A novel family of plant nuclear envelope-associated proteins.

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Pawar, Vidya; Poulet, Axel; Détourné, Gwénaëlle; Tatout, Christophe; Vanrobays, Emmanuel; Evans, David E; Graumann, Katja

2016-10-01

This paper describes the characterisation of a new family of higher plant nuclear envelope-associated proteins (NEAPs) that interact with other proteins of the nuclear envelope. In the model plant Arabidopsis thaliana, the family consists of three genes expressed ubiquitously (AtNEAP1-3) and a pseudogene (AtNEAP4). NEAPs consist of extensive coiled-coil domains, followed by a nuclear localisation signal and a C-terminal predicted transmembrane domain. Domain deletion mutants confirm the presence of a functional nuclear localisation signal and transmembrane domain. AtNEAP proteins localise to the nuclear periphery as part of stable protein complexes, are able to form homo- and heteromers, and interact with the SUN domain proteins AtSUN1 and AtSUN2, involved in the linker of nucleoskeleton and cytoskeleton (LINC) complex. An A. thaliana cDNA library screen identified a putative transcription factor called AtbZIP18 as a novel interactor of AtNEAP1, which suggest a connection between NEAP and chromatin. An Atneap1 Atneap3 double-knockout mutant showed reduced root growth, and altered nuclear morphology and chromatin structure. Thus AtNEAPs are suggested as inner nuclear membrane-anchored coiled-coil proteins with roles in maintaining nuclear morphology and chromatin structure. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Calcium signals can freely cross the nuclear envelope in hippocampal neurons: somatic calcium increases generate nuclear calcium transients

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Bading Hilmar

2007-07-01

Full Text Available Abstract Background In hippocampal neurons, nuclear calcium signaling is important for learning- and neuronal survival-associated gene expression. However, it is unknown whether calcium signals generated by neuronal activity at the cell membrane and propagated to the soma can unrestrictedly cross the nuclear envelope to invade the nucleus. The nuclear envelope, which allows ion transit via the nuclear pore complex, may represent a barrier for calcium and has been suggested to insulate the nucleus from activity-induced cytoplasmic calcium transients in some cell types. Results Using laser-assisted uncaging of caged calcium compounds in defined sub-cellular domains, we show here that the nuclear compartment border does not represent a barrier for calcium signals in hippocampal neurons. Although passive diffusion of molecules between the cytosol and the nucleoplasm may be modulated through changes in conformational state of the nuclear pore complex, we found no evidence for a gating mechanism for calcium movement across the nuclear border. Conclusion Thus, the nuclear envelope does not spatially restrict calcium transients to the somatic cytosol but allows calcium signals to freely enter the cell nucleus to trigger genomic events.

Three-Dimensional Reconstruction of Nuclear Envelope Architecture Using Dual-Color Metal-Induced Energy Transfer Imaging.

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Chizhik, Anna M; Ruhlandt, Daja; Pfaff, Janine; Karedla, Narain; Chizhik, Alexey I; Gregor, Ingo; Kehlenbach, Ralph H; Enderlein, Jörg

2017-12-26

The nuclear envelope, comprising the inner and the outer nuclear membrane, separates the nucleus from the cytoplasm and plays a key role in cellular functions. Nuclear pore complexes (NPCs), which are embedded in the nuclear envelope, control transport of macromolecules between the two compartments. Here, using dual-color metal-induced energy transfer (MIET), we determine the axial distance between Lap2β and Nup358 as markers for the inner nuclear membrane and the cytoplasmic side of the NPC, respectively. Using MIET imaging, we reconstruct the 3D profile of the nuclear envelope over the whole basal area, with an axial resolution of a few nanometers. This result demonstrates that optical microscopy can achieve nanometer axial resolution in biological samples and without recourse to complex interferometric approaches.

Structural and functional adaptations of the mammalian nuclear envelope to meet the meiotic requirements.

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Link, Jana; Jahn, Daniel; Alsheimer, Manfred

2015-01-01

Numerous studies in the past years provided definite evidence that the nuclear envelope is much more than just a simple barrier. It rather constitutes a multifunctional platform combining structural and dynamic features to fulfill many fundamental functions such as chromatin organization, regulation of transcription, signaling, but also structural duties like maintaining general nuclear architecture and shape. One additional and, without doubt, highly impressive aspect is the recently identified key function of selected nuclear envelope components in driving meiotic chromosome dynamics, which in turn is essential for accurate recombination and segregation of the homologous chromosomes. Here, we summarize the recent work identifying new key players in meiotic telomere attachment and movement and discuss the latest advances in our understanding of the actual function of the meiotic nuclear envelope.

Sorting nexin 6 enhances lamin a synthesis and incorporation into the nuclear envelope.

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Jose M González-Granado

Full Text Available Nuclear lamins are important structural and functional proteins in mammalian cells, but little is known about the mechanisms and cofactors that regulate their traffic into the nucleus. Here, we demonstrate that trafficking of lamin A, but not lamin B1, and its assembly into the nuclear envelope are regulated by sorting nexin 6 (SNX6, a major component of the retromer that targets proteins and other molecules to specific subcellular locations. SNX6 interacts with lamin A in vitro and in vivo and links it to the outer surface of the endoplasmic reticulum in human and mouse cells. SNX6 transports its lamin A cargo to the nuclear envelope in a process that takes several hours. Lamin A protein levels in the nucleus augment or decrease, respectively, upon gain or loss of SNX6 function. We further show that SNX6-dependent lamin A nuclear import occurs across the nuclear pore complex via a RAN-GTP-dependent mechanism. These results identify SNX6 as a key regulator of lamin A synthesis and incorporation into the nuclear envelope.

Sorting Nexin 6 Enhances Lamin A Synthesis and Incorporation into the Nuclear Envelope

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González-Granado, Jose M.; Navarro-Puche, Ana; Molina-Sanchez, Pedro; Blanco-Berrocal, Marta; Viana, Rosa; de Mora, Jaime Font; Andrés, Vicente

2014-01-01

Nuclear lamins are important structural and functional proteins in mammalian cells, but little is known about the mechanisms and cofactors that regulate their traffic into the nucleus. Here, we demonstrate that trafficking of lamin A, but not lamin B1, and its assembly into the nuclear envelope are regulated by sorting nexin 6 (SNX6), a major component of the retromer that targets proteins and other molecules to specific subcellular locations. SNX6 interacts with lamin A in vitro and in vivo and links it to the outer surface of the endoplasmic reticulum in human and mouse cells. SNX6 transports its lamin A cargo to the nuclear envelope in a process that takes several hours. Lamin A protein levels in the nucleus augment or decrease, respectively, upon gain or loss of SNX6 function. We further show that SNX6-dependent lamin A nuclear import occurs across the nuclear pore complex via a RAN-GTP-dependent mechanism. These results identify SNX6 as a key regulator of lamin A synthesis and incorporation into the nuclear envelope. PMID:25535984

Autoantibodies in chronic pancreatitis

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Rumessen, J J; Marner, B; Pedersen, N T

1985-01-01

In 60 consecutive patients clinically suspected of having chronic pancreatitis the serum concentration of the immunoglobulins (IgA, IgG, IgM), the IgG- and IgA-type non-organ-specific autoantibodies against nuclear material (ANA), smooth and striated muscle, mitochondria, basal membrane, and reti......In 60 consecutive patients clinically suspected of having chronic pancreatitis the serum concentration of the immunoglobulins (IgA, IgG, IgM), the IgG- and IgA-type non-organ-specific autoantibodies against nuclear material (ANA), smooth and striated muscle, mitochondria, basal membrane......, and reticulin, and the IgG- and IgA-type pancreas-specific antibodies against islet cells, acinus cells, and ductal cells (DA) were estimated blindly. In 23 of the patients chronic pancreatitis was verified, whereas chronic pancreatitis was rejected in 37 patients (control group). IgG and IgA were found...... in significantly higher concentrations in the patients with chronic pancreatitis than in the control group but within the normal range. ANA and DA occurred very frequently in both groups but with no statistical difference. Other autoantibodies only occurred sporadically. The findings of this study do not support...

Remodeling of the Nuclear Envelope and Lamina during Bovine Preimplantation Development and Its Functional Implications.

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Jens Popken

Full Text Available The present study demonstrates a major remodeling of the nuclear envelope and its underlying lamina during bovine preimplantation development. Up to the onset of major embryonic genome activation (MGA at the 8-cell stage nuclei showed a non-uniform distribution of nuclear pore complexes (NPCs. NPCs were exclusively present at sites where DNA contacted the nuclear lamina. Extended regions of the lamina, which were not contacted by DNA, lacked NPCs. In post-MGA nuclei the whole lamina was contacted rather uniformly by DNA. Accordingly, NPCs became uniformly distributed throughout the entire nuclear envelope. These findings shed new light on the conditions which control the integration of NPCs into the nuclear envelope. The switch from maternal to embryonic production of mRNAs was accompanied by multiple invaginations covered with NPCs, which may serve the increased demands of mRNA export and protein import. Other invaginations, as well as interior nuclear segments and vesicles without contact to the nuclear envelope, were exclusively positive for lamin B. Since the abundance of these invaginations and vesicles increased in concert with a massive nuclear volume reduction, we suggest that they reflect a mechanism for fitting the nuclear envelope and its lamina to a shrinking nuclear size during bovine preimplantation development. In addition, a deposit of extranuclear clusters of NUP153 (a marker for NPCs without associated lamin B was frequently observed from the zygote stage up to MGA. Corresponding RNA-Seq data revealed deposits of spliced, maternally provided NUP153 mRNA and little unspliced, newly synthesized RNA prior to MGA, which increased strongly at the initiation of embryonic expression of NUP153 at MGA.

Relationship between chromatin complexity and nuclear envelope circularity in hippocampal pyramidal neurons

International Nuclear Information System (INIS)

Pantic, Igor; Basailovic, Milos; Paunovic, Jovana; Pantic, Senka

2015-01-01

Highlights: •We analyzed chromatin structure and nuclear envelope of 200 hippocampal pyramidal neurons. •Fractal and GLCM mathematical parameters were calculated each chromatin structure. •Nuclear shape was quantified by calculating circularity of the nuclear envelope. •Circularity was in significant relationship with chromatin fractal dimension. •Strong correlation was detected between circularity and some GLCM parameters. -- Abstract: In this study we tested the existence and strength of the relationship between circularity of nuclear envelope and mathematical parameters of chromatin structure. Coronal sections of the brain were made in 10 male albino mice. The brain tissue was stained using a modification of Feulgen method for DNA visualization. A total of 200 hippocampal pyramidal neurons (20 per animal) were visualized using DEM 200 High-Speed Color CMOS Chip and Olympus CX21FS1 microscope. Circularity of the nuclear membrane was calculated in ImageJ (NIH, USA) after the nuclear segmentation, based on the freehand selection of the nuclear regions of interest. Circularity was determined from the values of area and perimeter. For each chromatin structure, using fractal and grey level co-occurrence matrix (GLCM) algorithms, we determined the values of fractal dimension, lacunarity, angular second moment, GLCM entropy, inverse difference moment, GLCM correlation, and GLCM contrast. It was found that circularity is in a significant correlation (p < 0.05) with fractal dimension as the main parameter of fractal complexity analysis. Also, circularity was in a very strong relationship (p < 0.001) with certain parameters of grey level co-occurrence matrix such as the angular second moment and GLCM correlation. This is the first study to indicate that nuclear shape is significantly related to mathematical parameters of higher chromatin organization. Also, it seems that circularity of the nuclear envelope is a good predictor of certain features of chromatin

Human Cytomegalovirus Nuclear Egress Proteins Ectopically Expressed in the Heterologous Environment of Plant Cells are Strictly Targeted to the Nuclear Envelope.

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Lamm, Christian E; Link, Katrin; Wagner, Sabrina; Milbradt, Jens; Marschall, Manfred; Sonnewald, Uwe

2016-03-10

In all eukaryotic cells, the nucleus forms a prominent cellular compartment containing the cell's nuclear genome. Although structurally similar, animal and plant nuclei differ substantially in details of their architecture. One example is the nuclear lamina, a layer of tightly interconnected filament proteins (lamins) underlying the nuclear envelope of metazoans. So far no orthologous lamin genes could be detected in plant genomes and putative lamin-like proteins are only poorly described in plants. To probe for potentially conserved features of metazoan and plant nuclear envelopes, we ectopically expressed the core nuclear egress proteins of human cytomegalovirus pUL50 and pUL53 in plant cells. pUL50 localizes to the inner envelope of metazoan nuclei and recruits the nuclear localized pUL53 to it, forming heterodimers. Upon expression in plant cells, a very similar localization pattern of both proteins could be determined. Notably, pUL50 is specifically targeted to the plant nuclear envelope in a rim-like fashion, a location to which coexpressed pUL53 becomes strictly corecruited from its initial nucleoplasmic distribution. Using pUL50 as bait in a yeast two-hybrid screening, the cytoplasmic re-initiation supporting protein RISP could be identified. Interaction of pUL50 and RISP could be confirmed by coexpression and coimmunoprecipitation in mammalian cells and by confocal laser scanning microscopy in plant cells, demonstrating partial pUL50-RISP colocalization in areas of the nuclear rim and other intracellular compartments. Thus, our study provides strong evidence for conserved structural features of plant and metazoan nuclear envelops and identifies RISP as a potential pUL50-interacting plant protein.

Old foes, new understandings: nuclear entry of small non-enveloped DNA viruses.

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Fay, Nikta; Panté, Nelly

2015-06-01

The nuclear import of viral genomes is an important step of the infectious cycle for viruses that replicate in the nucleus of their host cells. Although most viruses use the cellular nuclear import machinery or some components of this machinery, others have developed sophisticated ways to reach the nucleus. Some of these have been known for some time; however, recent studies have changed our understanding of how some non-enveloped DNA viruses access the nucleus. For example, parvoviruses enter the nucleus through small disruptions of the nuclear membranes and nuclear lamina, and adenovirus tugs at the nuclear pore complex, using kinesin-1, to disassemble their capsids and deliver viral proteins and genomes into the nucleus. Here we review recent findings of the nuclear import strategies of three small non-enveloped DNA viruses, including adenovirus, parvovirus, and the polyomavirus simian virus 40. Copyright © 2015 Elsevier B.V. All rights reserved.

Dynamic assembly of brambleberry mediates nuclear envelope fusion during early development.

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Abrams, Elliott W; Zhang, Hong; Marlow, Florence L; Kapp, Lee; Lu, Sumei; Mullins, Mary C

2012-08-03

To accommodate the large cells following zygote formation, early blastomeres employ modified cell divisions. Karyomeres are one such modification, mitotic intermediates wherein individual chromatin masses are surrounded by nuclear envelope; the karyomeres then fuse to form a single mononucleus. We identified brambleberry, a maternal-effect zebrafish mutant that disrupts karyomere fusion, resulting in formation of multiple micronuclei. As karyomeres form, Brambleberry protein localizes to the nuclear envelope, with prominent puncta evident near karyomere-karyomere interfaces corresponding to membrane fusion sites. brambleberry corresponds to an unannotated gene with similarity to Kar5p, a protein that participates in nuclear fusion in yeast. We also demonstrate that Brambleberry is required for pronuclear fusion following fertilization in zebrafish. Our studies provide insight into the machinery required for karyomere fusion and suggest that specialized proteins are necessary for proper nuclear division in large dividing blastomeres. Copyright © 2012 Elsevier Inc. All rights reserved.

The SUN protein Mps3 is required for spindle pole body insertion into the nuclear membrane and nuclear envelope homeostasis.

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Jennifer M Friederichs

2011-11-01

Full Text Available The budding yeast spindle pole body (SPB is anchored in the nuclear envelope so that it can simultaneously nucleate both nuclear and cytoplasmic microtubules. During SPB duplication, the newly formed SPB is inserted into the nuclear membrane. The mechanism of SPB insertion is poorly understood but likely involves the action of integral membrane proteins to mediate changes in the nuclear envelope itself, such as fusion of the inner and outer nuclear membranes. Analysis of the functional domains of the budding yeast SUN protein and SPB component Mps3 revealed that most regions are not essential for growth or SPB duplication under wild-type conditions. However, a novel dominant allele in the P-loop region, MPS3-G186K, displays defects in multiple steps in SPB duplication, including SPB insertion, indicating a previously unknown role for Mps3 in this step of SPB assembly. Characterization of the MPS3-G186K mutant by electron microscopy revealed severe over-proliferation of the inner nuclear membrane, which could be rescued by altering the characteristics of the nuclear envelope using both chemical and genetic methods. Lipid profiling revealed that cells lacking MPS3 contain abnormal amounts of certain types of polar and neutral lipids, and deletion or mutation of MPS3 can suppress growth defects associated with inhibition of sterol biosynthesis, suggesting that Mps3 directly affects lipid homeostasis. Therefore, we propose that Mps3 facilitates insertion of SPBs in the nuclear membrane by modulating nuclear envelope composition.

Transmission electron microscope studies of the nuclear envelope in Caenorhabditis elegans embryos.

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Cohen, Merav; Tzur, Yonatan B; Neufeld, Esther; Feinstein, Naomi; Delannoy, Michael R; Wilson, Katherine L; Gruenbaum, Yosef

2002-01-01

Nuclear membranes and nuclear pore complexes (NPCs) are conserved in both animals and plants. However, the lamina composition and the dimensions of NPCs vary between plants, yeast, and vertebrates. In this study, we established a protocol that preserves the structure of Caenorhabditis elegans embryonic cells for high-resolution studies with thin-section transmission electron microscopy (TEM). We show that the NPCs are bigger in C. elegans embryos than in yeast, with dimensions similar to those in higher eukaryotes. We also localized the C. elegans nuclear envelope proteins Ce-lamin and Ce-emerin by pre-embedding gold labeling immunoelectron microscopy. Both proteins are present at or near the inner nuclear membrane. A fraction of Ce-lamin, but not Ce-emerin, is present in the nuclear interior. Removing the nuclear membranes leaves both Ce-lamin and Ce-emerin associated with the chromatin. Eliminating the single lamin protein caused cell death as visualized by characteristic changes in nuclear architecture including condensation of chromatin, clustering of NPCs, membrane blebbing, and the presence of vesicles inside the nucleus. Taken together, these results show evolutionarily conserved protein localization, interactions, and functions of the C. elegans nuclear envelope.

Cdk1 Activates Pre-Mitotic Nuclear Envelope Dynein Recruitment and Apical Nuclear Migration in Neural Stem cells

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Baffet, Alexandre D.; Hu, Daniel J.; Vallee, Richard B.

2015-01-01

Summary Dynein recruitment to the nuclear envelope is required for pre-mitotic nucleus-centrosome interactions in nonneuronal cells, and for apical nuclear migration in neural stem cells. In each case, dynein is recruited to the nuclear envelope (NE) specifically during G2, via two nuclear pore-mediated mechanisms involving RanBP2-BicD2 and Nup133-CENP-F. The mechanisms responsible for cell cycle control of this behavior are unknown. We now find that Cdk1 serves as a direct master controller for NE dynein recruitment in neural stem cells and HeLa cells. Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. Late recruitment is triggered by a Cdk1-induced export of CENP-F from the nucleus. Forced NE targeting of BicD2 overrides Cdk1 inhibition, fully rescuing dynein recruitment and nuclear migration in neural stem cells. These results reveal how NE dynein recruitment is cell cycle regulated, and identify the trigger mechanism for apical nuclear migration in the brain. PMID:26051540

GAGE cancer-germline antigens are recruited to the nuclear envelope by germ cell-less (GCL)

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Gjerstorff, Morten F; Rösner, Heike I; Pedersen, Christina B

2012-01-01

GAGE proteins are highly similar, primate-specific molecules with unique primary structure and undefined cellular roles. They are restricted to cells of the germ line in adult healthy individuals, but are broadly expressed in a wide range of cancers. In a yeast two-hybrid screen we identified the...... different dsDNA fragments, suggesting sequence-nonspecific binding. Dual association of GAGE family members with GCL at the nuclear envelope inner membrane in cells, and with dsDNA in vitro, implicate GAGE proteins in chromatin regulation in germ cells and cancer cells....... the metazoan transcriptional regulator, Germ cell-less (GCL), as an interaction partner of GAGE12I. GCL directly binds LEM-domain proteins (LAP2β, emerin, MAN1) at the nuclear envelope, and we found that GAGE proteins were recruited to the nuclear envelope inner membrane by GCL. Based on yeast two...

The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation.

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Bermeo, Sandra; Al-Saedi, Ahmed; Kassem, Moustapha; Vidal, Christopher; Duque, Gustavo

2017-12-01

Mutations in MAN1, a protein of the nuclear envelope, cause bone phenotypes characterized by hyperostosis. The mechanism of this pro-osteogenic phenotype remains unknown. We increased and decreased MAN1 expression in mesenchymal stem cells (MSC) upon which standard osteogenic and adipogenic differentiation were performed. MAN1 knockdown increased osteogenesis and mineralization. In contrast, osteogenesis remained stable upon MAN1 overexpression. Regarding a mechanism, we found that low levels of MAN1 facilitated the nuclear accumulation of regulatory smads and smads-related complexes, with a concurrently high expression of nuclear β-Catenin. In addition, we found adipogenesis to be decreased in both conditions, although predominantly affected by MAN1 overexpression. Finally, lamin A, a protein of the nuclear envelope that regulates MSC differentiation, was unaffected by changes in MAN1. In conclusion, our studies demonstrated that lower levels of MAN1 in differentiating MSC are associated with higher osteogenesis and lower adipogenesis. High levels of MAN1 only affected adipogenesis. These effects could have an important role in the understanding of the role of the proteins of the nuclear envelope in bone formation. J. Cell. Biochem. 118: 4425-4435, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Clinical and Pathological Roles of Ro/SSA Autoantibody System

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Ryusuke Yoshimi

2012-01-01

Full Text Available Anti-Ro/SSA antibodies are among the most frequently detected autoantibodies against extractable nuclear antigens and have been associated with systemic lupus erythematosus (SLE and Sjögren's syndrome (SS. Although the presence of these autoantibodies is one of the criteria for the diagnosis and classification of SS, they are also sometimes seen in other systemic autoimmune diseases. In the last few decades, the knowledge of the prevalence of anti-Ro/SSA antibodies in various autoimmune diseases and symptoms has been expanded, and the clinical importance of these antibodies is increasing. Nonetheless, the pathological role of the antibodies is still poorly understood. In this paper, we summarize the milestones of the anti-Ro/SSA autoantibody system and provide new insights into the association between the autoantibodies and the pathogenesis of autoimmune diseases.

Clinical significance of autoantibodies in autoimmune hepatitis.

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Liberal, Rodrigo; Mieli-Vergani, Giorgina; Vergani, Diego

2013-10-01

The accurate diagnosis and classification of autoimmune hepatitis (AIH) rely upon the detection of characteristic autoantibodies. Positivity for anti-nuclear (ANA) and/or anti-smooth muscle (SMA) autoantibodies defines AIH type 1 (AIH-1), whereas anti-liver kidney microsomal type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) define AIH type 2 (AIH-2). ANA and SMA, and less commonly anti-LKM1, have also been detected in de-novo autoimmune hepatitis developing after liver transplantation, a condition that may affect patients transplanted for non-autoimmune liver disease. The diagnostic autoantibodies associated with AIH-1 are also detected in the paediatric AIH/sclerosing cholangitis overlap syndrome, referred to as autoimmune sclerosing cholangitis (ASC). ASC, like adult primary sclerosing cholangitis, is often associated with atypical perinuclear anti-neutrophil cytoplasmic autoantibodies (p-ANCA), although p-ANCA are also detected in other autoimmune liver diseases. These associations highlight the necessity for simple and prompt diagnostic autoantibody testing, and the requirement for the accurate interpretation of the results of the tests in the clinical context. Fine-mapping of antigenic autoantibody targets has facilitated the development of rapid molecular assays that have the potential to revolutionise the field if properly standardised and when used in combination with classical immunofluorescence. Despite their diagnostic significance, the pathogenic role of the various autoantibodies and the mechanisms by which they can potentially inflict damage onto the liver cell remain a topic for further research. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chromatin influence on the function and formation of the nuclear envelope shown by laser-induced psoralen photoreaction

International Nuclear Information System (INIS)

Peterson, S.P.; Berns, M.W.

1978-01-01

Potorous tridactylis (PTK 2 ) cells growing in culture were treated with psoralen derivatives and dividing cells were located by phase-contrast microscopy. Psoralens, light-sensitive DNA-photoadducting drugs, were reacted with mitotic chromosomes through exposure to 365-nm light from an argon laser micro-beam system. It was shown that following mitosis and photoreaction, cells without nuclear envelopes were produced when psoralen-treated cells received 60 light pulses over their entire chromosome complement. These 'non-nuclear membrane' cells were found to incorporate [ 3 H]uridine, and to a lesser extent, [ 3 H]thymidine by autoradiography. Reduction of the light exposure by half (30 near-u.v. pulses) over the entire chromosome complement in the presence of psoralen also produced non-nuclear-membrane cells as seen by light microscopy. Further examination of these cells (30 light pulses) by single-cell electron microscopy revealed that unlike the high light exposure (60 near-u.v. pulses), the low light dosage resulted in cells with membrane patches associated with their chromatin. Since neither actinomycin D nor cycloheximide impeded nuclear envelope reformation, the psoralen-DNA reaction is concluded to produce non-nuclear membrane by a mechanism other than transcription or translation inhibition. The association of Golgi with areas of nuclear membrane patches gives indirect evidence of a possible Golgi contribution to the reformation of the nuclear envelope after mitosis. It is concluded that DNA plays a role in envelope reformation. (author)

Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis

International Nuclear Information System (INIS)

Fernández Madrid, Félix; Maroun, Marie-Claire; Olivero, Ofelia A; Long, Michael; Stark, Azadeh; Grossman, Lawrence I; Binder, Walter; Dong, Jingsheng; Burke, Matthew; Nathanson, S David; Zarbo, Richard; Chitale, Dhananjay; Zeballos-Chávez, Rocío; Peebles, Carol

2015-01-01

The objective of this work was to demonstrate that autoantibodies in breast cancer sera are not epiphenomena, and exhibit unique immunologic features resembling the rheumatic autoimmune diseases. We performed a comprehensive study of autoantibodies on a collection of sera from women with breast cancer or benign breast disease, undergoing annual screening mammography. All women in this study had suspicious mammography assessment and underwent a breast biopsy. We used indirect immunofluorescence, the crithidia assay for anti-dsDNA antibodies, and multiple ELISAs for extractable nuclear antigens. Autoantibodies were detected in virtually all patients with breast cancer, predominantly of the IgG1 and IgG3 isotypes. The profile detected in breast cancer sera showed distinctive features, such as antibodies targeting mitochondria, centrosomes, centromeres, nucleoli, cytoskeleton, and multiple nuclear dots. The majority of sera showing anti-mitochondrial antibodies did not react with the M2 component of pyruvate dehydrogenase, characteristic of primary biliary cirrhosis. Anti-centromere antibodies were mainly anti-CENP-B. ELISAs for extractable nuclear antigens and the assays for dsDNA were negative. The distinctive autoantibody profile detected in BC sera is the expression of tumor immunogenicity. Although some of these features resemble those in the rheumatic autoimmune diseases and primary biliary cirrhosis, the data suggest the involvement of an entirely different set of epithelial antigens in breast cancer. High titer autoantibodies targeting centrosomes, centromeres, and mitochondria were detected in a small group of healthy women with suspicious mammography assessment and no cancer by biopsy; this suggests that the process triggering autoantibody formation starts in the pre-malignant phase and that future studies using validated autoantibody panels may allow detection of breast cancer risk in asymptomatic women. Autoantibodies developing in breast cancer are not

Inner nuclear envelope protein SUN1 plays a prominent role in mammalian mRNA export.

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Li, Ping; Noegel, Angelika A

2015-11-16

Nuclear export of messenger ribonucleoproteins (mRNPs) through the nuclear pore complex (NPC) can be roughly classified into two forms: bulk and specific export, involving an nuclear RNA export factor 1 (NXF1)-dependent pathway and chromosome region maintenance 1 (CRM1)-dependent pathway, respectively. SUN proteins constitute the inner nuclear envelope component of the l I: nker of N: ucleoskeleton and C: ytoskeleton (LINC) complex. Here, we show that mammalian cells require SUN1 for efficient nuclear mRNP export. The results indicate that both SUN1 and SUN2 interact with heterogeneous nuclear ribonucleoprotein (hnRNP) F/H and hnRNP K/J. SUN1 depletion inhibits the mRNP export, with accumulations of both hnRNPs and poly(A)+RNA in the nucleus. Leptomycin B treatment indicates that SUN1 functions in mammalian mRNA export involving the NXF1-dependent pathway. SUN1 mediates mRNA export through its association with mRNP complexes via a direct interaction with NXF1. Additionally, SUN1 associates with the NPC through a direct interaction with Nup153, a nuclear pore component involved in mRNA export. Taken together, our results reveal that the inner nuclear envelope protein SUN1 has additional functions aside from being a central component of the LINC complex and that it is an integral component of the mammalian mRNA export pathway suggesting a model whereby SUN1 recruits NXF1-containing mRNP onto the nuclear envelope and hands it over to Nup153. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Integrating complex functions: coordination of nuclear pore complex assembly and membrane expansion of the nuclear envelope requires a family of integral membrane proteins.

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Schneiter, Roger; Cole, Charles N

2010-01-01

The nuclear envelope harbors numerous large proteinaceous channels, the nuclear pore complexes (NPCs), through which macromolecular exchange between the cytosol and the nucleoplasm occurs. This double-membrane nuclear envelope is continuous with the endoplasmic reticulum and thus functionally connected to such diverse processes as vesicular transport, protein maturation and lipid synthesis. Recent results obtained from studies in Saccharomyces cerevisiae indicate that assembly of the nuclear pore complex is functionally dependent upon maintenance of lipid homeostasis of the ER membrane. Previous work from one of our laboratories has revealed that an integral membrane protein Apq12 is important for the assembly of functional nuclear pores. Cells lacking APQ12 are viable but cannot grow at low temperatures, have aberrant NPCs and a defect in mRNA export. Remarkably, these defects in NPC assembly can be overcome by supplementing cells with a membrane fluidizing agent, benzyl alcohol, suggesting that Apq12 impacts the flexibility of the nuclear membrane, possibly by adjusting its lipid composition when cells are shifted to a reduced temperature. Our new study now expands these findings and reveals that an essential membrane protein, Brr6, shares at least partially overlapping functions with Apq12 and is also required for assembly of functional NPCs. A third nuclear envelope membrane protein, Brl1, is related to Brr6, and is also required for NPC assembly. Because maintenance of membrane homeostasis is essential for cellular survival, the fact that these three proteins are conserved in fungi that undergo closed mitoses, but are not found in metazoans or plants, may indicate that their functions are performed by proteins unrelated at the primary sequence level to Brr6, Brl1 and Apq12 in cells that disassemble their nuclear envelopes during mitosis.

Regulation of nuclear envelope dynamics via APC/C is necessary for the progression of semi-open mitosis in Schizosaccharomyces japonicus.

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Aoki, Keita; Shiwa, Yuh; Takada, Hiraku; Yoshikawa, Hirofumi; Niki, Hironori

2013-09-01

Three types of mitosis, which are open, closed or semi-open mitosis, function in eukaryotic cells, respectively. The open mitosis involves breakage of the nuclear envelope before nuclear division, whereas the closed mitosis proceeds with an intact nuclear envelope. To understand the mechanism and significance of three types of mitotic division in eukaryotes, we investigated the process of semi-open mitosis, in which the nuclear envelope is only partially broken, in the fission yeast Schizosaccharomyces japonicus. In anaphase-promoting complex/cyclosome (APC/C) mutants of Sz. japonicus, the nuclear envelope remained relatively intact during anaphase, resulting in impaired semi-open mitosis. As a suppressor of apc2 mutant, a mutation of Oar2, which was a 3-oxoacyl-[acyl carrier protein] reductase, was obtained. The level of the Oar2, which had two destruction-box motifs recognized by APC/C, was increased in APC/C mutants. Furthermore, the defective semi-open mitosis observed in an apc2 mutant was restored by mutated oar2+. Based on these findings, we propose that APC/C regulates the dynamics of the nuclear envelope through degradation of Oar2 dependent on APC/C during the metaphase-to-anaphase transition of semi-open mitosis in Sz. japonicus. © 2013 The Authors Genes to Cells © 2013 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

Herpes simplex virus glycoproteins gB and gH function in fusion between the virion envelope and the outer nuclear membrane.

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Farnsworth, Aaron; Wisner, Todd W; Webb, Michael; Roller, Richard; Cohen, Gary; Eisenberg, Roselyn; Johnson, David C

2007-06-12

Herpesviruses must traverse the nuclear envelope to gain access to the cytoplasm and, ultimately, to exit cells. It is believed that herpesvirus nucleocapsids enter the perinuclear space by budding through the inner nuclear membrane (NM). To reach the cytoplasm these enveloped particles must fuse with the outer NM and the unenveloped capsids then acquire a second envelope in the trans-Golgi network. Little is known about the process by which herpesviruses virions fuse with the outer NM. Here we show that a herpes simplex virus (HSV) mutant lacking both the two putative fusion glycoproteins gB and gH failed to cross the nuclear envelope. Enveloped virions accumulated in the perinuclear space or in membrane vesicles that bulged into the nucleoplasm (herniations). By contrast, mutants lacking just gB or gH showed only minor or no defects in nuclear egress. We concluded that either HSV gB or gH can promote fusion between the virion envelope and the outer NM. It is noteworthy that fusion associated with HSV entry requires the cooperative action of both gB and gH, suggesting that the two types of fusion (egress versus entry) are dissimilar processes.

Kar5p is required for multiple functions in both inner and outer nuclear envelope fusion in Saccharomyces cerevisiae.

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Rogers, Jason V; Rose, Mark D

2014-12-02

During mating in the budding yeast Saccharomyces cerevisiae, two haploid nuclei fuse via two sequential membrane fusion steps. SNAREs (i.e., soluble N-ethylmaleimide-sensitive factor attachment protein receptors) and Prm3p mediate outer nuclear membrane fusion, but the inner membrane fusogen remains unknown. Kar5p is a highly conserved transmembrane protein that localizes adjacent to the spindle pole body (SPB), mediates nuclear envelope fusion, and recruits Prm3p adjacent to the SPB. To separate Kar5p's functions, we tested localization, Prm3p recruitment, and nuclear fusion efficiency in various kar5 mutants. All domains and the conserved cysteine residues were essential for nuclear fusion. Several kar5 mutant proteins localized properly but did not mediate Prm3p recruitment; other kar5 mutant proteins localized and recruited Prm3p but were nevertheless defective for nuclear fusion, demonstrating additional functions beyond Prm3p recruitment. We identified one Kar5p domain required for SPB localization, which is dependent on the half-bridge protein Mps3p. Electron microscopy revealed a kar5 mutant that arrests with expanded nuclear envelope bridges, suggesting that Kar5p is required after outer nuclear envelope fusion. Finally, a split-GFP assay demonstrated that Kar5p localizes to both the inner and outer nuclear envelope. These insights suggest a mechanism by which Kar5p mediates inner nuclear membrane fusion. Copyright © 2015 Rogers and Rose.

Radiation-induced invagination of the nuclear envelope

International Nuclear Information System (INIS)

Szekely, J.G.; Copps, T.P.; Morash, B.D.

1980-01-01

Using electron microscopy, we have measured radiation-induced invagination of the nuclear envelope of Chinese hamster V-79 and mouse L cells to produce a quantifiable radiation endpoint on a membrane system. In the dose ranges measured (800 to 3000 rad in L cells and 1270 to 5700 rad in V-79 cells), the amount of invagination increased with dose and continued to develop in intact cells for up to 72 hr after the original population was irradiated. Small vacuoles, which sometimes appeared in the nuclei of L cells, were also more numerous in irradiated cells and increased with dose and incubation time in a similar fashion to invagination development

Improving nuclear envelope dynamics by EBV BFRF1 facilitates intranuclear component clearance through autophagy.

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Liu, Guan-Ting; Kung, Hsiu-Ni; Chen, Chung-Kuan; Huang, Cheng; Wang, Yung-Li; Yu, Cheng-Pu; Lee, Chung-Pei

2018-02-26

Although a vesicular nucleocytoplasmic transport system is believed to exist in eukaryotic cells, the features of this pathway are mostly unknown. Here, we report that the BFRF1 protein of the Epstein-Barr virus improves vesicular transport of nuclear envelope (NE) to facilitate the translocation and clearance of nuclear components. BFRF1 expression induces vesicles that selectively transport nuclear components to the cytoplasm. With the use of aggregation-prone proteins as tools, we found that aggregated nuclear proteins are dispersed when these BFRF1-induced vesicles are formed. BFRF1-containing vesicles engulf the NE-associated aggregates, exit through from the NE, and putatively fuse with autophagic vacuoles. Chemical treatment and genetic ablation of autophagy-related factors indicate that autophagosome formation and autophagy-linked FYVE protein-mediated autophagic proteolysis are involved in this selective clearance of nuclear proteins. Remarkably, vesicular transport, elicited by BFRF1, also attenuated nuclear aggregates accumulated in neuroblastoma cells. Accordingly, induction of NE-derived vesicles by BFRF1 facilitates nuclear protein translocation and clearance, suggesting that autophagy-coupled transport of nucleus-derived vesicles can be elicited for nuclear component catabolism in mammalian cells.-Liu, G.-T., Kung, H.-N., Chen, C.-K., Huang, C., Wang, Y.-L., Yu, C.-P., Lee, C.-P. Improving nuclear envelope dynamics by EBV BFRF1 facilitates intranuclear component clearance through autophagy.

