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Journal articles on the topic 'IA-2'

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Published: 4 June 2021
Last updated: 1 February 2022

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1

Hu, Y. F., H. L. Zhang, T. Cai, S. Harashima, and A. L. Notkins. "The IA-2 interactome." Diabetologia 48, no. 12 (November 5, 2005): 2576–81. http://dx.doi.org/10.1007/s00125-005-0037-y.

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2

Notkins, Abner Louis, Michael S. Lan, and R. David G. Leslie. "IA-2 and IA-2β: the immune response in IDDM." Diabetes / Metabolism Reviews 14, no. 1 (March 1998): 85–93. http://dx.doi.org/10.1002/(sici)1099-0895(199803)14:1<85::aid-dmr205>3.0.co;2-i.

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3

Kubosaki, A., S. Nakamura, and A. L. Notkins. "Dense Core Vesicle Proteins IA-2 and IA-2 : Metabolic Alterations in Double Knockout Mice." Diabetes 54, Supplement 2 (November 23, 2005): S46—S51. http://dx.doi.org/10.2337/diabetes.54.suppl_2.s46.

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4

Landais, D., H. Matthes, C. Benoist, and D. Mathis. "A molecular basis for the Ia.2 and Ia.19 antigenic determinants." Proceedings of the National Academy of Sciences 82, no. 9 (May 1, 1985): 2930–34. http://dx.doi.org/10.1073/pnas.82.9.2930.

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5

Kawasaki, Eiji, Liping Yu, Roberto Gianani, Charles F. Verge, Sunanda Babu, Ezio Bonifacio, and George S. Eisenbarth. "Evaluation of Islet Cell Antigen (ICA) 512/IA-2 Autoantibody Radioassays Using Overlapping ICA512/IA-2 Constructs1." Journal of Clinical Endocrinology & Metabolism 82, no. 2 (February 1997): 375–80. http://dx.doi.org/10.1210/jcem.82.2.3723.

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6

Kawasaki, E. "Evaluation of Islet Cell Antigen (ICA) 512/IA-2 Autoantibody Radioassays Using Overlapping ICA512/IA-2 Constructs." Journal of Clinical Endocrinology & Metabolism 82, no. 2 (February 1, 1997): 375–80. http://dx.doi.org/10.1210/jc.82.2.375.

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7

Henquin, Jean-Claude, Myriam Nenquin, Andras Szollosi, Atsutaka Kubosaki, and Abner Louis Notkins. "Insulin secretion in islets from mice with a double knockout for the dense core vesicle proteins islet antigen-2 (IA-2) and IA-2β." Journal of Endocrinology 196, no. 3 (December 10, 2007): 573–81. http://dx.doi.org/10.1677/joe-07-0496.

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Islet antigen-2 (IA-2 or ICA 512) and IA-2β (or phogrin) are major autoantigens in type 1 diabetes. They are located in dense core secretory vesicles including insulin granules, but their role in β-cell function is unclear. Targeted disruption of either IA-2 or IA-2β, or both, impaired glucose tolerance, an effect attributed to diminution of insulin secretion. In this study, we therefore characterized the dynamic changes in cytosolic Ca2+([Ca2+]c) and insulin secretion in islets from IA-2/IA-2β double knockout (KO) mice. High glucose (15 mM) induced biphasic insulin secretion in IA-2/IA-2β KO islets, with a similar first phase and smaller second phase compared with controls. Since the insulin content of IA-2/IA-2β KO islets was ∼45% less than that of controls, fractional insulin secretion (relative to content) was thus increased during first phase and unaffected during second phase. This peculiar response occurred in spite of a slightly smaller rise in [Ca2+]c, could not be attributed to an alteration of glucose metabolism (NADPH fluorescence) and also was observed with tolbutamide. The dual control of insulin secretion via the KATP channel-dependent triggering pathway and KATP channel-independent amplifying pathway was unaltered in IA-2/IA-2β KO islets, and so were the potentiations by acetylcholine or cAMP (forskolin). Intriguingly, amino acids, in particular the cationic arginine and lysine, induced larger fractional insulin secretion in IA-2/IA-2β KO than control islets. In conclusion, IA-2 and IA-2β are dispensable for exocytosis of insulin granules, but are probably more important for cargo loading and/or stability of dense core vesicles.
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8

Courtois, Hélène M., and R. Brent Tully. "COSMICFLOWS-2: TYPE Ia SUPERNOVA CALIBRATION ANDH0." Astrophysical Journal 749, no. 2 (April 5, 2012): 174. http://dx.doi.org/10.1088/0004-637x/749/2/174.

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9

Piquer, Sandra, Lionel Valera, Vito Lampasona, Bénédicte Jardin-Watelet, Stéphanie Roche, Claude Granier, Francoise Roquet, et al. "Monoclonal antibody 76F distinguishes IA-2 from IA-2β and overlaps an autoantibody epitope." Journal of Autoimmunity 26, no. 3 (May 2006): 215–22. http://dx.doi.org/10.1016/j.jaut.2005.12.001.

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10

Kim, Soo Mi, Franziska Theilig, Yan Qin, Tao Cai, Diane Mizel, Robert Faulhaber-Walter, Hiroki Hirai, et al. "Dense-core vesicle proteins IA-2 and IA-2β affect renin synthesis and secretion through the β-adrenergic pathway." American Journal of Physiology-Renal Physiology 296, no. 2 (February 2009): F382—F389. http://dx.doi.org/10.1152/ajprenal.90543.2008.

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IA-2 and IA-2β, major autoantigens in type 1 diabetes, are transmembrane proteins in dense-core vesicles, and their expression influences the secretion of hormones and neurotransmitters. The present experiments were performed to examine whether IA-2 and IA-2β modulate the release of renin from dense-core vesicles of juxtaglomerular granular cells in the kidney. Plasma renin concentration (PRC; ng angiotensin I·ml−1·h−1) was significantly reduced in mice with null mutations in IA-2, IA-2β, or both IA-2 and IA-2β compared with wild-type mice (876 ± 113, 962 ± 130, and 596 ± 82 vs. 1,367 ± 93; P < 0.01, P < 0.02, and P < 0.001). Renin mRNA levels were reduced to 26.4 ± 5.1, 39 ± 5.4, and 35.3 ± 5.5% of wild-type in IA-2−/−, IA-2β−/−, and IA-2/IA-2β−/− mice. Plasma aldosterone levels were not significantly different among genotypes. The regulation of PRC by furosemide and salt intake, and of aldosterone by salt intake, was maintained in all genotypes. IA-2 and IA-2β expression did not colocalize with renin but showed overlapping immunoreactivity with tyrosine hydroxylase. While propranolol reduced PRC in wild-type mice, it had no effect on PRC in IA-2/ IA-2β−/− mice. Renal tyrosine hydroxylase mRNA and immunoreactivity were reduced in IA-2/IA-2β−/− mice as was the urinary excretion of catecholamines. We conclude that IA-2 and IA-2β are required to maintain normal levels of renin expression and renin release, most likely by permitting normal rates of catecholamine release from sympathetic nerve terminals.
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11

Chen, Shu, Jinny Willis, Clare Maclean, Rossitza Ananieva-Jordanova, Marie-Andrée Amoroso, Helen Brooking, Michael Powell, et al. "Sensitive non-isotopic assays for autoantibodies to IA-2 and to a combination of both IA-2 and GAD65." Clinica Chimica Acta 357, no. 1 (July 2005): 74–83. http://dx.doi.org/10.1016/j.cccn.2005.02.006.

