic splicing silencer (ESS16) that interacts with hnRNP A/B in heterologous cell context. We here show that ESS16 promotes the recruitment of a protein complex containing hnRNP A1 and a 79-kDa protein in nuclear extracts from either proliferative erythroleukemia cells or cells induced to terminal differentiation. By using 2D gel fractionation and mass spectrometry, we unambiguously identified KSRP as the 79-kDa component interacting with ESS16. Furthermore, we show that KSRP slightly decreases in erythroleukemia cells induced to terminal erythroid differentiation. Yet, KSRP inducible knockdown, through stable transfection of small hairpin KSRP RNA, did not alter exon 16 splicing, suggesting that KSRP alone does not modulate the splicing event. Interestingly, absence of hnRNP A1 prevented KSRP from binding to ESS16. Reciprocally, KSRP interaction with ESS16 was recovered when hnRNP A1 expression is restored in hnRNP A1-null cells. Collectively, this study establishes that hnRNPA1 is part of a KSRP-containing RNP complex, and emphasizes that, aside from its function in AU-rich element-mediated mRNA decay and its role in microRNA biogenesis, KSRP associates with hnRNP A1 to bind an ESS. These findings further support the role of members of the KH-domain protein family in organizing large RNA-protein complex formation, rather than primarily in modulating specific splicing events. PMID:26101706

  12. CD44 alternative splicing and hnRNP A1 expression are associated with the metastasis of breast cancer.

    PubMed

    Loh, Tiing Jen; Moon, Heegyum; Cho, Sunghee; Jang, Hana; Liu, Yong Chao; Tai, Hongmei; Jung, Da-Woon; Williams, Darren R; Kim, Hey-Ran; Shin, Myung-Geun; Liao, D Joshua; Zhou, Jianhua; Shi, Wei; Zheng, Xuexiu; Shen, Haihong

    2015-09-01

    CD44 is a transmembrane receptor for hyaluronic acid. CD44 pre-mRNA contains 19 exons, 9 of which are alternatively spliced. Among the CD44 spliced variants, the v4-7 variant, one of the v6 exon-containing isoforms that contains variable exon 4, 5, 6 and 7, confers metastatic potential to non-metastatic cells. Splicing of CD44 and the function of CD44 isoforms are different in breast cancer cells. hnRNP A1 is a ubiquitously expressed protein with an inhibitory function in pre-mRNA splicing. We showed that CD44v6 isoform, which includes all of the v6-containing mRNA isoforms, had the highest expression level in non-metatatic breast cancer cells (MCF7) when compared to the level in metastatic breast cancer cells (MDA-MB-231) and normal breast cells (MCF10A). Furthermore we showed that hnRNP A1 knockdown regulated splicing of CD44 differently in breast cancer cells. We showed here that CD44 isoform expression is completely different in MDA-MB-231 cells than that in MCF7 and MCF10A cells, whereas MCF7 and MCF10A cells had a similar expression pattern of CD44 isoforms. RT-PCR analysis of CD44v6 showed that MCF7 and MCF10A cells predominantly expressed the c5v6v7v8v9v10c6 isoform. However, in addition to this isoform, MDA-MB-231 cells also expressed the c5v6v8v9v10c6 and c5v6c6 isoforms. We also found that knockdown of hnRNP A1 significantly reduced the expression of c5v6v7v8v9v10c6 and c5v6v8v9v10c6, and promoted the expression of c5v6c6. hnRNP A1 knockdown significantly induced cell death. In addition, hnRNP A1 knockdown induced a decrease in cell invasion in the MDA-MB-231 cells. Our results indicate that the knockdown of hnRNP A1 has a specific function on the splicing of CD44 in breast cancer cells.

  13. hnRNP A1 controls HIV-1 mRNA splicing through cooperative binding to intron and exon splicing silencers in the context of a conserved secondary structure.

    PubMed Central

    Damgaard, Christian Kroun; Tange, Thomas Ostergaard; Kjems, Jørgen

    2002-01-01

    The removal of the second intron in the HIV-1 rev/tat pre-mRNAs, which involves the joining of splice site SD4 to SA7, is inhibited by hnRNP A1 by a mechanism that requires the intronic splicing silencer (ISS) and the exon splicing silencer (ESS3). In this study, we have determined the RNA secondary structure and the hnRNP A1 binding sites within the 3' splice site region by phylogenetic comparison and chemical/enzymatic probing. A biochemical characterization of the RNA/protein complexes demonstrates that hnRNP A1 binds specifically to primarily three sites, the ISS, a novel UAG motif in the exon splicing enhancer (ESE) and the ESS3 element, which are all situated in experimentally supported stem loop structures. A mutational analysis of the ISS region revealed that the core hnRNP A1 binding site directly overlaps with a major branchpoint used in splicing to SA7, thereby providing a direct explanation for the inhibition of U2 snRNP association with the pre-mRNA by hnRNP A1. Binding of hnRNP A1 to the ISS core site is inhibited by RNA structure but strongly stimulated by the exonic silencer, ESS3. Moreover, the ISS also stimulate binding of hnRNP A1 to the exonic splicing regulators ESS3 and the ESE. Our results suggest a model where a network is formed between hnRNP A1 molecules situated at discrete sites in the intron and exon and that these interactions preclude the recognition of essential splicing signals including the branch point. PMID:12458794

  14. Lipid accumulation stimulates the cap-independent translation of SREBP-1a mRNA by promoting hnRNP A1 binding to its 5'-UTR in a cellular model of hepatic steatosis.

    PubMed

    Siculella, Luisa; Tocci, Romina; Rochira, Alessio; Testini, Mariangela; Gnoni, Antonio; Damiano, Fabrizio

    2016-05-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic disease characterized by accumulation of lipid droplets in hepatocytes. Enhanced release of non-esterified fatty acids from adipose tissue accounts for a remarkable fraction of accumulated lipids. However, the de novo lipogenesis (DNL) is also implicated in the etiology of the NAFLD. Sterol Regulatory Element-Binding Protein-1 (SREBP-1) is a transcription factor modulating the expression of several lipogenic enzymes. In the present study, in order to investigate the effect of lipid droplet accumulation on DNL, we used a cellular model of steatosis represented by HepG2 cells cultured in a medium supplemented with free oleic and palmitic fatty acids (FFAs). We report that FFA supplementation induces the expression of genes coding for enzymes involved in the DNL as well as for the transcription factor SREBP-1a. The SREBP-1a mRNA translation, dependent on an internal ribosome entry site (IRES), and the SREBP-1a proteolytic cleavage are activated by FFAs. Furthermore, FFA treatment enhances the expression and the nucleus-cytosolic shuttling of hnRNP A1, a trans-activating factor of SREBP-1a IRES. The binding of hnRNP A1 to the SREBP-1a IRES is also increased upon FFA supplementation. The relocation of hnRNP A1 and the consequent increase of SREBP-1a translation are dependent on the p38 MAPK signal pathway, which is activated by FFAs. By RNA interference approach, we demonstrate that hnRNP A1 is implicated in the FFA-induced expression of SREBP-1a and of its target genes as well as in the lipid accumulation in cells. PMID:26869449

  15. Solution Structure of the HIV-1 Intron Splicing Silencer and Its Interactions with the UP1 Domain of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) A1.

    PubMed

    Jain, Niyati; Morgan, Christopher E; Rife, Brittany D; Salemi, Marco; Tolbert, Blanton S

    2016-01-29

    Splicing patterns in human immunodeficiency virus type 1 (HIV-1) are maintained through cis regulatory elements that recruit antagonistic host RNA-binding proteins. The activity of the 3' acceptor site A7 is tightly regulated through a complex network of an intronic splicing silencer (ISS), a bipartite exonic splicing silencer (ESS3a/b), and an exonic splicing enhancer (ESE3). Because HIV-1 splicing depends on protein-RNA interactions, it is important to know the tertiary structures surrounding the splice sites. Herein, we present the NMR solution structure of the phylogenetically conserved ISS stem loop. ISS adopts a stable structure consisting of conserved UG wobble pairs, a folded 2X2 (GU/UA) internal loop, a UU bulge, and a flexible AGUGA apical loop. Calorimetric and biochemical titrations indicate that the UP1 domain of heterogeneous nuclear ribonucleoprotein A1 binds the ISS apical loop site-specifically and with nanomolar affinity. Collectively, this work provides additional insights into how HIV-1 uses a conserved RNA structure to commandeer a host RNA-binding protein. PMID:26607354

  16. Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer.

    PubMed

    Chen, Chi-Yuan; Jan, Chia-Ing; Pi, Wen-Chieh; Wang, Wen-Lung; Yang, Pan-Chyr; Wang, Tong-Hong; Karni, Rotem; Wang, Tzu-Chien V

    2016-03-29

    The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various cancers, including head and neck cancer and non-small cell lung cancer (NSCLC). However, the molecular mechanism responsible for regulating the alternative splicing of Tid1 is not yet known. Two splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2, participate in alternative splicing and are known to be overexpressed in lung cancers. In this work, we examined if hnRNP A1 and A2 could regulate the alternative splicing of Tid1 to modulate tumorigenesis in NSCLC. We report that RNAi-mediated depletion of both hnRNP A1/A2 (but not single depletion of either) increased Tid1-L expression, inhibited cell proliferation and attenuated EGFR signaling. Analyses of the expression levels of hnRNP A1, hnRNP A2, EGFR and Tid1-L in NSCLC tissues revealed that hnRNP A1 and A2 are positively correlated with EGFR, but negatively correlated with Tid1-L. NSCLC patients with high-level expression of hnRNP A1, hnRNP A2 and EGFR combined with low-level expression of Tid1-L were associated with poor overall survival. Taken together, our results suggest that hnRNP A1 or A2 are both capable of facilitating the alternative splicing of exon 11 in the Tid1 pre-mRNA, thereby suppressing the expression of Tid1-L and allowing EGFR-related signaling to facilitate NSCLC tumorigenesis. PMID:26919236

  17. Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer

    PubMed Central

    Chen, Chi-Yuan; Jan, Chia-Ing; Pi, Wen-Chieh; Wang, Wen-Lung; Yang, Pan-Chyr; Wang, Tong-Hong; Karni, Rotem; Wang, Tzu-Chien V.

    2016-01-01

    The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various cancers, including head and neck cancer and non-small cell lung cancer (NSCLC). However, the molecular mechanism responsible for regulating the alternative splicing of Tid1 is not yet known. Two splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2, participate in alternative splicing and are known to be overexpressed in lung cancers. In this work, we examined if hnRNP A1 and A2 could regulate the alternative splicing of Tid1 to modulate tumorigenesis in NSCLC. We report that RNAi-mediated depletion of both hnRNP A1/A2 (but not single depletion of either) increased Tid1-L expression, inhibited cell proliferation and attenuated EGFR signaling. Analyses of the expression levels of hnRNP A1, hnRNP A2, EGFR and Tid1-L in NSCLC tissues revealed that hnRNP A1 and A2 are positively correlated with EGFR, but negatively correlated with Tid1-L. NSCLC patients with high-level expression of hnRNP A1, hnRNP A2 and EGFR combined with low-level expression of Tid1-L were associated with poor overall survival. Taken together, our results suggest that hnRNP A1 or A2 are both capable of facilitating the alternative splicing of exon 11 in the Tid1 pre-mRNA, thereby suppressing the expression of Tid1-L and allowing EGFR-related signaling to facilitate NSCLC tumorigenesis. PMID:26919236

  18. A1C test

    MedlinePlus

    HbA1C test; Glycated hemoglobin test; Glycosylated hemoglobin test; Hemoglobin glycosylated test; Glycohemoglobin test ... have recently eaten does not affect the A1C test, so you do not need to fast to ...

  19. 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 ...

  20. A1C Test

    MedlinePlus

    ... to minimize the complications caused by chronically elevated glucose levels, such as progressive damage to body organs like the kidneys, eyes, cardiovascular system, and nerves. The A1c test result ...

  1. Identification of DNA cleavage- and recombination-specific hnRNP cofactors for activation-induced cytidine deaminase.

    PubMed

    Hu, Wenjun; Begum, Nasim A; Mondal, Samiran; Stanlie, Andre; Honjo, Tasuku

    2015-05-01

    Activation-induced cytidine deaminase (AID) is essential for antibody class switch recombination (CSR) and somatic hypermutation (SHM). AID originally was postulated to function as an RNA-editing enzyme, based on its strong homology with apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 1 (APOBEC1), the enzyme that edits apolipoprotein B-100 mRNA in the presence of the APOBEC cofactor APOBEC1 complementation factor/APOBEC complementation factor (A1CF/ACF). Because A1CF is structurally similar to heterogeneous nuclear ribonucleoproteins (hnRNPs), we investigated the involvement of several well-known hnRNPs in AID function by using siRNA knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated disruption. We found that hnRNP K deficiency inhibited DNA cleavage and thereby induced both CSR and SHM, whereas hnRNP L deficiency inhibited only CSR and somewhat enhanced SHM. Interestingly, both hnRNPs exhibited RNA-dependent interactions with AID, and mutant forms of these proteins containing deletions in the RNA-recognition motif failed to rescue CSR. Thus, our study suggests that hnRNP K and hnRNP L may serve as A1CF-like cofactors in AID-mediated CSR and SHM.

  2. Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins

    PubMed Central

    Chen, Mo; David, Charles J.; Manley, James L.

    2013-01-01

    Expression of the mammalian pyruvate kinase M (PKM) gene provides an important example of mutually exclusive splicing. We showed previously that the hnRNP proteins A1, A2 and PTB play a critical role in this process. Here we provide evidence that concentration-dependent interactions involving a network of these proteins are sufficient to determine the outcome of PKM splicing. At high concentrations, such as found in most cancer cells, hnRNP A1 binding to two sites in the upstream regulated exon (exon 9) orchestrates cooperative interactions leading to exon 9 exclusion. At lower concentrations, binding shifts to downstream intronic sites such that exon 9 is included and exon 10 largely excluded, with any mRNA including both exons degraded by nonsense-mediated decay. Together our results provide a mechanism by which a small number of general factors control alternative splicing of a widely expressed transcript. PMID:22307054

  3. A1C Test and Diabetes

    MedlinePlus

    ... laboratory tests. How does the A1C relate to estimated average glucose? Estimated average glucose (eAG) is calculated from the A1C. ... levels have the A1C test twice a year. Estimated average glucose (eAG) is calculated from the A1C ...

  4. 32 CFR 169a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... § 169a.1(a). 3 Copies may be obtained if needed, from the Office of Management and Budget, Executive... and Industrial Activities Cost Comparison Handbook.” 4 See footnote 1 to § 169a.1(a)....

  5. 32 CFR 169a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... PROCEDURES General § 169a.1 Purpose. This part: (a) Reissues DoD Instruction 4100.33 1 to update policy... § 169a.1(a). 3 Copies may be obtained if needed, from the Office of Management and Budget, Executive... and Industrial Activities Cost Comparison Handbook.” 4 See footnote 1 to § 169a.1(a)....

  6. 22 CFR 3a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Definitions. 3a.1 Section 3a.1 Foreign Relations DEPARTMENT OF STATE GENERAL ACCEPTANCE OF EMPLOYMENT FROM FOREIGN GOVERNMENTS BY MEMBERS OF THE UNIFORMED SERVICES § 3a.1 Definitions. For purposes of this part— (a) Applicant means any person...

  7. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Definitions. 213a.1 Section 213a.1 Aliens... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... intention to maintain that residence for the foreseeable future. Federal poverty line means the level...

  8. 8 CFR 213a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Definitions. 213a.1 Section 213a.1 Aliens... BEHALF OF IMMIGRANTS § 213a.1 Definitions. As used in this part, the term: Domicile means the place where... intention to maintain that residence for the foreseeable future. Federal poverty line means the level...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  14. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  15. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  16. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  17. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  18. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 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...

  19. Reversibility of Intersystem Crossing in the {a}1A1(000) and {a}1A1(010) States of Methylene, CH_2

    NASA Astrophysics Data System (ADS)

    Le, Anh T.; Sears, Trevor; Hall, Gregory

    2015-06-01

    The lowest energy singlet ( {a}1A1) and triplet ( {X}3B1) electronic states of methylene, CH_2, are only separated by 3150 wn, but differ greatly in chemical reactivity. Overall methylene reaction rates and chemical behavior are therefore strongly dependent on collisionally-mediated singlet-triplet interconversion. Collisions with inert partners tend to depopulate the excited singlet state and populate vibrationally excited triplet levels in CH_2. This process is generally considered as irreversible for large molecules, however, this is not the case for small molecules such as CH_2. An investigation of the decay kinetics of CH_2 in the presence of argon and various amounts of oxygen has been carried out using transient frequency modulation (FM) absorption spectroscopy, to monitor ortho and para rotational levels in both the {a}1A1(000) and {a}1A1(010) states. In the {a}1A1(000) state, all observed rotational levels follow double exponential decay kinetics, a direct consequence of reversible intersystem crossing. The relative amplitude of the slower decay component is an indicator of how quickly the reverse crossing from excited triplet levels becomes significant during the reaction and relaxation of singlet methylene. The para rotational levels show more obvious signs of reversibility than ortho rotational levels. Adding oxygen enhances the visibility of reversibility for both ortho and para levels. However, in the {a}1A1(010) state where the FM signal is 5-10 times smaller than the {a}1A1(000) state, there is no evidence of double exponential decay kinetics. Acknowledgments: Work at Brookhaven National Laboratory was carried out under Contract No. DE-AC02-98CH10886 and DE-SC0012704 with the U.S. Department of Energy and supported by its Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences.

  20. 12 CFR 269a.1 - Party.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Party. 269a.1 Section 269a.1 Banks and Banking... Party. The term Party means any person, employee, group of employees, labor organization, or bank as... rules and regulations, (b) named as a party in a charge, complaint, petition, application, or...

  1. 12 CFR 269a.1 - Party.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Party. 269a.1 Section 269a.1 Banks and Banking... Party. The term Party means any person, employee, group of employees, labor organization, or bank as... rules and regulations, (b) named as a party in a charge, complaint, petition, application, or...

  2. 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...

  3. 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...

  4. 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....

  5. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... the term such alien actually served. Under this exception, for purposes of 8 CFR part 245a, the crime... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Definitions. 245a.1 Section 245a.1 Aliens...). (c)(1) Resided continuously as used in section 245A(a)(2) of the Act, means that the alien shall...

  6. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... the term such alien actually served. Under this exception, for purposes of 8 CFR part 245a, the crime... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Definitions. 245a.1 Section 245a.1 Aliens...). (c)(1) Resided continuously as used in section 245A(a)(2) of the Act, means that the alien shall...

  7. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Definitions. 245a.1 Section 245a.1 Aliens... the alien shall be regarded as having resided continuously in the United States if, at the time of filing of the application for temporary resident status: An alien who after appearing for a...

  8. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C. 2106... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.1 Definitions. (a) The term housing unit means a family dwelling or unit, together with...

  9. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Purpose. 383a.1 Section 383a.1 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS... the Defense Commissary Board (DCB), with responsibilities, functions, and authorities as...

  10. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...(a)) provides that “ he Secretary may authorize persons engaged in research on mental health... regulations in this part establish procedures under which any person engaged in research on mental health... 42 Public Health 1 2010-10-01 2010-10-01 false Applicability. 2a.1 Section 2a.1 Public...

  11. 42 CFR 2a.1 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...(a)) provides that “ he Secretary may authorize persons engaged in research on mental health... regulations in this part establish procedures under which any person engaged in research on mental health... 42 Public Health 1 2011-10-01 2011-10-01 false Applicability. 2a.1 Section 2a.1 Public...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. 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...

  17. EIYMNVPV Motif is Essential for A1CF Nucleus Localization and A1CF (-8aa) Promotes Proliferation of MDA-MB-231 Cells via Up-Regulation of IL-6

    PubMed Central

    Zhou, Li; Hao, Jin; Yuan, Yue; Peng, Rui; Wang, Honglian; Ni, Dongsheng; Gu, Yuping; Huang, Liyuan; Mao, Zhaomin; Lyu, Zhongshi; Du, Yao; Liu, Zhicheng; Li, Yiman; Ju, Pan; Long, Yaoshui; Liu, Jianing; Zhou, Qin

    2016-01-01

    Apobec-1 complementation factor (A1CF) is a heterogeneous nuclear ribonuceloprotein (hnRNP) and mediates apolipoprotein-B mRNA editing. A1CF can promote the regeneration of the liver by post-transcriptionally stabilizing Interleukin-6 (IL-6) mRNA. It also contains two transcriptional variants-A1CF64 and A1CF65, distinguished by the appearance of a 24-nucleotide motif which contributes to the corresponding eight-amino acid motif of EIYMNVPV. For the first time, we demonstrated that the EIYMNVPV motif was essential for A1CF nucleus localization, A1CF deficient of the EIYMNVPV motif, A1CF (-8aa) showed cytoplasm distribution. More importantly, we found that A1CF (-8aa), but not its full-length counterpart, can promote proliferation of MDA-MB-231 cells accompanied with increased level of IL-6 mRNA. Furthermore, silencing of IL-6 attenuated A1CF (-8aa)-induced proliferation in MDA-MB-231 cells. In conclusion, notably, these findings suggest that A1CF (-8aa) promoted proliferation of MDA-MB-231 cells in vitro viewing IL-6 as a target. Thus, the EIYMNVPV motif could be developed as a potential target for basal-like breast cancer therapy. PMID:27231908

  18. Blood Test: Hemoglobin A1C

    MedlinePlus

    ... the person's average blood sugar levels over that time. Why It's Done Doctors use the hemoglobin A1c test to determine if your child's diabetes management plan needs to be adjusted. Typically the test ...

  19. 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.

  20. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Stennis Space Center employees maneuver a new thrust measurement system in preparation for its installation on the A-1 Test Stand on March 3. The system was fabricated by Thrust Measurement Systems in Illinois and represents a state-of-the-art upgrade from the equipment used on the stand for more than 40 years. The A-1 Test Stand is being upgraded to provide testing for the next generation of rocket engines for America's space program.

  1. Nature of the a1(1420 )

    NASA Astrophysics Data System (ADS)

    Mikhasenko, M.; Ketzer, B.; Sarantsev, A.

    2015-05-01

    The resonancelike signal with axial-vector quantum numbers JP C=1++ at a mass of 1420 MeV and a width of 140 MeV, recently observed by the COMPASS and VES experiments in the f0(980 )π final state and tentatively called a1(1420 ), is discussed. Instead of a genuine new meson, we interpret this signal as a dynamical effect due to a singularity (branching point) in the triangle diagram formed by the processes a1(1260 )→K⋆K ¯, K⋆→K π , and K K ¯→f0(980 ) (+c .c ). The amplitude for this diagram is calculated. The result exhibits a peak in the intensity with a sharp phase motion with respect to the dominant a1(1260 )→ρ π S -wave decay, in good agreement with the data. The branching ratio of a1(1260 )→f0(980 )π via the triangle diagram is estimated and compared to the dominant decay a1(1260 )→ρ π .

  2. Methamphetamine Regulation of Sulfotransferase 1A1 and 2A1 Expression in Rat Brain Sections

    PubMed Central

    Zhou, Tianyan; Huang, Chaoqun; Chen, Yue; Xu, Jiaojiao; Shanbhag, Preeti Devaraya; Chen, Guangping

    2012-01-01

    Sulfotransferase catalyzed sulfation regulates the biological activities of various neurotransmitters/hormones and detoxifies xenobiotics. Rat sulfotransferase rSULT1A1 catalyzes the sulfation of neurotransmitters and xenobiotic phenolic compounds. rSULT2A1 catalyzes the sulfation of hydroxysteroids and xenobiotic alcoholic compounds. In this work, Western blot and real-time RT-PCR were used to investigate the effect of methamphetamine on rSULT1A1 and rSULT2A1 protein and mRNA expression in rat cerebellum, frontal cortex, hippocampus, and striatum. After 1-day treatment, significant induction of rSULT1A1 was observed only in the cerebellum; rSULT2A1 was induced significantly in the cerebellum, frontal cortex, and hippocampus. After 7-days of exposure, rSULT1A1 was induced in the cerebellum, frontal cortex, and hippocampus, while rSULT2A1 was induced significantly in all four regions. Western blot results agreed with the real-time RT-PCR results, suggesting that the induction occurred at the gene transcriptional level. Results indicate that rSULT1A1 and rSULT2A1 are expressed in rat frontal cortex, cerebellum, striatum, and hippocampus. rSULT1A1 and rSULT2A1are inducible by methamphetamine in rat brain sections in a time dependable manner. rSULT2A1 is more inducible than rSULT1A1 by methamphetamine in rat brain sections. Induction activity of methamphetamine is in the order of cerebellum > frontal cortex, hippocampus > striatum. These results suggest that the physiological functions of rSULT1A1 and rSULT2A1 in different brain regions can be affected by methamphetamine. PMID:23026138

  3. Pneumococcal IgA1 protease subverts specific protection by human IgA1.

    PubMed

    Janoff, E N; Rubins, J B; Fasching, C; Charboneau, D; Rahkola, J T; Plaut, A G; Weiser, J N

    2014-03-01

    Bacterial immunoglobulin A1 (IgA1) proteases may sabotage the protective effects of IgA. In vitro, both exogenous and endogenously produced IgA1 protease inhibited phagocytic killing of Streptococcus pneumoniae by capsule-specific IgA1 human monoclonal antibodies (hMAbs) but not IgA2. These IgA1 proteases cleaved and reduced binding of the the effector Fcα1 heavy chain but not the antigen-binding F(ab)/light chain to pneumococcal surfaces. In vivo, IgA1 protease-resistant IgA2, but not IgA1 protease-sensitive IgA1, supported 60% survival in mice infected with wild-type S. pneumoniae. IgA1 hMAbs protected mice against IgA1 protease-deficient but not -producing pneumococci. Parallel mouse sera with human IgA2 showed more efficient complement-mediated reductions in pneumococci with neutrophils than did IgA1, particularly with protease-producing organisms. After natural human pneumococcal bacteremia, purified serum IgG inhibited IgA1 protease activity in 7 of 11 patients (64%). These observations provide the first evidence in vivo that IgA1 protease can circumvent killing of S. pneumoniae by human IgA. Acquisition of IgA1 protease-neutralizing IgG after infection directs attention to IgA1 protease both as a determinant of successful colonization and infection and as a potential vaccine candidate.

  4. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., if any, or (2) a crime treated as a misdemeanor under 8 CFR 245a.1(p). For purposes of this... CFR part 245a, the crime shall be treated as a misdemeanor. (q) Subject of an Order to Show Cause... English language competency, and attainment of these skills is measured either by successful completion...

  5. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... necessary land therefor, that has been or will be purchased, constructed, or remodeled with a grant to meet... eligible veteran as his or her home, or a family dwelling or unit, including the necessary land...

  6. 32 CFR 168a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... which will be codified at 32 CFR part 168b. ... 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....

  7. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Employees at NASA's John C. Stennis Space Center complete installation of the new thrust measurement system on the A-1 Test Stand. The new TMS is a state-of-the-art upgrade from the previous system, which was installed when the testing structure was built in the 1960s. It is an advanced calibration system capable of measuring vertical and horizontal thrust loads with accuracy within 0.15 percent at 225,000 pounds. It also will allow engineers to measure thrust as they gimbal (or tilt) engines during tests. The new TMS is part of upgrades for the A-1 Test Stand in preparation for testing the next generation of American space program rocket engines.

  8. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    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.

  9. PLC Software Program for Leak Detector Station A1 SALW-LD-ST-A1

    SciTech Connect

    KOCH, M.R.

    2001-01-25

    This document describes the software program for the programmable logic controller for the leak detector station ''SALW-LD-ST-A1''. The appendices contains a copy of the printout of the software program.

  10. A 1-D dusty plasma photonic crystal

    SciTech Connect

    Mitu, M. L.; Ticoş, C. M.; Toader, D.; Banu, N.; Scurtu, A.

    2013-09-21

    It is demonstrated numerically that a 1-D plasma crystal made of micron size cylindrical dust particles can, in principle, work as a photonic crystal for terahertz waves. The dust rods are parallel to each other and arranged in a linear string forming a periodic structure of dielectric-plasma regions. The dispersion equation is found by solving the waves equation with the boundary conditions at the dust-plasma interface and taking into account the dielectric permittivity of the dust material and plasma. The wavelength of the electromagnetic waves is in the range of a few hundred microns, close to the interparticle separation distance. The band gaps of the 1-D plasma crystal are numerically found for different types of dust materials, separation distances between the dust rods and rod diameters. The distance between levitated dust rods forming a string in rf plasma is shown experimentally to vary over a relatively wide range, from 650 μm to about 1350 μm, depending on the rf power fed into the discharge.

  11. 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.

  12. HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis

    PubMed Central

    Chyu, Kuang-Yuh; Shah, Prediman K.

    2015-01-01

    The HDL hypothesis stating that simply raising HDL cholesterol (HDL-C) may produce cardiovascular benefits has been questioned recently based on several randomized clinical trials using CETP inhibitors or niacin to raise HDL-C levels. However, extensive pre-clinical data support the vascular protective effects of administration of exogenous ApoA-1 containing preβ-HDL like particles. Several small proof-of-concept clinical trials using such HDL/ApoA-1 infusion therapy have shown encouraging results but definitive proof of efficacy must await large scale clinical trials. In addition to HDL infusion therapy an alternative way to exploit beneficial cardiovascular effects of HDL/ApoA-1 is to use gene transfer. Preclinical studies have shown evidence of benefit using this approach; however clinical validation is yet lacking. This review summarizes our current knowledge of the aforementioned strategies. PMID:26388776

  13. STS payloads mission control study phase A-1, volume 1, phases A and A-1

    NASA Technical Reports Server (NTRS)

    1976-01-01

    The Space Transportation System (STS) Payloads Mission Control Phase A-1 Study results are summarized. The composite resources required to accomplish Joint STS-Payload preflight preparation for joint flight operations, including flight planning, training, and simulations are presented. The Standard Payload Operations Control Center (POCC) concept was developed.

  14. Polymorphisms of UGT1A1*6, UGT1A1*27 & UGT1A1*28 in three major ethnic groups from Malaysia

    PubMed Central

    Teh, L. K.; Hashim, H.; Zakaria, Z. A.; Salleh, M. Z.

    2012-01-01

    Background & objectives: Genetic polymorphisms of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) have been associated with a wide variation of responses among patients prescribed with irinotecan. Lack of this enzyme is known to be associated with a high incidence of severe toxicity. The objective of this study was to investigate the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28), which are associated with reduced enzyme activity and increased irinotecan toxicity, in the three main ethnic groups in Malaysia (Malays, Chinese and Indians). Methods: A total of 306 healthy unrelated volunteers were screened for UGT1A1*28, UGT1A1*6 and UGT1A1*27. Blood samples (5 ml) were obtained from each subject and DNA was extracted. PCR based methods were designed and validated for detection of UGT1A1*6, UGT1A1*27 and UGT1A1*28. Direct DNA sequencing was performed to validate the results of randomly selected samples. Results: Malays and Indian have two-fold higher frequency of homozygous of UGT1A1*28 (7TA/7TA) which was 8 and 8.8 per cent, respectively compared to the Chinese (4.9%). However, the distribution of UGT1A1*6 and UGT1A1*27 showed no significant differences among them. UGT1A1*27 which has not been detected in Caucasian and African American population, was found in the Malaysian Malays (3.33%) and Malaysian Chinese (2.0%). Interpretation & conclusions: There was interethnic variability in the frequency of UGT1A1*28 in the Malaysian population. Our results suggest that genotyping of UGT1A1*6, UGT1A1*28 and UGT1A1*27 need to be performed before patients are prescribed with irinotecan due to their high prevalence of allelic variant which could lead to adverse drug reaction. PMID:22960892

  15. 26 CFR 1.666(a)-1 - Amount allocated.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Amount allocated. 1.666(a)-1 Section 1.666(a)-1... Beginning Before January 1, 1969 § 1.666(a)-1 Amount allocated. (a)(1) If a trust other than a foreign trust... had the following amounts of undistributed net income: Year Undistributed net income—portion of...

  16. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 9 2012-07-01 2012-07-01 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....

  17. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 9 2013-07-01 2013-07-01 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....

  18. 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....

  19. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 9 2014-07-01 2014-07-01 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....

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

    SciTech Connect

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

    1998-05-11

    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 {pi}-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 pepper-pot emittance diagnostic. Details of the injector, beam line, and diagnostics are presented.

  1. Multiple and additive functions of ALDH3A1 and ALDH1A1: cataract phenotype and ocular oxidative damage in Aldh3a1(-/-)/Aldh1a1(-/-) knock-out mice.

    PubMed

    Lassen, Natalie; Bateman, J Bronwyn; Estey, Tia; Kuszak, Jer R; Nees, David W; Piatigorsky, Joram; Duester, Gregg; Day, Brian J; Huang, Jie; Hines, Lisa M; Vasiliou, Vasilis

    2007-08-31

    ALDH3A1 (aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower (catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out and Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out mice were evaluated for biochemical changes and cataract formation (lens opacification). The Aldh1a1/Aldh3a1- and Aldh3a1-null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life (6-9 months of age). One- to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(-/-) and Aldh3a1(-/-)/Aldh1a1(-/-) mice compared with Aldh1a1(-/-) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic (light filtering) and enzymatic (detoxification) functions. PMID:17567582

  2. Lattice equations arising from discrete Painlevé systems. I. (A2 + A1)(1) and ( A 1 + A1 ' ) ( 1 ) cases

    NASA Astrophysics Data System (ADS)

    Joshi, Nalini; Nakazono, Nobutaka; Shi, Yang

    2015-09-01

    We introduce the concept of ω-lattice, constructed from τ functions of Painlevé systems, on which quad-equations of ABS (Adler-Bobenko-Suris) type appear. In particular, we consider the A5 ( 1 ) - and A6 ( 1 ) -surface q-Painlevé systems corresponding affine Weyl group symmetries are of (A2 + A1)(1)- and (A1 + A1)(1)-types, respectively.

  3. 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)...

  4. 26 CFR 1.501(a)-1 - Exemption from taxation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 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)...

  5. 5 CFR Appendix A-1 to Subpart I... - Windchill Chart

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... ADMINISTRATION (GENERAL) Pay for Duty Involving Physical Hardship or Hazard Pt. 550, Subpt. I, App. A-1 Appendix A-1 to Subpart I of Part 550—Windchill Chart EC01SE91.002 windchill chart in non-metric units... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Windchill Chart A Appendix A-1 to...

  6. [UGT1A1 Genotyping for Proper Use of Irinotecan].

    PubMed

    Matsuoka, Ayumu; Ando, Yuichi

    2015-07-01

    Irinotecan is a camptothecin analog used worldwide for a broad range of solid tumors, including colorectal and lung cancers. It can cause severe adverse drug reactions, such as neutropenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by the UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Recent pharmacogenetic studies on irinotecan have revealed the impact of UGT1A1 polymorphisms on severe adverse effects. A variant in the promoter of the UGT1A1 gene, the UGT1A1 *28 allele, has been extensively studied, and pharmacogenetic relationships between the variant and severe toxicities of irinotecan have been reported. The US FDA and pharmaceutical companies revised the irinotecan label in 2005, and it now includes homozygosity for the UGT1A1*28 genotype as one of the risk factors for severe neutropenia. A variant in exon 1 of the UGT1A1 gene, the UGT1A1*6 allele, mainly found in East Asians, is also an important risk factor associated with severe neutropenia. The concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, markedly alters the disposition of irinotecan, potentially increasing toxicity, which is now written on the label of irinotecan in Japan. For patients showing homozygosity for UGT1A1*28, *6, or compound heterozygosity for UGT1A1*6 and *28, dose reduction of irinotecan is strongly recommended. Genotyping tests for UGT1A1 *6 and *28 have been approved in Japan and are currently used in oncology practice. Moreover, a recent Phase 2 trial for FOLFIRINOX in Japan excluded patients who showed homozygosity for UGT1A1*28, *6, or compound heterozygosity for UGT1A1*6 and *28. At present, irinotecan chemotherapy based on a patient's UGT1A1 genetic status is scientifically reasonable. PMID:26591441

  7. Accurate identification of UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibitors using UGT1A1-overexpressing HeLa cells.

    PubMed

    Sun, Hua; Zhou, Xiaotong; Wu, Baojian

    2015-01-01

    1. UDP-glucuronosyltransferase 1A1 (UGT1A1) plays an irreplaceable role in detoxification of bilirubin and many drugs (e.g., SN-38). Here we aimed to explore the potential of UGT1A1-overexpressing HeLa cells (or HeLa1A1 cells) as a tool to accurately identify UGT1A1 inhibitors. 2. Determination of glucuronidation rates (β-estradiol and SN-38 as the substrates) was performed using HeLa1A1 cells and uridine diphosphoglucuronic acid (UDPGA)-supplemented cDNA expressed UGT1A1 enzyme (or microsomes). The inhibitory effects (IC50 values) of 20 structurally diverse compounds on the UGT1A1 activity were determined using HeLa1A1 cells and microsomal incubations. 3. In HeLa1A1 cells, the IC50 values for inhibition of β-estradiol glucuronidation by the tested compounds ranged from 0.33 to 94.6 µM. In the microsomal incubations, the IC50 values ranged from 0.47 to 155 µM. It was found that the IC50 values of all test compounds derived from the cells were well consistent with those from the microsomes (deviated by less than two-fold). Further, the IC50 values from the cells were strongly correlated with those from microsomes (r = 0.944, p < 0.001). Likewise, the IC50 values (0.37-77.3 µM) for inhibition of SN-38 glucuronidation in the cells were close to those (0.42-122 µM) for glucuronidation inhibition in microsomes. A strong correlation was also observed between the two sets of IC50 values (r = 0.978, p < 0.001). 4. In conclusion, UGT1A1-overexpressing HeLa cells were an appropriate tool to accurately depict the inhibition profiles of chemicals against UGT1A1. PMID:26068529

  8. Pioneer oral streptococci produce immunoglobulin A1 protease.

    PubMed Central

    Cole, M F; Evans, M; Fitzsimmons, S; Johnson, J; Pearce, C; Sheridan, M J; Wientzen, R; Bowden, G

    1994-01-01

    As part of a longitudinal study of the relationship between bacterial colonization and the secretory immune response, 367 isolates of pioneer viridans streptococci collected from 40 breast- and bottle-fed neonates within the first month postpartum were tested for the production of immunoglobulin A1 (IgA1) protease and glycosidases. Fifty percent of the streptococci isolated produced IgA1 protease, including all isolates of Streptococcus oralis and S. sanguis, 60.7% of S. mitis biovar 1 isolates, and some isolates that could not be identified. Three cleavage patterns of alpha 1 heavy chains were observed. Six isolates of S. mitis biovar 1 that did not produce IgA1 protease attacked the alpha 1 chain. Incubation of IgA1 protease-negative S. mitis biovar 1 isolates with IgA1, either prior to or together with S. sanguis, rendered the IgA1 paraprotein resistant to cleavage by the IgA1 protease of S. sanguis. The ability of some pioneer streptococci in the human oral cavity to produce IgA1 protease and of others to modify the susceptibility of IgA1 to cleavage by IgA1 protease perhaps enhances their ability to survive in this habitat. Images PMID:8188337

  9. 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. PMID:26846809

  10. An abundant dysfunctional apolipoprotein A1 in human atheroma

    PubMed Central

    Huang, Ying; DiDonato, Joseph A.; Levison, Bruce S.; Schmitt, Dave; Li, Lin; Wu, Yuping; Buffa, Jennifer; Kim, Timothy; Gerstenecker, Gary; Gu, Xiaodong; Kadiyala, Chandra; Wang, Zeneng; Culley, Miranda K.; Hazen, Jennie E.; DiDonato, Anthony J.; Fu, Xiaoming; Berisha, Stela; Peng, Daoquan; Nguyen, Truc; Liang, Shaohong; Chuang, Chia-Chi; Cho, Leslie; Plow, Edward F.; Fox, Paul L.; Gogonea, Valentin; Tang, W.H. Wilson; Parks, John S.; Fisher, Edward A.; Smith, Jonathan D.; Hazen, Stanley L.

    2014-01-01

    Recent studies indicate high density lipoproteins (HDL) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma, are dysfunctional and extensively oxidized by myeloperoxidase (MPO), while in vitro oxidation of apoA1/HDL by MPO impairs its cholesterol acceptor function. We developed a high affinity monoclonal antibody (mAb) that specifically recognizes apoA1/HDL modified by the MPO/H2O2/Cl-system using phage display affinity maturation. An oxindolyl alanine (2-OH-Trp) moiety at tryptophan 72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirm a critical role for apoA1 Trp72 in MPO-mediated inhibition of ABCA1-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation, but accounts for 20% of the apoA1 in atherosclerotic plaque. OxTrp72-apoA1 recovered from human atheroma or plasma was lipid-poor, virtually devoid of cholesterol acceptor activity, and demonstrated both potent pro-inflammatory activities on endothelial cells and impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n=627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a pro-atherogenic process in the artery wall. PMID:24464187

  11. Apobec-1 Complementation Factor (A1CF) Inhibits Epithelial-Mesenchymal Transition and Migration of Normal Rat Kidney Proximal Tubular Epithelial Cells

    PubMed Central

    Huang, Liyuan; Wang, Honglian; Zhou, Yuru; Ni, Dongsheng; Hu, Yanxia; Long, Yaoshui; Liu, Jianing; Peng, Rui; Zhou, Li; Liu, Zhicheng; Lyu, Zhongshi; Mao, Zhaomin; Hao, Jin; Li, Yiman; Zhou, Qin

    2016-01-01

    Apobec-1 complementation factor (A1CF) is a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family, which participates in site-specific posttranscriptional RNA editing of apolipoprotein B (apoB) transcript. The posttranscriptional editing of apoB mRNA by A1CF in the small intestine is required for lipid absorption. Apart from the intestine, A1CF mRNA is also reported to be highly expressed in the kidneys. However, it is remained unknown about the functions of A1CF in the kidneys. The aim of this paper is to explore the potential functions of A1CF in the kidneys. Our results demonstrated that in C57BL/6 mice A1CF was weakly expressed in embryonic kidneys from E15.5dpc while strongly expressed in mature kidneys after birth, and it mainly existed in the tubules of inner cortex. More importantly, we identified A1CF negatively regulated the process of epithelial-mesenchymal transition (EMT) in kidney tubular epithelial cells. Our results found ectopic expression of A1CF up-regulated the epithelial markers E-cadherin, and down-regulated the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) in NRK52e cells. In addition, knockdown of A1CF enhanced EMT contrary to the overexpression effect. Notably, the two A1CF variants led to the similar trend in the EMT process. Taken together, these data suggest that A1CF may be an antagonistic factor to the EMT process of kidney tubular epithelial cells. PMID:26848653

  12. hnRNP I/PTB can antagonize the splicing repressor activity of SRp30c

    PubMed Central

    Paradis, Caroline; Cloutier, Philippe; Shkreta, Lulzim; Toutant, Johanne; Klarskov, Klaus; Chabot, Benoit

    2007-01-01

    The control of alternative pre-mRNA splicing often requires the participation of factors displaying synergistic or antagonistic activities. In the hnRNP A1 pre-mRNA, three elements promote the exclusion of alternative exon 7B, while a fourth intron element (CE9) represses splicing of exon 7B to the downstream exon. We have shown previously that the 5′ portion of the 38-nucleotide-long CE9 element is bound by SRp30c, and that this interaction is important for repression in vitro. To determine whether SRp30c alone can impose repression, we tested a high-affinity SRp30c binding site that we identified using the SELEX protocol. We find that multiple high-affinity SRp30c sites are required to replicate the level of repression obtained with CE9, and that both the 5′ and the 3′ portions of CE9 contribute to SRp30c binding. Performing RNA affinity chromatography with the complete CE9 element recovered hnRNP I/PTB. Surprisingly however, His-tagged PTB reduced the binding of SRp30c to CE9 in a nuclear extract, stimulated splicing to a downstream 3′ splice site, and relieved the CE9-mediated splicing repression in vitro. Our in vivo results are consistent with the notion that increasing PTB levels alleviates the repression imposed by CE9 to a downstream 3′ splice site. Thus, PTB can function as an anti-repressor molecule to counteract the splicing inhibitory activity of SRp30c. PMID:17548433

  13. 26 CFR 1.666(a)-1A - Amount allocated.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Amount allocated. 1.666(a)-1A Section 1.666(a... Beginning Before January 1, 1969 § 1.666(a)-1A Amount allocated. (a) In general. In the case of a trust that....665(e)-1A(a)(1)(ii) as those beginning after December 31, 1968) according to the amount...