[Autoantibodies as biomarkers].

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Tron, François

2014-01-01

Activation and differentiation of autoreactive B-lymphocytes lead to the production of autoantibodies, which are thus the direct consequence of the autoimmune process. They often constitute biomarkers of autoimmune diseases and are measured by tests displaying various diagnosis sensitivity and specificity. Autoantibody titers can be correlated to the disease activity and certain autoantibody populations associated with particular clinical manifestations or tissue lesions. The demonstration that autoantibodies appear years before the onset of autoimmune diseases indicates that their presence in healthy individuals may be a predictive marker of the occurrence of disease. Certain autoantibodies could also be predictive markers of a therapeutic response to biologics and of the occurrence of side effects as well. Thus, autoantibodies are useful tools in the diagnosis and the management of patients with organ specific or non-organ specific autoimmune diseases at different steps of the autoimmune process. Copyright © 2013. Published by Elsevier Masson SAS.

Channel Nucleoporins Recruit PLK-1 to Nuclear Pore Complexes to Direct Nuclear Envelope Breakdown in C. elegans.

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Martino, Lisa; Morchoisne-Bolhy, Stéphanie; Cheerambathur, Dhanya K; Van Hove, Lucie; Dumont, Julien; Joly, Nicolas; Desai, Arshad; Doye, Valérie; Pintard, Lionel

2017-10-23

In animal cells, nuclear envelope breakdown (NEBD) is required for proper chromosome segregation. Whereas mitotic kinases have been implicated in NEBD, how they coordinate their activity to trigger this event is unclear. Here, we show that both in human cells and Caenorhabditis elegans, the Polo-like kinase 1 (PLK-1) is recruited to the nuclear pore complexes, just prior to NEBD, through its Polo-box domain (PBD). We provide evidence that PLK-1 localization to the nuclear envelope (NE) is required for efficient NEBD. We identify the central channel nucleoporins NPP-1/Nup58, NPP-4/Nup54, and NPP-11/Nup62 as the critical factors anchoring PLK-1 to the NE in C. elegans. In particular, NPP-1, NPP-4, and NPP-11 primed at multiple Polo-docking sites by Cdk1 and PLK-1 itself physically interact with the PLK-1 PBD. We conclude that nucleoporins play an unanticipated regulatory role in NEBD, by recruiting PLK-1 to the NE thereby facilitating phosphorylation of critical downstream targets. Copyright © 2017 Elsevier Inc. All rights reserved.

Data on the association of the nuclear envelope protein Sun1 with nucleoli.

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Moujaber, Ossama; Omran, Nawal; Kodiha, Mohamed; Pié, Brigitte; Cooper, Ellis; Presley, John F; Stochaj, Ursula

2017-08-01

SUN proteins participate in diverse cellular activities, many of which are connected to the nuclear envelope. Recently, the family member SUN1 has been linked to novel biological activities. These include the regulation of nucleoli, intranuclear compartments that assemble ribosomal subunits. We show that SUN1 associates with nucleoli in several mammalian epithelial cell lines. This nucleolar localization is not shared by all cell types, as SUN1 concentrates at the nuclear envelope in ganglionic neurons and non-neuronal satellite cells. Database analyses and Western blotting emphasize the complexity of SUN1 protein profiles in different mammalian cells. We constructed a STRING network which identifies SUN1-related proteins as part of a larger network that includes several nucleolar proteins. Taken together, the current data highlight the diversity of SUN1 proteins and emphasize the possible links between SUN1 and nucleoli.

Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells

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Arantxa Cebrián-Silla

2017-07-01

Full Text Available Neural stem cells (B1 astrocytes; NSCs in the adult ventricular-subventricular-zone (V-SVZ originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS, reported in certain lymphocytes and some cancer cells. Using molecular markers, [3H]thymidine birth-dating, and Ara-C, we found that B1 cells with ELCS correspond to quiescent NSCs. ELCS begin forming in embryonic radial glia cells and represent a specific nuclear compartment containing particular epigenetic modifications and telomeres. These results reveal a unique nuclear compartment in quiescent NSCs, which is useful for identifying these primary progenitors and study their gene regulation.

Autoantibodies in Senear-Usher Syndrome: Cross-Reactivity or Multiple Autoimmunity?

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María Elena Pérez-Pérez

2012-01-01

Full Text Available Senear-Usher syndrome or pemphigus erythematosus is a pathology that overlaps clinically and serologically with pemphigus foliaceus and lupus erythematosus. Skin biopsies of patients with pemphigus erythematosus reveal acantholysis and deposits of immunoglobulins in desmosomes, and they are positive in the lupus band test. In the present paper, we determined whether the autoantibodies associated with pemphigus erythematosus targeted a single antigen or multiple antigens as a result of the stimulation of independent B cell clones. Our present paper demonstrates that patients with pemphigus erythematosus produce both antiepithelial antibodies specific for desmoglein 1 and 3 and antinuclear antibodies specific for Ro, La, Sm, and double-stranded DNA antigens. After eluting specific anti-epithelial or anti-nuclear antibodies, which were recovered and tested using double-fluorescence assays, a lack of cross-reactivity was demonstrated between desmosomes and nuclear and cytoplasmic lupus antigens. This result suggests that autoantibodies in pemphigus erythematosus are directed against different antigens and that these autoantibodies are produced by independent clones. Given these clinical and serological data, we suggest that pemphigus erythematosus behaves as a multiple autoimmune disease.

Analysis of the documents about the core envelopment of nuclear reactor at the Laguna Verde U-1 power plant

International Nuclear Information System (INIS)

Zamora R, L.; Medina F, A.

1999-01-01

The degradation of internal components at BWR type reactors is an important subject to consider in the performance availability of the power plant. The Wuergassen nuclear reactor license was confiscated due to the presence of cracking in the core envelopment. In consequence it is necessary carrying out a detailed study with the purpose to avoid these problems in the future. This report presents a review and analysis of documents and technical information referring to the core envelopment of a BWR/5/6 and the Laguna Verde Unit 1 nuclear reactor in Mexico. In this document are presented design data, documents about fabrication processes, and manufacturing of core envelopment. (Author)

MS2 VLP-based delivery of microRNA-146a inhibits autoantibody production in lupus-prone mice

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Pan Y

2012-12-01

Full Text Available Yang Pan,1,2 Tingting Jia,1,2 Yuan Zhang,1,2 Kuo Zhang,1 Rui Zhang,1 Jinming Li,1 Lunan Wang11National Center for Clinical Laboratories, Beijing Hospital of the Ministry of Health, Beijing, People’s Republic of China; 2Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaBackground: Systemic lupus erythematosus (SLE is a chronic autoimmune disease characterized by the presence of pathogenic autoantibodies. Recent studies suggest that microRNAs (miRNAs play an essential role in immunoregulation and may be involved in the pathogenesis of SLE. Therefore, it was of interest to investigate the potential therapeutic application of miRNAs in SLE, a concept that has not been thoroughly investigated thus far. Virus-like particles (VLPs are a type of recombinant nanoparticle enveloped by certain proteins derived from the outer coat of a virus. Herein, we describe a novel miRNA-delivery approach via bacteriophage MS2 VLPs and investigate the therapeutic effects of miR-146a, a well-studied and SLE-related miRNA, in BXSB lupus-prone mice.Methods: VLPs containing miR-146a, and the control VLPs, were prepared using an Escherichia coli expression system and then administered to lupus-prone mice over a 12-day period. We performed an enzyme-linked immunosorbent assay to evaluate the anti-dsDNA antibody, autoantibody to nuclear antigen (ANA, total IgG and total IgM levels in serum. The expression of miR-146a was analyzed by qRT-PCR. SLE-related cytokines as well as some toll-like receptor signaling pathway molecules were also measured.Results: Treatment with MS2-miR146a VLP showed profound effects on lupus-prone BXSB mice, including an increased level of mature miR-146a, which led to a significant reduction in the expression of autoantibodies and total IgG. Remarkably, these mice also exhibited reduced levels of proinflammatorycytokines, including IFN-Interferon-α (IFN-α, Interleukin-1β (Il-1

Venture from the Interior-Herpesvirus pUL31 Escorts Capsids from Nucleoplasmic Replication Compartments to Sites of Primary Envelopment at the Inner Nuclear Membrane.

Science.gov (United States)

Bailer, Susanne M.

2017-11-25

Herpesviral capsid assembly is initiated in the nucleoplasm of the infected cell. Size constraints require that newly formed viral nucleocapsids leave the nucleus by an evolutionarily conserved vescular transport mechanism called nuclear egress. Mature capsids released from the nucleoplasm are engaged in a membrane-mediated budding process, composed of primary envelopment at the inner nuclear membrane and de-envelopment at the outer nuclear membrane. Once in the cytoplasm, the capsids receive their secondary envelope for maturation into infectious virions. Two viral proteins conserved throughout the herpesvirus family, the integral membrane protein pUL34 and the phosphoprotein pUL31, form the nuclear egress complex required for capsid transport from the infected nucleus to the cytoplasm. Formation of the nuclear egress complex results in budding of membrane vesicles revealing its function as minimal virus-encoded membrane budding and scission machinery. The recent structural analysis unraveled details of the heterodimeric nuclear egress complex and the hexagonal coat it forms at the inside of budding vesicles to drive primary envelopment. With this review, I would like to present the capsid-escort-model where pUL31 associates with capsids in nucleoplasmic replication compartments for escort to sites of primary envelopment thereby coupling capsid maturation and nuclear egress.

GAGE cancer-germline antigens bind DNA and are recruited to the nuclear envelope by Germ cell-less

DEFF Research Database (Denmark)

Gjerstorff, Morten; Rösner, Heike; Pedersen, Christina Bøg

GAGE genes encode a highly similar, primate-specific protein family with unique primary structure and undefined roles in germ cells, various fetal cells and cancer cells. We report that GAGE proteins are intrinsically disordered proteins that provide novel interfaces between chromatin and the nuc......GAGE genes encode a highly similar, primate-specific protein family with unique primary structure and undefined roles in germ cells, various fetal cells and cancer cells. We report that GAGE proteins are intrinsically disordered proteins that provide novel interfaces between chromatin...... and the nuclear envelope. Structural analysis by NMR and CD spectroscopy showed GAGE proteins lack distinct secondary or tertiary structure and are therefore intrinsically disordered. In normal cells and cancer cells GAGE proteins localize predominantly in the nucleus; we found GAGE proteins formed stable......) at the nuclear envelope. Furthermore, exogenous and endogenous GAGE proteins were recruited to the nuclear envelope in GCL-overexpressing cells. Gene expression analysis and immunohistochemical staining suggest GAGE proteins and GCL interact physiologically in human cells that express both, including male germ...

Glimpsing over the event horizon: evolution of nuclear pores and envelope.

Science.gov (United States)

Jékely, Gáspár

2005-02-01

The origin of eukaryotes from prokaryotic ancestors is one of the major evolutionary transitions in the history of life. The nucleus, a membrane bound compartment for confining the genome, is a central feature of eukaryotic cells and its origin also has to be a central feature of any workable theory that ventures to explain eukaryotic origins. Recent bioinformatic analyses of components of the nuclear pore complex (NPC), the nuclear envelope (NE), and the nuclear transport systems revealed exciting evolutionary connections (e.g., between NPC and coated vesicles) and provided a useful record of the phyletic distribution and history of NPC and NE components. These analyses allow us to refine theories on the origin and evolution of the nucleus, and consequently, of the eukaryotic cell.

Control of nuclear β-dystroglycan content is crucial for the maintenance of nuclear envelope integrity and function.

Science.gov (United States)

Vélez-Aguilera, Griselda; de Dios Gómez-López, Juan; Jiménez-Gutiérrez, Guadalupe E; Vásquez-Limeta, Alejandra; Laredo-Cisneros, Marco S; Gómez, Pablo; Winder, Steve J; Cisneros, Bulmaro

2018-02-01

β-Dystroglycan (β-DG) is a plasma membrane protein that has ability to target to the nuclear envelope (NE) to maintain nuclear architecture. Nevertheless, mechanisms controlling β-DG nuclear localization and the physiological consequences of a failure of trafficking are largely unknown. We show that β-DG has a nuclear export pathway in myoblasts that depends on the recognition of a nuclear export signal located in its transmembrane domain, by CRM1. Remarkably, NES mutations forced β-DG nuclear accumulation resulting in mislocalization and decreased levels of emerin and lamin B1 and disruption of various nuclear processes in which emerin (centrosome-nucleus linkage and β-catenin transcriptional activity) and lamin B1 (cell cycle progression and nucleoli structure) are critically involved. In addition to nuclear export, the lifespan of nuclear β-DG is restricted by its nuclear proteasomal degradation. Collectively our data show that control of nuclear β-DG content by the combination of CRM1 nuclear export and nuclear proteasome pathways is physiologically relevant to preserve proper NE structure and activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Reduction of a 4q35-encoded nuclear envelope protein in muscle differentiation

International Nuclear Information System (INIS)

Ostlund, Cecilia; Guan, Tinglu; Figlewicz, Denise A.; Hays, Arthur P.; Worman, Howard J.; Gerace, Larry; Schirmer, Eric C.

2009-01-01

Muscular dystrophy and peripheral neuropathy have been linked to mutations in genes encoding nuclear envelope proteins; however, the molecular mechanisms underlying these disorders remain unresolved. Nuclear envelope protein p19A is a protein of unknown function encoded by a gene at chromosome 4q35. p19A levels are significantly reduced in human muscle as cells differentiate from myoblasts to myotubes; however, its levels are not similarly reduced in all differentiation systems tested. Because 4q35 has been linked to facioscapulohumeral muscular dystrophy (FSHD) and some adjacent genes are reportedly misregulated in the disorder, levels of p19A were analyzed in muscle samples from patients with FSHD. Although p19A was increased in most cases, an absolute correlation was not observed. Nonetheless, p19A downregulation in normal muscle differentiation suggests that in the cases where its gene is inappropriately re-activated it could affect muscle differentiation and contribute to disease pathology.

Reduction of a 4q35-encoded nuclear envelope protein in muscle differentiation

Energy Technology Data Exchange (ETDEWEB)

Ostlund, Cecilia [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Guan, Tinglu [Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037 (United States); Figlewicz, Denise A. [Department of Neurology, University of Michigan, Ann Arbor, MI 48109 (United States); Hays, Arthur P. [Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Worman, Howard J. [Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Gerace, Larry [Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037 (United States); Schirmer, Eric C., E-mail: e.schirmer@ed.ac.uk [Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037 (United States); Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR (United Kingdom)

2009-11-13

Muscular dystrophy and peripheral neuropathy have been linked to mutations in genes encoding nuclear envelope proteins; however, the molecular mechanisms underlying these disorders remain unresolved. Nuclear envelope protein p19A is a protein of unknown function encoded by a gene at chromosome 4q35. p19A levels are significantly reduced in human muscle as cells differentiate from myoblasts to myotubes; however, its levels are not similarly reduced in all differentiation systems tested. Because 4q35 has been linked to facioscapulohumeral muscular dystrophy (FSHD) and some adjacent genes are reportedly misregulated in the disorder, levels of p19A were analyzed in muscle samples from patients with FSHD. Although p19A was increased in most cases, an absolute correlation was not observed. Nonetheless, p19A downregulation in normal muscle differentiation suggests that in the cases where its gene is inappropriately re-activated it could affect muscle differentiation and contribute to disease pathology.

Humoral markers of active Epstein-Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus.

Science.gov (United States)

Rasmussen, N S; Nielsen, C T; Houen, G; Jacobsen, S

2016-12-01

We investigated if signs of active Epstein-Barr virus and cytomegalovirus infections associate with certain autoantibodies and a marker of type I interferon activity in patients with systemic lupus erythematosus. IgM and IgG plasma levels against Epstein-Barr virus early antigen diffuse and cytomegalovirus pp52 were applied as humoral markers of ongoing/recently active Epstein-Barr virus and cytomegalovirus infections, respectively. Plasma galectin-3 binding protein served as a surrogate marker of type I interferon activity. The measurements were conducted in 57 systemic lupus erythematosus patients and 29 healthy controls using ELISAs. Regression analyses and univariate comparisons were performed for associative evaluation between virus serology, plasma galectin-3 binding protein and autoantibodies, along with other clinical and demographic parameters. Plasma galectin-3 binding protein concentrations were significantly higher in systemic lupus erythematosus patients (P = 0.009) and associated positively with Epstein-Barr virus early antigen diffuse-directed antibodies and the presence of autoantibodies against extractable nuclear antigens in adjusted linear regressions (B = 2.02 and 2.02, P = 0.02 and P = 0.002, respectively). Furthermore, systemic lupus erythematosus patients with anti-extractable nuclear antigens had significantly higher antibody levels against Epstein-Barr virus early antigen diffuse (P = 0.02). Our study supports a link between active Epstein-Barr virus infections, positivity for anti-extractable nuclear antigens and increased plasma galectin-3 binding protein concentrations/type I interferon activity in systemic lupus erythematosus patients. © The Author(s) 2016.

Mechanisms of Autoantibody-Induced Pathology

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Ralf J. Ludwig

2017-05-01

Full Text Available Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves’ disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1 mimic receptor stimulation, (2 blocking of neural transmission, (3 induction of altered signaling, triggering uncontrolled (4 microthrombosis, (5 cell lysis, (6 neutrophil activation, and (7 induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

Autoantibody Profiling in Lupus Patients using Synthetic Nucleic Acids

DEFF Research Database (Denmark)

Klecka, Martin; Thybo, Christina; Macaubas, Claudia

2018-01-01

Autoantibodies to nuclear components of cells (antinuclear antibodies, ANA), including DNA (a-DNA), are widely used in the diagnosis and subtyping of certain autoimmune diseases, including systemic lupus erythematosus (SLE). Despite clinical use over decades, precise, reproducible measurement of a...

Autoantibodies in Neuropsychiatric Disorders

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Carolin Hoffmann

2016-04-01

Full Text Available Little is known about the etiology of neuropsychiatric disorders. The identification of autoantibodies targeting the N-methyl-d-aspartate receptor (NMDA-R, which causes neurological and psychiatric symptoms, has reinvigorated the hypothesis that other patient subgroups may also suffer from an underlying autoimmune condition. In recent years, a wide range of neuropsychiatric diseases and autoantibodies targeting ion-channels or neuronal receptors including NMDA-R, voltage gated potassium channel complex (VGKC complex, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R, γ-aminobutyric acid receptor (GABA-R and dopamine receptor (DR were studied and conflicting reports have been published regarding the seroprevalence of these autoantibodies. A clear causative role of autoantibodies on psychiatric symptoms has as yet only been shown for the NMDA-R. Several other autoantibodies have been related to the presence of certain symptoms and antibody effector mechanisms have been proposed. However, extensive clinical studies with large multicenter efforts to standardize diagnostic procedures for autoimmune etiology and animal studies are needed to confirm the pathogenicity of these autoantibodies. In this review, we discuss the current knowledge of neuronal autoantibodies in the major neuropsychiatric disorders: psychotic, major depression, autism spectrum, obsessive-compulsive and attention-deficit/hyperactivity disorders.

The Role of the Nuclear Envelope Protein MAN1 in Mesenchymal Stem Cell Differentiation

DEFF Research Database (Denmark)

Bermeo, Sandra; Al-Saedi, Ahmed; Kassem, Moustapha

2017-01-01

Mutations in MAN1, a protein of the nuclear envelope, cause bone phenotypes characterized by hyperostosis. The mechanism of this pro-osteogenic phenotype remains unknown. We increased and decreased MAN1 expression in mesenchymal stem cells (MSC) upon which standard osteogenic and adipogenic diffe...

Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models.

Science.gov (United States)

Yokoi, Fumiaki; Dang, Mai T; Yang, Guang; Li, Jindong; Doroodchi, Atbin; Zhou, Tong; Li, Yuqing

2012-02-01

Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for ɛ-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally inherited Sgce heterozygous knockout (Sgce KO) mice and reported that they had myoclonus and motor coordination and learning deficits in the beam-walking test. However, the specific brain regions that contribute to these phenotypes have not been identified. Since ɛ-sarcoglycan is highly expressed in the cerebellar Purkinje cells, here we examined the nuclear envelope in these cells using a transmission electron microscope and found that they are abnormal in Sgce KO mice. Our results put DYT11 M-D in a growing family of nuclear envelopathies. To analyze the effect of loss of ɛ-sarcoglycan function in the cerebellar Purkinje cells, we produced paternally inherited cerebellar Purkinje cell-specific Sgce conditional knockout (Sgce pKO) mice. Sgce pKO mice showed motor learning deficits, while they did not show abnormal nuclear envelope in the cerebellar Purkinje cells, robust motor deficits, or myoclonus. The results suggest that ɛ-sarcoglycan in the cerebellar Purkinje cells contributes to the motor learning, while loss of ɛ-sarcoglycan in other brain regions may contribute to nuclear envelope abnormality, myoclonus and motor coordination deficits. Copyright © 2011 Elsevier B.V. All rights reserved.

GTP-binding proteins in rat liver nuclear envelopes

International Nuclear Information System (INIS)

Rubins, J.B.; Benditt, J.O.; Dickey, B.F.; Riedel, N.

1990-01-01

Nuclear transport as well as reassembly of the nuclear envelope (NE) after completion of mitosis are processes that have been shown to require GTP and ATP. To study the presence and localization of GTP-binding proteins in the NE, we have combined complementary techniques of [alpha-32P]GTP binding to Western-blotted proteins and UV crosslinking of [alpha-32P]GTP with well-established procedures for NE subfractionation. GTP binding to blotted NE proteins revealed five low molecular mass GTP-binding proteins of 26, 25, 24.5, 24, and 23 kDa, and [alpha-32P]GTP photoaffinity labeling revealed major proteins with apparent molecular masses of 140, 53, 47, 33, and 31 kDa. All GTP-binding proteins appear to localize preferentially to the inner nuclear membrane, possibly to the interface between inner nuclear membrane and lamina. Despite the evolutionary conservation between the NE and the rough endoplasmic reticulum, the GTP-binding proteins identified differed between these two compartments. Most notably, the 68- and 30-kDa GTP-binding subunits of the signal recognition particle receptor, which photolabeled with [alpha-32P]GTP in the rough endoplasmic reticulum fraction, were totally excluded from the NE fraction. Conversely, a major 53-kDa photolabeled protein in the NE was absent from rough endoplasmic reticulum. Whereas Western-blotted NE proteins bound GTP specifically, all [alpha-32P]GTP photolabeled proteins could be blocked by competition with ATP, although with a competition profile that differed from that obtained with GTP. In comparative crosslinking studies with [alpha-32P]ATP, we have identified three specific ATP-binding proteins with molecular masses of 160, 78, and 74 kDa. The localization of GTP- and ATP-binding proteins within the NE appears appropriate for their involvement in nuclear transport and in the GTP-dependent fusion of nuclear membranes

Autoantibodies directed to centromere protein F in a patient with BRCA1 gene mutation

OpenAIRE

Moghaddas, Fiona; Joshua, Fredrick; Taylor, Roberta; Fritzler, Marvin J.; Toh, Ban Hock

2016-01-01

Background Autoantibodies directed to centromere protein F were first reported in 1993 and their association with malignancy has been well documented. Case We present the case of a 48-year-old Caucasian female with a BRCA1 gene mutation associated with bilateral breast cancer. Antinuclear autoantibody immunofluorescence performed for workup of possible inflammatory arthropathy showed a high titre cell cycle related nuclear speckled pattern, with subsequent confirmation by addressable laser be...

Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli.

Science.gov (United States)

Matsumoto, Ayaka; Sakamoto, Chiyomi; Matsumori, Haruka; Katahira, Jun; Yasuda, Yoko; Yoshidome, Katsuhide; Tsujimoto, Masahiko; Goldberg, Ilya G; Matsuura, Nariaki; Nakao, Mitsuyoshi; Saitoh, Noriko; Hieda, Miki

2016-01-01

A supervised machine learning algorithm, which is qualified for image classification and analyzing similarities, is based on multiple discriminative morphological features that are automatically assembled during the learning processes. The algorithm is suitable for population-based analysis of images of biological materials that are generally complex and heterogeneous. Here we used the algorithm wndchrm to quantify the effects on nucleolar morphology of the loss of the components of nuclear envelope in a human mammary epithelial cell line. The linker of nucleoskeleton and cytoskeleton (LINC) complex, an assembly of nuclear envelope proteins comprising mainly members of the SUN and nesprin families, connects the nuclear lamina and cytoskeletal filaments. The components of the LINC complex are markedly deficient in breast cancer tissues. We found that a reduction in the levels of SUN1, SUN2, and lamin A/C led to significant changes in morphologies that were computationally classified using wndchrm with approximately 100% accuracy. In particular, depletion of SUN1 caused nucleolar hypertrophy and reduced rRNA synthesis. Further, wndchrm revealed a consistent negative correlation between SUN1 expression and the size of nucleoli in human breast cancer tissues. Our unbiased morphological quantitation strategies using wndchrm revealed an unexpected link between the components of the LINC complex and the morphologies of nucleoli that serves as an indicator of the malignant phenotype of breast cancer cells.

Nuclear Facility Isotopic Content (NFIC) Waste Management System to provide input for safety envelope definition

International Nuclear Information System (INIS)

Genser, J.R.

1992-01-01

The Westinghouse Savannah River Company (WSRC) is aggressively applying environmental remediation and radioactive waste management activities at the US Department of Energy's Savannah River Site (SRS) to ensure compliance with today's challenging governmental laws and regulatory requirements. This report discusses a computer-based Nuclear Facility Isotopic Content (NFIC) Waste Management System developed to provide input for the safety envelope definition and assessment of site-wide facilities. Information was formulated describing the SRS ''Nuclear Facilities'' and their respective bounding inventories of nuclear materials and radioactive waste using the NFIC Waste Management System

Extrapancreatic Autoantibody Profiles in Type I Diabetes

Science.gov (United States)

Burbelo, Peter D.; Lebovitz, Evan E.; Bren, Kathleen E.; Bayat, Ahmad; Paviol, Scott; Wenzlau, Janet M.; Barriga, Katherine J.; Rewers, Marian; Harlan, David M.; Iadarola, Michael J.

2012-01-01

Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing β-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-β. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-β (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together

Mechanism of protein import across the chloroplast envelope.

Science.gov (United States)

Chen, K; Chen, X; Schnell, D J

2000-01-01

The development and maintenance of chloroplasts relies on the contribution of protein subunits from both plastid and nuclear genomes. Most chloroplast proteins are encoded by nuclear genes and are post-translationally imported into the organelle across the double membrane of the chloroplast envelope. Protein import into the chloroplast consists of two essential elements: the specific recognition of the targeting signals (transit sequences) of cytoplasmic preproteins by receptors at the outer envelope membrane and the subsequent translocation of preproteins simultaneously across the double membrane of the envelope. These processes are mediated via the co-ordinate action of protein translocon complexes in the outer (Toc apparatus) and inner (Tic apparatus) envelope membranes.

Shape Transformation of the Nuclear Envelope during Closed Mitosis.

Science.gov (United States)

Zhu, Qian; Zheng, Fan; Liu, Allen P; Qian, Jin; Fu, Chuanhai; Lin, Yuan

2016-11-15

The nuclear envelope (NE) in lower eukaryotes such as Schizosaccharomyces pombe undergoes large morphology changes during closed mitosis. However, which physical parameters are important in governing the shape evolution of the NE, and how defects in the dividing chromosomes/microtubules are reflected in those parameters, are fundamental questions that remain unresolved. In this study, we show that improper separation of chromosomes in genetically deficient cells leads to membrane tethering or asymmetric division in contrast to the formation of two equal-sized daughter nuclei in wild-type cells. We hypothesize that the poleward force is transmitted to the nuclear membrane through its physical contact with the separated sister chromatids at the two spindle poles. A theoretical model is developed to predict the morphology evolution of the NE where key factors such as the work done by the poleward force and bending and surface energies stored in the membrane have been taken into account. Interestingly, the predicted phase diagram, summarizing the dependence of nuclear shape on the size of the load transmission regions, and the pole-to-pole distance versus surface area relationship all quantitatively agree well with our experimental observations, suggesting that this model captures the essential physics involved in closed mitosis. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Herpesvirus gB-induced fusion between the virion envelope and outer nuclear membrane during virus egress is regulated by the viral US3 kinase.

Science.gov (United States)

Wisner, Todd W; Wright, Catherine C; Kato, Akihisa; Kawaguchi, Yasushi; Mou, Fan; Baines, Joel D; Roller, Richard J; Johnson, David C

2009-04-01

Herpesvirus capsids collect along the inner surface of the nuclear envelope and bud into the perinuclear space. Enveloped virions then fuse with the outer nuclear membrane (NM). We previously showed that herpes simplex virus (HSV) glycoproteins gB and gH act in a redundant fashion to promote fusion between the virion envelope and the outer NM. HSV mutants lacking both gB and gH accumulate enveloped virions in herniations, vesicles that bulge into the nucleoplasm. Earlier studies had shown that HSV mutants lacking the viral serine/threonine kinase US3 also accumulate herniations. Here, we demonstrate that HSV gB is phosphorylated in a US3-dependent manner in HSV-infected cells, especially in a crude nuclear fraction. Moreover, US3 directly phosphorylated the gB cytoplasmic (CT) domain in in vitro assays. Deletion of gB in the context of a US3-null virus did not add substantially to defects in nuclear egress. The majority of the US3-dependent phosphorylation of gB involved the CT domain and amino acid T887, a residue present in a motif similar to that recognized by US3 in other proteins. HSV recombinants lacking gH and expressing either gB substitution mutation T887A or a gB truncated at residue 886 displayed substantial defects in nuclear egress. We concluded that phosphorylation of the gB CT domain is important for gB-mediated fusion with the outer NM. This suggested a model in which the US3 kinase is incorporated into the tegument layer (between the capsid and envelope) in HSV virions present in the perinuclear space. By this packaging, US3 might be brought close to the gB CT tail, leading to phosphorylation and triggering fusion between the virion envelope and the outer NM.

Autoantibodies in Autoimmune Hepatitis.

Science.gov (United States)

Muratori, Luigi; Deleonardi, Gaia; Lalanne, Claudine; Barbato, Erica; Tovoli, Alessandra; Libra, Alessia; Lenzi, Marco; Cassani, Fabio; Muratori, Paolo

2015-01-01

The detection of diagnostic autoantibodies such as antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), anti-liver/kidney microsomal type 1 (anti-LKM1), anti-liver cytosol type 1 (anti-LC1) and anti-soluble liver antigen (anti-SLA) is historically associated with the diagnosis of autoimmune hepatitis. When autoimmune hepatitis is suspected, the detection of one or any combination of diagnostic autoantibodies, by indirect immunofluorescence or immuno-enzymatic techniques with recombinant antigens, is a pivotal step to reach a diagnostic score of probable or definite autoimmune hepatitis. Diagnostic autoantibodies (ANA, SMA, anti-LKM1, anti-LC1, anti-SLA) are a cornerstone in the diagnosis of autoimmune hepatitis. Other ancillary autoantibodies, associated with peculiar clinical correlations, appear to be assay-dependent and institution-specific, and validation studies are needed. © 2015 S. Karger AG, Basel.

Safe operating envelope

Energy Technology Data Exchange (ETDEWEB)

Oliva, N [Ontario Hydro, Toronto, ON (Canada)

1997-12-01

Safe Operating Envelope is described representing: The outer bound of plant conditions within which day-to-day plant operation must be maintained in order to comply with regulatory requirements, associated safety design criteria and corporate nuclear safety goals. Figs.

Safe operating envelope

International Nuclear Information System (INIS)

Oliva, N.

1997-01-01

Safe Operating Envelope is described representing: The outer bound of plant conditions within which day-to-day plant operation must be maintained in order to comply with regulatory requirements, associated safety design criteria and corporate nuclear safety goals. Figs

Nuclear envelope and genome interactions in cell fate

Science.gov (United States)

Talamas, Jessica A.; Capelson, Maya

2015-01-01

The eukaryotic cell nucleus houses an organism’s genome and is the location within the cell where all signaling induced and development-driven gene expression programs are ultimately specified. The genome is enclosed and separated from the cytoplasm by the nuclear envelope (NE), a double-lipid membrane bilayer, which contains a large variety of trans-membrane and associated protein complexes. In recent years, research regarding multiple aspects of the cell nucleus points to a highly dynamic and coordinated concert of efforts between chromatin and the NE in regulation of gene expression. Details of how this concert is orchestrated and how it directs cell differentiation and disease are coming to light at a rapid pace. Here we review existing and emerging concepts of how interactions between the genome and the NE may contribute to tissue specific gene expression programs to determine cell fate. PMID:25852741

Nuclear envelope expansion is crucial for proper chromosomal segregation during a closed mitosis.

Science.gov (United States)

Takemoto, Ai; Kawashima, Shigehiro A; Li, Juan-Juan; Jeffery, Linda; Yamatsugu, Kenzo; Elemento, Olivier; Nurse, Paul

2016-03-15

Here, we screened a 10,371 library of diverse molecules using a drug-sensitive fission yeast strain to identify compounds which cause defects in chromosome segregation during mitosis. We identified a phosphorium-ylide-based compound Cutin-1 which inhibits nuclear envelope expansion and nuclear elongation during the closed mitosis of fission yeast, and showed that its target is the β-subunit of fatty acid synthase. A point mutation in the dehydratase domain of Fas1 conferred in vivo and in vitro resistance to Cutin-1. Time-lapse photomicrography showed that the bulk of the chromosomes were only transiently separated during mitosis, and nucleoli separation was defective. Subsequently sister chromatids re-associated leading to chromosomal mis-segregation. These segregation defects were reduced when the nuclear volume was increased and were increased when the nuclear volume was reduced. We propose that there needs to be sufficient nuclear volume to allow the nuclear elongation necessary during a closed mitosis to take place for proper chromosome segregation, and that inhibition of fatty acid synthase compromises nuclear elongation and leads to defects in chromosomal segregation. © 2016. Published by The Company of Biologists Ltd.

Rheumatic Disease Autoantibodies in Patients with Autoimmune Thyroid Diseases.

Science.gov (United States)

Nisihara, Renato; Pigosso, Yasmine; Prado, Nathalia; Utiyama, Shirley R R; Carvalho, Gisah; Skare, Thelma

2018-06-04

Patients with autoimmune thyroid diseases (ATD) such as Graves' disease (GD) and Hashimoto thyroiditis (HT) may have non-organ specific autoantibodies such as ANA (antinuclear antibodies) and RF (rheumatoid factor). To study the prevalence of rheumatic autoantibodies in a group of ATD patients without known rheumatic diseases and to evaluate its association with the patients' epidemiological and treatment profile. To follow positive non-organ specific autoantibody-positive ATD individuals to investigate whether they will develop a rheumatic disorder. A sample of 154 ATD patients (70 HT and 84 GD; mean age 45.3 ± 14.2) had determination of ANA by immunofluorescence, using hep-2 cells as substrate, extractable nuclear antigen (ENA) profile by ELISA kits and RF by latex agglutination. Epidemiological and treatment profile were obtained through chart review. These patients were followed for the mean period of five years, between 2010 to 2015. Positive ANA was found in 17.5% (27/154) of the patients: anti-Ro/SS-A in 4/154 (2.5%); anti-RNP in 4/154 (2.5%) and anti-La/SS-B in 3/154 (1.9%). None had anti-Sm antibodies. RF was detected in 12/154 (7.7%) of ATD patients and was more common in older individuals (p = 0.007). There was a positive association between the presence of RF and ANA (p = 0.03; OR = 3.89; 95% CI = 1.1-13.3). None of the patients with positive autoantibodies developed clinical rheumatic diseases during the period of observation. We found rheumatic autoantibodies in 17.5% of ATD patients without rheumatic diseases. None of them were associated with the appearance of clinical rheumatic disorder during the period of five years. ©2018The Author(s). Published by S. Karger AG, Basel.

Humoral markers of active Epstein-Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus

DEFF Research Database (Denmark)

Rasmussen, N S; Nielsen, C T; Houen, G

2016-01-01

We investigated if signs of active Epstein-Barr virus and cytomegalovirus infections associate with certain autoantibodies and a marker of type I interferon activity in patients with systemic lupus erythematosus. IgM and IgG plasma levels against Epstein-Barr virus early antigen diffuse...... and cytomegalovirus pp52 were applied as humoral markers of ongoing/recently active Epstein-Barr virus and cytomegalovirus infections, respectively. Plasma galectin-3 binding protein served as a surrogate marker of type I interferon activity. The measurements were conducted in 57 systemic lupus erythematosus patients...... concentrations were significantly higher in systemic lupus erythematosus patients (P = 0.009) and associated positively with Epstein-Barr virus early antigen diffuse-directed antibodies and the presence of autoantibodies against extractable nuclear antigens in adjusted linear regressions (B = 2.02 and 2.02, P...

Female Infertility and Serum Auto-antibodies: a Systematic Review.