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12

Mäkinen, Anna, Taina Härkönen, Jorma Ilonen, Mikael Knip, and _. _. "Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes." European Journal of Endocrinology 159, no. 1 (July 2008): 19–26. http://dx.doi.org/10.1530/eje-07-0853.

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ObjectiveTo characterize the humoral immune response to islet antigen 2 (IA-2) in patients with newly diagnosed type 1 diabetes (T1D), we compared the profile of epitope- and isotype-specific IA-2 antibodies (IA-2A) between children with a humoral immune response restricted to IA-2 and children with a broad response including insulin autoantibodies (IAA) and antibodies to glutamic acid decarboxylase (GADA) in addition to IA-2A.MethodsThe study subjects (n=100) were derived from a consecutive series of 1108 patients from the Finnish Pediatric Diabetes Register (investigators listed in the Appendix). Islet cell antibodies, IAA, GADA, total IA-2A levels, IA-2/IA-2β epitopes, and isotypes were measured, and human leukocyte antigen (HLA) genotypes were analyzed.ResultsThere were no significant differences between the two groups in the frequency or levels of epitope-specific IA-2A. Those with an IA-2-restrictive response tested positive more frequently for IgA-IA-2A (P=0.001), had higher titers of IgE-IA-2A (P=0.025), tested positive for more IA-2A isotypes than the broad responders (P=0.04), and carried the high-risk HLA-(DR4)-DQB1*0302 haplotype more frequently than those with a broad antibody response (P=0.019).ConclusionsThese data show that children with newly diagnosed T1D, who test positive only for IA-2A out of the three molecular antibodies predictive of T1D, have a broader IA-2-specific isotype response and stronger association with the high-risk HLA haplotype than those testing positive for all three molecular antibodies. This may be indicative of a different pathogenetic mechanism in those with their humoral immune response restricted to IA-2 at the time of diagnosis.
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13

Hatfield, E. C. I., C. J. Hawkes, M. A. Payton, and M. R. Christie. "Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM." Diabetologia 40, no. 11 (November 1997): 1327–33. http://dx.doi.org/10.1007/s001250050828.

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14

Nishimura, Takuya, Shin-ichi Harashima, Hu Yafang, and Abner Louis Notkins. "IA-2 modulates dopamine secretion in PC12 cells." Molecular and Cellular Endocrinology 315, no. 1-2 (February 2010): 81–86. http://dx.doi.org/10.1016/j.mce.2009.09.023.

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15

KAWASAKI, EIJI, HIROKAZU YAMAGUCHI, HIROAKI HATTORI, TORU EGASHIRA, and KATSUMI EGUCHI. "Autoantibodies to IA-2 in Type 1 Diabetes." Annals of the New York Academy of Sciences 958, no. 1 (January 24, 2006): 241–46. http://dx.doi.org/10.1111/j.1749-6632.2002.tb02978.x.

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16

TIBERTI, C., A. VERRIENTI, B. FIORE, L. YU, G. EISENBARTH, F. DOTTA, and U. DIMARIO. "IA-2 combined epitope assay: A new, highly sensitive approach to evaluate IA-2 humoral autoimmunity in type 1 diabetes." Clinical Immunology 115, no. 3 (June 2005): 260–67. http://dx.doi.org/10.1016/j.clim.2005.01.015.

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17

Yuan, Min, Hui Han, Cong-Ran Li, Xin-Yi Yang, Guo-Qing Li, Shan Cen, Xi-Xiong Kang, Shu-Yi Si, Jian-Dong Jiang, and Xue-Fu You. "Susceptibility of Vertilmicin to Modifications by Three Types of Recombinant Aminoglycoside-Modifying Enzymes." Antimicrobial Agents and Chemotherapy 55, no. 8 (June 6, 2011): 3950–53. http://dx.doi.org/10.1128/aac.00300-11.

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ABSTRACTThe susceptibilities of vertilmicin and seven reference aminoglycosides to modifications by six recombinant aminoglycoside-modifying enzymes, AAC(6′)-Ie, APH(2′′)-Ia, AAC(6′)-Ie-APH(2′′)-Ia, ANT(2′′)-Ia, AAC(6′)-Ib, and AAC(6′)-Ib-cr, were studied by coupled spectrophotometric assays in microtiter plates. In comparison to other aminoglycosides, the susceptibility of vertilmicin was 45.8- to 250.0-fold lower for AAC(6′)-Ie acetylation, 39.2- to 116.7-fold lower for AAC(6′)-Ie-APH(2′′)-Ia acetylation, and 1.8- to 7.5-fold lower for ANT(2′′)-Ia adenylation (except that shown by amikacin) while relatively comparable for AAC(6′)-Ib acetylation, AAC(6′)-Ib-cr acetylation, APH(2′′)-Ia phosphorylation, and AAC(6′)-Ie-APH(2′′)-Ia phosphorylation.
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18

Bassenden, Angelia, Dmitry Rodionov, Nilu Sabet-Kassouf, Tahereh Haji, Kun Shi, and Albert Berghuis. ""Structural characterization of aminoglycoside modifying enzyme ANT(2"")-Ia"." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C702. http://dx.doi.org/10.1107/s2053273314092973.

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Aminoglycosides are a class of broad-spectrum antibiotics used in the treatment of serious Gram-negative bacterial infections, they target the 16S RNA subunit and upon binding cause errors in translation, eventually inducing a bactericidal effect [1]. Aminoglycoside nucleotidyltransferase (2")-Ia (ANT(2")-Ia) is an aminoglycoside modifying enzyme that prevents aminoglycosides from binding to the ribosomal subunit, making this enzyme a principle candidate structure-based drug design [2]. Characterization of ANT(2")-Ia has been proven to be difficult due to the low stability and solubility of overexpressed protein, where 95% of the protein being expressed is in the form of inclusion bodies [3]. We describe a protocol that has lead to successful expression and purification of ANT(2")-Ia. A successful enzymatic assay has also been adapted and the protein is active and stable under these conditions with a specific activity of 0.14 U/mg. Furthermore, nuclear magnetic resonance (NMR) studies have allowed for the assignment of 144 of the 176 non-proline backbone residues. Substrate binding NMR experiments have shown unique global chemical shift perturbations upon binding ATP and tobramycin, suggesting unique binding sites for each substrate. Structural determination of ANT(2")-Ia using NMR in conjunction with x-ray crystallography can be utilized in order to develop small molecules that will act as more effective aminoglycosides in order to inhibit ANT(2")-Ia from binding and modifying these antibiotics.
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19

Kubosaki, Atsutaka, Shinichiro Nakamura, Anne Clark, John F. Morris, and Abner L. Notkins. "Disruption of the Transmembrane Dense Core Vesicle Proteins IA-2 and IA-2β Causes Female Infertility." Endocrinology 147, no. 2 (February 1, 2006): 811–15. http://dx.doi.org/10.1210/en.2005-0638.