  14. Evidence for charged B meson decays to a1+/-(1260)pi0 and a1(0)(1260)pi+/-.

    PubMed

    Aubert, B; Bona, M; Boutigny, D; Karyotakis, Y; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Grauges, E; Lopez, L; Palano, A; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Ronan, M T; Tackmann, K; Wenzel, W A; Del Amo Sanchez, P; Hawkes, C M; Watson, A T; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Schroeder, T; Steinke, M; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Béquilleux, J; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, G; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Losecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Leruste, Ph; Malclès, J; Ocariz, J; Perez, A; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Haire, M; Biesiada, J; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; D'Orazio, A; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Ricciardi, S; Roethel, W; Wilson, F F; Aleksan, R; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Hryn'ova, T; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; van Bakel, N; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Pappagallo, M; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-12-31

    We present measurements of the branching fractions for the decays B;{+/-}-->a_{1};{+/-}(1260)pi;{0} and B;{+/-}-->a_{1};{0}(1260)pi;{+/-} from a data sample of 232x10;{6} BB[over ] pairs produced in e;{+}e;{-} annihilation through the Upsilon(4S) resonance. We measure the branching fraction B(B;{+/-}-->a_{1};{+/-}(1260)pi;{0})xB(a_{1};{+/-}(1260)-->pi;{-}pi;{+}pi;{+/-})=(13.2+/-2.7+/-2.1)x10;{-6} with a significance of 4.2sigma, and the branching fraction B(B;{+/-}-->a_{1};{0}(1260)pi;{+/-})xB(a_{1};{0}(1260)-->pi;{-}pi;{+}pi;{0})=(20.4+/-4.7+/-3.4)x10;{-6} with a significance of 3.8sigma, where the first error quoted is statistical and the second is systematic. PMID:18233566

  15. Observation and polarization measurement of B0→a1(1260)+a1(1260)- decay

    NASA Astrophysics Data System (ADS)

    Aubert, B.; Karyotakis, Y.; Lees, J. P.; Poireau, V.; Prencipe, E.; Prudent, X.; Tisserand, V.; Garra Tico, J.; Grauges, E.; Martinelli, M.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Sun, L.; Battaglia, M.; Brown, D. N.; Kerth, L. T.; Kolomensky, Yu. G.; Lynch, G.; Osipenkov, I. L.; Tackmann, K.; Tanabe, T.; Hawkes, C. M.; Soni, N.; Watson, A. T.; Koch, H.; Schroeder, T.; Asgeirsson, D. J.; Fulsom, B. G.; Hearty, C.; Mattison, T. S.; McKenna, J. A.; Barrett, M.; Khan, A.; Randle-Conde, A.; Blinov, V. E.; Bukin, A. D.; Buzykaev, A. R.; Druzhinin, V. P.; Golubev, V. B.; Onuchin, A. P.; Serednyakov, S. I.; Skovpen, Yu. I.; Solodov, E. P.; Todyshev, K. Yu.; Bondioli, M.; Curry, S.; Eschrich, I.; Kirkby, D.; Lankford, A. J.; Lund, P.; Mandelkern, M.; Martin, E. C.; Stoker, D. P.; Atmacan, H.; Gary, J. W.; Liu, F.; Long, O.; Vitug, G. M.; Yasin, Z.; Sharma, V.; Campagnari, C.; Hong, T. M.; Kovalskyi, D.; Mazur, M. A.; Richman, J. D.; Beck, T. W.; Eisner, A. M.; Heusch, C. A.; Kroseberg, J.; Lockman, W. S.; Martinez, A. J.; Schalk, T.; Schumm, B. A.; Seiden, A.; Wang, L.; Winstrom, L. O.; Cheng, C. H.; Doll, D. A.; Echenard, B.; Fang, F.; Hitlin, D. G.; Narsky, I.; Ongmongkolkul, P.; Piatenko, T.; Porter, F. C.; Andreassen, R.; Mancinelli, G.; Meadows, B. T.; Mishra, K.; Sokoloff, M. D.; Bloom, P. C.; Ford, W. T.; Gaz, A.; Hirschauer, J. F.; Nagel, M.; Nauenberg, U.; Smith, J. G.; Wagner, S. R.; Ayad, R.; Toki, W. H.; Wilson, R. J.; Feltresi, E.; Hauke, A.; Jasper, H.; Karbach, T. M.; Merkel, J.; Petzold, A.; Spaan, B.; Wacker, K.; Kobel, M. J.; Nogowski, R.; Schubert, K. R.; Schwierz, R.; Volk, A.; Bernard, D.; Latour, E.; Verderi, M.; Clark, P. J.; Playfer, S.; Watson, J. E.; Andreotti, M.; Bettoni, D.; Bozzi, C.; Calabrese, R.; Cecchi, A.; Cibinetto, G.; Fioravanti, E.; Franchini, P.; Luppi, E.; Munerato, M.; Negrini, M.; Petrella, A.; Piemontese, L.; Santoro, V.; Baldini-Ferroli, R.; Calcaterra, A.; de Sangro, R.; Finocchiaro, G.; Pacetti, S.; Patteri, P.; Peruzzi, I. M.; Piccolo, M.; Rama, M.; Zallo, A.; Contri, R.; Guido, E.; Lo Vetere, M.; Monge, M. R.; Passaggio, S.; Patrignani, C.; Robutti, E.; Tosi, S.; Chaisanguanthum, K. S.; Morii, M.; Adametz, A.; Marks, J.; Schenk, S.; Uwer, U.; Bernlochner, F. U.; Klose, V.; Lacker, H. M.; Bard, D. J.; Dauncey, P. D.; Tibbetts, M.; Behera, P. K.; Charles, M. J.; Mallik, U.; Cochran, J.; Crawley, H. B.; Dong, L.; Eyges, V.; Meyer, W. T.; Prell, S.; Rosenberg, E. I.; Rubin, A. E.; Gao, Y. Y.; Gritsan, A. V.; Guo, Z. J.; Arnaud, N.; Béquilleux, J.; D'Orazio, A.; Davier, M.; Derkach, D.; Firmino da Costa, J.; Grosdidier, G.; Le Diberder, F.; Lepeltier, V.; Lutz, A. M.; Malaescu, B.; Pruvot, S.; Roudeau, P.; Schune, M. H.; Serrano, J.; Sordini, V.; Stocchi, A.; Wormser, G.; Lange, D. J.; Wright, D. M.; Bingham, I.; Burke, J. P.; Chavez, C. A.; Fry, J. R.; Gabathuler, E.; Gamet, R.; Hutchcroft, D. E.; Payne, D. J.; Touramanis, C.; Bevan, A. J.; Clarke, C. K.; di Lodovico, F.; Sacco, R.; Sigamani, M.; Cowan, G.; Paramesvaran, S.; Wren, A. C.; Brown, D. N.; Davis, C. L.; Denig, A. G.; Fritsch, M.; Gradl, W.; Hafner, A.; Alwyn, K. E.; Bailey, D.; Barlow, R. J.; Jackson, G.; Lafferty, G. D.; West, T. J.; Yi, J. I.; Anderson, J.; Chen, C.; Jawahery, A.; Roberts, D. A.; Simi, G.; Tuggle, J. M.; Dallapiccola, C.; Salvati, E.; Cowan, R.; Dujmic, D.; Fisher, P. H.; Henderson, S. W.; Sciolla, G.; Spitznagel, M.; Yamamoto, R. K.; Zhao, M.; Patel, P. M.; Robertson, S. H.; Schram, M.; Biassoni, P.; Gandini, P.; Lazzaro, A.; Lombardo, V.; Palombo, F.; Stracka, S.; Bauer, J. M.; Cremaldi, L.; Godang, R.; Kroeger, R.; Sonnek, P.; Summers, D. J.; Zhao, H. W.; Simard, M.; Taras, P.; Nicholson, H.; de Nardo, G.; Lista, L.; Monorchio, D.; Onorato, G.; Sciacca, C.; Raven, G.; Snoek, H. L.; Jessop, C. P.; Knoepfel, K. J.; Losecco, J. M.; Wang, W. F.; Corwin, L. A.; Honscheid, K.; Kagan, H.; Kass, R.; Morris, J. P.; Rahimi, A. M.; Regensburger, J. J.; Sekula, S. J.; Wong, Q. K.; Blount, N. L.; Brau, J.; Frey, R.; Igonkina, O.; Kolb, J. A.; Lu, M.; Rahmat, R.; Sinev, N. B.; Strom, D.; Strube, J.; Torrence, E.; Castelli, G.; Gagliardi, N.; Margoni, M.; Morandin, M.; Posocco, M.; Rotondo, M.; Simonetto, F.; Stroili, R.; Voci, C.; Del Amo Sanchez, P.; Ben-Haim, E.; Bonneaud, G. R.; Briand, H.; Chauveau, J.; Hamon, O.; Leruste, Ph.; Marchiori, G.; Ocariz, J.; Perez, A.; Prendki, J.; Sitt, S.; Gladney, L.; Biasini, M.; Manoni, E.; Angelini, C.; Batignani, G.; Bettarini, S.; Calderini, G.; Carpinelli, M.; Cervelli, A.; Forti, F.; Giorgi, M. A.; Lusiani, A.; Morganti, M.; Neri, N.; Paoloni, E.; Rizzo, G.; Walsh, J. J.; Lopes Pegna, D.; Lu, C.; Olsen, J.; Smith, A. J. S.; Telnov, A. V.; Anulli, F.; Baracchini, E.; Cavoto, G.; Faccini, R.; Ferrarotto, F.; Ferroni, F.; Gaspero, M.; Jackson, P. D.; Li Gioi, L.; Mazzoni, M. A.; Morganti, S.; Piredda, G.; Renga, F.; Voena, C.; Ebert, M.; Hartmann, T.; Schröder, H.; Waldi, R.; Adye, T.; Franek, B.; Olaiya, E. O.; Wilson, F. F.; Emery, S.; Esteve, L.; de Monchenault, G. Hamel; Kozanecki, W.; Vasseur, G.; Yèche, Ch.; Zito, M.; Allen, M. T.; Aston, D.; Bartoldus, R.; Benitez, J. F.; Cenci, R.; Coleman, J. P.; Convery, M. R.; Dingfelder, J. C.; Dorfan, J.; Dubois-Felsmann, G. P.; Dunwoodie, W.; Field, R. C.; Franco Sevilla, M.; Gabareen, A. M.; Graham, M. T.; Grenier, P.; Hast, C.; Innes, W. R.; Kaminski, J.; Kelsey, M. H.; Kim, H.; Kim, P.; Kocian, M. L.; Leith, D. W. G. S.; Li, S.; Lindquist, B.; Luitz, S.; Luth, V.; Lynch, H. L.; Macfarlane, D. B.; Marsiske, H.; Messner, R.; Muller, D. R.; Neal, H.; Nelson, S.; O'Grady, C. P.; Ofte, I.; Perl, M.; Ratcliff, B. N.; Roodman, A.; Salnikov, A. A.; Schindler, R. H.; Schwiening, J.; Snyder, A.; Su, D.; Sullivan, M. K.; Suzuki, K.; Swain, S. K.; Thompson, J. M.; Va'Vra, J.; Wagner, A. P.; Weaver, M.; West, C. A.; Wisniewski, W. J.; Wittgen, M.; Wright, D. H.; Wulsin, H. W.; Yarritu, A. K.; Young, C. C.; Ziegler, V.; Chen, X. R.; Liu, H.; Park, W.; Purohit, M. V.; White, R. M.; Wilson, J. R.; Burchat, P. R.; Edwards, A. J.; Miyashita, T. S.; Ahmed, S.; Alam, M. S.; Ernst, J. A.; Pan, B.; Saeed, M. A.; Zain, S. B.; Soffer, A.; Spanier, S. M.; Wogsland, B. J.; Eckmann, R.; Ritchie, J. L.; Ruland, A. M.; Schilling, C. J.; Schwitters, R. F.; Wray, B. C.; Drummond, B. W.; Izen, J. M.; Lou, X. C.; Bianchi, F.; Gamba, D.; Pelliccioni, M.; Bomben, M.; Bosisio, L.; Cartaro, C.; Della Ricca, G.; Lanceri, L.; Vitale, L.; Azzolini, V.; Lopez-March, N.; Martinez-Vidal, F.; Milanes, D. A.; Oyanguren, A.; Albert, J.; Banerjee, Sw.; Bhuyan, B.; Choi, H. H. F.; Hamano, K.; King, G. J.; Kowalewski, R.; Lewczuk, M. J.; Nugent, I. M.; Roney, J. M.; Sobie, R. J.; Gershon, T. J.; Harrison, P. F.; Ilic, J.; Latham, T. E.; Mohanty, G. B.; Puccio, E. M. T.; Band, H. R.; Chen, X.; Dasu, S.; Flood, K. T.; Pan, Y.; Prepost, R.; Vuosalo, C. O.; Wu, S. L.

    2009-11-01

    We present measurements of the branching fraction B and longitudinal polarization fraction fL for B0→a1(1260)+a1(1260)- decays, with a1(1260)±→π-π+π±. The data sample, collected with the BABAR detector at the SLAC National Accelerator Laboratory, represents 465×106 produced BB¯ pairs. We measure B(B0→a1(1260)+a1(1260)-)×[B(a1(1260)+→π-π+π+)]2=(11.8±2.6±1.6)×10-6 and fL=0.31±0.22±0.10, where the first uncertainty is statistical and the second systematic. The decay mode is measured with a significance of 5.0 standard deviations including systematic uncertainties.

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    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 10 2010-04-01 2010-04-01 false Distributions to shareholders. 1.926(a)-1... to shareholders. (a) Treatment of distributions. . For guidance, see § 1.926(a)-1T(a). (b) Order of distribution—(1) In general—(i) Distributions by a FSC received by a shareholder in a taxable year of...

  13. Observation of B+-->a1+(1260)K0 and B0-->a1-(1260)K+.

    PubMed

    Aubert, B; Bona, M; Boutigny, D; Karyotakis, Y; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Grauges, E; Lopez, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabe, T; Wenzel, W A; Del Amo Sanchez, P; Hawkes, C M; Watson, A T; Koch, H; Schroeder, T; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Vitug, G M; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Bailey, D; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, G; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Leruste, Ph; Malclès, J; Ocariz, J; Perez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Biesiada, J; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Roethel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Ziegler, V; Burchat, P R; Edwards, A J; Majewski, S A; Miyashita, T S; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2008-02-01

    We present branching fraction measurements of the decays B(+)-->a(1)(+)(1260)K(0) and B(0)-->a(1)(-)(1260)K(+) with a(1)(+/-)(1260)-->pi(-/+)pi(+/-)pi(+/-). The data sample corresponds to 383 x 10(6) BB pairs produced in e(+)e(-) annihilation through the Upsilon(4S) resonance. We measure the products of the branching fractions B(B(+)-->a(1)(+)(1260)K(0)B(a(1)(+)(1260)-->pi(-)pi(+)pi(+))=(17.4+/-2.5+/-2.2) x 10(-6) and B(B(0)-->a(1)(-)(1260)K(+)B(a(1)(-)(1260)-->pi(+)pi(-)pi(-)) = (8.2+/-1.5+/-1.2) x 10(-6). We also measure the charge asymmetries A(ch)(B(+)-->a(1)(+)(1260)K(0) = 0.12+/-0.11+/-0.02 and A(ch)(B(0)-->a(1)(-)(1260)K+) = -0.16+/-0.12+/-0.01. The first uncertainty quoted is statistical and the second is systematic. PMID:18352360

  14. Tumor-Targeting Salmonella typhimurium A1-R: An Overview.

    PubMed

    Hoffman, Robert M

    2016-01-01

    The present chapter reviews the development of the tumor-targeting amino-acid auxotrophic strain S. typhimurium A1 and the in vivo selection and characterization of the high-tumor-targeting strain S. typhimurium A1-R. Efficacy of S. typhimurium A1-R in nude-mouse models of prostate, breast, pancreatic, and ovarian cancer, as well as sarcoma and glioma in orthotopic mouse models is described. Also reviewed is efficacy of S. typhimurium A1-R targeting of primary bone tumor and lung metastasis of high-grade osteosarcoma, breast-cancer brain metastasis, and experimental breast-cancer bone metastasis in orthotopic mouse models. The efficacy of S. typhimurium A1-R on pancreatic cancer stem cells, on pancreatic cancer in combination with anti-angiogenic agents, as well as on cervical cancer, soft-tissue sarcoma, and pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse models, is also described.

  15. Aldehyde dehydrogenase 1A1 in stem cells and cancer

    PubMed Central

    Tomita, Hiroyuki; Tanaka, Kaori; Tanaka, Takuji; Hara, Akira

    2016-01-01

    The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies. PMID:26783961

  16. [Glycosylated hemoglobin (HbA1) in pregnancy].

    PubMed

    Partida Hernández, G; Gómez García, A; Arreola Ortíz, J F

    2000-10-01

    The life style, genetic predisposition and metabolic changes occurring during pregnancy can modify the percent value of glycated hemoglobins (HbA1 and HbA1c). In addition, research papers from different laboratories in the world have reported contradictory results on this respect. The purpose of this trial was to know the percent value of HbA1 in healthy women, during the different trimesters of pregnancy. 206 pregnant (E) healthy women who came over for prenatal control to UMF No 80 IMSS in Morelia, Michoacan with no previous history of Diabetes mellitus or Essential Hypertension were classified by trimesters of pregnancy (1T, 2T, 3T) and chronological age (I, 18-24; 11, 25-30; III, 31-35 years). Their chronological and gestational ages, weight, height, body mass index and parity were recorded. % HbA1 (ion exchange chromatography) was determined on each patient. Control group was formed by 187 non pregnant healthy women (NE) chosen with same criterion that pregnant women. % HbA1 was lower in E during pregnancy (7.11 +/- 1.53 vs 7.78 +/- 1.12%, p < 0.0001) than NE group. % HbA1 in E group was lower in the 1T and 2T than in the 3T (p < 0.001), same situation was observed in 18 to 24 (group I) and 25 to 30 (group II) years old. In the other hand, in E from group II on the 2T the weeks of gestation were correlated with % HbA1 (r = 0.72, p < 0.05). This results show a diminished HbA1 percent in E group with a lower values in the 1T and 2T. Moreover, these results will allow us to know HbA1 appearance in diabetic pregnant women and to evaluate the degree of metabolic control.

  17. 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

  18. 26 CFR 48.4222(a)-1 - Registration.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Exemptions, Registration, Etc. § 48.4222(a)-1... section of the regulations, tax-free sales may not be made, except as indicated in § 48.4222(b)-1....

  19. A 1K Shadow RAM for circumvention applications

    SciTech Connect

    Murray, J.R.

    1991-01-01

    A 1K bit Shadow RAM has been developed for storage of critical data in a high transient radiation environment. The circuit includes a 1K bit (128 {times} 8) static RAM with two non-volatile (NV) shadows. The NV shadows are used to back-up the data in the static RAM allowing the circuit to be powered down during transient radiation without losing critical data. This paper will describe the circuit's operation and characterization results.

  20. Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity

    PubMed Central

    Brocker, Chad; Cantore, Miriam; Failli, Paola; Vasiliou, Vasilis

    2012-01-01

    Mammalian aldehyde dehydrogenase 7A1 (ALDH7A1) is homologous to plant ALDH7B1 which protects against various forms of stress such as increased salinity, dehydration and treatment with oxidants or pesticides. Deleterious mutations in human ALDH7A1 are responsible for pyridoxine-dependent and folinic acid-responsive seizures. In previous studies, we have shown that human ALDH7A1 protects against hyperosmotic stress presumably through the generation of betaine, an important cellular osmolyte, formed from betaine aldehyde. Hyperosmotic stress is coupled to an increase in oxidative stress and lipid peroxidation (LPO). In this study, cell viability assays revealed that stable expression of mitochondrial ALDH7A1 in Chinese hamster ovary (CHO) cells provides significant protection against treatment with the LPO-derived aldehydes hexanal and 4-hydroxy-2-nonenal (4HNE) implicating a protective function for the enzyme during oxidative stress. A significant increase in cell survival was also observed in CHO cells expressing either mitochondrial or cytosolic ALDH7A1 treated with increasing concentrations of hydrogen peroxide (H2O2) or 4HNE, providing further evidence for anti-oxidant activity. In vitro enzyme activity assays indicate that human ALDH7A1 is sensitive to oxidation and that efficiency can be at least partially restored by incubating recombinant protein with the thiol reducing agent β-mercaptoethanol (BME). We also show that after reactivation with BME, recombinant ALDH7A1 is capable of metabolizing the reactive aldehyde 4HNE. In conclusion, ALDH7A1 mechanistically appears to provide cells protection through multiple pathways including the removal of toxic LPO-derived aldehydes in addition to osmolyte generation. PMID:21338592

  1. hnRNP Q regulates Cdc42-mediated neuronal morphogenesis.

    PubMed

    Chen, Hung-Hsi; Yu, Hsin-I; Chiang, Wen-Cheng; Lin, Yu-De; Shia, Ben-Chang; Tarn, Woan-Yuh

    2012-06-01

    The RNA-binding protein hnRNP Q has been implicated in neuronal mRNA metabolism. Here, we show that knockdown of hnRNP Q increased neurite complexity in cultured rat cortical neurons and induced filopodium formation in mouse neuroblastoma cells. Reexpression of hnRNP Q1 in hnRNP Q-depleted cells abrogated the morphological changes of neurites, indicating a specific role for hnRNP Q1 in neuronal morphogenesis. A search for mRNA targets of hnRNP Q1 identified functionally coherent sets of mRNAs encoding factors involved in cellular signaling or cytoskeletal regulation and determined its preferred binding sequences. We demonstrated that hnRNP Q1 bound to a set of identified mRNAs encoding the components of the actin nucleation-promoting Cdc42/N-WASP/Arp2/3 complex and was in part colocalized with Cdc42 mRNA in granules. Using subcellular fractionation and immunofluorescence, we showed that knockdown of hnRNP Q reduced the level of some of those mRNAs in neurites and redistributed their encoded proteins from neurite tips to soma to different extents. Overexpression of dominant negative mutants of Cdc42 or N-WASP compromised hnRNP Q depletion-induced neurite complexity. Together, our results suggest that hnRNP Q1 may participate in localization of mRNAs encoding Cdc42 signaling factors in neurites, and thereby may regulate actin dynamics and control neuronal morphogenesis. PMID:22493061

  2. Nuclear receptor 4A1 (NR4A1) as a drug target for treating rhabdomyosarcoma (RMS)

    PubMed Central

    Lacey, Alexandra; Hedrick, Erik; Li, Xi; Patel, Ketan; Doddapaneni, Ravi; Singh, Mandip; Safe, Stephen

    2016-01-01

    The orphan nuclear receptor NR4A1 is expressed in tumors from rhabdomyosarcoma (RMS) patients and Rh30 and RD RMS cell lines, and we used RNA interference (RNAi) to investigate the role of this receptor in RMS cells. Knockdown of NR4A1 in Rh30 cells decreased cell proliferation, induced Annexin V staining and induced polyADPribose polymerase (PARP) cleavage and these results were similar to those observed in other solid tumors. Previous studies show that NR4A1 regulates expression of growth promoting/pro-survival genes with GC-rich promoters, activates mTOR through suppression of p53, and maintains low oxidative stress by regulating expression of isocitrate dehydrogenase 1 (IDH1) and thioredoxin domain containing 5 (TXNDC5). Results of RNAi studies demonstrated that NR4A1 also regulates these pathways and associated genes in RMS cells and thereby exhibits pro-oncogenic activity. 1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methane (C-DIM) analogs containing p-hydroxyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) substituents are NR4A1 ligands that decreased NR4A1-dependent transactivation in RMS cells and inhibited RMS cell and tumor growth and induced apoptosis. Moreover, the effects of NR4A1 knockdown and the C-DIM/NR4A1 antagonists were comparable as inhibitors of NR4A1-dependent genes/pathways. Both NR4A1 knockdown and treatment with DIM-C-pPhOH and DIM-C-pPhCO2Me also induced ROS which activated stress genes and induced sestrin 2 which activated AMPK and inhibited mTOR in the mutant p53 RMS cells. Since NR4A1 regulates several growth-promoting/pro-survival pathways in RMS, the C-DIM/NR4A1 antagonists represent a novel mechanism-based approach for treating this disease alone or in combination and thereby reducing the adverse effects of current cytotoxic therapies. PMID:27144436

  3. Insufficient Sensitivity of Hemoglobin A1C (A1C) Determination in Diagnosis or Screening of Early Diabetic States

    PubMed Central

    Fajans, Stefan S.; Herman, William H.; Oral, Elif A.

    2010-01-01

    An International Expert Committee made recommendations for using the hemoglobin A1C (A1C) assay as the preferred method for diagnosis of diabetes in nonpregnant individuals. A concentration of ≥ 6.5% was considered as diagnostic. It is the aim of this study to compare the sensitivity of A1C with that of plasma glucose concentrations in subjects with early diabetes or IGT. We chose two groups of subjects who had A1C of ≤ 6.4%. The first group of 89 subjects had family histories of diabetes (MODY or T2DM) and had OGTT and A1C determinations. They included 36 subjects with diabetes or IGT and 53 with normal OGTT. The second group of 58 subjects was screened for diabetes in our Diabetes Clinic by FPG or 2HPG or OGTT and A1C and similar comparisons were made. Subjects with diabetes or IGT, including those with fasting hyperglycemia, had A1C ranging from 5.0 – 6.4%, mean 5.8%. The subjects with normal OGTT had A1C of 4.2 – 6.3%, mean 5.4% or 5.5% for the two groups. A1C may be in the normal range in subjects with diabetes or IGT, including those with fasting hyperglycemia. Approximately one third of subjects with early diabetes and IGT have A1C <5.7%, the cut-point that ADA recommends as indicating the onset of risk of developing diabetes in the future. The results of our study are similar to those obtained by a large Dutch epidemiological study. If our aim is to recognize early diabetic states to apply effective prophylactic procedures to prevent or delay progression to more severe diabetes, A1C is not sufficiently sensitive or reliable for diagnosis of diabetes or IGT. A combination of A1C and plasma glucose determinations, where necessary, are recommended for diagnosis or screening of diabetes or IGT. PMID:20723948

  4. Glycated haemoglobin (HbA1c): today and tomorrow.

    PubMed

    Roszyk, L; Faye, B; Sapin, V; Somda, F; Tauveron, I

    2007-10-01

    The assay of glycated haemoglobin (HbA1c) is a gold standard in bioanalysis, and is essential to ensure the optimal care of diabetic patients. Accordingly, the principal scientific societies in diabetology and clinical chemistry have made efforts to standardize this assay in order to select and validate certain analytical methods and achieve consistency in the results obtained therewith. However, clinicians have to be aware of the caution required when interpreting HbA1c assay results owing to modified lifetime and (or) abnormal synthesis of haemoglobin. Although this biological examination has now become an essential part of diabetes monitoring, its status as a screening tool is still controversial, even after 30 years of debate. Other uses of HbA1c assay are currently being assessed in cardiology (coronary syndromes), vascular diseases (arteriopathy), nephrology (renal insufficiency), haematology (anaemia) and oncology (factors of predisposition). PMID:17904515

  5. MybA1 gene diversity across the Vitis genus.

    PubMed

    Péros, Jean-Pierre; Launay, Amandine; Berger, Gilles; Lacombe, Thierry; This, Patrice

    2015-06-01

    The MybA1 gene in the genus Vitis encodes a transcription factor, belonging to the R2R3 Myb family, that controls the last steps in the anthocyanins biosynthesis pathway. Polymorphism within MybA1 has been associated with color variation in berries of V. vinifera and other Vitis species. In this work, we analyzed the sequence variation in MybA1 both in the subg. Muscadinia and in an extended set of Asian, American and European genotypes of subg. Vitis. Our aims were to infer the evolution of this gene during the speciation process and to identify polymorphisms that could potentially generate changes in gene regulation. The results show that MybA1 experienced many insertions and deletions in non-coding regions but also in the third exon sequence. Owing to the larger set of Vitis species compared here, new indels were identified and the origin of previously described indels was reconsidered. A large number of single nucleotide polymorphisms were found in non-coding regions but also in the sequence coding for the R2R3 domain and the C terminal part of the protein. Some of these changes led to amino acid substitutions and therefore could have modified MybA1 protein activity. Bayesian phylogenetic analysis of all polymorphisms did not provide a consensus tree depicting the geographical partitioning of the species but allowed highlighting several species relationships within subgenus Vitis. Finally, the evolutionary events described could be useful to gain more insight into the role of MybA1 for anthocyanin biosynthesis in grapevine.

  6. Establishment of Salmonella strain expressing catalytically active human UDP-glucuronosyltransferase 1A1 (UGT1A1).

    PubMed

    Fujita, K; Mogami, A; Hayashi, A; Kamataki, T

    2000-04-01

    Human uridinediphosphate-glucuronosyltransferase 1A1 (UGT1A1) was expressed in Salmonella typhimurium TA1535 cells by transfection of the cells with plasmids carrying the UGT1A1 cDNA. UGT1A1 cDNA was isolated by a polymerase chain reaction from human liver total RNA and was inserted into the pSE420 plasmid, linked to the trc promoter and terminator. The plasmid thus constructed was introduced into Salmonella TA1535 cells. The expression of human UGT1A1 protein was confirmed by Western blot analysis. The maximal expression was observed at 24 h after the addition of isopropyl-beta-D-thiogalactopyranoside, an inducer. However, the bilirubin conjugation activity of the membrane fraction from the Salmonella cells was not detectable. When a beta-glucuronidase inhibitor such as saccharic acid 1,4-lactone, glycyrrhizin or 1-naphtyl-beta-D-glucuronide was added to the reaction mixture, the bilirubin conjugation activity of the human UGT1A1 was detected. When geniposide was added to the reaction mixture, the bilirubin conjugation activity of UGT1A1 was not seen. Taking these results into account, the established Salmonella strain possesses the beta-glucuronidase activity. Since the beta-glucuronidase activity of the Salmonella was lower than that of E. coli, it was concluded that Salmonella seemed to be a good host to express UGT protein. This is the first study to demonstrate the establishment of a bacterial strain expressing native human UGT protein showing catalytic activity. PMID:10821120

  7. Purification and structural characterisation of phospholipase A1 (Vespapase, Ves a 1) from Thai banded tiger wasp (Vespa affinis) venom.

    PubMed

    Sukprasert, Sophida; Rungsa, Prapenpuksiri; Uawonggul, Nunthawun; Incamnoi, Paroonkorn; Thammasirirak, Sompong; Daduang, Jureerut; Daduang, Sakda

    2013-01-01

    The Thai banded tiger wasp (Vespa affinis) is one of the most dangerous vespid species in Southeast Asia, and stinging accidents involving this species still cause fatalities. In the present study, four forms of V. affinis phospholipase A(1) were identified through a proteomics approach. Two of these enzymes were purified by reverse-phase chromatography, and their biochemical properties were characterised. These enzymes, designated Ves a 1s, are not glycoproteins and exist as 33441.5 and 33474.4 Da proteins, which corresponded with the 34-kDa band observed via SDS-PAGE. The thermal stabilities of these enzymes were stronger than snake venom. Using an in vivo assay, no difference was found in the toxicities of the different isoforms. Furthermore, the toxicity of these enzymes does not appear to be correlated with their PLA(1) activity. The cDNAs of the full-length version of Ves a 1s revealed that the Ves a 1 gene consists of a 1005-bp ORF, which encodes 334 amino acid residues, and 67- and 227-bp 5' and 3' UTRs, respectively. The two isoforms are different by three nucleotide substitutions, resulting in the replacement of two amino acids. Through sequence alignment, these enzymes were classified as members of the pancreatic lipase family. The structural modelling of Ves a 1 used the rat pancreatic lipase-related protein 2 (1bu8A) as a template because it has PLA(1) activity, which demonstrated that this enzyme belongs to the α/β hydrolase fold family. The Ves a 1 structure, which is composed of seven α-helixes and eleven β-strands, contains the β-strand/ɛSer/α-helix structural motif, which contains the Gly-X-Ser-X-Gly consensus sequence. The typical surface structures that play important roles in substrate selectivity (the lid domain and the β9 loop) were shortened in the Ves a 1 structure, which suggests that this enzyme may only exhibit phospholipase activity. Moreover, the observed insertion of proline into the lid domain of the Ves a 1 structure is rare

  8. 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

  9. 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 of 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.

  10. Dynamics and phase transitions in A 1C 60 compounds

    NASA Astrophysics Data System (ADS)

    Schober, H.; Renker, B.; Heid, R.; Tölle, A.

    1997-02-01

    We present an overview of extensive inelastic neutron scattering experiments carried out on powders of A 1C 60. The various phases leave strong fingerprints in the microscopic dynamics confirming the solid-state chemical reactions. The strong kinetic phase transitions can be followed in real time and turn out to be highly complex.

  11. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the plan. Q-13. Does a transaction or accounting methodology involving an employee's designated Roth... Roth Accounts. Q-1. What is a designated Roth account? A-1. A designated Roth account is a separate... § 1.403(b)-3(c) (in the case of a section 403(b) plan). Q-2. How is a distribution from a...

  12. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the plan. Q-13. Does a transaction or accounting methodology involving an employee's designated Roth... Roth Accounts. Q-1. What is a designated Roth account? A-1. A designated Roth account is a separate... § 1.403(b)-3(c) (in the case of a section 403(b) plan). Q-2. How is a distribution from a...

  13. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the plan. Q-13. Does a transaction or accounting methodology involving an employee's designated Roth... Roth Accounts. Q-1. What is a designated Roth account? A-1. A designated Roth account is a separate... § 1.403(b)-3(c) (in the case of a section 403(b) plan). Q-2. How is a distribution from a...

  14. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the plan. Q-13. Does a transaction or accounting methodology involving an employee's designated Roth.... Q-1. What is a designated Roth account? A-1. A designated Roth account is a separate account under a... case of a section 403(b) plan). Q-2. How is a distribution from a designated Roth account taxed?...

  15. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the plan. Q-13. Does a transaction or accounting methodology involving an employee's designated Roth... Roth Accounts. Q-1. What is a designated Roth account? A-1. A designated Roth account is a separate... § 1.403(b)-3(c) (in the case of a section 403(b) plan). Q-2. How is a distribution from a...

  16. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., consult with, and make recommendations to the Secretary of Labor and the Secretary of Health, Education... 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....

  17. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., consult with, and make recommendations to the Secretary of Labor and the Secretary of Health, Education... 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....

  18. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., consult with, and make recommendations to the Secretary of Labor and the Secretary of Health, Education... 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....

  19. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., consult with, and make recommendations to the Secretary of Labor and the Secretary of Health, Education... 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....

  20. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., consult with, and make recommendations to the Secretary of Labor and the Secretary of Health, Education... 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....

  1. 26 CFR 31.3306(a)-1 - Who are employers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE.... (a) Definition—(1) For calendar years 1956 through 1969, inclusive. Every person who employs 4...

  2. 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

  3. 26 CFR 1.167(a)-1 - Depreciation in general.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 2 2011-04-01 2011-04-01 false Depreciation in general. 1.167(a)-1 Section 1... Depreciation in general. (a) Reasonable allowance. Section 167(a) provides that a reasonable allowance for the exhaustion, wear and tear, and obsolescence of property used in the trade or business or of property held...

  4. 7 CFR 15a.1 - Purpose and effective date.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.1 Purpose and effective date. The purpose of this part is to effectuate title IX of the Education Amendments of 1972, as amended by Public Law 93-568, 88 Stat. 1855 and Public Law 94-482, 90 Stat. 2234 (except sections 904 and 906 of those Amendments)...

  5. The Heart of a 1:1 Classroom

    ERIC Educational Resources Information Center

    Tulbert, Carrie Ann

    2012-01-01

    Many educators believe that the act of building relationships is the core of learning. When technology is integrated into every classroom, do relationships improve or disintegrate among the key stakeholders in an educational environment? The purpose of this study is to determine the extent to which technology in a 1:1 school district can alter…

  6. Dietary Lecithin Decreases Skeletal Muscle COL1A1 and COL3A1 Gene Expression in Finisher Gilts

    PubMed Central

    Akit, Henny; Collins, Cherie; Fahri, Fahri; Hung, Alex; D’Souza, Daryl; Leury, Brian; Dunshea, Frank

    2016-01-01

    Simple Summary In this study, the effect of dietary lecithin on skeletal muscle gene expression of collagen precursors and enzymes was investigated in gilts. Thirty-six finisher gilts were fed with diets containing either 0, 4, 20 or 80 g/kg soybean lecithin for six weeks. Then, rectus abdominis muscle was sampled and analyzed for eight genes involved in collagen synthesis and degradation (COL1A1, COL3A1, MMP-1, MMP-13, TIMP-1, TIMP-3, lysyl oxidase and α-subunit P4H) using quantitative real-time PCR. The results showed that lecithin down-regulated COL1A1 and COL3A1 as well as tended to down-regulate α-subunit P4H expression. Abstract The purpose of this study was to investigate the effect of dietary lecithin on skeletal muscle gene expression of collagen precursors and enzymes involved in collagen synthesis and degradation. Finisher gilts with an average start weight of 55.9 ± 2.22 kg were fed diets containing either 0, 4, 20 or 80 g/kg soybean lecithin prior to harvest for six weeks and the rectus abdominis muscle gene expression profile was analyzed by quantitative real-time PCR. Lecithin treatment down-regulated Type I (α1) procollagen (COL1A1) and Type III (α1) procollagen (COL3A1) mRNA expression (p < 0.05, respectively), indicating a decrease in the precursors for collagen synthesis. The α-subunit of prolyl 4-hydroxylase (P4H) mRNA expression also tended to be down-regulated (p = 0.056), indicating a decrease in collagen synthesis. Decreased matrix metalloproteinase-1 (MMP-1) mRNA expression may reflect a positive regulatory response to the reduced collagen synthesis in muscle from the pigs fed lecithin (p = 0.035). Lecithin had no effect on tissue inhibitor metalloproteinase-1 (TIMP-1), matrix metalloproteinase-13 (MMP-13) and lysyl oxidase mRNA expression. In conclusion, lecithin down-regulated COL1A1 and COL3A1 as well as tended to down-regulate α-subunit P4H expression. However, determination of muscle collagen content and solubility are required

  7. Differential binding characteristics of native monomeric and polymeric immunoglobulin A1 (IgA1) on human mesangial cells and the influence of in vitro deglycosylation of IgA1 molecules.

    PubMed

    Gao, Y-H; Xu, L-X; Zhang, J-J; Zhang, Y; Zhao, M-H; Wang, H-Y

    2007-06-01

    Recent studies had demonstrated that serum and mesangial immunoglobulin A1 (IgA1) in patients with IgA nephropathy (IgAN) were polymeric and deglycosylated. The current study was to investigate the binding characteristics of monomeric and polymeric normal human IgA1 on mesangial cells and the influence of in vitro deglycosylation of IgA1 molecules. The normal human IgA1 was desialylated and degalactosylated with specific enzymes, respectively. The monomeric IgA1 (mIgA1) and polymeric IgA1 (pIgA1) were separated by Sephacryl S-300 chromatography. The binding capacities of the mIgA1 and pIgA1 to primary human mesangial cells (HMC) were evaluated by classical radioligand assay. Both the native mIgA1 and pIgA1 could bind to HMC in a dose-dependent and saturable manner. The maximal binding capacity of the native pIgA1 were significantly higher than that of the native mIgA1 (P < 0.05). However, the affinity of the native mIgA1 was almost 100 times higher than that of the native pIgA1. After deglycosylation, binding of the two deglycosylated mIgA1 to HMC could not be detected. However, the maximal binding capacities of the two deglycosylated pIgA1 to HMC were increased significantly compared with that of native pIgA1. The affinity of the two deglycosylated pIgA1 was similar to that of native pIgA1 (P > 0.05). The current study suggests differential binding characteristics of native monomeric and polymeric IgA1 on mesangial cells. Glycosylation of IgA1 molecules could significantly affect the binding of IgA1 on HMC.

  8. Differential binding characteristics of native monomeric and polymeric immunoglobulin A1 (IgA1) on human mesangial cells and the influence of in vitro deglycosylation of IgA1 molecules

    PubMed Central

    Gao, Y-H; Xu, L-X; Zhang, J-J; Zhang, Y; Zhao, M-H; Wang, H-Y

    2007-01-01

    Recent studies had demonstrated that serum and mesangial immunoglobulin A1 (IgA1) in patients with IgA nephropathy (IgAN) were polymeric and deglycosylated. The current study was to investigate the binding characteristics of monomeric and polymeric normal human IgA1 on mesangial cells and the influence of in vitro deglycosylation of IgA1 molecules. The normal human IgA1 was desialylated and degalactosylated with specific enzymes, respectively. The monomeric IgA1 (mIgA1) and polymeric IgA1 (pIgA1) were separated by Sephacryl S-300 chromatography. The binding capacities of the mIgA1 and pIgA1 to primary human mesangial cells (HMC) were evaluated by classical radioligand assay. Both the native mIgA1 and pIgA1 could bind to HMC in a dose-dependent and saturable manner. The maximal binding capacity of the native pIgA1 were significantly higher than that of the native mIgA1 (P < 0·05). However, the affinity of the native mIgA1 was almost 100 times higher than that of the native pIgA1. After deglycosylation, binding of the two deglycosylated mIgA1 to HMC could not be detected. However, the maximal binding capacities of the two deglycosylated pIgA1 to HMC were increased significantly compared with that of native pIgA1. The affinity of the two deglycosylated pIgA1 was similar to that of native pIgA1 (P > 0·05). The current study suggests differential binding characteristics of native monomeric and polymeric IgA1 on mesangial cells. Glycosylation of IgA1 molecules could significantly affect the binding of IgA1 on HMC. PMID:17386074

  9. A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1.

    PubMed

    Geissler, Rene; Simkin, Alfred; Floss, Doreen; Patel, Ravi; Fogarty, Elizabeth A; Scheller, Jürgen; Grimson, Andrew

    2016-05-01

    3'-untranslated regions (UTRs) specify post-transcriptional fates of mammalian messenger RNAs (mRNAs), yet knowledge of the underlying sequences and mechanisms is largely incomplete. Here, we identify two related novel 3' UTR motifs in mammals that specify transcript degradation. These motifs are interchangeable and active only within 3' UTRs, where they are often preferentially conserved; furthermore, they are found in hundreds of transcripts, many encoding regulatory proteins. We found that degradation occurs via mRNA deadenylation, mediated by the CCR4-NOT complex. We purified trans factors that recognize the motifs and identified heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2/B1, which are required for transcript degradation, acting in a previously unknown manner. We used RNA sequencing (RNA-seq) to confirm hnRNP A1 and A2/B1 motif-dependent roles genome-wide, profiling cells depleted of these factors singly and in combination. Interestingly, the motifs are most active within the distal portion of 3' UTRs, suggesting that their role in gene regulation can be modulated by alternative processing, resulting in shorter 3' UTRs.

  10. A widespread sequence-specific mRNA decay pathway mediated by hnRNPs A1 and A2/B1

    PubMed Central

    Geissler, Rene; Simkin, Alfred; Floss, Doreen; Patel, Ravi; Fogarty, Elizabeth A.; Scheller, Jürgen; Grimson, Andrew

    2016-01-01

    3′-untranslated regions (UTRs) specify post-transcriptional fates of mammalian messenger RNAs (mRNAs), yet knowledge of the underlying sequences and mechanisms is largely incomplete. Here, we identify two related novel 3′ UTR motifs in mammals that specify transcript degradation. These motifs are interchangeable and active only within 3′ UTRs, where they are often preferentially conserved; furthermore, they are found in hundreds of transcripts, many encoding regulatory proteins. We found that degradation occurs via mRNA deadenylation, mediated by the CCR4–NOT complex. We purified trans factors that recognize the motifs and identified heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2/B1, which are required for transcript degradation, acting in a previously unknown manner. We used RNA sequencing (RNA-seq) to confirm hnRNP A1 and A2/B1 motif-dependent roles genome-wide, profiling cells depleted of these factors singly and in combination. Interestingly, the motifs are most active within the distal portion of 3′ UTRs, suggesting that their role in gene regulation can be modulated by alternative processing, resulting in shorter 3′ UTRs. PMID:27151978

  11. SPICE macromodel for a 1-megawatt power MOSFET switch

    SciTech Connect

    Helms, C.; Ackermann, M.; Fischer, T.; Deveney, M.

    1993-08-01

    This paper presents a SPICE macromodel for a 1-megawatt high power electrical switch which uses power MOSFETs as the active switching elements. The model accurately predicts the time dependent switching current and provides a reasonable representation of the time dependent switch resistance and voltage drop across the switch. Techniques for extracting model parameters for commercial power MOSFETs are discussed along with suggestions for extending the model to spark gaps and other high power switches.

  12. X-ray variability observed with HEAO A-1

    NASA Technical Reports Server (NTRS)

    Friedman, H.

    1979-01-01

    Results from the HEAO A-1 instrument which observed X-ray source variability over a wide range of accessible timescales are surveyed. The objects observed include quasars, BL Lacertae, and active galactic nuclei. A high sensitivity search for X-ray pulsars, known black hole candidates, period fluctuation in binary pulsars, and X-ray and gamma ray bursts are among the topics covered.

  13. 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.

  14. Elucidating hydroxylation and methylation steps tailoring piericidin A1 biosynthesis.

    PubMed

    Chen, Yaolong; Zhang, Wenjun; Zhu, Yiguang; Zhang, Qingbo; Tian, Xinpeng; Zhang, Si; Zhang, Changsheng

    2014-02-01

    The piericidin A1 (1) gene cluster was identified from the deep-sea derived Streptomyces sp. SCSIO 03032. Our in vivo and in vitro experiments verified PieE as a 4'-hydroxylase and PieB2 as a 4'-O-methyltransferase, allowing the elucidation of the post-PKS modification steps involved in 1 biosynthesis. In addition, the shunt metabolite piericidin E1 (7) was identified as a novel analogue featuring a C-2/C-3 epoxy ring.

  15. The A1Σu+ system of Mg2

    NASA Astrophysics Data System (ADS)

    Knöckel, Horst; Rühmann, Steffen; Tiemann, Eberhard

    2014-10-01

    The A1Σu+-X1Σg+ UV spectrum of Mg2 has been investigated with high resolution employing Fourier-transform spectroscopy and laser excitation. Computer simulation and fit of line positions to the overlapping structures in the spectra yield precise transition frequencies. Starting with the well characterized ground state X1Σg+ from former work, we derived excited energy levels and report on the evaluation of the A1Σu+ excited state, which is found to interact with another electronic state, which we identify as the lower part of the (1)1Πu state. A coupled channels fit to the level energies of the upper state yields a reliable potential energy curve for the A1Σu+ state for the range of vibrational levels 1 ≤ v' ≤ 46. A potential energy curve for the (1)1Πu state is proposed, but the (1)1Πu state is only characterized by its coupling to the A state, and no direct transition to a level of the (1)1Πu state could be uniquely identified due to the overlapping spectral structures. Supplementary material in the form of one dat file available from the Journal web page at http://dx.doi.org/10.1140/epjd/e2014-50289-9

  16. 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.

  17. Dietary Lecithin Decreases Skeletal Muscle COL1A1 and COL3A1 Gene Expression in Finisher Gilts.

    PubMed

    Akit, Henny; Collins, Cherie; Fahri, Fahri; Hung, Alex; D'Souza, Daryl; Leury, Brian; Dunshea, Frank

    2016-01-01

    The purpose of this study was to investigate the effect of dietary lecithin on skeletal muscle gene expression of collagen precursors and enzymes involved in collagen synthesis and degradation. Finisher gilts with an average start weight of 55.9 ± 2.22 kg were fed diets containing either 0, 4, 20 or 80 g/kg soybean lecithin prior to harvest for six weeks and the rectus abdominis muscle gene expression profile was analyzed by quantitative real-time PCR. Lecithin treatment down-regulated Type I (α1) procollagen (COL1A1) and Type III (α1) procollagen (COL3A1) mRNA expression ( p < 0.05, respectively), indicating a decrease in the precursors for collagen synthesis. The α-subunit of prolyl 4-hydroxylase (P4H) mRNA expression also tended to be down-regulated ( p = 0.056), indicating a decrease in collagen synthesis. Decreased matrix metalloproteinase-1 (MMP-1) mRNA expression may reflect a positive regulatory response to the reduced collagen synthesis in muscle from the pigs fed lecithin ( p = 0.035). Lecithin had no effect on tissue inhibitor metalloproteinase-1 (TIMP-1), matrix metalloproteinase-13 (MMP-13) and lysyl oxidase mRNA expression. In conclusion, lecithin down-regulated COL1A1 and COL3A1 as well as tended to down-regulate α-subunit P4H expression. However, determination of muscle collagen content and solubility are required to support the gene functions. PMID:27338483

  18. 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

  19. Anisotropice superfluid fraction of3He A1 phase

    NASA Astrophysics Data System (ADS)

    Bastea, M.; Kojima, H.

    1995-11-01

    The superfluid fraction of3He a1 phase is computed from measurements of the velocity of spin/entropy waves induced in a cylindrical chamber, for two different directions of the magnetic field: parallel and perpendicular to the axis of the chamber. The ratio of the superfluid fractions in the parallel and perpendicular orientations is 1.85, and does not depend on the field between 1 and 5 Tesla. We adapt a theoretical texture model to account for the superfluid flow, and the results are consistent with the above ratio and direct estimates of superfluid velocity.

  20. CYP1A1 genetic polymorphisms in Ecuador, South America.

    PubMed

    Paz-y-Miño, César; Arévalo, Melissa; Muñoz G, María José; Leone, Paola E

    2005-01-01

    A total of 108 individuals from the Ecuadorian population from rural and urban places were analyzed for two CYP1A1 gene polymorphisms. The frequency of the val allele at codon 462 was 0.50, while the frequency of the Msp I restriction site, m2 allele at the T6235C position was 0.70. These polymorphisms in Ecuador have higher frequencies if we compare with others around the world, with the exception of some South American population in Brazil and Chile.

  1. Standardization of HbA1c: good or bad?

    PubMed

    Marshall, Sally M

    2010-07-01

    The development of a true reference measurement system by the International Federation for Clinical Chemistry (IFCC) for the first time allows reporting of true HbA(1c) results, standardized to an absolute value, worldwide. Regression equations between the IFCC assay and current harmonization assays, including the Diabetes Control and Complications Trial (DCCT) assay, are linear, tight, and stable over time. National and international setting of targets, audit and benchmarking of services will be easier than before, as will translation of research into clinical practice. Nevertheless, the main disadvantage of the IFCC assay is that the numbers and units reported (mmol/mol) are very different from the DCCT value (percentage). An extensive education program for patients and health-care professionals is, therefore, needed to prevent confusion and consequent deterioration in glycemic control. Furthermore, the IFCC system does not overcome difficulties inherent in the measurement and interpretation of HbA(1c), such as in the presence of abnormal turnover of red blood cells and hemoglobinopathies. PMID:20440288

  2. Dysspondyloenchondromatosis: Another COL2A1-Related Skeletal Dysplasia?

    PubMed Central

    Nakane, T.; Tando, T.; Aoyagi, K.; Hatakeyama, K.; Nishimura, G.; Coucke, I.P.J.; Mortier, G.; Sugita, K.