Science.gov (United States)

Deroux, Alban; Dumestre-Perard, Chantal; Dunand-Faure, Camille; Bouillet, Laurence; Hoffmann, Pascale

2017-08-01

On average, 10 % of infertile couples have unexplained infertility. Auto-immune disease (systemic lupus erythematosus, anti-phospholipid syndrome) accounts for a part of these cases. In the last 20 years, aspecific auto-immunity, defined as positivity of auto-antibodies in blood sample without clinical or biological criteria for defined diseases, has been evoked in a subpopulation of infertile women. A systematic review was performed (PUBMED) using the MESH search terms "infertility" and "auto-immunity" or "reproductive technique" or "assisted reproduction" or "in vitro fertilization" and "auto-immunity." We retained clinical and physiopathological studies that were applicable to the clinician in assuming joint management of both infertility associated with serum auto-antibodies in women. Thyroid auto-immunity which affects thyroid function could be a cause of infertility; even in euthyroidia, the presence of anti-thyroperoxydase antibodies and/or thyroglobulin are related to infertility. The presence of anti-phospholipid (APL) and/or anti-nuclear (ANA) antibodies seems to be more frequent in the population of infertile women; serum auto-antibodies are associated with early ovarian failure, itself responsible for fertility disorders. However, there exist few publications on this topic. The methods of dosage, as well as the clinical criteria of unexplained infertility deserve to be standardized to allow a precise response to the question of the role of serum auto-antibodies in these women. The direct pathogenesis of this auto-immunity is unknown, but therapeutic immunomodulators, prescribed on a case-by-case basis, could favor pregnancy even in cases of unexplained primary or secondary infertility.

Human Cytomegalovirus nuclear egress and secondary envelopment are negatively affected in the absence of cellular p53

Energy Technology Data Exchange (ETDEWEB)

Kuan, Man I; O’Dowd, John M.; Chughtai, Kamila; Hayman, Ian; Brown, Celeste J.; Fortunato, Elizabeth A., E-mail: lfort@uidaho.edu

2016-10-15

Human Cytomegalovirus (HCMV) infection is compromised in cells lacking p53, a transcription factor that mediates cellular stress responses. In this study we have investigated compromised functional virion production in cells with p53 knocked out (p53KOs). Infectious center assays found most p53KOs released functional virions. Analysis of electron micrographs revealed modestly decreased capsid production in infected p53KOs compared to wt. Substantially fewer p53KOs displayed HCMV-induced infoldings of the inner nuclear membrane (IINMs). In p53KOs, fewer capsids were found in IINMs and in the cytoplasm. The deficit in virus-induced membrane remodeling within the nucleus of p53KOs was mirrored in the cytoplasm, with a disproportionately smaller number of capsids re-enveloped. Reintroduction of p53 substantially recovered these deficits. Overall, the absence of p53 contributed to inhibition of the formation and function of IINMs and re-envelopment of the reduced number of capsids able to reach the cytoplasm. -- Highlights: •The majority of p53KO cells release fewer functional virions than wt cells. •Nucleocapsids do not efficiently exit the nucleus in p53KO cells. •Infoldings of the inner nuclear membrane are not efficiently formed in p53KO cells. •Cytoplasmic capsids are not efficiently re-enveloped in p53KO cells. •Reintroduction of p53 largely ameliorates these phenotypes.

Duplication and Nuclear Envelope Insertion of the Yeast Microtubule Organizing Centre, the Spindle Pole Body

Directory of Open Access Journals (Sweden)

Diana Rüthnick

2018-05-01

Full Text Available The main microtubule organizing centre in the unicellular model organisms Saccharomyces cerevisiae and Schizosaccharomyces pompe is the spindle pole body (SPB. The SPB is a multilayer structure, which duplicates exactly once per cell cycle. Unlike higher eukaryotic cells, both yeast model organisms undergo mitosis without breakdown of the nuclear envelope (NE, a so-called closed mitosis. Therefore, in order to simultaneously nucleate nuclear and cytoplasmic MTs, it is vital to embed the SPB into the NE at least during mitosis, similarly to the nuclear pore complex (NPC. This review aims to embrace the current knowledge of the SPB duplication cycle with special emphasis on the critical step of the insertion of the new SPB into the NE.

SAFEGUARDS ENVELOPE: PREVIOUS WORK AND EXAMPLES

International Nuclear Information System (INIS)

Metcalf, Richard; Bevill, Aaron; Charlton, William; Bean, Robert

2008-01-01

The future expansion of nuclear power will require not just electricity production but fuel cycle facilities such as fuel fabrication and reprocessing plants. As large reprocessing facilities are built in various states, they must be built and operated in a manner to minimize the risk of nuclear proliferation. Process monitoring has returned to the spotlight as an added measure that can increase confidence in the safeguards of special nuclear material (SNM). Process monitoring can be demonstrated to lengthen the allowable inventory period by reducing accountancy requirements, and to reduce the false positive indications. The next logical step is the creation of a Safeguards Envelope, a set of operational parameters and models to maximize anomaly detection and inventory period by process monitoring while minimizing operator impact and false positive rates. A brief example of a rudimentary Safeguards Envelope is presented, and shown to detect synthetic diversions overlaying a measured processing plant data set. This demonstration Safeguards Envelope is shown to increase the confidence that no SNM has been diverted with minimal operator impact, even though it is based on an information sparse environment. While the foundation on which a full Safeguards Envelope can be built has been presented in historical demonstrations of process monitoring, several requirements remain yet unfulfilled. Future work will require reprocessing plant transient models, inclusion of 'non-traditional' operating data, and exploration of new methods of identifying subtle events in transient processes

Increased immune complexes of hypocretin autoantibodies in narcolepsy.

Science.gov (United States)

Deloumeau, Aude; Bayard, Sophie; Coquerel, Quentin; Déchelotte, Pierre; Bole-Feysot, Christine; Carlander, Bertrand; Cochen De Cock, Valérie; Fetissov, Sergueï O; Dauvilliers, Yves

2010-10-13

Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.

Increased immune complexes of hypocretin autoantibodies in narcolepsy.

Directory of Open Access Journals (Sweden)

Aude Deloumeau

Full Text Available BACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.

Autoantibodies in cryptogenic fibrosing alveolitis

Directory of Open Access Journals (Sweden)

du Bois Ron

2001-02-01

Full Text Available Abstract The pathogenesis of cryptogenic fibrosing alveolitis (CFA involves injury, an immune/inflammatory response and fibrosis. The cause of the injury is unknown, but the identification of serum autoantibodies makes an autoimmune aetiology attractive. The core study on which this commentary is based used novel cloning and serum screening technologies in order to identify new public and private autoantibodies in sera from 12 patients with CFA. Largely negative conclusions were drawn from that study. However, we suggest that the prevalence of autoantibodies may have been underestimated, that the study was timely and that this approach is worth pursuing further.

The Role of Pathogenic Autoantibodies in Autoimmunity

Directory of Open Access Journals (Sweden)

Merrill J. Rowley

2015-11-01

Full Text Available The serological presence of autoantibodies is diagnostic of autoimmunity, and these autoantibodies may be present for many years before the presentation of autoimmune disease (AID. Although a pathogenic role has been demonstrated for various autoantibodies reactive with cell surface and extracellular autoantigens, studies using monoclonal antibodies (mAb show not all antibodies in the polyclonal response are pathogenic. Differences depend on Fab-mediated diversity in epitope specificity, Fc-mediated effects based on immunoglobulin (Ig class and subclass, activation of complement, and the milieu in which the reaction occurs. These autoantibodies often occur in organ-specific AID and this review illustrates their pathogenic and highly specific effects. The role of autoantibodies associated with intracellular antigens is less clear. In vitro they may inhibit or adversely affect well-defined intracellular biochemical pathways, yet, in vivo they are separated from their autoantigens by multiple cellular barriers. Recent evidence that Ig can traverse cell membranes, interact with intracellular proteins, and induce apoptosis has provided new evidence for a pathogenic role for such autoantibodies. An understanding of how autoantibodies behave in the polyclonal response and their role in pathogenesis of AID may help identify populations of culprit B-cells and selection of treatments that suppress or eliminate them.

Autoantibodies in systemic sclerosis: Unanswered questions

Directory of Open Access Journals (Sweden)

CRISTIANE eKAYSER

2015-04-01

Full Text Available Systemic sclerosis (SSc is an autoimmune disease characterized by vascular abnormalities, and cutaneous and visceral fibrosis. Serum autoantibodies directed to multiple intracellular antigens are present in more than 95% of patients and are considered a hallmark of SSc. They are helpful biomarkers for the early diagnosis of SSc and are associated with distinctive clinical manifestations. With the advent of more sensitive, multiplexed immunoassays, new and old questions about the relevance of autoantibodies in SSc are emerging. In this review we discuss the clinical relevance of autoantibodies in SSc emphasizing the more recently published data. Moreover, we will summarize recent advances regarding the stability of SSc autoantibodies over the course of disease, whether they are mutually exclusive and their potential roles in the disease pathogenesis.

Autoantibodies in infectious mononucleosis have specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen

Science.gov (United States)

1987-01-01

Viruses have been postulated to be involved in the induction of autoantibodies by: autoimmunization with tissue proteins released by virally induced tissue damage; immunization with virally encoded antigens bearing molecular similarities to normal tissue proteins; or nonspecific (polyclonal) B cell stimulation by the infection. Infectious mononucleosis (IM) is an experiment of nature that provides the opportunity for examining these possibilities. We show here that IgM antibodies produced in this disease react with at least nine normal tissue proteins, in addition to the virally encoded Epstein-Barr nuclear antigen (EBNA-1). The antibodies are generated to configurations in the glycine-alanine repeat region of EBNA-1 and are crossreactive with the normal tissue proteins through similar configurations, as demonstrated by the effectiveness of a synthetic glycine-alanine peptide in inhibiting the reactions. The antibodies are absent in preillness sera and gradually disappear over a period of months after illness, being replaced by IgG anti-EBNA-1 antibodies that do not crossreact with the normal tissue proteins but that are still inhibited by the glycine-alanine peptide. These findings are most easily explained by either a molecular mimicry model of IgM autoantibody production or by the polyclonal activation of a germline gene for a crossreactive antibody. It also indicates a selection of highly specific, non-crossreactive anti-EBNA-1 antibodies during IgM to IgG isotype switching. PMID:2435830

Analysis of the documents about the core envelopment of nuclear reactor at the Laguna Verde U-1 power plant; Analisis de documentos de los materiales de la envolvente del nucleo del reactor nuclear de la CLV U-1

Energy Technology Data Exchange (ETDEWEB)

Zamora R, L.; Medina F, A. [Instituto Nacional de Investigaciones Nucleares, A.P. 18-1027, 11801 Mexico D.F. (Mexico)

1999-07-01

The degradation of internal components at BWR type reactors is an important subject to consider in the performance availability of the power plant. The Wuergassen nuclear reactor license was confiscated due to the presence of cracking in the core envelopment. In consequence it is necessary carrying out a detailed study with the purpose to avoid these problems in the future. This report presents a review and analysis of documents and technical information referring to the core envelopment of a BWR/5/6 and the Laguna Verde Unit 1 nuclear reactor in Mexico. In this document are presented design data, documents about fabrication processes, and manufacturing of core envelopment. (Author)

NSF- and SNARE-mediated membrane fusion is required for nuclear envelope formation and completion of nuclear pore complex assembly in Xenopus laevis egg extracts.

Science.gov (United States)

Baur, Tina; Ramadan, Kristijan; Schlundt, Andreas; Kartenbeck, Jürgen; Meyer, Hemmo H

2007-08-15

Despite the progress in understanding nuclear envelope (NE) reformation after mitosis, it has remained unclear what drives the required membrane fusion and how exactly this is coordinated with nuclear pore complex (NPC) assembly. Here, we show that, like other intracellular fusion reactions, NE fusion in Xenopus laevis egg extracts is mediated by SNARE proteins that require activation by NSF. Antibodies against Xenopus NSF, depletion of NSF or the dominant-negative NSF(E329Q) variant specifically inhibited NE formation. Staging experiments further revealed that NSF was required until sealing of the envelope was completed. Moreover, excess exogenous alpha-SNAP that blocks SNARE function prevented membrane fusion and caused accumulation of non-flattened vesicles on the chromatin surface. Under these conditions, the nucleoporins Nup107 and gp210 were fully recruited, whereas assembly of FxFG-repeat-containing nucleoporins was blocked. Together, we define NSF- and SNARE-mediated membrane fusion events as essential steps during NE formation downstream of Nup107 recruitment, and upstream of membrane flattening and completion of NPC assembly.

Antinuclear Matrix Protein 2 Autoantibodies and Edema, Muscle Disease, and Malignancy Risk in Dermatomyositis Patients.

Science.gov (United States)

Albayda, Jemima; Pinal-Fernandez, Iago; Huang, Wilson; Parks, Cassie; Paik, Julie; Casciola-Rosen, Livia; Danoff, Sonye K; Johnson, Cheilonda; Christopher-Stine, Lisa; Mammen, Andrew L

2017-11-01

Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with autoantibodies recognizing the nuclear matrix protein NXP-2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti-NXP-2 autoantibodies. There were 235 DM patients who underwent testing for anti-NXP-2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti-NXP-2-positive subjects was compared with the number expected in the general population. Of the DM patients, 56 (23.8%) were anti-NXP-2-positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti-NXP-2. In contrast, anti-NXP-2-positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P edema (36% versus 19%; P = 0.01) than anti-NXP-2-negative patients. Five anti-NXP-2-positive subjects (9%) had cancer-associated myositis, representing a 3.68-fold increased risk (95% confidence interval 1.2-8.6) compared to the expected prevalence in the general population. In DM, anti-NXP-2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti-NXP-2-positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening. © 2017, American College of Rheumatology.

Autoantibodies from patients with systemic lupus erythematosus bind a shared sequence of SmD and Epstein-Barr virus-encoded nuclear antigen EBNA I.

Science.gov (United States)

Sabbatini, A; Bombardieri, S; Migliorini, P

1993-05-01

SmD is one of the small nuclear ribonucleoproteins frequently targeted by autoantibodies in systemic lupus erythematosus. We isolated and characterized the antibodies present in lupus sera that are specific for the C-terminal region of SmD (sequence 95-119). This region is highly homologous to sequence 35-58 of the EBNA I antigen, one of the nuclear antigens induced by infection with Epstein-Barr virus. Antibodies affinity purified over a peptide 95-119 column were able to recognize this sequence in the context of the whole SmD molecule, as they reacted with blotted recombinant SmD. Anti-SmD 95-119 antibodies bound also the EBNA I 35-58 peptide and detected the EBNA I molecule in a total cell extract from Epstein-Barr virus-infected lines. A population of anti-SmD antibodies is, therefore, able to bind an epitope shared by the autoantigen and the viral antigen EBNA I. To investigate the involvement of this shared epitope in the generation of anti-SmD antibodies, we immunized mice with the EBNA I 35-58 peptide. Sera from immunized animals displayed the same pattern of reactivity of spontaneously produced anti-SmD antibodies. They reacted in fact with the EBNA peptide as well as with SmD 95-119 and recombinant SmD. These data suggest that molecular mimicry may play a role in the induction of anti-SmD autoantibodies.

Myositis specific autoantibodies: changing insights in pathophysiology and clinical associations.

NARCIS (Netherlands)

Hengstman, G.J.D.; Engelen, B.G.M. van; Venrooij, W.J.W. van

2004-01-01

PURPOSE OF REVIEW: Defined autoantibodies are found in about half of the patients with myositis. Traditionally, these autoantibodies have been divided into myositis specific autoantibodies (MSAs) and myositis associated autoantibodies. Several studies have shown that MSAs are associated with

Origins of anti-DNA autoantibodies

International Nuclear Information System (INIS)

Schwartz, R.S.

1985-01-01

The direction of research in autoimmunity was strongly influenced by three notable discoveries made more than 25 year ago: anti-DNA anti-bodies in lupus serum, the immunofluorescent antinuclar antibody test and the NZB mouse. Now another turning point has been reached for three new reasons: the discovery of the hybridoma technic, advances in cellular immunology and the use of molecular biology to solve immunological problems. These developments have motivated fresh approaches to questions about the origins and pathogenic mechanisms of autoantibodies. Systemic lupus erythematosus (SLE) has a conspicuous position in the field of autoimmunity for several reasons. Its diverse manifestations have attracted a correspondingly diverse group of investigators whose interests range from molecular biology to therapeutic trials; superb models of the disease occur spontaneously in animals; and the extensive variety of autoantibodies in SLE provides an abundance of investigative reagents. An explanation of the origins of these autoantibodies is one of the major goals of research in the disease. The autoantibodies that bind to DNA are of central interest. They occur in almost all patients with active SLE, they often fluctuate with its clinical activity, and they participate in forming its lesions

Permeabilization of the nuclear envelope following nanosecond pulsed electric field exposure

Energy Technology Data Exchange (ETDEWEB)

Thompson, Gary L., E-mail: gary.l.thompson.3@gmail.com [Oak Ridge Institute for Science & Education, Joint Base San Antonio Fort Sam Houston, TX, 78234 (United States); Roth, Caleb C. [Department of Radiological Sciences, University of Texas Health Science Center at San Antonio, TX, 78234 (United States); Kuipers, Marjorie A. [Radio Frequency Radiation Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory, Joint Base San Antonio Fort Sam Houston, TX, 78234 (United States); Tolstykh, Gleb P. [General Dynamics IT, Joint Base San Antonio Fort Sam Houston, TX, 78234 (United States); Beier, Hope T. [Optical Radiation Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory, Joint Base San Antonio Fort Sam Houston, TX, 78234 (United States); Ibey, Bennett L. [Radio Frequency Radiation Branch, Bioeffects Division, Human Effectiveness Directorate, 711th Human Performance Wing, Air Force Research Laboratory, Joint Base San Antonio Fort Sam Houston, TX, 78234 (United States)

2016-01-29

Permeabilization of cell membranes occurs upon exposure to a threshold absorbed dose (AD) of nanosecond pulsed electric fields (nsPEF). The ultimate, physiological bioeffect of this exposure depends on the type of cultured cell and environment, indicating that cell-specific pathways and structures are stimulated. Here we investigate 10 and 600 ns duration PEF effects on Chinese hamster ovary (CHO) cell nuclei, where our hypothesis is that pulse disruption of the nuclear envelope membrane leads to observed cell death and decreased viability 24 h post-exposure. To observe short-term responses to nsPEF exposure, CHO cells have been stably transfected with two fluorescently-labeled proteins known to be sequestered for cellular chromosomal function within the nucleus – histone-2b (H2B) and proliferating cell nuclear antigen (PCNA). H2B remains associated with chromatin after nsPEF exposure, whereas PCNA leaks out of nuclei permeabilized by a threshold AD of 10 and 600 ns PEF. A downturn in 24 h viability, measured by MTT assay, is observed at the number of pulses required to induce permeabilization of the nucleus. - Highlights: • The ability of nsPEF to damage nuclear structures within cells is investigated. • Leakage of proliferating nuclear antigen from nuclei is induced by nsPEF. • High doses of nsPEF disrupt cortical lamin and cause chromatin decompaction. • Histone H2B remains attached to chromatin following nsPEF exposure. • DNA does not leak out of nsPEF-permeabilized nuclei.

Pituitary autoantibodies in endocrine disorders

OpenAIRE

Bensing, Sophie

2005-01-01

Autoimmune endocrine disorders are characterised by the development of autoantibodies to specific autoantigens in the target organs. Lymphocytic hypophysitis (LyH) is a disease characterised by inflammation of the pituitary gland, often resulting in hypopituitarism. The aetiology of LyH is considered to be autoimmune. However, only a few pituitary autoantigens have so far been identified. Reliable autoantibody markers are requested in the diagnostic procedure of LyH to avoid...

Antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis

NARCIS (Netherlands)

Kallenberg, Cees G. M.

Purpose of reviews This review focuses on recent advance in the diagnosis pathogenesis and treatment of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Recent findings Antineutrophil cytoplasmic autoantibodies are closely associated with Wegener's granulomatosis and

Studies of Filipino patients with systemic lupus erythematosus: autoantibody profile of first-degree relatives.

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Navarra, S V; Ishimori, M I; Uy, E A; Hamijoyo, L; Sama, J; James, J A; Holers, V M; Weisman, M H

2011-04-01

This study surveyed the frequency of autoantibodies among un-affected first-degree relatives (FDRs) of Filipino systemic lupus erythematosus (SLE) patients compared with healthy un-related Filipino controls. The sensitivity, specificity and predictive value of the autoantibodies for SLE diagnosis were also assessed in this Filipino cohort. Filipino patients included in the University of Santo Tomas (UST) Lupus Database and un-affected FDRs were recruited. Healthy controls included those with no known personal or family history of autoimmune disease. The following autoantibodies were tested in all subjects: anti-nuclear antibody (ANA), anti-dsDNA, anti-Ro/SSA, anti-chromatin, anti-thyroid microsome, and anti-cardiolipin antibodies. Participants included 232 SLE patients, 546 FDRs, and 221 healthy controls. Median age of patients was 27 (range 8-66) years with median disease duration of 27.5 (range 1-292) months. Median age of FDRs was 42.0 (range 5-87) years. Compared with healthy controls, there were significantly more FDRs with positive ANA at titers 1 : 40 to 1 : 160 (p Filipinos, with a significant proportion of un-affected FDRs of SLE patients testing positive for autoantibodies compared with healthy Filipino controls. A longitudinal observational study in this same cohort will determine which proportion of these un-affected FDRs will evolve into clinical SLE disease in the future.

An Lck-cre transgene accelerates autoantibody production and lupus development in (NZB × NZW)F1 mice

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Nelson, Richard K.; Gould, Karen A.

2015-01-01

Lupus is an autoimmune disease characterized by the development of antinuclear autoantibodies and immune complex-mediated tissue damage. T cells in lupus patients appear to undergo apoptosis at an increased rate, and this enhanced T cell apoptosis has been postulated to contribute to lupus pathogenesis by increasing autoantigen load. However, there is no direct evidence to support this hypothesis. In this study, we show that an Lck-cre transgene, which increases T cell apoptosis as a result of T cell specific expression of cre recombinase, accelerates the development of autoantibodies and nephritis in lupus-prone (NZB×NZW)F1 mice. Although the enhanced T cell apoptosis in Lck-cre transgenic mice resulted in an overall decrease in the relative abundance of splenic CD4+ and CD8+ T cells, the proportion of activated CD4+ T cells was increased and no significant change was observed in the relative abundance of suppressive T cells. We postulate that the Lck-cre transgene promoted lupus by enhancing T cells apoptosis, which, in conjunction with the impaired clearance of apoptotic cells in lupus-prone mice, increased the nuclear antigen load and accelerated the development of anti-nuclear autoantibodies. Furthermore, our results also underscore the importance of including cre-only controls in studies using the cre-lox system. PMID:26385218

Dual roles of TRF1 in tethering telomeres to the nuclear envelope and protecting them from fusion during meiosis.

Science.gov (United States)

Wang, Lina; Tu, Zhaowei; Liu, Chao; Liu, Hongbin; Kaldis, Philipp; Chen, Zijiang; Li, Wei

2018-01-08

Telomeres integrity is indispensable for chromosomal stability by preventing chromosome erosion and end-to-end fusions. During meiosis, telomeres attach to the inner nuclear envelope and cluster into a highly crowded microenvironment at the bouquet stage, which requires specific mechanisms to protect the telomeres from fusion. Here, we demonstrate that germ cell-specific knockout of a shelterin complex subunit, Trf1, results in arrest of spermatocytes at two different stages. The obliterated telomere-nuclear envelope attachment in Trf1-deficient spermatocytes impairs homologue synapsis and recombination, resulting in a pachytene-like arrest, while the meiotic division arrest might stem from chromosome end-to-end fusion due to the failure of recruiting meiosis specific telomere associated proteins. Further investigations uncovered that TRF1 could directly interact with Speedy A, and Speedy A might work as a scaffold protein to further recruit Cdk2, thus protecting telomeres from fusion at this stage. Together, our results reveal a novel mechanism of TRF1, Speedy A, and Cdk2 in protecting telomere from fusion in a highly crowded microenvironment during meiosis.

The nuclear envelopathies and human diseases

Directory of Open Access Journals (Sweden)

Jeang Kuan-Teh

2009-10-01

Full Text Available Abstract The nuclear envelope (NE consists of two membrane layers that segregate the nuclear from the cytoplasmic contents. Recent progress in our understanding of nuclear-lamina associated diseases has revealed intriguing connections between the envelope components and nuclear processes. Here, we review the functions of the nuclear envelope in chromosome organization, gene expression, DNA repair and cell cycle progression, and correlate deficiencies in envelope function with human pathologies.

Autoantibodies to Posttranslational Modifications in Rheumatoid Arthritis

Science.gov (United States)

Burska, Agata N.; Hunt, Laura; Strollo, Rocky; Ryan, Brent J.; Vital, Ed; Nissim, Ahuva; Winyard, Paul G.; Emery, Paul; Ponchel, Frederique

2014-01-01

Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential. PMID:24782594

Rheumatic Disease Autoantibodies in Autoimmune Liver Diseases.

Science.gov (United States)

Utiyama, Shirley R R; Zenatti, Katiane B; Nóbrega, Heloisa A J; Soares, Juliana Z C; Skare, Thelma L; Matsubara, Caroline; Muzzilo, Dominique A; Nisihara, Renato M

2016-08-01

Autoimmune liver diseases (ALDs) are known to be associated with systemic autoimmune rheumatic diseases (SARDs) and their autoantibodies. We aimed to study the prevalence of SARDs and related autoantibodies, as well as their prognostic implications in a group of patients with ALDs. This was a cross-sectional study. Sixty patients with ALDs (38.3% with autoimmune hepatitis; 11.7% with primary biliary cirrhosis; 25% with primary sclerosing cholangitis and 25% with overlap syndrome) were studied for the presence of SARDs and their autoantibodies. There was autoimmune rheumatic disease in 20% of the studied sample. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were the commonest (11.6% and 5%, respectively). Antinuclear antibodies (ANAs) were present in 35% of the patients, followed by anti-Ro (20.0%); anti-nucleosome (18.3%); rheumatoid factor (10%) anti-CCP (8.3%); anti-RNP (8.3%); anti-ds-DNA (6.6%); anti-La (3.3%); anti-Sm (3.3%), anti-ribosomal P (3.3%). Anti-Ro (p = 0.0004), anti-La (p = 0.03), anti-RNP (p = 0.04) and anti-Sm (p = 0.03) were commonly found in patients with SARD, but not anti-DNA, anti-nucleosome and anti-ribosomal P. No differences were found in liver function tests regarding to the presence of autoantibodies. There was a high prevalence of SARD and their autoantibodies in ALD patients. Anti-Ro, anti-La, anti-RNP and anti-Sm positivity points to an association with systemic autoimmune rheumatic diseases. The presence of autoantibodies was not related to liver function tests.

Anti-LC1 autoantibodies in patients with chronic hepatitis C virus infection.

Science.gov (United States)

Béland, Kathie; Lapierre, Pascal; Marceau, Gabriel; Alvarez, Fernando

2004-03-01

Various autoantibodies have been reported in patients chronically infected by hepatitis C virus. 2% to 10% of theses patients have anti-liver-kidney microsome type 1 (anti-LKM1) autoantibodies. In type 2 autoimmune hepatitis, anti-LKM1 autoantibodies are frequently associated with anti-liver-cytosol type 1 (anti-LC1) autoantibodies. To determine the prevalence of anti-LC1 autoantibodies in a hepatitis C-positive population and characterize their reactivity. 146 patients suffering from liver diseases, of which 99 were chronically infected by hepatitis C virus, were tested by Western blotting and immunoprecipitation to detect and characterize anti-LC1 autoantibodies. 12% of this hepatitis C population had anti-LC1 autoantibodies. LC1 positivity by Western blotting was 30% of LC1+ sera. Epitopes were found throughout the protein but linear epitopes were situated in the 395-541 amino acid region of formiminotransferase cyclodeaminase. Three putative conformational epitopes were identified by phage display. Anti-LC1 autoantibodies are as prevalent as anti-LKM1 autoantibodies in patients infected with hepatitis C virus and their production is not dependent of anti-LKM1 autoantibodies formation. Autoantibody reactivity against the anti-LC1 antigen is different in hepatitis C than in type 2 autoimmune hepatitis. Anti-LC1 autoantibodies can now be regarded as a serological marker of autoimmunity in chronic hepatitis C infection.

Myositis specific autoantibodies; specificity and clinical applications.

NARCIS (Netherlands)

Hengstman, G.J.D.

2005-01-01

The sera of about half of the patients with myositis contain autoantibodies that are specific for this group of diseases compared to other inflammatory connective tissue disorders. In a recent study we showed that these myositis specific autoantibodies (MSAs) are also specific for myositis as

The Prevalence of Antithyroid Autoantibodies in Normal Korean Population*

Science.gov (United States)

Lee, Myung Shik; Lee, Dong Soo; Han, Jin Suk; Cho, Bo Youn; Koh, Chang Soon; Lee, Munho

1986-01-01

The prevalence of antithyroid autoantibodies and the relationship between the presence of autoantibodies and thyroid functions were studied in 848 apparently normal Korean adults with tanned red cell agglutination technique. Results are summarized as follows: 1) The prevalence of antimicrosimal antibody (MCHA) and antithyroglobulin antibody (TGHA) were 4.4% and 1.9% in 458 males, and 12.4% and 5.0% in 390 females, respectively. Both autoantibodies were more prevalent in female (pantithyroid autoantibody of high titer (⩾1:1002) was related to alteration of thyroid functions suggesting the existence of “subclinical autoimmune thyroiditis” state. PMID:15759373

GPCR-autoantibodies in chronic heart failure.

Science.gov (United States)

Boivin-Jahns, Valerie; Jahns, Roland

2018-06-01

Chronic heart failure (CHF) is a syndrome characterized by shortness of breath, fluid retention, and a progressive reduction in cardiac function. More than 60% of the cases are ischemic in origin (i.e., due to myo-cardial infarction) and about 30% are caused by non-ischemic myocardial damage (i.e., due to genetic or non-genetic causes like myocardial inflammation). Because of alterations in both cellular and humoral immunity patients with non-ischemic CHF often develop abnormal or misled immune responses, including cross-reacting antibodies and/or autoantibodies to various cardiac anti-gens. Non-ischemic myo-cardial damage was found to progress to CHF particularly, when associated (a) with the generation of autoantibodies directed against distinct myocyte membrane proteins critically involved in cardiac function - like G-protein coup-led membrane receptors (GPCRs), or (b) with virus persistence in the myocardium. This article will review current knowledge on the pathophysiological relevance of GPCR-autoreactivity in CHF by giving an overview on the so far available evidence from pre-clinical, clinical and epidemiological studies on the CHF-inducing potential of GPCR-autoantibodies and thereon based novel therapeutic approaches in GPCR autoantibody-associated CHF.

Structural insights into SUN-KASH complexes across the nuclear envelope

Institute of Scientific and Technical Information of China (English)

Wenjia Wang; Zhaocai Zhou; Zhubing Shi; Shi Jiao; Cuicui Chen; Huizhen Wang; Guoguang Liu; Qiang Wang; Yun Zhao; Mark I Greene

2012-01-01

Linker of the nucleoskeleton and the cytoskeleton (LINC) complexes are composed of SUN and KASH domaincontaining proteins and bridge the inner and outer membranes of the nuclear envelope.LINC complexes play critical roles in nuclear positioning,cell polarization and cellular stiffness.Previously,we reported the homotrimeric structure of human SUN2.We have now determined the crystal structure of the human SUN2-KASH complex.In the complex structure,the SUN domain homotrimer binds to three independent "hook"-like KASH peptides.The overall conformation of the SUN domain in the complex closely resembles the SUN domain in its apo state.A major conformational change involves the AA'-loop of KASH-bound SUN domain,which rearranges to form a mini β-sheet that interacts with the KASH peptide.The PPPT motif of the KASH domain fits tightly into a hydrophobic pocket on the homotrimeric interface of the SUN domain,which we termed the BI-pocket.Moreover,two adjacent protomers of the SUN domain homotrimer sandwich the KASH domain by hydrophobic interaction and hydrogen bonding.Mutations of these binding sites disrupt or reduce the association between the SUN and KASH domains in vitro.In addition,transfection of wild-type,but not mutant,SUN2 promotes cell migration in Ovcar-3 cells.These results provide a structural model of the LINC complex,which is essential for additional study of the physical and functional coupling between the cytoplasm and the nucleoplasm.

The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients.

Science.gov (United States)

Sosenko, Jay M; Skyler, Jay S; Palmer, Jerry P; Krischer, Jeffrey P; Yu, Liping; Mahon, Jeffrey; Beam, Craig A; Boulware, David C; Rafkin, Lisa; Schatz, Desmond; Eisenbarth, George

2013-09-01

We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D). TrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity. The ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23-3.31], P < 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78-0.90] at 2 years, 0.81 [0.74-0.89] at 3 years, P < 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P < 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88-0.98] at 2 years, 0.91 [0.83-0.99] at 3 years) than either the DPTRS or the ABRS alone (P ≤ 0.01 for all comparisons). These findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D.

Rapid induction of autoantibodies during ARDS and septic shock

Directory of Open Access Journals (Sweden)

Meduri G Umberto

2010-10-01

Full Text Available Abstract Background Little is known about the induction of humoral responses directed against human autoantigens during acute inflammation. We utilized a highly sensitive antibody profiling technology to study autoantibodies in patients with acute respiratory distress syndrome (ARDS and severe sepsis, conditions characterized by intensive immune activation leading to multiple organ dysfunction. Methods Using Luciferase Immunoprecipitation Systems (LIPS, a cohort of control, ARDS and sepsis patients were tested for antibodies to a panel of autoantigens. Autoantibody titers greater than the mean plus 3 SD of the 24 control samples were used to identify seropositive samples. Available longitudinal samples from different seropositive ARDS and sepsis patient samples, starting from within the first two days after admission to the intensive care, were then analyzed for changes in autoantibody over time. Results From screening patient plasma, 57% of ARDS and 46% of septic patients without ARDS demonstrated at least one statistically significant elevated autoantibody compared to the controls. Frequent high titer antibodies were detected against a spectrum of autoantigens including potassium channel regulator, gastric ATPase, glutamic decarboxylase-65 and several cytokines. Analysis of serial samples revealed that several seropositive patients had low autoantibodies at early time points that often rose precipitously and peaked between days 7-14. Further, the use of therapeutic doses of corticosteroids did not diminish the rise in autoantibody titers. In some cases, the patient autoantibody titers remained elevated through the last serum sample collected. Conclusion The rapid induction of autoantibodies in ARDS and severe sepsis suggests that ongoing systemic inflammation and associated tissue destruction mediate the break in tolerance against these self proteins.

The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes.

Science.gov (United States)

Bingley, Polly J; Boulware, David C; Krischer, Jeffrey P

2016-03-01

Autoantibodies directed at single islet autoantigens are associated with lower overall risk of type 1 diabetes than multiple autoantibodies, but individuals with one autoantibody may progress to higher risk categories. We examined the characteristics of this progression in relatives followed prospectively in the TrialNet Pathway to Prevention. The study population comprised 983 relatives who were single autoantibody positive with normal baseline glucose tolerance (median age 16.2 years). Samples were screened for antibodies to GAD, insulinoma-associated antigen 2 (IA-2) and insulin, and all positive samples tested for antibodies to zinc transporter 8 and islet cell antibodies. Antibodies to at least one additional islet autoantigen appeared in 118 of 983 relatives (overall 5 year risk 22%, 95% CI [17.9, 26.1]). At baseline, antibodies to GAD alone (68%) were more frequent than antibodies to insulin (26%) or IA-2 (6%), but all were associated with a similar risk of developing additional autoantibodies. Risk was associated with younger age (p = 0.002) and HLA class II genotype, but was similar in high and intermediate genetic risk groups (p = 0.65). Relatives who became multiple autoantibody positive during the follow-up had increased risk of developing diabetes comparable with the risk in relatives with multiple autoantibodies at study entry. Progression of islet autoimmunity in single autoantibody positive relatives in late childhood/adult life is associated with a predominance of autoantibodies to GAD and a distinct HLA risk profile. This heterogeneity in type 1 diabetes autoimmunity has potentially important implications for disease prevention.

Extrahepatic Manifestations and Autoantibodies in Patients with Hepatitis C Virus Infection

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Takashi Himoto

2012-01-01

Full Text Available Patients with chronic hepatitis C virus (HCV infection frequently have many extrahepatic manifestations, as persistent HCV infection often triggers lymphoproliferative disorders and metabolic abnormalities. These manifestations primarily include autoimmune disorders such as cryoglobulinemia, Sjögren’s syndrome, and autoimmune thyroid disorders. It has been well established that chronic HCV infection plays important roles in the production of non-organ-specific autoantibodies, including antinuclear antibodies and smooth muscle antibodies, and organ-specific autoantibodies such as thyroid autoantibodies. However, the clinical significance of autoantibodies associated with the extrahepatic manifestations caused by HCV infection has not been fully recognized. In this paper, we mainly focus on the relationship between extrahepatic manifestations and the emergence of autoantibodies in patients with HCV infection and discuss the clinical relevance of the autoantibodies in the extrahepatic disorders.

Expression of Leukemia-Associated Nup98 Fusion Proteins Generates an Aberrant Nuclear Envelope Phenotype.