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Female infertility is a worldwide problem affecting 10–15% of the population. The cause of the infertility in many cases is not known. In the present report, we demonstrate that alterations in two transmembrane structural proteins, IA-2 and IA-2β, located in dense core secretory vesicles (DCV) of many endocrine and neuroendocrine cells, can result in female infertility. IA-2 and IA-2β are best known as major autoantigens in type 1 diabetes, but their normal function has remained an enigma. Recently we showed in mice that deletion of IA-2 and/or IA-2β results in impaired insulin secretion and glucose intolerance. We now report that double knockout (DKO), but not single knockout, female mice are essentially infertile. Vaginal smears showed a totally abnormal estrous cycle, and examination of the ovaries revealed normal-appearing oocytes but the absence of corpora lutea. The LH surge that is required for ovulation occurred in wild-type mice but not in DKO mice. Additional studies showed that the LH level in the pituitary of DKO female mice was decreased compared with wild-type mice. Treatment of DKO females with gonadotropins restored corpora lutea formation. In contrast to DKO female mice, DKO male mice were fertile and LH levels in the serum and pituitary were within the normal range. From these studies we conclude that the DCV proteins, IA-2 and IA-2β, play an important role in LH secretion and that alterations in structural proteins of DCV can result in female infertility.
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20

Atkinson, D. Scott, and Betsy Fahlman. "IA: The Journal of the Society for Industrial Archeology. Vol. 12, No. 2: IA in Art." Technology and Culture 30, no. 2 (April 1989): 460. http://dx.doi.org/10.2307/3105115.

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21

Hildebrandt, G., E. Holler, M. Woenkhaus, G. Quarch, A. Reichle, B. Schalke, and R. Andreesen. "Acute Deterioration Of Charcot‐Marie‐Tooth Disease IA (CMT IA) Following 2 MG Of Vincristine Chemotherapy." Journal of the Peripheral Nervous System 6, no. 1 (March 2001): 62. http://dx.doi.org/10.1046/j.1529-8027.2001.01008-9.x.

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22

Doi, A., T. Shono, M. Nishi, H. Furuta, H. Sasaki, and K. Nanjo. "IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion." Proceedings of the National Academy of Sciences 103, no. 4 (January 17, 2006): 885–90. http://dx.doi.org/10.1073/pnas.0502470102.

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23

Punia, Sohan, Kyle K. Rumery, Elizabeth A. Yu, Christopher M. Lambert, Abner L. Notkins, and David R. Weaver. "Disruption of gene expression rhythms in mice lacking secretory vesicle proteins IA-2 and IA-2β." American Journal of Physiology-Endocrinology and Metabolism 303, no. 6 (September 15, 2012): E762—E776. http://dx.doi.org/10.1152/ajpendo.00513.2011.

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Insulinoma-associated protein (IA)-2 and IA-2β are transmembrane proteins involved in neurotransmitter secretion. Mice with targeted disruption of both IA-2 and IA-2β (double-knockout, or DKO mice) have numerous endocrine and physiological disruptions, including disruption of circadian and diurnal rhythms. In the present study, we have assessed the impact of disruption of IA-2 and IA-2β on molecular rhythms in the brain and peripheral oscillators. We used in situ hybridization to assess molecular rhythms in the hypothalamic suprachiasmatic nuclei (SCN) of wild-type (WT) and DKO mice. The results indicate significant disruption of molecular rhythmicity in the SCN, which serves as the central pacemaker regulating circadian behavior. We also used quantitative PCR to assess gene expression rhythms in peripheral tissues of DKO, single-knockout, and WT mice. The results indicate significant attenuation of gene expression rhythms in several peripheral tissues of DKO mice but not in either single knockout. To distinguish whether this reduction in rhythmicity reflects defective oscillatory function in peripheral tissues or lack of entrainment of peripheral tissues, animals were injected with dexamethasone daily for 15 days, and then molecular rhythms were assessed throughout the day after discontinuation of injections. Dexamethasone injections improved gene expression rhythms in liver and heart of DKO mice. These results are consistent with the hypothesis that peripheral tissues of DKO mice have a functioning circadian clockwork, but rhythmicity is greatly reduced in the absence of robust, rhythmic physiological signals originating from the SCN. Thus, IA-2 and IA-2β play an important role in the regulation of circadian rhythms, likely through their participation in neurochemical communication among SCN neurons.
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24

Chen, Wentong, Hui Luo, Zhuanxia Zhang, Longzhen Lin, and Wenjing Tao. "Preparation and characterization of {[La2(IA)4(H2O)4][μ3-(IA)]2[Mn(H2O)4]}n2nCl." Journal of the Iranian Chemical Society 17, no. 1 (July 30, 2019): 37–42. http://dx.doi.org/10.1007/s13738-019-01742-y.

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25

Macinga, David R., Michael R. Paradise, Milica M. Parojcic, and Philip N. Rather. "Activation of the 2′- N -Acetyltransferase Gene [aac(2′)-Ia] inProvidencia stuartii by an Interaction of AarP with the Promoter Region." Antimicrobial Agents and Chemotherapy 43, no. 7 (July 1, 1999): 1769–72. http://dx.doi.org/10.1128/aac.43.7.1769.

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ABSTRACT The aac(2′)-Ia gene inProvidencia stuartii encodes a 2′-N-acetyltransferase capable of acetylating both peptidoglycan and certain aminoglycoside antibiotics. Regulation of theaac(2′)-Ia gene is influenced in a positive manner by the product of the aarP gene, which encodes a small transcriptional activator of the AraC (XylS) family. In this study, we demonstrate the sequence requirements at theaac(2′)-Ia promoter for AarP binding and activation.
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26

Cunningham, JL, ET Janson, B. Eriksson, K. Oberg, and AE Gobl. "Transmembrane protein tyrosine phosphatase IA-2 (ICA512) is expressed in human midgut carcinoids but is not detectable in normal enterochromaffin cells." Journal of Endocrinology 164, no. 3 (March 1, 2000): 315–22. http://dx.doi.org/10.1677/joe.0.1640315.

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A potential upregulation of receptor type protein tyrosine phosphatase IA-2 (ICA512) expression was detected by differential display and investigated in midgut carcinoid tumours. Normal intestine tissue and tumour tissue from 13 midgut carcinoid patients were studied by in situ hybridisation using an IA-2 ribonucleotide probe and confocal microscopy using specific IA-2 antibodies. Previously, it had been shown that IA-2 is located in the secretory granules of virtually all neuroendocrine cells. However, we found that IA-2 was not detectable in resting normal enterochromaffin (EC) cells of the small intestine, while high expression of IA-2 mRNA and protein was confirmed in both primary and metastatic carcinoid tissue. This difference in expression was not observed with chromogranin A or serotonin, two secretory granule hormones known to be expressed in EC cells, indicating that IA-2 was seemingly not necessary for the basal production and packaging of these hormones. When comparing patients receiving biotherapy before operation with untreated patients, we found expression of IA-2 to be lower in tumours from patients that had been treated with a combination of alpha-interferon and the somatostatin analogue, octreotide. There was no correlation between IA-2 expression and proliferation rates as measured by immunohistochemistry with antibodies against the Ki 67 antigen. Furthermore, we show that IA-2 is co-localised with serotonin in carcinoid tumours as well as in the pancreatic tumour cell line, BON1, which is interesting as serotonin secretion rate is presumably higher in tumour cells than in resting EC cells. Taken together, these findings may indicate a role for IA-2 in the later stages of the regulated secretory process.
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27

Cai, T., J. Xie, J. X. She, and A. L. Notkins. "Analysis of the Coding and Promoter Regions of the Autoantigen IA-2 in Subjects With and Without Autoantibodies to IA-2." Diabetes 50, no. 10 (October 1, 2001): 2406–9. http://dx.doi.org/10.2337/diabetes.50.10.2406.