    2011-01-01

    Dysspondyloenchondromatosis (DSC) is a rare skeletal dysplasia that has currently been classified into the group of spondylometaphyseal dysplasias. To date, only 12 affected individuals have been reported. All cases are sporadic, and the etiology remains unknown. Distinctive features of DSC are anisospondyly and enchondroma-like lesions in the metaphyseal and diaphyseal portions of the long tubular bones. Affected individuals usually develop kyphoscoliosis and asymmetric limb shortening at an early age. Interestingly, some of the skeletal changes overlap with spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, a rare type II collagen disorder. Based on this resemblance we postulated that DSC may be allelic to SEMD Strudwick type and therefore performed a COL2A1 analysis in an affected boy who was diagnosed as having DSC at the age of 3 years. The identification of a novel heterozygous COL2A1 missense mutation (p.Gly753Asp) in the proband confirms our hypothesis and suggests that DSC may be another type II collagen disorder. PMID:22570642

  3. COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type

    PubMed Central

    Matsubayashi, S.; Ikema, M.; Ninomiya, Y.; Yamaguchi, K.; Ikegawa, S.; Nishimura, G.

    2013-01-01

    Spondylometaphyseal dysplasia Algerian type (SMD-A) is an autosomal dominant disorder that was first reported in an Algerian family by Kozlowski et al. [Pediatr Radiol 1988;18:221-226]. Kozlowski's group reported a sporadic case in a 12-year-old Polish boy. They proposed SMD-A as a distinctive skeletal dysplasia and also suggested that a case of SMD reported by Schmidt et al. [J Pediatr 1963;63:106-112] might have had the same disorder. Afterwards, however, no additional report has emerged to date. In addition, the question whether SMD-A belongs to type II collagenopathy (a group of disorders due to a heterozygous mutation of COL2A1) has been continuously under debate. Here we report a 7-year-old Japanese boy with a heterozygous missense mutation in COL2A1, 2582G>T (Gly861Val), whose phenotype matched that of SMD-A. Our observation supports the hypothesis that SMD-A is a variant of type II collagenopathy. PMID:23653587

  4. Concept of a (1-. cap alpha. ) performance confidence interval

    SciTech Connect

    Leong, H.H.; Johnson, G.R.; Bechtel, T.N.

    1980-01-01

    A multi-input, single-output system is assumed to be represented by some model. The distribution functions of the input and the output variables are considered to be at least obtainable through experimental data. Associated with the computer response of the model corresponding to given inputs, a conditional pseudoresponse set is generated. This response can be constructed by means of the model by using the simulated pseudorandom input variates from a neighborhood defined by a preassigned probability allowance. A pair of such pseudoresponse values can then be computed by a procedure corresponding to a (1-..cap alpha..) probability for the conditional pseudoresponse set. The range defined by such a pair is called a (1-..cap alpha..) performance confidence interval with respect to the model. The application of this concept can allow comparison of the merit of two models describing the same system, or it can detect a system change when the current response is out of the performance interval with respect to the previously identified model. 6 figures.

  5. Collisionally-Mediated Singlet-Triplet Crossing in ˜{a}1A1 CH_2 Revisited: (010) Coupling

    NASA Astrophysics Data System (ADS)

    Le, Anh T.; Hall, Gregory; Sears, Trevor

    2014-06-01

    Methylene, CH2, possesses a ground ˜{X}3B1 ground electronic state and an excited ˜{a}1A1 state only 3150cm-1 higher in energy. The collision-induced singlet-triplet crossing in the gaseous mixtures is important in determining overall reaction rates and chemical behavior. Accidental near-degeneracies between rotational levels of the singlet state and the vibrationally excited triplet state result in a few gateway rotational levels that mediate collision-induced intersystem crossing. The mixed states can be recognized and quantified by deperturbation, knowing the zero-order singlet and triplet energy levels. Hyperfine structure can be used as alternative indicator of singlet-triplet mixing. Non-zero mixing will induce hyperfine splittings intermediate between the unresolved hyperfine structure of pure singlet and the resolvable (≈50MHz) splittings of pure triplet, arising from the (I\\cdotS) interaction in the ortho states, where nuclear spin I=1. Collision-induced intersystem crossing rates from the (010) state are comparable to those for (000), yet the identities and characters of the presumed gateway states are unknown. A new spectrometer is under construction to investigate triplet mixing rotational levels of ˜{a}1A1(010) by sub-Doppler measurements of perturbation-induced hyperfine splittings. Their observation will permit the identification of gateway states and quantification of the degree of triplet contamination of the singlet wavefunction. Progress in the measurements and the analysis of rotational energy transfer in (010) will be reported. Acknowledgments: Work at Brookhaven National Laboratory was carried out under Contract No. DE-AC02-98CH10886 with the U.S. Department of Energy and supported by its Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences. C.-H. Chang, G. E. Hall, T. J. Sears, J. Chem. Phys 133, 144310(2010) G. E. Hall, A. V. Komissarov, and T. J. Sears, J. Phys. Chem. A 108 7922-7927 (2004)

  6. [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

    Antecedentes: la arteria cerebral anterior se origina de la bifurcación de la arteria carótida interna lateral al quiasma óptico, posteriormente se une con su homóloga contralateral mediante la arteria comunicante anterior. El complejo precomunicante(A1)-arteria comunicante anterior es el lugar más frecuente de variantes anatómicas y el sitio con mayor cantidad de aneurismas (30 a 37%). Objetivo: conocer la anatomía microquirúrgica, las variantes anatómicas y la importancia del complejo segmento precomunicante-arteria comunicante anterior en cirugía neurológica de la patología vascular, principalmente aneurismas, en población mexicana. Material y métodos: estudio prospectivo y descriptivo efectuado en el Departamento de Anatomía de la Facultad de Medicina (UNAM) en 30 encéfalos inyectados. Se estudió la anatomía microquirúrgica (longitud y calibre) del complejo segmento precomunicante-arteria comunicante anterior de la arteria cerebral anterior y sus variantes. Resultados: se encontraron 60 segmentos precomunicantes. La longitud promedio del lado izquierdo fue de 11.35 mm y del derecho de 11.84 mm. El calibre medio en el lado izquierdo fue de 1.67 mm y en el derecho de 1.64 mm. El número promedio de perforantes en el lado izquierdo fue de 7.9 y en el derecho de 7.5. La arteria comunicante anterior se encontró en 29 encéfalos sobre el quiasma óptico, su trayecto dependió de la longitud del segmento A1. La longitud media del segmento fue de 2.84 mm, el calibre fue de 1.41 mm y el número promedio de perforantes de 3.27. En 18 encéfalos (60%) se encontraron variantes del complejo A1-arteria comunicante anterior y dos aneurismas tipo blíster. Conclusión: es necesario entender la anatomía microquirúrgica del complejo segmento precomunicante-arteria comunicante anterior y conocer las variantes para tener una visión en tercera dimensión durante la cirugía de aneurismas.

  7. Pulmonary toxicity of cyclophosphamide: a 1-year study

    SciTech Connect

    Morse, C.C.; Sigler, C.; Lock, S.; Hakkinen, P.J.; Haschek, W.M.; Witschi, H.P.

    1985-01-01

    The development of cyclophosphamide-induced pulmonary lesions over a 1-year period was studied in mice. Male BALB/c mice received a single intraperitoneal injection of 100 mg/kg of cyclophosphamide. Within 3 weeks there were scattered foci of intraalveolar foamy macrophages. With time, these foci increased in size and, 1 year later, occupied large areas in all lung lobes. There was also diffuse interstitial fibrosis. Chemical determination done 3, 12, 24, and 52 weeks after cyclophosphamide showed that lungs of animals treated with cyclophosphamide had significantly more hydroxyproline per lung than controls. One year after cyclophosphamide pressure - volume curves measured in vivo were shifted down and to the right and total lung volumes were decreased. A single injection of cyclophosphamide produced an irreversible and progressive pulmonary lesion. 16 references, 5 figures, 3 tables.

  8. A 1,3-Dihydro-1,3-azaborine Debuts

    PubMed Central

    Xu, Senmiao; Zakharov, Lev N.

    2011-01-01

    We present the first synthesis and characterization of a 1,3-dihydro-1,3-azaborine, a long-sought BN isostere of benzene. 1,3-Dihydro-1,3-azaborine is a stable structural motif with considerable aromatic character as evidenced by structural analysis and its reaction chemistry. Single crystal X-ray analysis indicates bonding consistent with significant electron delocalization. 1,3-Dihydro-1,3-azaborines also undergo nucleophilic substitutions at boron and electrophilic aromatic substitution reactions. In view of the versatility and impact of aromatic compounds in the biomedical field and in materials science, the present study further expands the available chemical space of arenes via BN/CC isosterism. PMID:22091703

  9. Optical design of a 1-to-1 lithography projection

    NASA Astrophysics Data System (ADS)

    Huang, Jiun-Woei

    2016-08-01

    A 1:1 lithography projection has been designed and is fabricated for a 3D integrated circuit fabrication platform. Using a dual triplet as an initial type to form a one-to-one lens and applying a tele-centric structure, the optical common components of an optical system have been designed. The tolerance of the mechanical mounts is simulated by tilting the mounts to single and two aspheric surfaces of lens to show the degradation in the modulation transfer function; thus, the single aspheric-tilted mount in a system is suggested to reach the precision. Furthermore, Koehler illumination is used. By applying partial coherence analysis, the optimized relative numerical aperture was found. As the system is built, optimized performance should be expected.

  10. Underwater Imaging Using a 1 × 16 CMUT Linear Array

    PubMed Central

    Zhang, Rui; Zhang, Wendong; He, Changde; Zhang, Yongmei; Song, Jinlong; Xue, Chenyang

    2016-01-01

    A 1 × 16 capacitive micro-machined ultrasonic transducer linear array was designed, fabricated, and tested for underwater imaging in the low frequency range. The linear array was fabricated using Si-SOI bonding techniques. Underwater transmission performance was tested in a water tank, and the array has a resonant frequency of 700 kHz, with pressure amplitude 182 dB (μPa·m/V) at 1 m. The −3 dB main beam width of the designed dense linear array is approximately 5 degrees. Synthetic aperture focusing technique was applied to improve the resolution of reconstructed images, with promising results. Thus, the proposed array was shown to be suitable for underwater imaging applications. PMID:26938536

  11. Underwater Imaging Using a 1 × 16 CMUT Linear Array.

    PubMed

    Zhang, Rui; Zhang, Wendong; He, Changde; Zhang, Yongmei; Song, Jinlong; Xue, Chenyang

    2016-03-01

    A 1 × 16 capacitive micro-machined ultrasonic transducer linear array was designed, fabricated, and tested for underwater imaging in the low frequency range. The linear array was fabricated using Si-SOI bonding techniques. Underwater transmission performance was tested in a water tank, and the array has a resonant frequency of 700 kHz, with pressure amplitude 182 dB (μPa·m/V) at 1 m. The -3 dB main beam width of the designed dense linear array is approximately 5 degrees. Synthetic aperture focusing technique was applied to improve the resolution of reconstructed images, with promising results. Thus, the proposed array was shown to be suitable for underwater imaging applications.

  12. Optical design of a 1-to-1 lithography projection

    NASA Astrophysics Data System (ADS)

    Huang, Jiun-Woei

    2016-10-01

    A 1:1 lithography projection has been designed and is fabricated for a 3D integrated circuit fabrication platform. Using a dual triplet as an initial type to form a one-to-one lens and applying a tele-centric structure, the optical common components of an optical system have been designed. The tolerance of the mechanical mounts is simulated by tilting the mounts to single and two aspheric surfaces of lens to show the degradation in the modulation transfer function; thus, the single aspheric-tilted mount in a system is suggested to reach the precision. Furthermore, Koehler illumination is used. By applying partial coherence analysis, the optimized relative numerical aperture was found. As the system is built, optimized performance should be expected.

  13. Study of the Comet C/2013 A1 (Siding Spring)

    NASA Astrophysics Data System (ADS)

    Vodniza, Alberto Q.; Pereira, Mario R.

    2014-11-01

    The comet called C/2013 A1 (SIDING SPRING) was discovered on January 3, 2013 in Australia. In January 28/2014, NASA announced that is preparing for the close encounter that will happen between the comet C/2013 A1 and Mars on October 19-2014. The Mission called “MAVEN” will insert in Mars orbit on september 21—2014. The comet will pass just 138,000 kilometers far from the surface of Mars. The probability that the comet collides with Mars is small but the dust particles emitted by the comet can cause damage to spacecrafts and probes that are in orbit around that planet. NASA is making preparations to take all precautions. If the comet is quite active, there will be almost no time to take security measures with Mars orbiters. For that reason NASA is already ahead of the facts. According to scientists of the "JET PROPULSION LABORATORY-JPL", dust particles spewing from the comet may be traveling at 56 km / sec in relation to the orbiters, fifty times faster than the speed of a bullet. From our Observatory, located in Pasto-Colombia, we captured several pictures, videos and astrometry data during several days. The pictures of the asteroid were captured with the following equipment: CGE PRO 1400 CELESTRON (f/11 Schmidt-Cassegrain Telescope) and STL-1001 SBIG camera. Astrometry was carried out, and we calculated the orbital elements.Summary And Conclusions: We obtained the following orbital parameters: eccentricity = 1.0003983, orbital inclination = 129.03078 deg, longitude of the ascending node = 300.99538 deg, argument of perihelion = 2.42310 deg, perihelion distance = 1.40023196 A.U. The parameters were calculated based on 20 observations (Jan 21 to April 02) with mean residual = 0.334 arcseconds. We also obtained the light curve of the body with our data (January to November/2014)Acknowledgements: The authors would like to thank to University of Narino-Pasto-Colombia.

  14. Elevated CSF dynorphin A [1-8] in Tourette's syndrome.

    PubMed

    Leckman, J F; Riddle, M A; Berrettini, W H; Anderson, G M; Hardin, M; Chappell, P; Bissette, G; Nemeroff, C B; Goodman, W K; Cohen, D J

    1988-01-01

    A recent neuropathological study has reported decreased levels of dynorphin A immunoreactivity in striato-pallidal fibers in the brain of a patient with severe Gilles de la Tourette's syndrome (TS). This observation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS. We report on the presence of elevated concentrations of dynorphin A [1-8] in the CSF of 7 TS patients, aged 20 to 45 years. The increase in CSF dynorphin was found to be associated with the severity of the obsessive compulsive symptoms but not with tic severity in these patients. Although CSF studies lack the precision necessary to address questions of selective involvement of neuronal system in specific CNS locations, these findings suggest that endogenous opioids are involved in the pathobiology of TS and related disorders. Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) (1). Once thought to be a rare condition, the prevalence of TS is now estimated to be one case per 1,000 boys and one case per 10,000 girls, and milder variants of the syndrome are likely to occur in a sizeable percentage of the population (2). Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consistent with an autosomal dominant form of inheritance (3,4). Neurobiologic and pharmacological data have implicated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and basal ganglia structures remain the prime candidates as the neuroanatomical origin for TS and related conditions (1). Endogenous opioids, including dynorphin and met-enkephalin are concentrated in structures of the basal ganglia (5), are known to

  15. Splicing analysis of unclassified variants in COL2A1 and COL11A1 identifies deep intronic pathogenic mutations

    PubMed Central

    Richards, Allan J; McNinch, Annie; Whittaker, Joanne; Treacy, Becky; Oakhill, Kim; Poulson, Arabella; Snead, Martin P

    2012-01-01

    UK NHS diagnostic service sequence analysis of genes generally examines and reports on variations within a designated region 5′ and 3′ of each exon, typically 30 bp up and downstream. However, because of the degenerate nature of the splice sites, intronic variants outside the AG and GT dinucleotides of the acceptor and donor splice sites (ASS and DSS) are most often classified as being of unknown clinical significance, unless there is some functional evidence of their pathogenicity. It is now becoming clear that mutations deep within introns can also interfere with normal processing of pre-mRNA and result in pathogenic effects on the mature transcript. In diagnostic laboratories, these deep intronic variants most often fall outside of the regions analysed and so are rarely reported. With the likelihood that next generation sequencing will identify more of these unclassified variants, it will become important to perform additional studies to determine the pathogenicity of such sequence anomalies. Here, we analyse variants detected in either COL2A1 or COL11A1 in patients with Stickler syndrome. These have been analysed both in silico and functionally using either RNA isolated from the patient's cells or, more commonly, minigenes as splicing reporters. We show that deep intronic mutations are not a rare occurrence, including one variant that results in multiple transcripts, where both de novo donor and ASS are created by the mutation. Another variant produces transcripts that result in either haploinsufficiency or a dominant negative effect, potentially modifying the disease phenotype. PMID:22189268

  16. Evaluation of a 1% iodophor postmilking teat sanitizer.

    PubMed

    Goldberg, J J; Murdough, P A; Howard, A B; Drechsler, P A; Pankey, J W; Ledbetter, G A; Richards, D A; Day, L L

    1994-03-01

    A natural exposure field trial a with positive control was conducted to evaluate bacteriological efficacy and teat conditioning qualities of an experimental postmilking teat dip. An experimental 1% iodine postmilking teat sanitizer with a 10% emollient system was compared with a 1% iodine plus 10% glycerin teat sanitizer. Efficacy of the two sanitizers was equivalent for all new IMI, major pathogens, and environmental pathogens. The products were not equivalent for efficacy against coliforms and coagulase-negative staphylococci. Fewer coliform IMI were diagnosed in the control group than in the treatment group. Differences were determined for efficacy against coagulase-negative staphylococci in favor of the treatment product. The products were equivalent for all clinical mastitis, including previously existing IMI that became clinical. The products were not equivalent for all or new clinical IMI with major pathogens, all environmental pathogens, or coliforms. Fewer infections were diagnosed in the control group than in the treatment group. Teat end and teat skin conditions improved with the use of the triple emollient, postmilking teat sanitizer under the winter conditions experienced during this field trial. PMID:8169282

  17. Transport of gibberellin a(1) in cowpea membrane vesicles.

    PubMed

    O'neill, S D; Keith, B; Rappaport, L

    1986-04-01

    The permeability properties of gibberellin A(1) (GA(1)) were examined in membrane vesicles isolated from cowpea hypocotyls. The rate of GA(1) uptake was progressively greater as pH decreased, indicating that the neutral molecule is more permeable than anionic GA(1). Membrane vesicles used in this study possessed a tonoplast-type H(+)-translocating ATPase as assayed by MgATP-dependent quenching of acridine orange fluorescence and methylamine uptake. However, GA(1) uptake was not stimulated by MgATP. At concentrations in excess of 1 micromolar, GA(1), GA(5), and GA, collapsed both MgATP-generated and artifically imposed pH gradients, apparently by shuttling H(+) across the membrane as neutral GA. The relatively high permeability of neutral GA and the potentially detrimental effects of GA in uncoupling pH gradients across intracellular membranes supports the view that GA(1) accumulation and compartmentation must occur by conversion of GA(1) to more polar metabolites.

  18. In Vitro Gibberellin A(1) Binding in Zea mays L.

    PubMed

    Keith, B; Rappaport, L

    1987-12-01

    The first and second leaf sheaths of Zea mays L. cv Golden Jubilee were extracted and the extract centrifuged at 100,000g to yield a supernatant or cytosol fraction. Binding of [(3)H]gibberellin A(1) (GA(1)) to a soluble macromolecular component present in the cytosol was demonstrated at 4 degrees C by Sephadex G-200 chromatography. The binding component was of high molecular weight (HMW) and greater than 500 kilodaltons. The HMW component was shown to be a protein and the (3)H-activity bound to this protein was largely [(3)H]GA(1) and not a metabolite. Binding was pH sensitive but only a small percentage (20%) appeared to be exchangeable on addition of unlabeled GA(1). Both biologically active and inactive GAs and non-GAs were able to inhibit GA(1) binding. [(3)H]GA(1) binding to an intermediate molecular weight (IMW) fraction (40-100 kilodaltons) was also detected, provided cytosol was first desalted using Sephadex G-200 chromatography. Gel filtration studies suggest that the HMW binding component is an aggregate derived from the IMW fraction. The HMW binding fraction can be separated into two components using anion exchange chromatography.

  19. Development of a 1×2 piezoelectric optical fiber switch

    NASA Astrophysics Data System (ADS)

    Leung, M.; Yue, J.; Razak, K. A.; Haemmerle, E.; Hodgson, M.; Gao, W.

    2008-03-01

    This paper presents the design, fabrication and performance of a 1×2 piezoelectric optical switch. The optical switch is developed based on the concept that the input fiber is directly moved by the deflection of a piezoelectric tube actuator. The piezoelectric tube actuator used in this switch is manufactured through an electrophoretic deposition process. The tube is inexpensive to produce and compact in size with high mechanical performance. It has a maximum deflection of 30μm which is capable to actuate the input fiber for switching. The multimode fiber optical switch has been successfully assembled. To reduce the misalignment loss between the fibers, the output fibers are precisely aligned in silicon vgrooves. Different components are bonded with low shrinkage adhesive in order to minimize their position inaccuracy. The performance characteristics of the optical switch have been measured, with an insertion loss of 1dB, crosstalk of -45dB and switching speed from 5 to 10ms. The switch also shows good reliability and requires small driving power. The development of multimode optical switch prototypes proves that the idea of piezoelectric switching is feasible. Further developments include the improvement of switching performance, reduction of the prototype size and the fabrication of multiple output prototypes.

  20. A 1-Joule laser for a 16-fiber injection system

    SciTech Connect

    Honig, J

    2004-04-06

    A 1-J laser was designed to launch light down 16, multi-mode fibers (400-{micro}m-core dia.). A diffractive-optic splitter was designed in collaboration with Digital Optics Corporation (DOC), and was delivered by DOC. Using this splitter, the energy injected into each fiber varied <1%. The spatial profile out of each fiber was such that there were no ''hot spots,'' a flyer could successfully be launched and a PETN pellet could be initiated. Preliminary designs of the system were driven by system efficiency where a pristine TEM{sub 00} laser beam would be required. The laser is a master oscillator, power amplifier (MOPA) consisting of a 4-mm-dia. Nd:YLF rod in the stable, q-switched oscillator and a 9.5-mm-dia. Nd:YLF rod in the double-passed amplifier. Using a TEM{sub 00} oscillator beam resulted in excellent transmission efficiencies through the fibers at lower energies but proved to be quite unreliable at higher energies, causing premature fiber damage, flyer plate rupture, stimulated Raman scattering (SRS), and stimulated Brillouin scattering (SBS). Upon further investigation, it was found that both temporal and spatial beam formatting of the laser were required to successfully initiate the PETN. Results from the single-mode experiments, including fiber damage, SRS and SBS losses, will be presented. In addition, results showing the improvement that can be obtained by proper laser beam formatting will also be presented.

  1. Towards a 1km resolution global flood risk model

    NASA Astrophysics Data System (ADS)

    Bates, Paul; Neal, Jeff; Sampson, Chris; Smith, Andy

    2014-05-01

    Recent advances in computationally efficient numerical algorithms and new High Performance Computing architectures now make high (1-2km) resolution global hydrodynamic models a realistic proposition. However in many areas of the world the data sets and tools necessary to undertake such modelling do not currently exist. In particular, five major problems need to be resolved: (1) the best globally available terrain data (SRTM) was generated from X-band interferometric radar data which does not penetrate vegetation canopies and which has significant problems in determining ground elevations in urban areas; (2) a global river bathymetry data set does not currently exist; (3) most river channels globally are less than the smallest currently resolvable grid scale (1km) and therefore require a sub-grid treatment; (4) a means to estimate the magnitude of the T year flood at any point along the global river network does not currently exist; and (5) a large proportion of flood losses are generated by off-floodplain surface water flows which are not well represented in current hydrodynamic modelling systems. In this paper we propose solutions to each of these five issues as part of a concerted effort to develop a 1km (or better) resolution global flood hazard model. We describe the new numerical algorithms, computer architectures and computational resources used, and demonstrate solutions to the five previously intractable problems identified above. We conduct a validation study of the modelling against satellite imagery of major flooding on the Mississippi-Missouri confluence plain in the central USA before outlining a proof-of-concept regional study for SE Asia as a step towards a global scale model. For SE Asia we simulate flood hazard for ten different flood return periods over the entire Thailand, Cambodia, Vietnam, Malaysia and Laos region at 1km resolution and show that the modelling produces coherent, consistent and sensible simulations of extent and water depth.

  2. Varicella paediatric hospitalisations in Belgium: a 1-year national survey

    PubMed Central

    Blumental, Sophie; Sabbe, Martine; Lepage, Philippe

    2016-01-01

    Background Varicella universal vaccination (UV) has been implemented in many countries for several years. Nevertheless, varicella UV remains debated in Europe and few data are available on the real burden of infection. We assessed the burden of varicella in Belgium through analysis of hospitalised cases during a 1-year period. Methods Data on children admitted to hospital with varicella were collected through a national network from November 2011 to October 2012. Inclusion criteria were either acute varicella or related complications up to 3 weeks after the rash. Results Participation of 101 hospitals was obtained, covering 97.7% of the total paediatric beds in Belgium. 552 children were included with a median age of 2.1 years. Incidence of paediatric varicella hospitalisations reached 29.5/105 person-years, with the highest impact among those 0–4 years old (global incidence and odds of hospitalisation: 79/105 person-years and 1.6/100 varicella cases, respectively). Only 14% (79/552) of the cohort had an underlying chronic condition. 65% (357/552) of children had ≥1 complication justifying their admission, 49% were bacterial superinfections and 10% neurological disorders. Only a quarter of children (141/552) received acyclovir. Incidence of complicated hospitalised cases was 19/105 person-years. Paediatric intensive care unit admission and surgery were required in 4% and 3% of hospitalised cases, respectively. Mortality among Belgian paediatric population was 0.5/106 and fatality ratio 0.2% among our cohort. Conclusions Varicella demonstrated a substantial burden of disease in Belgian children, especially among the youngest. Our thorough nationwide study, run in a country without varicella UV, offers data to support varicella UV in Belgium. PMID:26130380

  3. Dynamical functions of a 1D correlated quantum liquid

    NASA Astrophysics Data System (ADS)

    Carmelo, J. M. P.; Bozi, D.; Penc, K.

    2008-10-01

    The dynamical correlation functions in one-dimensional electronic systems show power-law behaviour at low energies and momenta close to integer multiples of the charge and spin Fermi momenta. These systems are usually referred to as Tomonaga-Luttinger liquids. However, near well defined lines of the (k,ω) plane the power-law behaviour extends beyond the low-energy cases mentioned above, and also appears at higher energies, leading to singular features in the photoemission spectra and other dynamical correlation functions. The general spectral-function expressions derived in this paper were used in recent theoretical studies of the finite-energy singular features in photoemission of the organic compound tetrathiafulvalene-tetracyanoquinodimethane (TTF-TCNQ) metallic phase. They are based on a so-called pseudofermion dynamical theory (PDT), which allows us to systematically enumerate and describe the excitations in the Hubbard model starting from the Bethe ansatz, as well as to calculate the charge and spin object phase shifts appearing as exponents of the power laws. In particular, we concentrate on the spin-density m\\rightarrow 0 limit and on effects in the vicinity of the singular border lines, as well as close to half filling. Our studies take into account spectral contributions from types of microscopic processes that do not occur for finite values of the spin density. In addition, the specific processes involved in the spectral features of TTF-TCNQ are studied. Our results are useful for the further understanding of the unusual spectral properties observed in low-dimensional organic metals and also provide expressions for the one- and two-atom spectral functions of a correlated quantum system of ultracold fermionic atoms in a 1D optical lattice with on-site two-atom repulsion.

  4. TRAPPIST monitoring of comet C/2013 A1 (Siding Spring)

    NASA Astrophysics Data System (ADS)

    Opitom, Cyrielle; Jehin, Emmanuël; Manfroid, Jean; Hutsemékers, Damien; Gillon, Michaël

    2014-11-01

    C/2013 A1 (Siding Spring) is a long period comet discovered by Robert H McNaught at Siding Spring Observatory in Australia on January 3, 2013 at 7.2 au from the Sun. This comet will make a close encounter with Mars on October 19, 2014. At this occasion the comet will be extensively observed both from Earth and from several orbiters around Mars.On September 20, 2013 when the comet was around 5 au from the Sun, we started a monitoring with the TRAPPIST robotic telescope installed at La Silla observatory [1]. A set of narrowband cometary filters designed by the NASA for the Hale-Bopp Observing Campaign [2] is permanently mounted on the telescope along with classic Johnson-Cousins B, V, Rc, and Ic filters.We observed the comet continuously at least once a week from September 20, 2013 to April 6, 2014 with broad band filters. We then recovered the comet on May 20. At this time we could detect the gas and started the observations with narrow band filters until early November, covering the close approach to Mars and the perihelion passage.We present here our first results about comet Siding Springs. From the images in the broad band filters and in the dust continuum filters we derived A(θ)fρ values [3] and studied the evolution of the comet activity with the heliocentric distance from September 20, 2013 to early November 2014. We could also detect gas since May 20, 2014. We thus derived gas production rates using a Haser model [4]. We present the evolution of gas production rates and gas production rates ratios with the heliocentric distance.Finally, we discuss the dust and gas coma morphology.

  5. Feasibility study of a 1-MW pulsed spallation source

    SciTech Connect

    Cho, Y.; Chae, Y.C.; Crosbie, E.

    1995-12-31

    A feasibility study of a 1-MW pulsed spallation source based on a rapidly cycling proton synchrotron (RCS) has been completed. The facility consists of a 400-MeV HP{sup -} linac, a 30-Hz RCS that accelerates the 400-MeV beam to 2 GeV, and two neutron-generating target stations. The design time-averaged current of the accelerator system is 0.5 mA, or 1.04{times}1014 protons per pulse. The linac system consists of an H{sup -}ion source, a 2-MeV RFQ, a 70-MeV DTL and a 330-MeV CCL. Transverse phase space painting to achieve a Kapchinskij-Vladimirskij (K-V) distribution of the injected particles in the RCS is accomplished by charge exchange injection and programming of the closed orbit during injection. The synchrotron lattice uses FODO cells of {approx}90{degrees} phase advance. Dispersion-free straight sections are obtained by using a missing magnet scheme. Synchrotron magnets are powered by a dual-frequency resonant circuit that excites the magnets at a 20-Hz rate and de-excites them at a 60-Hz rate, resulting in an effective rate of 30 Hz, and reducing the required peak rf voltage by 1/3. A key feature, of the design of this accelerator system is that beam losses are from injection to extraction, reducing activation to levels consistent with hands-on maintenance. Details of the study are presented.

  6. 17 CFR 270.3a-1 - Certain prima facie investment companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 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 companies. Notwithstanding section 3(a)(1)(C) of the Act (15 U.S.C. 80a-3(a)(1)(c)), an issuer will...

  7. Sites in the CH3 domain of human IgA1 that influence sensitivity to bacterial IgA1 proteases.

    PubMed

    Senior, Bernard W; Woof, Jenny M

    2006-09-15

    The influence of regions, other than the hinge, on the susceptibility of human IgA1 to cleavage by diverse bacterial IgA1 proteases, was examined using IgA1 mutants bearing amino acid deletions, substitutions, and domain swaps. IgA1 lacking the tailpiece retained its susceptibility to cleavage by all of the IgA1 proteases. The domain swap molecule alpha1alpha2gamma3, in which the CH3 domain of IgA1 was exchanged for that of human IgG1, was resistant to cleavage with the type 1 and 2 serine IgA1 proteases of Neisseria meningitidis, Neisseria gonorrhoeae, and Haemophilus influenzae, but remained sensitive to cleavage with the metallo-IgA1 proteases of Streptococcus pneumoniae, Streptococcus oralis, Streptococcus sanguis, and Streptococcus mitis. Substitution of the IgA1 Calpha3 domain motif Pro440 -Phe443 into the corresponding position in the Cgamma3 domain of alpha1alpha2gamma3 resulted now in sensitivity to the type 2 IgA1 protease of N. meningitidis, indicating the possible requirement of these amino acids for sensitivity to this protease. For the H. influenzae type 2 protease, resistance of an IgA1 mutant in which the CH3 domain residues 399-409 were exchanged with those from IgG1, but sensitivity of mutant HuBovalpha3 in which the Calpha3 domain of bovine IgA replaces that of human IgA1, suggests that CH3 domain residues Glu403, Gln406, and Thr409 influence sensitivity to this enzyme. Hence, unlike the situation with the metallo-IgA1 proteases of Streptococcus spp., the sensitivity of human IgA1 to cleavage with the serine IgA1 proteases of Neisseria and Haemophilus involves their binding to different sites specifically in the CH3 domain.

  8. 17 CFR 240.11a1-1(T) - Transactions yielding priority, parity, and precedence.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... section 11(a)(1) of the Act or specified in 17 CFR 240.11a1-4(T) shall be deemed to be revenue derived..., 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...

  9. 17 CFR 240.11a1-1(T) - Transactions yielding priority, parity, and precedence.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... section 11(a)(1) of the Act or specified in 17 CFR 240.11a1-4(T) shall be deemed to be revenue derived..., 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...

  10. 17 CFR 240.11a1-1(T) - Transactions yielding priority, parity, and precedence.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... section 11(a)(1) of the Act or specified in 17 CFR 240.11a1-4(T) shall be deemed to be revenue derived..., 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...

  11. 17 CFR 240.11a1-1(T) - Transactions yielding priority, parity, and precedence.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... section 11(a)(1) of the Act or specified in 17 CFR 240.11a1-4(T) shall be deemed to be revenue derived..., 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...

  12. 17 CFR 240.11a1-1(T) - Transactions yielding priority, parity, and precedence.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... section 11(a)(1) of the Act or specified in 17 CFR 240.11a1-4(T) shall be deemed to be revenue derived..., 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...

  13. Differential effect of over-expressing UGT1A1 and CYP1A1 on xenobiotic assault in MCF-7 cells.

    PubMed

    Leung, Hau Y; Wang, Yun; Leung, Lai K

    2007-12-01

    Gene mutation has been considered as a major step of carcinogenesis. Some defective genes may induce spontaneous tumorigenesis, while others are required to interact with the environment to induce cancer. CYP1A1 and UGT1A1 are encoded for the respective phase I and II drug-metabolizing enzymes. Their expressions have been associated with breast cancer incidence in women, and some xenobiotics are substrates of these two enzymes. In the current study, cytochrome P450 (CYP) 1A1 and UDP-glucuronosyltransferase (UGT) 1A1 were over-expressed in the breast cancer MCF-7 cells, and potential interactions between these enzymes and estrogen or polycyclic aromatic hydrocarbon were evaluated. Compared with control cells (MCF-7(VEC)), reduced cell proliferation was seen in cells expressing UGT1A1 (MCF-7(UGT1A1)) under estradiol treatment. 7,12-Dimethylbenz[a]anthracene (DMBA) is an established breast cancer initiator in animal model. Over-expressing UGT1A1 reduced the binding of DMBA to DNA, and increased MCF-7(UGT1A1) intact cells under DMBA treatment was verified by comet assay. On the other hand, intensified DMBA binding and damages were observed in MCF-7(CYP1A1) cells. This study supported that UGT1A1 but not CYP1A1 expression could protect against xenobiotic assault. PMID:17981384

  14. Severe irinotecan-induced toxicity in a patient with UGT1A1 28 and UGT1A1 6 polymorphisms.

    PubMed

    Xu, Jian-Ming; Wang, Yan; Ge, Fei-Jiao; Lin, Li; Liu, Ze-Yuan; Sharma, Manish R

    2013-06-28

    Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bearing UGT1A1 28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1 28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UGT1A1 28 (TA 7/7), while UGT1A1 6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1 28 polymorphism (TA 6/7) as well as the UGT1A1 6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinotecan dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1 28 and UGT1A1 6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinotecan. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1 28 and UGT1A1 6 polymorphisms. PMID:23840132

  15. The Impacts of SLC22A1 rs594709 and SLC47A1 rs2289669 Polymorphisms on Metformin Therapeutic Efficacy in Chinese Type 2 Diabetes Patients.

    PubMed

    Xiao, Di; Guo, Yu; Li, Xi; Yin, Ji-Ye; Zheng, Wei; Qiu, Xin-Wen; Xiao, Ling; Liu, Rang-Ru; Wang, Sai-Ying; Gong, Wei-Jing; Zhou, Hong-Hao; Liu, Zhao-Qian

    2016-01-01

    Background. We aimed to investigate the distributive characteristics of SLC22A1 rs594709 and SLC47A1 rs2289669 polymorphisms and their influence on metformin efficacy in Chinese T2DM patients. Methods. The distributions of SLC22A1 rs594709 and SLC47A1 rs2289669 polymorphisms were determined in 267 T2DM patients and 182 healthy subjects. Subsequently, 53 newly diagnosed patients who received metformin monotherapy were recruited to evaluate metformin efficacy. Results. No significant difference was found between T2DM patients and healthy subjects in SLC22A1 rs594709 and SLC47A1 rs2289669 allele frequencies and genotype frequencies. After metformin treatment, SLC22A1 rs594709 GG genotype patients showed a higher increase in FINS (p = 0.015) and decrease in HOMA-IS (p = 0.001) and QUICKI (p = 0.002) than A allele carriers. SLC47A1 rs2289669 GG genotype patients had a higher decrease in TChol (p = 0.030) and LDL-C (p = 0.049) than A allele carriers. Among SLC22A1 rs594709 AA genotype, patients with SLC47A1 rs2289669 AA genotype showed a higher decrease in FBG (p = 0.015), PINS (p = 0.041), and HOMA-IR (p = 0.014) than G allele carriers. However, among SLC22A1 rs594709 G allele carriers, SLC47A1 rs2289669 AA genotype patients showed a higher decrease in TChol (p = 0.013) than G allele carriers. Conclusion. Our data suggest that SLC22A1 rs594709 and SLC47A1 rs2289669 polymorphisms may influence metformin efficacy together in Chinese T2DM patients. PMID:26977146

  16. Retinoic acid-metabolizing enzyme cytochrome P450 26a1 (cyp26a1) is essential for implantation: functional study of its role in early pregnancy.

    PubMed

    Han, Bing-Chen; Xia, Hong-Fei; Sun, Jing; Yang, Ying; Peng, Jing-Pian

    2010-05-01

    Vitamin A (VA) is required for normal fetal development and successful pregnancy. Excessive VA intake during pregnancy may lead to adverse maternal and fetal effects. Cytochrome P450 26A1 (cyp26a1), a retinoic acid (RA)-metabolizing enzyme, is involved in VA metabolism. It has been shown that cyp26a1 is expressed in female reproductive tract, especially in uterus. In order to investigate the role of cyp26a1 during pregnancy, we constructed a recombinant plasmid DNA vaccine encoding cyp26a1 protein and immunized mice with the plasmid. Compared to control groups, the pregnancy rate of the cyp26a1 plasmid-immunized mice were significantly decreased (P < 0.01). Further results showed that both cyp26a1 mRNA and protein were specifically induced in the uterus during implantation period and localized in the uterine luminal epithelium. Importantly, the number of implantation sites was also significantly reduced (P < 0.05) after the uterine injection of cyp26a1-specific antisense oligos or anti-cyp26a1 antibody on day 3 of pregnancy. Accordingly, the expression of RA-related cellular retinoic acid binding protein 1 and tissue transglutaminase was markedly increased (P < 0.05) in the uterine luminal epithelium after intrauterine injection treatments. These data demonstrate that uterine cyp26a1 activity is important for the maintenance of pregnancy, especially during the process of blastocyst implantation.

  17. Acquired thermotolerance independent of heat shock factor A1 (HsfA1), the master regulator of the heat stress response.

    PubMed

    Liu, Hsiang-chin; Charng, Yee-yung

    2012-05-01

    The heat stress (HS) response in eukaryotes is mainly regulated by heat shock factors (HSFs). Genetic disruption of the master HSF gene leads to dramatically reduced HS response and thermotolerance in several model organisms. However, it is not clear whether organisms devoid of the master regulator can still acclimate to heat. Previously, we showed that Arabidopsis HsfA1a, HsfA1b, and HsfA1d act as master regulators in the HS response. In this study, we examined the heat acclimation capacity of the Arabidopsis quadruple and triple T-DNA knockout mutants of HsfA1a, HsfA1b, HsfA1d, and HsfA1e. Our data showed that in the absence of the master regulators, a minimal but significant level of acquired thermotolerance could be attained in the Arabidopsis mutants after acclimation. The optimum acclimation temperature for the HsfA1 quadruple mutant was lower than that for the wild type plants, suggesting that plant cells have two HS-sensing mechanisms that can be distinguished genetically. The acquired thermotolerance of the quadruple mutant was likely due to the induction of a small number of HsfA1-independent HS response genes regulated by other transcription factors. Here, we discuss the possible candidates and propose a working model of the transcription network of the HS response by including the HsfA1-dependent and -independent pathways.

  18. The A1 Subunit of Shiga Toxin 2 Has Higher Affinity for Ribosomes and Higher Catalytic Activity than the A1 Subunit of Shiga Toxin 1.

    PubMed

    Basu, Debaleena; Li, Xiao-Ping; Kahn, Jennifer N; May, Kerrie L; Kahn, Peter C; Tumer, Nilgun E

    2016-01-01

    Shiga toxin (Stx)-producing Escherichia coli (STEC) infections can lead to life-threatening complications, including hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS), which is the most common cause of acute renal failure in children in the United States. Stx1 and Stx2 are AB5 toxins consisting of an enzymatically active A subunit associated with a pentamer of receptor binding B subunits. Epidemiological evidence suggests that Stx2-producing E. coli strains are more frequently associated with HUS than Stx1-producing strains. Several studies suggest that the B subunit plays a role in mediating toxicity. However, the role of the A subunits in the increased potency of Stx2 has not been fully investigated. Here, using purified A1 subunits, we show that Stx2A1 has a higher affinity for yeast and mammalian ribosomes than Stx1A1. Biacore analysis indicated that Stx2A1 has faster association and dissociation with ribosomes than Stx1A1. Analysis of ribosome depurination kinetics demonstrated that Stx2A1 depurinates yeast and mammalian ribosomes and an RNA stem-loop mimic of the sarcin/ricin loop (SRL) at a higher catalytic rate and is a more efficient enzyme than Stx1A1. Stx2A1 depurinated ribosomes at a higher level in vivo and was more cytotoxic than Stx1A1 in Saccharomyces cerevisiae. Stx2A1 depurinated ribosomes and inhibited translation at a significantly higher level than Stx1A1 in human cells. These results provide the first direct evidence that the higher affinity for ribosomes in combination with higher catalytic activity toward the SRL allows Stx2A1 to depurinate ribosomes, inhibit translation, and exhibit cytotoxicity at a significantly higher level than Stx1A1.

  19. Cellular RNA Binding Proteins NS1-BP and hnRNP K Regulate Influenza A Virus RNA Splicing

    PubMed Central

    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. PMID:23825951

  20. Vibrational energies for the X1A1, A1B1, and B1A1 states of SiH2/SiD2 and related transition probabilities based on global potential energy surfaces.

    PubMed

    Tokue, Ikuo; Yamasaki, Katsuyoshi; Nanbu, Shinkoh

    2005-04-01

    Transition probabilities were evaluated for the X(1)A(1)-A(1)B(1) and A(1)B(1)-B(1)A(1) systems of SiH(2) and SiD(2) to analyze the X-->A-->B photoexcitation. The Franck-Condon factors (FCFs) and Einstein's B coefficients were computed by quantum vibrational calculations using the three-dimensional potential energy surfaces (PESs) of the SiH(2)(X(1)A(1),A(1)B(1),B(1)A(1)) electronic states and the electronic transition moments for the X-A, X-B, and A-B system. The global PESs were determined by the multireference configuration interaction calculations with the Davidson correction and the interpolant moving least-squares method combined with the Shepard interpolation. The obtained FCFs for the X-A and A-B systems exhibit that the bending mode is strongly enhanced in the excitation since the equilibrium bond angle greatly varies with the three states; the barrier to linearity is evaluated to be 21,900 cm(-1) for the X state, 6400 cm(-1) for the A state, and 230-240 cm(-1) for the B state. The theoretical lifetimes for the pure bending levels of the A and B states were calculated from the fluorescence decay rates for the A-X, B-A, and B-X emissions.

  1. 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.

  2. Binding capacity of in vitro deglycosylated IgA1 to human mesangial cells.

    PubMed

    Zhang, Jun-jun; Xu, Li-xia; Zhang, Ying; Zhao, Ming-hui

    2006-04-01

    IgA nephropathy (IgAN) is the most common glomerular disease and it is characterized by deposition of IgA1 molecules in mesangium. Recent studies had demonstrated that serum and mesangial IgA1 in IgAN were deglycosylated and IgA1 could bind to human mesangial cells (HMC) through a novel receptor. The aim of the current study is to investigate and compare the binding capacities of different in vitro deglycosylated IgA1 on human mesangial cells. Serum IgA1 was purified by jacalin affinity chromatography and then was desialylated (DesIgA1) and/or degalactosylated (Des/DeGalIgA1) with neuraminidase and/or beta-galactosidase. The efficacy of deglycosylations was assessed by Peanut agglutinin (PNA) and Vicia villosa (VV) lectin. The sizes of normal IgA1 and deglycosylated IgA1 were determined by Sephacryl S-300 chromatography and binding capacities to primary HMC were evaluated by radioligand binding assays. Normal IgA1 and deglycosylated IgA1 could bind to HMC in a dose-dependent, saturable manner. The maximal binding capacities and binding sites/cell of DesIgA1 and Des/DeGalIgA were significantly higher than that of normal IgA1. However, more aggregated IgA1 was found in DesIgA1 and Des/DeGalIgA1. Scatchard analysis revealed a similar Kd of normal IgA1 and deglycosylated IgA1. The current study suggested that the binding capacities of DesIgA1 and Des/DeGalIgA1 to HMC were significantly higher than that of normal IgA1, which at least in part was due to more macromolecular IgA1 in deglycoslated IgA1. However, there were no significant differences in the affinities of normal IgA1, DesIgA1 and Des/DeGalIgA1 with HMC. Deglycosylated IgA1 might play an important role in pathogenesis of IgAN.

  3. Development of Selective Inhibitors for Human Aldehyde Dehydrogenase 3A1 (ALDH3A1) for the Enhancement of Cyclophosphamide Cytotoxicity

    PubMed Central

    Parajuli, Bibek; Georgiadis, Taxiarchis M.; Fishel, Melissa L.; Hurley, Thomas D.