Science.gov (United States)

Fahrenkrog, Birthe; Martinelli, Valérie; Nilles, Nadine; Fruhmann, Gernot; Chatel, Guillaume; Juge, Sabine; Sauder, Ursula; Di Giacomo, Danika; Mecucci, Cristina; Schwaller, Jürg

2016-01-01

Chromosomal translocations involving the nucleoporin NUP98 have been described in several hematopoietic malignancies, in particular acute myeloid leukemia (AML). In the resulting chimeric proteins, Nup98's N-terminal region is fused to the C-terminal region of about 30 different partners, including homeodomain (HD) transcription factors. While transcriptional targets of distinct Nup98 chimeras related to immortalization are relatively well described, little is known about other potential cellular effects of these fusion proteins. By comparing the sub-nuclear localization of a large number of Nup98 fusions with HD and non-HD partners throughout the cell cycle we found that while all Nup98 chimeras were nuclear during interphase, only Nup98-HD fusion proteins exhibited a characteristic speckled appearance. During mitosis, only Nup98-HD fusions were concentrated on chromosomes. Despite the difference in localization, all tested Nup98 chimera provoked morphological alterations in the nuclear envelope (NE), in particular affecting the nuclear lamina and the lamina-associated polypeptide 2α (LAP2α). Importantly, such aberrations were not only observed in transiently transfected HeLa cells but also in mouse bone marrow cells immortalized by Nup98 fusions and in cells derived from leukemia patients harboring Nup98 fusions. Our findings unravel Nup98 fusion-associated NE alterations that may contribute to leukemogenesis.

The Use of Electrochemiluminescence Assays to Predict Autoantibody and Glycemic Progression Toward Type 1 Diabetes in Individuals with Single Autoantibodies.

Science.gov (United States)

Sosenko, Jay M; Yu, Liping; Skyler, Jay S; Krischer, Jeffrey P; Gottlieb, Peter A; Boulware, David; Miao, Dongmei; Palmer, Jerry P; Steck, Andrea K

2017-03-01

Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies. TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL + ) were compared with those ECL negative (ECL - ) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D. The progression to multiple autoantibodies was significantly higher for those GADA/ECL + (n = 107) than those GADA/ECL - (n = 78) (P = 0.001) and for those mIAA/ECL + (n = 24) than those mIAA/ECL - (n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58-7.39; P < 0.01) for GADA and 8.15 (3.02-22.00; P < 0.001) for mIAA. GADA/ECL + and mIAA/ECL + participants had significantly higher PS6M values than their ECL - counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL + , 14% progressed to T1D; of those mIAA/ECL + , 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL - progressed to T1D (median follow-up: 5 years). ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL + are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL - are at very low risk.

Autoantibody profiling on human proteome microarray for biomarker discovery in cerebrospinal fluid and sera of neuropsychiatric lupus.

Directory of Open Access Journals (Sweden)

Chaojun Hu

Full Text Available Autoantibodies in cerebrospinal fluid (CSF from patients with neuropsychiatric systemic lupus erythematosus (NPSLE may be potential biomarkers for prediction, diagnosis, or prognosis of NPSLE. We used a human proteome microarray with~17,000 unique full-length human proteins to investigate autoantibodies associated with NPSLE. Twenty-nine CSF specimens from 12 NPSLE, 7 non-NPSLE, and 10 control (non-systemic lupus erythematosuspatients were screened for NPSLE-associated autoantibodies with proteome microarrays. A focused autoantigen microarray of candidate NPSLE autoantigens was applied to profile a larger cohort of CSF with patient-matched sera. We identified 137 autoantigens associated with NPSLE. Ingenuity Pathway Analysis revealed that these autoantigens were enriched for functions involved in neurological diseases (score = 43.Anti-proliferating cell nuclear antigen (PCNA was found in the CSF of NPSLE and non-NPSLE patients. The positive rates of 4 autoantibodies in CSF specimens were significantly different between the SLE (i.e., NPSLE and non-NPSLE and control groups: anti-ribosomal protein RPLP0, anti-RPLP1, anti-RPLP2, and anti-TROVE2 (also known as anti-Ro/SS-A. The positive rate for anti-SS-A associated with NPSLE was higher than that for non-NPSLE (31.11% cf. 10.71%; P = 0.045.Further analysis showed that anti-SS-A in CSF specimens was related to neuropsychiatric syndromes of the central nervous system in SLE (P = 0.009. Analysis with Spearman's rank correlation coefficient indicated that the titers of anti-RPLP2 and anti-SS-A in paired CSF and serum specimens significantly correlated. Human proteome microarrays offer a powerful platform to discover novel autoantibodies in CSF samples. Anti-SS-A autoantibodies may be potential CSF markers for NPSLE.

Induced wave propagation from a vibrating containment envelope

International Nuclear Information System (INIS)

Stout, R.B.; Thigpen, L.; Rambo, J.T.

1985-09-01

Low frequency wave forms are observed in the particle velocity measurements around the cavity and containment envelope formed by an underground nuclear test. The vibration solution for a spherical shell is used to formulate a model for the low frequency wave that propagates outward from this region. In this model the containment envelope is the zone of material that is crushed by the compressive shock wave of the nuclear explosion. The containment envelope is approximated by a spherical shell of material. The material in the spherical shell is densified and is given a relatively high kinetic energy density because of the high compressive stress and particle velocity of the shock wave. After the shock wave has propagated through the spherical shell, the spherical shell vibrates in order to dissipate the kinetic energy acquired from the shock wave. Based on the model, the frequency of vibration depends on the dimensions and material properties of the spherical shell. The model can also be applied in an inverse mode to obtain global estimates of averaged materials properties. This requires using experimental data and semi-empirical relationships involving the material properties. A particular case of estimating a value for shear strength is described. Finally, the oscillation time period of the lowest frequency from five nuclear tests is correlated with the energy of the explosion. The correlation provides another diagnostic to estimate the energy of a nuclear explosion. Also, the longest oscillation time period measurement provides additional experimental data that can be used to assess and validate various computer models. 11 refs., 2 figs

Immunospecific red cell binding of iodine 125-labeled immunoglobulin G erythrocyte autoantibodies

International Nuclear Information System (INIS)

Masouredis, S.P.; Branks, M.J.; Garratty, G.; Victoria, E.J.

1987-01-01

The primary interaction of autoantibodies with red cells has been studied by using labeled autoantibodies. Immunoglobulin G red cell autoantibodies obtained from IgG antiglobulin-positive normal blood donors were labeled with radioactive iodine and compared with alloanti-D with respect to their properties and binding behavior. Iodine 125 -labeled IgG autoantibody migrated as a single homogeneous peak with the same relative mobility as human IgG on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The isoelectric focusing pattern of labeled autoantibodies varied from donor to donor but was similar to that of alloanti-D, consisting of multiple IgG populations with isoelectric points in the neutral to alkaline range. 125 I-autoantibody bound to all human red cells of common Rh phenotypes. Evidence for immunospecific antibody binding of the labeled autoantibody was based on variation in equilibrium binding to nonhuman and human red cells of common and rare phenotypes, enhanced binding after red cell protease modification, antiglobulin reactivity of cell-bound IgG comparable to that of cell-bound anti-D, and saturation binding in autoantibody excess. Scatchard analysis of two 125 I-autoantibody preparations yielded site numbers of 41,500 and 53,300 with equilibrium constants of 3.7 and 2.1 X 10(8) L X mol-1. Dog, rabbit, rhesus monkey, and baboon red cells were antigen(s) negative by quantitative adsorption studies adsorbing less than 3% of the labeled autoantibody. Reduced ability of rare human D--red blood cells to adsorb the autoantibody and identification of donor autoantibodies that bind to Rh null red blood cells indicated that eluates contained multiple antibody populations of complex specificities in contrast to anti-D, which consists of a monospecific antibody population. Another difference is that less than 70% of the autoantibody IgG was adsorbed by maximum binding red blood cells as compared with greater than 85% for alloanti-D

An Lck-cre transgene accelerates autoantibody production and lupus development in (NZB × NZW)F1 mice.

Science.gov (United States)

Nelson, R K; Gould, K A

2016-02-01

Lupus is an autoimmune disease characterized by the development of antinuclear autoantibodies and immune complex-mediated tissue damage. T cells in lupus patients appear to undergo apoptosis at an increased rate, and this enhanced T cell apoptosis has been postulated to contribute to lupus pathogenesis by increasing autoantigen load. However, there is no direct evidence to support this hypothesis. In this study, we show that an Lck-cre transgene, which increases T cell apoptosis as a result of T cell-specific expression of cre recombinase, accelerates the development of autoantibodies and nephritis in lupus-prone (NZB × NZW)F1 mice. Although the enhanced T cell apoptosis in Lck-cre transgenic mice resulted in an overall decrease in the relative abundance of splenic CD4(+) and CD8(+) T cells, the proportion of activated CD4(+) T cells was increased and no significant change was observed in the relative abundance of suppressive T cells. We postulate that the Lck-cre transgene promoted lupus by enhancing T cell apoptosis, which, in conjunction with the impaired clearance of apoptotic cells in lupus-prone mice, increased the nuclear antigen load and accelerated the development of anti-nuclear autoantibodies. Furthermore, our results also underscore the importance of including cre-only controls in studies using the cre-lox system. © The Author(s) 2015.

The determination of thyroid hormone autoantibodies and its clinical significance

International Nuclear Information System (INIS)

Zhu Li; Zhao Zhiying; Wang Zhenghua Lian Xiaolan; Guo Zhisheng; Bai Yao; Su Wei

2003-01-01

To study the reasons of falsely high concentrations of serum thyroid hormone and the way of determination of thyroid hormone autoantibodies, the experiments of thyroid hormone autoantibodies binding reaction, dilution testing, calibration curves and their check analysis were performed. Results showed that the combination of the autoantibodies with 125 I-T 3 or 125 I-T 4 was specific, the binding rates were 58.77% and 49.05% respectively and 7-12 times higher than control groups. The radioactive peaks of the autoantibodies and rabbit anti-T 3 or T 4 antibody appeared on the same position in radio electrophoretogram analysis and these antibodies were considered as IgG. The important reasons of falsely high concentrations of serum thyroid hormone are the presence of anti-thyroid hormone antibodies. Determination of thyroid hormone autoantibodies significantly benefits diagnosis and treatment of thyroid disease

Chronic malaria revealed by a new fluorescence pattern on the antinuclear autoantibodies test.

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Benjamin Hommel

Full Text Available BACKGROUND: Several clinical forms of malaria such as chronic carriage, gestational malaria or hyper-reactive malarial splenomegaly may follow a cryptic evolution with afebrile chronic fatigue sometimes accompanied by anemia and/or splenomegaly. Conventional parasitological tests are often negative or not performed, and severe complications may occur. Extensive explorations of these conditions often include the search for antinuclear autoantibodies (ANA. METHODS: We analysed fluorescence patterns in the ANA test in patients with either chronic cryptic or acute symptomatic malaria, then conducted a one-year prospective study at a single hospital on all available sera drawn for ANA detections. We then identified autoantibodies differentially expressed in malaria patients and in controls using human protein microarray. RESULTS: We uncovered and defined a new, malaria-related, nucleo-cytoplasmic ANA pattern displaying the specific association of a nuclear speckled pattern with diffuse cytoplasmic perinuclearly-enhanced fluorescence. In the one-year prospective analysis, 79% of sera displaying this new nucleo-cytoplasmic fluorescence were from patients with malaria. This specific pattern, not seen in other parasitic diseases, allowed a timely reorientation of the diagnosis toward malaria. To assess if the autoantibody immune response was due to autoreactivity or molecular mimicry we isolated 42 autoantigens, targets of malarial autoantibodies. BLAST analysis indicated that 23 of recognized autoantigens were homologous to plasmodial proteins suggesting autoimmune responses directly driven by the plasmodial infection. CONCLUSION: In patients with malaria in whom parasitological tests have not been performed recognition of this new, malaria-related fluorescence pattern on the ANA test is highly suggestive of the diagnosis and triggers immediate, easy confirmation and adapted therapy.

Myositis-specific autoantibodies: an important tool to support diagnosis of myositis.

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Betteridge, Z; McHugh, N

2016-07-01

The idiopathic inflammatory myopathies are characterized by muscle weakness, skin disease and internal organ involvement. Autoimmunity is known to have a role in myositis pathogenesis, and myositis-specific autoantibodies, targeting important intracellular proteins, are regarded as key biomarkers aiding in the diagnosis of patients. In recent years, a number of novel myositis autoantibodies including anti-TIF1, anti-NXP2, anti-MDA5, anti-SAE, anti-HMGCR and anti-cN1A have been identified in both adult and juvenile patients. These autoantibodies correlate with distinct clinical manifestations and importantly are found in inclusion body, statin-induced, clinically amyopathic and juvenile groups of myositis patients, previously believed to be mainly autoantibody negative. In this review, we will describe the main myositis-specific and myositis-associated autoantibodies and their frequencies and clinical associations across different ages and ethnic groups. We will also discuss preliminary studies investigating correlations between specific myositis autoantibody titres and clinical markers of disease course, collectively demonstrating the utility of myositis autoantibodies as both diagnostic and prognostic markers of disease. © 2015 The Association for the Publication of the Journal of Internal Medicine.

Autoantibodies in SLE: Specificities, Isotypes and Receptors

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Barbara Dema

2016-01-01

Full Text Available Systemic Lupus Erythematosus (SLE is characterized by a wide spectrum of auto-antibodies which recognize several cellular components. The production of these self-reactive antibodies fluctuates during the course of the disease and the involvement of different antibody-secreting cell populations are considered highly relevant for the disease pathogenesis. These cells are developed and stimulated through different ways leading to the secretion of a variety of isotypes, affinities and idiotypes. Each of them has a particular mechanism of action binding to a specific antigen and recognized by distinct receptors. The effector responses triggered lead to a chronic tissue inflammation. DsDNA autoantibodies are the most studied as well as the first in being characterized for its pathogenic role in Lupus nephritis. However, others are of growing interest since they have been associated with other organ-specific damage, such as anti-NMDAR antibodies in neuropsychiatric clinical manifestations or anti-β2GP1 antibodies in vascular symptomatology. In this review, we describe the different auto-antibodies reported to be involved in SLE. How autoantibody isotypes and affinity-binding to their antigen might result in different pathogenic responses is also discussed.

Binding of two desmin derivatives to the plasma membrane and the nuclear envelope of avian erythrocytes: evidence for a conserved site-specificity in intermediate filament-membrane interactions

International Nuclear Information System (INIS)

Georgatos, S.D.; Weber, K.; Geisler, N.; Blobel, G.

1987-01-01

Using solution binding assays, the authors found that a 45-kDa fragment of 125 I-labelled desmin, lacking 67 residues from the N terminus, could specifically associate with avian erythrocyte nuclear envelopes but not with plasma membranes from the same cells. It was also observed that a 50-kDa desmin peptide, missing 27 C-terminal residues, retained the ability to bind to both membrane preparations. Displacement experiments with an excess of purified vimentin suggested that the two desmin derivatives were interacting with a previously identified vimentin receptor at the nuclear envelope, the protein lamin B. Additional analysis by affinity chromatography confirmed this conclusion. Employing an overlay assay, they demonstrated that the 50-kDa fragment, but not the 45-kDa desmin peptide, was capable of interacting with the plasma membrane polypeptide ankyrin (a known vimentin attachment site), as was intact vimentin. Conversely, the nuclear envelope protein lamin B was recognized by both fragments but not by a chymotryptic peptide composed solely of the helical rod domain of desmin. These data imply that the lamin B-binding site on desmin resides within the 21 residues following its helical rod domain, whereas the ankyrin-associating region is localized within its N-terminal head domain, exactly as in the case of vimentin

GPIHBP1 autoantibodies in a patient with unexplained chylomicronemia

DEFF Research Database (Denmark)

Hu, Xuchen; Dallinga-Thie, Geesje M.; Hovingh, G. Kees

2017-01-01

into the frequency of the GPIHBP1 autoantibody syndrome in patients with unexplained chylomicronemia. Methods We used enzyme-linked immunosorbent assays to screen for GPIHBP1 autoantibodies in 33 patients with unexplained chylomicronemia and then used Western blots and immunocytochemistry studies to characterize....... The patient had no history of autoimmune disease, but his plasma was positive for antinuclear antibodies. Conclusions One of 33 patients with unexplained chylomicronemia had the GPIHBP1 autoantibody syndrome. Additional studies in large lipid clinics will be helpful for better defining the frequency...

Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies.

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Heneberg, Petr; Malá, Milena; Yorifuji, Tohru; Gat-Yablonski, Galia; Lebenthal, Yael; Tajima, Toshihiro; Nogaroto, Viviane; Rypáčková, Blanka; Kocková, Lucie; Urbanová, Jana; Anděl, Michal

2015-01-01

The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies. We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil). The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity. MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders. © 2015 S. Karger AG, Basel.

21 CFR 866.5870 - Thyroid autoantibody immunological test system.

Science.gov (United States)

2010-04-01

... the thyroid autoantibodies (antibodies produced against the body's own tissues). Measurement of thyroid autoantibodies may aid in the diagnosis of certain thyroid disorders, such as Hashimoto's disease (chronic lymphocytic thyroiditis), nontoxic goiter (enlargement of thyroid gland), Grave's disease...

Measurement of anti- acetylcholine receptor auto-antibodies in ...

African Journals Online (AJOL)

auto-antibodies in myasthenia gravis. K. J. Steenkamp, W. Duim, M. s. Myer,. S. C. K. Malfeld, R. Anderson. Two different acetylcholine receptor (AChR) preparations derived from ... the detection of AChR auto-antibodies in serum specimens from 20 ... 4°C. Thereafter, 1 ml of washing solution (phosphate- buffered saline ...

The prevalence of autoantibody and its relationship with genotypes of hepatitis C virus in patients with chronic hepatitis C virus infection.

Science.gov (United States)

Kirdar, Sevİn; Sener, Asli Gamze; Cengİz, Merve; Aydin, Nerİman

2016-11-01

The prevalence of autoantibody in the patients with chronic hepatitis C infection, and the relationship between the autoantibodies and HCV genotypes were investigated in this study. One hundred and eight anti-HCV positive and 86 anti-HCV negative patients were included in the study. Anti-HCV were studied by enzyme immunassay (EIA). HCV RNA was determined by real time polymerase chain reaction (PCR) and HCV genotypes were determined by a reverse-line blot hybridization. Anti-nuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA), Anti-mitochondrial antibodies (AMA), liver kidney microsomal antibodies (LKM) were detected by indirect immunofluorescence assay. Among patients, 13 (12.03%) of 108 were positive for at least one autoantibody. The positivity was not observed in control group. The most prevalent autoantibody in anti-HCV positive group was ANA. ANA was positive in six HCV patients with genotype 1. In HCV patients with genotype 1, the frequencies of ANA, ASMA, AMA and LKM1 were six, two, three and one, respectively. In HCV patients with genotype 2, ANA was positive one patient and ASMA, AMA and LKM1 were not detected in HCV patients with genotype 2. In conclusion, the autoantibodies in patients with chronic hepatitis C in the study were low as compared to those reported in previous studies. © 2016 APMIS. Published by John Wiley & Sons Ltd.

The Malleable Nature of the Budding Yeast Nuclear Envelope: Flares, Fusion, and Fenestrations.

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Meseroll, Rebecca A; Cohen-Fix, Orna

2016-11-01

In eukaryotes, the nuclear envelope (NE) physically separates nuclear components and activities from rest of the cell. The NE also provides rigidity to the nucleus and contributes to chromosome organization. At the same time, the NE is highly dynamic; it must change shape and rearrange its components during development and throughout the cell cycle, and its morphology can be altered in response to mutation and disease. Here we focus on the NE of budding yeast, Saccharomyces cerevisiae, which has several unique features: it remains intact throughout the cell cycle, expands symmetrically during interphase, elongates during mitosis and, expands asymmetrically during mitotic delay. Moreover, its NE is safely breached during mating and when large structures, such as nuclear pore complexes and the spindle pole body, are embedded into its double membrane. The budding yeast NE lacks lamins and yet the nucleus is capable of maintaining a spherical shape throughout interphase. Despite these eccentricities, studies of the budding yeast NE have uncovered interesting, and likely conserved, processes that contribute to NE dynamics. In particular, we discuss the processes that drive and enable NE expansion and the dramatic changes in the NE that lead to extensions and fenestrations. J. Cell. Physiol. 231: 2353-2360, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Significance of myositis autoantibody in patients with idiopathic interstitial lung disease.

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Song, Ju Sun; Hwang, Jiwon; Cha, Hoon-Suk; Jeong, Byeong-Ho; Suh, Gee Young; Chung, Man Pyo; Kang, Eun-Suk

2015-05-01

Some patients with interstitial lung disease (ILD) related to connective tissue disease (CTD) have a delayed diagnosis of the underlying CTD when the ILD is categorized as idiopathic. In this study, we evaluated the frequency of myositis autoantibodies in patients diagnosed with idiopathic ILD and investigated the clinical significance stemming from the presence of the antibodies. A total 32 patients diagnosed with idiopathic ILD were enrolled in this study. We analyzed a panel of 11 myositis autoantibody specificities in the patients using a line blot immunoassay. Then, we divided them into myositis autoantibody-positive and -negative groups and compared the clinical features and laboratory data between the two groups. Of the 32 idiopathic ILD patients, 12 patients had myositis autoantibodies encompassing 9 specificities, except for anti-Mi-2 and anti-PM-Scl 100 (12/32, 38%). Anti-synthetase autoantibodies including Jo-1, EJ, OJ, PL-7, and PL-12 were present in 7 patients (7/32, 22%). The group with myositis autoantibodies presented more frequently with the symptom of mechanic's hand and showed abnormal pulmonary function test results with low forced vital capacity, diffusing capacity for carbon monoxide, total lung capacity, and high lactate dehydrogenase values in blood when compared with the group without myositis antibodies. We strongly suggest that patients undergo an evaluation of myositis autoantibodies, if they are diagnosed with idiopathic ILD in the presence of clinical characteristics including mechanic's hand, arthralgia, and autoantibodies which are insufficient to make a diagnosis of a specific CTD category.

Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies

International Nuclear Information System (INIS)

Stagnaro-Green, A.; Roman, S.H.; Cobin, R.H.; El-Harazy, E.; Alvarez-Marfany, M.; Davies, T.F.

1990-01-01

The authors screened 552 women who presented to their obstetrician in the first trimester of pregnancy using highly sensitive enzyme-linked immunosorbent assays for the presence of thyroglobulin and thyroidperoxidase autoantibodies and found an incidence of positivity of 19.6%. The tendency to secrete detectable levels of thyroid autoantibodies was significantly correlated with an increased rate of miscarriage. Thyroid autoantibody-positive women miscarried at a rate of 17%, compared with 8.4% for the autoantibody-negative women. Individual levels of thyroglobulin and thyroidperoxidase autoantibodies were similarly related to this increased miscarriage rate, with no evidence of autoantibody specificity in the relationship. Furthermore, the increase in miscarriages could not be explained by differences in thyroid hormone levels, the presence of cardiolipin autoantibodies, maternal age, gestational age at the time of maternal entry into the study, or previous obstetric history. They conclude that thyroid autoantibodies are an independent marker of at-risk pregnancy

A-type and B-type lamins initiate layer assembly at distinct areas of the nuclear envelope in living cells

Energy Technology Data Exchange (ETDEWEB)

Furukawa, Kazuhiro, E-mail: furukawa@chem.sc.niigata-u.ac.jp [Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181 (Japan); Ishida, Kazuya; Tsunoyama, Taka-aki; Toda, Suguru; Osoda, Shinichi; Horigome, Tsuneyoshi [Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181 (Japan); Fisher, Paul A. [Department of Pharmacological Sciences, School of Medicine, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651 (United States); Sugiyama, Shin [Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602 (Japan)

2009-04-15

To investigate nuclear lamina re-assembly in vivo, Drosophila A-type and B-type lamins were artificially expressed in Drosophila lamin Dm{sub 0}null mutant brain cells. Both exogenous lamin C (A-type) and Dm{sub 0} (B-type) formed sub-layers at the nuclear periphery, and efficiently reverted the abnormal clustering of the NPC. Lamin C initially appeared where NPCs were clustered, and subsequently extended along the nuclear periphery accompanied by the recovery of the regular distribution of NPCs. In contrast, lamin Dm{sub 0} did not show association with the clustered NPCs during lamina formation and NPC spacing recovered only after completion of a closed lamin Dm{sub 0} layer. Further, when lamin Dm{sub 0} and C were both expressed, they did not co-polymerize, initiating layer formation in separate regions. Thus, A and B-type lamins reveal differing properties during lamina assembly, with A-type having the primary role in organizing NPC distribution. This previously unknown complexity in the assembly of the nuclear lamina could be the basis for intricate nuclear envelope functions.

Anti-IL-1alpha autoantibodies in early rheumatoid arthritis

DEFF Research Database (Denmark)

Forslind, K; Svensson, Birte; Svenson, M

2001-01-01

To investigate the potential predictive value of autoantibodies against IL1-alpha (anti-IL-1alpha) in patients with early rheumatoid arthritis (RA).......To investigate the potential predictive value of autoantibodies against IL1-alpha (anti-IL-1alpha) in patients with early rheumatoid arthritis (RA)....

Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis.

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Michael Donahoe

Full Text Available Severe acute exacerbations (AE of idiopathic pulmonary fibrosis (IPF are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients.Eleven (11 critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG. Plasma anti-epithelial (HEp-2 autoantibodies and matrix metalloproteinase-7 (MMP7 were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial.Nine (9 trial subjects (82% had improvements of pulmonary gas exchange after treatment, compared to one (5% historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications.This pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE

Early Site Permit Demonstration Program: Plant parameters envelope report

International Nuclear Information System (INIS)

1993-03-01

The Early Site Permit (ESP) Demonstration Program is the nuclear industry's initiative for piloting the early resolution of siting-related issues before the detailed design proceedings of the combined operating license review. The ESP Demonstration Program consists of three phases. The plant parameters envelopes task is part of Phase 1, which addresses the generic review of applicable federal regulations and develops criteria for safety and environmental assessment of potential sites. The plant parameters envelopes identify parameters that characterize the interface between an ALWR design and a potential site, and quantify the interface through values selected from the Utility Requirements Documents, vendor design information, or engineering assessments. When augmented with site-specific information, the plant parameters envelopes provide sufficient information to allow ESPs to be granted based on individual ALWR design information or enveloping design information for the evolutionary, passive, or generic ALWR plants. This document is expected to become a living document when used by future applicants

P53 autoantibodies in 1006 patients followed up for breast cancer

International Nuclear Information System (INIS)

Metcalfe, Su; Wheeler, Terence K; Picken, Sheila; Negus, Susanne; Jo Milner, A

2000-01-01

Serial plasma samples from 1006 patients with breast cancer revealed: (i) no correlation of p53 autoantibody status with disease status at the time of sample collection, or with menopausal status at time of primary diagnosis of breast cancer; (ii) 155 out of 1006 (15%) of patients were positive for p53 autoantibodies, and these patients tended to have a persistent autoantibody status throughout follow up, irrespective of disease behaviour; and (iii) where a negative autoantibody status was found at primary diagnosis of breast cancer, this negative status persisted throughout follow up, irrespective of later disease behaviour. We conclude that screening for p53 autoantibody status is not informative on residual tumour activity nor on therapeutic responsiveness. Dysfunction of the tumour-suppressor protein, p53, may be due to either mutational or epigenetic factors, each of which may lead to accumulation of cytoplasmic p53. Abnormal accumulation of p53 in breast cancer tissue is predictive of poor prognosis [1,2]. Humoral studies [3,4] have shown that cancer patients may develop immunity to abnormally expressed p53, as revealed by p53 autoantibodies in the blood. Again, prognostic correlates have been noted, with presence of circulating p53 autoantibodies at diagnosis of breast cancer being associated with reduced overall survival [5,6] and with poor prognostic factors such as high histological grade and the absence of hormone receptors [5,7,8]. Little is known of the potential value of p53 autoantibody in follow up of cancer. In lung cancer there is evidence that autoantibodies to p53 may provide a useful tool to monitor response to therapy [9,10], whereas serial measurements of autoantibodies to p53 in 40 patients with advanced ovarian cancer were not found to be clinically useful [11]. In breast cancer some 30% of node-negative patients will relapse within 5 years, but there is no current means to predict those who are at risk. We performed the present study to

Nesprin-1α-Dependent Microtubule Nucleation from the Nuclear Envelope via Akap450 Is Necessary for Nuclear Positioning in Muscle Cells.

Science.gov (United States)

Gimpel, Petra; Lee, Yin Loon; Sobota, Radoslaw M; Calvi, Alessandra; Koullourou, Victoria; Patel, Rutti; Mamchaoui, Kamel; Nédélec, François; Shackleton, Sue; Schmoranzer, Jan; Burke, Brian; Cadot, Bruno; Gomes, Edgar R

2017-10-09

The nucleus is the main microtubule-organizing center (MTOC) in muscle cells due to the accumulation of centrosomal proteins and microtubule (MT) nucleation activity at the nuclear envelope (NE) [1-4]. The relocalization of centrosomal proteins, including Pericentrin, Pcm1, and γ-tubulin, depends on Nesprin-1, an outer nuclear membrane (ONM) protein that connects the nucleus to the cytoskeleton via its N-terminal region [5-7]. Nesprins are also involved in the recruitment of kinesin to the NE and play a role in nuclear positioning in skeletal muscle cells [8-12]. However, a function for MT nucleation from the NE in nuclear positioning has not been established. Using the proximity-dependent biotin identification (BioID) method [13, 14], we found several centrosomal proteins, including Akap450, Pcm1, and Pericentrin, whose association with Nesprin-1α is increased in differentiated myotubes. We show that Nesprin-1α recruits Akap450 to the NE independently of kinesin and that Akap450, but not other centrosomal proteins, is required for MT nucleation from the NE. Furthermore, we demonstrate that this mechanism is disrupted in congenital muscular dystrophy patient myotubes carrying a nonsense mutation within the SYNE1 gene (23560 G>T) encoding Nesprin-1 [15, 16]. Finally, using computer simulation and cell culture systems, we provide evidence for a role of MT nucleation from the NE on nuclear spreading in myotubes. Our data thus reveal a novel function for Nesprin-1α/Nesprin-1 in nuclear positioning through recruitment of Akap450-mediated MT nucleation activity to the NE. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Autoantibody Profiling in Lupus Patients using Synthetic Nucleic Acids

DEFF Research Database (Denmark)

Klecka, Martin; Thybo, Christina; Macaubas, Claudia

2018-01-01

specificity and reproducibility. Applying the ELISA tests to serological studies of pediatric and adult SLE, we identified novel clinical correlations. We also observed preferential recognition of a specific synthetic antigen by antibodies in SLE sera. We determined the probable basis for this finding using...... computational analyses, providing valuable structural information for future development of DNA antigens. Synthetic nucleic acid molecules offer the opportunity to standardize assays and to dissect antibody-antigen interactions.......Autoantibodies to nuclear components of cells (antinuclear antibodies, ANA), including DNA (a-DNA), are widely used in the diagnosis and subtyping of certain autoimmune diseases, including systemic lupus erythematosus (SLE). Despite clinical use over decades, precise, reproducible measurement of a...

Autoantibodies and their antigens in autoimmune hepatitis.

Science.gov (United States)

Bogdanos, Dimitrios P; Mieli-Vergani, Giorgina; Vergani, Diego

2009-08-01

Autoantibody detection assists in the diagnosis and allows differentiation of autoimmune hepatitis (AIH) type 1 (AIH-1), characterized by antinuclear antibody (ANA) and/or smooth muscle antibody (SMA), and type 2 (AIH-2), distinguished by the presence of antibodies to liver-kidney microsome type 1 (anti-LKM1) and/or antibodies to liver cytosol type 1 (anti-LC1). Detection of atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-soluble liver antigen (SLA) antibodies can act as an additional pointer toward the diagnosis of AIH, particularly in the absence of the conventional autoantibodies. Routine autoantibody testing by indirect immunofluorescence has been recently complemented by molecular assays based on purified or recombinant antigens. Although the AIH-1-specific ANA and SMA targets need better definition, those of anti-LKM1 and anti-LC1 in AIH-2 have been clearly identified; the fine specificity of antibody reactivity and its clinical relevance to disease pathogenesis are the focus of ongoing investigation. This article critically discusses the current knowledge of the diagnostic and clinical significance of AIH-related autoantibody reactivities, focusing on key issues that the physician needs to be aware of to be able to request the appropriate testing and to interpret correctly the laboratory results within the clinical context of the patient. Copyright Thieme Medical Publishers.

SEPT12/SPAG4/LAMINB1 complexes are required for maintaining the integrity of the nuclear envelope in postmeiotic male germ cells.

Science.gov (United States)

Yeh, Chung-Hsin; Kuo, Pao-Lin; Wang, Ya-Yun; Wu, Ying-Yu; Chen, Mei-Feng; Lin, Ding-Yen; Lai, Tsung-Hsuan; Chiang, Han-Sun; Lin, Ying-Hung

2015-01-01

Male infertility affects approximately 50% of all infertile couples. The male-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile or immature sperm, and sperm with structural defects such as those caused by premature chromosomal condensation and DNA damage. Our previous studies based on a knockout mice model indicated that SEPT12 proteins are critical for the terminal morphological formation of sperm. SEPT12 mutations in men result in teratozospermia and oligozospermia. In addition, the spermatozoa exhibit morphological defects of the head and tail, premature chromosomal condensation, and nuclear damage. However, the molecular functions of SEPT12 during spermatogenesis remain unclear. To determine the molecular functions of SEPT12, we applied a yeast 2-hybrid system to identify SEPT12 interactors. Seven proteins that interact with SEPT12 were identified: SEPT family proteins (SEPT4 and SEPT6), nuclear or nuclear membrane proteins (protamine 2, sperm-associated antigen 4, and NDC1 transmembrane nucleoproine), and sperm-related structural proteins (pericentriolar material 1 and obscurin-like 1). Sperm-associated antigen 4 (SPAG4; also known as SUN4) belongs to the SUN family of proteins and acts as a linker protein between nucleoskeleton and cytoskeleton proteins and localizes in the nuclear membrane. We determined that SEPT12 interacts with SPAG4 in a male germ cell line through coimmunoprecipitation. During human spermiogenesis, SEPT12 is colocalized with SPAG4 near the nuclear periphery in round spermatids and in the centrosome region in elongating spermatids. Furthermore, we observed that SEPT12/SPAG4/LAMINB1 formed complexes and were coexpressed in the nuclear periphery of round spermatids. In addition, mutated SEPT12, which was screened from an infertile man, affected the integration of these nuclear envelope complexes through coimmunoprecipitation. This was the first study that suggested that SEPT proteins link to

SEPT12/SPAG4/LAMINB1 complexes are required for maintaining the integrity of the nuclear envelope in postmeiotic male germ cells.

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Chung-Hsin Yeh

Full Text Available Male infertility affects approximately 50% of all infertile couples. The male-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile or immature sperm, and sperm with structural defects such as those caused by premature chromosomal condensation and DNA damage. Our previous studies based on a knockout mice model indicated that SEPT12 proteins are critical for the terminal morphological formation of sperm. SEPT12 mutations in men result in teratozospermia and oligozospermia. In addition, the spermatozoa exhibit morphological defects of the head and tail, premature chromosomal condensation, and nuclear damage. However, the molecular functions of SEPT12 during spermatogenesis remain unclear. To determine the molecular functions of SEPT12, we applied a yeast 2-hybrid system to identify SEPT12 interactors. Seven proteins that interact with SEPT12 were identified: SEPT family proteins (SEPT4 and SEPT6, nuclear or nuclear membrane proteins (protamine 2, sperm-associated antigen 4, and NDC1 transmembrane nucleoproine, and sperm-related structural proteins (pericentriolar material 1 and obscurin-like 1. Sperm-associated antigen 4 (SPAG4; also known as SUN4 belongs to the SUN family of proteins and acts as a linker protein between nucleoskeleton and cytoskeleton proteins and localizes in the nuclear membrane. We determined that SEPT12 interacts with SPAG4 in a male germ cell line through coimmunoprecipitation. During human spermiogenesis, SEPT12 is colocalized with SPAG4 near the nuclear periphery in round spermatids and in the centrosome region in elongating spermatids. Furthermore, we observed that SEPT12/SPAG4/LAMINB1 formed complexes and were coexpressed in the nuclear periphery of round spermatids. In addition, mutated SEPT12, which was screened from an infertile man, affected the integration of these nuclear envelope complexes through coimmunoprecipitation. This was the first study that suggested that SEPT

Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models

OpenAIRE

Yokoi, Fumiaki; Dang, Mai T.; Yang, Guang; Li, JinDong; Doroodchi, Atbin; Zhou, Tong; Li, Yuqing

2011-01-01

Myoclonus-dystonia (M-D) is a movement disorder characterized by myoclonic jerks with dystonia. DYT11 M-D is caused by mutations in SGCE which codes for ε-sarcoglycan. SGCE is maternally imprinted and paternally expressed. Abnormal nuclear envelope has been reported in mouse models of DYT1 generalized torsion dystonia. However, it is not known whether similar alterations occur in DYT11 M-D. We developed a mouse model of DYT11 M-D using paternally-inherited Sgce heterozygous knockout (Sgce KO)...

Autoantibody profile in individuals with chronic hepatitis C.