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28

DRAKE, Paul G., Günther H. PETERS, Henrik Sune ANDERSEN, Wiljan HENDRIKS, and Niels Peter H. MØLLER. "A novel strategy for the development of selective active-site inhibitors of the protein tyrosine phosphatase-like proteins islet-cell antigen 512 (IA-2) and phogrin (IA-2beta)." Biochemical Journal 373, no. 2 (July 15, 2003): 393–401. http://dx.doi.org/10.1042/bj20021851.

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Islet-cell antigen 512 (IA-2) and phogrin (IA-2β) are atypical members of the receptor protein tyrosine phosphatase (PTP) family that are characterized by a lack of activity against conventional PTP substrates. The physiological role(s) of these proteins remain poorly defined, although recent studies indicate that IA-2 may be involved in granule trafficking and exocytosis. To further understand their function, we have embarked upon developing low-molecular-mass inhibitors of IA-2 and IA-2β. Previously, we have shown that a general PTP inhibitor, 2-(oxalylamino)benzoic acid (OBA), can be developed into highly selective and potent inhibitors of PTP1B. However, since wild-type IA-2 and IA-2β lack conventional PTP activity, a novel strategy was designed whereby catalytically active species were generated by ‘back-mutating’ key non-consensus catalytic region residues to those of PTP1B. These mutants were then used as tools with which to test the potency and selectivity of OBA and a variety of its derivatives. Catalytically competent IA-2 and IA-2β species were generated by ‘back-mutation’ of only three key residues (equivalent to Tyr46, Asp181 and Ala217 using the human PTP1B numbering) to those of PTP1B. Importantly, enzyme kinetic analyses indicated that the overall fold of both mutant and wild-type IA-2 and IA-2β was similar to that of classic PTPs. In particular, one derivative of OBA, namely 7-(1,1-dioxo-1H-benzo[d]isothiazol-3-yloxymethyl)-2-(oxalylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3 -carboxylic acid (‘Compound 6’ shown in the main paper), which inhibited IA-2β(S762Y/Y898P/D933A) (IA-2β in which Ser762 has been mutated to tyrosine, Tyr898 to proline, and Asp933 to alanine) with a Ki value of ≈8 μM, appeared ideal for future lead optimization. Thus molecular modelling of this classical, competitive inhibitor in the catalytic site of wild-type IA-2β identified two residues (Ser762 and Asp933) that offer the possibility for unique interaction with an appropriately modified ‘Compound 6’. Such a compound has the potential to be a highly selective and potent active-site inhibitor of wild-type IA-2β.
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29

Smith, Clyde A., Marta Toth, Monolekha Bhattacharya, Hilary Frase, and Sergei B. Vakulenko. "Structure of the phosphotransferase domain of the bifunctional aminoglycoside-resistance enzyme AAC(6′)-Ie-APH(2′′)-Ia." Acta Crystallographica Section D Biological Crystallography 70, no. 6 (May 23, 2014): 1561–71. http://dx.doi.org/10.1107/s1399004714005331.

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The bifunctional acetyltransferase(6′)-Ie-phosphotransferase(2′′)-Ia [AAC(6′)-Ie-APH(2′′)-Ia] is the most important aminoglycoside-resistance enzyme in Gram-positive bacteria, conferring resistance to almost all known aminoglycoside antibiotics in clinical use. Owing to its importance, this enzyme has been the focus of intensive research since its isolation in the mid-1980s but, despite much effort, structural details of AAC(6′)-Ie-APH(2′′)-Ia have remained elusive. The structure of the Mg2GDP complex of the APH(2′′)-Ia domain of the bifunctional enzyme has now been determined at 2.3 Å resolution. The structure of APH(2′′)-Ia is reminiscent of the structures of other aminoglycoside phosphotransferases, having a two-domain architecture with the nucleotide-binding site located at the junction of the two domains. Unlike the previously characterized APH(2′′)-IIa and APH(2′′)-IVa enzymes, which are capable of utilizing both ATP and GTP as the phosphate donors, APH(2′′)-Ia uses GTP exclusively in the phosphorylation of the aminoglycoside antibiotics, and in this regard closely resembles the GTP-dependent APH(2′′)-IIIa enzyme. In APH(2′′)-Ia this GTP selectivity is governed by the presence of a `gatekeeper' residue, Tyr100, the side chain of which projects into the active site and effectively blocks access to the adenine-binding template. Mutation of this tyrosine residue to a less bulky phenylalanine provides better access for ATP to the NTP-binding template and converts APH(2′′)-Ia into a dual-specificity enzyme.
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30

Singh, Sandeep, Deepak Gumber, and Hemant Kalra. "IA-automorphisms of finitely generated nilpotent groups." Journal of Algebra and Its Applications 13, no. 07 (May 2, 2014): 1450027. http://dx.doi.org/10.1142/s0219498814500273.

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An automorphism of a group G is called an IA-automorphism if it induces the identity automorphism on the abelianized group G/G′. Let IA (G) denote the group of all IA-automorphisms of G. We classify all finitely generated nilpotent groups G of class 2 for which IA (G) ≃ Inn (G). In particular, we classify all finite nilpotent groups of class 2 for which each IA-automorphism is inner.
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31

Masuda, Masato, Michael Powell, Shu Chen, Carolyn Beer, Piotr Fichna, Bernard Rees Smith, and Jadwiga Furmaniak. "Autoantibodies to IA-2 in insulin-dependent diabetes mellitus." Clinica Chimica Acta 291, no. 1 (January 2000): 53–66. http://dx.doi.org/10.1016/s0009-8981(99)00199-0.

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32

Keller, Sascha, Joachim Nickel, Jin-Li Zhang, Walter Sebald, and Thomas D. Mueller. "Molecular recognition of BMP-2 and BMP receptor IA." Nature Structural & Molecular Biology 11, no. 5 (April 4, 2004): 481–88. http://dx.doi.org/10.1038/nsmb756.

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33

Bearzatto, Massimo, Vito Lampasona, Cristina Belloni, and Ezio Bonifacio. "Fine mapping of diabetes-associated IA-2 specific autoantibodies." Journal of Autoimmunity 21, no. 4 (December 2003): 377–82. http://dx.doi.org/10.1016/j.jaut.2003.08.002.

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34

Grünewald, Stephanie. "The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia)." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1792, no. 9 (September 2009): 827–34. http://dx.doi.org/10.1016/j.bbadis.2009.01.003.

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35

Morran, Michael P., Anna Casu, Vincent C. Arena, Susan Pietropaolo, Ying-Jian Zhang, Leslie S. Satin, Patrick Nelson, et al. "Humoral Autoimmunity against the Extracellular Domain of the Neuroendocrine Autoantigen IA-2 Heightens the Risk of Type 1 Diabetes." Endocrinology 151, no. 6 (April 9, 2010): 2528–37. http://dx.doi.org/10.1210/en.2009-1257.