    2014-01-01

    Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemo-resistance by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues such as mafosfamide (MF), ifosfamide (IFM), 4-hydroperoxycyclophosphamide (4-HPCP). Compounds that can selectively target ALDH3A1 may permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1 selective inhibitor, CB29, previously identified in a high throughput screen. Kinetic and crystallographic studies demonstrate that CB29 binds within the aldehyde substrate-binding site of ALDH3A1. Cellular proliferation of ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cell lines, as well as the ALDH3A1 non-expressing lung fibroblast cells, CCD-13Lu, is unaffected by treatment with CB29 and its analogues alone. However, the sensitivity toward the anti-proliferative effects of mafosfamide is enhanced by treatment with CB29 and its analogue in the tumour cells. In contrast, the sensitivity of CCD-13Lu cells toward mafosfamide was unaffected by the addition of these same compounds. CB29 is chemically distinct from the previously reported small molecule inhibitors of ALDH isoenzymes and does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1 or ALDH2 isoenzymes at concentrations up to 250 μM. Thus, CB29 is a novel small molecule inhibitor of ALDH3A1, which may be useful as a chemical tool to delineate the role of ALDH3A1 in numerous metabolic pathways, including sensitizing ALDH3A1-positive cancer cells to oxazaphosphorines. PMID:24677340

  4. Mutation survey and genotype-phenotype analysis of COL2A1 and COL11A1 genes in 16 Chinese patients with Stickler syndrome

    PubMed Central

    Wang, Xun; Jia, Xiaoyun; Xiao, Xueshan; Li, Shiqiang; Li, Jie; Li, Yadi; Wei, Yantao; Liang, Xiaoling

    2016-01-01

    Purpose To identify mutations in COL2A1 and COL11A1 genes and to examine the genotype-phenotype correlation in a cohort of Chinese patients with Stickler syndrome. Methods A total of 16 Chinese probands with Stickler syndrome were recruited, including nine with a family history of an autosomal dominant pattern and seven sporadic cases. All patients underwent full ocular and systemic examinations. Sanger sequencing was used to analyze all coding and adjacent regions of the COL2A1 and COL11A1 genes. Multiplex ligation-dependent probe amplification was performed to detect the gross indels of COL2A1 and COL11A1. Bioinformatics analysis was performed to evaluate the pathogenicity of the variants. Results Five mutations in COL2A1 were identified in six of 16 probands, including three novel (c.85C>T, c.3356delG, c.3401delG) mutations and two known mutations (c.1693C>T, c.2710C>T). Of the five mutations, three were truncated mutations, and the other two were missense mutations. Putative pathogenic mutations of the COL11A1 gene were absent in this cohort of patients. Gross indels were not found in COL2A1 or COL11A1 in any of the probands. High myopia was the most frequent initial ocular phenotype of Stickler syndrome. In this study, 12 Chinese probands lacked obvious systemic phenotypes. Conclusions In this study, three novel and two known mutations in the COL2A1 gene were identified in six of 16 Chinese patients with Stickler syndrome. This is the first study in a cohort of Chinese patients with Stickler syndrome, and the results expand the mutation spectrum of the COL2A1 gene. Analysis of the genotype-phenotype correlation showed that the early onset of high myopia with vitreous abnormalities may serve as a key indicator of Stickler syndrome, while the existence of mandibular protrusion in pediatric patients may be an efficient indicator for the absence of mutations in COL2A1 and COL11A1. PMID:27390512

  5. Knowledge of A1c Predicts Diabetes Self-Management and A1c Level among Chinese Patients with Type 2 Diabetes.

    PubMed

    Yang, Shengnan; Kong, Weimin; Hsue, Cunyi; Fish, Anne F; Chen, Yufeng; Guo, Xiaohui; Lou, Qingqing; Anderson, Robert

    2016-01-01

    This study was to identify current A1c understanding status among Chinese patients with type 2 diabetes, assess if knowledge of A1c affects their diabetes self-management and their glycemic control and recognize the factors influencing knowledge of A1c among patients with type 2 diabetes. A multi-center, cross-sectional survey was conducted between April and July 2010 in 50 medical centers in the Mainland China. Participants were recruited from inpatients and outpatients who were admitted to or visited those medical centers. The survey included core questions about their demographic characteristics, diabetes self-management behavior, and A1c knowledge. Overall, of 5957 patients, the percentage of patients with good understanding was 25.3%. In the multivariable logistic regression model, the variables related to the knowledge of A1c status are presented. We discovered that patients with longer diabetes duration (OR = 1.05; 95%CI = 1.04-1.06) and having received diabetes education (OR = 1.80; 95%CI = 1.49-2.17) were overrepresented in the good understanding of A1c group. In addition, compared to no education level, higher education level was statistically associated with good understanding of A1c (P<0.001). The percentage of patients with good understanding varied from region to region (P<0.001), with Eastern being highest (OR = 1.54; 95%CI = 1.32-1.80), followed by Central (OR = 1.25; 95%CI = 1.02-1.53), when referring to Western. Only a minority of patients with type 2 diabetes in China understood their A1c value. The patients who had a good understanding of their A1c demonstrated significantly better diabetes self-management behavior and had lower A1c levels than those who did not.

  6. Sheep lung cytochrome P4501A1 (CYP1A1): cDNA cloning and transcriptional regulation by oxygen tension.

    PubMed

    Hazinski, T A; Noisin, E; Hamon, I; DeMatteo, A

    1995-10-01

    Lung cytochrome P450 activity has been linked to neoplasia and may produce reactive oxidant species and potent arachidonic acid metabolites. In lamb lung, oxygen breathing increases lung P450 activity, and inhibition of lung cytochrome P450 activity reduces oxygen-induced lung injury. The P4501A1 (CYP1A1) isozyme is present in many lung cells, including endothelial cells, and may therefore be involved in the pathogenesis of hyperoxic injury to microvascular endothelium. Therefore, to test the hypothesis that oxygen regulates P4501A1 gene expression in the lung, we cloned the sheep P4501A1 cDNA, and examined its regulation by oxygen breathing significantly increased lung P4501A1 RNA levels and that this increase preceded the increase in isozyme activity. Oxygen exposure also promptly increased P4501A1 RNA levels in cultured lamb lung microvascular endothelial cells but not in endothelial cells isolated from the main pulmonary artery or in lung smooth muscle cells. The oxygen-stimulated increase in P4501A1 RNA levels was not serum dependent, was unaffected by cycloheximide treatment, and could not be mimicked by treatment of the cells with oxygenated medium, conditioned medium, or by chemical oxidants. By nuclear run-on assay in cultured lung endothelial cells, oxygen increased the transcription rate of P4501A1 by almost fourfold after 90 min of oxygen exposure but had no significant effect on P4501A1 RNA stability. We conclude that oxygen tension, but not chemical oxidants, increases P4501A1 gene expression pretranslationally in lung microvascular endothelial cells. We speculate that oxygen induction of P450 activity in these cells may contribute to microvascular injury during oxygen breathing. PMID:7560103

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

    PubMed Central

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

    2016-01-01

    Glycated haemoglobin (HbA1c) 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 HbA1c 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 HbA1c. 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 HbA1c 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 HbA1c.
Capillary electrophoresis is a good method for detecting HbJ but does not seem suitable for evaluation of HbA1C value in patients in presence of HbJ variant. PMID:27346969

  8. 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.

  9. Sensor sensationalism? Alternative views on the nature and role of 'cytochrome a1' in bacteria.

    PubMed

    Poole, R K; Baines, B S; Williams, H D

    1985-01-01

    Replying to a recent proposal that 'cytochrome a1' functions as an oxygen sensor, we argue that this speculation is flawed by the failure to appreciate that cytochrome a1-like haemoproteins are a diverse group of haemoproteins. PMID:3939981

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., particularly sections 11(a) and 23(a) thereof, and Rule 11a-1 (17 CFR 240.11a-1) under the Act, deeming it... 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...

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

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., particularly sections 11(a) and 23(a) thereof, and Rule 11a-1 (17 CFR 240.11a-1) under the Act, deeming it... 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...

  12. 26 CFR 301.6231(a)(1)-1 - Exception for small partnerships.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....6231(a)(1)-1T contained in 26 CFR part 1, revised April 1, 2001. ... 26 Internal Revenue 18 2011-04-01 2011-04-01 false Exception for small partnerships. 301.6231(a)(1)-1 Section 301.6231(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE...

  13. 26 CFR 301.6231(a)(1)-1 - Exception for small partnerships.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ....6231(a)(1)-1T contained in 26 CFR part 1, revised April 1, 2001. ... 26 Internal Revenue 18 2014-04-01 2014-04-01 false Exception for small partnerships. 301.6231(a)(1)-1 Section 301.6231(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE...

  14. 26 CFR 31.3121(a)(1)-1 - Annual wage limitation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Annual wage limitation. 31.3121(a)(1)-1 Section 31.3121(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... § 31.3121(a)(1)-1 Annual wage limitation. (a) In general. (1) The term “wages” does not include...

  15. 26 CFR 301.6231(a)(1)-1 - Exception for small partnerships.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....6231(a)(1)-1T contained in 26 CFR part 1, revised April 1, 2001. ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Exception for small partnerships. 301.6231(a)(1)-1 Section 301.6231(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE...

  16. 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,...

  17. 26 CFR 301.6031(a)-1 - Return of partnership income.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Return of partnership income. 301.6031(a)-1....6031(a)-1 Return of partnership income. For provisions relating to the requirement of returns of partnership income, see § 1.6031(a)-1 of this chapter....

  18. 26 CFR 1.1314(a)-1 - Ascertainment of amount of adjustment in year of error.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... of error. 1.1314(a)-1 Section 1.1314(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... Years and Special Limitations § 1.1314(a)-1 Ascertainment of amount of adjustment in year of error. (a... ascertained the amount of the tax previously determined for the taxpayer as to whom the error was made for...

  19. 26 CFR 1.1314(a)-1 - Ascertainment of amount of adjustment in year of error.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... of error. 1.1314(a)-1 Section 1.1314(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... Years and Special Limitations § 1.1314(a)-1 Ascertainment of amount of adjustment in year of error. (a... ascertained the amount of the tax previously determined for the taxpayer as to whom the error was made for...

  20. 26 CFR 1.1314(a)-1 - Ascertainment of amount of adjustment in year of error.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... of error. 1.1314(a)-1 Section 1.1314(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... Years and Special Limitations § 1.1314(a)-1 Ascertainment of amount of adjustment in year of error. (a... ascertained the amount of the tax previously determined for the taxpayer as to whom the error was made for...

  1. 42 CFR 63a.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? 63a.1 Section 63a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.1 To what programs do...

  2. 42 CFR 63a.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? 63a.1 Section 63a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.1 To what programs do...

  3. 42 CFR 63a.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? 63a.1 Section 63a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.1 To what programs do...

  4. 26 CFR 1.1314(a)-1 - Ascertainment of amount of adjustment in year of error.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... of error. 1.1314(a)-1 Section 1.1314(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF... Years and Special Limitations § 1.1314(a)-1 Ascertainment of amount of adjustment in year of error. (a... ascertained the amount of the tax previously determined for the taxpayer as to whom the error was made for...

  5. 26 CFR 1.6031(a)-1 - Return of partnership income.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Return of partnership income. 1.6031(a)-1 Section 1.6031(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6031(a)-1 Return of partnership income. (a) Domestic partnerships—(1)...

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

    MedlinePlus

    ... COL4A1-related brain small-vessel disease COL4A1-related brain small-vessel disease Enable Javascript to view the ... PDF Open All Close All Description COL4A1 -related brain small-vessel disease is part of a group ...

  7. 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...

  8. 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...

  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...

  10. 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...

  11. 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 §§...

  12. 47 CFR 80.1087 - Ship radio equipment-Sea area A1.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea area A1. 80.1087... Requirements for Ship Stations § 80.1087 Ship radio equipment—Sea area A1. This section contains the additional equipment requirements for ships that remain within sea area A1 at all times. (a) In addition to meeting...

  13. 47 CFR 80.1087 - Ship radio equipment-Sea area A1.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Ship radio equipment-Sea area A1. 80.1087... Requirements for Ship Stations § 80.1087 Ship radio equipment—Sea area A1. This section contains the additional equipment requirements for ships that remain within sea area A1 at all times. (a) In addition to meeting...

  14. 47 CFR 80.1087 - Ship radio equipment-Sea area A1.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Ship radio equipment-Sea area A1. 80.1087... Requirements for Ship Stations § 80.1087 Ship radio equipment—Sea area A1. This section contains the additional equipment requirements for ships that remain within sea area A1 at all times. (a) In addition to meeting...

  15. 47 CFR 80.1087 - Ship radio equipment-Sea area A1.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea area A1. 80.1087... Requirements for Ship Stations § 80.1087 Ship radio equipment—Sea area A1. This section contains the additional equipment requirements for ships that remain within sea area A1 at all times. (a) In addition to meeting...

  16. 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...

  17. 26 CFR 1.926(a)-1T - Temporary regulations; distributions to shareholders.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... shareholders. 1.926(a)-1T Section 1.926(a)-1T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE...(a)-1T Temporary regulations; distributions to shareholders. (a) Treatment of distributions. Any distribution by a FSC (or former FSC) to its shareholder with respect to its stock will be includible in...

  18. Decays B(s)→a1(b1)D(s), a1(b1)D(s)* in the perturbative QCD approach

    NASA Astrophysics Data System (ADS)

    Zhang, Zhi-Qing

    2013-04-01

    Within the framework of the perturbative QCD approach, we study the branching ratios of the two-body charmed decays B(s)→a1(b1)D(s), a1(b1)D(s)*, which, including Cabibbo-Kobayashi-Maskawa, allowed and suppressed decays. Our calculations are consistent with the currently available data and the experimental upper limits. Certainly, many of these predicted channels have not been measured by experiments and can be confronted with the future experimental data. We also discuss the polarization factions of the decays B(s)→a1(b1)D(s)*, some of which are sensitive to the distinct Gegenbauer moments of the wave functions and the decay constants of mesons a1 and b1.

  19. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1).

    PubMed

    Yang, Shyh-Ming; Yasgar, Adam; Miller, Bettina; Lal-Nag, Madhu; Brimacombe, Kyle; Hu, Xin; Sun, Hongmao; Wang, Amy; Xu, Xin; Nguyen, Kimloan; Oppermann, Udo; Ferrer, Marc; Vasiliou, Vasilis; Simeonov, Anton; Jadhav, Ajit; Maloney, David J

    2015-08-13

    Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17β4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted. PMID:26207746

  20. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1).

    PubMed

    Yang, Shyh-Ming; Yasgar, Adam; Miller, Bettina; Lal-Nag, Madhu; Brimacombe, Kyle; Hu, Xin; Sun, Hongmao; Wang, Amy; Xu, Xin; Nguyen, Kimloan; Oppermann, Udo; Ferrer, Marc; Vasiliou, Vasilis; Simeonov, Anton; Jadhav, Ajit; Maloney, David J

    2015-08-13

    Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and possess important physiological and toxicological functions in areas such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g., ALDH1A1) gene expression and catalytic activity are vital biomarkers in a number of malignancies and cancer stem cells, highlighting the need for the identification and development of small molecule ALDH inhibitors. A new series of theophylline-based analogs as potent ALDH1A1 inhibitors is described. The optimization of hits identified from a quantitative high throughput screening (qHTS) campaign led to analogs with improved potency and early ADME properties. This chemotype exhibits highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1, and ALDH2 isozymes as well as other dehydrogenases such as HPGD and HSD17β4. Moreover, the pharmacokinetic evaluation of selected analog 64 (NCT-501) is also highlighted.

  1. 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.

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

    PubMed Central

    Kubota, Akira; O'Meara, Conor M.; Lamb, David C.; Tanguay, Robert L.; Goldstone, Jared V.

    2016-01-01

    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 in the I-helix and the heme-binding CYP signature motifs. CYP20A1 mRNA expression was observed in adult zebrafish organs including liver, heart, gonads, spleen and brain, as well as 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. PMID:26853319

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

    PubMed

    Lemaire, Benjamin; Kubota, Akira; O'Meara, Conor M; Lamb, David C; Tanguay, Robert L; Goldstone, Jared V; Stegeman, John J

    2016-04-01

    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 in 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. PMID:26853319

  4. Identification and characterization of CMP-NeuAc:GalNAc-IgA1 alpha2,6-sialyltransferase in IgA1-producing cells.

    PubMed

    Raska, Milan; Moldoveanu, Zina; Suzuki, Hitoshi; Brown, Rhubell; Kulhavy, Rose; Andrasi, Judit; Hall, Stacy; Vu, Huong L; Carlsson, Fredric; Lindahl, Gunnar; Tomana, Milan; Julian, Bruce A; Wyatt, Robert J; Mestecky, Jiri; Novak, Jan

    2007-05-25

    Glycosylation defects occur in several human diseases. In IgA nephropathy, IgA1 contains O-glycans that are galactose-deficient and consist mostly of core 1 alpha2,6 sialylated N-acetylgalactosamine, a configuration suspected to prevent beta1,3 galactosylation. We confirmed the same aberrancy in IgA1 secreted by the human DAKIKI B cell line. Biochemical assays indicated CMP-NeuAc:GalNAc-IgA1 alpha2,6-sialyltransferase activity in this cell line. However, a candidate enzyme, ST6-GalNAcI, was not transcribed in DAKIKI cells, B cells isolated from blood, or Epstein-Barr virus (EBV)-immortalized IgA1-producing cells from the blood of IgAN patients and healthy controls. Instead, ST6-GalNAcII transcription was detected at a high level. Expression of the ST6-GalNAcII gene and activity of the CMP-NeuAc:GalNAc-IgA1 alpha2,6-sialyltransferase were higher in IgA1-producing cell lines from IgAN patients than in such cells from healthy controls. These data are the first evidence that human cells that lack ST6-GalNAcI can sialylate core 1 GalNAc-Ser/Thr.

  5. Identification and characterization of CMP-NeuAc:GalNAc-IgA1 α2,6-sialyltransferase in IgA1-producing cells

    PubMed Central

    Raska, Milan; Moldoveanu, Zina; Suzuki, Hitoshi; Brown, Rhubell; Kulhavy, Rose; Andrasi, Judit; Hall, Stacy; Vu, Huong L.; Carlsson, Frederic; Lindahl, Gunnar; Tomana, Milan; Julian, Bruce A.; Wyatt, Robert J.; Mestecky, Jiri; Novak, Jan

    2007-01-01

    Summary Glycosylation defects occur in several human diseases. In IgA nephropathy, IgA1 contains O-glycans that are galactose-deficient and consist mostly of core 1 α2,6 sialylated N-acetylgalactosamine, a configuration suspected to prevent β1,3 galactosylation. We confirmed the same aberrancy in IgA1 secreted by the human DAKIKI B cell line. Biochemical assays indicated CMP-NeuAc:GalNAc-IgA1 α2,6-sialyltransferase activity in this cell line. However, a candidate enzyme, ST6-GalNAcI, was not transcribed in DAKIKI cells, B cells isolated from blood, or Epstein-Barr virus (EBV)-immortalized IgA1-producing cells from the blood of IgAN patients and healthy controls. Instead, ST6-GalNAcII transcription was detected at a high level. Expression of the ST6-GalNAcII gene and activity of the CMP-NeuAc:GalNAc-IgA1 α2,6-sialyltransferase were higher in IgA1-producing cell lines from IgAN patients than in such cells from healthy controls. These data are the first evidence that human cells that lack ST6-GalNAcI can sialylate core 1 GalNAc-Ser/Thr. PMID:17418236

  6. hnRNP G: sequence and characterization of a glycosylated RNA-binding protein.

    PubMed Central

    Soulard, M; Della Valle, V; Siomi, M C; Piñol-Roma, S; Codogno, P; Bauvy, C; Bellini, M; Lacroix, J C; Monod, G; Dreyfuss, G

    1993-01-01

    The autoantigen p43 is a nuclear protein initially identified with autoantibodies from dogs with a lupus-like syndrome. Here we show that p43 is an RNA-binding protein, and identify it as hnRNP G, a previously described component of heterogeneous nuclear ribonucleoprotein complexes. We demonstrate that p43/hnRNP G is glycosylated, and identify the modification as O-linked N-acetylglucosamine. A full-length cDNA clone for hnRNP G has been isolated and sequenced, and the predicted amino acid sequence for hnRNP G shows that it contains one RNP-consensus RNA binding domain (RBD) at the amino terminus and a carboxyl domain rich in serines, arginines and glycines. The RBD of human hnRNP G shows striking similarities with the RBDs of several plant RNA-binding proteins. Images PMID:7692398

  7. 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

  8. IgA nephropathy and aberrant glycosylation of tonsillar, serum and glomerular IgA1.

    PubMed

    Hiki, Yoshiyuki; Ito, Akihiko; Yamamoto, Yoshihiro; Yamamoto, Koichiro; Iwase, Hitoo

    2011-01-01

    Human IgA1, which is the predominant subtype deposited in the glomeruli in IgA nephropathy (IgAN), has a unique mucin-like structure in its hinge region. Several studies suggested that the IgA1 molecules in IgAN patients had an aberrant structure of O-glycans. The paper summarizes the analyses of O-glycan structure in the IgA1 molecules taken from tonsils, sera and glomeruli of patients with IgAN. Hypoglycosylation, especially hypogalactosylation of O-glycans has been observed not only in serum and glomerular IgA1 but also in tonsillar IgA1.

  9. Immunoglobulin A1 protease production by Haemophilus influenzae and Streptococcus pneumoniae.

    PubMed Central

    Male, C J

    1979-01-01

    Bacterial strains of Haemophilus species and Streptococcus pneumoniae were examined for synthesis of the enzyme immunoglobulin A1 (IgA1) protease. Of 36 H. influenzae strains examined, 35 produced IgA1 protease; strains included all six capsular types, unencapsulated variants of types b and d, and untypable H. influenzae. Eight Haemophilus strains (non-H. influenzae) were studied, and two produced IgA1 protease. All 10 strains of S. pneumoniae produced IgA1 protease; these strains included 9 different capsular polysaccharide types and 1 untypable strain. Both IgA1 proteases cleaved myeloma IgA1 and secretory IgA but not myeloma IgA2, IgM, or IgG as determined by immunoelectrophoresis. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that both enzymes cleaved IgA1 myeloma sera, but not IgA2, into two fragments. The apparent molecular weight of the cleaved fragments was dependent both on the apparent molecular weight of the cleaved fragments was dependent both on the specific IgA1 protease assayed and the specific IgA1 substrate utilized. It is postulated that both carbohydrate variation between the IgA1 substrates studied and the ability of S. pneumoniae glycosidases to cleave carbohydrates from glycoprotein offer an explanation for the different fragment sizes observed. Images PMID:40880

  10. A1 demonstrates restricted tissue distribution during embryonic development and functions to protect against cell death.

    PubMed Central

    Carrió, R.; López-Hoyos, M.; Jimeno, J.; Benedict, M. A.; Merino, R.; Benito, A.; Fernández-Luna, J. L.; Núñez, G.; García-Porrero, J. A.; Merino, J.

    1996-01-01

    Members of the bcl-2 gene family are essential regulators of cell survival in a wide range of biological processes. A1, a member of the family, is known to be expressed in certain adult tissues. However, the precise tissue distribution and function of A1 remains poorly understood. We show here that A1 is expressed in multiple tissues during murine embryonic development. In the embryo, A1 was detected first at embryonic day 11.5 in liver, brain, and limbs. At day 13.5 of gestation, A1 expression was observed in the central nervous system, liver, perichondrium, and digital zones of developing limbs in a pattern different from that of bcl-X. In the central nervous system of 15.5-day embryos, A1 was expressed at high levels in the ventricular zone and cortical plate of brain cortex. Significantly, the interdigital zones of limbs and the intermediate region of the developing brain cortex, two sites associated with extensive cell death, were devoid of A1 and bcl-X. The expression of A1 was retained in many adult tissues. To assess the ability of A1 to modulate cell death, stable transfectants expressing different amounts of A1 protein were generated in K562 cells. Expression of A1 was associated with retardation of apoptotic cell death induced by actinomycin D and cycloheximide as well as by okadaic acid. Confocal microscopy showed that the A1 protein was localized to the cytoplasm in a pattern similar to that of Bcl-2. These results demonstrate that the expression of A1 is wider than previously reported in adult tissues. Furthermore, its distribution in multiple tissues of the embryo suggests that A1 plays a role in the regulation of physiological cell death during embryonic development. Images Figure 1 Figure 2 Figure 3 Figure 5 PMID:8952545

  11. Identification of Interacting Motifs Between Armadillo Repeat Containing 1 (ARC1) and Exocyst 70 A1 (Exo70A1) Proteins in Brassica oleracea.

    PubMed

    Liu, Jing; Zhang, Hecui; Lian, Xiaoping; Converse, Richard; Zhu, Liquan

    2016-02-01

    In order to identify the functional domains which regulate the interaction between the self-incompatibility proteins armadillo repeat containing 1 (ARC1) and exocyst 70 A1 (Exo70A1) in Brassica oleracea, fragments containing selected motifs of ARC1 (ARC1210, ARC1246, ARC1279, ARC1354) and site-specific mutants with substitutions at possible interaction sites (ARC1354m, ARC1664m) were PCR amplified and inserted into pGADT7, while coding sequences from Exo70A1 (Exo70A185, Exo70A1) were subcloned into pGBKT7. The interactions between the protein products produced by these constructs were then analyzed utilizing a yeast two-hybrid system. Our data indicate that both ARC1210 and ARC1246 interact strongly with Exo70A185 and Exo70A1, while ARC1279, ARC1354, ARC1354m and ARC1664m exhibited a weak interaction, indicating that the recognition sites are located within the 210 N-terminal amino acids of ARC1 and the 85 N-terminal amino acids of Exo70A1. This was further verified by GST pull-down analysis. This supports a model in which the N-terminal leucine zipper of ARC1 and the first 85 N-terminal amino acids of Exo70A1 mediate the interaction between these two proteins. Bioinformatic and phylogenetic analysis demonstrated that these motifs were highly conserved across different species, indicating that the interaction characterized in B. oleracea may operate in a wide array of cultivars. PMID:26696546

  12. Identification of Interacting Motifs Between Armadillo Repeat Containing 1 (ARC1) and Exocyst 70 A1 (Exo70A1) Proteins in Brassica oleracea.

    PubMed

    Liu, Jing; Zhang, Hecui; Lian, Xiaoping; Converse, Richard; Zhu, Liquan

    2016-02-01

    In order to identify the functional domains which regulate the interaction between the self-incompatibility proteins armadillo repeat containing 1 (ARC1) and exocyst 70 A1 (Exo70A1) in Brassica oleracea, fragments containing selected motifs of ARC1 (ARC1210, ARC1246, ARC1279, ARC1354) and site-specific mutants with substitutions at possible interaction sites (ARC1354m, ARC1664m) were PCR amplified and inserted into pGADT7, while coding sequences from Exo70A1 (Exo70A185, Exo70A1) were subcloned into pGBKT7. The interactions between the protein products produced by these constructs were then analyzed utilizing a yeast two-hybrid system. Our data indicate that both ARC1210 and ARC1246 interact strongly with Exo70A185 and Exo70A1, while ARC1279, ARC1354, ARC1354m and ARC1664m exhibited a weak interaction, indicating that the recognition sites are located within the 210 N-terminal amino acids of ARC1 and the 85 N-terminal amino acids of Exo70A1. This was further verified by GST pull-down analysis. This supports a model in which the N-terminal leucine zipper of ARC1 and the first 85 N-terminal amino acids of Exo70A1 mediate the interaction between these two proteins. Bioinformatic and phylogenetic analysis demonstrated that these motifs were highly conserved across different species, indicating that the interaction characterized in B. oleracea may operate in a wide array of cultivars.

  13. 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; Jones, I M; Bell, D A

    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 genotype 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 genetic

  14. Annexin A1 Deficiency does not Affect Myofiber Repair but Delays Regeneration of Injured Muscles

    PubMed Central

    Leikina, Evgenia; Defour, Aurelia; Melikov, Kamran; Van der Meulen, Jack H.; Nagaraju, Kanneboyina; Bhuvanendran, Shivaprasad; Gebert, Claudia; Pfeifer, Karl; Chernomordik, Leonid V.; Jaiswal, Jyoti K.

    2015-01-01

    Repair and regeneration of the injured skeletal myofiber involves fusion of intracellular vesicles with sarcolemma and fusion of the muscle progenitor cells respectively. In vitro experiments have identified involvement of Annexin A1 (Anx A1) in both these fusion processes. To determine if Anx A1 contributes to these processes during muscle repair in vivo, we have assessed muscle growth and repair in Anx A1-deficient mouse (AnxA1−/−). We found that the lack of Anx A1 does not affect the muscle size and repair of myofibers following focal sarcolemmal injury and lengthening contraction injury. However, the lack of Anx A1 delayed muscle regeneration after notexin-induced injury. This delay in muscle regeneration was not caused by a slowdown in proliferation and differentiation of satellite cells. Instead, lack of Anx A1 lowered the proportion of differentiating myoblasts that managed to fuse with the injured myofibers by days 5 and 7 after notexin injury as compared to the wild type (w.t.) mice. Despite this early slowdown in fusion of Anx A1−/− myoblasts, regeneration caught up at later times post injury. These results establish in vivo role of Anx A1 in cell fusion required for myofiber regeneration and not in intracellular vesicle fusion needed for repair of myofiber sarcolemma. PMID:26667898

  15. Versatile substrates and probes for IgA1 protease activity.

    PubMed

    Choudary, Santosh K; Qiu, Jiazhou; Plaut, Andrew G; Kritzer, Joshua A

    2013-10-11

    Bacterial meningitis is a severe infectious disease with high mortality. Gram-positive and Gram-negative bacteria that cause meningitis secrete immunoglobulin A1 (IgA1) proteases to assist in mucosal colonization, invasion, and immune evasion. IgA1 proteases have unique selectivity, with few reported substrates other than IgA1 from human tissue. Here we describe the design, characterization, and application of peptide substrates for diverse IgA1 proteases from Neisseria, Haemophilus, and Streptococcus bacteria. IgA1 proteases from diverse strains showed unexpected selectivity profiles among peptide substrates derived from autoproteolytic sites. A fluorescence probe derived from one of these peptides was used to quantitate IgA1 protease activity in buffer and in human cerebrospinal fluid; it was able to detect recombinant Haemophilus influenzae type 1 IgA1 protease at less than 1 μg mL(-1) . We also used the probe to establish the first high-throughput screen for IgA1 protease inhibitors. This work provides tools that will help investigate the roles of IgA1 proteases in bacterial colonization, immune evasion, and infection.

  16. Circuit mechanisms of GluA1-dependent spatial working memory.

    PubMed

    Freudenberg, Florian; Marx, Verena; Seeburg, Peter H; Sprengel, Rolf; Celikel, Tansu

    2013-12-01

    Spatial working memory (SWM), the ability to process and manipulate spatial information over a relatively short period of time, requires an intact hippocampus, but also involves other forebrain nuclei in both in rodents and humans. Previous studies in mice showed that the molecular mechanism of SWM includes activation of AMPA receptors containing the GluA1 subunit (encoded by gria1) as GluA1 deletion in the whole brain (gria1(-/-)) results in strong SWM deficit. However, since these mice globally lack GluA1, the circuit mechanisms of GluA1 contribution to SWM remain unknown. In this study, by targeted expression of GluA1 containing AMPA receptors in the forebrain of gria1(-/-) mice or by removing GluA1 selectively from hippocampus of mice with "floxed" GluA1 alleles (gria1(fl/fl) ), we show that SWM requires GluA1 action in cortical circuits but is only partially dependent on GluA1-containing AMPA receptors in hippocampus. We further show that hippocampal GluA1 contribution to SWM is temporally restricted and becomes prominent at longer retention intervals (≥ 30 s). These findings provide a novel insight into the neural circuits required for SWM processing and argue that AMPA mediated signaling across forebrain and hippocampus differentially contribute to encoding of SWM.

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

    PubMed

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

    2016-10-01

    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.

  18. Annexin A1 Deficiency does not Affect Myofiber Repair but Delays Regeneration of Injured Muscles.

    PubMed

    Leikina, Evgenia; Defour, Aurelia; Melikov, Kamran; Van der Meulen, Jack H; Nagaraju, Kanneboyina; Bhuvanendran, Shivaprasad; Gebert, Claudia; Pfeifer, Karl; Chernomordik, Leonid V; Jaiswal, Jyoti K

    2015-01-01

    Repair and regeneration of the injured skeletal myofiber involves fusion of intracellular vesicles with sarcolemma and fusion of the muscle progenitor cells respectively. In vitro experiments have identified involvement of Annexin A1 (Anx A1) in both these fusion processes. To determine if Anx A1 contributes to these processes during muscle repair in vivo, we have assessed muscle growth and repair in Anx A1-deficient mouse (AnxA1-/-). We found that the lack of Anx A1 does not affect the muscle size and repair of myofibers following focal sarcolemmal injury and lengthening contraction injury. However, the lack of Anx A1 delayed muscle regeneration after notexin-induced injury. This delay in muscle regeneration was not caused by a slowdown in proliferation and differentiation of satellite cells. Instead, lack of Anx A1 lowered the proportion of differentiating myoblasts that managed to fuse with the injured myofibers by days 5 and 7 after notexin injury as compared to the wild type (w.t.) mice. Despite this early slowdown in fusion of Anx A1-/- myoblasts, regeneration caught up at later times post injury. These results establish in vivo role of Anx A1 in cell fusion required for myofiber regeneration and not in intracellular vesicle fusion needed for repair of myofiber sarcolemma. PMID:26667898

  19. 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

  20. Transcriptome-wide RNA interaction profiling reveals physical and functional targets of hnRNP L in human T cells.

    PubMed

    Shankarling, Ganesh; Cole, Brian S; Mallory, Michael J; Lynch, Kristen W

    2014-01-01

    The RNA processing factor hnRNP L is required for T cell development and function. However, the spectrum of direct targets of hnRNP L activity in T cells has yet to be defined. In this study, we used cross-linking and immunoprecipitation followed by high-throughput sequencing (CLIP-seq) to identify the RNA binding sites of hnRNP L within the transcriptomes of human CD4(+) and cultured Jurkat T cells. We find that hnRNP L binds preferentially to transcripts encoding proteins involved in RNA processing and in Wnt and T cell receptor (TCR) signaling. This binding is largely conserved across both quiescent and activated T cells, in agreement with the critical role of hnRNP L throughout T cell biology. Importantly, based on the binding profile of hnRNP L, we validate numerous instances of hnRNP L-dependent alternative splicing of genes critical to T cell function. We further show that alternative exons with weak 5' splice site sequences specifically show a strong correlation between hnRNP L binding and hnRNP L-dependent splicing regulation. Together, these data provide the first transcriptome-wide analysis of the RNA targets of hnRNP L in lymphoid cells and add to the functional understanding of hnRNP L in human biology.

  1. Glycated Hemoglobin (HbA1c): Clinical Applications of a Mathematical Concept

    PubMed Central

    Leow, Melvin Khee Shing

    2016-01-01

    Background and purpose: Glycated hemoglobin (HbA1c) reflects the cumulative glucose exposure of erythrocytes over a preceding time frame proportional to erythrocyte survival. HbA1c is thus an areal function of the glucose-time curve, an educationally useful concept to aid teaching and clinical judgment. Methods: An ordinary differential equation is formulated as a parsimonious model of HbA1c. The integrated form yields HbA1c as an area-under-the-curve (AUC) of a glucose-time profile. The rate constant of the HbA1c model is then derived using the validated regression equation in the ADAG study that links mean blood glucose and HbA1c with a very high degree of goodness-of-fit. Results: This model has didactic utility to enable patients, biomedical students and clinicians to appreciate how HbA1c may be conceptually inferred from discrete blood glucose values using continuous glucose monitoring system (CGMS) or self-monitored blood glucose (SMBG) glucometer readings as shown in the examples. It can be appreciated how hypoglycemia can occur with rapid HbA1c decline despite poor glycemic control. Conclusions: Being independent of laboratory assay pitfalls, computed ‘virtual’ HbA1c serves as an invaluable internal consistency cross-check against laboratory-measured HbA1c discordant with SMBG readings suggestive of inaccurate/fraudulent glucometer records or hematologic disorders including thalassemia and hemoglobinopathy. This model could be implemented within portable glucometers, CGMS devices and even smartphone apps for deriving tentative ‘virtual’ HbA1c from serial glucose readings as an adjunct to measured HbA1c. Such predicted ‘virtual’ HbA1c readily accessible via glucometers may serve as feedback to modify behavior and empower diabetic patients to achieve better glycemic control. PMID:27708483

  2. 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.

  3. Carbon monoxide-releasing molecule-A1 (CORM-A1) improves clinical signs of experimental autoimmune uveoretinitis (EAU) in rats.

    PubMed

    Fagone, Paolo; Mangano, Katia; Mammana, Santa; Cavalli, Eugenio; Di Marco, Roberto; Barcellona, Maria Luisa; Salvatorelli, Lucia; Magro, Gaetano; Nicoletti, Ferdinando

    2015-04-01

    Uveitis is a sight-threatening inflammatory disease of the eye which represents the third leading cause of blindness in the developed countries. The conventional pharmacological treatment includes corticosteroids and immunosuppressive agents, which are limited by their side effects. New therapeutic strategies are thus strongly needed. Exogenously-administered carbon monoxide (CO) may represent an effective treatment for conditions characterized by a dysregulated inflammatory response. Carbon monoxide-releasing molecules (CORMs) are a novel group of compounds capable of carrying and liberating controlled quantities of CO. Among CORMs, CORM-A1 represents the first example of water soluble CO releaser. We show here that CORM-A1 under a late prophylactic regime is able to significantly ameliorate the natural course of experimental autoimmune uveoretinitis, a rodent model of immunoinflammatory posterior uveitis. The present study strongly supports the development of CORM-A1 as a potential new drug for treatment of patients with non-infectious posterior uveitis.

  4. 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.

  5. Adenosine A1 receptors determine effects of caffeine on total fluid intake but not caffeine appetite.

    PubMed

    Rieg, Timo; Schnermann, Jürgen; Vallon, Volker

    2007-01-26

    Adenosine A1 receptor wild-type (+/+) and knockout (-/-) mice were used to elucidate the role of adenosine A1 receptors in caffeine self-administration in a two-bottle choice test and in the effect of caffeine on total fluid intake and plasma renin concentration. With access to water only, adenosine A1 receptor -/- mice showed greater basal fluid intake and greater plasma renin concentration than +/+ mice. Free access to both water and a caffeinated solution (30 mg/100 ml) for 14 days increased total fluid intake only in adenosine A1 receptor +/+ mice (by 23+/-3%), and both total fluid intake and plasma renin concentration were no longer different between genotypes. Mean intake of water and caffeinated solution was not different between adenosine A1 receptor +/+ and -/- mice. These data reveal that adenosine A1 receptors do not contribute to caffeine consumption, but determine the effects of caffeine on fluid intake and plasma renin concentration. PMID:17126319

  6. Antimicrobial lipopeptide tridecaptin A1 selectively binds to Gram-negative lipid II

    PubMed Central

    Cochrane, Stephen A.; Findlay, Brandon; Bakhtiary, Alireza; Acedo, Jeella Z.; Rodriguez-Lopez, Eva M.; Mercier, Pascal; Vederas, John C.

    2016-01-01

    Tridecaptin A1 (TriA1) is a nonribosomal lipopeptide with selective antimicrobial activity against Gram-negative bacteria. Here we show that TriA1 exerts its bactericidal effect by binding to the bacterial cell-wall precursor lipid II on the inner membrane, disrupting the proton motive force. Biochemical and biophysical assays show that binding to the Gram-negative variant of lipid II is required for membrane disruption and that only the proton gradient is dispersed. The NMR solution structure of TriA1 in dodecylphosphocholine micelles with lipid II has been determined, and molecular modeling was used to provide a structural model of the TriA1–lipid II complex. These results suggest that TriA1 kills Gram-negative bacteria by a mechanism of action using a lipid-II–binding motif. PMID:27688760

  7. [Indicators of glycemic control --hemoglobin A1c (HbA1c), glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG)].

    PubMed

    Sato, Asako

    2014-01-01

    The clinical goal of diabetes management is a good quality of life that is not different from that of a healthy subjects. To fulfill the goal, prevention of complications is needed under good glycemic control. Although blood glucose measurement is essential for glycemic control, there are diurnal variations in blood glucose levels. An indicator of long-term glycemic control is necessary. HbA1c is the gold standard measurement for the assessment of glycemic control, and worldwide large scale clinical studies of diabetes complications have greatly valued HbA1c as an indicator of glycemic control. In addition, recently, HbA1c was recommended for use in the diagnosis of diabetes in Japan and in the United States. Although HbA1c is used widely and internationally, international standardization of the HbA1c value has not been achieved. In Japan, from April 2014, it has been decided to adopt the National Glycohemoglobin Standardization Program (NGSP) value, which is used by many countries globally, as the first step toward internationalization. Recently, cardiovascular disease in diabetic patients has been increasing in Japan. Relationships between postprandial hyperglycemia and cardiovascular disease have been noted. Therefore, the correction of postprandial hyperglycemia is one of the important goals of glycemic control to prevent cardiovascular disease. HbA1c or glycated albumin (GA) results from the glycation of hemoglobin or serum albumin and represents 2-month or 2-week glycemia, respectively. In addition, the glycation speed of GA is ten times faster than HbA1c, so GA is likely to reflect the variation in blood glucose and postprandial hyperglycemia in combination with HbA1c and its value. 1,5-anhydroglucitol (AG) is a marker of glycemia-induced glycosuria, since reabsorption of filtered 1,5-AG in the proximal tubule is competitively inhibited by glucose. It is an indicator to identify rapid changes in hyperglycemia. Understanding the characteristics of the

  8. Catalytic and Immunochemical Detection of Hepatic and Extrahepatic Microsomal Cytochrome P450 1A1 (CYP1A1) in White-sided Dolphin (Lagenorhynchus acutus)

    PubMed Central

    Wilson, Joanna Y.; Moore, Michael J.; Stegeman, John J.

    2009-01-01

    We have characterized microsomal systems and measured the levels of microsomal cytochrome P450 1A1 (CYP1A1) and ethoxyresorufin-O-deethylase activity in multiple internal organs of male and female white-sided dolphin (Lagenorhynchus acutus) from the northwest Atlantic Ocean. Internal organs were sampled within 24 hours of death, sometimes in a period of hours, collection times which are significantly less than usually seen for marine mammals. Tissue autolysis, as assessed by histological analysis of liver, was minimal to none in all individuals. Total P420 did not correlate with time from death to sampling, suggesting that it is a poor indicator of P450 degradation in cetacean tissues where perfusion isn’t practical. The total hepatic microsomal P450 content, cytochrome b5 content, and NADPH-cytochrome c (P450) reductase (CPR) activity averaged 0.29 nmol mg−1, 0.12 nmol mg−1, and 238 nmol mg−1 min−1, respectively. Microsomal CPR activity in liver was higher than that in lung and kidney, and was higher than that reported in liver of most other cetacean species. Immunodetected CYP1A1 content was low in all organs, less than 3 pmoles CYP1A equivalents mg−1. EROD activity ranged from 9 – 376 pmoles mg−1 min−1 and was greater in liver than in other tissues. Hepatic microsomal EROD activity and CYP1A1 content did not correlate. However, hepatic EROD activity, but not CYP1A1 protein content, was well correlated with both total PCB and Σmono-ortho PCB concentrations in blubber. Length, as a proxy for age, did not correlate with hepatic EROD activity or CYP1A1 protein levels, and sex did not influence the relationship between EROD and contaminant concentrations. We cannot easily control for the extent of tissue degradation in cetacean studies nor do we have a complete history of these animals. Therefore, other factors such as degradation or hormonal state may have a role in the observed relationships. Yet, as in other mammals, hepatic tissues appear to be

  9. 26 CFR 31.6161(a)(1)-1 - Extensions of time for paying tax.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Extensions of time for paying tax. 31.6161(a)(1)-1 Section 31.6161(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Provisions of Subtitle F, Internal Revenue Code of 1954) § 31.6161(a)(1)-1 Extensions of time for paying...

  10. 26 CFR 31.6161(a)(1)-1 - Extensions of time for paying tax.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Extensions of time for paying tax. 31.6161(a)(1)-1 Section 31.6161(a)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Provisions of Subtitle F, Internal Revenue Code of 1954) § 31.6161(a)(1)-1 Extensions of time for paying...

  11. 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.

  12. Evaluation of Hemoglobin A1c Criteria to Assess Preoperative Diabetes Risk in Cardiac Surgery Patients

    PubMed Central

    Saberi, Sima; Zrull, Christina A.; Patil, Preethi V.; Jha, Leena; Kling-Colson, Susan C.; Gandia, Kenia G.; DuBois, Elizabeth C.; Plunkett, Cynthia D.; Bodnar, Tim W.; Pop-Busui, Rodica

    2011-01-01

    Abstract Objective Hemoglobin A1c (A1C) has recently been recommended for diagnosing diabetes mellitus and diabetes risk (prediabetes). Its performance compared with fasting plasma glucose (FPG) and 2-h post-glucose load (2HPG) is not well delineated. We compared the performance of A1C with that of FPG and 2HPG in preoperative cardiac surgery patients. Methods Data from 92 patients without a history of diabetes were analyzed. Patients were classified with diabetes or prediabetes using established cutoffs for FPG, 2HPG, and A1C. Sensitivity and specificity of the new A1C criteria were evaluated. Results All patients diagnosed with diabetes by A1C also had impaired fasting glucose, impaired glucose tolerance, or diabetes by other criteria. Using FPG as the reference, sensitivity and specificity of A1C for diagnosing diabetes were 50% and 96%, and using 2HPG as the reference they were 25% and 95%. Sensitivity and specificity for identifying prediabetes with FPG as the reference were 51% and 51%, respectively, and with 2HPG were 53% and 51%, respectively. One-third each of patients with prediabetes was identified using FPG, A1C, or both. When testing A1C and FPG concurrently, the sensitivity of diagnosing dysglycemia increased to 93% stipulating one or both tests are abnormal; specificity increased to 100% if both tests were required to be abnormal. Conclusions In patients before cardiac surgery, A1C criteria identified the largest number of patients with diabetes and prediabetes. For diagnosing prediabetes, A1C and FPG were discordant and characterized different groups of patients, therefore altering the distribution of diabetes risk. Simultaneous measurement of FGP and A1C may be a more sensitive and specific tool for identifying high-risk individuals with diabetes and prediabetes. PMID:21854260

  13. Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis

    PubMed Central

    Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

    2015-01-01

    Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1+ tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the “classical-like” (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients’ outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1+ cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1- cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1+ cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

  14. Type 2 Diabetes Prevention: Implications of Hemoglobin A1c Genetics.

    PubMed

    Leong, Aaron; Meigs, James B

    2015-01-01

    Hemoglobin A1c (HbA1c) is a biomarker used for population-level screening of type 2 diabetes (T2D) and risk stratification. Large-scale, genome-wide association studies have identified multiple genomic loci influencing HbA1c. We discuss the challenges of classifying these genomic loci as influencing HbA1c through glycemic or nonglycemic pathways, based on their probable biology and pleiotropic associations with erythrocyte traits. We show that putative nonglycemic genetic variants have a measurable, albeit small, impact on the classification of T2D status by HbA1c in white and Asian populations. Accounting for their effect on HbA1c may be relevant when screening populations with higher frequencies of nonglycemic HbA1c-altering alleles. As carriers of such HbA1c-altering alleles have HbA1c levels that may not accurately reflect overall glycemia, we describe how accounting for genotype may improve the performance of HbA1c in T2D prediction models and risk stratification, allowing for lifestyle intervention strategies to be directed towards those who are truly at elevated risk for developing T2D. In a Mendelian randomization framework, genetic variants can be used as instrumental variables to estimate causal relationships between HbA1c and T2D-related complications. This approach may help to support or refute HbA1c as an appropriate biomarker for long-term health outcomes in the general population. PMID:27111120

  15. 17 CFR 240.36a1-2 - Exemption from SIPA for OTC derivatives dealers.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Exemption from SIPA for OTC... § 240.36a1-2 Exemption from SIPA for OTC derivatives dealers. Preliminary Note: OTC derivatives dealers... (§ 240.36a1-1), and application of the Securities Investor Protection Act of 1970 (§ 240.36a1-2)....

  16. 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... § 240.36a1-2 Exemption from SIPA for OTC derivatives dealers. Preliminary Note: OTC derivatives dealers... (§ 240.36a1-1), and application of the Securities Investor Protection Act of 1970 (§ 240.36a1-2)....

  17. Galactosylation of serum IgA1 O-glycans in celiac disease.

    PubMed

    Lindfors, Katri; Suzuki, Hitoshi; Novak, Jan; Collin, Pekka; Saavalainen, Päivi; Koskinen, Lotta L E; Mäki, Markku; Kaukinen, Katri

    2011-02-01

    In celiac disease, gluten ingestion provokes small-bowel mucosal injury and production of IgA autoantibodies against transglutaminase 2 (TG2). It has been suggested that in celiac patients IgA could mediate the transepithelial passage of gluten peptides in a mechanism involving the transferrin receptor. As IgA1 with galactose-deficient O-linked glycans has elevated affinity for the transferrin receptor, we assessed whether total serum IgA1 and IgA1 anti-TG2 autoantibodies in celiac patients are aberrantly glycosylated. We report that males with celiac disease have higher total serum levels of galactose-deficient IgA1 than non-celiac males. Furthermore, O-glycans of the disease-specific TG2 IgA1 autoantibodies in celiac patients exhibited elevated galactose deficiency. A gluten-free diet had no effect on the total serum levels of galactose-deficient IgA1, whereas the amount of galactose-deficient anti-TG2 IgA1 decreased. Thus, the undergalactosylated IgA1 molecules are not pathognomonic for celiac disease, but galactose deficiency in IgA1 could be an aggravating factor.