Science.gov (United States)

Marconcini, Maíra Luciana; Fayad, Leonardo; Shiozawa, Maria Beatriz Cacese; Dantas-Correa, Esther Buzaglo; Lucca Schiavon, Leonardo de; Narciso-Schiavon, Janaína Luz

2013-01-01

Autoantibodies are often produced during infection with chronic hepatitis C virus (HCV), but it remains controversial whether they influence the biochemical profile and histological features of this disease. Therefore, this current study sought to describe these autoantibodies and evaluate their impact on the clinical and histological presentation of hepatitis C. This cross-sectional analytical study assessed patients with HCV (RNA+) from October 2011 to July 2012. This study included 66 patients, with a mean age of 53.2±10.5 years. Of these patients, 60.6% were male, and 54.3% presented with genotype 1. Non-organ-specific autoantibodies (NOSA) were detected in 24% of the patients; of these, 7.6% were anti-mitochondrial antibodies (AMA+), 26.7% were anti-smooth muscle antibodies (SMA+) and 6.8% were liver kidney microsomal type 1 antibodies (LKM1+). With respect to the thyroid autoantibodies, 7.4% were anti-peroxidase (ATPO+) antibodies, and none were anti-thyroglobulin (ATG+) antibodies. Regarding celiac disease autoantibodies, 5.8% were endomysial antibodies (EMA+), and no transglutaminase (TTG+) antibodies were detected. Cryoglobulins were found in 2.1% of patients. When NOSA+ individuals were compared to patients without the presence of NOSAs, they exhibited higher median alkaline phosphatase (0.7 vs. 0.6 xULN; p=0.041), lower median platelet counts (141,500.0 vs. 180,500.0/mm 3 ; p=0.036), lower mean prothrombin activity (72.6±11.5% vs. 82.2±16.0%; p=0.012) and an increased prevalence of significant fibrosis (E≥2) (45.5% vs. 18.2%; p=0.012). There was also a tendency for a greater proportion of NOSA+ cases to have marked periportal activity (APP≥3) (44.5% vs. 15.6%; p=0.087). In addition to the high prevalence of autoantibodies associated with HCV infection, it was observed that NOSA positivity was associated with a more severe histological and biochemical profile of hepatitis C infection.

Autoantibody profile in individuals with chronic hepatitis C

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Maíra Luciana Marconcini

2013-04-01

Full Text Available Introduction Autoantibodies are often produced during infection with chronic hepatitis C virus (HCV, but it remains controversial whether they influence the biochemical profile and histological features of this disease. Therefore, this current study sought to describe these autoantibodies and evaluate their impact on the clinical and histological presentation of hepatitis C. Methods This cross-sectional analytical study assessed patients with HCV (RNA+ from October 2011 to July 2012. Results This study included 66 patients, with a mean age of 53.2±10.5 years. Of these patients, 60.6% were male, and 54.3% presented with genotype 1. Non-organ-specific autoantibodies (NOSA were detected in 24% of the patients; of these, 7.6% were anti-mitochondrial antibodies (AMA+, 26.7% were anti-smooth muscle antibodies (SMA+ and 6.8% were liver kidney microsomal type 1 antibodies (LKM1+. With respect to the thyroid autoantibodies, 7.4% were anti-peroxidase (ATPO+ antibodies, and none were anti-thyroglobulin (ATG+ antibodies. Regarding celiac disease autoantibodies, 5.8% were endomysial antibodies (EMA+, and no transglutaminase (TTG+ antibodies were detected. Cryoglobulins were found in 2.1% of patients. When NOSA+ individuals were compared to patients without the presence of NOSAs, they exhibited higher median alkaline phosphatase (0.7 vs. 0.6 xULN; p=0.041, lower median platelet counts (141,500.0 vs. 180,500.0/mm 3 ; p=0.036, lower mean prothrombin activity (72.6±11.5% vs. 82.2±16.0%; p=0.012 and an increased prevalence of significant fibrosis (E≥2 (45.5% vs. 18.2%; p=0.012. There was also a tendency for a greater proportion of NOSA+ cases to have marked periportal activity (APP≥3 (44.5% vs. 15.6%; p=0.087. Conclusions In addition to the high prevalence of autoantibodies associated with HCV infection, it was observed that NOSA positivity was associated with a more severe histological and biochemical profile of hepatitis C infection.

Biological variation of thyroid autoantibodies and thyroglobulin

DEFF Research Database (Denmark)

Jensen, Esther; Petersen, Per Hyltoft; Blaabjerg, Ole

2007-01-01

BACKGROUND: It has been shown that the level of serum thyroid antibodies affects serum thyrotropin (TSH) concentrations in men and women, and that these autoantibodies in combination with serum TSH are predictive of future thyroid disease. As the biological variation of these autoantibodies.......5-258 kIU/L), the CV biological was 11.3%, while the CV analytical was 10.6%. For TgAb (5.6 to 148 kIU/L) CV biological was 8.5% and CV analytical was 9.0%. The woman with TRAb had a CV biological of 4.8%, while the analytical variation in duplicates was 3.9% at a level of 2.8 IU/L. CONCLUSIONS......: It is possible to measure TPOAb and TgAb in all samples with the AutoDELFIA. There is no systematic variation in autoantibodies during the menstrual cycle. The biological coefficient of variation for TPOAb and TgAb was 11.3% and 8.5%, respectively...

Natural autoantibodies: from 'horror autotoxicus' to 'gnothi seauton'.

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Avrameas, S

1991-05-01

The immune system of normal unimmunized animals is characterized by the presence of B cells synthesizing and secreting mainly polyreactive, but also monoreactive, IgM and IgG natural antibodies that can react with a variety of self constituents. These antibodies, like the autoantibodies appearing in several immunopathological states, use the same genetic elements as the antibodies directed against environmental antigens, and seem to be encoded by unmutated germ-line genes. Accumulating evidence indicates that these natural auto-antibodies exert various biological roles, both related and unrelated to the immune system. In this article, Stratis Avrameas proposes that natural auto-antibodies, by interacting with the large number of self constituents present in an organism, establish an extensive dynamic network that contributes to the general homeostasis of the organism.

Comparison of clinical and laboratory characteristics in children with type 1 diabetes according to pancreatic autoantibodies

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Ji Hae Choi

2010-03-01

Full Text Available Purpose:The purpose of this study was to determine whether there is any difference in the clinical and laboratory characteristics of patients with autoantibody-positive and patients with autoantibody-negative type 1 diabetes at initial presentation. Methods:We analyzed 96 patients under 18 years of age with newly diagnosed type 1 diabetes. One or both of the pancreatic autoantibodies-glutamic acid decarboxylase autoantibodies (GADA and insulin autoantibody (IAA-were measured in all patients, and we reviewed clinical and laboratory characteristics according to the presence of these autoantibodies. Results:GADA was examined in 48 of 87 patients, and 55.2% of patients were positive. IAA was checked in 88 patients, and 39.8% were positive. Both GADA and IAA were measured in 83 patients, and 22.8% had both antibodies. The patients who had one or both autoantibodies (autoantibody-positive group were younger than those not having any autoantibody (autoantibody-negative group. The autoantibody-positive group had lower BMI, corrected sodium level, and serum effective osmolarity, compared to the autoantibody-negative group (P&lt;0.05. Similar differences were found between the GADA-positive and GADA-negative groups. However, there were no significant differences between the IAA- positive and IAA-negative groups. Conclusion:The prevalence of pancreatic autoantibodies was significantly higher in the under-6 years age group than in the other age groups. These findings suggest that measurement of autoantibodies at the initial diagnosis of diabetes is very useful for detecting immune-mediated type 1 diabetes and providing intensive insulin therapy, especially in younger children.

LKM3 autoantibodies in hepatitis C cirrhosis: a further phenomenon of the HCV-induced autoimmunity.

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Csepregi, A; Nemesánszky, E; Luettig, B; Obermayer-Straub, P; Manns, M P

2001-03-01

Chronic hepatitis C is frequently associated with laboratory markers-including LKM1 autoantibodies--of autoimmunity. A 62-yr-old woman with hepatitis C cirrhosis presented autoantibodies against liver and kidney microsomal proteins. By further evaluation of autoantibodies using ELISA and immunoblotting LKM1 and LKM3 autoantibodies could be revealed. The target antigen of LKM3 autoantibodies proved to be UGT-1.1 isoenzyme. In the absence of chronic hepatitis D infection or autoimmune hepatitis type 2, this is the first case that reports the occurrence of LKM3 autoantibodies in HCV-induced chronic liver disease.

Use of Dried Capillary Blood Sampling for Islet Autoantibody Screening in Relatives: A Feasibility Study.

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Bingley, Polly J; Rafkin, Lisa E; Matheson, Della; Steck, Andrea K; Yu, Liping; Henderson, Courtney; Beam, Craig A; Boulware, David C

2015-12-01

Islet autoantibody testing provides the basis for assessment of risk of progression to type 1 diabetes. We set out to determine the feasibility and acceptability of dried capillary blood spot-based screening to identify islet autoantibody-positive relatives potentially eligible for inclusion in prevention trials. Dried blood spot (DBS) and venous samples were collected from 229 relatives participating in the TrialNet Pathway to Prevention Study. Both samples were tested for glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8 autoantibodies, and venous samples were additionally tested for insulin autoantibodies and islet cell antibodies. We defined multiple autoantibody positive as two or more autoantibodies in venous serum and DBS screen positive if one or more autoantibodies were detected. Participant questionnaires compared the sample collection methods. Of 44 relatives who were multiple autoantibody positive in venous samples, 42 (95.5%) were DBS screen positive, and DBS accurately detected 145 of 147 autoantibody-negative relatives (98.6%). Capillary blood sampling was perceived as more painful than venous blood draw, but 60% of participants would prefer initial screening using home fingerstick with clinic visits only required if autoantibodies were found. Capillary blood sampling could facilitate screening for type 1 diabetes prevention studies.

Development of Type 1 Diabetes in Wild Bank Voles Associated With Islet Autoantibodies and the Novel Ljungan Virus

DEFF Research Database (Denmark)

Niklasson, Bo; Heller, Knud Erik; Schønecker, Bryan

2003-01-01

Clethrionomys Glareolus, Glutamic Acid Decarboxylase Autoantibodies, IA-2 Autoantibodies, Insulin Autoantibodies, Insulin-Dependent Diabetes Mellitus, Ljungan Virus, Parechovirus, Picorna Virus......Clethrionomys Glareolus, Glutamic Acid Decarboxylase Autoantibodies, IA-2 Autoantibodies, Insulin Autoantibodies, Insulin-Dependent Diabetes Mellitus, Ljungan Virus, Parechovirus, Picorna Virus...

Glycotoxin and Autoantibodies Are Additive Environmentally Determined Predictors of Type 1 Diabetes

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Beyan, Huriya; Riese, Harriette; Hawa, Mohammed I.; Beretta, Guisi; Davidson, Howard W.; Hutton, John C.; Burger, Huibert; Schlosser, Michael; Snieder, Harold; Boehm, Bernhard O.; Leslie, R. David

2012-01-01

In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum Nε-carboxymethyl-lysine (CML), an advanced glycation end product, is associated with proinflammation. We assessed whether serum CML and autoantibodies predicted type 1 diabetes and to what extent they were determined by genetic or environmental factors. Of 7,287 unselected schoolchildren screened, 115 were ICA+ and were tested for baseline CML and diabetes autoantibodies and followed (for median 7 years), whereas a random selection (n = 2,102) had CML tested. CML and diabetes autoantibodies were determined in a classic twin study of twin pairs discordant for type 1 diabetes (32 monozygotic, 32 dizygotic pairs). CML was determined by enzyme-linked immunosorbent assay, autoantibodies were determined by radioimmunoprecipitation, ICA was determined by indirect immunofluorescence, and HLA class II genotyping was determined by sequence-specific oligonucleotides. CML was increased in ICA+ and prediabetic schoolchildren and in diabetic and nondiabetic twins (all P < 0.001). Elevated levels of CML in ICA+ children were a persistent, independent predictor of diabetes progression, in addition to autoantibodies and HLA risk. In twins model fitting, familial environment explained 75% of CML variance, and nonshared environment explained all autoantibody variance. Serum CML, a glycotoxin, emerged as an environmentally determined diabetes risk factor, in addition to autoimmunity and HLA genetic risk, and a potential therapeutic target. PMID:22396204

Thyroid Autoantibodies and the Clinical Presentation of Moyamoya Disease: A Prospective Study.

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Lanterna, Luigi A; Galliani, Silvia; Zangari, Rosalia; Conti, Luciano; Brembilla, Carlo; Gritti, Paolo; Colleoni, Maria Luisa; Bernucci, Claudio

2018-05-01

Moyamoya is a rare cerebrovascular disease characterized by the progressive occlusion of the intracranial carotid artery. Thyroid autoantibodies have been found to be associated with the disease, but their clinical significance has never been studied. The objective of this study was to investigate the relationship between thyroid autoantibodies and the clinical presentation of moyamoya. This is a prospective study including 37 patients with moyamoya disease (MMD) or unilateral moyamoya (uMM). Thyroid function and thyroid autoantibodies (e.g., antithyroperoxidase and antithyroglobulin) were investigated. We studied the effect of gender, age, type of moyamoya (uMM versus MMD), and thyroid autoantibodies on the clinical presentation, dichotomized into aggressive (hemorrhage, major stroke, or frequent transient ischemic attack [TIA]) and nonaggressive presentation (headache, rare TIAs, and incidental diagnosis) according to the criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis. Of the 37 patients included in the study, the autoantibodies were elevated in 9 (24.3%). An aggressive presentation occurred in 21 patients (hemorrhage in 11, major stroke in 9, frequent TIAs in 1). The autoantibodies were elevated in 8 of the 21 patients (38.09%) with an aggressive presentation and in 1 of those presenting with minor symptoms (6.2%). The presence of elevated autoantibodies was the only variable associated with an aggressive presentation in the multivariate logistic analysis (P = .048). When the serum concentration of the thyroid autoantibodies is increased, the patients have a higher risk of an aggressive presentation. Our results support the hypothesis that activation of immune-mediated processes affects the moyamoya physiopathology. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Two cases of erosive oral lichen planus with autoantibodies to desmoglein 3.

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Muramatsu, Ken; Nishie, Wataru; Natsuga, Ken; Fujita, Yasuyuki; Iwata, Hiroaki; Yamada, Tamaki; Yamashita, Emi; Asaka, Takuya; Shimizu, Hiroshi

2016-11-01

Oral lichen planus (OLP) is a chronic inflammatory disorder of the oral mucosa of unknown etiology. Clinically, the erosive type of OLP (erosive OLP) can show features similar to those of pemphigus vulgaris (PV), an autoimmune blistering disorder in which desmoglein (Dsg)3 is targeted. In addition to clinical and histopathological findings, immunological studies, including direct immunofluorescence (IF), indirect IF and enzyme-linked immunosorbent assay (ELISA) that detect autoantibodies to Dsg3, are helpful in differentiating erosive OLP from PV. Here, we show two cases of erosive OLP with autoantibodies to Dsg3. Patient 1 was a 68-year-old woman with chronic erosions of the oral mucosa, in which elevated levels of immunoglobulin (Ig)G autoantibodies to Dsg1 and Dsg3 were detected by ELISA. Patient 2 was an 85-year-old woman with white striae with erosions on the lateral sides of the buccal mucosa with elevated levels of IgG autoantibodies to Dsg3 detected by ELISA. Histopathological findings from both cases showed lichenoid dermatitis, and both direct and indirect IF showed no tissue-bound IgG autoantibodies. From these findings, the diagnosis of erosive OLP was made. Immunological assays revealed both cases to have IgG-directing calcium-independent linear epitopes on Dsg3, which are suggestive of non-pathogenic autoantibodies. In addition, autoantibodies to Dsg3 in patient 2 reacted with a prosequence-possessing precursor form of Dsg3 but not with the mature form of the molecule. The present study suggests that erosive OLP may develop anti-Dsg3 autoantibodies, which should be carefully assessed. © 2016 Japanese Dermatological Association.

Brief Communication: Maternal Plasma Autoantibodies Screening in Fetal Down Syndrome

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Karol Charkiewicz

2016-01-01

Full Text Available Imbalance in the metabolites levels which can potentially be related to certain fetal chromosomal abnormalities can stimulate mother’s immune response to produce autoantibodies directed against proteins. The aim of the study was to determine the concentration of 9000 autoantibodies in maternal plasma to detect fetal Down syndrome. Method. We performed 190 amniocenteses and found 10 patients with confirmed fetal Down syndrome (15th–18th weeks of gestation. For the purpose of our control we chose 11 women without confirmed chromosomal aberration. To assess the expression of autoantibodies in the blood plasma, we used a protein microarray, which allows for simultaneous determination of 9000 proteins per sample. Results. We revealed 213 statistically significant autoantibodies, whose expression decreased or increased in the study group with fetal Down syndrome. The second step was to create a classifier of Down syndrome pregnancy, which includes 14 antibodies. The predictive value of the classifier (specificity and sensitivity is 100%, classification errors, 0%, cross-validation errors, 0%. Conclusion. Our findings suggest that the autoantibodies may play a role in the pathophysiology of Down syndrome pregnancy. Defining their potential as biochemical markers of Down syndrome pregnancy requires further investigation on larger group of patients.

Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis.

LENUS (Irish Health Repository)

Gunawardena, H

2009-06-01

OBJECTIVE: The identification of novel autoantibodies in juvenile dermatomyositis (DM) may have etiologic and clinical implications. The aim of this study was to describe autoantibodies to a 140-kd protein in children recruited to the Juvenile DM National Registry and Repository for UK and Ireland. METHODS: Clinical data and sera were collected from children with juvenile myositis. Sera that recognized a 140-kd protein by immunoprecipitation were identified. The identity of the p140 autoantigen was investigated by immunoprecipitation\\/immunodepletion, using commercial monoclonal antibodies to NXP-2, reference anti-p140, and anti-p155\\/140, the other autoantibody recently described in juvenile DM. DNA samples from 100 Caucasian children with myositis were genotyped for HLA class II haplotype associations and compared with those from 864 randomly selected UK Caucasian control subjects. RESULTS: Sera from 37 (23%) of 162 patients with juvenile myositis were positive for anti-p140 autoantibodies, which were detected exclusively in patients with juvenile DM and not in patients with juvenile DM-overlap syndrome or control subjects. No anti-p140 antibody-positive patients were positive for other recognized autoantibodies. Immunodepletion suggested that the identity of p140 was consistent with NXP-2 (the previously identified MJ autoantigen). In children with anti-p140 antibodies, the association with calcinosis was significant compared with the rest of the cohort (corrected P < 0.005, odds ratio 7.0, 95% confidence interval 3.0-16.1). The clinical features of patients with anti-p140 autoantibodies were different from those of children with anti-p155\\/140 autoantibodies. The presence of HLA-DRB1*08 was a possible risk factor for anti-p140 autoantibody positivity. CONCLUSION: This study has established that anti-p140 autoantibodies represent a major autoantibody subset in juvenile DM. This specificity may identify a further immunogenetic and clinical phenotype within the

The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies.

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Rider, Lisa G; Shah, Mona; Mamyrova, Gulnara; Huber, Adam M; Rice, Madeline Murguia; Targoff, Ira N; Miller, Frederick W

2013-07-01

The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, "shawl-sign" rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and "mechanic's hands," and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high

Pathological features of liver tissue in autoantibody-positive chronic hepatitis C patients after plasmaphoresis

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WU Huili

2018-02-01

Full Text Available ObjectiveTo investigate the detection rate and features of autoantibodies in chronic hepatitis C (CHC patients after plasmaphoresis, as well as the liver pathological features of autoantibody-positive CHC patients. MethodsA total of 120 patients who were infected with hepatitis C virus after plasmaphoresis in the Hospital of Dingxi County and Dingxi Hospital of Infectious Diseases from January 1992 to December 1995 were selected as test group; 11 healthy people from the same region were selected as control group. Autoantibody detection was performed for the 120 CHC patients, and liver pathological features were compared between the autoantibody-positive group(n=44 and autoantibody-negative group(n=76 of these patients. The t test was used for comparison of continuous data, and the chi-square test was used for comparison of categorical data. ResultsOf all 120 CHC patients who underwent plasmaphoresis, 44 (36.7% were found to have serum autoantibodies, with antinuclear antibodies as the most common type (21.7%. Compared with the autoantibody-negative group, the autoantibody-positive group had significantly higher scores of focal necrosis inside the hepatic lobules (211±0.88 vs 164±0.88, t=2.349，P=0.021 and ductular reaction inside the portal area (1.86±0.71 vs 1.13±0.66, t=4.217，P＜0.001, as well as a significantly higher rate of interlobular bile duct injury (86.4% vs 55.3%, χ2=12.129，P=0.001. There were no significant differences between the two groups in the degree of liver fibrosis and hepatic steatosis (both P＞0.05. ConclusionAutoantibody-positive are common in CHC patients after plasmaphoresis, and autoantibody-positive patients tend to have more severe injuries of the liver.

Detection of autoantibodies to cytokines

DEFF Research Database (Denmark)

Bendtzen, K; Hansen, M B; Ross, C

2000-01-01

Autoantibodies to various cytokines have been reported in normal individuals and in patients with various infectious and immunoinflammatory disorders, and similar antibodies (Ab) may be induced in patients receiving human recombinant cytokines. The clinical relevance of these Ab is often difficul...

Neuronal Surface Autoantibodies in Neuropsychiatric Disorders: Are There Implications for Depression?

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Shenghua Zong

2017-07-01

Full Text Available Autoimmune diseases are affecting around 7.6–9.4% of the general population. A number of central nervous system disorders, including encephalitis and severe psychiatric disorders, have been demonstrated to associate with specific neuronal surface autoantibodies (NSAbs. It has become clear that specific autoantibodies targeting neuronal surface antigens and ion channels could cause severe mental disturbances. A number of studies have focused or are currently investigating the presence of autoantibodies in specific mental conditions such as schizophrenia and bipolar disorders. However, less is known about other conditions such as depression. Depression is a psychiatric disorder with complex etiology and pathogenesis. The diagnosis criteria of depression are largely based on symptoms but not on the origin of the disease. The question which arises is whether in a subgroup of patients with depression, the symptoms might be caused by autoantibodies targeting membrane-associated antigens. Here, we describe how autoantibodies targeting membrane proteins and ion channels cause pathological effects. We discuss the physiology of these antigens and their role in relation to depression. Finally, we summarize a number of studies detecting NSAbs with a special focus on cohorts that include depression diagnosis and/or show depressive symptoms.

Autoantibodies associated with prenatal and childhood exposure to environmental chemicals in faroese children

DEFF Research Database (Denmark)

Osuna, Christa E; Grandjean, Philippe; Weihe, Pál

2014-01-01

to both neural (neurofilaments, cholineacetyltransferase, astrocyte glial fibrillary acidic protein, and myelin basic protein) and non-neural (actin, desmin, and keratin) antigens were measured and the associations of these autoantibody concentrations with chemical exposures were assessed using linear...... of autoantibodies. However, it is not known if autoantibodies similarly will be generated and detectable in humans following toxicant exposures. Therefore, we conducted a pilot study to investigate if autoantibodies specific for neural and non-neural antigens could be detected in children at age 7 years who have...... been exposed to environmental chemicals. Both prenatal and age-7 exposures to mercury, PCBs, and PFCs were measured in 38 children in the Faroe Islands who were exposed to widely different levels of these chemicals due to their seafood-based diet. Concentrations of IgM and IgG autoantibodies specific...

Anti-C1q autoantibodies in patients with neuromyelitis optica spectrum disorders.

Science.gov (United States)

Yoshikura, Nobuaki; Kimura, Akio; Hayashi, Yuichi; Inuzuka, Takashi

2017-09-15

We examined anti-complement C1q (C1q) autoantibody levels in serum and cerebrospinal fluid (CSF) samples of patients with neuromyelitis optica spectrum disorders (NMOSD). We analyzed the correlations between anti-C1q autoantibody levels and the clinical and other CSF characteristics of NMOSD. Serum and CSF anti-C1q autoantibody levels increased during the acute phase of NMOSD, reverting to the same levels as controls during remission. CSF anti-C1q autoantibody levels during the acute phase correlated with several markers reflecting disease severity, Expanded Disability Status Scale worsening, spinal cord lesion length in cases with myelitis, CSF protein and interleukin-6 levels, and CSF/serum albumin ratios. Copyright © 2017 Elsevier B.V. All rights reserved.

Cancer biomarkers defined by autoantibody signatures to aberrant O-glycopeptide epitopes

DEFF Research Database (Denmark)

Wandall, Hans H; Blixt, Ola; Tarp, Mads A

2010-01-01

Autoantibodies to cancer antigens hold promise as biomarkers for early detection of cancer. Proteins that are aberrantly processed in cancer cells are likely to present autoantibody targets. The extracellular mucin MUC1 is overexpressed and aberrantly glycosylated in many cancers; thus, we evalua...

Rare myositis-specific autoantibody associations among Hungarian patients with idiopathic inflammatory myopathy.

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Bodoki, L; Nagy-Vincze, M; Griger, Z; Betteridge, Z; Szöllősi, L; Jobanputra, R; Dankó, K

2015-01-01

Idiopathic inflammatory myopathies are systemic, chronic autoimmune diseases characterized by symmetrical, proximal muscle weakness. Homogeneous groups present with similar symptoms. The response to therapy and prognosis could be facilitated by myositis-specific autoantibodies, and in this way, give rise to immunoserological classification. The myositis-specific autoantibodies are directed against specific proteins found in the cytoplasm or in the nucleus of the cells. To date, literature suggests the rarity of the co-existence of two myositis-specific autoantibodies. In this study the authors highlight rare associations of myositis-specific autoantibodies. Three hundred and thirty-seven Hungarian patients with polymyositis or dermatomyositis were studied. Their clinical findings were noted retrospectively. Specific blood tests identified six patients with the rare co-existence of myositis-specific autoantibodies, anti-Jo-1 and anti-SRP, anti-Jo-1 and anti-Mi-2, anti-Mi-2 and anti-PL-12, anti-Mi-2 and anti-SRP, and anti-SRP and anti-PL-7, respectively. This case review aims to identify the clinical importance of these rare associations and their place within the immunoserological classification.

Circulating autoantibodies to phosphorylated α-enolase are a hallmark of pancreatic cancer.

Science.gov (United States)

Tomaino, Barbara; Cappello, Paola; Capello, Michela; Fredolini, Claudia; Sperduti, Isabella; Migliorini, Paola; Salacone, Paola; Novarino, Anna; Giacobino, Alice; Ciuffreda, Libero; Alessio, Massimo; Nisticò, Paola; Scarpa, Aldo; Pederzoli, Paolo; Zhou, Weidong; Petricoin Iii, Emanuel F; Liotta, Lance A; Giovarelli, Mirella; Milella, Michele; Novelli, Francesco

2011-01-07

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and no diagnostic markers have, as of yet, been defined. In PDAC patients, α-enolase (ENOA) is up-regulated and elicits the production of autoantibodies. Here, we analyzed the autoantibody response to post-translational modifications of ENOA in PDAC patients. ENOA isolated from PDAC tissues and cell lines was characterized by two-dimensional electrophoresis (2-DE) Western blot (WB), revealing the expression of six different isoforms (named ENOA1,2,3,4,5,6) whereas only 4 isoforms (ENOA3,4,5,6) were detectable in normal tissues. As assessed by 2-DE WB, 62% of PDAC patients produced autoantibodies to the two more acidic isoforms (ENOA1,2) as opposed to only 4% of controls. Mass spectrometry showed that ENOA1,2 isoforms were phosphorylated on serine 419. ROC analysis demonstrated that autoantibodies to ENOA1,2 usefully complement the diagnostic performance of serum CA19.9 levels, achieving approximately 95% diagnostic accuracy in both advanced and resectable PDAC. Moreover, the presence of autoantibodies against ENOA1,2 correlated with a significantly better clinical outcome in advanced patients treated with standard chemotherapy. In conclusion, our results demonstrate that ENOA phosphorylation is associated with PDAC and induces specific autoantibody production in PDAC patients that may have diagnostic value.

Clinical utility of anti-p53 auto-antibody: systematic review and focus on colorectal cancer.

Science.gov (United States)

Suppiah, Aravind; Greenman, John

2013-08-07

Mutation of the p53 gene is a key event in the carcinogenesis of many different types of tumours. These can occur throughout the length of the p53 gene. Anti-p53 auto-antibodies are commonly produced in response to these p53 mutations. This review firstly describes the various mechanisms of p53 dysfunction and their association with subsequent carcinogenesis. Following this, the mechanisms of induction of anti-p53 auto-antibody production are shown, with various hypotheses for the discrepancies between the presence of p53 mutation and the presence/absence of anti-p53 auto-antibodies. A systematic review was performed with a descriptive summary of key findings of each anti-p53 auto-antibody study in all cancers published in the last 30 years. Using this, the cumulative frequency of anti-p53 auto-antibody in each cancer type is calculated and then compared with the incidence of p53 mutation in each cancer to provide the largest sample calculation and correlation between mutation and anti-p53 auto-antibody published to date. Finally, the review focuses on the data of anti-p53 auto-antibody in colorectal cancer studies, and discusses future strategies including the potentially promising role using anti-p53 auto-antibody presence in screening and surveillance.

Phytochrome regulates GTP-binding protein activity in the envelope of pea nuclei

Science.gov (United States)

Clark, G. B.; Memon, A. R.; Thompson, G. A. Jr; Roux, S. J.

1993-01-01

Three GTP-binding proteins with apparent molecular masses of 27, 28 and 30 kDa have been detected in isolated nuclei of etiolated pea plumules. After LDS-PAGE and transfer to nitrocellulose these proteins bind [32P]GTP in the presence of excess ATP, suggesting that they are monomeric G proteins. When nuclei are disrupted, three proteins co-purify with the nuclear envelope fraction and are highly enriched in this fraction. The level of [32P]GTP-binding for all three protein bands is significantly increased when harvested pea plumules are irradiated by red light, and this effect is reversed by far-red light. The results indicate that GTP-binding activity associated with the nuclear envelope of plant cells is photoreversibly regulated by the pigment phytochrome.

Early Site Permit Demonstration Program: Plant parameters envelope report. Volume 1

Energy Technology Data Exchange (ETDEWEB)

1993-03-01

The Early Site Permit (ESP) Demonstration Program is the nuclear industry`s initiative for piloting the early resolution of siting-related issues before the detailed design proceedings of the combined operating license review. The ESP Demonstration Program consists of three phases. The plant parameters envelopes task is part of Phase 1, which addresses the generic review of applicable federal regulations and develops criteria for safety and environmental assessment of potential sites. The plant parameters envelopes identify parameters that characterize the interface between an ALWR design and a potential site, and quantify the interface through values selected from the Utility Requirements Documents, vendor design information, or engineering assessments. When augmented with site-specific information, the plant parameters envelopes provide sufficient information to allow ESPs to be granted based on individual ALWR design information or enveloping design information for the evolutionary, passive, or generic ALWR plants. This document is expected to become a living document when used by future applicants.

Autoantibody Profiling in a Cohort of Pediatric and Adult Patients With Autoimmune Hepatitis.

Science.gov (United States)

Villalta, Danilo; Girolami, Elia; Alessio, Maria Grazia; Sorrentino, Maria Concetta; Tampoia, Marilina; Brusca, Ignazio; Daves, Massimo; Porcelli, Brunetta; Barberio, Giuseppina; Conte, Mariaelisabetta; Pantarotto, Lisa; Bizzaro, Nicola

2016-01-01

Autoimmune hepatitis (AIH) is a rare condition characterized by the presence of autoantibodies distinctive of type 1 AIH (AIH-1) and type 2 AIH (AIH-2). The aim of this study was to evaluate the autoantibody profile in a cohort of pediatric and adult AIH patients, using both indirect immunofluorescence (IIF) and a new multiplexed line-blot assay. Sera from 63 pediatric and 53 adult AIH patients were tested for antinuclear (ANA), antismooth muscle (SMA), anti-liver kidney microsome 1 (anti-LKM1), anti-liver cytosol 1 (anti-LC1) autoantibodies using IIF methods; for anti-LKM1, anti-LC1, and soluble liver antigen/liver-pancreas (anti-SLA/LP) autoantibodies using the line-blot; for anti-F-actin autoantibodies using IIF both on VSM47 cell-line and on rat intestinal epithelial cells. AIH-1 was the most common type of AIH in the adult cohort (73.6%), while AIH-2 was the most common AIH in the pediatric cohort (61.9%). Both in adult and pediatric AIH-2 anti-LKM1 were the prevalent autoantibodies. In pediatric AIH-2 anti-LC1 autoantibodies were more frequent than in adult AIH-2 (59 vs. 28.6%), and in 35.9% of cases they were present alone. In 17 patients anti-LC1 autoantibodies were detected only with the line-blot assay. The levels of anti-LKM1 and of anti-LC1 were not different between adult and pediatric AIH, and the overall agreement between the results obtained with the two IIF methods for F-actin detection was 98.8% (CI 95%: 94.4-99.7%). The line-blot assay showed a higher sensitivity than IIF for anti-LC1 detection. Anti-LKM1 and anti-LC1 autoantibody levels are not different in adults and children. An almost perfect agreement between the two IIF methods for anti-F-actin detection has been observed. © 2014 Wiley Periodicals, Inc.

Specific removal of autoantibodies by extracorporeal immunoadsorption ameliorates experimental autoimmune myasthenia gravis.

Science.gov (United States)

Lazaridis, Konstantinos; Dalianoudis, Ioannis; Baltatzidi, Vasiliki; Tzartos, Socrates J

2017-11-15

Myasthenia gravis (MG) is caused by autoantibodies, the majority of which target the muscle acetylcholine receptor (AChR). Plasmapheresis and IgG-immunoadsorption are useful therapy options, but are highly non-specific. Antigen-specific immunoadsorption would remove only the pathogenic autoantibodies, reducing the possibility of side effects while maximizing the benefit. We have extensively characterized such adsorbents, but in vivo studies are missing. We used rats with experimental autoimmune MG to perform antigen-specific immunoadsorptions over three weeks, regularly monitoring symptoms and autoantibody titers. Immunoadsorption was effective, resulting in a marked autoantibody titer decrease while the immunoadsorbed, but not the mock-treated, animals showed a dramatic symptom improvement. Overall, the procedure was found to be efficient, suggesting the subsequent initiation of clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Immunoregulation by naturally occurring and disease-associated autoantibodies

DEFF Research Database (Denmark)

Nielsen, Claus H; Bendtzen, Klaus

2012-01-01

The role of naturally occurring autoantibodies (NAbs) in homeostasis and in disease manifestations is poorly understood. In the present chapter, we review how NAbs may interfere with the cytokine network and how NAbs, through formation of complement-activating immune complexes with soluble self......-antigens, may promote the uptake and presentation of self-molecules by antigen-presenting cells. Both naturally occurring and disease-associated autoantibodies against a variety of cytokines have been reported, including NAbs against interleukin (IL)-1α, IL-6, IL-8, IL-10, granulocyte-macrophage colony...

14-3-3η Autoantibodies: Diagnostic Use in Early Rheumatoid Arthritis

NARCIS (Netherlands)

Maksymowych, Walter P.; Boire, Gilles; van Schaardenburg, Dirkjan; Wichuk, Stephanie; Turk, Samina; Boers, Maarten; Siminovitch, Katherine A.; Bykerk, Vivian; Keystone, Ed; Tak, Paul Peter; van Kuijk, Arno W.; Landewé, Robert; van der Heijde, Desiree; Murphy, Mairead; Marotta, Anthony

2015-01-01

To describe the expression and diagnostic use of 14-3-3η autoantibodies in early rheumatoid arthritis (RA). 14-3-3η autoantibody levels were measured using an electrochemiluminescent multiplexed assay in 500 subjects (114 disease-modifying antirheumatic drug-naive patients with early RA, 135 with

Nuclear and nuclear reprogramming during the first cell cycle in bovine nuclear transfer embryos

DEFF Research Database (Denmark)

Østrup, Olga; Petrovicova, Ida; Strejcek, Frantisek

2009-01-01

Abstract The immediate events of genomic reprogramming at somatic cell nuclear transfer (SCNT) are to high degree unknown. This study was designed to evaluate the nuclear and nucleolar changes during the first cell cycle. Bovine SCNT embryos were produced from starved bovine fibroblasts and fixed......, somatic cell nuclei introduced into enucleated oocytes displayed chromatin condensation, partial nuclear envelope breakdown, nucleolar desegregation and transcriptional quiescence already at 0.5 hpa. Somatic cell cytoplasm remained temporally attached to introduced nucleus and nucleolus was partially...... restored indicating somatic influence in the early SCNT phases. At 1-3 hpa, chromatin gradually decondensed toward the nucleus periphery and nuclear envelope reformed. From 4 hpa, the somatic cell nucleus gained a PN-like appearance and displayed NPBs suggesting ooplasmic control of development....

[Glucose-6-phosphatase from nuclear envelope in rat liver].

Science.gov (United States)

González-Mujica, Freddy

2008-06-01

Nuclear envelope (NE) and microsomal glucosa-6-phosphatase (G-6-Pase) activities were compared. Intact microsomes were unable to hydrolyze mannose-6-phosphate (M-6-P), on the other hand, intact NE hydrolyzes this substrate. Galactose-6-phosphate showed to be a good substrate for both NE and microsomal enzymes, with similar latency to that obtained with M-6-P using microsomes. In consequence, this substrate was used to measure the NE integrity. The kinetic parameters (Kii and Kis) of the intact NE G-6-Pase for the phlorizin inhibition using glucose-6-phosphate (G-6-P) and M-6-P as substrates, were very similar. The NE T1 transporter was more sensitive to amiloride than the microsomal T1. The microsomal system was more sensitive to N-ethylmalemide (NEM) than the NE and the latter was insensitive to anion transport inhibitors DIDS and SITS, which strongly affect the microsomal enzyme. The above results allowed to postulate the presence of a hexose-6-phosphate transporter in the NE which is able to carry G-6-P and M-6-P, and perhaps other hexose-6-phosphate which could be different from that present in microsomes or, if it is the same, its activity could by modified by the membrane system where it is included. The higher PPi hydrolysis activity of the intact NE G-6-Pase in comparison to the intact microsomal, suggests differences between the Pi/PPi transport (T2) of both systems. The lower sensitivity of the NE G-6-Pase to NEM suggests that the catalytic subunit of this system has some differences with the microsomal isoform.

Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes

DEFF Research Database (Denmark)

Brorsson, Caroline A; Onengut, Suna; Chen, Wei-Min

2015-01-01

Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array...... and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes-affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs...... and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity....

Safeguards Envelope Progress FY10

International Nuclear Information System (INIS)

Metcalf, Richard

2010-01-01

The Safeguards Envelope is a strategy to determine a set of specific operating parameters within which nuclear facilities may operate to maximize safeguards effectiveness without sacrificing safety or plant efficiency. This paper details the additions to the advanced operating techniques that will be applied to real plant process monitoring (PM) data from the Idaho Chemical Processing Plant (ICPP). Research this year focused on combining disparate pieces of data together to maximize operating time with minimal downtime due to safeguards. A Chi-Square and Croiser's cumulative sum were both included as part of the new analysis. Because of a major issue with the original data, the implementation of the two new tests did not add to the existing set of tests, though limited one-variable optimization made a small increase in detection probability. Additional analysis was performed to determine if prior analysis would have caused a major security or safety operating envelope issue. It was determined that a safety issue would have resulted from the prior research, but that the security may have been increased under certain conditions.

Analysis of novel Sjogren's syndrome autoantibodies in patients with dry eyes.

Science.gov (United States)

Everett, Sandra; Vishwanath, Sahana; Cavero, Vanessa; Shen, Long; Suresh, Lakshmanan; Malyavantham, Kishore; Lincoff-Cohen, Norah; Ambrus, Julian L

2017-03-07

Dry eye is a common problem in Ophthalmology and may occur for many reasons including Sjogren's syndrome (SS). Recent studies have identified autoantibodies, anti-salivary gland protein 1 (SP1), anti-carbonic anhydrase 6 (CA6) and anti-parotid secretory protein (PSP), which occur early in the course of SS. The current studies were designed to evaluate how many patients with idiopathic dry eye and no evidence of systemic diseases from a dry eye practice have these autoantibodies. Patients from a dry eye clinic and normal controls were assessed by Schirmer's test for tear flow. Sera were assessed for autoantibodies using ELISA assays. Statistics was performed with Prism 7 software and student's unpaired t test. In this study 60% of the dry eye patients expressed one of these autoantibodies. Only 30% expressed one of the autoantibodies associated with long-standing SS, which are included in the diagnostic criteria for SS, anti-Ro and anti-La. Patients with disease for less than 2 years and mild dry eyes did not express anti-Ro or anti-La, while 25% expressed anti-SP1. Similar observations, with smaller numbers, were made when patients had not only dry eye but also dry mouth. Antibodies to SP1, CA6 and PSP occur in some patients with idiopathic dry eyes. Further studies will be needed to determine how many of these patients go on to develop systemic manifestations of SS. Testing for these autoantibodies may allow early recognition of patients with SS. This will lead to improved management of the patients and the development of new strategies to maintain normal lacrimal and salivary gland function in patients with SS.

Lack of association between folate-receptor autoantibodies and neural-tube defects.

LENUS (Irish Health Repository)

Molloy, Anne M

2009-07-09

BACKGROUND: A previous report described the presence of autoantibodies against folate receptors in 75% of serum samples from women with a history of pregnancy complicated by a neural-tube defect, as compared with 10% of controls. We sought to confirm this finding in an Irish population, which traditionally has had a high prevalence of neural-tube defects. METHODS: We performed two studies. Study 1 consisted of analysis of stored frozen blood samples collected from 1993 through 1994 from 103 mothers with a history of pregnancy complicated by a neural-tube defect (case mothers), 103 mothers with a history of pregnancy but no complication by a neural-tube defect (matched with regard to number of pregnancies and sampling dates), 58 women who had never been pregnant, and 36 men. Study 2, conducted to confirm that the storage of samples did not influence the folate-receptor autoantibodies, included fresh samples from 37 case mothers, 22 control mothers, 10 women who had never been pregnant, and 9 men. All samples were assayed for blocking and binding autoantibodies against folate receptors. RESULTS: In Study 1, blocking autoantibodies were found in 17% of case mothers, as compared with 13% of control mothers (odds ratio, 1.54; 95% confidence interval [CI], 0.70 to 3.39), and binding autoantibodies in 29%, as compared with 32%, respectively (odds ratio, 0.82; 95% CI, 0.44 to 1.50). Study 2 showed similar results, indicating that sample degradation was unlikely. CONCLUSIONS: The presence and titer of maternal folate-receptor autoantibodies were not significantly associated with a neural-tube defect-affected pregnancy in this Irish population.

Design of a small nuclear reactor for extending the operational envelope of the Victoria Class Submarine

International Nuclear Information System (INIS)

Cole, C.J.P.

2003-01-01

The purpose of this research is to conceptually design a small, inherently safe, quasi-homogeneous nuclear reactor that will provide enough power to maintain the hotel load of the Victoria Class Submarine and extend her operational envelope. This research is in its early stages. The purpose of this paper is to outline the background of the research, present results found to date, and indicate the direction of the research over the next two years. The Canadian Forces has recently acquired four U.K. built Upholder Class submarines to replace the ageing Oberon Class submarines purchased in the early 1960's. The Upholders, like the Oberons, are diesel-electric powered. The Upholders were renamed the Victoria Class upon commissioning in Canada. Submarines are strategic military weapons that have several roles including: intelligence gathering, inflicting surprise attacks, controlling shipping lanes and covert operations. For each of these roles the submarine must remain undetected. To remain undetected, it is imperative that the submarine remains submerged. To remain submerged and continue to function, a submarine requires an air-independent power generation system, such as a nuclear reactor. (author)

Vault mobility depends in part on microtubules and vaults can be recruited to the nuclear envelope

International Nuclear Information System (INIS)

Zon, Arend van; Mossink, Marieke H.; Houtsmuller, Adriaan B.; Schoester, Martijn; Scheffer, George L.; Scheper, Rik J.; Sonneveld, Pieter; Wiemer, Erik A.C.

2006-01-01

Vaults are ribonucleoproteins that may function in intracellular transport processes. We investigated the intracellular distribution and dynamics of vaults in non-small cell lung cancer cells in which vaults are labeled with the green fluorescent protein. Immunofluorescence experiments showed that vaults are dispersed throughout the cytoplasm; a small fraction is found in close proximity to microtubules. Immunoprecipitation experiments corroborated these results showing co-precipitation of MVP and β-tubulin. Using quantitative fluorescence-recovery after photobleaching (FRAP), we demonstrated that vault mobility over longer distances in part depends on intact microtubules; vaults moving slower when microtubules are depolymerized by nocodazole. Biochemical fractionation indicated a small fraction of MVP associated with the nucleus, however, no GFP-tagged vaults could be observed inside the nucleus. We observed an accumulation of vaults at the nuclear envelope upon treatment of cells with the protein synthesis inhibitor cycloheximide. Analysis of nucleo-cytoplasmic transport using a fluorescent substrate containing a classical NLS and NES expressed in MVP +/+ and MVP -/- mouse embryonic fibroblasts indicated no differences in nuclear import/export kinetics, suggesting no role for vaults in these processes. We hypothesize that a subset of vaults moves directionally via microtubules, possibly towards the nucleus

Diagnostic Utility of Auto-Antibodies in Inflammatory Muscle Diseases.

Science.gov (United States)

Allenbach, Y; Benveniste, O

2015-01-01

To date, there are four main groups of idiopathic inflammatory myopathies (IIM): polymyositis (PM), dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM) and sporadic inclusion body myositis; based on clinical presentation and muscle pathology. Nevertheless, important phenotypical differences (either muscular and/or extra-muscular manifestations) within a group persist. In recent years, the titration of different myositis-specific (or associated) auto-antibodies as a diagnostic tool has increased. This is an important step forward since it may facilitate, at a viable cost, the differential diagnosis between IIM and other myopathies. We have now routine access to assays for the detection of different antibodies. For example, IMNM are related to the presence of anti-SRP or anti-HMGCR. PM is associated with anti-synthetase antibodies (anti-Jo-1, PL-7, PL-12, OJ, and EJ) and DM with anti-Mi-2, anti-SAE, anti-TIF-1-γ and anti-NXP2 (both associated with cancer) or anti-MDA5 antibodies (associated with interstitial lung disease). Today, over 30 myositis specific and associated antibodies have been characterised, and all groups of myositis may present one of those auto-antibodies. Most of them allow identification of homogenous patient groups, more precisely than the classical international classifications of myositis. This implies that classification criteria could be modified accordingly, since these auto-antibodies delineate groups of patients suffering from myositis with consistent clinical phenotype (muscular and extra-muscular manifestations), common prognostic (cancer association, presence of interstitial lung disease, mortality and risk of relapse) and treatment responses. Nevertheless, since numerous auto-antibodies have been recently characterised, the exact prevalence of myositis specific antibodies remains to be documented, and research of new auto-antibodies in the remaining seronegative group is still needed.

Autoantibodies and human immunodeficiency viruses infection: a case-control study.

Science.gov (United States)

Chretien, P; Monier, J C; Oksman, F; San Marco, M; Escande, A; Goetz, J; Cohen, J; Baquey, A; Humbel, R L; Sibilia, J

2003-01-01

To determine the prevalence of organ-specific and non-specific autoantibodies in HIV-infected patients. A multicentric collaborative case-control study including 105 HIV patients and 100 sex- and age-matched HIV-negative healthy volunteers. Antinuclear, anti-ds DNA, anti-histone, anti-Sm, rheumatoid factor(IgM), anti-beta 2 glycoprotein 1, antineutrophil cytoplasmic, anti-LKM1, anti-LCA1, anti-gastric parietal cell, antiplatelet, anti-intermediate filament, anti-mitotic spindle apparatus, anti-Golgi, anti-ribosome and anti-thyroid autoantibodies were screened in six European laboratories. Only IgG and IgM anticardiolipin, IgG antiplatelet, anti-smooth muscle and anti-thyroglobulin antibodies were statistically more frequent in HIV patients. There was no correlation with the numbers of CD4+ cells except in the case of anti-smooth muscle antibodies. We were unable to find specific autoantibodies such as anti-ds DNA, anti-Sm, AMA, anti-LKM1, anti-LCA1 or anti-beta 2 GP1 antibodies in these patients. Our results indicate that the autoantibody profile of HIV infections is comparable to those of other chronic viral infections. HIV does not seem to be more autoimmunogenic than other viruses.

Do Electrochemiluminescence Assays Improve Prediction of Time to Type 1 Diabetes in Autoantibody-Positive TrialNet Subjects?

OpenAIRE

Fouts, Alexandra; Pyle, Laura; Yu, Liping; Miao, Dongmei; Michels, Aaron; Krischer, Jeffrey; Sosenko, Jay; Gottlieb, Peter; Steck, Andrea K.

2016-01-01

OBJECTIVE To explore whether electrochemiluminescence (ECL) assays can help improve prediction of time to type 1 diabetes in the TrialNet autoantibody-positive population. RESEARCH DESIGN AND METHODS TrialNet subjects who were positive for one or more autoantibodies (microinsulin autoantibody, GAD65 autoantibody [GADA], IA-2A, and ZnT8A) with available ECL-insulin autoantibody (IAA) and ECL-GADA data at their initial visit were analyzed; after a median follow-up of 24 months, 177 of these 1,2...

Novel monoclonal autoantibody specificity associated with ribonucleoprotein complexes

International Nuclear Information System (INIS)

Winkler, A.; Watson-McKown, R.; Wise, K.

1986-01-01

The authors describe an IgG/sub 2a/, kappa monoclonal autoantibody (mAb) F78 derived from a 6-month old MRL-Mp lpr/lpr mouse that recognizes a novel epitope associated with small nuclear ribonuclear protein complexes (snRNP). Indirect immunofluorescent staining of HEp-2 cells with F78 showed a nonnucleolar speckled nuclear pattern characteristic of anti-RNP and anti-Sm mAbs which could be abrogated by pretreating fixed cells with 0.1M HCl prior to staining. Immunoblots of whole cell extracts (dissociated in SDS, urea and mercaptan at 4 0 C then subjected to SDS-PAGE) showed that F78 selectively bound to a component of M/sub r/ = 100,000 clearly distinct from components recognized by two mAbs described by Billings et al that detected, respectively, proteins of M/sub r/ = 70,000 associated with RNP and M/sub r/ = 13,000 associated with Sm. Incubation of extracts at 100 0 C prior to SDS-PAGE eliminated subsequent binding of F78 but not of the other nAbs. F78 as well as the other mAbs selectively immunoprecipitated characteristic patterns of small nuclear RNAs (U 1 , U 2 , U 4 , U 5 , U 6 ) from extracts of 32 P-phosphate labeled HeLa cells. These results suggest a new specificity associated with snRNP that is recognized in the MRL autoimmune response

Non-organ specific autoantibodies in children with chronic hepatitis C.

Science.gov (United States)

Bortolotti, F; Vajro, P; Balli, F; Giacchino, R; Crivellaro, C; Barbera, C; Cataleta, M; Muratori, L; Pontisso, P; Nebbia, G; Zancan, L; Bertolini, A; Alberti, A; Bianchi, F

1996-11-01

Recent studies in adult patients have established a relationship between hepatitis C virus infection and the presence of liver-kidney microsomal autoantibody type 1 (LKM1). Conversely, little is known regarding the relationship between hepatitis C and autoimmunity in children. In this study, we investigated non-organ specific autoantibodies in 40 otherwise healthy Italian children with chronic hepatitis C. All but four patients included in the study were asymptomatic. Liver histology, obtained in 35, showed features ranging from minimal to mild chronic hepatitis. Autoantibodies were investigated by indirect immunofluorescence. HCV RNA was assayed by the polymerase chain reaction in 34 cases and viral genotypes were determined. Antinuclear antibodies were detected in three (7.5%) cases, one with a homogeneous pattern; smooth muscle autoantibodies in seven (17.5%) cases, always with V (vessels only) specificity and LKM1 in four (10%), at titers ranging from 1:20 and 1:2560. Clinical and virologic features did not significantly differ between autoantibody positive and negative cases, although infections with HCV genotypes 1a and 2 were more frequent in LKM1-positive patients. During observation, the child with the highest LKM1 titre was unsuccessfully treated with alpha interferon but responded to steroids. Twelve LKM1 negative children were also treated with interferon and one developed low LKM1 titers concomitant with an alanine aminotransferase flare. The sera of the five LKM1-positive children with investigated by immunoblotting with a human microsomal fraction and peptide 257-269 of cytochrome P450IID6. Only the serum of the child with the highest LKM1 titers was reactive. These results show that a consistent proportion of children with chronic hepatitis C circulate non-organ specific autoantibodies. The prevalence of LKM1 is greater than in adults and this could raise problems for the treatment of the disease with interferon. The analysis of LKM1 target antigens

Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

Science.gov (United States)

Bkaily, Ghassan; El-Bizri, Nesrine; Bui, Michel; Sukarieh, Rami; Jacques, Danielle; Fu, Michael L X

2003-03-01

The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine.

Characterization and potential clinical applications of autoantibodies against cytokines

DEFF Research Database (Denmark)

de Lemos Rieper, Carina; Galle, Pia; Hansen, Morten Bagge

2009-01-01

Autoantibodies recognizing cytokines arise in certain patients during the course of therapy with recombinant cytokines, although they may arise spontaneously as well. They are typically high avidity and in vitro neutralizing IgG antibodies present in picomolar to nanomolar concentrations. Methodo......Autoantibodies recognizing cytokines arise in certain patients during the course of therapy with recombinant cytokines, although they may arise spontaneously as well. They are typically high avidity and in vitro neutralizing IgG antibodies present in picomolar to nanomolar concentrations...

Red cell autoantibodies characterized by competitive inhibition of iodine 125 Rh alloantibody binding and by immunoprecipitation of membrane proteins

International Nuclear Information System (INIS)

Pierce, S.W.; Victoria, E.J.; Masouredis, S.P.

1990-01-01

The relationship between determinants recognized by warm-type immunoglobulin G red cell autoantibodies and the Rh antigens was characterized by autoantibody competitive inhibition of iodine 125 Rh alloantibody binding and autoantibody immunoprecipitation of iodine 125 red blood cell membrane proteins. The majority of blood donor autoantibody recognized epitopes that are closely related to Rh antigens as determined by competitive inhibition studies. Eighteen of 20 (90%) autoantibodies inhibited anti-Rh(c) binding, 15 inhibited anti-Rh(E), 5 inhibited anti-Rh(D), and only 2 failed to inhibit any of the three Rh alloantibodies tested. Autoantibodies that inhibited anti-Rh(D) also inhibited anti-Rh(c) and anti-Rh(E) and all those that inhibited anti-Rh(E) also inhibited anti-Rh(c). Autoantibodies that inhibited all three Rh alloantibodies immunoprecipitated 30 kd membrane polypeptides, as did two of the three autoantibodies that inhibited only anti-Rh(c) and anti-Rh(E). One autoantibody in this group and two autoantibodies that inhibited only anti-Rh(c), as well as an autoantibody that did not inhibit any of the Rh alloantibodies, immunoprecipitated only a single membrane polypeptide identified as band 3. The majority of normal donor red blood cell autoantibodies inhibited the binding of Rh alloantibodies, which indicates that they either bound to the Rh polypeptides or to epitopes on band 3 that were closely associated with the Rh complex

Enveloping Aerodynamic Decelerator

Science.gov (United States)

Nock, Kerry T. (Inventor); Aaron, Kim M. (Inventor); McRonald, Angus D. (Inventor); Gates, Kristin L. (Inventor)

2018-01-01

An inflatable aerodynamic deceleration method and system is provided for use with an atmospheric entry payload. The inflatable aerodynamic decelerator includes an inflatable envelope and an inflatant, wherein the inflatant is configured to fill the inflatable envelope to an inflated state such that the inflatable envelope surrounds the atmospheric entry payload, causing aerodynamic forces to decelerate the atmospheric entry payload.

[Significance of non-organ-specific autoantibodies in HCV-related chronic hepatitis].

Science.gov (United States)

Guidi, Marcello; Muratori, Paolo; Granito, Alessandro; Muratori, Luigi; Pappas, Georgios; Bianchi, Francesco B

2005-12-01

The preliminary question regarding the clinical issue of the antiviral therapy in the HCV related chronic hepatitis patients is: is it mandatory the research for the autoantibodies in the eligible patients for the antiviral treatment? This issue is of particular interest at the light of the the reported cases of HCV positive patients with positivity for liver kidney microsome type 1 antibody who developed a hepatitic flare during the antiviral treatment. The data from literature about the efficacy and safety on the antiviral treatment in patients with autoantibodies are few and controversial, particularly if the ones regarding antiviral drugs and more recent treatment regimens are taking into account (peg-interferon, combined therapy of interferon and ribavirin). Large and prospective studies are needed for a thorough evaluation about the potential impact of autoantibodies reactivity on the therapeutic outcome. To date, it must be confirmed that a strict monitoring of hepatic parameters is to recommend during the whole treatment phase. This in the light of a potential appearance of significant flares of aminotransferases, particularly in subjects with anti LKM-1 autoantibodies, during interferon therapy.

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications.

Science.gov (United States)

Cardinal, Héloise; Dieudé, Mélanie; Hébert, Marie-Josée

2017-02-01

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular injury, and/or rejection creates permissive conditions for the expression of cryptic autoantigens, allowing these autoantibodies to bind antigenic targets and further enhance vascular inflammation and renal dysfunction. Antiperlecan/LG3 antibodies and antiangiotensin II type 1 receptor antibodies have been found before transplant in patients with de novo transplants and portend negative long-term outcome in patients with renal transplants. Here, we review mounting evidence suggesting an important role for autoantibodies to cryptic antigens as novel accelerators of kidney dysfunction and acute or chronic allograft rejection. Copyright © 2017 by the American Society of Nephrology.

Coeliac disease autoantibodies mediate significant inhibition of tissue transglutaminase.

LENUS (Irish Health Repository)

Byrne, Greg

2012-02-01

The detection of antibodies directed against tissue transglutaminase (tTG) in serum is a sensitive and specific test for suspected coeliac disease. tTG is a ubiquitous, multifunctional enzyme that has been implicated in many important physiological processes as well as the site-specific deamidation of glutamine residues in gluten-derived peptides. This modification of gluten peptides facilitates their binding to HLA-DQ2, which results in amplification of the T-cell response to gluten. The purpose of this study was to investigate the possibility that patient IgA autoantibodies directed against tTG interfere with the crosslinking activity of the enzyme. IgA autoantibodies against tTG were isolated\\/depleted from patient serum and tested for their capacity to interfere with tTG activity in vitro using a sensitive fluorescence-based activity assay. We have demonstrated that autoantibodies cause significant inhibition of tTG-mediated crosslinking at equimolar and 2:1 ratios of antibody to enzyme.

Increasing ICA512 autoantibody titers predict development of abnormal oral glucose tolerance tests.

Science.gov (United States)

Sanda, Srinath

2018-03-01

Determine if autoantibody titer magnitude and variability predict glucose abnormalities in subjects at risk for type 1 diabetes. Demographic information, longitudinal autoantibody titers, and oral glucose tolerance test (OGTT) data were obtained from the TrialNet Pathway to Prevention study. Subjects (first and second degree relatives of individuals with type 1 diabetes) with at least 2 diabetes autoantibodies were selected for analysis. Autoantibody titer means were calculated for each subject for the duration of study participation and the relationship between titer tertiles and glucose value tertiles from OGTTs (normal, impaired, and diabetes) was assessed with a proportional odds ordinal regression model. A matched pairs analysis was used to examine the relationship between changes in individual autoantibody titers and 120-minute glucose values. Titer variability was quantified using cumulative titer standard deviations. We studied 778 subjects recruited in the TrialNet Pathway to Prevention study between 2006 and 2014. Increased cumulative mean titer values for both ICA512 and GAD65 (estimated increase in proportional odds = 1.61, 95% CI = 1.39, 1.87, P < 1 × 10 -9 and 1.17, 95% CI = 1.03, 1.32, P = .016, respectively) were associated with peak 120-minute glucose values. While fluctuating titer levels were observed in some subjects, no significant relationship between titer standard deviation and glucose values was observed. ICA512 autoantibody titers associate with progressive abnormalities in glucose metabolism in subjects at risk for type 1 diabetes. Fluctuations in autoantibody titers do not correlate with lower rates of progression to clinical disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

(Quasi-)Poisson enveloping algebras

OpenAIRE

Yang, Yan-Hong; Yao, Yuan; Ye, Yu

2010-01-01

We introduce the quasi-Poisson enveloping algebra and Poisson enveloping algebra for a non-commutative Poisson algebra. We prove that for a non-commutative Poisson algebra, the category of quasi-Poisson modules is equivalent to the category of left modules over its quasi-Poisson enveloping algebra, and the category of Poisson modules is equivalent to the category of left modules over its Poisson enveloping algebra.

Ly108 expression distinguishes subsets of invariant NKT cells that help autoantibody production and secrete IL-21 from those that secrete IL-17 in lupus prone NZB/W mice.

Science.gov (United States)

Tang, Xiaobin; Zhang, Bo; Jarrell, Justin A; Price, Jordan V; Dai, Hongjie; Utz, Paul J; Strober, Samuel

2014-05-01

Lupus is a systemic autoimmune disease characterized by anti-nuclear antibodies in humans and genetically susceptible NZB/W mice that can cause immune complex glomerulonephritis. T cells contribute to lupus pathogenesis by secreting pro-inflammatory cytokines such as IL-17, and by interacting with B cells and secreting helper factors such as IL-21 that promote production of IgG autoantibodies. In the current study, we determined whether purified NKT cells or far more numerous conventional non-NKT cells in the spleen of NZB/W female mice secrete IL-17 and/or IL-21 after TCR activation in vitro, and provide help for spontaneous IgG autoantibody production by purified splenic CD19(+) B cells. Whereas invariant NKT cells secreted large amounts of IL-17 and IL-21, and helped B cells, non-NKT cells did not. The subset of IL-17 secreting NZB/W NKT cells expressed the Ly108(lo)CD4(-)NK1.1(-) phenotype, whereas the IL-21 secreting subset expressed the Ly108(hi)CD4(+)NK1.1(-) phenotype and helped B cells secrete a variety of IgG anti-nuclear antibodies. α-galactocylceramide enhanced the helper activity of NZB/W and B6.Sle1b NKT cells for IgG autoantibody secretion by syngeneic B cells. In conclusion, different subsets of iNKT cells from mice with genetic susceptibility to lupus can contribute to pathogenesis by secreting pro-inflammatory cytokines and helping autoantibody production. Copyright © 2014 Elsevier Ltd. All rights reserved.

The presence of non-organ-specific autoantibodies is associated with a negative response to combination therapy with interferon and ribavirin for chronic hepatitis C

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Matern Siegfried

2004-02-01

Full Text Available Abstract Background Non-organ-specific autoantibodies are found in a considerable number of anti-HCV positive patients. Previous studies investigated the clinical relevance of these antibodies in patients treated with interferon monotherapy, but not combination therapies. Methods Anti-nuclear, anti-smooth muscle, anti-mitochondrial, anti-neutrophil-cytoplasmatic and anti-liver/kidney microsomal antibodies were determined in 78 consecutive anti-HCV positive patients by indirect immunofluorescence. The presence of these antibodies was related to demographic variables and to the outcome of antiviral combination therapy with interferon-α and ribavirin in 65 patients. Results In our study, positivity for autoantibodies was associated with higher alanine aminotransferase levels and higher mean values for HCV-RNA (p Conclusions The absence of non-organ-specific autoantibodies might indicate a significantly higher chance for viral clearance in response to combination therapy for chronic hepatitis C infection. Therefore, despite of an overall higher treatment response, the addition of the immunomodulatory drug ribavirin could accentuate immunological differences that affect treatment outcome and might have been less obvious in earlier studies analysing interferon monotherapy.

Monte Carlo investigation of the low-dose envelope from scanned proton pencil beams

International Nuclear Information System (INIS)

Sawakuchi, Gabriel O; Titt, Uwe; Mirkovic, Dragan; Ciangaru, George; Zhu, X Ronald; Sahoo, Narayan; Gillin, Michael T; Mohan, Radhe

2010-01-01

Scanned proton pencil beams carry a low-dose envelope that extends several centimeters from the individual beam's central axis. Thus, the total delivered dose depends on the size of the target volume and the corresponding number and intensity of beams necessary to cover the target volume uniformly. This dependence must be considered in dose calculation algorithms used by treatment planning systems. In this work, we investigated the sources of particles contributing to the low-dose envelope using the Monte Carlo technique. We used a validated model of our institution's scanning beam line to determine the contributions to the low-dose envelope from secondary particles created in a water phantom and particles scattered in beam line components. Our results suggested that, for high-energy beams, secondary particles produced by nuclear interactions in the water phantom are the major contributors to the low-dose envelope. For low-energy beams, the low-dose envelope is dominated by particles undergoing multiple Coulomb scattering in the beam line components and water phantom. Clearly, in the latter situation, the low-dose envelope depends directly on beam line design features. Finally, we investigated the dosimetric consequences of the low-dose envelope. Our results showed that if not modeled properly the low-dose envelope may cause clinically relevant dose disturbance in the target volume. This work suggested that this low-dose envelope is beam line specific for low-energy beams, should be thoroughly experimentally characterized and validated during commissioning of the treatment planning system, and therefore is of great concern for accurate delivery of proton scanning beam doses.

Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading

OpenAIRE

McLachlan, Sandra M.; Rapoport, Basil

2017-01-01

Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit. In contrast, antibodies induced by immunization of rabbits or mice recognize diverse epitopes. Recognition of immunodominant regions persists despite fluctuations in autoantibody levels following treatment or over time. The enhancement of...

First results with a radioreceptor-assay (TRAK-Assay) for TSH-receptor-autoantibodies

International Nuclear Information System (INIS)

Becker, W.; Reiners, C.; Boerner, W.

1983-01-01

A new radioreceptor-assay (TRAK-assay) for autoantibodies against TSH-receptors was tested in 48 untreated thyrotoxic patients (26 regional autonomies, 22 toxic diffuse goiters). None of the 26 patients with regional autonomy showed positive autoantibody-titers. 4 patients with toxic diffuse goiter and thyrotoxic exophthalmos were TRAK-positive. Positive titers of microsomal and thyreoglobulin autoantibodies could be seen in 8 of 9 patients with positive TRAK-titers. In accordance with the conventional methods for detecting thyroid-stimulating immunoglobulins the new TRAK-assay seems to be suited for differentiating between immunogenic toxic diffuse goiter (Graves' disease) and goiter with disseminated autonomy as well as for prediction of relapse. (orig.) [de

Anti-pentraxin 3 auto-antibodies might be protective in lupus nephritis: a large cohort study.

Science.gov (United States)

Yuan, Mo; Tan, Ying; Pang, Yun; Li, Yong-Zhe; Song, Yan; Yu, Feng; Zhao, Ming-Hui

2017-11-01

Anti-pentraxin 3 (PTX3) auto-antibodies were found to be associated with the absence of renal involvement in systemic lupus erythematosus (SLE). This study is to investigate the prevalence of anti-PTX3 auto-antibodies and their clinical significance based on a large Chinese lupus nephritis cohort. One hundred and ninety-six active lupus nephritis patients, 150 SLE patients without clinical renal involvement, and 100 healthy controls were enrolled. Serum anti-PTX3 auto-antibodies and PTX3 levels were screened by enzyme-linked immunosorbent assay (ELISA). The associations between anti-PTX3 auto-antibodies and clinicopathological parameters in lupus nephritis were further analyzed. Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement (19.4% (38/196) versus 40.7% (61/150), p auto-antibodies were negatively correlated with proteinuria in lupus nephritis (r = -.143, p = .047). The levels of proteinuria, serum creatinine, and the prevalence of thrombotic microangiopathy were significantly higher in patients with higher PTX3 levels (≥3.207 ng/ml) and without anti-PTX3 auto-antibodies compared with patients with lower PTX3 levels (auto-antibodies (4.79 (3.39-8.28) versus 3.95 (1.78-7.0), p = .03; 168.84 ± 153.63 versus 101.44 ± 47.36, p = .01; 34.1% (14/41) versus 0% (0/9), p = .04; respectively). Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement and associated with less severe renal damage, especially with the combined evaluation of serum PTX3 levels.

Nuclear Envelope Phosphatase 1-Regulatory Subunit 1 (Formerly TMEM188) Is the Metazoan Spo7p Ortholog and Functions in the Lipin Activation Pathway*

Science.gov (United States)

Han, Sungwon; Bahmanyar, Shirin; Zhang, Peixiang; Grishin, Nick; Oegema, Karen; Crooke, Roseann; Graham, Mark; Reue, Karen; Dixon, Jack E.; Goodman, Joel M.

2012-01-01

Lipin-1 catalyzes the formation of diacylglycerol from phosphatidic acid. Lipin-1 mutations cause lipodystrophy in mice and acute myopathy in humans. It is heavily phosphorylated, and the yeast ortholog Pah1p becomes membrane-associated and active upon dephosphorylation by the Nem1p-Spo7p membrane complex. A mammalian ortholog of Nem1p is the C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1, formerly “dullard”), but its Spo7p-like partner is unknown, and the need for its existence is debated. Here, we identify the metazoan ortholog of Spo7p, TMEM188, renamed nuclear envelope phosphatase 1-regulatory subunit 1 (NEP1-R1). CTDNEP1 and NEP1-R1 together complement a nem1Δspo7Δ strain to block endoplasmic reticulum proliferation and restore triacylglycerol levels and lipid droplet number. The two human orthologs are in a complex in cells, and the amount of CTDNEP1 is increased in the presence of NEP1-R1. In the Caenorhabditis elegans embryo, expression of nematode CTDNEP1 and NEP1-R1, as well as lipin-1, is required for normal nuclear membrane breakdown after zygote formation. The expression pattern of NEP1-R1 and CTDNEP1 in human and mouse tissues closely mirrors that of lipin-1. CTDNEP1 can dephosphorylate lipins-1a, -1b, and -2 in human cells only in the presence of NEP1-R1. The nuclear fraction of lipin-1b is increased when CTDNEP1 and NEP1-R1 are co-expressed. Therefore, NEP1-R1 is functionally conserved from yeast to humans and functions in the lipin activation pathway. PMID:22134922

Use of total lymphoid irradiation (TLI) in studies of the T cell dependence of autoantibody production in rheumatoid arthritis

International Nuclear Information System (INIS)

Tanay, A.; Strober, S.; Logue, G.L.; Schiffman, G.

1984-01-01

The effect of total lymphoid irradiation (TLI) on T cell-dependent and -independent humoral immune responses was studied in patients with intractable rheumatoid arthritis (RA). The serum levels of several autoantibodies and of antibodies to diphtheria (DT) and tetanus (TT) toxoids and to pneumococcal polysaccharide (PPS; 12 antigenic types) were studied before and after TLI. In addition, the patients were given a booster injection of DT and TT and a single injection of pneumococcal vaccine after radiotherapy. Antibody levels to DT and TT decreased about twofold after TLI and did not rise significantly after a booster injection. However, there was no reduction in antibody levels to PPS after TLI, and a significant rise in titers was observed after a single vaccination. The serum levels of rheumatoid factor (RF), anti-nuclear antibody (ANA), and granulocyte associated IgG rose slightly after TLI. Thus, the autoantibodies and antibodies to polysaccharides appear to be relatively independent of helper T cell function, which is markedly reduced after TLI. On the other hand, antibodies to protein antigens such as DT and TT appear to be more closely dependent upon T helper function in man, as has been reported in rodents. The findings suggest that T cell-independent autoantibody responses alone do not maintain the joint disease activity in RA, because improvement in joint disease after TLI has been reported

Do Electrochemiluminescence Assays Improve Prediction of Time to Type 1 Diabetes in Autoantibody-Positive TrialNet Subjects?

Science.gov (United States)

Fouts, Alexandra; Pyle, Laura; Yu, Liping; Miao, Dongmei; Michels, Aaron; Krischer, Jeffrey; Sosenko, Jay; Gottlieb, Peter; Steck, Andrea K

2016-10-01

To explore whether electrochemiluminescence (ECL) assays can help improve prediction of time to type 1 diabetes in the TrialNet autoantibody-positive population. TrialNet subjects who were positive for one or more autoantibodies (microinsulin autoantibody, GAD65 autoantibody [GADA], IA-2A, and ZnT8A) with available ECL-insulin autoantibody (IAA) and ECL-GADA data at their initial visit were analyzed; after a median follow-up of 24 months, 177 of these 1,287 subjects developed diabetes. Univariate analyses showed that autoantibodies by radioimmunoassays (RIAs), ECL-IAA, ECL-GADA, age, sex, number of positive autoantibodies, presence of HLA DR3/4-DQ8 genotype, HbA1c, and oral glucose tolerance test (OGTT) measurements were all significantly associated with progression to diabetes. Subjects who were ECL positive had a risk of progression to diabetes within 6 years of 58% compared with 5% for the ECL-negative subjects (P < 0.0001). Multivariate Cox proportional hazards models were compared, with the base model including age, sex, OGTT measurements, and number of positive autoantibodies by RIAs. The model with positivity for ECL-GADA and/or ECL-IAA was the best, and factors that remained significantly associated with time to diabetes were area under the curve (AUC) C-peptide, fasting C-peptide, AUC glucose, number of positive autoantibodies by RIAs, and ECL positivity. Adding ECL to the Diabetes Prevention Trial risk score (DPTRS) improved the receiver operating characteristic curves with AUC of 0.83 (P < 0.0001). ECL assays improved the ability to predict time to diabetes in these autoantibody-positive relatives at risk for developing diabetes. These findings might be helpful in the design and eligibility criteria for prevention trials in the future. © 2016 by the American Diabetes Association.

Storage envelopes or sleeves

International Nuclear Information System (INIS)

Freshwater, J.R.; Wagman, P.I.

1980-01-01

A storage envelope or sleeve particularly for processed X-ray films is described. It consists of front and back panels joined together at a hinge line and connected along the intermediate sides by connecting flaps. An inner pocket is formed from a third flap which is folded to lie against the inner face of the back panel. The panels may have additional score lines parallel to the closed sides of the envelope and the inner pocket so that the envelope and the inner pocket can accommodate bulky contents. The free edge of the pocket is inset from the open side of the envelope, and finger cut-outs may be provided to facilitate access to the contents of the envelope and the pocket. (author)

Protective plasma envelope

International Nuclear Information System (INIS)

Bocharov, V.N.; Konstantinov, S.G.; Kudryavtsev, A.M.; Myskin, O.K.; Panasyuk, V.M.; Tsel'nik, F.A.

1984-06-01

A method of creating an annular plasma envelope used to protect the hot plasma from flows of impurities and gases from the walls of the vacuum chamber is described. The diameter of the envelope is 30 cm, the thickness of the wall is 1.5 cm, the length is 2.5 m, and its density is from 10 13 to 10 14 cm -3 . The envelope attenuates the incident (from outside) flow of helium 10-fold and the low of hydrogen 20-fold

Generation of Antigen Microarrays to Screen for Autoantibodies in Heart Failure and Heart Transplantation.