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The objective of this study was to determine whether antigenic determinants localized within the extracellular domain of the neuroendocrine autoantigen tyrosine phosphatase-like protein IA-2 are targets of humoral responses in type 1 diabetes (T1DM). Previous studies indicated that the immunodominant region of IA-2 is localized within its intracellular domain (IA-2ic; amino acids 601–979). We analyzed 333 subjects from the Children’s Hospital of Pittsburgh study, 102 of whom progressed to insulin-requiring diabetes (prediabetics). Autoantibodies from these individuals were initially assayed for ICA512bdc (Barbara Davis Center amino acids 257–556; 630–979), IA-2ic (amino acids 601–979), and IA-2 full-length (amino acids 1–979) in addition to islet cell antibody (ICA), glutamic acid decarboxylase, 65-kDa isoform, and insulin autoantibodies. We identified an autoantibody response reactive with the extracellular domain of IA-2 that is associated with very high risk of T1DM progression. Relatives with no detectable autoantibodies against ICA512bdc (or IA-2ic) exhibited antibody responses against the IA-2 full-length peptide (log rank, P = 0.008). This effect was also observed in first-degree relatives who were positive for glutamic acid decarboxylase, 65–kDa isoform (log rank, P = 0.026) or at least two islet autoantibodies but were negative for ICA512bdc (log rank, P = 0.022). Competitive binding experiments and immunoprecipitation of the IA-2 extracellular domain (amino acid residues 26–577) further lend support for the presence of autoantibodies reactive with new antigenic determinants within the extracellular domain of IA-2. In summary, the addition of measurements of autoantibodies reactive with the IA-2 extracellular domain to assays geared to assess the progression of autoimmunity to clinical T1DM may more accurately characterize this risk. This has considerable implications not only for stratifying high diabetes risk but also facilitating the search for pathogenic epitopes to enable the design of peptide-based immunotherapies that may prevent the progression to overt T1DM at its preclinical stages.
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Carmona, G. N., T. Nishimura, C. W. Schindler, L. V. Panlilio, and A. L. Notkins. "The dense core vesicle protein IA-2, but not IA-2β, is required for active avoidance learning." Neuroscience 269 (June 2014): 35–42. http://dx.doi.org/10.1016/j.neuroscience.2014.03.023.

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37

Shabani Attar, M. "Semicomplete Finite p-Groups of Class 2." Algebra Colloquium 23, no. 04 (September 26, 2016): 651–56. http://dx.doi.org/10.1142/s1005386716000547.

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Let G be a group and G' be its commutator subgroup. An automorphism α of a group G is called an IA-automorphism if x-1 α(x) ∈ G' for each x ∈ G. The set of all IA-automorphisms of G is denoted by IA (G). A group G is called semicomplete if and only if IA (G)= Inn (G), where Inn (G) is the inner automorphism group of G. In this paper we completely characterize semicomplete finite p-groups of class 2; we also classify all semicomplete finite p-groups of order pn (n ≤ 5), where p is an odd prime. This completes our work in 2011.
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38

Nassar, Aziza, Cynthia Cohen, Sally S. Agersborg, Weidong Zhou, Kathleen A. Lynch, Maher Albitar, Edward A. Barker, et al. "Trainable Immunohistochemical HER2/neu Image Analysis: A Multisite Performance Study Using 260 Breast Tissue Specimens." Archives of Pathology & Laboratory Medicine 135, no. 7 (July 1, 2011): 896–902. http://dx.doi.org/10.5858/2010-0418-oar1.1.

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Abstract Context.—Aperio Technologies, Inc (Vista, California) provides a new immunohistochemistry (IHC) HER2 Image Analysis (IA) system that allows tuning of the intensity thresholds of the HER2/neu scoring scheme to adapt to the staining characteristics of different reagents. Objective.—To compare the trainable IHC HER2 IA system for different reagents to conventional manual microscopy (MM) in a multisite study. Design.—Two hundred sixty formalin-fixed, paraffin-embedded breast cancer specimens from 3 clinical sites were assayed: 180 specimens stained with Dako's HercepTest (Carpinteria, California), and 80 specimens stained with Ventana's PATHWAY HER-2/neu (Tucson, California). At each site, 3 pathologists performed a blinded reading of the glass slides with the use of a light microscope. The glass slides were then scanned and after a wash-out period and randomization, the same pathologists outlined a representative set of tumor regions to be analyzed by IHC HER2 IA. Each of the methods, MM and IA, was evaluated separately and comparatively by using κ statistics of negative HER2/neu scores (0, 1+) versus equivocal HER2/neu scores (2+) versus positive HER2/neu scores (3+) among the different pathologists. Results.—κ Values for IA and MM were obtained across all sites. MM: 0.565–0.864; IA: 0.895–0.947; MM versus IA: 0.683–0.892 for site 1; MM: 0.771–0.837; IA: 0.726–0.917; MM versus IA: 0.687–0.877 for site 2; MM: 0.463–0.674; IA: 0.864–0.918; MM versus IA: 0.497–0.626 for site 3. Conclusion.—Aperio's trainable IHC HER2 IA system shows substantial equivalence to MM for Dako's HercepTest and Ventana's PATHWAY HER-2/neu at 3 clinical sites. Image analysis improved interpathologist agreement in the different clinical sites.
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Shen, Lili, Shiping Lu, Dongcheng Huang, Guoliang Li, Kunfeng Liu, Rongyue Cao, Li Zong, Liang Jin, and Jie Wu. "A rationally designed peptide IA-2-P2 against type 1 diabetes in streptozotocin-induced diabetic mice." Diabetes and Vascular Disease Research 14, no. 3 (March 1, 2017): 184–90. http://dx.doi.org/10.1177/1479164116664189.

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Recent studies have investigated the potential of type 1 diabetes mellitus–related autoantigens, such as heat shock protein 60, to induce immunological tolerance or to suppress the immune response. A functional 24-residue peptide derived from heat shock protein 60 (P277) has shown anti-type 1 diabetes mellitus potential in experimental animals and in clinical studies, but it also carries a potential atherogenic effect. In this study, we have modified P277 to retain an anti-type 1 diabetes mellitus effect and minimize the atherogenic potential by replacing the P277 B epitope with another diabetes-associated autoantigen, insulinoma antigen-2 (IA-2), to create the fusion peptide IA-2-P2. In streptozotocin-induced diabetic C57BL/6J mice, the IA-2-P2 peptide displayed similar anti-diabetic effects to the control P277 peptide. Also, the IA-2-P2 peptide did not show atherogenic activity in a rabbit model. Our findings indicate the potential of IA-2-P2 as a promising vaccine against type 1 diabetes mellitus.
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40

Toth, Marta, Hilary Frase, Nuno T. Antunes, and Sergei B. Vakulenko. "Novel Aminoglycoside 2″-Phosphotransferase Identified in a Gram-Negative Pathogen." Antimicrobial Agents and Chemotherapy 57, no. 1 (November 5, 2012): 452–57. http://dx.doi.org/10.1128/aac.02049-12.

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ABSTRACTAminoglycoside 2″-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci. We describe a novel aminoglycoside 2″-phosphotransferase from the Gram-negative pathogenCampylobacter jejuni, which shares 78% amino acid sequence identity with the APH(2″)-Ia domain of the bifunctional aminoglycoside-modifying enzyme aminoglycoside (6′) acetyltransferase-Ie/aminoglycoside 2″-phosphotransferase-Ia or AAC(6′)-Ie/APH(2″)-Ia from Gram-positive cocci, which we called APH(2″)-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin, but not to any of the 4,5-disubstituted antibiotics tested. Steady-state kinetic studies demonstrated that GTP, and not ATP, is the preferred cosubstrate for APH(2″)-If. The enzyme phosphorylates the majority of 4,6-disubstituted aminoglycosides with high catalytic efficiencies (kcat/Km= 105to 107M−1s−1), while the catalytic efficiencies against the 4,6-disubstituted antibiotics amikacin and isepamicin are 1 to 2 orders of magnitude lower, due mainly to the low apparent affinities of these substrates for the enzyme. Both 4,5-disubstituted antibiotics and the atypical aminoglycoside neamine are not substrates of APH(2″)-If, but are inhibitors. The antibiotic susceptibility and substrate profiles of APH(2″)-If are very similar to those of the APH(2″)-Ia phosphotransferase domain of the bifunctional AAC(6′)-Ie/APH(2″)-Ia enzyme.
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41

Sprent, J., and M. Schaefer. "Properties of purified T cell subsets. I. In vitro responses to class I vs. class II H-2 alloantigens." Journal of Experimental Medicine 162, no. 6 (December 1, 1985): 2068–88. http://dx.doi.org/10.1084/jem.162.6.2068.