  18. NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration.

    PubMed

    Hedrick, Erik; Lee, Syng-Ook; Doddapaneni, Ravi; Singh, Mandip; Safe, Stephen

    2016-05-01

    Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-β independent and dependent on regulation of β1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3'-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-β-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-β-induced cell migration. We also observed that NR4A1 regulates expression of both β1- and β3-integrins, and unlike other β1-integrin inhibitors which induce prometastatic β3-integrin, NR4A1 antagonists inhibit expression of both β1- and β3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis. PMID:26929200

  19. Transcriptional regulation of human hydroxysteroid sulfotransferase SULT2A1 by LXRα.

    PubMed

    Ou, Zhimin; Jiang, Mengxi; Hu, Bingfang; Huang, Yixian; Xu, Meishu; Ren, Songrong; Li, Song; Liu, Suhuan; Xie, Wen; Huang, Min

    2014-10-01

    The nuclear receptor liver X receptor (LXR) plays an important role in the metabolism and homeostasis of cholesterol, lipids, bile acids, and steroid hormones. In this study, we uncovered a function of LXRα (NR1H3) in regulating the human hydroxysteroid sulfotransferase SULT2A1, a phase II conjugating enzyme known to sulfonate bile acids, hydroxysteroid dehydroepiandrosterone, and related androgens. We showed that activation of LXR induced the expression of SULT2A1 at mRNA, protein, and enzymatic levels. A combination of promoter reporter gene and chromatin immunoprecipitation assays showed that LXRα transactivated the SULT2A1 gene promoter through its specific binding to the -500- to -258-base pair region of the SULT2A1 gene promoter. LXR small interfering RNA knockdown experiments suggested that LXRα, but not LXRβ, played a dominant role in regulating SULT2A1. In primary human hepatocytes, we found a positive correlation between the expression of SULT2A1 and LXRα, which further supported the regulation of SULT2A1 by LXRα. In summary, our results established human SULT2A1 as a novel LXRα target gene. The expression of LXRα is a potential predictor for the expression of SULT2A1 in human liver. PMID:25028566

  20. FoxA1 as a lineage-specific oncogene in luminal type breast cancer

    SciTech Connect

    Yamaguchi, Noritaka; Ito, Emi; Azuma, Sakura; Honma, Reiko; Yanagisawa, Yuka; Nishikawa, Akira; Kawamura, Mika; Imai, Jun-ichi

    2008-01-25

    The forkhead transcription factor FoxA1 is thought to be involved in mammary tumorigenesis. However, the precise role of FoxA1 in breast cancer development is controversial. We examined expression of FoxA1 in 35 human breast cancer cell lines and compared it with that of ErbB2, a marker of poor prognosis in breast cancer. We found that FoxA1 is expressed at high levels in all ErbB2-positive cell lines and a subset of ErbB2-negative cell lines. Down-regulation of FoxA1 by RNA interference significantly suppressed proliferation of ErbB2-negative and FoxA1-positive breast cancer cell lines. Down-regulation of FoxA1 also enhanced the toxic effect of Herceptin on ErbB2-positive cell lines through induction of apoptosis. Taken together with previous data that FoxA1 is a marker of luminal cells in mammary gland, our present results suggest that FoxA1 plays an important role as a lineage-specific oncogene in proliferation of cancer cells derived from mammary luminal cells.

  1. Observation of B0 meson decay to a 1 +/(1260)pi /+.

    PubMed

    Aubert, B; Barate, R; Bona, M; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges, E; Palano, A; Pappagallo, M; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Cottingham, W N; Walker, D; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Khan, A; Kyberd, P; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Best, D S; Bondioli, M; Bruinsma, M; Chao, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Zhang, L; Hadavand, H K; Hill, E J; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dvoretskii, A; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Andreassen, R; Mancinelli, G; Meadows, B T; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nauenberg, U; Olivas, A; Ruddick, W O; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Chen, A; Eckhart, E A; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Zeng, Q; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Spaan, B; Brandt, T; Klose, V; Lacker, H M; Mader, W F; Nogowski, R; Petzold, A; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Grenier, P; Latour, E; Thiebaux, Ch; Verderi, M; Bard, D J; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Brandenburg, G; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Flack, R L; Gaillard, J R; Nash, J A; Nikolich, M B; Panduro Vazquez, W; Chai, X; Charles, M J; Mallik, U; Meyer, N T; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gritsan, A V; Fritsch, M; Schott, G; Arnaud, N; Davier, M; Grosdidier, G; Höcker, A; Le Diberder, F; Lepeltier, V; Lutz, A M; Oyanguren, A; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Stocchi, A; Wang, W F; Wormser, G; Cheng, C H; Lange, D J; Wright, D M; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; George, K A; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; Di Lodovico, F; Menges, W; Sacco, R; Brown, C L; Cowan, G; Flaecher, H U; Hopkins, D A; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Kelly, M P; Lafferty, G D; Naisbit, M T; Williams, J C; Yi, J I; Chen, C; Hulsbergen, W D; Jawahery, A; Lae, C K; Roberts, D A; Simi, G; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Saremi, S; Staengle, H; Willocq, S Y; Cowan, R; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Kim, H; Patel, P M; Potter, C T; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; Cavallo, N; Nardo, G De; del Re, D; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Piccolo, D; Sciacca, C; Baak, M; Bulten, H; Raven, G; Snoek, H L; Jessop, C P; LoSecco, J M; Allmendinger, T; Benelli, G; Gan, K K; Honscheid, K; Hufnagel, D; Jackson, P D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Galeazzi, F; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F

    2006-08-01

    We present a measurement of the branching fraction of the decay B(0)-->a1 (+/)(1260)pi(/+) with a1 (+/)(1260)-->pi(/+)pi(+/)pi(+/). The data sample corresponds to 218 x 10(6) BB[over ] pairs produced in e+e- annihilation through the Upsilon(4S) resonance. We measure the branching fraction Beta(B(0)-->a1(+/)(1260)pi(/+))Beta(a1(+/)(1260)-->pi(/+)pi(+/)pi(+/)) = (16.6+/1.9+/1.5) x 10(-6), where the first error quoted is statistical and the second is systematic. PMID:17026094

  2. Observation of B0 meson decay to a 1 +/(1260)pi /+.

    PubMed

    Aubert, B; Barate, R; Bona, M; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges, E; Palano, A; Pappagallo, M; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Cottingham, W N; Walker, D; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Khan, A; Kyberd, P; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Best, D S; Bondioli, M; Bruinsma, M; Chao, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Zhang, L; Hadavand, H K; Hill, E J; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dvoretskii, A; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Andreassen, R; Mancinelli, G; Meadows, B T; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nauenberg, U; Olivas, A; Ruddick, W O; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Chen, A; Eckhart, E A; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Zeng, Q; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Spaan, B; Brandt, T; Klose, V; Lacker, H M; Mader, W F; Nogowski, R; Petzold, A; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Grenier, P; Latour, E; Thiebaux, Ch; Verderi, M; Bard, D J; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Brandenburg, G; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Flack, R L; Gaillard, J R; Nash, J A; Nikolich, M B; Panduro Vazquez, W; Chai, X; Charles, M J; Mallik, U; Meyer, N T; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gritsan, A V; Fritsch, M; Schott, G; Arnaud, N; Davier, M; Grosdidier, G; Höcker, A; Le Diberder, F; Lepeltier, V; Lutz, A M; Oyanguren, A; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Stocchi, A; Wang, W F; Wormser, G; Cheng, C H; Lange, D J; Wright, D M; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; George, K A; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; Di Lodovico, F; Menges, W; Sacco, R; Brown, C L; Cowan, G; Flaecher, H U; Hopkins, D A; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Kelly, M P; Lafferty, G D; Naisbit, M T; Williams, J C; Yi, J I; Chen, C; Hulsbergen, W D; Jawahery, A; Lae, C K; Roberts, D A; Simi, G; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Saremi, S; Staengle, H; Willocq, S Y; Cowan, R; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Kim, H; Patel, P M; Potter, C T; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; Cavallo, N; Nardo, G De; del Re, D; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Piccolo, D; Sciacca, C; Baak, M; Bulten, H; Raven, G; Snoek, H L; Jessop, C P; LoSecco, J M; Allmendinger, T; Benelli, G; Gan, K K; Honscheid, K; Hufnagel, D; Jackson, P D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Galeazzi, F; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Benayoun, M; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Hartfiel, B L; John, M J J; Leruste, Ph; Malclès, J; Ocariz, J; Roos, L; Therin, G; Behera, P K; Gladney, L; Panetta, J; Biasini, M; Covarelli, R; Pioppi, M; Angelini, C; Batignani, G; Bettarini, S; Bucci, F; Calderini, G; Carpinelli, M; Cenci, R; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J; Haire, M; Judd, D; Wagoner, D E; Biesiada, J; Danielson, N; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; D'Orazio, A; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Safai Tehrani, F; Voena, C; Ebert, M; Schröder, H; Waldi, R; Adye, T; De Groot, N; Franek, B; Olaiya, E O; Wilson, F F; Emery, S; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Legendre, M; Mayer, B; Vasseur, G; Yèche, Ch; Zito, M; Park, W; Purohit, M V; Weidemann, A W; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Boyarski, A M; Claus, R; Coleman, J P; Convery, M R; Cristinziani, M; Dingfelder, J C; Dong, D; Dorfan, J; Dubois-Felsmann, G P; Dujmic, D; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Libby, J; Luitz, S; Luth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; van Bakel, N; Weaver, M; Weinstein, A J R; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Roat, C; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Satpathy, A; Schilling, C J; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Dittongo, S; Grancagnolo, S; Lanceri, L; Vitale, L; Azzolini, V; Martinez-Vidal, F; Banerjee, Sw; Bhuyan, B; Brown, C M; Fortin, D; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Back, J J; Harrison, P F; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Cheng, B; Dasu, S; Datta, M; Eichenbaum, A M; Flood, K T; Hollar, J J; Johnson, J R; Kutter, P E; Li, H; Liu, R; Mellado, B; Mihalyi, A; Mohapatra, A K; Pan, Y; Pierini, M; Prepost, R; Tan, P; Wu, S L; Yu, Z; Neal, H

    2006-08-01

    We present a measurement of the branching fraction of the decay B(0)-->a1 (+/)(1260)pi(/+) with a1 (+/)(1260)-->pi(/+)pi(+/)pi(+/). The data sample corresponds to 218 x 10(6) BB[over ] pairs produced in e+e- annihilation through the Upsilon(4S) resonance. We measure the branching fraction Beta(B(0)-->a1(+/)(1260)pi(/+))Beta(a1(+/)(1260)-->pi(/+)pi(+/)pi(+/)) = (16.6+/1.9+/1.5) x 10(-6), where the first error quoted is statistical and the second is systematic.

  3. Genomic organization of SLC3A1, a transporter gene mutated in cystinuria

    SciTech Connect

    Pras, E.; Sood, R.; Raben, N.

    1996-08-15

    The SLC3A1 gene encodes a transport protein for cystine and the dibasic amino acids. Recently mutations in this gene have been shown to cause cystinuria. We report the genomic structure and organization of SLC3A1, which is composed of 10 exons and spans nearly 45 kb. Until now screening for mutations in SLC3A1 has been based on RT-PCR amplification of illegitimate mRNA transcripts from white blood cells. In this report we provide primers for amplification of exons from genomic DNA, thus simplifying the process of screening for SLC3A1 mutations in cystinuria. 20 refs., 3 figs., 2 tabs.

  4. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing

    PubMed Central

    Gammal, RS; Court, MH; Haidar, CE; Iwuchukwu, OF; Gaur, AH; Alvarellos, M; Guillemette, C; Lennox, JL; Whirl‐Carrillo, M; Brummel, SS; Ratain, MJ; Klein, TE; Schackman, BR; Caudle, KE

    2015-01-01

    The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin‐related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org). PMID:26417955

  5. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing.

    PubMed

    Gammal, R S; Court, M H; Haidar, C E; Iwuchukwu, O F; Gaur, A H; Alvarellos, M; Guillemette, C; Lennox, J L; Whirl-Carrillo, M; Brummel, S S; Ratain, M J; Klein, T E; Schackman, B R; Caudle, K E; Haas, D W

    2016-04-01

    The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org). PMID:26417955

  6. Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

    PubMed Central

    Bethke, Lara; Webb, Emily; Sellick, Gabrielle; Rudd, Matthew; Penegar, Stephen; Withey, Laura; Qureshi, Mobshra; Houlston, Richard

    2007-01-01

    Background Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. Methods To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. Results There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03–1.80 and OR = 1.34, 95% CI: 1.00–1.79 respectively). Conclusion This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility. PMID:17615053

  7. Homology model of human retinoic acid metabolising enzyme cytochrome P450 26A1 (CYP26A1): active site architecture and ligand binding.

    PubMed

    Gomaa, Mohamed Sayed; Yee, Sook Wah; Milbourne, Ceri Elizabeth; Barbera, Maria Chiara; Simons, Claire; Brancale, Andrea

    2006-08-01

    Homology models of cytochrome P450 RA1 (CYP26A1) were constructed using three human P450 structures, CYP2C8, CYP2C9 and CYP3A4 as templates for the model building. Using MOE software the lowest energy CYP26A1 model was then assessed for stereochemical quality and side chain environment. Further active site optimisation of the CYP26A1 model built using the CYP3A4 template was performed by molecular dynamics to generate a final CYP26A1 model. The natural substrate, all-trans-retinoic acid (atRA), and inhibitor R 15866, were docked into the model allowing further validation of the active site architecture. Using the docking studies structurally and functionally important residues were identified with subsequent characterisation of secondary structure. Multiple hydrophobic interactions, including the side chains of TRP112, PHE299, PHE222, PHE84, PHE374 and PRO371, are important for binding of atRA and R115866. Additional hydrogen bonding interactions were noted as follows: atRA-- C==O of the atRA carboxylate group and ARG86; R115866--benzothiazole nitrogen and the backbone NH of SER115.

  8. Improved method for measuring absolute O2(a1Δg) concentration by O2(a1Δg-->X3Σg-) IR radiation

    NASA Astrophysics Data System (ADS)

    Deng, Liezheng; Shi, Wenbo; Yang, Heping; Sha, Guohe; Zhang, Cunhao

    2004-11-01

    We describe an improved technique for measuring the absolute O2(a1Δ) concentration via the quantitative determination of IR radiation from O2(a1Δg→X3Σg-) transition. An exact geometrical optical model was first established, in which the influence of reflection and refraction on the radiation characteristics of a luminous volume source was given full consideration, making possible the accurate calculation of the coupling efficiency between the volume source and a receiving area. Then, an IR radiation receiving apparatus (IRRRA) was constructed and its responsivity (mV/W) to the power of IR radiation calibrated by a tungsten standard lamp. An optical detection system was, in turn, built according to the optical model with fine alignment between the IRRRA and an optical cell. We then demonstrate the procedure to obtain the absolute concentration of O2(a1Δ) flowing through the optical cell from a jet singlet oxygen generator from the signal of the IRRRA, the optical cell volume, and the coupling efficiency between the cell and the IRRRA. Moreover, to verify the accuracy of this method, the absolute O2(a1Δ) concentration was compared to that measured by an established isothermal calorimetry method. Based on the comparison of the O2(a1Δ) concentrations determined by the two methods, the Einstein A-coefficient was estimated as (2.70±0.84)×10-4 s-1, which agrees with Badger's value of 2.58×10-4, Špalek's of 2.24×10-4, Newman's of 2.19×10-4, and Miller's of 2.3×10-4 within the uncertainty of the experimental techniques. The method advanced in this article is worthwhile for the measurement of absolute O2(a1Δ) concentration in a chemical oxygen iodine laser or a singlet oxygen generator. It can also provide a general technique for the measurement of absolute concentrations of long-lifetime luminous species other than O2(a1Δ).

  9. Methods, units and quality requirements for the analysis of haemoglobin A1c in diabetes mellitus

    PubMed Central

    Penttilä, Ilkka; Penttilä, Karri; Holm, Päivi; Laitinen, Harri; Ranta, Päivi; Törrönen, Jukka; Rauramaa, Rainer

    2016-01-01

    The formation of glycohemoglobin, especially the hemoglobin A1c (HbA1c) fraction, occurs when glucose becomes coupled with the amino acid valine in the β-chain of Hb; this reaction is dependent on the plasma concentration of glucose. Since the early 1970s it has been known that diabetics display higher values OF HbA1C because they have elevated blood glucose concentrations. Thus HbA1c has acquired a very important role in the treatment and diagnosis of diabetes mellitus. After the introduction of the first quantitative measurement OF HbA1C, numerous methods for glycohemoglobin have been introduced with different assay principles: From a simple mini-column technique to the very accurate automated high-pressure chromatography and lastly to many automated immunochemical or enzymatic assays. In early days, the results of the quality control reports for HbA1c varied extensively between laboratories, therefore in United States and Canada working groups (WG) of the Diabetes Controls and Complications Trial (DCCT) were set up to standardize the HbA1c assays against the DCCT/National Glycohemoglobin Standardization Program reference method based on liquid chromatography. In the 1990s, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) appointed a new WG to plan a reference preparation and method for the HBA1c measurement. When the reference procedures were established, in 2004 IFCC recommended that all manufacturers for equipment used in HbA1c assays should calibrate their methods to their proposals. This led to an improvement in the coefficient of variation (CV%) associated with the assay. In this review, we describe the glycation of Hb, methods, standardization of the HbA1c assays, analytical problems, problems with the units in which HbA1c values are expressed, reference values, quality control aspects, target requirements for HbA1c, and the relationship of the plasma glucose values to HbA1c concentrations. We also note that the acceptance

  10. Cytochrome P450 1A1 Regulates Breast Cancer Cell Proliferation and Survival

    PubMed Central

    Rodriguez, Mariangellys; Potter, David A.

    2013-01-01

    Cytochrome P450 1A1 (CYP1A1) is an extrahepatic phase I metabolizing enzyme whose expression is suppressed under physiologic conditions, but can be induced by substrates via the aryl hydrocarbon receptor (AhR). Nonetheless, recent studies show that the majority of breast tumors constitutively express CYP1A1. These findings led us to test the hypothesis that CYP1A1 promotes breast cancer progression by evaluating the effects of CYP1A1 knock down on the proliferation and survival of the MCF7 and MDA-MB-231 lines. Independently of estrogen receptor status, CYP1A1 knock down decreases cell proliferation, decreases colony formation, blocks the cell cycle at G0/G1 associated with reduction of cyclin D1, and increases apoptosis associated with reduction of survivin. CYP1A1 knock down markedly increases phosphorylation of AMP-activated protein kinase (AMPK) and decreases phosphorylation of AKT, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and 70kDa ribosomal protein S6 kinase (P70S6K). AMPK inhibition by compound C partially abrogates the pro-apoptotic effects of CYP1A1siRNA, suggesting that CYP1A1siRNA effects are mediated, in part, through AMPK signaling. Consistent with CYP1A1 knock down results, pharmacologic reduction of CYP1A1 levels by the phytopolyphenol carnosol also correlates with impaired proliferation and induced AMPK phosphorylation. These results indicate that reduction of basal CYP1A1 expression is critical for inhibition of proliferation, which is not affected by alpha-naphthoflavone-mediated inhibition of CYP1A1 activity nor modulated by AhR silencing. This study supports that CYP1A1 may promote breast cancer proliferation and survival, at least in part, through AMPK signaling and that reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics. PMID:23576571

  11. Organic anion transporting polypeptide 1a1 null mice are sensitive to cholestatic liver injury.

    PubMed

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

    2012-06-01

    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.

  12. Methods, units and quality requirements for the analysis of haemoglobin A1c in diabetes mellitus.

    PubMed

    Penttilä, Ilkka; Penttilä, Karri; Holm, Päivi; Laitinen, Harri; Ranta, Päivi; Törrönen, Jukka; Rauramaa, Rainer

    2016-06-26

    The formation of glycohemoglobin, especially the hemoglobin A1c (HbA1c) fraction, occurs when glucose becomes coupled with the amino acid valine in the β-chain of Hb; this reaction is dependent on the plasma concentration of glucose. Since the early 1970s it has been known that diabetics display higher values OF HbA1C because they have elevated blood glucose concentrations. Thus HbA1c has acquired a very important role in the treatment and diagnosis of diabetes mellitus. After the introduction of the first quantitative measurement OF HbA1C, numerous methods for glycohemoglobin have been introduced with different assay principles: From a simple mini-column technique to the very accurate automated high-pressure chromatography and lastly to many automated immunochemical or enzymatic assays. In early days, the results of the quality control reports for HbA1c varied extensively between laboratories, therefore in United States and Canada working groups (WG) of the Diabetes Controls and Complications Trial (DCCT) were set up to standardize the HbA1c assays against the DCCT/National Glycohemoglobin Standardization Program reference method based on liquid chromatography. In the 1990s, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) appointed a new WG to plan a reference preparation and method for the HBA1c measurement. When the reference procedures were established, in 2004 IFCC recommended that all manufacturers for equipment used in HbA1c assays should calibrate their methods to their proposals. This led to an improvement in the coefficient of variation (CV%) associated with the assay. In this review, we describe the glycation of Hb, methods, standardization of the HbA1c assays, analytical problems, problems with the units in which HbA1c values are expressed, reference values, quality control aspects, target requirements for HbA1c, and the relationship of the plasma glucose values to HbA1c concentrations. We also note that the acceptance

  13. Ultraviolet radiation decreases expression and induces aggregation of corneal ALDH3A1.

    PubMed

    Manzer, Rizwan; Pappa, Aglaia; Estey, Tia; Sladek, Norman; Carpenter, John F; Vasiliou, Vasilis

    2003-02-01

    Substantial reduction in corneal ALDH3A1 enzymatic activity associated with eye pathology was previously reported in C57BL/6J mice subjected to ultraviolet radiation (UVR). The aim of this study was to examine whether UVR diminishes corneal ALDH3A1 expression through modifications at the transcriptional, translational, or post-translational level. Adult C57BL/6J mice were subjected to UVR exposure (302 nm peak wavelength) for various periods of time, and corneal ALDH3A1 mRNA and protein levels were monitored by Northern and Western blot analysis, respectively. In addition, ALDH3A1 enzymatic activity was determined as a measure of post-translational modification. Mice exposed to 0.2 J/cm(2) UVB radiation demonstrated an extensive decrease, approximately 80%, in mRNA and protein levels, as well as enzymatic activity of corneal ALDH3A1. Significant reductions in corneal ALDH3A1 enzymatic activity were detected in mice 96 h after exposure to 0.05 and 0.1 J/cm(2) UVB radiation; no significant changes were observed in mRNA and protein levels. These data suggest that UVB down-regulates corneal ALDH3A1 expression at the transcriptional and/or post-translational level depending on the dose of UVB. Reduction in gene transcription requires UVB doses greater than or equal to 0.2 J/cm(2). In vitro experiments with human corneal epithelial cell lines stably transfected with human ALDH3A1 cDNA, and with purified recombinant human ALDH3A1 protein, indicated that ALDH3A1 undergoes post-translational modifications after UVR exposure. These modifications result in both covalent and non-covalent aggregation of the protein with no detectable precipitation. Such conformational changes may be associated with the function of ALDH3A1 as a chaperone-like molecule in the cornea. PMID:12604188

  14. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy.

    PubMed

    Gharavi, Ali G; Moldoveanu, Zina; Wyatt, Robert J; Barker, Catherine V; Woodford, Susan Y; Lifton, Richard P; Mestecky, Jiri; Novak, Jan; Julian, Bruce A

    2008-05-01

    IgA nephropathy (IgAN) is a complex trait determined by genetic and environmental factors. Most IgAN patients exhibit a characteristic undergalactosylation of the O-glycans of the IgA1 hinge region, which promotes formation and glomerular deposition of immune complexes. It is not known whether this aberrant glycosylation is the result of an acquired or inherited defect, or whether the presence of aberrant IgA1 glycoforms alone can produce IgAN. A newly validated lectin enzyme-linked immunosorbent assay (ELISA) was used to determine the serum level of galactose-deficient IgA1 (Gd-IgA1) in a cohort of 89 IgAN patients and 266 of their relatives. High Gd-IgA1 levels (> or =95th percentile for controls) were observed in all 5 available patients with familial IgAN, in 21 of 45 (47%) of their at-risk relatives (assuming autosomal dominant inheritance), and in only 1 of 19 (5%) of unrelated individuals who married into the family. This provides evidence that abnormal IgA1 glycosylation is an inherited rather than acquired trait. Similarly, Gd-IgA1 levels were high in 65 of 84 (78%) patients with sporadic IgAN and in 50 of 202 (25%) blood relatives. Heritability of Gd-IgA1 was estimated at 0.54 (P = 0.0001), and segregation analysis suggested the presence of a major dominant gene on a polygenic background. Because most relatives with abnormal IgA1 glycoforms were asymptomatic, additional cofactors must be required for IgAN to develop. The fact that abnormal IgA1 glycosylation clusters in most but not all families suggests that measuring Gd-IgA1 may help distinguish patients with different pathogenic mechanisms of disease.

  15. 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

  16. The in vivo respiratory phenotype of the adenosine A1 receptor knockout mouse.

    PubMed

    Heitzmann, Dirk; Buehler, Philipp; Schweda, Frank; Georgieff, Michael; Warth, Richard; Thomas, Joerg

    2016-02-01

    The nucleoside adenosine has been implicated in the regulation of respiration, especially during hypoxia in the newborn. In this study the role of adenosine A1 receptors for the control of respiration was investigated in vivo. To this end, respiration of unrestrained adult and neonatal adenosine A1 receptor knockout mice (A1R(-/-)) was measured in a plethysmographic device. Under control conditions (21% O2) and mild hypoxia (12-15% O2) no difference of respiratory parameters was observed between adult wildtype (A1R(+/+)) and A1R(-/-) mice. Under more severe hypoxia (6-10% O2) A1R(+/+) mice showed, after a transient increase of respiration, a decrease of respiration frequency (fR) and tidal volume (VT) leading to a decrease of minute volume (MV). This depression of respiration during severe hypoxia was absent in A1R(-/-) mice which displayed a stimulated respiration as indicated by the enhancement of MV by some 50-60%. During hypercapnia-hyperoxia (3-10% CO2/97-90 % O2), no obvious differences in respiration of A1R(-/-) and A1R(+/+) was observed. In neonatal mice, the respiratory response to hypoxia was surprisingly similar in both genotypes. However, neonatal A1R(-/-) mice appeared to have more frequently periods of apnea during hypoxia and in the post-hypoxic control period. In conclusion, these data indicate that the adenosine A1 receptor is an important molecular component mediating hypoxic depression in adult mice and it appears to stabilize respiration of neonatal mice. PMID:26593641

  17. [Analytical problems in determination of hemoglobin A1c and the different ways of its interpretation].

    PubMed

    Góth, László

    2009-04-19

    Glycated proteins are formed during the nonenzymatic reaction of glucose and amino groups of proteins. Hemoglobin A1c is formed by the condensation of glucose with the N-terminal valine residue of each beta-chain of hemoglobin A. The amount of glycated hemoglobin in blood depends on both life-span of red blood cells and blood glucose concentration. As the rate of formation of hemoglobin A1c is directly proportional to the concentration of glucose in the blood, it represent the integrated values for glucose over the preceding 6 to 8 weeks. Hemoglobin A1c determination is widely used for monitoring long-term glycemic control, and it is a risk factor for complications of diabetes. The concentration of blood hemoglobin A1c depends on further factors such as half-life of hemoglobin, blood carbohydrates, blood analytes, methods of determination and calibration. Committees were established under the auspices of the American Association of Clinical Chemistry, American Diabetes Association, International Federation of Clinical Chemistry (IFCC) to standardize HbA1c assays (DCCT: Diabetes Control and Complications Trial, NGSP: National Glycohemoglobin Standardization Program, IFCC reference method for measurement of HbA1c). The NGSP recommends to report HbA1c result in % (g HbA1c/g hemoglobin) while IFCC suggests mmol HbA1c/mol hemoglobin A. Reports are presenting mathematical relationship between HbA1c and average glucose concentration in blood, however, the clinical usefulness of estimating average serum glucose from HbA1c level is under discussion. PMID:19362928

  18. Induction of human UGT1A1 by bilirubin through AhR dependent pathway.

    PubMed

    Togawa, Hiroshi; Shinkai, Shigeko; Mizutani, Takaharu

    2008-12-01

    UDP-glucuronosyltransferase1A1 (UGT1A1) plays a key role to conjugate bilirubin and preventing jaundice, but there is no report showing the induction of human UGT1A1 (UGT1A1) by bilirubin. In this report, we show findings of the induction of the reporter gene (-3475/+14) of UGT1A1 in HepG2 cells by bilirubin at 50 microM, 100 microM, with human aryl hydrocarbon receptor (hAhR). We confirmed that induction of the reporter gene by bilirubin is dependent on the position of the xenobiotic responsive element (XRE) (-3328/-3319) of UGT1A1, because the XRE deletion UGT1A1 gene did not respond to stimulation by a complex of bilirubin and hAhR. alpha-Naphthoflavone (alpha-NF) of a typical AhR antagonist at 50 microM inhibited induction by bilirubin, suggesting that bilirubin stimulates through binding with hAhR. Meanwhile, bilirubin itself did not stimulate the induction of AhR, because we detected no-elevation of the mRNA level of AhR by RT-PCR. These results indicate that the induction of UGT1A1 by bilirubin-AhR did not depend on the elevation of AhR but on ligand binding. From this result, we considered that high bilirubin in neonates must induce the elevation of UGT1A1 after birth to prevent jaundice, and bilirubin in adults also regulates the level of UGT1A1. This is the first report showing direct induction of UGT1A1 by a bilirubin through AhR pathway. PMID:19356098

  19. The clinical application of UGT1A1 pharmacogenetic testing: Gene-environment interactions

    PubMed Central

    2010-01-01

    Over the past decade, the number of pharmacogenetic tests has increased considerably, allowing for the development of our knowledge of their clinical application. The uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) assay is an example of a pharmacogenetic test. Numerous variants have been found in UGT1A1, the main conjugating enzyme of bilirubin and drugs such as the anticancer drug irinotecan. Recently, the US Food and Drug Administration (FDA) recommended testing for the presence of UGT1A1*28, an allele correlated with decreased transcriptional activity, to predict patients at risk of irinotecan toxicity. The administration of other drugs -- such as inhibitors of the UGT1A1 enzyme -- can clinically mimic the *28 phenotype, whereas inducers of UGT1A1 can increase the glucuronidation rate of the enzyme. The *28 polymorphism is not present in all ethnicities at a similar frequency, which suggests that it is important to study different populations to determine the clinical relevance of testing for UGT1A1*28 and to identify other clinically relevant UGT1A1 variants. Environmental factors such as lifestyle can also affect UGT1A1 activity. This review is a critical analysis of studies on drugs that can be affected by the presence of UGT1A1*28, the distribution of this polymorphism around the globe, distinct variants that may be clinically significant in African and Asian populations and how lifestyle can affect treatment outcomes that depend on UGT1A1 activity. PMID:20511137

  20. Axonal patterns and targets of dA1 interneurons in the chick hindbrain.

    PubMed

    Kohl, Ayelet; Hadas, Yoav; Klar, Avihu; Sela-Donenfeld, Dalit

    2012-04-25

    Hindbrain dorsal interneurons that comprise the rhombic lip relay sensory information and coordinate motor outputs. The progenitor dA1 subgroup of interneurons, which is formed along the dorsal-most region of the caudal rhombic lip, gives rise to the cochlear and precerebellar nuclei. These centers project sensory inputs toward upper-brain regions. The fundamental role of dA1 interneurons in the assembly and function of these brainstem nuclei is well characterized. However, the precise en route axonal patterns and synaptic targets of dA1 interneurons are not clear as of yet. Novel genetic tools were used to label dA1 neurons and trace their axonal trajectories and synaptic connections at various stages of chick embryos. Using dA1-specific enhancers, two contralateral ascending axonal projection patterns were identified; one derived from rhombomeres 6-7 that elongated in the dorsal funiculus, while the other originated from rhombomeres 2-5 and extended in the lateral funiculus. Targets of dA1 axons were followed at later stages using PiggyBac-mediated DNA transposition. dA1 axons were found to project and form synapses in the auditory nuclei and cerebellum. Investigation of mechanisms that regulate the patterns of dA1 axons revealed a fundamental role of Lim-homeodomain (HD) proteins. Switch in the expression of the specific dA1 Lim-HD proteins Lhx2/9 into Lhx1, which is typically expressed in dB1 interneurons, modified dA1 axonal patterns to project along the routes of dB1 subgroup. Together, the results of this research provided new tools and knowledge to the assembly of trajectories and connectivity of hindbrain dA1 interneurons and of molecular mechanisms that control these patterns.

  1. Attenuation of Cigarette Smoke-Induced Emphysema in Mice by Apolipoprotein A-1 Overexpression.

    PubMed

    Kim, Chorong; Lee, Ji-Min; Park, Sung-Woo; Kim, Ki-Sun; Lee, Myoung Won; Paik, Sanghyun; Jang, An Soo; Kim, Do Jin; Uh, Sootaek; Kim, Yonghoon; Park, Choon-Sik

    2016-01-01

    Chronic inflammation, oxidative stress, and proteolysis participate primarily in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. COPD is a highly prevalent smoking-related disease for which no effective therapy exists to improve the disease course. Although apolipoprotein A-1 (ApoA1) has antiinflammatory and antioxidant properties as well as cholesterol efflux potential, its role in cigarette smoke (CS)-induced emphysema has not been determined. Therefore, we investigated whether human ApoA1 transgenic (TG) mice, with conditionally induced alveolar epithelium to overexpress ApoA1, are protected against the CS-induced lung inflammatory response and development of emphysema. In this study, ApoA1 levels were significantly decreased in the lungs of patients with COPD and in the lungs of mice exposed to CS. ApoA1 TG mice did not develop emphysema when chronically exposed to CS. Compared with the control TG mice, ApoA1 overexpression attenuated lung inflammation, oxidative stress, metalloprotease activation, and apoptosis in CS-exposed mouse lungs. To explore a plausible mechanism of antiapoptotic activity of ApoA1, alveolar epithelial cells (A549) were treated with CS extract (CSE). ApoA1 prevented CSE-induced translocation of Fas and downstream death-inducing signaling complex into lipid rafts, thereby inhibiting Fas-mediated apoptosis. Taken together, the data showed that ApoA1 overexpression attenuated CS-induced lung inflammation and emphysema in mice. Augmentation of ApoA1 in the lung may have therapeutic potential in preventing smoking-related COPD/emphysema.

  2. 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. PMID:26608888

  3. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1.

    PubMed

    Suzuki, Hitoshi; Moldoveanu, Zina; Hall, Stacy; Brown, Rhubell; Vu, Huong L; Novak, Lea; Julian, Bruce A; Tomana, Milan; Wyatt, Robert J; Edberg, Jeffrey C; Alarcón, Graciela S; Kimberly, Robert P; Tomino, Yasuhiko; Mestecky, Jiri; Novak, Jan

    2008-02-01

    Aberrant glycosylation of IgA1 plays an essential role in the pathogenesis of IgA nephropathy. This abnormality is manifested by a deficiency of galactose in the hinge-region O-linked glycans of IgA1. Biosynthesis of these glycans occurs in a stepwise fashion beginning with the addition of N-acetylgalactosamine by the enzyme N-acetylgalactosaminyltransferase 2 and continuing with the addition of either galactose by beta1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine-specific alpha2,6-sialyltransferase. To identify the molecular basis for the aberrant IgA glycosylation, we established EBV-immortalized IgA1-producing cells from peripheral blood cells of patients with IgA nephropathy. The secreted IgA1 was mostly polymeric and had galactose-deficient O-linked glycans, characterized by a terminal or sialylated N-acetylgalactosamine. As controls, we showed that EBV-immortalized cells from patients with lupus nephritis and healthy individuals did not produce IgA with the defective galactosylation pattern. Analysis of the biosynthetic pathways in cloned EBV-immortalized cells from patients with IgA nephropathy indicated a decrease in beta1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine-specific alpha2,6-sialyltransferase activity. Also, expression of beta1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine-specific alpha2,6-sialyltransferase was significantly higher than the expression of these genes in the control cells. Thus, our data suggest that premature sialylation likely contributes to the aberrant IgA1 glycosylation in IgA nephropathy and may represent a new therapeutic target.

  4. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1

    PubMed Central

    Suzuki, Hitoshi; Moldoveanu, Zina; Hall, Stacy; Brown, Rhubell; Vu, Huong L.; Novak, Lea; Julian, Bruce A.; Tomana, Milan; Wyatt, Robert J.; Edberg, Jeffrey C.; Alarcón, Graciela S.; Kimberly, Robert P.; Tomino, Yasuhiko; Mestecky, Jiri; Novak, Jan

    2008-01-01

    Aberrant glycosylation of IgA1 plays an essential role in the pathogenesis of IgA nephropathy. This abnormality is manifested by a deficiency of galactose in the hinge-region O-linked glycans of IgA1. Biosynthesis of these glycans occurs in a stepwise fashion beginning with the addition of N-acetylgalactosamine by the enzyme N-acetylgalactosaminyltransferase 2 and continuing with the addition of either galactose by β1,3-galactosyltransferase or a terminal sialic acid by a N-acetylgalactosamine–specific α2,6-sialyltransferase. To identify the molecular basis for the aberrant IgA glycosylation, we established EBV-immortalized IgA1-producing cells from peripheral blood cells of patients with IgA nephropathy. The secreted IgA1 was mostly polymeric and had galactose-deficient O-linked glycans, characterized by a terminal or sialylated N-acetylgalactosamine. As controls, we showed that EBV-immortalized cells from patients with lupus nephritis and healthy individuals did not produce IgA with the defective galactosylation pattern. Analysis of the biosynthetic pathways in cloned EBV-immortalized cells from patients with IgA nephropathy indicated a decrease in β1,3-galactosyltransferase activity and an increase in N-acetylgalactosamine–specific α2,6-sialyltransferase activity. Also, expression of β1,3-galactosyltransferase was significantly lower, and that of N-acetylgalactosamine–specific α2,6-sialyltransferase was significantly higher than the expression of these genes in the control cells. Thus, our data suggest that premature sialylation likely contributes to the aberrant IgA1 glycosylation in IgA nephropathy and may represent a new therapeutic target. PMID:18172551

  5. 17 CFR 275.202(a)(1)-1 - Certain transactions not deemed assignments.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Certain transactions not deemed assignments. 275.202(a)(1)-1 Section 275.202(a)(1)-1 Commodity and Securities Exchanges SECURITIES...)(1)-1 Certain transactions not deemed assignments. A transaction which does not result in a change...

  6. 17 CFR 275.202(a)(1)-1 - Certain transactions not deemed assignments.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Certain transactions not deemed assignments. 275.202(a)(1)-1 Section 275.202(a)(1)-1 Commodity and Securities Exchanges SECURITIES...)(1)-1 Certain transactions not deemed assignments. A transaction which does not result in a change...

  7. 17 CFR 275.202(a)(1)-1 - Certain transactions not deemed assignments.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Certain transactions not deemed assignments. 275.202(a)(1)-1 Section 275.202(a)(1)-1 Commodity and Securities Exchanges SECURITIES...)(1)-1 Certain transactions not deemed assignments. A transaction which does not result in a change...

  8. Genome Sequence of Bacillus cereus Strain A1, an Efficient Starch-Utilizing Producer of Hydrogen.

    PubMed

    Zhang, Ting; Bao, Meidan; Wang, Yu; Su, Haijia; Tan, Tianwei

    2014-01-01

    Bacillus cereus strain A1 is a newly isolated hydrogen producer capable of utilizing bioresources and biowaste, such as starch and starch wastewater. Here, we present a 5.67-Mb assembly of the genome sequence of strain A1, which may provide insights into the molecular mechanism of hydrogen production from bioresources and biowaste.

  9. 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...

  10. 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...

  11. Production of the allergenic protein Alt a 1 by Alternaria isolates from working environments.

    PubMed

    Skóra, Justyna; Otlewska, Anna; Gutarowska, Beata; Leszczyńska, Joanna; Majak, Iwona; Stępień, Łukasz

    2015-02-16

    The aim of the study was to evaluate the ability of Alternaria isolates from workplaces to produce Alt a 1 allergenic protein, and to analyze whether technical materials (cellulose, compost, leather) present within the working environment stimulate or inhibit Alt a 1 production (ELISA test). Studies included identification of the isolated molds by nucleotide sequences analyzing of the ITS1/ITS2 regions, actin, calmodulin and Alt a 1 genes. It has been shown that Alternaria molds are significant part of microbiocenosis in the archive, museum, library, composting plant and tannery (14%-16% frequency in the air). The presence of the gene encoding the Alt a 1 protein has been detected for the strains: Alternaria alternata, A. lini, A. limoniasperae A. nobilis and A. tenuissima. Environmental strains produced Alt a 1 at higher concentrations (1.103-6.528 ng/mL) than a ATCC strain (0.551-0.975 ng/mL). It has been shown that the homogenization of the mycelium and the use of ultrafiltration allow a considerable increase of Alt a 1 concentration. Variations in the production of Alt a 1 protein, depend on the strain and extraction methods. These studies revealed no impact of the technical material from the workplaces on the production of Alt a 1 protein.

  12. Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia.

    PubMed

    Coulon, Séverine; Dussiot, Michaël; Grapton, Damien; Maciel, Thiago Trovati; Wang, Pamella Huey Mei; Callens, Celine; Tiwari, Meetu Kaushik; Agarwal, Saurabh; Fricot, Aurelie; Vandekerckhove, Julie; Tamouza, Houda; Zermati, Yael; Ribeil, Jean-Antoine; Djedaini, Kamel; Oruc, Zeliha; Pascal, Virginie; Courtois, Geneviève; Arnulf, Bertrand; Alyanakian, Marie-Alexandra; Mayeux, Patrick; Leanderson, Tomas; Benhamou, Marc; Cogné, Michel; Monteiro, Renato C; Hermine, Olivier; Moura, Ivan C

    2011-10-23

    Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.

  13. A Limited Role for the Cell Cycle Regulator Cyclin A1 in Murine Leukemogenesis

    PubMed Central

    Bäumer, Nicole; Bäumer, Sebastian; Haak, Miriam; Koschmieder, Steffen; Schönig, Kai; Berdel, Wolfgang E.; Müller-Tidow, Carsten

    2015-01-01

    The quest for novel therapeutic targets in acute myeloid leukemia (AML) is still ongoing. One of such targets, cyclin A1, was shown to be overexpressed in AML including AML stem cells. However, the function of cyclin A1 in AML is largely unknown, and the data on its impact on patients´ survival remain controversial. Therefore, we developed a transgenic mouse model of stem cell-directed inducible cyclin A1 overexpression and crossed these mice with PML-RARα-knockin mice, which develop an AML M3-like phenotype. To observe the effects of cyclin A1 loss-of-function, we also crossed PML-RARα-knockin mice to cyclin A1-knockout mice. Neither overexpression nor loss of cyclin A1 significantly altered leukemogenesis in PML-RARα-knockin mice. These findings imply that upregulation of cyclin A1 is not essential for leukemogenesis. Our data suggest that cyclin A1 does not represent a suitable target for AML therapy. PMID:26080083

  14. Production of the Allergenic Protein Alt a 1 by Alternaria Isolates from Working Environments

    PubMed Central

    Skóra, Justyna; Otlewska, Anna; Gutarowska, Beata; Leszczyńska, Joanna; Majak, Iwona; Stępień, Łukasz

    2015-01-01

    The aim of the study was to evaluate the ability of Alternaria isolates from workplaces to produce Alt a 1 allergenic protein, and to analyze whether technical materials (cellulose, compost, leather) present within the working environment stimulate or inhibit Alt a 1 production (ELISA test). Studies included identification of the isolated molds by nucleotide sequences analyzing of the ITS1/ITS2 regions, actin, calmodulin and Alt a 1 genes. It has been shown that Alternaria molds are significant part of microbiocenosis in the archive, museum, library, composting plant and tannery (14%–16% frequency in the air). The presence of the gene encoding the Alt a 1 protein has been detected for the strains: Alternaria alternata, A. lini, A. limoniasperae A. nobilis and A. tenuissima. Environmental strains produced Alt a 1 at higher concentrations (1.103–6.528 ng/mL) than a ATCC strain (0.551–0.975 ng/mL). It has been shown that the homogenization of the mycelium and the use of ultrafiltration allow a considerable increase of Alt a 1 concentration. Variations in the production of Alt a 1 protein, depend on the strain and extraction methods. These studies revealed no impact of the technical material from the workplaces on the production of Alt a 1 protein. PMID:25689994

  15. 17 CFR 275.204A-1 - Investment adviser codes of ethics.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... enforce a written code of ethics that, at a minimum, includes: (1) A standard (or standards) of business... 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...

  16. 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…

  17. 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...

  18. 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...

  19. 42 CFR 63a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... for research training with respect to the human diseases, disorders, or other aspects of human health... 42 Public Health 1 2010-10-01 2010-10-01 false To what programs do these regulations apply? 63a.1 Section 63a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  20. 42 CFR 63a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... for research training with respect to the human diseases, disorders, or other aspects of human health... 42 Public Health 1 2011-10-01 2011-10-01 false To what programs do these regulations apply? 63a.1 Section 63a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

  1. NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

    PubMed Central

    Xia, Jiliang; Gu, Zhimin; Wendlandt, Erik; Zhan, Xin; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang

    2014-01-01

    We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expression of ALDH1A1 in myeloma cells led to increased clonogenicity, tumor formation in mice, and resistance to myeloma drugs in vitro and in vivo. The mechanism underlying these phenotypes included the ALDH1A1-dependent activation of drug-efflux pump, ABCB1, and survival proteins, AKT and BCL2. Over expression of ALDH1A1 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 (NEK2), whereas shRNA-mediated knock down of NEK2 decreased drug efflux pump activity and drug resistance. The activation of NEK2 in myeloma cells relied on the ALDH1A1-dependent generation of the retinoid X receptor α (RXRα) ligand, 9-cis retinoic acid (9CRA) – not the retinoic acid receptor α (RARα) ligand, all-trans retinoic acid (ATRA). These findings implicate the ALDH1A1-RXRα-NEK2 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of ALDH1A1 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma. PMID:25230277

  2. FBG1 Is the Final Arbitrator of A1AT-Z Degradation

    PubMed Central

    Wen, John H.; Wen, Hsiang; Gibson-Corley, Katherine N.; Glenn, Kevin A.

    2015-01-01

    Alpha-1 antitrypsin deficiency is the leading cause of childhood liver failure and one of the most common lethal genetic diseases. The disease-causing mutant A1AT-Z fails to fold correctly and accumulates in the endoplasmic reticulum (ER) of the liver, resulting in hepatic fibrosis and hepatocellular carcinoma in a subset of patients. Furthermore, A1AT-Z sequestration in hepatocytes leads to a reduction in A1AT secretion into the serum, causing panacinar emphysema in adults. The purpose of this work was to elucidate the details by which A1AT-Z is degraded in hepatic cell lines. We identified the ubiquitin ligase FBG1, which has been previously shown to degrade proteins by both the ubiquitin proteasome pathway and autophagy, as being key to A1AT-Z degradation. Using chemical and genetic approaches we show that FBG1 degrades A1AT-Z through both the ubiquitin proteasome system and autophagy. Overexpression of FBG1 decreases the half-life of A1AT-Z and knocking down FBG1 in a hepatic cell line, and in mice results in an increase in ATAT. Finally, we show that FBG1 degrades A1AT-Z through a Beclin1-dependent arm of autophagy. In our model, FBG1 acts as a safety ubiquitin ligase, whose function is to re-ubiquitinate ER proteins that have previously undergone de-ubiquitination to ensure they are degraded. PMID:26295339

  3. Production of the allergenic protein Alt a 1 by Alternaria isolates from working environments.

    PubMed

    Skóra, Justyna; Otlewska, Anna; Gutarowska, Beata; Leszczyńska, Joanna; Majak, Iwona; Stępień, Łukasz

    2015-02-01

    The aim of the study was to evaluate the ability of Alternaria isolates from workplaces to produce Alt a 1 allergenic protein, and to analyze whether technical materials (cellulose, compost, leather) present within the working environment stimulate or inhibit Alt a 1 production (ELISA test). Studies included identification of the isolated molds by nucleotide sequences analyzing of the ITS1/ITS2 regions, actin, calmodulin and Alt a 1 genes. It has been shown that Alternaria molds are significant part of microbiocenosis in the archive, museum, library, composting plant and tannery (14%-16% frequency in the air). The presence of the gene encoding the Alt a 1 protein has been detected for the strains: Alternaria alternata, A. lini, A. limoniasperae A. nobilis and A. tenuissima. Environmental strains produced Alt a 1 at higher concentrations (1.103-6.528 ng/mL) than a ATCC strain (0.551-0.975 ng/mL). It has been shown that the homogenization of the mycelium and the use of ultrafiltration allow a considerable increase of Alt a 1 concentration. Variations in the production of Alt a 1 protein, depend on the strain and extraction methods. These studies revealed no impact of the technical material from the workplaces on the production of Alt a 1 protein. PMID:25689994

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  5. NR4A1 promotes PDGF-BB-induced cell colony formation in soft agar.