Directory of Open Access Journals (Sweden)

Andrzej Chruscinski

Full Text Available Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen. Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient

Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production

Science.gov (United States)

Chung, Sharon A.; Taylor, Kimberly E.; Graham, Robert R.; Nititham, Joanne; Lee, Annette T.; Ortmann, Ward A.; Jacob, Chaim O.; Alarcón-Riquelme, Marta E.; Tsao, Betty P.; Harley, John B.; Gaffney, Patrick M.; Moser, Kathy L.; Petri, Michelle; Demirci, F. Yesim; Kamboh, M. Ilyas; Manzi, Susan; Gregersen, Peter K.; Langefeld, Carl D.; Behrens, Timothy W.; Criswell, Lindsey A.

2011-01-01

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE. PMID

Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production.

Directory of Open Access Journals (Sweden)

Sharon A Chung

2011-03-01

Full Text Available Systemic lupus erythematosus (SLE is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811 and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906 SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20 compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04, with p(heterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE.

Absence of anti-HMG-CoA reductase autoantibodies in severe self-limited statin-related myopathy.

Science.gov (United States)

Floyd, James S; Brody, Jennifer A; Tiniakou, Eleni; Psaty, Bruce M; Mammen, Andrew

2016-06-01

Patients with self-limited statin-related myopathy improve spontaneously when statins are stopped. In contrast, patients with statin-associated autoimmune myopathy have autoantibodies recognizing 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and usually require immunosuppressive therapy to control their disease. On initial presentation, it can sometimes be difficult to distinguish between these 2 diseases, as both present with muscle pain, weakness, and elevated serum creatine kinase (CK) levels. The goal of this study was to determine whether patients with severe self-limited statin-related myopathy also make anti-HMGCR autoantibodies. We screened 101 subjects with severe self-limited cerivastatin-related myopathy for anti-HMGCR autoantibodies. No patient with severe self-limited cerivastatin-related myopathy had anti-HMGCR autoantibodies. Anti-HMGCR autoantibody testing can be used to help differentiate whether a patient has self-limited myopathy due to cerivastatin or autoimmune statin-associated myopathy; these findings may apply to other statins as well. Muscle Nerve 54: 142-144, 2016. © 2016 Wiley Periodicals, Inc.

Stress-induced rise in serum anti-brain autoantibody levels in the rat.

Science.gov (United States)

Andrejević, S; Bukilica, M; Dimitrijević, M; Laban, O; Radulovic, J; Kovacevic-Jovanovic, V; Stanojevic, S; Vasiljevic, T; Marković, B M

1997-02-01

Sera from Wistar rats subjected to different stress procedures were tested by ELISA for the presence of autoantibodies with specificity for neuron-specific enolase (NSE) and S100 protein that are preferentially localized in neurons and glia, respectively. Autoantibodies were present in sera of animals before exposure to stress, and raised with age. Anti-NSE and anti-S100 autoantibody levels were increased one day after termination of restraint (2 hours daily, 10 days) and electric tail shock (80 shocks daily, 19 days), and in fifth and tenth week of overcrowding stress. Differences between stressed and control animals were not present one month following restraint and electric tail shock and in twentieth week of overcrowding.

Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia

DEFF Research Database (Denmark)

Beigneux, Anne P; Miyashita, Kazuya; Ploug, Michael

2017-01-01

lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay......-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.)........ Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1...

Antineuronal Autoantibodies : Molecular Characterization and Clinical Implication

NARCIS (Netherlands)

Hameete, M.H.|info:eu-repo/dai/nl/371750539

2017-01-01

Neurological autoimmune disorders associated with antineuronal autoantibodies result from an immune reaction directed at neuronal self-antigens. When affecting the central nervous system these can be divided into two subgroups: ‘classical’ paraneoplastic neurological syndromes (PNS) and autoimmune

Contactin-1 and Neurofascin-155/-186 Are Not Targets of Auto-Antibodies in Multifocal Motor Neuropathy.

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Kathrin Doppler

Full Text Available Multifocal motor neuropathy is an immune mediated disease presenting with multifocal muscle weakness and conduction block. IgM auto-antibodies against the ganglioside GM1 are detectable in about 50% of the patients. Auto-antibodies against the paranodal proteins contactin-1 and neurofascin-155 and the nodal protein neurofascin-186 have been detected in subgroups of patients with chronic inflammatory demyelinating polyneuropathy. Recently, auto-antibodies against neurofascin-186 and gliomedin were described in more than 60% of patients with multifocal motor neuropathy. In the current study, we aimed to validate this finding, using a combination of different assays for auto-antibody detection. In addition we intended to detect further auto-antibodies against paranodal proteins, specifically contactin-1 and neurofascin-155 in multifocal motor neuropathy patients' sera. We analyzed sera of 33 patients with well-characterized multifocal motor neuropathy for IgM or IgG anti-contactin-1, anti-neurofascin-155 or -186 antibodies using enzyme-linked immunosorbent assay, binding assays with transfected human embryonic kidney 293 cells and murine teased fibers. We did not detect any IgM or IgG auto-antibodies against contactin-1, neurofascin-155 or -186 in any of our multifocal motor neuropathy patients. We conclude that auto-antibodies against contactin-1, neurofascin-155 and -186 do not play a relevant role in the pathogenesis in this cohort with multifocal motor neuropathy.

Strategies for building reference standards for autoantibodies

Directory of Open Access Journals (Sweden)

Joanna eSheldon

2015-04-01

Full Text Available Producing robust, certified, traceable reference material for autoantibody testing is a vital element in maintaining the validity of results that are generated in the daily clinical laboratory routine. This is a huge challenge because of the high number of variables involved in the detection and measurement of the autoantibodies. The production of such materials is time consuming and needs rigorous attention to detail; this is best achieved by an overarching independent body who will oversee the process in a not for profit manner.Much effort has been made to build international standards for quantitative and qualitative assays based on monoclonal antibodies, obtained from affinity purification and plasmapheresis. The big challenge is to respect individual differences in immune response to the same antigen. A promising ongoing initiative is the construction of pools with monospecific samples from different individuals.

Use of self-collected capillary blood samples for islet autoantibody screening in relatives: a feasibility and acceptability study.

Science.gov (United States)

Liu, Y; Rafkin, L E; Matheson, D; Henderson, C; Boulware, D; Besser, R E J; Ferrara, C; Yu, L; Steck, A K; Bingley, P J

2017-07-01

To evaluate the feasibility of using self-collected capillary blood samples for islet autoantibody testing to identify risk in relatives of people with Type 1 diabetes. Participants were recruited via the observational TrialNet Pathway to Prevention study, which screens and monitors relatives of people with Type 1 diabetes for islet autoantibodies. Relatives were sent kits for capillary blood collection, with written instructions, an online instructional video link and a questionnaire. Sera from capillary blood samples were tested for autoantibodies to glutamic acid decarboxylase, islet antigen-2, insulin and zinc transporter 8. 'Successful' sample collection was defined as obtaining sufficient volume and quality to provide definitive autoantibody results, including confirmation of positive results by repeat assay. In 240 relatives who returned samples, the median (range) age was 15.5 (1-49) years and 51% were male. Of these samples, 98% were sufficient for glutamic acid decarboxylase, islet antigen-2 and zinc transporter 8 autoantibody testing and 84% for insulin autoantibody testing and complete autoantibody screen. The upper 90% confidence bound for unsuccessful collection was 4.4% for glutamic acid decarboxylase, islet antigen-2 and/or zinc transporter 8 autoantibody assays, and 19.3% for insulin autoantibodies. Despite 43% of 220 questionnaire respondents finding capillary blood collection uncomfortable or painful, 82% preferred home self-collection of capillary blood samples compared with outpatient venepuncture (90% of those aged 18 years). The perceived difficulty of collecting capillary blood samples did not affect success rate. Self-collected capillary blood sampling offers a feasible alternative to venous sampling, with the potential to facilitate autoantibody screening for Type 1 diabetes risk. © 2017 Diabetes UK.

Frequency of autoimmune disorders and autoantibodies in patients with neuromyelitis optica.

Science.gov (United States)

Pereira, Wildéa Lice de Carvalho Jennings; Reiche, Edna Maria Vissoci; Kallaur, Ana Paula; Oliveira, Sayonara Rangel; Simão, Andréa Name Colado; Lozovoy, Marcell Alysson Batisti; Schiavão, Lucas José Vaz; Rodrigues, Paula Raquel do Vale Pascoal; Alfieri, Daniela Frizon; Flauzino, Tamires; Kaimen-Maciel, Damacio Ramón

2017-06-01

The aim of this study was to report the frequency of autoimmune disorders and autoantibodies in 22 patients with neuromyelitis optica (NMO), as well as whether the seropositivity for autoantibodies differs between anti-aquaporin 4 (AQP4) positive and AQP4 negative NMO patients. Demographic, medical records, and a profile of autoantibodies were evaluated in 22 NMO patients, including AQP4, anti-thyroid-stimulating hormone receptor, antinuclear antibodies (ANA), anti-thyroperoxidase (anti-TPO), anti-thyroglobulin (anti-Tg), anti-double-stranded DNA, anti-neutrophil cytoplasmic, anti-cyclic citrullinate peptide, rheumatoid factor, anti-SSA/Ro, anti-SSB/La, anti-Smith antibodies (anti-Sm), anti-ribonucleoprotein, anti-nucleosome, and anti-Scl70. Thyroid-stimulating hormone and free thyroxin were measured. The frequency of women was higher than men (95.5% vs. 4.5%) and 68.2% were Afro-Brazilians. Six (27.3%) patients presented other autoimmune disorders, such as Hashimoto thyroiditis (n=2), Graves' disease (n=1), juvenile idiopathic arthritis (n=1), systemic lupus erythematosus and systemic sclerosis (n=1), and Raynaud's phenomenon (n=1). The most frequent autoantibodies were anti-AQP4 (54.5%), anti-nucleosome (31.8%), ANA (27.3%), anti-TPO (22.7%), and anti-Tg (22.7%). Difference was not observed in the frequency of autoimmune disorders when the patients were compared according to their anti-AQP4 status. The results of the present study underscored that the NMO patients present high frequency of autoantibodies against cellular antigens and the presence of autoimmune disorders. Further studies with large number of NMO patients may contribute to advances in the understanding of NMO disease mechanisms.

Thyroid Autoantibodies Display both “Original Antigenic Sin” and Epitope Spreading

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Sandra M. McLachlan

2017-12-01

Full Text Available Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg, thyroid peroxidase (TPO, and the thyrotropin receptor (TSHR A-subunit. In contrast, antibodies induced by immunization of rabbits or mice recognize diverse epitopes. Recognition of immunodominant regions persists despite fluctuations in autoantibody levels following treatment or over time. The enhancement of spontaneously arising pathogenic TSHR antibodies in transgenic human thyrotropin receptor/NOD.H2h4 mice by injecting a non-pathogenic form of TSHR A-subunit protein also provides evidence for original antigenic sin. From other studies, antigen presentation by B cells, not dendritic cells, is likely responsible for original antigenic sin. Recognition of restricted epitopes on the large glycosylated thyroid autoantigens (60-kDa A-subunit, 100-kDa TPO, and 600-kDa Tg facilitates exploring the amino acid locations in the immunodominant regions. Epitope spreading has also been revealed by autoantibodies in thyroid autoimmunity. In humans, and in mice that spontaneously develop autoimmunity to all three thyroid autoantigens, autoantibodies develop first to Tg and later to TPO and the TSHR A-subunit. The pattern of intermolecular epitope spreading is related in part to the thyroidal content of Tg, TPO and TSHR A-subunit and to the molecular sizes of these proteins. Importantly, the epitope spreading pattern provides a rationale for future antigen-specific manipulation to block the development of all thyroid autoantibodies by inducing tolerance to Tg, first in the autoantigen cascade. Because of its abundance, Tg may be the autoantigen of choice to explore antigen-specific treatment, preventing the development of pathogenic TSHR antibodies.

Autoantibodies Affect Brain Density Reduction in Nonneuropsychiatric Systemic Lupus Erythematosus Patients

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Jian Xu

2015-01-01

Full Text Available This study explores the relationship between autoantibodies and brain density reduction in SLE patients without major neuropsychiatric manifestation (NPSLE. Ninety-five NPSLE patients without obvious cerebral deficits, as determined by conventional MRI, as well as 89 control subjects, underwent high-resolution structural MRI. Whole-brain density of grey matter (GMD and white matter (WMD were calculated for each individual, and correlations between the brain density, symptom severity, immunosuppressive agent (ISA, and autoantibody levels were assessed. The GMD and WMD of the SLE group decreased compared to controls. GMD was negatively associated with SLE activity. The WMD of patients who received ISA treatment were higher than that in the patients who did not. The WMD of patients with anticardiolipin (ACL or anti-SSB/La antibodies was lower than in patients without these antibodies, while the GMD was lower in patients with anti-SM or anti-U1RNP antibodies. Thus, obvious brain atrophy can occur very early even before the development of significant symptoms and specific autoantibodies might contribute to the reduction of GMD or WMD in NPSLE patients. However, ISAs showed protective effects in minimizing GMD and WMD reduction. The presence of these specific autoantibodies might help identify early brain damage in NPSLE patients.

Flow cytometric immunobead assay for quantitative detection of platelet autoantibodies in immune thrombocytopenia patients.

Science.gov (United States)

Zhai, Juping; Ding, Mengyuan; Yang, Tianjie; Zuo, Bin; Weng, Zhen; Zhao, Yunxiao; He, Jun; Wu, Qingyu; Ruan, Changgeng; He, Yang

2017-10-23

Platelet autoantibody detection is critical for immune thrombocytopenia (ITP) diagnosis and prognosis. Therefore, we aimed to establish a quantitative flow cytometric immunobead assay (FCIA) for ITP platelet autoantibodies evaluation. Capture microbeads coupled with anti-GPIX, -GPIb, -GPIIb, -GPIIIa and P-selectin antibodies were used to bind the platelet-bound autoantibodies complex generated from plasma samples of 250 ITP patients, 163 non-ITP patients and 243 healthy controls, a fluorescein isothiocyanate (FITC)-conjugated secondary antibody was the detector reagent and mean fluorescence intensity (MFI) signals were recorded by flow cytometry. Intra- and inter-assay variations of the quantitative FCIA assay were assessed. Comparisons of the specificity, sensitivity and accuracy between quantitative and qualitative FCIA or monoclonal antibody immobilization of platelet antigen (MAIPA) assay were performed. Finally, treatment process was monitored by our quantitative FCIA in 8 newly diagnosed ITPs. The coefficient of variations (CV) of the quantitative FCIA assay were respectively 9.4, 3.8, 5.4, 5.1 and 5.8% for anti-GPIX, -GPIb, -GPIIIa, -GPIIb and -P-selectin autoantibodies. Elevated levels of autoantibodies against platelet glycoproteins GPIX, GPIb, GPIIIa, GPIIb and P-selectin were detected by our quantitative FCIA in ITP patients compared to non-ITP patients or healthy controls. The sensitivity, specificity and accuracy of our quantitative assay were respectively 73.13, 81.98 and 78.65% when combining all 5 autoantibodies, while the sensitivity, specificity and accuracy of MAIPA assay were respectively 41.46, 90.41 and 72.81%. A quantitative FCIA assay was established. Reduced levels of platelet autoantibodies could be confirmed by our quantitative FCIA in ITP patients after corticosteroid treatment. Our quantitative assay is not only good for ITP diagnosis but also for ITP treatment monitoring.

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications

OpenAIRE

Cardinal, Héloise; Dieudé, Mélanie; Hébert, Marie-Josée

2016-01-01

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular ...

Biomimetic Envelopes

OpenAIRE

Ilaria Mazzoleni

2010-01-01

How to translate the lessons learned from the analysis and observation of the animal world is the design learning experience presented in this article. Skin is a complex and incredibly sophisticated organ that performs various functions, including protection, sensation and heat and water regulation. In a similar way building envelopes serve multiple roles, as they are the interface between the building inhabitants and environmental elements. The resulting architectural building envelopes prot...

Autoantibodies persist in relatives to systemic lupus erythematosus patients during 12 years follow-up

DEFF Research Database (Denmark)

Langkilde, Henrik; Voss, A; Heegaard, N

2017-01-01

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with presence of autoantibodies and characteristic multi-organ involvement. Relatives of SLE patients have an increased risk of autoantibody production and autoimmune diseases. METHODS: In 2001, 226 first degree relatives (FDRs...

Electrophoretic characterization of the Mammalian nuclear matrix proteome, nuclear envelope, nucleoli and covalently bound ADP-ribose polymers: potential applications to cancer.

Science.gov (United States)

Aranda, Xavier G; Racho, Ronald G; Pacheco-Rodríguez, Gustavo; Alvarez-González, Rafael

2014-01-01

Nucleic acid metabolism is biochemically compartmentalized to the nucleus. Thus, it is necessary to define the proteome of the various macromolecular structures within this organelle. We isolated the nuclear matrix (NM) fraction from rat liver by sequential centrifugation steps at 13,000 rpm, staggered between endogenous nuclease treatment for 2 h at 37°C, followed by high-salt (H.S.; 2.0 M NaCl) and non-ionic detergent extractions (0.1%- or 1.0% Triton X-100) to eliminate the bulk of chromosomal DNA/RNA, histone proteins and the nuclear envelope (NE). Integrity of the NM and NE structures was confirmed by electron microscopy. Next, we analyzed the NM proteome on a 20% polyacrylamide gel using the PhastSystem. We observed the absence of histone proteins and the characteristic presence of the lamins by Coomassie blue staining. By contrast, upon silver staining, following electrophoretic separation with a Tris-Borate-EDTA buffer, we observed the NM-associated nucleic RNA and protein-free ADP-ribose polymers. While polymers are found in much lower concentration than RNA in NM, they were purified by affinity chromatography on boronate resin prior to electrophoresis. We observed the electrophoretic resolution of free ADP-ribose chains (5-25 units) by silver staining. The significance of our observations to cancer studies and carcinogenesis is discussed. Copyright© 2014, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease.

Science.gov (United States)

Akhtar, Rizwan S; Licata, Joseph P; Luk, Kelvin C; Shaw, Leslie M; Trojanowski, John Q; Lee, Virginia M-Y

2018-03-03

Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto-antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared to HC, whereas serum levels were not significantly different. CSF auto-antibody levels did not associate with amyloid-β 1-42 , total tau, or phosphorylated tau. CSF auto-antibody levels correlated with performance on the Montreal Cognitive Assessment, even when controlled for CSF amyloidβ 1-42 . CSF hemoglobin levels, as a proxy for contamination of CSF by blood during lumbar puncture, did not influence these observations. Using recombinant α-synuclein with N- and C-terminal truncations, we found that CSF auto-antibodies target amino acids 100 through 120 of α-synuclein. We conclude that endogenous CSF auto-antibodies are significantly higher in PD patients as compared to HC, suggesting that they could indicate the presence of underlying synucleinopathy. These auto-antibodies associate with poor cognition, independently of CSF amyloidβ 1-42 ., and target a select C-terminal region of α-synuclein. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

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Tyler Cutforth

2017-04-01

Full Text Available Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS targets must gain access to the brain and spinal cord by crossing the blood–brain barrier (BBB, a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies.

Hello from the Other Side: How Autoantibodies Circumvent the Blood-Brain Barrier in Autoimmune Encephalitis.

Science.gov (United States)

Platt, Maryann P; Agalliu, Dritan; Cutforth, Tyler

2017-01-01

Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood-brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies.

IgG4 autoantibodies are inhibitory in the autoimmune disease bullous pemphigoid.

Science.gov (United States)

Zuo, Yagang; Evangelista, Flor; Culton, Donna; Guilabert, Antonio; Lin, Lin; Li, Ning; Diaz, Luis; Liu, Zhi

2016-09-01

The IgG4 subclass of antibodies exhibits unique characteristics that suggest it may function in an immunoregulatory capacity. The inhibitory function of IgG4 has been well documented in allergic disease by the demonstration of IgG4 blocking antibodies, but similar functions have not been explored in autoimmune disease. Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease characterized by autoantibodies directed against BP180 and an inflammatory infiltrate including eosinophils and neutrophils. Animal models have revealed that the NC16A region within BP180 harbors the critical epitopes necessary for autoantibody mediated disease induction. BP180 NC16A-specific IgG belong to the IgG1, IgG3, and IgG4 subclasses. The purpose of this study was to determine effector functions of different IgG subclasses of NC16A-specific autoantibodies in BP. We find that IgG4 anti-NC16A autoantibodies inhibit the binding of IgG1 and IgG3 autoantibodies to the NC16A region. Moreover, IgG4 anti-NC16A blocks IgG1 and IgG3 induced complement fixation, neutrophil infiltration, and blister formation clinically and histologically in a dose-dependent manner following passive transfer to humanized BP180-NC16A mice. These findings highlight the inhibitory role of IgG4 in autoimmune disease and have important implications for the treatment of BP as well as other antibody mediated inflammatory and autoimmune diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Autoantibodies in Chronic Obstructive Pulmonary Disease

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Lifang Wen

2018-01-01

Full Text Available Chronic obstructive pulmonary disease (COPD, the fourth leading cause of death worldwide, is characterized by irreversible airflow limitation based on obstructive bronchiolitis, emphysema, and chronic pulmonary inflammation. Inhaled toxic gases and particles, e.g., cigarette smoke, are major etiologic factors for COPD, while the pathogenesis of the disease is only partially understood. Over the past decade, an increasing body of evidence has been accumulated for a link between COPD and autoimmunity. Studies with clinical samples have demonstrated that autoantibodies are present in sera of COPD patients and some of these antibodies correlate with specific disease phenotypes. Furthermore, evidence from animal models of COPD has shown that autoimmunity against pulmonary antigens occur during disease development and is capable of mediating COPD-like symptoms. The idea that autoimmunity could contribute to the development of COPD provides a new angle to understand the pathogenesis of the disease. In this review article, we provide an advanced overview in this field and critically discuss the role of autoantibodies in the pathogenesis of COPD.

The near boiling reactor: design of a small nuclear reactor for extending the operational envelope of the Victoria Class Submarine

International Nuclear Information System (INIS)

Cole, C.; Bonin, H.

2005-01-01

A small, inherently safe nuclear reactor that will provide enough power to maintain the hotel load of the Victoria Class Submarine and extend her operational envelope, has been conceptually designed. The final reactor concept, named the Near Boiling (NB) Reactor, employs TRISO fuel particles in Zirconium cladded fuel rods. The reactor is light water moderated and cooled. The core life is specifically designed to coincide with the refit cycle of the Victoria Class Submarine. The reactor employs a simple and reliable control and shut down system that requires little intervention on the part of the submarine's crew. Also, a kinetic model is developed that demonstrates the inherent safety features of the reactor during several accident scenarios. (author)

The near boiling reactor: design of a small nuclear reactor for extending the operational envelope of the Victoria Class Submarine

Energy Technology Data Exchange (ETDEWEB)

Cole, C.; Bonin, H. [Royal Military College of Canada, Dept. of Chemistry and Chemical Engineering, Kingston, Ontario (Canada)]. E-mail: chris.cole@rmc.ca; bonin-h@rmc.ca

2005-07-01

A small, inherently safe nuclear reactor that will provide enough power to maintain the hotel load of the Victoria Class Submarine and extend her operational envelope, has been conceptually designed. The final reactor concept, named the Near Boiling (NB) Reactor, employs TRISO fuel particles in Zirconium cladded fuel rods. The reactor is light water moderated and cooled. The core life is specifically designed to coincide with the refit cycle of the Victoria Class Submarine. The reactor employs a simple and reliable control and shut down system that requires little intervention on the part of the submarine's crew. Also, a kinetic model is developed that demonstrates the inherent safety features of the reactor during several accident scenarios. (author)

Non-organ-specific autoantibodies in chronic hepatitis C patients: association with histological activity and fibrosis.

Science.gov (United States)

Chrétien, P; Chousterman, M; Abd Alsamad, I; Ozenne, V; Rosa, I; Barrault, C; Lons, T; Hagège, H

2009-01-01

Non-organ-specific autoantibodies (NOSAs) are frequently found in the sera of patients with Hepatitis C Virus (HCV) infection. However, no conclusive answers have been produced concerning the clinical relevance of these antibodies. To determine whether a relationship might exist between the presence of NOSA and the severity of liver disease in chronic hepatitis C. 186 treatment-naïve chronic hepatitis C patients were studied consecutively for autoantibodies. Liver biopsies were analyzed according to the Metavir score. NOSAs were present in 75 patients (40%). Anti-nuclear antibodies were found in 32% of patients (speckled pattern), anti-smooth muscle in 15% without F-actin specificity, anti-mitochondria in 0.5%, and anti-LKM1 in 0.5%, respectively. No liver-cytosol1 or soluble liver antigen antibodies were detected. There was a highly significant correlation between the positivity of NOSA and the degree of inflammation and hepatocellular injury (p = 0.001) and also with the degree of fibrosis (p < 0.0001). The presence of NOSA was associated with higher aspartate aminotransferase, gamma-glutamyl-transpeptidase, gamma-globulin and immunoglobulin G levels. By contrast, no differences were observed regarding age, gender, route of infection, duration of disease, HCV genotypes or viral load. NOSAs were associated with the most severe forms of chronic HCV infections.

Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability.

Science.gov (United States)

Takaki, Tohru; Montagner, Marco; Serres, Murielle P; Le Berre, Maël; Russell, Matt; Collinson, Lucy; Szuhai, Karoly; Howell, Michael; Boulton, Simon J; Sahai, Erik; Petronczki, Mark

2017-07-24

Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability.

Association between anti-thyroid peroxidase and anti-cytokeratin 18 autoantibodies and bronchial asthma in women

Directory of Open Access Journals (Sweden)

Hala A. Mohammad

2016-01-01

Conclusion: Positive anti-TPO autoantibodies and anti-CK18 autoantibodies in asthmatic patients and their higher level in the non-allergic asthma group may strengthen the presence of a hidden autoimmune phenomenon in non-allergic asthma.

Building envelope

CSIR Research Space (South Africa)

Gibberd, Jeremy T

2009-01-01

Full Text Available for use in the building. This is done through photovoltaic and solar water heating panels and wind turbines. Ideally these are integrated in the design of the building envelope to improve the aesthetic quality of the building and minimise material... are naturally ventilated. Renewable energy The building envelope includes renewable energy generation such as photovoltaics, wind turbines and solar water heaters and 10% of the building’s energy requirements are generated from these sources. Views All...

Autoantibodies, histocompatibility antigens and testosterone in males with alcoholic liver cirrhosis

DEFF Research Database (Denmark)

Gluud, C; Tage-Jensen, Ulrik Viggo; Bahnsen, M

1981-01-01

Titres and immunoglobulin classes of autoantibodies were examined in 69 male patients with alcoholic liver cirrhosis and the findings were related to particular human leucocyte antigens and serum concentration of testosterone. Both anti-nuclear antibodies (ANA) and smooth muscle antibodies (SMA...... had higher titres of ANA (n.s.) and SMA (P less than 0.05) than patients without these HLA antigens. Serum concentrations of testosterone were significantly lower in ANA-positive patients than in those negative (P less than 0.05), and a similar tendency was found in SMA-positive patients....... With increasing titres of ANA the concentration of testosterone fell. Serum concentration of testosterone correlated inversely (P less than 0.05) with plasma immunoglobulin G and A. It is concluded that both genetic and hormonal factors may influence the humoral immune response in these patients....

An autoantibody against Nε-(carboxyethyl)lysine (CEL): Possible involvement in the removal of CEL-modified proteins by macrophages

International Nuclear Information System (INIS)

Mera, Katsumi; Nagai, Ryoji; Takeo, Kazuhiro; Izumi, Miyoko; Maruyama, Toru; Otagiri, Masaki

2011-01-01

Highlights: → A higher amount of autoantibody against CEL than that of other AGEs was observed in human plasma. → The purified human anti-CEL autoantibody specifically reacted with CEL. → Anti-CEL antibody accelerated the uptake of 125 I-CEL-HSA by macrophage in vitro. → Endocytic uptake of 125 I-CEL-HSA by mice liver was accelerated in the presence of anti-CEL antibody. -- Abstract: Advanced glycation end products (AGEs) are believed to play a significant role in the development of diabetic complications. In this study, we measured the levels of autoantibodies against several AGE structures in healthy human plasma and investigated the physiological role of the autoantibodies. A high titer of the autoantibody against N ε -(carboxyethyl)lysine (CEL) was detected in human plasma compared with other AGE structures such as CML and pentosidine. The purified human anti-CEL autoantibody reacted with CEL-modified human serum albumin (CEL-HSA), but not CML-HSA. A rabbit polyclonal anti-CEL antibody, used as a model autoantibody against CEL, accelerated the uptake of CEL-HSA by macrophages, but did not enhance the uptake of native HSA. Furthermore, when 125 I-labeled CEL-HSA was injected into the tail vein of mice, accumulation of 125 I-CEL-HSA in the liver was accelerated by co-injection of the rabbit anti-CEL antibody. These results demonstrate that the autoantibody against CEL in plasma may play a role in the macrophage uptake of CEL-modified proteins.

Association of Autoantibodies to BP180 with Disease Activity in Greek Patients with Bullous Pemphigoid

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Aikaterini Patsatsi

2012-01-01

Full Text Available 39 bullous pemphigoid (BP patients were studied to assess the clinical significance of anti-BP180 and anti-BP230 circulating autoantibodies of BP and correlate their titers with the clinical scores of the BP Disease Area Index (BPDAI and the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS as well as with the intensity of pruritus measured by the BPDAI pruritus component. All parameters were evaluated by the time of diagnosis (baseline, month 3, and month 6. Titers of anti-BP180 autoantibodies were strongly correlated with BPDAI (, and ABSIS (, values, as well as with BPDAI component for the intensity of pruritus (, at baseline. At month 3, titers of anti-BP180 autoantibodies were strongly correlated with BPDAI (, and ABSIS (, values, as well as with the BPDAI component for the intensity of pruritus (, . At month 6, titers of anti-BP180 autoantibodies were strongly correlated with BPDAI (, and ABSIS (, values, as well as with the BPDAI component for the intensity of pruritus (, . There was no statistically significant correlation between titers of anti-BP230 autoantibodies and the BPDAI, ABSIS, and BPDAI component for the intensity of pruritus at the same time points.

Multiple Autoantibodies Display Association with Lymphopenia, Proteinuria, and Cellular Casts in a Large, Ethnically Diverse SLE Patient Cohort

Directory of Open Access Journals (Sweden)

Rufei Lu

2012-01-01

Full Text Available Purpose. This study evaluates high-throughput autoantibody screening and determines associated systemic lupus erythematosus (SLE clinical features in a large lupus cohort. Methods. Clinical and demographic information, along with serum samples, were obtained from each SLE study participant after appropriate informed consent. Serum samples were screened for 10 distinct SLE autoantibody specificities and examined for association with SLE ACR criteria and subcriteria using conditional logistic regression analysis. Results. In European-American SLE patients, autoantibodies against 52 kD Ro and RNP 68 are independently enriched in patients with lymphopenia, anti-La, and anti-ribosomal P are increased in patients with malar rash, and anti-dsDNA and anti-Sm are enriched in patients with proteinuria. In African-American SLE patients, cellular casts associate with autoantibodies against dsDNA, Sm, and Sm/nRNP. Conclusion. Using a high-throughput, bead-based method of autoantibody detection, anti-dsDNA is significantly enriched in patienets with SLE ACR renal criteria as has been previously described. However, lymphopenia is associated with several distinct autoantibody specificities. These findings offer meaningful information to allow clinicians and clinical investigators to understand which autoantibodies correlate with select SLE clinical manifestations across common racial groups using this novel methodology which is expanding in clinical use.

Muscle autoantibodies in myasthenia gravis: beyond diagnosis?

Science.gov (United States)

Meriggioli, Matthew N; Sanders, Donald B

2012-01-01

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. A number of molecules, including ion channels and other proteins at the neuromuscular junction, may be targeted by autoantibodies leading to abnormal neuromuscular transmission. In approximately 85% of patients, autoantibodies, directed against the postsynaptic nicotinic acetylcholine receptor can be detected in the serum and confirm the diagnosis, but in general, do not precisely predict the degree of weakness or response to therapy. Antibodies to the muscle-specific tyrosine kinase are detected in approximately 50% of generalized myasthenia gravis patients who are seronegative for anti-acetylcholine receptor antibodies, and levels of anti-muscle-specific tyrosine kinase antibodies do appear to correlate with disease severity and treatment response. Antibodies to other muscle antigens may be found in the subsets of myasthenia gravis patients, potentially providing clinically useful diagnostic information, but their utility as relevant biomarkers (measures of disease state or response to treatment) is currently unclear. PMID:22882218

The LHC on an envelope

CERN Multimedia

2007-01-01

The series of envelopes featuring CERN issued this summer was a huge success. The French postal services of the Pays de Gex will shortly be launching the second set of pre-paid envelopes issued in collaboration with the Laboratory this year, this time highlighting the LHC. Five thousand envelopes describing the accelerator’s capabilities will go on sale on 12 November, and some of the packs will even contain a small sample of the cables from the heart of the LHC magnets. The sets of ten pre-paid envelopes will tell you everything about CERN’s flagship accelerator, from its astounding technical capabilities to its spin-offs in the fields of technology and human resources. Each envelope will feature a different attribute or spin-off of the LHC. People will be invited to consult CERN’s public website for more detailed explanations if they want to know more. The new envelopes will be available from five post offices in the Pays ...

Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.

Directory of Open Access Journals (Sweden)

Vincent Plagnol

2011-08-01

Full Text Available The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC human leukocyte antigen (HLA region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP data in type 1 diabetes (T1D patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506, insulinoma-associated antigen 2 (IA-2A, n = 2,498, antibodies to the autoimmune thyroid (Graves' disease (AITD autoantigen thyroid peroxidase (TPOA, n = 8,300, and antibodies against gastric parietal cells (PCA, n = 4,328 that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10: 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A.

GAD65 autoantibodies in women with gestational or insulin dependent diabetes mellitus diagnosed during pregnancy

DEFF Research Database (Denmark)

Petersen, J S; Dyrberg, Torben Bech; Damm, P

1996-01-01

We have studied the presence of GAD65 autoantibodies in women with insulin-dependent diabetes mellitus (IDDM) (n = 28) or gestational diabetes (GDM) (n = 139) diagnosed during pregnancy and investigated the temporal relationship between these autoantibodies and the subsequent recurrence...

Prevalence of serum anti-neuronal autoantibodies in patients admitted to acute psychiatric care

DEFF Research Database (Denmark)

Schou, M; Sæther, S G; Borowski, K

2016-01-01

BACKGROUND: Autoimmune encephalitis associated with anti-neuronal antibodies may be challenging to distinguish from primary psychiatric disorders. The significance of anti-neuronal antibodies in psychiatric patients without clear evidence of autoimmune encephalitis is unknown. We investigated...... the serum prevalence of six anti-neuronal autoantibodies in a cohort of unselected patients admitted to acute psychiatric care. METHOD: Serum was drawn from 925 patients admitted to acute psychiatric in-patient care. Psychiatric diagnoses were set according to International Classification of Diseases (ICD......)-10 criteria. Antibody analysis was performed with an indirect immunofluorescence test for N-methyl d-aspartate receptor (NMDAR) antibodies and five other anti-neuronal autoantibodies of the immunoglobulin (Ig) classes IgA, IgG and IgM isotype. RESULTS: Anti-neuronal autoantibodies were found in 11...

Measurement of antiacetylcholine receptor auto-antibodies in ...

African Journals Online (AJOL)

Two different acetylcholine receptor (AChR) preparations derived from amputated human muscle (AChRAMP) and from the human rhabdomyosarcoma cell line TE671 (AChRTE67,) were compared in radio-immunoprecipitation assays for the detection of AChR auto-antibodies in serum specimens from 20 patients with ...

Utility of Novel Autoantibodies in the Diagnosis of Sjögren's Syndrome Among Patients With Dry Eye.

Science.gov (United States)

Karakus, Sezen; Baer, Alan N; Agrawal, Devika; Gurakar, Merve; Massof, Robert W; Akpek, Esen K

2018-04-01

To investigate the value of 3 novel autoantibodies [salivary protein 1 (SP1), carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP)] in differentiating Sjögren's syndrome (SS)-related dry eye from non-SS dry eye. Forty-six dry eye patients with SS (SS dry eye), 14 dry eye patients without SS (non-SS dry eye), and 25 controls were included. The 2012 American College of Rheumatology classification criteria were used for the diagnosis of SS. After a detailed review of systems, the Ocular Surface Disease Index questionnaire, Schirmer test without anesthesia, tear film breakup time, and ocular surface staining were performed to assess dry eye. All participants underwent serological testing using a commercially available finger prick kit. Thirty-seven patients with SS (80.4%) had a positive traditional autoantibody and 28 (60.9%) had a positive novel autoantibody. Traditional autoantibodies were absent in all non-SS dry eye patients and controls. Novel autoantibodies were present in 7/14 (50%) non-SS dry eye patients and 4/25 (16%) controls. Among 3 novel autoantibodies, anti-CA6 was significantly more prevalent in the SS and non-SS dry eye groups than in controls (52.2% vs. 42.9% vs. 8.0%, P = 0.001). Dry eye patients with positive anti-CA6 alone were significantly younger than patients with only traditional autoantibodies. Anti-CA6 was associated with worse dry eye signs and symptoms. Anti-CA6 was the most prevalent novel autoantibody in patients with dry eye, and was associated with younger age and more severe disease. Longitudinal studies are needed to determine whether anti-CA6 is a marker for early SS or perhaps another form of an autoimmune dry eye disease.