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In light of the widely accepted view that Ia-restricted L3T4+ T helper cells play a decisive role in controlling the differentiation of Lyt-2+ cells, experiments were designed to examine whether Lyt-2+ cells can respond to antigen in the absence of L3T4+ cells. The results showed that highly purified Lyt-2+ cells gave high primary mixed lymphocyte reactions (MLR) to various class I differences, including both mutant and allelic differences; responses to class II (Ia) differences were generally undetectable with Lyt-2+ cells. The intensity of MLR to class I differences was not affected by addition of anti-L3T4 monoclonal antibodies (mAb) to the cultures or by removing T cells from the stimulator populations. Negative selection experiments showed that Lyt-2+ cells could respond to class I differences across Ia barriers. MLR of purified Lyt-2+ cells peaked on days 3-4 and then fell sharply; background responses with syngeneic stimulators (auto-MLR) were virtually absent. Parallel experiments with purified L3T4+ cells showed that this subset responded in MLR only to class II (Ia) and not class I differences, reached peak responses only on day 6 rather than days 3-4, and often gave high auto-MLR. Within the first 3-4 d of culture, MLR were generally higher with Lyt-2+ cells than L3T4+ cells. Although no evidence could be found that Ia-restricted L3T4+ cells were required for the response of Lyt-2+ cells, presentation of antigen by Ia+ cells appeared to be essential. Thus, responses were ablated by pretreating stimulator cells with anti-Ia mAb plus C'. Significantly the failure of Lyt-2+ cells to respond to anti-Ia plus C'-treated stimulators could not be restored by adding syngeneic spleen cells; addition of IL-2 led to only a minor (15%) restoration of the response. It is suggested that Ia+ cells provide an obligatory second signal required by Lyt-2+ cells.
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42

Rather, P. N., M. M. Parojcic, and M. R. Paradise. "An extracellular factor regulating expression of the chromosomal aminoglycoside 2'-N-acetyltransferase of Providencia stuartii." Antimicrobial Agents and Chemotherapy 41, no. 8 (August 1997): 1749–54. http://dx.doi.org/10.1128/aac.41.8.1749.

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The chromosomal aac(2')-Ia gene in Providencia stuartii encodes a housekeeping 2'-N-acetyltransferase [AAC(2')-Ia] involved in the acetylation of peptidoglycan. In addition, the AAC(2')-Ia enzyme also acetylates and confers resistance to the clinically important aminoglycoside antibiotics gentamicin, tobramycin, and netilmicin. Expression of the aac(2')-Ia gene was found to be strongly influenced by cell density, with a sharp decrease in aac(2')-Ia mRNA accumulation as cells approached stationary phase. This decrease was mediated by the accumulation of an extracellular factor, designated AR (for acetyltransferase repressing)-factor. AR-factor was produced in both minimal and rich media and acted in a manner that was strongly dose dependent. The activity of AR-factor was also pH dependent, with optimal activity at pH 8.0 and above. Biochemical characterization of conditioned media from P. stuartii has shown that AR-factor is between 500 and 1,000 Da in molecular size and is heat stable. In addition, AR-factor was inactivated by a variety of proteases, suggesting that it may be a small peptide.
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43

Westerlund-Karlsson, Annette, Katriina Suonpää, Matti Ankelo, Jorma Ilonen, Mikael Knip, and Ari E. Hinkkanen. "Detection of Autoantibodies to Protein Tyrosine Phosphatase-like Protein IA-2 with a Novel Time-resolved Fluorimetric Assay." Clinical Chemistry 49, no. 6 (June 1, 2003): 916–23. http://dx.doi.org/10.1373/49.6.916.

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Abstract Background: Circulating autoantibodies to pancreatic glutamic acid decarboxylase (GAD65; the 65-kDa isoform of glutamic acid decarboxylase), protein tyrosine phosphatase-like protein IA-2, and insulin can be used as predictive markers of type 1 diabetes. We developed a novel assay for the detection of IA-2 autoantibodies (IA-2As) in serum based on time-resolved fluorimetry, hypothesizing that this kind of assay could provide several advantages over methods described to date, including radiobinding assays (RBAs) and ELISAs. Methods: The intracellular part of IA-2 (IA-2ic) was biotinylated and bound to streptavidin-coated 96-well plates by simultaneous incubation with serum samples and glutathione S-transferase (GST)-IA-2ic fusion protein. GST-IA-2ic captured by autoantibodies in the serum was detected with europium-labeled anti-GST antibody, and the signal was measured in a time-resolved fluorimeter. A serum sample panel from 100 patients with newly diagnosed type 1 diabetes and 100 unaffected controls was analyzed with the new assay and a conventional RBA. Results: Among the 100 serum samples from patients with type 1 diabetes, the time-resolved fluorimetric assay identified 74 IA-2A-containing sera, whereas the RBA detected 80 IA-2A-positive samples. Five of the six samples positive in the RBA but not detected by the time-resolved fluorimetric assay were only weakly positive in the RBA. The performance time of the time-resolved fluorimetric assay was 2.5 h compared with 10–12 h required by the RBA. Conclusions: The time-resolved fluorimetric assay provides a simple, nonradioactive analysis method for the detection of IA-2As with a specificity and a sensitivity comparable to the RBA method. This assay allows substantial reduction in performance time compared with the conventional RBA.
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44

Mine, Benjamin, Alexandra Goutte, Denis Brisbois, and Boris Lubicz. "Endovascular treatment of intracranial aneurysms with the Woven EndoBridge device: mid term and long term results." Journal of NeuroInterventional Surgery 10, no. 2 (February 20, 2017): 127–32. http://dx.doi.org/10.1136/neurintsurg-2016-012964.

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PurposeTo evaluate the clinical and anatomical results of treatment of intracranial aneurysms (IA) with the Woven EndoBridge (WEB) device, with emphasis on mid term and long term follow-up.MethodsBetween November 2010 and November 2015, we retrospectively identified, in our prospectively maintained database, all patients treated by WEB device placement for an IA at three institutions. Clinical charts, procedural data, and angiographic results were reviewed.Results48 patients with 49 IAs were identified. There were 35 women and 13 men with a mean age of 57 years (range 35–76 years). All IA were wide necked. Mean aneurysm size was 8.6 mm. There were 44 unruptured IA and 5 ruptured IA. During endovascular treatment (EVT), adjunctive devices were used in 22.4% of procedures. A good clinical outcome (modified Rankin Scale score ≤2) was achieved in 44/48 patients (92%). There was no mortality. Mean follow-up was 25 months (range 3–72 months; median 24 months). Between mid term and long term follow-up, occlusion was stable in 19/23 IA (82.6%), improved in 2/23 IA (8.7%), and worsened in 2/23 IA (8.7%). Retreatment was performed in 8/49 IA (16.3%). At the latest available follow-up, there were 34/47 (72.3%) complete occlusions and 13/47 (27.7%) neck remnants.ConclusionsOur study suggests that EVT of IA with the WEB device provides adequate and stable long term occlusion.
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45

Chen, You-Han, Shang-Yi Lin, Yu-Tzu Lin, Sung-Pin Tseng, Chen-Chia Chang, Song-Yih Yu, Wei-Wen Hung, et al. "Emergence of aac(6′)-Ie-aph(2′′)-Ia-positive enterococci with non-high-level gentamicin resistance mediated by IS1216V: adaptation to decreased aminoglycoside usage in Taiwan." Journal of Antimicrobial Chemotherapy 76, no. 7 (April 2, 2021): 1689–97. http://dx.doi.org/10.1093/jac/dkab071.