    PubMed

    Eger, Glenda; Papadopoulos, Natalia; Lennartsson, Johan; Heldin, Carl-Henrik

    2014-01-01

    The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth. PMID:25269081

  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 Name CAS No. Chemical formula Global warming potential(100 yr.) Carbon dioxide 124-38-9 CO2 1 Methane 74-82-8 CH4 a...

  7. 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 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... A-1 to Subpart A of Part 98—Global Warming Potentials Name CAS No. Chemical formula Global...

  8. 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 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... A-1 to Subpart A of Part 98—Global Warming Potentials Name CAS No. Chemical formula Global...

  9. 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 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR... A-1 to Subpart A of Part 98—Global Warming Potentials Name CAS No. Chemical formula Global...

  10. 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 Name CAS No. Chemical formula Global warming potential(100 yr.) Carbon dioxide 124-38-9 CO2 1 Methane 74-82-8 CH4...

  11. 26 CFR 1.6050A-1 - Reporting requirements of certain fishing boat operators.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Reporting requirements of certain fishing boat operators. 1.6050A-1 Section 1.6050A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... requirements of certain fishing boat operators. (a) Requirement of reporting. The operator of a boat on...

  12. 26 CFR 1.6050A-1 - Reporting requirements of certain fishing boat operators.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 13 2013-04-01 2013-04-01 false Reporting requirements of certain fishing boat operators. 1.6050A-1 Section 1.6050A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... requirements of certain fishing boat operators. (a) Requirement of reporting. The operator of a boat on...

  13. 26 CFR 1.6050A-1 - Reporting requirements of certain fishing boat operators.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Reporting requirements of certain fishing boat operators. 1.6050A-1 Section 1.6050A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... certain fishing boat operators. (a) Requirement of reporting. The operator of a boat on which one or...

  14. 26 CFR 1.6050A-1 - Reporting requirements of certain fishing boat operators.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 13 2012-04-01 2012-04-01 false Reporting requirements of certain fishing boat operators. 1.6050A-1 Section 1.6050A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... requirements of certain fishing boat operators. (a) Requirement of reporting. The operator of a boat on...

  15. 26 CFR 1.6050A-1 - Reporting requirements of certain fishing boat operators.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 13 2014-04-01 2014-04-01 false Reporting requirements of certain fishing boat operators. 1.6050A-1 Section 1.6050A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... requirements of certain fishing boat operators. (a) Requirement of reporting. The operator of a boat on...

  16. 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.

  17. 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

    ... AGENCY 40 CFR Part 52 Approval and Promulgation of Implementation Plans; Tennessee; 110(a)(1) and (2... conditionally approve in part, portions of the State Implementation Plan (SIP) submission, submitted by the... demonstrate that the State meets the requirements of sections 110(a)(1) and (2) of the Clean Air Act (CAA...

  18. 26 CFR 53.4941(a)-1 - Imposition of initial taxes.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(a)-1 Imposition of initial taxes. (a) Tax on self-dealer—(1) In general. Section 4941(a)(1) of the code imposes an excise tax on each act of self-dealing between a disqualified person (as defined in section 4946(a))...

  19. 26 CFR 53.4941(a)-1 - Imposition of initial taxes.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(a)-1 Imposition of initial taxes. (a) Tax on self-dealer—(1) In general. Section 4941(a)(1) of the code imposes an excise tax on each act of self-dealing between a disqualified person (as defined in section 4946(a))...

  20. 26 CFR 53.4941(a)-1 - Imposition of initial taxes.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(a)-1 Imposition of initial taxes. (a) Tax on self-dealer—(1) In general. Section 4941(a)(1) of the code imposes an excise tax on each act of self-dealing between a disqualified person (as defined in section 4946(a))...

  1. 26 CFR 53.4941(a)-1 - Imposition of initial taxes.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) MISCELLANEOUS EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(a)-1 Imposition of initial taxes. (a) Tax on self-dealer—(1) In general. Section 4941(a)(1) of the code imposes an excise tax on each act of self-dealing between a disqualified person (as defined in section 4946(a))...

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

    PubMed Central

    Morgan, Cynthia A.; Hurley, Thomas D.

    2015-01-01

    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 structures 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. 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. PMID:25634381

  3. Apolipoprotein A1/C3/A5 haplotypes and serum lipid levels

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The association of single nucleotide polymorphisms (SNPs) in the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster and serum lipid profiles is inconsistent. The present study was undertaken to detect the association between the ApoA1/C3/A5 gene polymorphisms and their haplotypes with serum lipid levels ...

  4. 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...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Estates, Trusts, and Beneficiaries § 1.642(a)(1)-1 Partially tax-exempt interest. An estate or trust is allowed the credit against tax for partially...

  5. 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....

  6. 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....

  7. 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....

  8. 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....

  9. 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....

  10. 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...) INCOME TAX (CONTINUED) INCOME TAXES Earned Income of Citizens of United States § 1.925(a)-1 Transfer... grouping. The language “or grouping of transactions” is removed from the fourth sentence of §...

  11. 26 CFR 1.6031(a)-1 - Return of partnership income.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 13 2014-04-01 2014-04-01 false Return of partnership income. 1.6031(a)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Information Returns § 1.6031(a)-1 Return of partnership income. (a) Domestic partnerships—(1) Return required. Except as provided in paragraphs (a)(3) and (c)...

  12. 16 CFR Appendix A1 to Part 305 - Refrigerators With Automatic Defrost

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Refrigerators With Automatic Defrost A1 Appendix A1 to Part 305 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC ACTS OF CONGRESS RULE CONCERNING DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME...

  13. 16 CFR Appendix A1 to Part 305 - Refrigerators With Automatic Defrost

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Refrigerators With Automatic Defrost A1 Appendix A1 to Part 305 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC ACTS OF CONGRESS RULE CONCERNING DISCLOSURES REGARDING ENERGY CONSUMPTION AND WATER USE OF CERTAIN HOME...

  14. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  15. NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar

    PubMed Central

    Eger, Glenda; Papadopoulos, Natalia; Lennartsson, Johan; Heldin, Carl-Henrik

    2014-01-01

    The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth. PMID:25269081

  16. NR4A1 promotes PDGF-BB-induced cell colony formation in soft agar.

    PubMed

    Eger, Glenda; Papadopoulos, Natalia; Lennartsson, Johan; Heldin, Carl-Henrik

    2014-01-01

    The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth.

  17. FBG1 Is the Final Arbitrator of A1AT-Z Degradation.

    PubMed

    Wen, John H; Wen, Hsiang; Gibson-Corley, Katherine N; Glenn, Kevin A

    2015-01-01

    Alpha-1 antitrypsin deficiency is the leading cause of childhood liver failure and one of the most common lethal genetic diseases. The disease-causing mutant A1AT-Z fails to fold correctly and accumulates in the endoplasmic reticulum (ER) of the liver, resulting in hepatic fibrosis and hepatocellular carcinoma in a subset of patients. Furthermore, A1AT-Z sequestration in hepatocytes leads to a reduction in A1AT secretion into the serum, causing panacinar emphysema in adults. The purpose of this work was to elucidate the details by which A1AT-Z is degraded in hepatic cell lines. We identified the ubiquitin ligase FBG1, which has been previously shown to degrade proteins by both the ubiquitin proteasome pathway and autophagy, as being key to A1AT-Z degradation. Using chemical and genetic approaches we show that FBG1 degrades A1AT-Z through both the ubiquitin proteasome system and autophagy. Overexpression of FBG1 decreases the half-life of A1AT-Z and knocking down FBG1 in a hepatic cell line, and in mice results in an increase in ATAT. Finally, we show that FBG1 degrades A1AT-Z through a Beclin1-dependent arm of autophagy. In our model, FBG1 acts as a safety ubiquitin ligase, whose function is to re-ubiquitinate ER proteins that have previously undergone de-ubiquitination to ensure they are degraded.

  18. 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 §...

  19. 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 §...

  20. 26 CFR 1.509(a)-1 - Definition of private foundation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Definition of private foundation. 1.509(a)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(a)-1 Definition of private foundation. In general. Section 509(a) defines the term private foundation to mean any domestic or...

  1. 26 CFR 1.509(a)-1 - Definition of private foundation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Definition of private foundation. 1.509(a)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(a)-1 Definition of private foundation. In general. Section 509(a) defines the term private foundation to mean any domestic or...

  2. 26 CFR 1.509(a)-1 - Definition of private foundation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Definition of private foundation. 1.509(a)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(a)-1 Definition of private foundation. In general. Section 509(a) defines the term private foundation to mean any domestic or...

  3. 26 CFR 1.509(a)-1 - Definition of private foundation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Definition of private foundation. 1.509(a)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(a)-1 Definition of private foundation. In general. Section 509(a) defines the term private foundation to mean any domestic or...

  4. 26 CFR 1.509(a)-1 - Definition of private foundation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Definition of private foundation. 1.509(a)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(a)-1 Definition of private foundation. In general. Section 509(a) defines the term private foundation to mean any domestic or...

  5. 26 CFR 1.817A-1 - Certain modified guaranteed contracts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Section 1.817A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Miscellaneous Provisions § 1.817A-1 Certain modified..., an MGC must provide either for a net surrender value or for a policyholder's fund (as defined...

  6. Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia.

    PubMed

    Aoshima, Naoya; Fujie, Yoshiko; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2014-01-01

    Inadequate calorie intake or starvation has been suggested as a cause of neonatal jaundice, which can further cause permanent brain damage, kernicterus. This study experimentally investigated whether additional glucose treatments induce the bilirubin-metabolizing enzyme--UDP-glucuronosyltransferase (UGT) 1A1--to prevent the onset of neonatal hyperbilirubinemia. Neonatal humanized UGT1 (hUGT1) mice physiologically develop jaundice. In this study, UGT1A1 expression levels were determined in the liver and small intestine of neonatal hUGT1 mice that were orally treated with glucose. In the hUGT1 mice, glucose induced UGT1A1 in the small intestine, while it did not affect the expression of UGT1A1 in the liver. UGT1A1 was also induced in the human intestinal Caco-2 cells when the cells were cultured in the presence of glucose. Luciferase assays demonstrated that not only the proximal region (-1300/-7) of the UGT1A1 promoter, but also distal region (-6500/-4050) were responsible for the induction of UGT1A1 in the intestinal cells. Adequate calorie intake would lead to the sufficient expression of UGT1A1 in the small intestine to reduce serum bilirubin levels. Supplemental treatment of newborns with glucose solution can be a convenient and efficient method to treat neonatal jaundice while allowing continuous breastfeeding. PMID:25209391

  7. NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells

    PubMed Central

    Zhao, Di; Mo, Yan; Li, Meng-Tian; Zou, Shao-Wu; Cheng, Zhou-Li; Sun, Yi-Ping; Xiong, Yue; Guan, Kun-Liang; Lei, Qun-Ying

    2014-01-01

    High aldehyde dehydrogenase (ALDH) activity is a marker commonly used to isolate stem cells, particularly breast cancer stem cells (CSCs). Here, we determined that ALDH1A1 activity is inhibited by acetylation of lysine 353 (K353) and that acetyltransferase P300/CBP–associated factor (PCAF) and deacetylase sirtuin 2 (SIRT2) are responsible for regulating the acetylation state of ALDH1A1 K353. Evaluation of breast carcinoma tissues from patients revealed that cells with high ALDH1 activity have low ALDH1A1 acetylation and are capable of self-renewal. Acetylation of ALDH1A1 inhibited both the stem cell population and self-renewal properties in breast cancer. Moreover, NOTCH signaling activated ALDH1A1 through the induction of SIRT2, leading to ALDH1A1 deacetylation and enzymatic activation to promote breast CSCs. In breast cancer xenograft models, replacement of endogenous ALDH1A1 with an acetylation mimetic mutant inhibited tumorigenesis and tumor growth. Together, the results from our study reveal a function and mechanism of ALDH1A1 acetylation in regulating breast CSCs. PMID:25384215

  8. 17 CFR 270.55a-1 - Investment activities of business development companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... business development companies. 270.55a-1 Section 270.55a-1 Commodity and Securities Exchanges SECURITIES... Investment activities of business development companies. Notwithstanding section 55(a) of the Act (15 U.S.C. 80a-54(a)), a business development company may acquire securities purchased in transactions...

  9. 17 CFR 270.55a-1 - Investment activities of business development companies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... business development companies. 270.55a-1 Section 270.55a-1 Commodity and Securities Exchanges SECURITIES... Investment activities of business development companies. Notwithstanding section 55(a) of the Act (15 U.S.C. 80a-54(a)), a business development company may acquire securities purchased in transactions...

  10. 42 CFR 65a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false To what programs do these regulations apply? 65a.1 Section 65a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  11. 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 Section 65a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  12. 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 Section 65a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  13. 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 Section 65a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  14. 42 CFR 65a.1 - To what programs do these regulations apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false To what programs do these regulations apply? 65a.1 Section 65a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC...

  15. 76 FR 56637 - Airworthiness Directives; Lycoming Engines Model IO-720-A1B Reciprocating Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-14

    ... Policies and Procedures (44 FR 11034, February 26, 1979), (3) Will not affect intrastate aviation in Alaska... Model IO-720-A1B Reciprocating Engines AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Final... model IO-720-A1B Lycoming Engines reciprocating engines. This AD requires a crankshaft inspection...

  16. The effect of CYP7A1 polymorphisms on lipid responses to fenofibrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: CYP7A1 encodes cholesterol 7a-hydroxylase, an enzyme crucial to cholesterol homeostasis. Its transcriptional activity is downregulated by fenofibrate. The goal of this study s to determine the effect of CYP7A1 polymorphisms on lipid changes in response to fenofibrate. Methods: We exam...

  17. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  18. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  19. 47 CFR 80.1089 - Ship radio equipment-Sea areas A1 and A2.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Ship radio equipment-Sea areas A1 and A2. 80... RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1089 Ship radio equipment—Sea areas A1 and A2. This...

  20. 26 CFR 54.4981A-1T - Tax on excess distributions and excess accumulations (temporary).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 17 2011-04-01 2011-04-01 false Tax on excess distributions and excess accumulations (temporary). 54.4981A-1T Section 54.4981A-1T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES (CONTINUED) PENSION EXCISE TAXES §...

  1. 26 CFR 54.4981A-1T - Tax on excess distributions and excess accumulations (temporary).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 17 2010-04-01 2010-04-01 false Tax on excess distributions and excess accumulations (temporary). 54.4981A-1T Section 54.4981A-1T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES (CONTINUED) PENSION EXCISE TAXES §...

  2. 26 CFR 54.4981A-1T - Tax on excess distributions and excess accumulations (temporary).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 17 2014-04-01 2014-04-01 false Tax on excess distributions and excess accumulations (temporary). 54.4981A-1T Section 54.4981A-1T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES (CONTINUED) PENSION EXCISE TAXES §...

  3. Genome sequence of Citrobacter sp. strain A1, a dye-degrading bacterium.

    PubMed

    Chan, Giek Far; Gan, Han Ming; Rashid, Noor Aini Abdul

    2012-10-01

    Citrobacter sp. strain A1, isolated from a sewage oxidation pond, is a facultative aerobe and mesophilic dye-degrading bacterium. This organism degrades azo dyes efficiently via azo reduction and desulfonation, followed by the successive biotransformation of dye intermediates under an aerobic environment. Here we report the draft genome sequence of Citrobacter sp. A1.

  4. 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 §...

  5. 42 CFR 59a.1 - Programs to which these regulations apply.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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..., materials, or both, for establishing, expanding, and improving basic medical library resources as...

  6. An enzymatic method for the determination of hemoglobinA(1C).

    PubMed

    Hirokawa, Kozo; Shimoji, Kazuhiko; Kajiyama, Naoki

    2005-07-01

    Fructosyl peptide oxidase is a flavoenzyme that catalyzes the oxidative deglycation of N-(1-deoxyfructosyl)-Val-His, a model compound of hemoglobin (Hb)A(1C). To develop an enzymatic method for the measurement of HbA(1C), we screened for a proper protease using N-(1-deoxyfructosyl)-hexapeptide as a substrate. Several proteases, including Neutral protease from Bacillus polymyxa, were found to release N-(1-deoxyfructosyl)-Val-His efficiently, however no protease was found to release N-(1-deoxyfructosyl)-Val. Neutral protease also digested HbA(1C) to release N-(1-deoxyfructosyl)-Val-His, and then the fructosyl peptide was detected using fructosyl peptide oxidase. The linear relationship was observed between the concentration of HbA(1C) and the absorbancy of fructosyl peptide oxidase reaction, hence this new method is a practical means for measuring HbA(1C.).

  7. Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents.

    PubMed

    Mast, Natalia; Linger, Marlin; Pikuleva, Irina A

    2013-05-22

    In vertebrates, the biosynthesis of steroid hormones is initiated by cytochrome P450 CYP11A1 which converts cholesterol to pregnenolone. We investigated whether some of the experimental and FDA-approved therapeutic agents alter the activity of CYP11A1 in the reconstituted system in vitro. We found that under the experimental conditions used and when phospholipids are included, ketoconazole, posaconazole, carbenoxolone, and selegiline inhibit CYP11A1-mediated production of pregnenolone by at least 67%. Conversely, pemirolast, clobenpropit, desogestrel, dexmedetomidine, and tizanidine stimulate the enzyme activity by up to 70%. We then evaluated the identified inhibitors and activators for spectral binding to CYP11A1 and their effect on enzyme activity in the absence of phospholipids. The data obtained provide insight into how different drugs interact with CYP11A1 and demonstrate that P450 association with the lipid bilayer determines, in many cases, a drug's effect on enzyme activity.

  8. Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents

    PubMed Central

    Mast, Natalia; Linger, Marlin; Pikuleva, Irina A.

    2012-01-01

    In vertebrates, the biosynthesis of steroid hormones is initiated by cytochrome P450 CYP11A1 which converts cholesterol to pregnenolone. We investigated whether some of the experimental and FDA-approved therapeutic agents alter the activity of CYP11A1 in the reconstituted system in vitro. We found that under the experimental conditions used and when phospholipids are included, ketoconazole, posaconazole, carbenoxolone, and selegiline inhibit CYP11A1-mediated production of pregnenolone by at least 67%. Conversely, pemirolast, clobenpropit, desogestrel, dexmedetomidine, and tizanidine stimulate the enzyme activity by up to 70%. We then evaluated the identified inhibitors and activators for spectral binding to CYP11A1 and their effect on enzyme activity in the absence of phospholipids. The data obtained provide insight into how different drugs interact with CYP11A1 and demonstrate that P450 association with the lipid bilayer determines, in many cases, a drug’s effect on enzyme activity. PMID:23089212

  9. Structural and magnetic properties of L1(0)/A1, FePt nanocomposites

    SciTech Connect

    Giannopoulos, G; Speliotis, T; Li, WF; Hadjipanayis, G; Niarchos, D

    2013-01-01

    In this work structural and magnetic properties of (L1(0)-FePt/A1-FePt) exchange coupled nanocomposites are presented. Semi spherical "dome-like" nanocomposites with L1(0) FePt isolated nanoparticles and A1 FePt (fcc) cap layers were obtained by depositing A1-FePt on type L1(0) FePt nanoparticles in order to understand the influence of the soft magnetic layer thickness on the magnetic properties of the system. Epitaxial growth is confirmed by X-ray diffraction and TEM, while the coercivity decreases dramatically for the L1(0)/A1-FePt system when the thickness of the A1-FePt cap layers is increased. This result can be used to realize ultrahigh magnetic recording media with tunable coercivity, suitable for conventional write heads. (C) 2012 Elsevier B.V. All rights reserved.

  10. SLC11A1 is expressed by innate lymphocytes and augments their activation1

    PubMed Central

    Hedges, Jodi F.; Kimmel, Emily; Snyder, Deann T.; Jerome, Maria; Jutila, Mark A.

    2013-01-01

    SLC11A1 is a divalent ion transporter formerly known as the natural resistance-associated macrophage protein (NRAMP1) and the Bcg/Lsh/Ity locus. SLC11A1 was thought to be exclusively expressed in monocyte/macrophages and to have roles in phagosome maturation and cell activation. We characterized the expression of SLC11A1 in the majority of human and bovine γδ T cells and NK cells, and in human CD3+CD45RO+ T cells. Consistent with a role for iron-dependent inhibition of protein tyrosine phosphatases, SLC11A1+ lymphocytes were moreprone to activation and retained tyrosine phosphorylation. Transfection of SLC11A1 into a human γδ T cell-like line rendered the cells more prone to activation. Non-adherent splenocytes from wild type mice expressed significantly greater IFN-γ compared to cells from Sv/129 (SLC11A1−/−) mice. Our data suggest that SLC11A1 has a heretofore unknown role in activation of a large subset of innate lymphocytes that are critical sources of IFN-γ. SLC11A1+ animals have enhanced innate IFN-γ expression in response to Salmonella infection compared to SLC11A1−mice, which includes commonly used inbred laboratory mice. Expression of SLC11A1 in innate lymphocytes and its role in augmenting their activation may account for inconsistencies in studies of innate lymphocytes in different animal models. PMID:23509347

  11. S100A1 transgenic treatment of acute heart failure causes proteomic changes in rats

    PubMed Central

    Guo, Yichen; Cui, Lianqun; Jiang, Shiliang; Wang, Dongmei; Jiang, Shu; Xie, Chen; Jia, Yanping

    2016-01-01

    S100 Ca2+-binding protein A1 (S100A1) is an important regulator of myocardial contractility. The aim of the present study was to identify the underlying mechanisms of S100A1 activity via profiling the protein expression in rats administered with an S100A1 adenovirus (Ad-S100A1-EGFP) following acute myocardial infarction (AMI). LTQ OrbiTrap mass spectrometry was used to profile the protein expression in the Ad-S100A1-EGFP and control groups post-AMI. Using Protein Analysis Through Evolutionary Relationships (PANTHER) analysis, 134 energy metabolism-associated proteins, which comprised 20 carbohydrate metabolism-associated and 27 lipid metabolism associated proteins, were identified as differentially expressed in the Ad-S100A1-EGFP hearts compared with controls. The majority of the differentially expressed proteins identified were important enzymes involved in energy metabolism. The present study identified 12 Ca2+-binding proteins and 22 cytoskeletal proteins. The majority of the proteins expressed in the Ad-S100A1-EGFP group were upregulated compared with the control group. These results were further validated using western blot analysis. Following AMI, Ca2+ is crucial for the recovery of myocardial function in S100A1 transgenic rats as indicated by the upregulation of proteins associated with energy metabolism and Ca2+-binding. Thus, the current study ascertained that energy production and contractile ability were enhanced after AMI in the ventricular myocardium of the Ad-S100A1-EGFP group. PMID:27357314

  12. Expression of COL6A1 predicts prognosis in cervical cancer patients

    PubMed Central

    Hou, Teng; Tong, Chongjie; Kazobinka, Gallina; Zhang, Weijing; Huang, Xin; Huang, Yongwen; Zhang, Yanna

    2016-01-01

    COL6A1 has been shown to play an important role in tumor initiation and progression. The present study is to investigate the clinical significance of COL6A1 in cervical cancer. In this study, the COL6A1 expression levels in 10 paired cervical cancer tissues and the adjacent non-tumor tissues were examined by real-time PCR. The expression of COL6A1 protein was examined in 162 cervical cancer samples by immunohistochemistry, and the correlation of COL6A1 expression with clinicopathologic factors was analyzed. The overall and recurrent-free survival rates were estimated using Kaplan-Meier method and compared with the log-rank test. The prognostic analysis was carried out with multivariate Cox regressions model. The result showed that COL6A1 expression was up-regulated in cervical cancer tissues in compared with that in non-tumor tissues. High expression of COL6A1 was significantly correlated with FIGO stage (P<0.001), tumor size (P=0.025) and lymph node metastasis (P=0.028) of the disease. Moreover, survival analysis showed that high expression of COL6A1 was significantly associated with poorer overall (OS) and recurrent free (RFS) survival (p=0.004 and =0.001, respectively) of cervical cancer patients. Multivariate analysis suggested that COL6A1 expression was an independent prognostic marker of cervical cancer (P=0.029). Thus, COL6A1 may serve as an oncogene in the initiation and progression of cervical cancer, and as a predictor of poor prognosis in cervical cancer patients. PMID:27398167

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

    SciTech Connect

    El Gendy, Mohamed A.M.; El-Kadi, Ayman O.S.

    2010-11-15

    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 in 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.

  14. S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction.

    PubMed

    Pleger, Sven T; Remppis, Andrew; Heidt, Beatrix; Völkers, Mirko; Chuprun, J Kurt; Kuhn, Matthew; Zhou, Rui-Hai; Gao, Erhe; Szabo, Gabor; Weichenhan, Dieter; Müller, Oliver J; Eckhart, Andrea D; Katus, Hugo A; Koch, Walter J; Most, Patrick

    2005-12-01

    Myocardial infarction (MI) represents an enormous clinical challenge as loss of myocardium due to ischemic injury is associated with compromised left ventricular (LV) function often leading to acute cardiac decompensation or chronic heart failure. S100A1 was recently identified as a positive inotropic regulator of myocardial contractility in vitro and in vivo. Here, we explore the strategy of myocardial S100A1 gene therapy either at the time of, or 2 h after, MI to preserve global heart function. Rats underwent cryothermia-induced MI and in vivo intracoronary delivery of adenoviral transgenes (4 x 10(10) pfu). Animals received saline (MI), the S100A1 adenovirus (MI/AdS100A1), a control adenovirus (MI/AdGFP), or a sham operation. S100A1 gene delivery preserved global in vivo LV function 1 week after MI. Preservation of LV function was due mainly to S100A1-mediated gain of contractility of the remaining, viable myocardium since contractile parameters and Ca(2+) transients of isolated MI/AdS100A1 myocytes were significantly enhanced compared to myocytes isolated from both MI/AdGFP and sham groups. Moreover, S100A1 gene therapy preserved the cardiac beta-adrenergic inotropic reserve, which was associated with the attenuation of GRK2 up-regulation. Also, S100A1 overexpression reduced cardiac hypertrophy 1 week post-MI. Overall, our data indicate that S100A1 gene therapy provides a potential novel treatment strategy to maintain contractile performance of the post-MI heart.

  15. Regulation of cyp26a1 on Th17 cells in mouse peri-implantation

    PubMed Central

    Liu, Hai-Yan; Chao, Huhe; Liu, Zhen-Kun; Xia, Hong-Fei; Song, Zhihui; Yang, Ying; Peng, Jing-Pian

    2014-01-01

    Cytochrome P450 26A1 (cyp26a1) is expressed in the mouse uterus during peri-implantation. The repression of this protein is closely associated with a reduction in implantation sites, suggesting a specific role for cyp26a1 in pregnancy and prompting questions concerning how a metabolic enzyme can generate this distinct outcome. To explore the effective downstream targets of cyp26a1 and confirm if its role in peri-implantation depends on its metabolic substrate RA (retinoic acid), we characterized the changes in the peripheral blood, spleen and uterine implantation sites using the cyp26a1 gene vaccine constructed before. Flow cytometry results showed a significant increase in CD4+RORγt+ Th17 cells in both the peripheral blood and spleen in the experimental group. The expression of RORγt and IL-17 presented the Th17 cells reduction in uterus followed by the suppression of cyp26a1 expression. For greater certainty, cyp26a1 antibody blocking model and RNA interference model were constructed to determine the precise target immune cell group. High performance liquid chromatography results showed a significant increase in uterine at-RA followed by the immunization of cyp26a1 gene vaccine. Both the ascertain by measuring RARα protein levels in peri-implantation uterus after gene vaccine immunization and researches using the specific agonist and antagonist against RARα suggested that RARα may be the main RA receptor for signal transduction. These results provided more evidence for the signal messenger role of RA in cyp26a1 regulation from the other side. Here, we showed that the cyp26a1-regulated Th17 cells are dependent on at-RA signalling, which is delivered through RARα in mouse peri-implantation. PMID:24325348

  16. A Critical Role for the GluA1 Accessory Protein, SAP97, in Cocaine Seeking.

    PubMed

    White, Samantha L; Ortinski, Pavel I; Friedman, Shayna H; Zhang, Lei; Neve, Rachael L; Kalb, Robert G; Schmidt, Heath D; Pierce, R Christopher

    2016-02-01

    A growing body of evidence indicates that the transport of GluA1 subunit-containing calcium-permeable AMPA receptors (CP-AMPARs) to synapses in subregions of the nucleus accumbens promotes cocaine seeking. Consistent with these findings, the present results show that administration of the CP-AMPAR antagonist, Naspm, into the caudal lateral core or caudal medial shell of the nucleus accumbens attenuated cocaine priming-induced reinstatement of drug seeking. Moreover, viral-mediated overexpression of 'pore dead' GluA1 subunits (via herpes simplex virus (HSV) GluA1-Q582E) in the lateral core or medial shell attenuated the reinstatement of cocaine seeking. The overexpression of wild-type GluA1 subunits (via HSV GluA1-WT) in the medial shell, but not the lateral core, enhanced the reinstatement of cocaine seeking. These results indicate that activation of GluA1-containing AMPARs in subregions of the nucleus accumbens reinstates cocaine seeking. SAP97 and 4.1N are proteins involved in GluA1 trafficking to and stabilization in synapses; SAP97-GluA1 interactions also influence dendritic growth. We next examined potential roles of SAP97 and 4.1N in cocaine seeking. Viral-mediated expression of a microRNA that reduces SAP97 protein expression (HSV miSAP97) in the medial accumbens shell attenuated cocaine seeking. In contrast, a virus that overexpressed a dominant-negative form of a 4.1N C-terminal domain (HSV 4.1N-CTD), which prevents endogenous 4.1N binding to GluA1 subunits, had no effect on cocaine seeking. These results indicate that the GluA1 subunit accessory protein SAP97 may represent a novel target for pharmacotherapeutic intervention in the treatment of cocaine craving.

  17. Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons.

    PubMed

    Cole, Brian S; Tapescu, Iulia; Allon, Samuel J; Mallory, Michael J; Qiu, Jinsong; Lake, Robert J; Fan, Hua-Ying; Fu, Xiang-Dong; Lynch, Kristen W

    2015-12-01

    HnRNP L is a ubiquitous splicing-regulatory protein that is critical for the development and function of mammalian T cells. Previous work has identified a few targets of hnRNP L-dependent alternative splicing in T cells and has described transcriptome-wide association of hnRNP L with RNA. However, a comprehensive analysis of the impact of hnRNP L on mRNA expression remains lacking. Here we use next-generation sequencing to identify transcriptome changes upon depletion of hnRNP L in a model T-cell line. We demonstrate that hnRNP L primarily regulates cassette-type alternative splicing, with minimal impact of hnRNP L depletion on transcript abundance, intron retention, or other modes of alternative splicing. Strikingly, we find that binding of hnRNP L within or flanking an exon largely correlates with exon repression by hnRNP L. In contrast, exons that are enhanced by hnRNP L generally lack proximal hnRNP L binding. Notably, these hnRNP L-enhanced exons share sequence and context features that correlate with poor nucleosome positioning, suggesting that hnRNP may enhance inclusion of a subset of exons via a cotranscriptional or epigenetic mechanism. Our data demonstrate that hnRNP L controls inclusion of a broad spectrum of alternative cassette exons in T cells and suggest both direct RNA regulation as well as indirect mechanisms sensitive to the epigenetic landscape.

  18. Substrate Specificity and Ligand Interactions of CYP26A1, the Human Liver Retinoic Acid Hydroxylase

    PubMed Central

    Thatcher, Jayne E.; Buttrick, Brian; Shaffer, Scott A.; Shimshoni, Jakob A.; Goodlett, David R.; Nelson, Wendel L.

    2011-01-01

    All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA) metabolism have been developed. The hepatic clearance of atRA is mediated primarily by CYP26A1, but design of CYP26A1 inhibitors is hindered by lack of information on CYP26A1 structure and structure-activity relationships of its ligands. The aim of this study was to identify the primary metabolites of atRA formed by CYP26A1 and to characterize the ligand selectivity and ligand interactions of CYP26A1. On the basis of high-resolution tandem mass spectrometry data, four metabolites formed from atRA by CYP26A1 were identified as 4-OH-RA, 4-oxo-RA, 16-OH-RA and 18-OH-RA. 9-cis-RA and 13-cis-RA were also substrates of CYP26A1. Forty-two compounds with diverse structural properties were tested for CYP26A1 inhibition using 9-cis-RA as a probe, and IC50 values for 10 inhibitors were determined. The imidazole- and triazole-containing inhibitors [S-(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010) and (R)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (R115866) were the most potent inhibitors of CYP26A1 with IC50 values of 4.3 and 5.1 nM, respectively. Liarozole and ketoconazole were significantly less potent with IC50 values of 2100 and 550 nM, respectively. The retinoic acid receptor (RAR) γ agonist CD1530 was as potent an inhibitor of CYP26A1 as ketoconazole with an IC50 of 530 nM, whereas the RARα and RARβ agonists tested did not significantly inhibit CYP26A1. The pan-RAR agonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and the peroxisome proliferator-activated receptor ligands rosiglitazone and pioglitazone inhibited CYP26A1 with IC50 values of 3.7, 4.2, and 8.6 μM, respectively. These data demonstrate that CYP26A1 has high ligand selectivity but accepts structurally related nuclear

  19. Initial formation of zebrafish brain ventricles occurs independently of circulation and requires the nagie oko and snakehead/atp1a1a.1 gene products.

    PubMed

    Lowery, Laura Anne; Sive, Hazel

    2005-05-01

    The mechanisms by which the vertebrate brain develops its characteristic three-dimensional structure are poorly understood. The brain ventricles are a highly conserved system of cavities that form very early during brain morphogenesis and that are required for normal brain function. We have initiated a study of zebrafish brain ventricle development and show here that the neural tube expands into primary forebrain, midbrain and hindbrain ventricles rapidly, over a 4-hour window during mid-somitogenesis. Circulation is not required for initial ventricle formation, only for later expansion. Cell division rates in the neural tube surrounding the ventricles are higher than between ventricles and, consistently, cell division is required for normal ventricle development. Two zebrafish mutants that do not develop brain ventricles are snakehead and nagie oko. We show that snakehead is allelic to small heart, which has a mutation in the Na+K+ ATPase gene atp1a1a.1. The snakehead neural tube undergoes normal ventricle morphogenesis; however, the ventricles do not inflate, probably owing to impaired ion transport. By contrast, mutants in nagie oko, which was previously shown to encode a MAGUK family protein, fail to undergo ventricle morphogenesis. This correlates with an abnormal brain neuroepithelium, with no clear midline and disrupted junctional protein expression. This study defines three steps that are required for brain ventricle development and that occur independently of circulation: (1) morphogenesis of the neural tube, requiring nok function; (2) lumen inflation requiring atp1a1a.1 function; and (3) localized cell proliferation. We suggest that mechanisms of brain ventricle development are conserved throughout the vertebrates.

  20. 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.

  1. Ethanol up-regulates phenol sulfotransferase (SULT1A1) and hydroxysteroid sulfotransferase (SULT2A1) in rat liver and intestine.

    PubMed

    Maiti, Smarajit; Chen, Guangping

    2015-05-01

    Ethanol-consumption impairs physiological-efficiency/endurance, expedites senescence. Impaired-regulations of steroids/biomolecules link these processes. Steroids are catabolized by cytosolic-sulfotransferases (SULTs). Ethanol-induction of eukaryotic-SULTs-expression is scanty. Plant (Brassica-napus) steroid-sulfotransferase; BNST3/BNST4 (gene/BNST) is highly ethanol-inducible (protein/mRNA). Resembling mammalian-SULTs catalytic-mechanism BNSTs show broad substrate-specificities (mammalian-steroids; estradiol/dehydroepiandrosterone/pregnanolone). Recently, ethanol-regulation of SULTs-expression is verified in rat liver/intestine/cultured human-hepatocarcinoma (Hep-G2) cells at enzyme-activity/protein-expression (Western-blot) level. Here, two week's ethanol ingestion by male rat significantly increased SULT2A1 in their liver/intestine (p < 0.05-p < 0.001) and phenol-sulfotransferase (SULT1A1) in intestine (p < 0.001) at enzyme-activity/protein levels. In human cells, ethanol significantly (2-fold) increased hSULT1A1/hSULT1E (2-3 fold) protein expressions paralleling their enzymatic-activities (p < 0.05-p < 0.01). The earlier finding of alcohol-association to the physiological impairment may be corroborated by our present findings. Inductions of SULT-expressions by ethanol have significant physiological/pharmacological consequences.

  2. Luminol chemiluminescence biosensor for glycated hemoglobin (HbA1c) in human blood samples.

    PubMed

    Ahn, Kwang-Soo; Lee, JungHoon; Park, Jong-Myeon; Choi, Han Nim; Lee, Won-Yong

    2016-01-15

    Luminol chemiluminescence (CL) biosensor based on boronic acid modified gold substrate has been developed for the determination of glycated hemoglobin (HbA1c) in human blood samples. In order to selectively capture HbA1c in sample, carboxy-EG6-undecanethiol was self-assembled on a gold thin-film substrate, followed by covalent coupling of 3-aminophenyl boronic acid (3-APBA). The captured HbA1c containing four iron heme groups plays as a catalyst for luminol CL reaction in the presence of hydrogen peroxide, and thus the luminol CL response is linearly proportional to the amount of HbA1c captured on the biosensor surface. The present biosensor showed linear dynamic range of HbA1c from 2.5% to 17.0%, which well covers the clinically important concentration range. In addition, the present biosensor exhibited negligible response to interfering species such as hemoglobin, fructose, and sorbitol. The present HbA1c biosensor was applied to the determination of HbA1c in human blood samples and the results were well agreed with that obtained with a conventional method.

  3. 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

  4. Deregulated SLC2A1 Promotes Tumor Cell Proliferation and Metastasis in Gastric Cancer

    PubMed Central

    Yan, Shiyan; Wang, Yuqin; Chen, Meimei; Li, Guangming; Fan, Jiangao

    2015-01-01

    Gastric cancer (GC) is one of the common reasons of cancer-related death with few biomarkers for diagnosis and prognosis. Solute carrier family 2 (facilitated glucose transporter) member 1 protein SLC2A1, also known as glucose transporter type 1 (GLUT1), has been associated with tumor progression, metastasis, and poor prognosis in many human solid tumors. However, little is reported about its clinical significance and biological functions in GC. Here we observed a strong up-regulation of SLC2A1 in patients with GC and found that SLC2A1 was significantly correlated with depth of invasion and clinical stage. Additionally, over-expression of SLC2A1 in GC cells promotes cellular proliferation and metastasis in vitro and enhances tumor growth in vivo as well as enhancement of glucose utilization. Meanwhile, elevated SLC2A1 also contributes to tumor metastasis in vitro. Our results indicate SLC2A1 exhibits a pivotal role in tumor growth, metastasis and glucose metabolism, and also suggest SLC2A1 as a promising target for gastric cancer therapy. PMID:26193257

  5. 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

    2016-01-01

    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. Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo

    PubMed Central

    Iqbal, Asif J; Barrett, Tessa J; Taylor, Lewis; McNeill, Eileen; Manmadhan, Arun; Recio, Carlota; Carmineri, Alfredo; Brodermann, Maximillian H; White, Gemma E; Cooper, Dianne; DiDonato, Joseph A; Zamanian-Daryoush, Maryam; Hazen, Stanley L; Channon, Keith M

    2016-01-01

    Apolipoprotein A1 (apoA1) is the major protein component of high-density lipoprotein (HDL) and has well documented anti-inflammatory properties. To better understand the cellular and molecular basis of the anti-inflammatory actions of apoA1, we explored the effect of acute human apoA1 exposure on the migratory capacity of monocyte-derived cells in vitro and in vivo. Acute (20–60 min) apoA1 treatment induced a substantial (50–90%) reduction in macrophage chemotaxis to a range of chemoattractants. This acute treatment was anti-inflammatory in vivo as shown by pre-treatment of monocytes prior to adoptive transfer into an on-going murine peritonitis model. We find that apoA1 rapidly disrupts membrane lipid rafts, and as a consequence, dampens the PI3K/Akt signalling pathway that coordinates reorganization of the actin cytoskeleton and cell migration. Our data strengthen the evidence base for therapeutic apoA1 infusions in situations where reduced monocyte recruitment to sites of inflammation could have beneficial outcomes. DOI: http://dx.doi.org/10.7554/eLife.15190.001 PMID:27572261

  7. Functional characterization of steroid hydroxylase CYP106A1 derived from Bacillus megaterium.

    PubMed

    Lee, Ga-Young; Kim, Dong-Hyun; Kim, Donghak; Ahn, Taeho; Yun, Chul-Ho

    2015-01-01

    In this study, we examined the catalytic activity of CYP106A1 from the Bacillus megaterium American Type Culture Collection 14581 strain. The CYP106A1 gene was cloned from B. megaterium, heterologously expressed in Escherichia coli, and purified. Potential electron partners and possible bacterial CYP106A1 substrates were identified by examining the oxidative activity toward a set of steroids in the presence of several reductase systems. The activities of CYP106A1 in a reconstituted system could not be achieved using rat NADPH-P450 reductase or a putidaredoxin reductase-putidaredoxin pair. However, the spinach redox proteins, a ferredoxin reductase-ferredoxin pair, were found to be efficient redox partners for CYP106A1. CYP106A1 catalyzes the hydroxylation of a set of steroids including testosterone, progesterone, 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol to produce monohydroxylated products as the major metabolites. These results suggest that CYP106A1 would be useful for the bioconversion of steroid hormones to hydroxylated products that can be used for industrial applications. PMID:24988988

  8. Spatially controlled expression of the Drosophila pseudouridine synthase RluA-1.

    PubMed

    Wang, Chung-Chi; Lo, Jun-Chih; Chien, Cheng-Ting; Huang, Min-Lang

    2011-01-01

    Pseudouridine (Ψ) synthases function in the formation of Ψ, the most abundant of the modified RNA residues. All Ψ synthases in E. coli are classified into one of five families according to their sequences. Among them, members of the RluA Ψ synthase family catalyze certain Ψ formations in ribosomal RNA. RluA family members are required for ribosomal assembly and bacterial growth. None of the RluA in multicellular organisms has been studied. In the Drosophila peripheral nervous system, multiple dendritic (MD) neurons are recognized by their dendritic arbors. MD neurons can also be identified by using the enhancer trap line E7-2-36, which expresses the lacZ gene in MD neurons. Here, we show that the P-element of E7-2-36 inserts into the Drosophila RluA-1 gene. RluA-1 is homologous to E. coli RluA family members and is evolutionarily conserved in multicellular organisms. In situ hybridization and immunocytochemistry revealed that RluA-1 is expressed in MD neurons. We investigated the RluA-1 enhancer responsible for MD expression and found that the membrane-tethered green fluorescent protein driven by RluA-1-GAL4 was expressed in the dendritic arbors of MD neurons, confirming that RluA-1 is indeed expressed in MD neurons. Thus, the expression of RluA-1 is spatially controlled during development.

  9. Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo.

    PubMed

    Iqbal, Asif J; Barrett, Tessa J; Taylor, Lewis; McNeill, Eileen; Manmadhan, Arun; Recio, Carlota; Carmineri, Alfredo; Brodermann, Maximillian H; White, Gemma E; Cooper, Dianne; DiDonato, Joseph A; Zamanian-Daryoush, Maryam; Hazen, Stanley L; Channon, Keith M; Greaves, David R; Fisher, Edward A

    2016-01-01

    Apolipoprotein A1 (apoA1) is the major protein component of high-density lipoprotein (HDL) and has well documented anti-inflammatory properties. To better understand the cellular and molecular basis of the anti-inflammatory actions of apoA1, we explored the effect of acute human apoA1 exposure on the migratory capacity of monocyte-derived cells in vitro and in vivo. Acute (20-60 min) apoA1 treatment induced a substantial (50-90%) reduction in macrophage chemotaxis to a range of chemoattractants. This acute treatment was anti-inflammatory in vivo as shown by pre-treatment of monocytes prior to adoptive transfer into an on-going murine peritonitis model. We find that apoA1 rapidly disrupts membrane lipid rafts, and as a consequence, dampens the PI3K/Akt signalling pathway that coordinates reorganization of the actin cytoskeleton and cell migration. Our data strengthen the evidence base for therapeutic apoA1 infusions in situations where reduced monocyte recruitment to sites of inflammation could have beneficial outcomes. PMID:27572261

  10. 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.

  11. IN VITRO ORGANIC NITRATE BIOACTIVATION TO NITRIC OXIDE BY RECOMBINANT ALDEHYDE DEHYDROGENASE 3A1

    PubMed Central

    Lin, Shunxin; Page, Nathaniel A.; Fung, Sun Mi; Fung, Ho-Leung

    2013-01-01

    Organic nitrates (ORNs) are commonly used anti-ischemic and anti-anginal agents, which serve as an exogenous source of the potent vasodilator nitric oxide (NO). Recently, both mitochondrial aldehyde dehydrogenase-2 (ALDH2) and cytosolic aldehyde dehydrogenase-1a1 (ALDH1A1) have been shown to exhibit the ability to selectively bioactivate various ORNs in vitro. The objective of the present research was to examine the potential role of ALDH3A1, another major cytosolic isoform of ALDH, in the in vitro bioactivation of various ORNs, and to estimate the enzyme kinetic parameters toward ORNs through mechanistic modeling. The extent of bioactivation was assayed by exposing recombinant ALDH3A1 to various concentrations of ORNs, and measuring the concentration-time profiles of released NO via a NO-specific electrode. Metabolite formation kinetics was monitored for nitroglycerin (NTG) using LC/MS/MS. Our results showed that ALDH3A1 mRNA and protein were highly expressed in C57BL/6 mouse aortic, cardiac, and hepatic tissues, and it was able to release NO from several ORNs, including NTG, isosorbide dinitrate (ISDN), isosorbide-2-mononitrate (IS-2-MN), and nicorandil with similar Vmax (0.175 – 0.503 nmol/min/mg of ALDH3A1), and Km values of 4.01, 46.5, 818 and 5.75 × 103 μM respectively. However, activation of isosorbide-5-mononitrate (IS-5-MN) by ALDH3A1 was undetectable in vitro. ALDH3A1 was also shown to denitrate NTG, producing primarily glyceryl 1, 2-dinitrate (1, 2-GDN) in preference to glyceryl 1, 3-dinitrate (1, 3-GDN). Therefore, ALDH3A1 may contribute to the bioactivation of ORNs in vivo. PMID:24126018

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

    SciTech Connect

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

    2014-04-28

    The light axial-vector resonances $a_1(1260)$ 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 $m_{b_1}^{res}=1.414(36)(^{+0}_{-83})$.