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Abstract Objectives To explore the mechanisms mediating the different levels of gentamicin resistance in enterococci. Methods Susceptibility testing with gentamicin and PCR of resistance determinants were performed in 149 enterococcal isolates. Genetic relatedness was characterized by MLST and PFGE analysis. Sequences of the aac(6′)-Ie-aph(2′′)-Ia gene and its surrounding environment were determined by Illumina sequencing. Stability assays of gentamicin resistance were carried out to evaluate the probability of loss of the high-level gentamicin resistance (HLGR) phenotype. Results A total of 17 (11.4%) aac(6′)-Ie-aph(2′′)-Ia-positive enterococcal isolates (2 Enterococcus faecalis and 15 Enterococcus faecium) with non-HLGR phenotype were found. MLST analysis revealed that the 2 E. faecalis belonged to ST116 and ST618, while all the 15 E. faecium belonged to clonal complex 17. Sequence analysis demonstrated that IS1216V was inserted into the 5′-end of aac(6′)-Ie-aph(2′′)-Ia, leading to loss of HLGR phenotype. Three IS1216V insertion types were found, and type II and III were frequently found in E. faecium. Interestingly, a total of 38 aac(6′)-Ie-aph(2′′)-Ia-positive E. faecium with HLGR phenotype also had type II or type III IS1216V insertion. Sequencing of the aac(6′)-Ie-aph(2′′)-Ia-positive HLGR E. faecium E37 revealed that an intact aac(6′)-Ie-aph(2′′)-Ia was located adjacent to IS1216V-disrupted aac(6′)-Ie-aph(2′′)-Ia. In a non-antibiotic environment, E37 tended to lose HLGR phenotype with a probability of 1.57 × 10−4, which was largely attributed to homologous recombination between the intact and disrupted aac(6′)-Ie-aph(2′′)-Ia. Conclusions This is first study to elucidate that the E. faecium is capable of changing its HLGR phenotype, which may contribute to adaptation to hospital environments with decreased usage of gentamicin.
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46

Månsson, Lisa, Carina Törn, and Mona Landin-Olsson. "Islet Cell Antibodies Represent Autoimmune Response Against Several Antigens." International Journal of Experimental Diabetes Research 2, no. 2 (2001): 85–90. http://dx.doi.org/10.1155/edr.2001.85.

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To study the antigens involved in the islet cell antibody (ICA) reaction we selected 30 patient serum samples (ten in each group) positive for ICA and one other additional autoantibody, such as glutamic acid decarboxylase antibodies (GADA), thyrosine phosphatase antibodies (IA-2A) or insulin autoantibodies (IAA). The serum samples were incubated with the specific antigen (GAD65, IA-2 or insulin) and the ICA analysis and the corresponding immunoprecipitation assay were performed before and after the absorption.We could then demonstrate that specific autoantibodies against GAD65 and IA-2 could be absorbed with the corresponding antigen, since ten GADA positive and six IA-2A samples turned completely negative. However, the ICA reaction after absorption with GADA, IA-2A and insulin was still present, although at significantly lower levels. The results strongly indicate that the ICA reaction represents simultaneous autoimmunity against several other antigens beside GAD65, IA-2 and insulin.
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47

Caldwell, Shane J., and Albert M. Berghuis. "Plasticity of Aminoglycoside Binding to Antibiotic Kinase APH(2″)-Ia." Antimicrobial Agents and Chemotherapy 62, no. 7 (April 16, 2018): e00202-18. http://dx.doi.org/10.1128/aac.00202-18.

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ABSTRACTThe APH(2″)-Ia aminoglycoside resistance enzyme forms the C-terminal domain of the bifunctional AAC(6′)-Ie/APH(2″)-Ia enzyme and confers high-level resistance to natural 4,6-disubstituted aminoglycosides. In addition, reports have suggested that the enzyme can phosphorylate 4,5-disubstituted compounds and aminoglycosides with substitutions at the N1 position. Previously determined structures of the enzyme with bound aminoglycosides have not indicated how these noncanonical substrates may bind and be modified by the enzyme. We carried out crystallographic studies to directly observe the interactions of these compounds with the aminoglycoside binding site and to probe the means by which these noncanonical substrates interact with the enzyme. We find that APH(2″)-Ia maintains a preferred mode of binding aminoglycosides by using the conserved neamine rings when possible, with flexibility that allows it to accommodate additional rings. However, if this binding mode is made impossible because of additional substitutions to the standard 4,5- or 4,6-disubstituted aminoglycoside architecture, as in lividomycin A or the N1-substituted aminoglycosides, it is still possible for these aminoglycosides to bind to the antibiotic binding site by using alternate binding modes, which explains the low rates of noncanonical phosphorylation activities seen in enzyme assays. Furthermore, structural studies of a clinically observed arbekacin-resistant mutant of APH(2″)-Ia revealed an altered aminoglycoside binding site that can stabilize an alternative binding mode for N1-substituted aminoglycosides. This mutation may alter and expand the aminoglycoside resistance spectrum of the wild-type enzyme in response to newly developed aminoglycosides.
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48

Shukla, Vijay K., Simon Lemaire, Ibrahim H. Ibrahim, Terry D. Cyr, Yanmin Chen, and Robert Michelot. "Design of potent and selective dynorphin A related peptides devoid of supraspinal motor effects in mice." Canadian Journal of Physiology and Pharmacology 71, no. 3-4 (March 1, 1993): 211–16. http://dx.doi.org/10.1139/y93-033.

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Dynorphin A-(1 – 13)-Tyr-Leu-Phe-Asn-Gly-Pro (Dyn Ia) was previously shown to be a highly potent and selective κ opioid peptide. Four analogs of Dyn Ia are synthesized by the solid-phase procedure, introducing pseudo CH2NH linkage between positions 6 and 7 as follows: analog 1, [6ψ7 (CH2NH)]Dyn Ia; analog 2, [6ψ7 (CH2NH), D-Leu8]Dyn Ia; analog 3, [N(Me)-Tyr1, 6ψ7 (CH2NH)]Dyn Ia; and analog 4, [N(Me)-Tyr1, 6ψ7 (CH2NH), D-Leu8]Dyn Ia. The purified peptides are compared in vitro with Dyn Ia for their ability to compete with the binding of selective κ, μ, and δ opioid ligands using membrane preparations of guinea pig cerebellum (κ) and rat brain (μ and δ). The synthetic compounds are also compared in vivo in mice (intracerebroventricularly administered) for their analgesic activity against acetic acid induced writhing and their ability to produce motor dysfunction. All compounds display a high affinity (Ki = 0.5 – 1.8 nM) and a good selectivity for the κ opioid receptor, and their rank order of potency on the κ site (analog 2 > analog 1 > analog 3 > analog 4) closely parallels their potency (AD50 = 1.57–5 nmol/mouse) in inhibiting acetic acid induced writhing in mice (analog 2 > analog 1 > analog 4 > analog 3). On the other hand, all the synthetic analogs are less potent than Dyn Ia in producing motor effects, analog 2 being the least potent (CD50 = 15.4 nM as compared with 2.9 nM for Dyn Ia). Thus, analog 2 is a good model for developing Dyn A related peptides with selective antinociceptive activity.Key words: dynorphin, opioid receptors, analgesia, motor effects.
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Smith, Clyde A., Marta Toth, Thomas M. Weiss, Hilary Frase, and Sergei B. Vakulenko. "Structure of the bifunctional aminoglycoside-resistance enzyme AAC(6′)-Ie-APH(2′′)-Ia revealed by crystallographic and small-angle X-ray scattering analysis." Acta Crystallographica Section D Biological Crystallography 70, no. 10 (September 27, 2014): 2754–64. http://dx.doi.org/10.1107/s1399004714017635.

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Broad-spectrum resistance to aminoglycoside antibiotics in clinically important Gram-positive staphylococcal and enterococcal pathogens is primarily conferred by the bifunctional enzyme AAC(6′)-Ie-APH(2′′)-Ia. This enzyme possesses an N-terminal coenzyme A-dependent acetyltransferase domain [AAC(6′)-Ie] and a C-terminal GTP-dependent phosphotransferase domain [APH(2′′)-Ia], and together they produce resistance to almost all known aminoglycosides in clinical use. Despite considerable effort over the last two or more decades, structural details of AAC(6′)-Ie-APH(2′′)-Ia have remained elusive. In a recent breakthrough, the structure of the isolated C-terminal APH(2′′)-Ia enzyme was determined as the binary Mg2GDP complex. Here, the high-resolution structure of the N-terminal AAC(6′)-Ie enzyme is reported as a ternary kanamycin/coenzyme A abortive complex. The structure of the full-length bifunctional enzyme has subsequently been elucidated based upon small-angle X-ray scattering data using the two crystallographic models. The AAC(6′)-Ie enzyme is joined to APH(2′′)-Ia by a short, predominantly rigid linker at the N-terminal end of a long α-helix. This α-helix is in turn intrinsically associated with the N-terminus of APH(2′′)-Ia. This structural arrangement supports earlier observations that the presence of the intact α-helix is essential to the activity of both functionalities of the full-length AAC(6′)-Ie-APH(2′′)-Ia enzyme.
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50

Kapadia, M., T. Pannellini, C. Moezinia, A. Miller, M. Figgie, P. Sculco, M. Cross, et al. "FRI0403 CLINICAL FEATURES OF PROSTHETIC JOINT INFECTIONS DIFFER IN PATIENTS WITH INFLAMMATORY ARTHRITIS AND OSTEOARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 799.2–800. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4777.

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Background:Inflammatory arthritis (IA) patients are at increased risk for prosthetic joint infections (PJI). However, because active IA patients without infections can have elevated inflammatory markers that mimic joint infection, PJI diagnosis is challenging in this population.Objectives:We used an institutional PJI registry to identify and compare the clinical, microbiologic, and histopathologic features of culture positive (CP) and culture negative (CN) total hip and knee PJI in IA and OA patients. We also evaluated the relationship between culture positivity, IA, and clinical outcomes.Methods:A retrospective cohort of THA/TKA PJIs, from 2009 to 2016, were identified by ICD codes, and confirmed by chart review. IA diagnosis was also confirmed by use of IA-specific medications. CN cases were defined as PJIs with no evidence of microbial growth in intraoperative cultures and CP PJI cases were defined by positive microbial growth in intraoperative cultures. Treatment failure was defined as subsequent surgical treatment for infection after the initial infection surgery. H&E slides of OA and IA PJI cases matched by age (+/-5) sex, and culture status were reviewed by a pathologist for evidence of the histopathologic features listed in Table 2. Fisher’s exact test, chi-square test, and Kaplan-Meier estimates were used.TABLE 1.Patient characteristics in IA and OA PJIsIAOAN%/SDN%/SDp-valueTotal36771Age58.511.466.812<.001BMI30.26.7306.70.861Female2877.833243.1<.001CCI2.81.71.72.10.002Smoking411.18611.20.792Glucorticoids1027.8395.1<.001Culture Negative1027.810914.10.024Treatment Success at 2 years1952.8509660.146IA- inflammatory arthritis; OA – osteoarthritis; PJI -prosthetic joint infection; CCI – Charlson Comorbidity IndexTABLE 2.Histopathology and clinical presentation in IA and OA PJIsOA (N=57)IA (N= 31)CP-IA (N=23)CN-IA (N=8)N (%)p-valueN (%)p-valuePathology Review>10 PMN per HPF42 (74)22 (71)0.80620 (87)2 (25)0.003Chronic Inflammation13 (23)23 (74)0.00118 (78)5 (63)0.393Necrosis17 (30)9 (29)18 (35)1 (13)0.38Clinical PresentationMSIS50 (88)26 (84)0.74722 (96)4 (50)0.009Sinus Tract7 (12)7 (23)0.2335 (22)2 (25)1Elevated ESR or CRP41 (72)24 (77)0.62217 (74)7 (88)1Elevated Synovial WBC33 (58)19 (61)0.82313 (57)6 (75)1Elevated Synovial %PMN31 (54)20 (65)0.37714 (61)6 (75)0.333OA – osteoarthritis; IA – inflammatory arthritis; CP – culture positive; CN – culture negative; MSIS – meets Musculoskeletal Infection Society diagnostic criteriaResults:807 PJI cases were identified including 36 IA (33 RA and 3 SLE) and 771 OA. A higher proportion of IA PJI were CN (N=10, 27%) vs. OA PJI (N=109, 14%, p=0.02). IA-PJI were younger, female, on glucocorticoids, and with more comorbidities. Type of surgical treatment did not differ significantly between IA and OA groups. Comparing CN-IA vs. CP-IA, no difference was observed in age, smoking, diabetes, surgical treatment, IA-specific meds or Charlson comorbidities. One-year survivorship of CN-IA and CN-OA were 66% and 87% (p>0.05). Across all CP cases, 57% were staphylococcal, with no differences between groups. Treatment failure was more frequent for CP-IA (42%) compared to CP-OA (30%), (p=0.2).Histopathology of 88 PJIs (31 IA and 57 OA) was reviewed. The IA cohort presented with more chronic inflammation (p=0.001) than the OA cohort. Within the IA cohort, a higher proportion of CP-IA had >10PMN per HPF (p= 0.003) and met MSIS criteria (p=0.009). Comparing CP-OA and CN-OA, there were no significant differences in histopathology findings or number of patients meeting MSIS criteria.Conclusion:IA PJIs are more likely to be culture negative than OA PJIs. Although our analysis was limited by our cohort size, our findings including differences in histopathology, and better clinical outcomes suggest the presence of biologic differences between CN and CP PJI that require further study.Disclosure of Interests:Milan Kapadia: None declared, Tania Pannellini: None declared, Carine Moezinia: None declared, Andy Miller: None declared, Mark Figgie: None declared, Peter Sculco: None declared, Michael Cross: None declared, Michael Henry: None declared, Linda Russell: None declared, Laura Donlin Consultant of: Consultant – Genentech/Roche, Allina Nocon: None declared, Susan Goodman Shareholder of: Reginosine- Investment, Grant/research support from: Novartis, Horizon, Consultant of: Novartis, Celgene, UCB
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