  13. CYP18A1 regulates tissue-specific steroid hormone inactivation in Bombyx mori

    PubMed Central

    Li, Zhiqian; Ge, Xie; Ling, Lin; Zeng, Baosheng; Xu, Jun; Aslam, Abu F.M.; You, Lang; Palli, Subba Reddy; Huang, Yongping; Tan, Anjiang

    2015-01-01

    Insect development and metamorphosis are regulated by two major hormones, juvenile hormone and ecdysteroids. Despite being the key regulator of insect developmental transitions, the metabolic pathway of the primary steroid hormone, 20-hydroxyecdysone (20E), especially its inactivation pathway, is still not completely elucidated. A cytochrome P450 enzyme, CYP18A1, has been shown to play key roles in insect steroid hormone inactivation through 26-hydroxylation. Here, we identified two CYP18 (BmCYP18A1 and BmCYP18B1) orthologs in the lepidopteran model insect, Bombyx mori. Interestingly, BmCYP18A1 gene is predominantly expressed in the middle silk gland (MSG) while BmCYP18B1 expresses ubiquitously in B. mori. BmCYP18A1 is induced by 20E in vitro, suggesting its role in 20E metabolism. Using the binary Gal4/UAS transgenic system, we ectopically overexpressed BmCYP18A1 in a MSG-specific manner with a Sericin1-Gal4 (Ser-Gal4) driver or in a ubiquitous manner with an Actin3-Gal4 (A3-Gal4) driver. Ectopic overexpression of BmCYP18A1 in MSG or in all tissues resulted in developmental arrestment of transgenic animals during the final instar larval stage. The 20E titers in the transgenic animals expressing BmCYP18A1 were lower compared to the levels in the control animals. Although the biological significance of MSG-specific expression of BmCYP18A1 is unclear, our results provide the first evidence that BmCYP18A1, which is conserved in most arthropods, is involved in a tissue-specific steroid hormone inactivation in B. mori. PMID:25173591

  14. [Comparison of the chemoimmunotherapeutic effect of doxorubicin and bafilomycin-A1 in mouse neuroblastoma cells].

    PubMed

    Inoue, Seiichiro; Setoyama, Yumiko; Odaka, Akio

    2014-05-01

    The aim of this study was to compare the ability of the drugs doxorubicin and Bafilomycin-A1(Baf-A1)to promote an immune reaction following the induction of cell death in a mouse neuroblastoma model. Neuro-2a cells were cultured in medium containing doxorubicin or Baf-A1. Bone marrow-derived dendritic cells(BM-DCs)were co-cultured with neuro-2A cells that were grown in doxorubicin- or Baf-A1-containing media, and phagocytosis of neuro-2a cells by the BN-DCs was evaluated. Additionally, dead neuro-2a cells were co-cultured with CD8a + lymphocytes and BM-DCs, and the proliferation of CD8a + cells was evaluated. Interferon-g(IFN-g)production was used as an indexof the immune response. Dead neuro-2a cells treated with doxorubicin were phagocytosed effectively compared to the cells treated with Baf-A1. However, phagocytosis of cells treated with Baf-A1 was promoted after stimulation with CpG oligodeoxynucleotide (CpG-ODN). When CD8a + cells were co-cultured with BM-DCs and doxorubicin-treated neuro-2a cells, CD8a + lymphocyte proliferation was observed. There was no statistical difference in IFN-g secretion between the doxorubicin-treated and Baf-A1-treated cells. However, after stimulation by CpG-ODN, IFN-g production was more effectively observed in the Baf-A1-treated cells. Induction of cell death by doxorubicin or Baf-A1 could possibly enhance antitumor immunity in patients receiving chemotherapy for neuroblastoma. Selection of anti-tumor agents and stimulation of BM-DCs with a toll-like receptor (TLR) agonist is considered important in promoting antitumor activity after chemotherapy.

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

    DOE PAGES

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

    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

  16. Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1

    PubMed Central

    2016-01-01

    Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD+-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural study of human ALDH7A1 focused on substrate recognition. Five crystal structures and small-angle X-ray scattering data are reported, including the first crystal structure of any ALDH7 family member complexed with α-aminoadipate. The product binds with the ε-carboxylate in the oxyanion hole, the aliphatic chain packed into an aromatic box, and the distal end of the product anchored by electrostatic interactions with five conserved residues. This binding mode resembles that of glutamate bound to the proline catabolic enzyme ALDH4A1. Analysis of ALDH7A1 and ALDH4A1 structures suggests key interactions that underlie substrate discrimination. Structures of apo ALDH7A1 reveal dramatic conformational differences from the product complex. Product binding is associated with a 16 Å movement of the C-terminus into the active site, which stabilizes the active conformation of the aldehyde substrate anchor loop. The fact that the C-terminus is part of the active site was hitherto unknown. Interestingly, the C-terminus and aldehyde anchor loop are disordered in a new tetragonal crystal form of the apoenzyme, implying that these parts of the enzyme are highly flexible. Our results suggest that the active site of ALDH7A1 is disassembled when the aldehyde site is vacant, and the C-terminus is a mobile element that forms quaternary structural interactions that aid aldehyde binding. These results are relevant to the c.1512delG genetic deletion associated with pyridoxine-dependent epilepsy, which alters the C-terminus of ALDH7A1. PMID:26260980

  17. Modulation of the Bacillus anthracis Secretome by the Immune Inhibitor A1 Protease

    PubMed Central

    Pflughoeft, Kathryn J.; Swick, Michelle C.; Engler, David A.; Yeo, Hye-Jeong

    2014-01-01

    The Bacillus anthracis secretome includes protective antigen, lethal factor, and edema factor, which are the components of anthrax toxin, and other proteins with known or potential roles in anthrax disease. Immune inhibitor A1 (InhA1) is a secreted metalloprotease that is unique to pathogenic members of the Bacillus genus and has been associated with cleavage of host proteins during infection. Here, we report the effect of InhA1 on the B. anthracis secretome. Differential in-gel electrophoresis of proteins present in culture supernatants from a parent strain and an isogenic inhA1-null mutant revealed multiple differences. Of the 1,340 protein spots observed, approximately one-third were less abundant and one-third were more abundant in the inhA1 secretome than in the parent strain secretome. Proteases were strongly represented among those proteins exhibiting a 9-fold or greater change. InhA1 purified from a B. anthracis culture supernatant directly cleaved each of the anthrax toxin proteins as well as an additional secreted protease, Npr599. The conserved zinc binding motif HEXXH of InhA1 (HEYGH) was critical for its proteolytic activity. Our data reveal that InhA1 directly and indirectly modulates the form and/or abundance of over half of all the secreted proteins of B. anthracis. The proteolytic activity of InhA1 on established secreted virulence factors, additional proteases, and other secreted proteins suggests that this major protease plays an important role in virulence not only by cleaving mammalian substrates but also by modulating the B. anthracis secretome itself. PMID:24214942

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

    SciTech Connect

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

    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 an 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.

  19. 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

  20. Fasting blood glucose and HbA1c in children with ADHD.

    PubMed

    Lindblad, Frank; Eickhoff, Malin; Forslund, Anders H; Isaksson, Johan; Gustafsson, Jan

    2015-04-30

    Reports of hypocortisolism and overweight in pediatric ADHD motivate an investigation of blood glucose regulation in this group. Fasting blood glucose and HbA1c were investigated in 10 children (10-15 years) with ADHD and 22 comparisons. Fasting blood glucose was similar in both groups. HbA1c values were higher in the ADHD-group. BMI-SDS was also higher in the ADHD-group but did not predict HbA1c. The results suggest an association between ADHD and an altered blood glucose homeostasis.

  1. Glycosylation of IgA1 and pathogenesis of IgA nephropathy.

    PubMed

    Novak, Jan; Julian, Bruce A; Mestecky, Jiri; Renfrow, Matthew B

    2012-05-01

    IgA nephropathy, described in 1968 as IgA-IgG immune-complex disease, is an autoimmune disease. Galactose-deficient IgA1 is recognized by unique autoantibodies, resulting in the formation of pathogenic immune complexes that ultimately induce glomerular injury. Thus, formation of the galactose-deficient IgA1-containing immune complexes is a critical factor in the pathogenesis of IgA nephropathy. Studies of molecular defects of IgA1 can define new biomarkers specific for IgA nephropathy that can be developed into clinical assays to aid in the diagnosis, assessment of prognosis, and monitoring of disease progression.

  2. Effect of Long-Term Periodontal Care on Hemoglobin A1c in Type 2 Diabetes.

    PubMed

    Merchant, A T; Georgantopoulos, P; Howe, C J; Virani, S S; Morales, D A; Haddock, K S

    2016-04-01

    This was a prospective cohort study evaluating 126,805 individuals with diabetes and periodontal disease receiving care at all Veterans Administration medical centers and clinics in the United States from 2005 through 2012. The exposures were periodontal treatment at baseline (PT0) and at follow-up (PT2). The outcomes were change in HbA1c following initial treatment (ΔHbA1c1) and follow-up treatment (ΔHbA1c2), and diabetes control was defined as HbA1c at <7% and <9% following initial and follow-up treatment, respectively. Marginal structural models were used to account for potential confounding and selection bias. The objective was to evaluate the impact of long-term treatment of periodontal disease on glycemic control among individuals with type 2 diabetes. Participants were 64 y old on average, 97% were men, and 71% were white. At baseline, the average diabetes duration was 4 y, 12% of participants were receiving insulin, and 60% had HbA1c <7%. After an average 1.7 y of follow-up, the mean HbA1c increased from 7.03% to 7.21%. About 29.4% of participants attended their periodontal maintenance visit following baseline. Periodontal treatment at baseline and follow-up reduced HbA1c by -0.02% and -0.074%, respectively. Treatment at follow-up increased the likelihood of individuals achieving diabetes control by 5% and 3% at the HbA1c <7% and HbA1c <9% thresholds, respectively, and was observed even among never smokers. HbA1c reduction after periodontal treatment at follow-up was greater (ΔHbA1c2 = -0.25%) among individuals with higher baseline HbA1c. Long-term periodontal care provided in a clinical setting improved long-term glycemic control among individuals with type 2 diabetes and periodontal disease. PMID:26701348

  3. Fasting blood glucose and HbA1c in children with ADHD.

    PubMed

    Lindblad, Frank; Eickhoff, Malin; Forslund, Anders H; Isaksson, Johan; Gustafsson, Jan

    2015-04-30

    Reports of hypocortisolism and overweight in pediatric ADHD motivate an investigation of blood glucose regulation in this group. Fasting blood glucose and HbA1c were investigated in 10 children (10-15 years) with ADHD and 22 comparisons. Fasting blood glucose was similar in both groups. HbA1c values were higher in the ADHD-group. BMI-SDS was also higher in the ADHD-group but did not predict HbA1c. The results suggest an association between ADHD and an altered blood glucose homeostasis. PMID:25747679

  4. Effect of Long-Term Periodontal Care on Hemoglobin A1c in Type 2 Diabetes.

    PubMed

    Merchant, A T; Georgantopoulos, P; Howe, C J; Virani, S S; Morales, D A; Haddock, K S

    2016-04-01

    This was a prospective cohort study evaluating 126,805 individuals with diabetes and periodontal disease receiving care at all Veterans Administration medical centers and clinics in the United States from 2005 through 2012. The exposures were periodontal treatment at baseline (PT0) and at follow-up (PT2). The outcomes were change in HbA1c following initial treatment (ΔHbA1c1) and follow-up treatment (ΔHbA1c2), and diabetes control was defined as HbA1c at <7% and <9% following initial and follow-up treatment, respectively. Marginal structural models were used to account for potential confounding and selection bias. The objective was to evaluate the impact of long-term treatment of periodontal disease on glycemic control among individuals with type 2 diabetes. Participants were 64 y old on average, 97% were men, and 71% were white. At baseline, the average diabetes duration was 4 y, 12% of participants were receiving insulin, and 60% had HbA1c <7%. After an average 1.7 y of follow-up, the mean HbA1c increased from 7.03% to 7.21%. About 29.4% of participants attended their periodontal maintenance visit following baseline. Periodontal treatment at baseline and follow-up reduced HbA1c by -0.02% and -0.074%, respectively. Treatment at follow-up increased the likelihood of individuals achieving diabetes control by 5% and 3% at the HbA1c <7% and HbA1c <9% thresholds, respectively, and was observed even among never smokers. HbA1c reduction after periodontal treatment at follow-up was greater (ΔHbA1c2 = -0.25%) among individuals with higher baseline HbA1c. Long-term periodontal care provided in a clinical setting improved long-term glycemic control among individuals with type 2 diabetes and periodontal disease.

  5. Identification and characterization of an hnRNP E1 translational silencing motif

    PubMed Central

    Brown, Andrew S.; Mohanty, Bidyut K.; Howe, Philip H.

    2016-01-01

    Non-canonical transforming growth factor β (TGFβ) signaling through protein kinase B (Akt2) induces phosphorylation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) at serine-43 (p-hnRNP E1). This post-translational modification (PTM) of hnRNP E1 promotes its dissociation from a 3′ untranslated region (UTR) nucleic acid regulatory motif, driving epithelial to mesenchymal transition (EMT) and metastasis. We have identified an hnRNP E1 consensus-binding motif and genomically resolved a subset of genes in which it is contained. This study characterizes the binding kinetics of the consensus-binding motif and hnRNP E1, its various K-homology (KH) domains and p-hnRNP E1. Levels of p-hnRNP E1 are highly upregulated in metastatic cancer cells and low in normal epithelial tissue. We show a correlation between this PTM and levels of Akt2 and its activated form, phosphorylated serine-474 (p-Akt2). Using cellular progression models of metastasis, we observed a signature high level of Akt2, p-Akt2 and p-hnRNP E1 protein expression, coupled to a significantly reduced level of total hnRNP E1 in metastatic cells. Genes that are translationally silenced by hnRNP E1 and expressed by its dissociation are highly implicated in the progression of EMT and metastasis. This study provides insight into a non-canonical TGFβ signaling cascade that is responsible for inducing EMT by aberrant expression of hnRNP E1 silenced targets. The relevance of this system in metastatic progression is clearly shown in cellular models by the high abundance of p-hnRNP E1 and low levels of hnRNP E1. New insights provided by the resolution of this molecular mechanism provide targets for therapeutic intervention and give further insight into the role of the TGFβ microenvironment. PMID:27067543

  6. Translational control mediated by hnRNP K links NMHC IIA to erythroid enucleation.

    PubMed

    Naarmann-de Vries, Isabel S; Brendle, Annika; Bähr-Ivacevic, Tomi; Benes, Vladimir; Ostareck, Dirk H; Ostareck-Lederer, Antje

    2016-03-15

    Post-transcriptional regulation is crucial for structural and functional alterations in erythropoiesis. Enucleation of erythroid progenitors precedes reticulocyte release into circulation. In enucleated cells, reticulocyte 15-lipoxygenase (r15-LOX, also known as ALOX15) initiates mitochondria degradation. Regulation of r15-LOX mRNA translation by hnRNP K determines timely r15-LOX synthesis in terminal maturation. K562 cells induced for erythroid maturation recapitulate enucleation and mitochondria degradation. HnRNP K depletion from maturing K562 cells results in enhanced enucleation, which even occurs independently of maturation. We performed RIP-Chip analysis to identify hnRNP K-interacting RNAs comprehensively. Non-muscle myosin heavy chain (NMHC) IIA (also known as MYH9) mRNA co-purified with hnRNP K from non-induced K562 cells, but not from mature cells. NMHC IIA protein increase in erythroid maturation at constant NMHC IIA mRNA levels indicates post-transcriptional regulation. We demonstrate that binding of hnRNP K KH domain 3 to a specific sequence element in the NMHC IIA mRNA 3'UTR mediates translation regulation in vitro Importantly, elevated NMHC IIA expression results in erythroid-maturation-independent enucleation as shown for hnRNP K depletion. Our data provide evidence that hnRNP-K-mediated regulation of NMHC IIA mRNA translation contributes to the control of enucleation in erythropoiesis. PMID:26823606

  7. Evidence for cooperative tandem binding of hnRNP C RRMs in mRNA processing

    PubMed Central

    Cieniková, Zuzana; Jayne, Sandrine; Damberger, Fred Franz; Allain, Frédéric Hai-Trieu; Maris, Christophe

    2015-01-01

    The human hnRNP C is a ubiquitous cellular protein involved in mRNA maturation. Recently, we have shown that this protein specifically recognizes uridine (U) pentamers through its single RNA recognition motif (RRM). However, a large fraction of natural RNA targets of hnRNP C consists of much longer contiguous uridine stretches. To understand how these extended sites are recognized, we studied the binding of the RRM to U-tracts of 8–11 bases. In vivo investigation of internal translation activation of unr (upstream of N-ras) mRNA indicates that the conservation of the entire hnRNP C binding site, UC(U)8, is required for hnRNP C-dependent IRES activation. The assays further suggest a synergistic interplay between hnRNP C monomers, dependent on the protein's ability to oligomerize. In vitro spectroscopic and thermodynamic analyses show that isolated RRMs bind to (U)11 oligomers as dimers. Structural modeling of a ternary double-RRM/RNA complex indicates additionally that two RRM copies can be accommodated on the canonical sequence UC(U)8. The proposed tandem RRM binding is in very good agreement with the transcriptome-wide recognition of extended U-tracts by full-length hnRNP C, which displays a cross-linking pattern consistent with a positively cooperative RRM dimer binding model. PMID:26370582

  8. In Silico Adoption of an Orphan Nuclear Receptor NR4A1

    PubMed Central

    Lanig, Harald; Reisen, Felix; Whitley, David; Schneider, Gisbert; Banting, Lee; Clark, Timothy

    2015-01-01

    A 4.1μs molecular dynamics simulation of the NR4A1 (hNur77) apo-protein has been undertaken and a previously undetected druggable pocket has become apparent that is located remotely from the ‘traditional’ nuclear receptor ligand-binding site. A NR4A1/bis-indole ligand complex at this novel site has been found to be stable over 1 μs of simulation and to result in an interesting conformational transmission to a remote loop that has the capacity to communicate with a NBRE within a RXR-α/NR4A1 heterodimer. Several features of the simulations undertaken indicate how NR4A1 can be affected by alternate-site modulators. PMID:26270486

  9. Novel mutations in the COL2A1 gene in Japanese patients with Stickler syndrome.

    PubMed

    Kondo, Hiroyuki; Matsushita, Itsuka; Nagata, Tatsuo; Hayashi, Takaaki; Kakinoki, Masashi; Uchio, Eiichi; Kondo, Mineo; Ohji, Masahito; Kusaka, Shunji

    2016-01-01

    Stickler syndrome is an inherited connective tissue disorder that affects the eyes, cartilage and articular tissues. The phenotypes of Stickler syndrome include congenital high myopia, retinal detachment, premature joint degeneration, hearing impairment and craniofacial anomalies, such as cleft palate and midline facial hypoplasia. The disease is genetically heterogeneous, and the majority of the cases are caused by mutations in the COL2A1 gene. We examined 40 Japanese patients with Stickler syndrome from 23 families to determine whether they had mutations in the COL2A1 gene. This analysis was conducted by examining each patient's genomic DNA by Sanger sequencing. Five nonsense, 4 splicing and 8 deletion mutations in the COL2A1 gene were identified, accounting for 21 of the 23 families. Different mutations of the COL2A1 gene were associated with similar phenotypes but with different degrees of expressivity. PMID:27408751

  10. Novel mutations in the COL2A1 gene in Japanese patients with Stickler syndrome

    PubMed Central

    Kondo, Hiroyuki; Matsushita, Itsuka; Nagata, Tatsuo; Hayashi, Takaaki; Kakinoki, Masashi; Uchio, Eiichi; Kondo, Mineo; Ohji, Masahito; Kusaka, Shunji

    2016-01-01

    Stickler syndrome is an inherited connective tissue disorder that affects the eyes, cartilage and articular tissues. The phenotypes of Stickler syndrome include congenital high myopia, retinal detachment, premature joint degeneration, hearing impairment and craniofacial anomalies, such as cleft palate and midline facial hypoplasia. The disease is genetically heterogeneous, and the majority of the cases are caused by mutations in the COL2A1 gene. We examined 40 Japanese patients with Stickler syndrome from 23 families to determine whether they had mutations in the COL2A1 gene. This analysis was conducted by examining each patient’s genomic DNA by Sanger sequencing. Five nonsense, 4 splicing and 8 deletion mutations in the COL2A1 gene were identified, accounting for 21 of the 23 families. Different mutations of the COL2A1 gene were associated with similar phenotypes but with different degrees of expressivity. PMID:27408751

  11. 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

  12. 26 CFR 1.667(a)-1A - Denial of refund to trusts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 1.667(a)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Treatment of Excess Distributions of Trusts Applicable to Taxable Years... distributions in the preceding taxable year....

  13. Cytochrome P450 CYP307A1/Spook: a regulator for ecdysone synthesis in insects.

    PubMed

    Namiki, Toshiki; Niwa, Ryusuke; Sakudoh, Takashi; Shirai, Ken-Ichi; Takeuchi, Hideaki; Kataoka, Hiroshi

    2005-11-11

    The prothoracic gland (PG) has essential roles in synthesizing and secreting a steroid hormone called ecdysone that is critical for molting and metamorphosis of insects. However, little is known about the genes controlling ecdysteroidogenesis in the PG. To identify genes functioning in the PG of the silkworm, Bombyx mori, we used differential display PCR and focused on a cytochrome P450 gene designated Cyp307a1. Its expression level positively correlates with a change in the hemolymph ecdysteroid titer. In addition, Drosophila Cyp307a1 is encoded in the spook locus, one of the Halloween mutant family members showing a low ecdysone titer in vivo, suggesting that Cyp307a1 is involved in ecdysone synthesis. While Drosophila Cyp307a1 is expressed in the early embryos and adult ovaries, the expression is not observed in the PGs of embryos or third instar larvae. These results suggest a difference in the ecdysone synthesis pathways during larval development in these insects.

  14. 49 CFR 173.435 - Table of A1 and A2 values for radionuclides.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...-GENERAL REQUIREMENTS FOR SHIPMENTS AND PACKAGINGS Class 7 (Radioactive) Materials § 173.435 Table of A1... Terabecquerels (TBq), (see § 171.10). c The quantity may be determined from a measurement of the rate of decay...

  15. 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

  16. 26 CFR 48.4062(a)-1 - Specific parts or accessories.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., 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...

  17. 26 CFR 48.4062(a)-1 - Specific parts or accessories.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., 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...

  18. 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...

  19. [Physiological variations of LpA1, HDL2 and principal lipid markers in athletes].

    PubMed

    Choukaifé, A; Fradin, S; Bureau, F; Sesboüe, B; Arhan, P; Drosdowsky, M A

    1994-01-01

    An original approach of the influence of physical activities on lipid metabolism is presented in this work: the authors studied the physiological variations of the lipoparticle LpA1, high-density lipoprotein subfraction HDL2 and the most important lipid markers in serum of a presumably healthy population of 55 high-level sportsmen. They were 18-45 years old and practised endurance sports, whether individual (cycling, long-distance running), or collective activities (soccer, basketball). The authors observed an important increase of LpA1 (+20%, p < 0.001) and C-HDL2 (+23.3%, p < 0.01) after an intense physical activity (CK = 430 +/- 312 U/l); they also found a good correlation between LpA1 and HDL2 (r = 0.85, p < 0.0001) and between LpA1 and CK (r = 0.62, p < 0.001).

  20. 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

  1. Apolipoprotein A-1 regulates osteoblast and lipoblast precursor cells in mice.

    PubMed

    Blair, Harry C; Kalyvioti, Elena; Papachristou, Nicholaos I; Tourkova, Irina L; Syggelos, Spryros A; Deligianni, Despina; Orkoula, Malvina G; Kontoyannis, Christos G; Karavia, Eleni A; Kypreos, Kyriakos E; Papachristou, Dionysios J

    2016-07-01

    Imbalances in lipid metabolism affect bone homeostasis, altering bone mass and quality. A link between bone mass and high-density lipoprotein (HDL) has been proposed. Indeed, it has been recently shown that absence of the HDL receptor scavenger receptor class B type I (SR-B1) causes dense bone mediated by increased adrenocorticotropic hormone (ACTH). In the present study we aimed at further expanding the current knowledge as regards the fascinating bone-HDL connection studying bone turnover in apoA-1-deficient mice. Interestingly, we found that bone mass was greatly reduced in the apoA-1-deficient mice compared with their wild-type counterparts. More specifically, static and dynamic histomorphometry showed that the reduced bone mass in apoA-1(-/-) mice reflect decreased bone formation. Biochemical composition and biomechanical properties of ApoA-1(-/-) femora were significantly impaired. Mesenchymal stem cell (MSC) differentiation from the apoA-1(-/-) mice showed reduced osteoblasts, and increased adipocytes, relative to wild type, in identical differentiation conditions. This suggests a shift in MSC subtypes toward adipocyte precursors, a result that is in line with our finding of increased bone marrow adiposity in apoA-1(-/-) mouse femora. Notably, osteoclast differentiation in vitro and osteoclast surface in vivo were unaffected in the knock-out mice. In whole bone marrow, PPARγ was greatly increased, consistent with increased adipocytes and committed precursors. Further, in the apoA-1(-/-) mice marrow, CXCL12 and ANXA2 levels were significantly decreased, whereas CXCR4 were increased, consistent with reduced signaling in a pathway that supports MSC homing and osteoblast generation. In keeping, in the apoA-1(-/-) animals the osteoblast-related factors Runx2, osterix, and Col1a1 were also decreased. The apoA-1(-/-) phenotype also included augmented CEPBa levels, suggesting complex changes in growth and differentiation that deserve further investigation. We

  2. 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

  3. CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss.

    PubMed

    Rodríguez-Sanz, M; García-Giralt, N; Prieto-Alhambra, D; Servitja, S; Balcells, S; Pecorelli, R; Díez-Pérez, A; Grinberg, D; Tusquets, I; Nogués, X

    2015-08-01

    Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona-Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (P<0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss. PMID:26108486

  4. Pathogenetic significance of aberrant glycosylation of IgA1 in IgA nephropathy.

    PubMed

    Narita, Ichiei; Gejyo, Fumitake

    2008-10-01

    IgA nephropathy (IgAN), the most common form of primary glomerulonephritis worldwide, is defined by predominant IgA1 deposits in the glomerular mesangium. Among abnormalities of the IgA immune system reported so far in IgAN, aberrant O-linked glycosylation in the hinge region of IgA1 is the most consistent finding. IgA1 molecules bearing abnormal glycosylation have been found in serum, in tonsillar lymphocytes, and in eluate from mesangial deposits, and characterized by decreased O-linked N-acetylgalactosamine residues with or without alteration in the terminal sialylation of the O-linked sugars. IgA1 with incomplete galactosylation has a tendency to accumulate in glomerular mesangium by self-aggregation or immune complex formation. Glomerular mesangial cells exposed to immune complexes of these IgA1 can proliferate and secrete cytokines, chemokines, growth factors, and extracellular matrix components promoting inflammatory reactions in the glomeruli. Although genes encoding enzymes involved in the O-glycosylation process, such as C1GALT1, have been reported to be responsible for susceptibility to IgAN, recent evidence suggests that the abnormality is restricted to a small fraction of B cell populations and arises from dysregulated IgA1 production and secretion in mucosal immune system. This review will focus on and discuss the role of incompleteness of IgA1 O-galactosylation in the pathogenesis of IgAN and propose a possible mechanism in which abnormal IgA1 occurs in IgAN.

  5. CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss.

    PubMed

    Rodríguez-Sanz, M; García-Giralt, N; Prieto-Alhambra, D; Servitja, S; Balcells, S; Pecorelli, R; Díez-Pérez, A; Grinberg, D; Tusquets, I; Nogués, X

    2015-08-01

    Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona-Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (P<0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss.

  6. Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma

    PubMed Central

    Xu, Sen-Lin; Zeng, Dong-Zu; Dong, Wei-Guo; Ding, Yan-Qing; Rao, Jun; Duan, Jiang-Jie; Liu, Qing; Yang, Jing; Zhan, Na; Liu, Ying; Hu, Qi-Ping; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Yu, Shi-Cang; Bian, Xiu-Wu

    2014-01-01

    Purpose: Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed as a candidate biomarker for colorectal carcinoma (CRC). However, the heterogeneity of its expression makes it difficult to predict the outcome of CRC. The aim of this study was to evaluate the diagnostic and prognostic value of this molecule in CRC. Methods and Results: In this study, we examined ALDH1A1 expression by immunohistochemistry including 406 cases of primary CRC with corresponding adjacent mucosa, with confirmation of real-time PCR and Western blotting. We found that the expression patterns of ALDH1A1 were heterogeneous in the CRC and corresponding adjacent tissues. We defined the ratio of ALDH1A1 level in adjacent mucosa to that in tumor tissues as RA/C and found that the capabilities of tumor invasion and metastasis in the tumors with RA/C < 1 were significantly higher than those with RA/C ≥ 1. Follow-up data showed the worse prognoses in the CRC patients with RA/C < 1. For understanding the underlying mechanism, the localization of β-catenin was detected in the CRC tissues with different patterns of ALDH1A1 expression from 221 patients and β-catenin was found preferentially expressed in cell nuclei of the tumors with RA/C < 1 and ALDH1A1high expression of HT29 cell line, indicating that nuclear translocation of β-catenin might contribute to the increased potentials of invasion and metastasis. Conclusion: Our results indicate that RA/C is a novel biomarker to reflect the distinct expression patterns of ALDH1A1 for predicting metastasis and prognosis of CRC. PMID:25031716

  7. Deletion of the Platelet-Specific Alloantigen PlA1 from Platelets in Glanzmann's Thrombasthenia

    PubMed Central

    Kunicki, Thomas J.; Aster, Richard H.

    1978-01-01

    Expression of a Platelet-specific alloantigen (PlA1) was studied in five unrelated patients with Glanzmann's thrombasthenia using immunologic techniques based on release of 51Cr from tagged platelets by PlA1-specific antibody. Less than 1% of the normal quantity of PlA1 could be detected on platelets of patients 1, 2, and 3; platelets from patients 4 and 5 contained 22 and 12% of normal levels, respectively. After treatment with bromelain, platelets from patients 4 and 5, but not those from patients 1, 2, and 3, released 51Cr as well as normal PlA1-positive platelets when exposed to anti-PlA1. Platelets from each of the five patients reacted normally with drug-dependent antibodies and with autoantibodies specific for platelets. Polyacrylamide gel electrophoresis of thrombasthenic platelets showed marked deficiencies of glycoproteins IIbα and III (P < 0.0005), confirming recent reports of others. Deficiency of the two proteins as determined by gel scanning was more pronounced in patients 1, 2, and 3 than in patients 4 and 5. Normal levels of glycoproteins IIbα and III were found in platelets from normal subjects negative for PlA1. These observations are consistent with the possibility that the PlA1 antigen is located on one or both of the glycoproteins lacking in Glanzmann's thrombasthenia, although other explanations are possible. They further suggest that patients with thrombasthenia may be heterogeneous in respect to the degree to which these glycoproteins are deleted. The PlA1 antigen can be measured with considerable precision and may provide a marker useful for the diagnosis and study of Glanzmann's disease. PMID:566280

  8. 26 CFR 1.665(a)-1A - Undistributed net income.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Undistributed net income. 1.665(a)-1A Section 1... Or After January 1, 1969 § 1.665(a)-1A Undistributed net income. (a) Domestic trusts. The term undistributed net income, in the case of a trust (other than a foreign trust created by a U.S. person)...

  9. Beta-Catenin Regulated ALDH1A1 is a Target in Ovarian Cancer Spheroids

    PubMed Central

    Condello, Salvatore; Morgan, Cynthia A.; Nagdas, Sarbajeet; Cao, Liyun; Turek, John; Hurley, Thomas D.; Matei, Daniela

    2014-01-01

    Cancer cells form three dimensional (3D) multicellular aggregates (or spheroids) under non-adherent culture conditions. In ovarian cancer (OC), spheroids serve as a vehicle for cancer cell dissemination in the peritoneal cavity, protecting cells from environmental stress-induced anoikis. To identify new targetable molecules in OC spheroids, we investigated gene expression profiles and networks upregulated in three dimensional (3D) versus traditional monolayer culture conditions. We identified ALDH1A1, a cancer stem cell marker as being overexpressed in OC spheroids and directly connected to key elements of the β-catenin pathway. B-catenin function and ALDH1A1 expression were increased in OC spheroids vs. monolayers and in successive spheroid generations, suggesting that 3D aggregates are enriched in cells with stem cell characteristics. B-catenin knockdown decreased ALDH1A1 expression levels and β-catenin coimmunoprecipitated with the ALDH1A1 promoter, suggesting that ALDH1A1 is a direct β-catenin target. Both siRNA mediated β-catenin knockdown and A37, a novel ALDH1A1 small molecule enzymatic inhibitor described here for the first time, disrupted OC spheroid formation and cell viability (p<0.001). B-catenin knockdown blocked tumor growth and peritoneal metastasis in an OC xenograft model. These data strongly support the role of β-catenin regulated ALDH1A1 in the maintenance of OC spheroids and propose new ALDH1A1 inhibitors targeting this cell population. PMID:24954508

  10. Cell division suppression in the Bacillus subtilis div IC-A1 minicell-producing mutant.

    PubMed

    Mendelson, N H

    1975-03-01

    Growth and division patterns of Bacillus subtilis wild-type (div IV-A1+) and minicell-producing mutant (div IV-A1) clones were studied after spore germination during microcolony development in chambers that facilitate continuous observation with a phase contrast microscope. Data obtained from 13 div IV-A1+ clones were used to derive the equation DE equals [(mum minus 17.6)/8.8], which expresses the relationship of cell divisions present in clones of various lengths. This equation was used to determine the number of divisions expected in div IV-A1 clones if the mutant clones were able to divide as often as wild-type clones. The observed number of divisions present in mutant clones was found to be only 25.27% of the number expected on the basis of this equation. Although individual div IV-A1 clones varied in the percentage of division equivalents expressed, there appeared to be no correlation between the overall clone growth rate and the number of divisions expressed. Culturing div IV-A1+ and div IV-A1 clones together in the same growth chamber revealed that there were no diffusible interactions influencing the division phenotypes of either mutant or wild-type cells. At later stages of growth, mixed microcolonies containing cells of both genotypes were formed. A length analysis of individual cells in these populations indicated that the relative division suppression of mutant compared with wild-type cells characteristic of the initial stages of clone development was maintained. It is likely, therefore, that the excessive length of minicell-producing cells (div IV-A1) is a reflection primarily of division suppression in the mutant and not simply of mislocation of division along cell length.

  11. Characterization of CYP1A1 regulatory elements in Atlantic tomcod

    SciTech Connect

    Roy, N.; Wirgin, I.; Courtenay, S.

    1995-12-31

    Coplanar PCBs, TCDD, and PAHs induce cytochrome P4501A1 (CYP1A1) mRNA in Atlantic tomcod from the Miramichi River (MR), whereas only PAHs induce gene expression in tomcod from the Hudson River (HR). Relative to the highly industrialized HR, MR is relatively clean. The authors hypothesize that non-inducibility of CYP1A1 mRNA in PCB (TCB) or TCDD treated tomcod from the HR is due to prior exposure to environmentally-borne xenobiotics. To evaluate the mechanisms which selectively inhibit CYP1A1 inducibility, they isolated and characterized 5{tilde O}and intronic CYP1A1 regulatory elements from tomcod genomic DNA. Tomcod 5{tilde O} CYP1A1 contains four motifs with core sequences identical to the aromatic hydrocarbon receptor elements (AhREs) identified in mammals. Electrophoretic mobility shift assays (EMSAs) with nuclear extracts prepared form the livers of B[a]P treated HR tomcod showed protein binding to 142 and 156 bp tomcod DNA fragments each containing two tomcod AhREs. EMSAs with nuclear extracts prepared from DMBA treated rat livers and human MOLT4 cells also showed protein binding to the fish AhREs. Protein binding at individual tomcod AhREs was characterized with hepatic protein extracts prepared from TCB, B[a]P, and vehicle treated tomcod from the HR and MR. Preliminary studies showed a difference in protein binding between HR and MR tomcod i.p. injected with TCB 1d, 5d, or 15d previous, but not B[a]P 6 hr or 24 hr previous. These results suggest that the mechanisms of CYP1A1 transcription are similar tomcod and mammals and that variation in levels of gene inducibility among individual tomcod may be due to differences in inducible protein binding to CYP1A1 AhREs.

  12. Natural furocoumarins as inducers and inhibitors of cytochrome P450 1A1 in rat hepatocytes.

    PubMed

    Baumgart, Annette; Schmidt, Melanie; Schmitz, Hans-Joachim; Schrenk, Dieter

    2005-02-15

    Furocoumarins are natural plant constituents present in medicinal plants and in a variety of foods such as grapefruit juice. They are phototoxic and act as potent inhibitors of drug metabolism. We have investigated the interaction of four furocoumarins angelicin, bergamottin, isopimpinellin, and 8-methoxypsoralen with the expression and activity of aryl hydrocarbon receptor (AhR)-regulated CYP1A1 in rat hepatocytes in primary culture, both in the presence and absence of light. In intact hepatocytes pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin and in microsomes isolated thereof, all furocoumarins tested acted as potent inhibitors of CYP1A1 activity bergamottin being the most potent inhibitor in microsomes with an IC(50) of 10 nM in the presence and 60 nM in the absence of light. 8-Methoxypsoralen and angelicin led to a significant induction of CYP1A1 mRNA in hepatocytes, while all furocoumarins except bergamottin increased xenobiotic-responsive element-driven reporter gene expression in transfected H4IIE rat hepatoma cells when light was excluded. Furthermore, all furocoumarins tested induced the expression of endogenous, immunoreactive CYP1A1 protein, primarily in the dark. In conclusion, our results demonstrate that individual furocoumarins present in food and medicinal plants can interfere with AhR-regulated CYP1A1 expression and activity in at least three major ways, i.e., (i) act as highly potent inhibitors of the catalytic activity of CYP1A1 both in the presence and absence of light, (ii) induce CYP1A1 gene expression in the absence of light via activation of the AhR, and (iii) induce CYP1A1 gene expression without activation of the AhR.

  13. O-linked glycosylation in maize-expressed human IgA1.

    PubMed

    Karnoup, Anton S; Turkelson, Virgil; Anderson, W H Kerr

    2005-10-01

    O-Linked glycans vary between eukaryotic cell types and play an important role in determining a glycoprotein's properties, including stability, target recognition, and potentially immunogenicity. We describe O-linked glycan structures of a recombinant human IgA1 (hIgA1) expressed in transgenic maize. Up to six proline/hydroxyproline conversions and variable amounts of arabinosylation (Pro/Hyp + Ara) were found in the hinge region of maize-expressed hIgA1 heavy chain (HC) by using a combination of matrix-assisted laser-desorption ionization mass spectrometry (MALDI MS), chromatography, and amino acid analysis. Approximately 90% of hIgA1 was modified in this way. An average molar ratio of six Ara units per molecule of hIgA1 was revealed. Substantial sequence similarity was identified between the HC hinge region of hIgA1 and regions of maize extensin-family of hydroxyproline-rich glycoproteins (HRGP). We propose that because of this sequence similarity, the HC hinge region of maize-expressed hIgA1 can become a substrate for posttranslational conversion of Pro to Hyp by maize prolyl-hydroxylase(s) with the subsequent arabinosylation of the Hyp residues by Hyp-glycosyltransferase(s) in the Golgi apparatus in maize endosperm tissue. The observation of up to six Pro/Hyp hydroxylations combined with extensive arabinosylation in the hIgA1 HC hinge region is well in agreement with the Pro/Hyp hydroxylation model and the Hyp contiguity hypothesis suggested earlier in literature for plant HRGP. For the first time, the extensin-like Hyp/Pro conversion and O-linked arabinosylation are described for a recombinant therapeutic protein expressed in transgenic plants. Our findings are of significance to the field of plant biotechnology and biopharmaceutical industry-developing transgenic plants as a platform for the production of recombinant therapeutic proteins. PMID:15901675

  14. Induction of human UDP-glucuronosyltransferase 1A1 by cortisol-GR.

    PubMed

    Usui, Toru; Kuno, Takuya; Mizutani, Takaharu

    2006-06-01

    During the course of the study of UGT1A1 induction by bilirubin, we could not detect the induction of the reporter gene (-3174/+14) of human UGT1A1 in HepG2 by bilirubin (Mol. Biol. Rep. 31: 151-158 (2004)). In this report, we show the finding of the induction of the reporter gene of UGT1A1 by cortisol at 1 microM, a major natural cortico-steroid, with human glucocorticoid receptor (GR). RU486 of a typical GR antagonist at 10 microM inhibited the induction by cortisol from 5.9- to 1.8-fold. This result indicates that the induction by cortisol-GR is dependence on ligand-binding. This induction is caused by the UGT reporter gene itself, from the results of noinduction with control vector pGL2 (equal to pGV-C) in the presence of cortisol-GR. We confirmed that the induction of the reporter gene by cortisol is dependent on the position of proximal element (-97/-53) of UGT1A1. From this result, we concluded that the increase of corticosteroid in neonates must induce the elevation of UGT1A1 after birth and prevent jaundice. With the study of induction by corisol, we studied the influence of co-expression of PXR (pregnenolone xenobiotic receptor) with the UGT1A1 reporter gene and we could not find the induction of UGT1A1 expression in the presence of dexamethasone, rifampicin, or pregnenolone 16alpha-carbonitrile of the PXR ligands. These results suggest that the induction of UGT1A1 expression by GR is not mediated by PXR, unlike the induction of CYP3A4 through PXR. PMID:16817017

  15. [Interest of UGT1A1 genotyping within digestive cancers treatment by irinotecan].

    PubMed

    Boyer, Jean-Christophe; Etienne-Grimaldi, Marie-Christine; Thomas, Fabienne; Quaranta, Sylvie; Picard, Nicolas; Loriot, Marie-Anne; Poncet, Delphine; Gagnieu, Marie-Claude; Ged, Cécile; Broly, Franck; Le Morvan, Valérie; Bouquié, Régis; Gaub, Marie-Pierre; Philibert, Laurent; Ghiringhelli, François; Le Guellec, Chantal

    2014-06-01

    Irinotecan is a cytotoxic agent administered by IV infusion in the treatment of advanced colorectal cancer. Its anticancer activity results from its bioactivation into SN-38 metabolite, which is cleared through glucuronidation by the hepatic enzyme uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). In the general population, there is wide inter-subject variability in UGT1A1 enzyme activity related to UGT1A1 gene polymorphisms. The French joint workgroup coming from the National Pharmacogenetic Network (RNPGx) and the Group of Clinical Oncologic Pharmacology (GPCO) herein presents an updated review dealing with efficacy and toxicity clinical studies related to UGT1A1 genetic variants. From a critical analysis of this review it clearly emerges that, for doses higher than 180 mg/m(2), hematologic and digestive irinotecan-induced toxicities could be prevented in daily clinical practice by generalizing the use of a simple pharmacogenetic test before starting treatment. The clinical relevance of this test is also discussed in terms of treatment efficacy improvement, with the possibility of increasing the irinotecan dose in patients not bearing the deleterious allele. This test involves using a blood sample to analyze the promoter region of the UGT1A1 gene (UGT1A1*28 allele). Best execution practices, laboratory costs, as well as results interpretation are described with the aim of facilitating the implementation of this analysis in clinical routine. The existence of a French laboratories network performing this test in clinical routine makes it possible to generalize UGT1A1 deficiency screening, so as to guarantee equal access to safe treatment and optimized irinorecan-based therapy for the many patients receiving irinotecan-based therapy in advanced colorectal cancer. PMID:24977443

  16. [Interest of UGT1A1 genotyping within digestive cancers treatment by irinotecan].

    PubMed

    Boyer, Jean-Christophe; Etienne-Grimaldi, Marie-Christine; Thomas, Fabienne; Quaranta, Sylvie; Picard, Nicolas; Loriot, Marie-Anne; Poncet, Delphine; Gagnieu, Marie-Claude; Ged, Cécile; Broly, Franck; Le Morvan, Valérie; Bouquié, Régis; Gaub, Marie-Pierre; Philibert, Laurent; Ghiringhelli, François; Le Guellec, Chantal

    2014-06-01

    Irinotecan is a cytotoxic agent administered by IV infusion in the treatment of advanced colorectal cancer. Its anticancer activity results from its bioactivation into SN-38 metabolite, which is cleared through glucuronidation by the hepatic enzyme uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). In the general population, there is wide inter-subject variability in UGT1A1 enzyme activity related to UGT1A1 gene polymorphisms. The French joint workgroup coming from the National Pharmacogenetic Network (RNPGx) and the Group of Clinical Oncologic Pharmacology (GPCO) herein presents an updated review dealing with efficacy and toxicity clinical studies related to UGT1A1 genetic variants. From a critical analysis of this review it clearly emerges that, for doses higher than 180 mg/m(2), hematologic and digestive irinotecan-induced toxicities could be prevented in daily clinical practice by generalizing the use of a simple pharmacogenetic test before starting treatment. The clinical relevance of this test is also discussed in terms of treatment efficacy improvement, with the possibility of increasing the irinotecan dose in patients not bearing the deleterious allele. This test involves using a blood sample to analyze the promoter region of the UGT1A1 gene (UGT1A1*28 allele). Best execution practices, laboratory costs, as well as results interpretation are described with the aim of facilitating the implementation of this analysis in clinical routine. The existence of a French laboratories network performing this test in clinical routine makes it possible to generalize UGT1A1 deficiency screening, so as to guarantee equal access to safe treatment and optimized irinorecan-based therapy for the many patients receiving irinotecan-based therapy in advanced colorectal cancer.

  17. 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.

  18. [IgA1 aberrant glycosylation in the pathogenesis of IgA nephropathy: an overivew].

    PubMed

    Xie, Linshen; Wang, Li; Huang, Jan; Fan, Junming

    2010-02-01

    IgA nephropathy is the most common form of primary glomerulonephritis which mainly accounts for the development of end-stage renal diseases. It is characterized by deposits of IgA1 in mesangium. The pathogenesis of IgA nephropathy is complicated. Moreover, there is a wide range of clinical features and variable histomorphologies in the diagnosed cases of IgA nephropathy. It was demonstrated that the galactose-deficient of IgA1 O-glycan chains led IgA1 to self-aggregation and eventual deposition in mesangium. Abnormality of glycosyltransferases, genetic mutation and immunologic disorder were involved in the aberrant glycosylation of IgA1 which was recognized as the key etiopathogenisis of IgA nephropathy. However, the exact source and the pathogenic mechanism of aberrantly glycosylated IgA1 remain obscure. The further studies on aberrant O-glycosylation of IgA1 would contribute to the understanding of IgA nephropathy and provide new therapeutical strategy.

  19. Seasonal variation in hemoglobin a1c in korean patients with type 2 diabetes mellitus.

    PubMed

    Kim, Yoon Ji; Park, Seongkeun; Yi, Wangjin; Yu, Kyung-Sang; Kim, Tae Hyuk; Oh, Tae Jung; Choi, Jinwook; Cho, Young Min

    2014-04-01

    A seasonal variation of glucose homeostasis in humans has been reported in various geographic regions. In this study, we examined seasonal variations in hemoglobin A1c (HbA1c) in patients with type 2 diabetes living in Korea. We analyzed 57,970 HbA1c values from 4,191 patients and the association of these values with ambient temperature for 3.5 yr. Overall, HbA1c exhibited its highest values from February to March and its lowest values from September to October (coefficient for cos t = -0.0743, P = 0.058) and the difference between the peak and nadir in a year was 0.16%-0.25%. A statistically significant seasonal variation was observed in the patients who were taking oral anti-diabetic drugs (OADs) without insulin treatment (coefficient for cos t = -0.0949, P < 0.05). The Spearman correlation coefficient between daily HbA1c values and the corresponding 3-month moving average ambient temperature was -0.2154 (95% confidence interval [CI]: -0.2711, -0.1580; P < 0.05). In conclusion, HbA1c values exhibited a seasonal variation in Korean patients with type 2 diabetes, with the highest values during the cold season, particularly in those who were treated with OADs, which should be taken into account in clinical practice for stable glucose control during the cold season.

  20. Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients.

    PubMed

    Sherwani, Shariq I; Khan, Haseeb A; Ekhzaimy, Aishah; Masood, Afshan; Sakharkar, Meena K

    2016-01-01

    Diabetes is a global endemic with rapidly increasing prevalence in both developing and developed countries. The American Diabetes Association has recommended glycated hemoglobin (HbA1c) as a possible substitute to fasting blood glucose for diagnosis of diabetes. HbA1c is an important indicator of long-term glycemic control with the ability to reflect the cumulative glycemic history of the preceding two to three months. HbA1c not only provides a reliable measure of chronic hyperglycemia but also correlates well with the risk of long-term diabetes complications. Elevated HbA1c has also been regarded as an independent risk factor for coronary heart disease and stroke in subjects with or without diabetes. The valuable information provided by a single HbA1c test has rendered it as a reliable biomarker for the diagnosis and prognosis of diabetes. This review highlights the role of HbA1c in diagnosis and prognosis of diabetes patients. PMID:27398023

  1. Posttranslational modification by an isolevuglandin diminishes activity of the mitochondrial cytochrome P450 27A1.

    PubMed

    Charvet, Casey D; Laird, James; Xu, Yunfeng; Salomon, Robert G; Pikuleva, Irina A

    2013-05-01

    Posttranslational modification by isolevuglandins (isoLGs), arachidonate oxidation products, is an important yet understudied process associated with altered protein properties. This type of modification is detected in cytochrome P450 27A1 (CYP27A1), a multifunction enzyme expressed in almost every cell and involved in the metabolism of cholesterol and other sterols. Previously, the CYP27A1 Lys(358)-isoLG adduct was found in human retina afflicted with age-related macular degeneration. Yet, the effect of Lys(358) modification on enzyme activity was not investigated. Herein, we characterized catalytic properties of Lys(358) as well as Lys(476) CYP27A1 mutants before and after isoLG treatment and quantified the extent of modification by multiple reaction monitoring. The K358R mutant was less susceptible to isoLG-induced loss of catalytic activity than the wild type (WT), whereas the K476R mutant was nearly as vulnerable as the WT. Both mutants showed less isoLG modification than WT. Thus, modification of Lys(358), a residue involved in redox partner interactions, is the major contributor to isoLG-associated loss of CYP27A1 activity. Our data show the specificity of isoLG modification, provide direct evidence that isoLG adduction impairs enzyme activity, and support our hypothesis that isoLG modification in the retina is detrimental to CYP27A1 enzyme activity, potentially disrupting cholesterol homeostasis. PMID:23479405

  2. Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients

    PubMed Central

    Sherwani, Shariq I.; Khan, Haseeb A.; Ekhzaimy, Aishah; Masood, Afshan; Sakharkar, Meena K.

    2016-01-01

    Diabetes is a global endemic with rapidly increasing prevalence in both developing and developed countries. The American Diabetes Association has recommended glycated hemoglobin (HbA1c) as a possible substitute to fasting blood glucose for diagnosis of diabetes. HbA1c is an important indicator of long-term glycemic control with the ability to reflect the cumulative glycemic history of the preceding two to three months. HbA1c not only provides a reliable measure of chronic hyperglycemia but also correlates well with the risk of long-term diabetes complications. Elevated HbA1c has also been regarded as an independent risk factor for coronary heart disease and stroke in subjects with or without diabetes. The valuable information provided by a single HbA1c test has rendered it as a reliable biomarker for the diagnosis and prognosis of diabetes. This review highlights the role of HbA1c in diagnosis and prognosis of diabetes patients. PMID:27398023

  3. Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance

    PubMed Central

    Sugimoto, Michelle Amantéa; Vago, Juliana Priscila; Teixeira, Mauro Martins; Sousa, Lirlândia Pires

    2016-01-01

    Neutrophils (also named polymorphonuclear leukocytes or PMN) are essential components of the immune system, rapidly recruited to sites of inflammation, providing the first line of defense against invading pathogens. Since neutrophils can also cause tissue damage, their fine-tuned regulation at the inflammatory site is required for proper resolution of inflammation. Annexin A1 (AnxA1), also known as lipocortin-1, is an endogenous glucocorticoid-regulated protein, which is able to counterregulate the inflammatory events restoring homeostasis. AnxA1 and its mimetic peptides inhibit neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. AnxA1 also promotes monocyte recruitment and clearance of apoptotic leukocytes by macrophages. More recently, some evidence has suggested the ability of AnxA1 to induce macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. The combination of these mechanisms results in an effective resolution of inflammation, pointing to AnxA1 as a promising tool for the development of new therapeutic strategies to treat inflammatory diseases. PMID:26885535

  4. Inhibition of human and rat CYP1A1 enzyme by grapefruit juice compounds.

    PubMed

    Santes-Palacios, Rebeca; Romo-Mancillas, Antonio; Camacho-Carranza, Rafael; Espinosa-Aguirre, Jesús Javier

    2016-09-01

    Cytochrome P4501A1 is involved in the metabolism of carcinogenic polycyclic aromatic hydrocarbons; therefore, its inhibition interferes with the carcinogenesis process induced by these compounds in rats. The human and rat CYP1A1 differ by 21% in amino acid sequence, including the active site of the enzyme; this difference may be an important factor when results obtained using animal models are interpolated to humans. Based on its previously reported CYP inhibitory properties, we studied the effects of two molecules contained within grapefruit juice, naringenin and 6',7'-dihydroxybergamottin, on human and rat CYP1A1 activity. For this purpose, the kinetics of inhibition as well as computational simulations were used. Naringenin and 6',7'-dihydroxybergamottin were found to be competitive inhibitors of human and rat CYP1A1. Additionally, naringenin exerted a mixed type inhibition effect on rat CYP1A1. Computational docking showed that inhibitors might block the oxidation of 7-ethoxyresorufin by binding to the CYP1A1 active site. Our results demonstrate the differences in CYP inhibitory mechanisms for the same molecule when CYP from different species are considered. PMID:27444380

  5. ENDOR and special triple resonance spectroscopy of A1.- of photosystem 1.

    PubMed

    Rigby, S E; Evans, M C; Heathcote, P

    1996-05-28

    The photoaccumulated radical state of the photosystem 1 secondary electron acceptor A1, A1.-, has been studied in spinach and the cyanobacterium Anabaena variabilis strain Met27 using electron nuclear double resonance (ENDOR) and electron--nuclear--nuclear special triple (ST) resonance spectroscopies. Spectra of A1.- in both these species are very similar. ENDOR spectra of the phylloquinone anion radical in solvent glass were also obtained. Comparison of the spectra of the in vivo and in vitro radicals shows that A1.- is a phylloquinone anion radical with a distorted electron spin density distribution. Hyperfine couplings to the A1.- methyl group and to two protons hydrogen bonded to the quinone oxygens have been identified using biosynthetic deuteration in A. variabilis. Possible hyperfine coupling to a methylene proton of the phytyl side chain of the quinone has also been identified. These results are compared with those from previous studies of protein-bound semiquinones in the light of the unusual redox potential of A1.

  6. Inhibition of human and rat CYP1A1 enzyme by grapefruit juice compounds.

    PubMed

    Santes-Palacios, Rebeca; Romo-Mancillas, Antonio; Camacho-Carranza, Rafael; Espinosa-Aguirre, Jesús Javier

    2016-09-01

    Cytochrome P4501A1 is involved in the metabolism of carcinogenic polycyclic aromatic hydrocarbons; therefore, its inhibition interferes with the carcinogenesis process induced by these compounds in rats. The human and rat CYP1A1 differ by 21% in amino acid sequence, including the active site of the enzyme; this difference may be an important factor when results obtained using animal models are interpolated to humans. Based on its previously reported CYP inhibitory properties, we studied the effects of two molecules contained within grapefruit juice, naringenin and 6',7'-dihydroxybergamottin, on human and rat CYP1A1 activity. For this purpose, the kinetics of inhibition as well as computational simulations were used. Naringenin and 6',7'-dihydroxybergamottin were found to be competitive inhibitors of human and rat CYP1A1. Additionally, naringenin exerted a mixed type inhibition effect on rat CYP1A1. Computational docking showed that inhibitors might block the oxidation of 7-ethoxyresorufin by binding to the CYP1A1 active site. Our results demonstrate the differences in CYP inhibitory mechanisms for the same molecule when CYP from different species are considered.

  7. Activity of rat UGT1A1 towards benzo[a]pyrene phenols and dihydrodiols.

    PubMed

    Webb, Laura; Miles, Kristini; Kessler, Fay; Ritter, Joseph K

    2006-05-01

    Four UDP-glucuronosyltransferases from the rat UGT1A family were tested for activity towards benzo[a]pyrene phenols and dihydrodiols. UGT1A1 and UGT1A7 were found to be broadly active towards BaP metabolites. Antisera recognizing rat UGT1A1 and UGT1A7 were used to assess UGT levels in relation to UGT activity towards benzo[a]pyrene-7,8-dihydrodiol (BPD). The rank BPD UGT activities were liver=intestine≫kidney, whereas UGT1A1 was highest in liver and UGT1A7 was highest in intestine. Phenobarbital, an inducer of hepatic UGT1A1, only slightly increased BPD UGT activity, whereas UGT1A7 inducers more potently increased the activity. Inhibition studies using the differential UGT1A1 inhibitor, bilirubin, suggest that UGT1A1 is not a major contributor to the constitutive BPD glucuronidating activity of control rat liver microsomes. These data suggest that multiple UGT1A enzymes contribute to glucuronidation of BPD and other BaP metabolites, and that their relative contributions depend on tissue- and environmental-specific factors. PMID:21783661

  8. Association of COL2A1 Gene Polymorphism with Degenerative Lumbar Scoliosis

    PubMed Central

    Hwang, Dae Woo; Lee, Sang Hoon; Kim, Jung Youn; Kim, Dong Hwan

    2014-01-01

    Background Degenerative lumbar scoliosis (DLS) progresses with aging after 50-60 years, and the genetic association of DLS remains largely unclear. In this study, the genetic association between collagen type II alpha 1 (COL2A1) gene and DLS was investigated. Methods COL2A1 gene polymorphism was investigated in DLS subjects compared to healthy controls to investigate the possibility of its association with COL2A1 gene. Based on a single nucleotide polymorphism (SNP) database, SNP (rs2276454) in COL2A1 were selected and genotyped using direct sequencing in 51 patients with DLS and 235 healthy controls. The SNP effects were analyzed using three models of codominant, dominant, and recessive. Logistic regression models were calculated for odds ratios (ORs) with 95% confidence intervals (CIs) and corresponding p-values, controlling age and gender as co-variables. Results SNP (rs2276454) in COL2A1 was significantly associated with the degenerative lumbar scoliosis in the codominant (OR, 1.90; 95% CI, 1.17 to 3.10; p = 0.008) and dominant models (OR, 3.58; 95% CI, 1.59 to 9.29; p = 0.001). Conclusions The results suggest that COL2A1 is associated with the risk of DLS in Korean population. PMID:25436060

  9. GluA1 phosphorylation alters evoked firing pattern in vivo.

    PubMed

    Barkóczi, Balázs; Juhász, Gábor; Averkin, Robert G; Vörös, Imre; Vertes, Petra; Penke, Botond; Szegedi, Viktor

    2012-01-01

    AMPA and NMDA receptors convey fast synaptic transmission in the CNS. Their relative contribution to synaptic output and phosphorylation state regulate synaptic plasticity. The AMPA receptor subunit GluA1 is central in synaptic plasticity. Phosphorylation of GluA1 regulates channel properties and trafficking. The firing rate averaged over several hundred ms is used to monitor cellular input. However, plasticity requires the timing of spiking within a few ms; therefore, it is important to understand how phosphorylation governs these events. Here, we investigate whether the GluA1 phosphorylation (p-GluA1) alters the spiking patterns of CA1 cells in vivo. The antidepressant Tianeptine was used for inducing p-GluA1, which resulted in enhanced AMPA-evoked spiking. By comparing the spiking patterns of AMPA-evoked activity with matched firing rates, we show that the spike-trains after Tianeptine application show characteristic features, distinguishing from spike-trains triggered by strong AMPA stimulation. The interspike-interval distributions are different between the two groups, suggesting that neuronal output may differ when new inputs are activated compared to increasing the gain of previously activated receptors. Furthermore, we also show that NMDA evokes spiking with different patterns to AMPA spike-trains. These results support the role of the modulation of NMDAR/AMPAR ratio and p-GluA1 in plasticity and temporal coding. PMID:22567428

  10. Craniofacial and Dental Defects in the Col1a1Jrt/+ Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Eimar, H; Tamimi, F; Retrouvey, J-M; Rauch, F; Aubin, J E; McKee, M D

    2016-07-01

    Certain mutations in the COL1A1 and COL1A2 genes produce clinical symptoms of both osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) that include abnormal craniofacial growth, dental malocclusion, and dentinogenesis imperfecta. A mouse model (Col1a1(Jrt)/+) was recently developed that had a skeletal phenotype and other features consistent with moderate-to-severe OI and also with EDS. The craniofacial phenotype of 4- and 20-wk-old Col1a1(Jrt)/+ mice and wild-type littermates was assessed by micro-computed tomography (µCT) and morphometry. Teeth and the periodontal ligament compartment were analyzed by µCT, light microscopy/histomorphometry, and electron microscopy. Over time, at 20 wk, Col1a1(Jrt)/+ mice developed smaller heads, a shortened anterior cranial base, class III occlusion, and a mandibular side shift with shorter morphology in the masticatory region (maxilla and mandible). Col1a1(Jrt)/+ mice also had changes in the periodontal compartment and abnormalities in the dentin matrix and mineralization. These findings validate Col1a1(Jrt)/+ mice as a model for OI and EDS in humans. PMID:26951553

  11. Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity.

    PubMed

    Martin, S; Richards, A J; Yates, J R; Scott, J D; Pope, M; Snead, M P

    1999-01-01

    Stickler syndrome (hereditary arthro-ophthalmopathy) is a dominantly inherited connective tissue disorder with ocular, oro-facial, auditory and skeletal manifestations. It is genetically and phenotypically heterogeneous with the majority of families having mutations in the gene encoding type II collagen (COL2A1) and exhibiting a characteristic 'membranous' or type 1 vitreous phenotype. More recently a novel mutation in the gene encoding the alpha1 chain of type XI collagen (COL11A1) was reported in a Stickler syndrome pedigree with a different 'beaded' or type 2 vitreous phenotype. In the present study five more families with the type 2 vitreous phenotype were examined for linkage to four candidate genes: COL2A1, COL5A2, COL11A1 and COL11A2. Two families were linked to COL11A1 and sequencing identified mutations resulting in shortened alphal(XI) collagen chains, one via exon skipping and the other via a multiexon deletion. One of the families showed weak linkage to COL5A2 but sequencing the open reading frame failed to identify a mutation. In the remaining two families all four loci were excluded by linkage analysis. These data confirm that mutations in COL11A1 cause Stickler syndrome with the type2 vitreous phenotype and also reveal further locus heterogeneity.

  12. Aryl morpholino triazenes inhibit cytochrome P450 1A1 and 1B1.

    PubMed

    Lee, Daniel; Perez, Pedro; Jackson, William; Chin, Taylor; Galbreath, Michael; Fronczek, Frank R; Isovitsch, Ralph; Iimoto, Devin S

    2016-07-15

    Many cytochrome P450 1A1 and 1B1 (CYP1A1 and CYP1B1) inhibitors, such as resveratrol, have planar, hydrophobic, aromatic rings in their structure and exhibit anti-cancer activity. Aryl morpholino triazenes have similar structural features and in addition contain a triazene unit consisting of three consecutive, conjugated nitrogen atoms. Several aryl morpholino triazenes, including 4-[(E)-2-(3,4,5-trimethoxyphenyl)diazenyl]-morpholine (2), were prepared from a reaction involving morpholine and a diazonium ion produced from different aniline derivatives, such as 3,4,5-trimethoxyaniline. The aryl morpholino triazenes were then screened at 100μM for their ability to inhibit CYP1A1 and CYP1B1 using ethoxyresorufin as the substrate. Triazenes that inhibited the enzymes to less than 80% of the uninhibited enzyme activity were assayed to determine their IC50 value. Compound 2 was the only triazene to inhibit both CYP1A1 and CYP1B1 to the same degree as resveratrol with IC50 values of 10μM and 18μM, respectively. Compounds 3 and 6 selectively inhibited CYP1B1 over CYP1A1 with IC values of 2μM and 7μM, respectively. Thus, aryl morpholino triazenes are a new class of compounds that can inhibit CYP1A1 and CYP1B1 and potentially prevent cancer. PMID:27265259

  13. Effects of Teratogenic Drugs on CYP1A1 Activity in Differentiating Rat Embryo Cells.

    PubMed

    Tayeboon, Gh S; Ostad, S N; Nasri, S; Nili-Ahmadabadi, A; Tavakoli, F; Sabzevari, O

    2015-05-01

    CYP1A1, a P450 isoenzyme, is involved in the phase I xenobiotic metabolism including teratogen drugs. In the present study, the ability of teratogens to elevate the embryonic expression of CYP1A1 was examined. Micromass cell cultures prepared from day 13 rat embryo limb buds (LB). LB cells were cultivated and exposed for 5 days to retinoic acid (RA), hydrocortisone (HC), caffeine (CA) and quinine (QN). CYP1A1 protein expression and activity were measured using immunofluorescence staining and ethoxyresorufin O-deethylation (EROD) assay, respectively. The EROD activity increased significantly following LB cells exposure to RA and HC (p<0.05) but the expression of CYP1A1 protein was reduced by these drugs, whereas the expression of CYP1A1 protein and EROD activity decreased significantly following the addition of CA and QN (p<0.05, p<0.01). Our findings show that studied teratogens have potency to increase CYP1A1 activity.

  14. 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

  15. Serum galactose-deficient IgA1 levels in children with IgA nephropathy.

    PubMed

    Jiang, Mengjie; Jiang, Xiaoyun; Rong, Liping; Xu, Yuanyuan; Chen, Lizhi; Qiu, Zeting; Mo, Ying

    2015-01-01

    Immunoglobulin A nephropathy (IgAN) is an immunopathologic diagnosis based on a renal biopsy, it is characterized by deposits of IgA-containing immune complexes in the mesangium. Adults with IgAN have a galactose-deficient IgA1 in the circulation and glomerular deposition. There are few studies on the glycosylation of serum IgA1 in children with IgAN. To measure the serum levels of galactose-deficient IgA1 in pediatric patients with IgAN, 72 biopsy-proven IgAN children were divided into 3 groups based on the clinical features: isolated hematuria group (24 patients), hematuria and proteinuria group (22 patients), and nephritic syndrome group (26 patients). They were also divided into 3 groups according to pathologic grading: grade I + II group (25 patients), grade III group (33 patients) and grade IV + V group (14 patients). 30 healthy children were recruited as a control group. We used vicia villosa lectin binding enzyme-linked immunosorbent assay to measure the serum levels of galactose-deficient IgA1 in all groups and controls. Serum levels of galactose-deficient IgA1 in children with IgAN were higher than controls (P < 0.01). There were no significant differences in serum levels of galactose-deficient IgA1 among the different clinical and pathologic grading groups. The values of the area under the curve for galactose-deficient IgA1 levels were 0.976 (95% CI, 0.953-1.000). The cutoff point for galactose-deficient IgA1 levels was 0.125, with a sensitivity of 87.5% and a specificity of 83.3%, with a positive predictive value of 92.6% and a negative predictive value of 73.5% (P < 0.01). Children with IgAN presented serum galactose-deficient IgA1, which has shown no relationship with the clinical manifestations and pathologic grading of the disease. Detection of serum galactose-deficient IgA1 levels by vicia villosa lectin binding enzyme-linked immunosorbent assay has a certain clinical value in diagnosis of children with IgAN.

  16. Challenges in HbA1c Analysis and Reporting in Patients with Variant Hemoglobins.

    PubMed

    Sultana, T A; Sheme, Z A; Sultana, G S; Sultana, B; Mishu, F A; Khan, N Z; Sarkar, B C; Muttalib, M A; Khan, S A; Choudhury, S; Mahtab, H

    2016-04-01

    Hemoglobin A1c (HbA(1)c) is a well-established indicator of mean glycemia. The presence of genetic variants of hemoglobin can profoundly affect the accuracy of HbA(1)c measurements. Variants of hemoglobin especially Hemoglobin E (HbE) is prevalent in South East Asia including Bangladesh. The objective of our study is to compare the HbA(1)c values measured on high performance liquid chromatography (HPLC) and Turbidimetric Inhibition Immunoassay (TINIA) in diabetic patients with variant hemoglobins including HbE. A total of 7595 diabetic patients receiving treatment at BIRDEM General Hospital were analyzed for HbA(1)c results within a period of two months from December 2013 to January 2014. Seventy two cases out of 7595 (0.95%) had either undetectable or below normal HbA(1)c levels (males-33 and females-39; ratio = 0.82:1) by HPLC method. In 34(0.45%) cases, HbA(1)c value was undetectable by HPLC method but was in the reportable range by TINIA method. In the other 38 (0.55%) cases, HbA(1)c levels were below the reportable range (<4%) by HPLC method but were in the normal or higher range by TINIA method. TINIA method did not agree with HPLC method on Bland Altman plot in the 38 cases with below normal HbA(1)c levels, [Mean bias -5.2(-9.3 to 1.0), 95% CI] but agreed very well [mean bias -0.21 (-0.84 to 0.42), y=1.1037+0.776X; r(2)=0.30, p<0.01] in controls. In control group mean MCV was 83.80±7.48 and in study group was 73.65±10.44. Alkaline electrophoresis confirmed the variant hemoglobin to be HbE. The fasting blood sugar levels of all the 72 cases correlated strongly with TINIA method (r(2) =0.75, p<0.0001) but not with HPLC (r = 0.24, p=0.13). In our regions where populations have a high prevalence of Hb variant, proper knowledge of hemoglobin variants which affect the measurements HbA(1)c level is essential. MCV of 80fl or below may serve as a rough guide to select samples that require analysis by TINIA method. Moreover, HPLC may be a convenient and inexpensive

  17. 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

  18. Identification and characterization of the novel Col10a1 regulatory mechanism during chondrocyte hypertrophic differentiation

    PubMed Central

    Gu, J; Lu, Y; Li, F; Qiao, L; Wang, Q; Li, N; Borgia, J A; Deng, Y; Lei, G; Zheng, Q

    2014-01-01

    The majority of human skeleton develops through the endochondral pathway, in which cartilage-forming chondrocytes proliferate and enlarge into hypertrophic chondrocytes that eventually undergo apoptosis and are replaced by bone. Although at a terminal differentiation stage, hypertrophic chondrocytes have been implicated as the principal engine of bone growth. Abnormal chondrocyte hypertrophy has been seen in many skeletal dysplasia and osteoarthritis. Meanwhile, as a specific marker of hypertrophic chondrocytes, the type X collagen gene (COL10A1) is also critical for endochondral bone formation, as mutation and altered COL10A1 expression are often accompanied by abnormal chondrocyte hypertrophy in many skeletal diseases. However, how the type X collagen gene is regulated during chondrocyte hypertrophy has not been fully elucidated. We have recently demonstrated that Runx2 interaction with a 150-bp mouse Col10a1 cis-enhancer is required but not sufficient for its hypertrophic chondrocyte-specific reporter expression in transgenic mice, suggesting requirement of additional Col10a1 regulators. In this study, we report in silico sequence analysis of this 150-bp enhancer and identification of its multiple binding factors, including AP1, MEF2, NFAT, Runx1 and TBX5. Using this enhancer as bait, we performed yeast one-hybrid assay and identified multiple candidate Col10a1-interacting genes, including cyclooxygenase 1 (Cox-1) and Cox-2. We have also performed mass spectrometry analysis and detected EF1-alpha, Fus, GdF7 and Runx3 as components of the specific complex formed by the cis-enhancer and nuclear extracts from hypertrophic MCT (mouse chondrocytes immortalized with large T antigen) cells that express Col10a1 abundantly. Notably, some of the candidate genes are differentially expressed in hypertrophic MCT cells and have been associated with chondrocyte hypertrophy and Runx2, an indispensible Col10a1 regulator. Intriguingly, we detected high-level Cox-2 expression in

  19. The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer.

    PubMed

    Matherly, Larry H; Wilson, Mike R; Hou, Zhanjun

    2014-04-01

    This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.

  20. Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

    PubMed Central

    Chen, Che-Hong; Cruz, Leslie A.; Mochly-Rosen, Daria

    2015-01-01

    Correcting a genetic mutation that leads to a loss of function has been a challenge. One such mutation is in aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2. This mutation is present in ∼0.6 billion East Asians and results in accumulation of toxic acetaldehyde after consumption of ethanol. To temporarily increase metabolism of acetaldehyde in vivo, we describe an approach in which a pharmacologic agent recruited another ALDH to metabolize acetaldehyde. We focused on ALDH3A1, which is enriched in the upper aerodigestive track, and identified Alda-89 as a small molecule that enables ALDH3A1 to metabolize acetaldehyde. When given together with the ALDH2-specific activator, Alda-1, Alda-89 reduced acetaldehyde-induced behavioral impairment by causing a rapid reduction in blood ethanol and acetaldehyde levels after acute ethanol intoxication in both wild-type and ALDH2-deficient, ALDH2*1/*2, heterozygotic knock-in mice. The use of a pharmacologic agent to recruit an enzyme to metabolize a substrate that it usually does not metabolize may represent a novel means to temporarily increase elimination of toxic agents in vivo. PMID:25713355

  1. Mechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1)

    PubMed Central

    Simonov, Alexandr N.; Holien, Jessica K.; Yeung, Joyee Chun In; Nguyen, Ann D.; Corbin, C. Jo; Zheng, Jie; Kuznetsov, Vladimir L.; Auchus, Richard J.; Conley, Alan J.; Bond, Alan M.; Parker, Michael W.; Rodgers, Raymond J.; Martin, Lisandra L.

    2015-01-01

    Cytochrome P450c17 (P450 17A1, CYP17A1) is a critical enzyme in the synthesis of androgens and is now a target enzyme for the treatment of prostate cancer. Cytochrome P450c17 can exhibit either one or two physiological enzymatic activities differentially regulated by cytochrome b5. How this is achieved remains unknown. Here, comprehensive in silico, in vivo and in vitro analyses were undertaken. Fluorescence Resonance Energy Transfer analysis showed close interactions within living cells between cytochrome P450c17 and cytochrome b5. In silico modeling identified the sites of interaction and confirmed that E48 and E49 residues in cytochrome b5 are essential for activity. Quartz crystal microbalance studies identified specific protein-protein interactions in a lipid membrane. Voltammetric analysis revealed that the wild type cytochrome b5, but not a mutated, E48G/E49G cyt b5, altered the kinetics of electron transfer between the electrode and the P450c17. We conclude that cytochrome b5 can influence the electronic conductivity of cytochrome P450c17 via allosteric, protein-protein interactions. PMID:26587646

  2. The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

    PubMed Central

    Wilson, Mike R.; Hou, Zhanjun

    2014-01-01

    This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases. PMID:24396145

  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. Increased APRIL Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy.

    PubMed

    Zhai, Ya-Ling; Zhu, Li; Shi, Su-Fang; Liu, Li-Jun; Lv, Ji-Cheng; Zhang, Hong

    2016-03-01

    Aberrant glycosylated IgA1 molecules, mainly galactose-deficient IgA1 (Gd-IgA1), are important causal factors in IgA nephropathy; however, the underlying mechanism for the production of aberrantly glycosylated IgA1 is unknown. A recent genome-wide association study identified a novel IgAN susceptibility gene, TNFSF13, which encoded a proliferation-inducing ligand (APRIL) that promotes lymphocyte proliferation and IgA class switching. We aimed to explore the mechanism of APRIL's involvement in IgAN. We enrolled 166 patients with IgAN and 77 healthy controls and detected the plasma APRIL levels by the ELISA method, identified the mRNA expression of APRIL and its receptors by relative quantitative PCR, and confirmed by in vitro experiment. We identified increased plasma APRIL levels in IgAN, which was further proved by upregulated mRNA expression in B-lymphocytes from 27 IgAN patients. Analysis of the clinical characteristics of patients with IgAN showed that higher plasma APRIL level was associated with more severe clinical presentations (high proteinuria and low eGFR). The plasma APRIL level was positively correlated with Gd-IgA1 levels. Furthermore, exogenous APRIL could induce more production of Gd-IgA1 in cultured lymphocytes from patients with IgAN, compared with that from healthy controls. And, the relative higher expression of receptors of APRIL, that is, BCMA and TACI, in B-lymphocytes from IgAN patients were observed. Our findings implied that in patients with IgAN, increased APRIL is accompanied elevated expression of its receptors in B-lymphocytes, which induces overproduction of Gd-IgA1, ultimately contributing to the pathogenesis of IgAN.

  5. Naturally occurring structural isomers in serum IgA1 o-glycosylation.

    PubMed

    Takahashi, Kazuo; Smith, Archer D; Poulsen, Knud; Kilian, Mogens; Julian, Bruce A; Mestecky, Jiri; Novak, Jan; Renfrow, Matthew B

    2012-02-01

    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. Thr(225), Thr(228), Ser(230), Ser(232) and Thr(236) 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 Ser(230), Thr(233) or Thr(236) 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.

  6. Thermal unfolding of apolipoprotein A-1. Evaluation of methods and models.

    PubMed

    Schulthess, Therese; Schönfeld, Hans-Joachim; Seelig, Joachim

    2015-05-19

    Human apolipoprotein A-1 (Apo A-1) was used as a model protein to compare experimental methods and theoretical models for protein unfolding. Thermal unfolding was investigated in aqueous buffer, in β-octylglucoside solution, and with phospholipid bilayer vesicles. The α-helix content of Apo A-1 increased from 50% in aqueous buffer to 75% in the presence of lipid vesicles, but remained constant in solutions of β-octyl glucoside. Differential scanning calorimetry (DSC) measured the thermodynamic properties of the unfolding process and was our reference method. The increased heat capacity of the unfolded protein made an important contribution to the total enthalpy of unfolding. The structural properties of Apo A-1 were studied with circular dichroism (CD) spectroscopy. The CD-recorded unfolding transitions were broader than the corresponding DSC transitions and were shifted toward higher temperatures. DSC and CD data were analyzed with the two-state model and the Zimm-Bragg theory. The two-state model assumes just two species in solution, native (N) and unfolded (U) Apo A-1. However, Apo A-1 unfolding is a highly cooperative event with helical amino acid residues unfolding and refolding rapidly. For such a sequential process, the Zimm-Bragg theory provides an alternative and physically more realistic model. The Zimm-Bragg theory allowed perfect simulations of the DSC and CD experiments. In contrast, incorrect thermodynamic results were obtained with the two-state model. The Zimm-Bragg theory also provided a physically well-defined analysis of the cooperativity of the folding ⇄ unfolding equilibrium. The cooperative unfolding of Apo A-1 increased upon addition of lipids and decreased in detergent solution.

  7. NR5A1/SF-1 and development and function of the ovary.

    PubMed

    Bashamboo, A; McElreavey, K

    2010-05-01

    Primary ovarian insufficiency (POI) is defined as cessation of menstruation with associated elevation of gonadotropin levels as a result of decreased ovarian function before the age of 40. The incidence of POI is 1% in women prior to age 40, and 0.1% prior to age 30. There is evidence of a strong genetic component associated with POI. However, the gene mutations/variations influencing POI still remain uncharacterized. NR5A1, a member of the nuclear receptor superfamily, is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-gonadal steroidogenic axis. Newborn mice deficient in NR5A1 lack both gonads and adrenal glands and have impaired expression of pituitary gonadotrophins. NR5A1 is also expressed in multiple cell types in the fetal, postnatal, prepubertal and mature ovary. Until 2008, 18 NR5A1 mutations were described in the human. Three of these were identified in individuals with adrenal insufficiency, two associated with 46,XY disorders of sex development (DSD) and the third a 46,XX female with conserved ovarian function. Other mutations were associated with various anomalies of testis development with no evidence of adrenal failure. We have identified further 19 mutations in NR5A1 including mutations in four familial cases having individuals with 46,XY DSD as well as POI. A further analysis of 25 sporadic cases of POI revealed two additional mutations. Functional analysis revealed that each mutant protein had altered transactivational properties on gonadal promoters. These data reveal novels insights into the role of NR5A1 in ovarian developmental and function and indicate that mutations of the NR5A1 gene may be a significant cause of human ovarian insufficiency.

  8. Heterologous expression and characterization of CYP61A1 from dandruff-causing Malassezia globosa.

    PubMed

    Ohk, Seul-Ong; Park, Hyoung-Goo; Lee, Hwayoun; Kwon, Yeo-Jung; Kim, Beom Joon; Kim, Donghak; Chun, Young-Jin

    2015-10-01

    Malassezia globosa is pathogenic fungus that causes skin disorders including dandruff in humans. Many yeast cytochrome CYP enzymes are involved in the biosynthesis of sterols and are considered major targets of azole antifungal agents. Here, we report on the expression and characterization of the MGL_0310 gene product (CYP61A1), a sterol C-22 desaturase in M. globosa. The open reading frame of the CYP61A1 gene was amplified by PCR from M. globosa CBS 7966 genomic DNA and cloned into a pCW vector. The CYP61A1 gene was heterologously expressed in Escherichia coli and purified using a Ni(2+)-NTA affinity column. The purified CYP61A1 protein exhibited a CO-difference spectrum typical of CYPs with a maximum absorption at 452nm. Binding spectral titration with β-sitosterol and campesterol demonstrated the type I binding mode with an increase at 411nm and a decrease at 432nm. The calculated Kd values are 5.4±0.6μM and 6.1±1.0μM for β-sitosterol and campesterol, respectively. No metabolic product, however, was observed in the CYP61A1-supported enzyme reaction with these sterols. The purified CYP61A1 protein exhibited tight binding to azole agents, suggesting that this enzyme may be a target for the pathogenic M. globosa fungus. Moreover, several fatty acids were found to bind to CYP61A1, indicating that the architecture of the enzyme includes a relatively large active site space. This study provides new insight into the biosynthesis of fungal sterols in M. globosa and a basis for the development of antifungal as potential therapeutic agents to treat dandruff. PMID:26160660

  9. S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction

    PubMed Central

    Ritterhoff, Julia; Völkers, Mirko; Seitz, Andreas; Spaich, Kristin; Gao, Erhe; Peppel, Karsten; Pleger, Sven T; Zimmermann, Wolfram H; Friedrich, Oliver; Fink, Rainer H A; Koch, Walter J; Katus, Hugo A; Most, Patrick

    2015-01-01

    Restoring expression levels of the EF-hand calcium (Ca2+) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca2+ handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca2+ resequestration appears critical for S100A1's cyclic adenosine monophosphate-independent inotropic effects but raises concerns about potential diastolic SR Ca2+ leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and ryanodine receptors (RyR2s) in experimental HF. Restoring this link in failing cardiomyocytes, engineered heart tissue and mouse hearts, respectively, by means of adenoviral and adeno-associated viral S100A1 cDNA delivery normalizes diastolic RyR2 function and protects against Ca2+- and β-adrenergic receptor-triggered proarrhythmogenic SR Ca2+ leakage in vitro and in vivo. S100A1 inhibits diastolic SR Ca2+ leakage despite aberrant RyR2 phosphorylation via protein kinase A and calmodulin-dependent kinase II and stoichiometry with accessory modulators such as calmodulin, FKBP12.6 or sorcin. Our findings demonstrate that S100A1 is a regulator of diastolic RyR2 activity and beneficially modulates diastolic RyR2 dysfunction. S100A1 interaction with the RyR2 is sufficient to protect against basal and catecholamine-triggered arrhythmic SR Ca2+ leak in HF, combining antiarrhythmic potency with chronic inotropic actions. PMID:26005840

  10. Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis

    PubMed Central

    Connelly, Jessica J.; Cherepanova, Olga A.; Doss, Jennifer F.; Karaoli, Themistoclis; Lillard, Travis S.; Markunas, Christina A.; Nelson, Sarah; Wang, Tianyuan; Ellis, Peter D.; Langford, Cordelia F.; Haynes, Carol; Seo, David M.; Goldschmidt-Clermont, Pascal J.; Shah, Svati H.; Kraus, William E.; Hauser, Elizabeth R.; Gregory, Simon G.

    2013-01-01

    Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by ‘genomic convergence’ for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2′-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease. PMID:23912340

  11. IL-11 Is Required for A1 Adenosine Receptor–Mediated Protection against Ischemic AKI

    PubMed Central

    Kim, Joo Yun; Kim, Mihwa; Ham, Ahrom; Brown, Kevin M.; Greene, Robert W.; D’Agati, Vivette D.

    2013-01-01

    A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor–based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targets within this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor–mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro-N(6)-cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal–regulated kinase–dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor–deficient mice. Administration of an IL-11–neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPA did not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor–deficient or renal proximal tubule A1 adenosine receptor–deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor–mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI. PMID:23813214

  12. Precision Measurement of the Neutron Asymmetry A_1^n at Large Bjorken x

    NASA Astrophysics Data System (ADS)

    Zheng, Xiaochao

    2002-04-01

    Experiment E99-117(Jlab E99-117, J. P. Chen, Z. -E. Meziani, P. Souder,et al. al.); hspace2cm http://hallaweb.jlab.org/physics/experiments/he3/A1n/ in Hall A of the Thomas Jefferson National Accelerator Facility (Jefferson Lab) measured the neutron spin asymmetry A_1^n in the large Bjorken x region. A_1^n is predicted to be 0 by the basic SU(6) quark model. In broken SU(6) constituent quark models and perturbative QCD, A_1^n is predicted to approach 1 as xarrow1, and should be positive for large x (N. Isgur, Phys. Rev.) D59 (1999) 034013.. All present data above x=0.4 have large statistical errors and are consistent with A_1^n<= 0. Experiment E99-117 has the sensitivity to determine if this prediction is valid. To extract A_1^n, longitudinal and transverse spin asymmetries have been measured for inclusive (\\overrightarrow^3He(\\overrightarrowe,e') ) scattering in the deep-inelastic region. This experiment used a polarized electron beam at JLab with the highest available energy of 5.7 GeV, together with a high-density polarized ( ^3 )He target at Hall A, which provide the highest polarized luminosity of the world. Precise data were obtained at three x values (0.33, 0.47, and 0.61), with reasonably high Q^2 (2.8<= Q^2<= 4.8 GeV^2). Preliminary results of A_1^n will be presented.

  13. KW-3902, a selective high affinity antagonist for adenosine A1 receptors.

    PubMed Central

    Nonaka, H.; Ichimura, M.; Takeda, M.; Kanda, T.; Shimada, J.; Suzuki, F.; Kase, H.

    1996-01-01

    1. We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2. In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine (CHA), KW-3902 had a Ki value of 0.19 nM, whereas it showed a Ki value of 170 nM in rat striatal A2A receptors labelled with [3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoad enosine (CGS21680), indicating 890 fold A1 receptor selectivity versus the A2A receptor. KW-3902 at 10 microM showed no effect on recombinant rat A3 receptors expressed on CHO cells. 3. Saturation studies with [3H]-KW-3902 revealed that it bound with high affinity (Kd = 77 pM) and limited capacity (Bmax = 470 fmol mg-1 of protein) to a single class of recognition sites. A high positive correlation was observed between the pharmacological profile of adenosine ligands inhibiting the binding of [3H]-KW-3902 and that of [3H]-CHA. 4. KW-3902 showed potent A1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A1-selective agonist, cyclopentyladenosine with a dissociation constant (KB value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A2B receptors with a KB value of 52 nM. 5. KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A1 receptor (ki = 0.19 nM) and these values for guinea-pig and dog A1 receptors were 1.3 and 10 nM, respectively. PMID:8732272

  14. Epistatic Interaction of CYP1A1 and COMT Polymorphisms in Cervical Cancer

    PubMed Central

    Castelão, Cindy; Pereira da Silva, Alda; Alho, Irina; Bicho, Manuel; Medeiros, Rui; Clara Bicho, Maria

    2016-01-01

    There is a clear association between the excessive and cumulative exposure to estrogens and the development of cancer in hormone-sensitive tissues, such as the cervix. We studied the association of CYP1A1 M1 (rs4646903) and COMT (rs4680) polymorphisms in 130 cervical cancer cases (c-cancer) and 179 controls. The CYP1A1 TT genotype was associated with a lower risk for c-cancer (OR = 0.39, p = 0.002). The allele C of CYP1A1 was a risk for c-cancer (OR = 2.29, p = 0.002). Women with COMT LL genotype had a higher risk of developing c-cancer (OR = 4.83, p < 0.001). For the interaction of the CYP1A1&COMT, we observed that TC&HL genotypes had a greater risk for c-cancer (OR = 6.07, p = 0.006) and TT&HL genotypes had a protection effect (OR = 0.24, p < 0.001). The CYP1A1 TT and COMT LL genotypes had higher estradiol levels in c-cancer (p < 0.001 and p = 0.037, resp.). C-cancer is associated with less production of 2-methoxy-estradiol resultant of functional polymorphisms of CYP1A1 and COMT, separately. CYP1A1 and COMT work in a metabolic sequence and their interaction could lead to an alternative pathway of estrogen metabolism with production of 16-OH-estrone that is more proliferative. PMID:26798414

  15. Two different forms of lethal chondrodysplasias caused by COL2A1 gene mutations

    SciTech Connect

    Winterpacht, A.; Hilbert, K.; Schwarze, U.

    1994-09-01

    Two bone dysplasia families seem to be due to mutations in the type II procollagen gene (COL2A1): the so-called spondyloepiphyseal dysplasia congenita (SEDC) group with achondrogenesis II, hypochondrogenesis, SEDC, osteoarthrosis and the Stickler-Kniest pattern that include different forms of Kniest and Stickler dysplasia. Both groups comprise a clinical spectrum ranging from lethal to mild. COL2A1-mutations have been identified in lethal forms of the SEDC family but not in lethal forms of the Stickler/Kniest group. We now report a COL2A-1 mutation in an additional case of hypochondrogenesis (patient S) and in a lethal case of Kniest dysplasia (patient B). We amplified all 54 exons of the COL2A1 gene in both patients and screened the PCR products for mutations by SSCP analysis and sequencing. In patient B, we identified an 18 bp deletion in exon 34 which removes 6 amino acids from the mature protein. In patient S, we were able to identify a two base pair exchange (GG to AT) in exon 31, which leads to the very unusual conversion of Gly to Ile. To our knowledge, this is the first report of a Gly to Ile conversion in the COL2A1 gene, and the first report of a COL2A1 gene mutation in a lethal form of Kniest dysplasia. On the basis of the known COL2A1 gene mutations and the genotype-phenotype correlations established so far, we provide molecular data (an in frame deletion in patient B and a Gly conversion in patient S) that support their clinical classification as Kniest dysplasia and hypochondrogenesis, respectively.

  16. CYP1A1 gene polymorphisms in modifying association between Passive smoking and primary dysmenorrheal

    PubMed Central

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

    2009-01-01

    Purpose This study is to investigate whether the association between passive smoking exposure and primary dysmenorrhea is modified by two susceptibility genes, CYP1A1MspI and CYP1A1HincII. Methods We recruited 1645 women textile workers from 1997 to 2000 in Anqing, China, collecting the information about passive smoking, status of primary dysmenorrheal, and blood samples. We analyzed the association of CYP1A1 gene polymorphisms and passive smoking exposure with primary dysmenorrheal using multiple logistic regression. Results In the passive smoking group, women who have C/C6235 genotype (OR = 1.8, 95%CI = 1.0–3.3) in CYP1A1MspI and Ile/Ile462 genotype (OR = 2.9, 95%CI =1.1–7.7) in CYP1A1HincII was associated with an increased risk of dysmenorrhea. When stratified by women genotype, the adjusted OR of dysmenorrhea was 1.6 (95%CI = 1.2–2.1) for passive smoking group with Ile/Ile462 genotype, and 1.5 (95%CI = 1.0–2.1) 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=2.4, 95%CI =1.2–4.9). Conclusions CYP1A1 MspI and HincII genotypes modified the association between passive smoking and primary dysmenorrhea. PMID:17728147

  17. Association of Neonatal Hyperbilirubinemia with UGT1A1 Gene Polymorphisms: A Meta-Analysis

    PubMed Central

    Yu, Zibi; Zhu, Kaichang; Wang, Li; Liu, Ying; Sun, Jianmei

    2015-01-01

    Background The results of studies on association between the polymorphisms in the coding region and the promoter of uridine diphosphateglucuronosyl transferase 1A1 (UGT1A1) and neonatal hyperbilirubinemia are controversial. This study aimed to determine whether the UGT1A1 gene polymorphisms of Gly71Arg and TATA promoter were significant risk factors associated with neonatal hyperbilirubinemia. Material/Methods The PubMed, Cochrane Library, and Embase databases were searched for papers that describe the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effects model or random-effects model, depending on the absence or presence of significant heterogeneity. Results A total of 32 eligible studies and 6520 participants were identified. Among them, 24 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, and a significant difference was found for the comparison of AA vs. AG+GG (OR=3.47, 95% CI=2.29–5.28, P<0.0001). We included 19 studies on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphism, which also found a statistically significant difference between 7/7 and 6/7 + 6/6 (OR=2.24, 95% CI=1.29–3.92, P=0.004). Conclusions This meta-analysis demonstrated that UGT1A1 polymorphisms (Gly71Arg and TATA promoter) significantly increase the risk of neonatal hyperbilirubinemia. PMID:26467199

  18. Expression profile and role of EphrinA1 ligand after spinal cord injury.

    PubMed

    Arocho, Luz C; Figueroa, Johnny D; Torrado, Aranza I; Santiago, José M; Vera, Ariel E; Miranda, Jorge D

    2011-10-01

    Spinal cord injury (SCI) triggers the re-expression of inhibitory molecules present in early stages of development, contributing to prevention of axonal regeneration. Upregulation of EphA receptor tyrosine kinases after injury suggest their involvement in the nervous system's response to damage. However, the expression profile of their ephrinA ligands after SCI is unclear. In this study, we determined the expression of ephrinA ligands after contusive SCI. Adult Sprague-Dawley female rats were injured using the MASCIS impactor device at the T10 vertebrae, and levels of ephrinA mRNA and protein determined at different time points. Identification of the cell phenotype expressing the ephrin ligand and colocalization with Eph receptors was performed with immunohistochemistry and confocal microscopy. Behavioral studies were made, after blocking ephrinA1 expression with antisense (AS) oligonucleotides, to assess hindlimb locomotor activity. Real-time PCR demonstrated basal mRNA levels of ephrin (A1, A2, A3, and A5) in the adult spinal cord. Interestingly, ephrinA1 was the only ligand whose mRNA levels were significantly altered after SCI. Although ephrinA1 mRNA levels increased after 2 weeks and remain elevated, we did not observe this pattern at the protein level as revealed by western blot analysis. Immunohistochemical studies showed ephrinA1 expression in reactive astrocytes, axons, and neurons and also their colocalization with EphA4 and A7 receptors. Behavioral studies revealed worsening of locomotor activity when ephrinA1 expression was reduced. This study suggests that ephrinA1 ligands play a role in the pathophysiology of SCI. PMID:21603973

  19. Differential surface activation of the A1 domain of von Willebrand factor

    PubMed Central

    Tronic, Elaine H.; Yakovenko, Olga; Weidner, Tobias; Baio, Joe E.; Penkala, Rebecca; Castner, David G.; Thomas, Wendy E.

    2016-01-01

    The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibα (GPIbα) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbα-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF-SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID:26968213

  20. Differential surface activation of the A1 domain of von Willebrand factor.

    PubMed

    Tronic, Elaine H; Yakovenko, Olga; Weidner, Tobias; Baio, Joe E; Penkala, Rebecca; Castner, David G; Thomas, Wendy E

    2016-06-01

    The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibα (GPIbα) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbα-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF-SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID:26968213