Protoparvovirus Knocking at the Nuclear Door.

Science.gov (United States)

Mäntylä, Elina; Kann, Michael; Vihinen-Ranta, Maija

2017-10-02

Protoparvoviruses target the nucleus due to their dependence on the cellular reproduction machinery during the replication and expression of their single-stranded DNA genome. In recent years, our understanding of the multistep process of the capsid nuclear import has improved, and led to the discovery of unique viral nuclear entry strategies. Preceded by endosomal transport, endosomal escape and microtubule-mediated movement to the vicinity of the nuclear envelope, the protoparvoviruses interact with the nuclear pore complexes. The capsids are transported actively across the nuclear pore complexes using nuclear import receptors. The nuclear import is sometimes accompanied by structural changes in the nuclear envelope, and is completed by intranuclear disassembly of capsids and chromatinization of the viral genome. This review discusses the nuclear import strategies of protoparvoviruses and describes its dynamics comprising active and passive movement, and directed and diffusive motion of capsids in the molecularly crowded environment of the cell.

Low prevalence of liver-kidney microsomal autoantibodies of type 1 (LKM1) in hepatitis C seropositive subjects on Crete, Greece.

Science.gov (United States)

Drygiannakis, D; Lionis, C; Drygiannakis, I; Pappas, G; Kouroumalis, E

2001-01-01

Hepatitis C is a serious problem on the Greek island of Crete, where a high prevalence of antibodies against hepatitis C (anti-HCV) has recently been reported. This article reports the findings of a study carried out in Crete, which investigated the prevalence of serum autoantibodies in patients with chronic hepatitis C. One hundred and forty two patients (59 men and 83 women), who were found anti-HCV seropositive in two hospitals and two Primary Health Care Centres in Crete, were eligible. Sixty healthy blood donors (46 men, 14 women), which were negative to anti-HCV, were used as the control group. They were randomly selected from those attending Rethymnon Hospital. Autoantibodies were identified using the indirect immunofluorescence (IFL) technique on human epithelial cells from larynx cancer (HEp-2 cells), rat liver-kidney-stomach substrate (CT3) and Chrithidia Luciliae (CL). Serum autoantibodies were detected in 104 HCV patients, yielding an overall prevalence of 73.2%. The most frequent autoantibodies were antinuclear antibodies (ANA), positive in 72 patients (50.7%). Anti-smooth muscle antibodies (ASMA) were detected in 33 patients (23.2%). Only one patient was positive for LKM1 autoantibodies. No autoantibodies were found in 38 patients (26.7%). Autoantibodies were also found in 5 out of the 60 examined healthy blood donors (8.3%). Autoantibodies, mainly ANA and ASMA are very common in HCV seropositive patients from Crete. By contrast LKM1 autoantibodies are exceptionally rare in these patients.

Zeeman perturbed nuclear quadrupole spin echo envelope modulations for spin 3/2 nuclei in polycrystalline specimens

Science.gov (United States)

Ramachandran, R.; Narasimhan, P. T.

The results of theoretical and experimental studies of Zeeman-perturbed nuclear quadrupole spin echo envelope modulations (ZSEEM) for spin 3/2 nuclei in polycrystalline specimens are presented. The response of the Zeeman-perturbed spin ensemble to resonant two pulse excitations has been calculated using the density matrix formalism. The theoretical calculation assumes a parallel orientation of the external r.f. and static Zeeman fields and an arbitrary orientation of these fields to the principal axes system of the electric field gradient. A numerical powder averaging procedure has been adopted to simulate the response of the polycrystalline specimens. Using a coherent pulsed nuclear quadrupole resonance spectrometer the ZSEEM patterns of the 35Cl nuclei have been recorded in polycrystalline specimens of potassium chlorate, barium chlorate, mercuric chloride (two sites) and antimony trichloride (two sites) using the π/2-τ-π/2 sequence. The theoretical and experimental ZSEEM patterns have been compared. In the case of mercuric chloride, the experimental 35Cl ZSEEM patterns are found to be nearly identical for the two sites and correspond to a near-zero value of the asymmetry parameter, η, of the electric field gradient tensor. The difference in the η values for the two 35Cl sites (η ˜0·06 and η˜0·16) in antimony trichloride is clearly reflected in the experimental and theoretical ZSEEM patterns. The present study indicates the feasibility of evaluating η for spin 3/2 nuclei in polycrystalline specimens from ZSEEM investigations.

The LHC in an envelope

CERN Multimedia

2007-01-01

The series of envelopes featuring CERN issued this summer was a huge success. The French postal services of the Pays de Gex will shortly be launching the second set of pre-paid envelopes issued in collaboration with the Laboratory this year, this time highlighting the LHC. Five thousand envelopes describing the accelerator’s capabilities will go on sale on 12 November, and some of the packs will even contain a small sample of the cables from the heart of the LHC magnets. The sets of ten pre-paid envelopes will tell you everything about CERN’s flagship accelerator, from its astounding technical capabilities to its spin-offs in the fields of technology and human resources. Each envelope will feature a different attribute or spin-off of the LHC. People will be invited to consult CERN’s public website for more detailed explanations if they want to know more. The new envelopes will be available from five post offices in the Pays de Gex (Ferney-Voltaire, Prévessin...

Nuclear envelope-distributed CD147 interacts with and inhibits the transcriptional function of RING1 and promotes melanoma cell motility.

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Junchen Chen

Full Text Available Melanoma accounts for nearly 80% of all deaths associated with skin cancer.CD147 plays a very important role in melanoma progression and the expression level may correlate with tumor malignancy. RING1 can bind DNA and act as a transcriptional repressor, play an important role in the aggressive phenotype in melanoma. The interactions between CD147 and RING1 were identified with a yeast two-hybrid and RING1 interacted with CD147 through the transmembrane domain. RING1 inhibits CD147's capability promoting melanoma cell migration. In conclusion, the study identified novel interactions between CD147 and RING1, recovered CD147 nuclear envelope distribution in melanoma cells, and suggested a new mechanism underlying how cytoplasmic CD147 promotes melanoma development.

Nuclear envelope-distributed CD147 interacts with and inhibits the transcriptional function of RING1 and promotes melanoma cell motility.

Science.gov (United States)

Chen, Junchen; Peng, Cong; Lei, Li; Zhang, Jianglin; Zeng, Weiqi; Chen, Xiang

2017-01-01

Melanoma accounts for nearly 80% of all deaths associated with skin cancer.CD147 plays a very important role in melanoma progression and the expression level may correlate with tumor malignancy. RING1 can bind DNA and act as a transcriptional repressor, play an important role in the aggressive phenotype in melanoma. The interactions between CD147 and RING1 were identified with a yeast two-hybrid and RING1 interacted with CD147 through the transmembrane domain. RING1 inhibits CD147's capability promoting melanoma cell migration. In conclusion, the study identified novel interactions between CD147 and RING1, recovered CD147 nuclear envelope distribution in melanoma cells, and suggested a new mechanism underlying how cytoplasmic CD147 promotes melanoma development.

Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies

Science.gov (United States)

Wiberg, A; Granstam, A; Ingvast, S; Härkönen, T; Knip, M; Korsgren, O; Skog, O

2015-01-01

In this study we aim to describe the characteristics of non-diabetic organ donors with circulating diabetes-associated autoantibodies collected within the Nordic Network for Islet Transplantation. One thousand and thirty organ donors have been screened in Uppsala for antibodies against glutamic acid decarboxylase (GADA) and islet antigen-2 (IA-2A). The 32 non-diabetic donors that tested positive for GADA (3·3% of all non-diabetic donors) were studied in more detail, together with 32 matched controls. Mean age among the autoantibody-positive donors was 52·6 (range 21–74), family history of type 1 diabetes (T1D) was unknown, and no donor was genetically predisposed for T1D regarding the human leucocyte antigen (HLA) locus. Subjects were analysed for islet cell antibodies (ICA), insulin autoantibodies (IAA) and zinc transporter 8 antibodies (ZnT8A), and pancreas morphology and clinical data were examined. Eight non-diabetic donors tested positive for two antibodies and one donor tested positive for four antibodies. No insulitis or other signs of a diabetic process were found in any of the donors. While inflammatory cells were present in all donors, subjects with high GADA titres had significantly higher CD45 cell numbers in exocrine tissue than controls. The extent of fibrosis was more pronounced in autoantibody-positive donors, even in subjects with lower GADA titres. Notably, it is possible that events not related directly to T1D (e.g. subclinical pancreatitis) may induce autoantibodies in some cases. PMID:26313035

The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome.

Science.gov (United States)

Lega, Jean-Christophe; Fabien, Nicole; Reynaud, Quitterie; Durieu, Isabelle; Durupt, Stéphane; Dutertre, Marine; Cordier, Jean-François; Cottin, Vincent

2014-09-01

To describe the clinical spectrum associated with aminoacyl-transfer RNA synthetase (ARS) autoantibodies in patients with idiopathic inflammatory myositis defined according to Peter and Bohan's criteria. Cohort studies were selected from MEDLINE and Embase up to August 2013. Two investigators independently extracted data on study design, patient characteristics, and clinical features (interstitial lung disease [ILD], fever, mechanic's hands [MH], Raynaud's phenomenon [RPh], arthralgia, sclerodactyly, cancer and dermatomyositis-specific rash) according to the presence of myositis-specific (anti-aminoacyl-transfer RNA synthetase [ARS], anti-signal recognition particle [anti-SRP] and anti-Mi2) and myositis-associated (anti-PM/Scl, anti-U1-RNP and anti-Ku) autoantibodies. 27 studies (3487 patients) were included in the meta-analysis. Arthralgia (75%, CI 67-81) and ILD (69%, CI 63-74) were the most prevalent clinical signs associated with anti-ARS autoantibodies. Anti-Mi2 and anti-SRP autoantibodies were associated with few extramuscular signs. ARS autoantibodies were identified in 13% of patients with cancer-associated myositis (5-25). Patients with non-anti-Jo1 ARS had greater odds of presenting fever (RR 0.63, CI 0.52-0.90) and ILD (RR 0.87, CI 0.81-0.93) compared to those with anti-Jo1 autoantibodies. The frequencies of myositis (RR 1.60, CI 1.38-1.85), arthralgia (RR 1.52, CI 1.32-1.76) and MH (RR 1.47, CI 1.11-1.94) were almost 50% higher in patients with anti-Jo1 compared to non-anti-Jo1 ARS autoantibodies. Patients with anti-PM/Scl differed from those with anti-ARS autoantibodies by a greater prevalence of RPh (RR 0.70, CI 0.53-0.94) and sclerodactyly (RR 0.47, CI 0.25-0.89). ILD was less frequent in patients with anti-U1-RNP autoantibodies (RR 3.35, CI 1.07-10.43). No difference was observed between anti-ARS and myositis-associated autoantibodies for other outcomes. The presence of anti-ARS autoantibodies delimits a heterogeneous subset of patients with a high

Autoantibodies in a Three-Year-Old Girl with Visceral Leishmaniasis: A Potential Diagnostic Pitfall

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Gholamreza Pouladfar

2016-01-01

Full Text Available Visceral leishmaniasis (VL, a life-threatening parasitic infection, is endemic in the Mediterranean region. Diagnosis of VL is based on epidemiologic, clinical, and laboratory findings. However, sometimes, clinical features and laboratory findings overlap with those of autoimmune diseases. In some cases, autoantibodies are detected in patients with VL and this could be a potential diagnostic pitfall. In this study, we have reported on a three-year-old girl from a VL-endemic area in Iran, who presented with prolonged fever and splenomegaly. Bone marrow examination, serologic tests, and the molecular PCR assay were performed; however, results were inconclusive. The levels of anti-double stranded DNA, cytoplasmic antineutrophil cytoplasmic autoantibody, and perinuclear antineutrophil cytoplasmic autoantibody were elevated and, at the end, splenic biopsy was performed. The splenic tissue PCR test detected the DNA of Leishmania infantum. The patient’s condition improved with anti-Leishmania therapy, and the autoantibodies disappeared within the following four months. Clinical presentations and laboratory findings of VL and autoimmune diseases may overlap in some patients.

Low prevalence of liver-kidney microsomal autoantibodies of type 1 (LKM1 in hepatitis C seropositive subjects on Crete, Greece

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Pappas Georgios

2001-06-01

Full Text Available Abstract Background Hepatitis C is a serious problem on the Greek island of Crete, where a high prevalence of antibodies against hepatitis C (anti-HCV has recently been reported. This article reports the findings of a study carried out in Crete, which investigated the prevalence of serum autoantibodies in patients with chronic hepatitis C. Patients and Methods One hundred and forty two patients (59 men and 83 women, who were found anti-HCV seropositive in two hospitals and two Primary Health Care Centres in Crete, were eligible. Sixty healthy blood donors (46 men, 14 women, which were negative to anti-HCV, were used as the control group. They were randomly selected from those attending Rethymnon Hospital. Autoantibodies were identified using the indirect immunofluorescence (IFL technique on human epithelial cells from larynx cancer (HEp-2 cells, rat liver-kidney-stomach substrate (CT3 and Chrithidia Luciliae (CL. Results Serum autoantibodies were detected in 104 HCV patients, yielding an overall prevalence of 73.2%. The most frequent autoantibodies were antinuclear antibodies (ANA, positive in 72 patients (50.7%. Anti-smooth muscle antibodies (ASMA were detected in 33 patients (23.2%. Only one patient was positive for LKM1 autoantibodies. No autoantibodies were found in 38 patients (26.7%. Autoantibodies were also found in 5 out of the 60 examined healthy blood donors (8.3%. Conclusions Autoantibodies, mainly ANA and ASMA are very common in HCV seropositive patients from Crete. By contrast LKM1 autoantibodies are exceptionally rare in these patients.

Autoantibody to MDM2: A Potential Serological Marker of Systemic Lupus Erythematosus

OpenAIRE

Liu, Yuan; Dai, Liping; Liu, Weihong; Shi, Guixiu; Zhang, Jianying

2015-01-01

Introduction. Systemic lupus erythematosus (SLE) is one of the systemic autoimmune diseases characterized by the polyclonal autoantibody production. The human homologue of the mouse double minute 2 (MDM2) is well known as the negative regulator of p53. MDM2 has been reported to be overexpressed in SLE animal model and to promote SLE. Since abnormally expressed proteins can induce autoimmune response, anti-MDM2 autoantibody was examined in SLE patients. Methods. Anti-MDM2 antibody in sera from...

A study of the epitopes on steroid 21-hydroxylase recognized by autoantibodies in patients with or without Addison's disease

Science.gov (United States)

Volpato, M; Prentice, L; Chen, S; Betterle, C; Rees Smith, B; Furmaniak, J

1998-01-01

Steroid 21-hydroxylase (21-OH) autoantibodies are found in patients with autoimmune Addison's disease (AAD), either isolated or associated with autoimmune polyglandular syndrome (APS) type I and II and in adrenal-cortex autoantibody (ACA)-positive patients without AAD. In order to assess any differences in the 21-OH autoantibodies in these different patient groups, we have studied their reactivity with different epitopes on 21-OH using full length and modified 35S-labelled 21-OH proteins produced in an in vitro transcription/translation system. There were no major differences in the pattern of autoantibody reactivity with the different modified 21-OH proteins in patients with isolated AAD or with APS types I and II, and in 21-OH autoantibody-positive patients with clinical AAD, subclinical AAD and those maintaining a normal adrenal function. Our studies also indicate that the main epitopes for 21-OH autoantibodies in patients with different forms of autoimmune adrenal disease are located in the C-terminal end and in a central region of 21-OH. PMID:9486414

Thyrotropin-Blocking Autoantibodies and Thyroid-Stimulating Autoantibodies: Potential Mechanisms Involved in the Pendulum Swinging from Hypothyroidism to Hyperthyroidism or Vice Versa

Science.gov (United States)

Rapoport, Basil

2013-01-01

Background Thyrotropin receptor (TSHR) antibodies that stimulate the thyroid (TSAb) cause Graves' hyperthyroidism and TSHR antibodies which block thyrotropin action (TBAb) are occasionally responsible for hypothyroidism. Unusual patients switch from TSAb to TBAb (or vice versa) with concomitant thyroid function changes. We have examined case reports to obtain insight into the basis for “switching.” Summary TBAb to TSAb switching occurs in patients treated with levothyroxine (LT4); the reverse switch (TBAb to TSAb) occurs after anti-thyroid drug therapy; TSAb/TBAb alterations may occur during pregnancy and are well recognized in transient neonatal thyroid dysfunction. Factors that may impact the shift include: (i) LT4 treatment, usually associated with decreased thyroid autoantibodies, in unusual patients induces or enhances thyroid autoantibody levels; (ii) antithyroid drug treatment decreases thyroid autoantibody levels; (iii) hyperthyroidism can polarize antigen-presenting cells, leading to impaired development of regulatory T cells, thereby compromising control of autoimmunity; (iv) immune-suppression/hemodilution reduces thyroid autoantibodies during pregnancy and rebounds postpartum; (v) maternally transferred IgG transiently impacts thyroid function in neonates until metabolized; (vi) a Graves' disease model involving immunizing TSHR-knockout mice with mouse TSHR-adenovirus and transfer of TSHR antibody-secreting splenocytes to athymic mice demonstrates the TSAb to TBAb shift, paralleling the outcome of maternally transferred “term limited” TSHR antibodies in neonates. Finally, perhaps most important, as illustrated by dilution analyses of patients' sera in vitro, TSHR antibody concentrations and affinities play a critical role in switching TSAb and TBAb functional activities in vivo. Conclusions Switching between TBAb and TSAb (or vice versa) occurs in unusual patients after LT4 therapy for hypothyroidism or anti-thyroid drug treatment for Graves

Clinical Significance of Autoantibodies in Some Thyroid Disorders

International Nuclear Information System (INIS)

Choi, Sung Kyu; Han, Sang Ho; Kim, Young Ju; Song, Jun Ho; Lee, Man Ho; Chung, Eul Sun; Lee, Sang Jong

1984-01-01

Clinical measurement of thyroid autoantibodies in sera of some thyroid disorders have been widely applied since about twenty years ago. We investigated the incidence and titers of both antimicrosomal and antithyroglobulin antibodies in forty eight cases with controls and one hundred and thirty three patients with some form of thyroid disorders. The results were as follows; 1) In controls, antimicrosomal antibodies were positive in 2% but antithyroglobulin antibodies were all negative. 2) In a series of one hundred and thirty three patients with thyroid disease, antimicrosomal antibodies were positive in 44% but antithyroglobulin antibodies were positive in only 15%. 3) The rate disclosing the positive results of antimicrosomal antibodies were 71% in Hashimoto disease, 60% in Graves' disease, and 38% in primary hypothyroidism, respectively. On the other hand, the positive results of antithyroglobulin antibodies showed 21% in Graves' disease, 19% in primary hypothyroidism, and 18% in Hashimoto, disease, respectively. Though there were relatively high rate of both antimicrosomal and antithyroglobulin antibodies in patients with nodular goiter, they were only seven cases in our series. 4) The rate with the extremely high titers of antimicrosomal and antithyroglobulin antibodies (>1 : 160 2 ) was 83% and 67% in Hashimoto's disease, 50% and 67% in primary hypothyroidism, and 41% and 18% in Graves' disease. Accordingly, the thyroid autoantibodies, were commonly found higher positive rate in patients with Hashimoto disease, primary hypothyroidism, and Graves' disease. Among these disorders, the extremely high positive rate of the thyroid autoantibodies was found in patients with Hashimoto's disease.

Role of Natural Autoantibodies in Ugandans With Rheumatic Heart Disease and HIV☆

Science.gov (United States)

Huck, Daniel M.; Okello, Emmy; Mirembe, Grace; Ssinabulya, Isaac; Zidar, David A.; Silverman, Gregg J.; Getu, Lelise; Nowacki, Amy S.; Calabrese, Leonard H.; Salata, Robert A.; Longenecker, Chris T.

2016-01-01

Background Rheumatic heart disease (RHD) and HIV are prevalent diseases in sub-Saharan Africa, but little is known about their potential interrelationships. The objective of this study was to assess the prevalence of protective natural autoantibodies among patients with RHD in Uganda, and to determine whether the levels of these autoantibodies are affected by HIV status. Methods Participants were grouped according to RHD and HIV status. The three control groups (RHD − HIV −, RHD − HIV +, RHD + HIV −) were age-matched to the RHD + HIV + participants. All participants underwent HIV testing and echocardiography to evaluate for RHD. Natural autoantibody levels reactive with phosphorylcholine (PC) and malondialdehyde (MDA) were measured. Findings We enrolled 220 participants; 21 with both RHD and HIV. Ages ranged from 10 to 60 years, with female predominance (144/220, 65%). After adjusting for age and gender, HIV infection and RHD were each associated with low IgM anti-PC (HIV: p disease. PMID:27077123

Autoantibodies Against Carbonic Anhydrase I and II in Patients with Acute Myeloid Leukemia

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Ahmet Menteşe

2017-12-01

Full Text Available Objective: Cancer, one of the principal causes of death, is a global social health problem. Autoantibodies developed against the organism’s self-antigens are detected in the sera of subjects with cancer. In recent years carbonic anhydrase (CA I and II autoantibodies have been shown in some autoimmune diseases and carcinomas, but the mechanisms underlying this immune response have not yet been explained. The aim of this study was to evaluate CA I and II autoantibodies in patients with acute myeloid leukemia (AML and to provide a novel perspective regarding the autoimmune basis of the disease. Materials and Methods: Anti-CA I and II antibody levels were investigated using ELISA in serum samples from 30 patients with AML and 30 healthy peers. Results: Anti-CA I and II antibody titers in the AML group were significantly higher compared with the control group (p=0.0001 and 0.018, respectively. A strong positive correlation was also determined between titers of anti-CA I and II antibodies (r=0.613, p=0.0001. Conclusion: Our results suggest that these autoantibodies may be involved in the pathogenesis of AML. More extensive studies are now needed to reveal the entire mechanism.

Cytokines in relation to autoantibodies before onset of symptoms for systemic lupus erythematosus.

Science.gov (United States)

Eriksson, C; Rantapää-Dahlqvist, S

2014-06-01

A number of cytokines and chemokines were analysed and related to autoantibodies in blood samples pre-dating the onset of symptoms of systemic lupus erythematosus. Thirty-five patients with systemic lupus erythematosus (American College of Rheumatology criteria) were identified as having donated blood samples, prior to symptom onset, to the Biobank of northern Sweden. Altogether, 140 age- and sex-matched controls were also identified. The concentrations of interferon-α, interleukin-4, interleukin-9, interleukin-10, interferon inducible protein-10 and monocyte chemotactic protein-1 were analysed using multiplex technology and related to autoantibodies (ANA, ENA, anti-dsDNA and anti-histone antibodies) analysed from the same blood sample. The interferon-γ inducible protein-10 levels were higher in the pre-symptomatic individuals than in controls (p systemic lupus erythematosus. An increased concentration of interferon-γ inducible protein-10 pre-dated the onset of systemic lupus erythematosus and was related to autoantibodies before the onset of disease. The levels of interferon-γ inducible protein-10 and interferon-α were correlated. These findings support the proposal that the interferon system is important early in the pathogenesis of systemic lupus erythematosus and autoantibody formation. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Serum tumor-associated autoantibodies as diagnostic biomarkers for lung cancer: A systematic review and meta-analysis.

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Zhen-Ming Tang

Full Text Available We performed a comprehensive review and meta-analysis to evaluate the diagnostic values of serum single and multiplex tumor-associated autoantibodies (TAAbs in patients with lung cancer (LC.We searched the MEDLINE and EMBASE databases for relevant studies investigating serum TAAbs for the diagnosis of LC. The primary outcomes included sensitivity, specificity and accuracy of the test.The systematic review and meta-analysis included 31 articles with single autoantibody and 39 with multiplex autoantibodies. Enzyme-linked immunosorbent assay (ELISA was the most common detection method. For the diagnosis of patients with all stages and early-stage LC, different single or combinations of TAAbs demonstrated different diagnostic values. Although individual TAAbs showed low diagnostic sensitivity, the combination of multiplex autoantibodies offered relatively high sensitivity. For the meta-analysis of a same panel of autoantibodies in patients at all stages of LC, the pooled results of the panel of 6 TAAbs (p53, NY-ESO-1, CAGE, GBU4-5, Annexin 1 and SOX2 were: sensitivity 38% (95% CI 0.35-0.40, specificity 89% (95% CI 0.86-0.91, diagnostic accuracy 65.9% (range 62.5-81.8%, AUC 0.52 (0.48-0.57, while the summary estimates of 7 TAAbs (p53, CAGE, NY-ESO-1, GBU4-5, SOX2, MAGE A4 and Hu-D were: sensitivity 47% (95% CI 0.34-0.60, specificity 90% (95% CI 0.89-0.92, diagnostic accuracy 78.4% (range 67.5-88.8%, AUC 0.90 (0.87-0.93. For the meta-analysis of the same panel of autoantibodies in patients at early-stage of LC, the sensitivities of both panels of 7 TAAbs and 6 TAAbs were 40% and 29.7%, while their specificities were 91% and 87%, respectively.Serum single or combinations of multiplex autoantibodies can be used as a tool for the diagnosis of LC patients at all stages or early-stage, but the combination of multiplex autoantibodies shows a higher detection capacity; the diagnostic value of the panel of 7 TAAbs is higher than the panel of 6 TAAbs, which

Cortical processing of dynamic sound envelope transitions.

Science.gov (United States)

Zhou, Yi; Wang, Xiaoqin

2010-12-08

Slow envelope fluctuations in the range of 2-20 Hz provide important segmental cues for processing communication sounds. For a successful segmentation, a neural processor must capture envelope features associated with the rise and fall of signal energy, a process that is often challenged by the interference of background noise. This study investigated the neural representations of slowly varying envelopes in quiet and in background noise in the primary auditory cortex (A1) of awake marmoset monkeys. We characterized envelope features based on the local average and rate of change of sound level in envelope waveforms and identified envelope features to which neurons were selective by reverse correlation. Our results showed that envelope feature selectivity of A1 neurons was correlated with the degree of nonmonotonicity in their static rate-level functions. Nonmonotonic neurons exhibited greater feature selectivity than monotonic neurons in quiet and in background noise. The diverse envelope feature selectivity decreased spike-timing correlation among A1 neurons in response to the same envelope waveforms. As a result, the variability, but not the average, of the ensemble responses of A1 neurons represented more faithfully the dynamic transitions in low-frequency sound envelopes both in quiet and in background noise.

Detection of autoantibodies to cytokines

DEFF Research Database (Denmark)

Bendtzen, K; Hansen, M B; Ross, C

2000-01-01

Autoantibodies to various cytokines have been reported in normal individuals and in patients with various infectious and immunoinflammatory disorders, and similar antibodies (Ab) may be induced in patients receiving human recombinant cytokines. The clinical relevance of these Ab is often difficult...... to evaluate. Not only are in vitro neutralizing cytokine Ab not necessarily neutralizing in vivo, but assays for binding and neutralizing Ab to cytokines are often difficult to interpret. For example, denaturation of immobilized cytokines in immunoblotting techniques and immunometric assays may leave Ab...

Induction of polyploidy by nuclear fusion mechanism upon decreased expression of the nuclear envelope protein LAP2β in the human osteosarcoma cell line U2OS.

Science.gov (United States)

Ben-Shoshan, Shirley Oren; Simon, Amos J; Jacob-Hirsch, Jasmine; Shaklai, Sigal; Paz-Yaacov, Nurit; Amariglio, Ninette; Rechavi, Gideon; Trakhtenbrot, Luba

2014-01-28

Polyploidy has been recognized for many years as an important hallmark of cancer cells. Polyploid cells can arise through cell fusion, endoreplication and abortive cell cycle. The inner nuclear membrane protein LAP2β plays key roles in nuclear envelope breakdown and reassembly during mitosis, initiation of replication and transcriptional repression. Here we studied the function of LAP2β in the maintenance of cell ploidy state, a role which has not yet been assigned to this protein. By knocking down the expression of LAP2β, using both viral and non-viral RNAi approaches in osteosarcoma derived U2OS cells, we detected enlarged nuclear size, nearly doubling of DNA content and chromosomal duplications, as analyzed by fluorescent in situ hybridization and spectral karyotyping methodologies. Spectral karyotyping analyses revealed that near-hexaploid karyotypes of LAP2β knocked down cells consisted of not only seven duplicated chromosomal markers, as could be anticipated by genome duplication mechanism, but also of four single chromosomal markers. Furthermore, spectral karyotyping analysis revealed that both of two near-triploid U2OS sub-clones contained the seven markers that were duplicated in LAP2β knocked down cells, whereas the four single chromosomal markers were detected only in one of them. Gene expression profiling of LAP2β knocked down cells revealed that up to a third of the genes exhibiting significant changes in their expression are involved in cancer progression. Our results suggest that nuclear fusion mechanism underlies the polyploidization induction upon LAP2β reduced expression. Our study implies on a novel role of LAP2β in the maintenance of cell ploidy status. LAP2β depleted U2OS cells can serve as a model to investigate polyploidy and aneuploidy formation by nuclear fusion mechanism and its involvement in cancerogenesis.

Cramp-fasciculation syndrome in patients with and without neural autoantibodies.

Science.gov (United States)

Liewluck, Teerin; Klein, Christopher J; Jones, Lyell K

2014-03-01

We investigated the clinical, electrophysiological and neural autoantibody characteristics in cramp-fasciculation syndrome (CFS) patients. We reviewed Mayo Clinic records from 2000 to 2011 to identify clinically defined CFS patients who underwent neural autoantibody testing. Stored sera of patients who tested positive for antibodies to voltage-gated potassium channel complex (VGKC complex) were analyzed further for leucine-rich glioma-inactivated 1 (LGI1) or contactin-associated protein-2 immunoglobulin G (CASPR2-IgG) antibodies. Thirty-seven patients were identified. Twelve were seropositive for neural autoantibodies. Clinical manifestations were similar in seropositive and seronegative patients, although central and autonomic neuronal hyperexcitability symptoms were more common in seropositive cases. No patients had a malignancy. Repetitive tibial nerve stimulation at 10 Hz revealed longer afterdischarges in seropositive patients. Two of 7 patients with VGKC-complex autoimmunity demonstrated LGI1 or CASPR2-IgG antibodies. Only 2 of 12 seropositive patients required immunotherapy. VGKC-complex autoimmunity occurs in a minority of CFS patients. Antibody positivity was associated with extramuscular manifestations, typically without malignancy. Target antigens within the VGKC complex remain unknown in most patients. Published 2013 by Wiley Periodicals, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.

Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases.

Directory of Open Access Journals (Sweden)

Guo Luo

Full Text Available A recent publication suggested molecular mimicry of a nucleoprotein (NP sequence from A/Puerto Rico/8/1934 (PR8 strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT receptor 2 (anti-HCRTR2 autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera. In this study, we re-examined this hypothesis through mass spectrometry (MS characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies.MS characterization of Pandemrix® (2 batches, Arepanrix® (4 batches and Focetria® (1 batch was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N cases and 18 age-matched post Pandemrix® controls (PP-C, and 48 recent (≤6 months early onset narcolepsy (EO-N cases and 70 age-matched other controls (O-C. Anti-HCRTR2 autoantibodies were detected using three strategies: (1 Human embryonic kidney (HEK 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2 In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3 Optical density (OD at 450 nm (OD450 of human serum immunoglobulin G (IgG binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO-K1 cell line was measured using an in-cell enzyme-linked immunosorbent assay (ELISA.NP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123 (ILYDKEEIRRIWRQA, a mimic to HCRTR234-45 (YDDEEFLRYLWR, was not found to bind to DQ0602. Three or four subjects were found positive

Autoantibodies to neuronal antigens in children with focal epilepsy and no prima facie signs of encephalitis.

Science.gov (United States)

Borusiak, Peter; Bettendorf, Ulrich; Wiegand, Gert; Bast, Thomas; Kluger, Gerhard; Philippi, Heike; Münstermann, Dieter; Bien, Christian G

2016-07-01

There is increasing awareness of neuronal autoantibodies and their impact on the pathogenesis of epilepsy. We investigated children with focal epilepsy in order to provide an estimate of autoantibody frequency within a pediatric population without prima facie evidence of encephalitis using a broad panel of autoantibodies. This was done to assess the specificity of antibodies and to see whether antibodies might be of modifying influence on the course of focal epilepsies. We searched for autoantibodies in 124 patients with focal epilepsy (1-18 years; mean 10; 6 years). Sera were tested using a broad panel of surface and intracellular antigens. We found autoantibodies in 5/124 patients (4%): high-positive GAD65 antibodies (n = 1), low-positive GAD65 antibodies (N = 1), VGKC complex antibodies not reactive with LGI1 or CASPR2 (n = 3). We did not find any distinctive features distinguishing antibody positive patients from those without antibodies. The antibodies found in this cohort are probably neither disease-specific nor pathogenic. This has been suggested before for these antigenic targets. Moreover, they do not seem to modify disease severity in the antibody-positive epilepsy patients. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Cluster analysis of autoantibodies in 852 patients with systemic lupus erythematosus from a single center.

Science.gov (United States)

Artim-Esen, Bahar; Çene, Erhan; Şahinkaya, Yasemin; Ertan, Semra; Pehlivan, Özlem; Kamali, Sevil; Gül, Ahmet; Öcal, Lale; Aral, Orhan; Inanç, Murat

2014-07-01

Associations between autoantibodies and clinical features have been described in systemic lupus erythematosus (SLE). Herein, we aimed to define autoantibody clusters and their clinical correlations in a large cohort of patients with SLE. We analyzed 852 patients with SLE who attended our clinic. Seven autoantibodies were selected for cluster analysis: anti-DNA, anti-Sm, anti-RNP, anticardiolipin (aCL) immunoglobulin (Ig)G or IgM, lupus anticoagulant (LAC), anti-Ro, and anti-La. Two-step clustering and Kaplan-Meier survival analyses were used. Five clusters were identified. A cluster consisted of patients with only anti-dsDNA antibodies, a cluster of anti-Sm and anti-RNP, a cluster of aCL IgG/M and LAC, and a cluster of anti-Ro and anti-La antibodies. Analysis revealed 1 more cluster that consisted of patients who did not belong to any of the clusters formed by antibodies chosen for cluster analysis. Sm/RNP cluster had significantly higher incidence of pulmonary hypertension and Raynaud phenomenon. DsDNA cluster had the highest incidence of renal involvement. In the aCL/LAC cluster, there were significantly more patients with neuropsychiatric involvement, antiphospholipid syndrome, autoimmune hemolytic anemia, and thrombocytopenia. According to the Systemic Lupus International Collaborating Clinics damage index, the highest frequency of damage was in the aCL/LAC cluster. Comparison of 10 and 20 years survival showed reduced survival in the aCL/LAC cluster. This study supports the existence of autoantibody clusters with distinct clinical features in SLE and shows that forming clinical subsets according to autoantibody clusters may be useful in predicting the outcome of the disease. Autoantibody clusters in SLE may exhibit differences according to the clinical setting or population.

Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease.

Directory of Open Access Journals (Sweden)

Eric P Nagele

Full Text Available The presence of self-reactive IgG autoantibodies in human sera is largely thought to represent a breakdown in central tolerance and is typically regarded as a harbinger of autoimmune pathology. In the present study, immune-response profiling of human serum from 166 individuals via human protein microarrays demonstrates that IgG autoantibodies are abundant in all human serum, usually numbering in the thousands. These IgG autoantibodies bind to human antigens from organs and tissues all over the body and their serum diversity is strongly influenced by age, gender, and the presence of specific diseases. We also found that serum IgG autoantibody profiles are unique to an individual and remarkably stable over time. Similar profiles exist in rat and swine, suggesting conservation of this immunological feature among mammals. The number, diversity, and apparent evolutionary conservation of autoantibody profiles suggest that IgG autoantibodies have some important, as yet unrecognized, physiological function. We propose that IgG autoantibodies have evolved as an adaptive mechanism for debris-clearance, a function consistent with their apparent utility as diagnostic indicators of disease as already established for Alzheimer's and Parkinson's diseases.

Comparison of Serum Autoantibodies to Desmogleins I, III in Patients with Oral Lichen Planus and Healthy Controls.

Science.gov (United States)

Gholizadeh, Narges; Khoini Poorfar, Hossein; TaghaviZenouz, Ali; Vatandoost, Masoumeh; Mehdipour, Masoumeh

2015-01-01

Lichen planus is a mucocutaneous disease which is relatively common and in 30-70% of patients, mucosal lesions can be seen and known as a precancerous lesion but its etiology is not completely understood. Desmogleins I and III are the main desmosomal transmembrane proteins. These proteins have been identified as the autoantigen of the autoimmune disease. The aim of this study was evaluation of serum autoantibodies against desmogleins Ι, ΙΙΙ in oral lichen planus . We attempted to determine the etiology of this disease with evaluation of these serum factors. Thirty-five patients with oral lichen planus and 35 healthy controls were recruited and tested for serum autoantibodies against desmogleins Ι, ΙΙΙ and indirect immunofluorescence also performed. Data were analyzed by statistical-analytical methods (Independent sample t -test) with using the SPSS.15 software. Serum autoantibody against desmoglein Ι had no significant difference in the two groups ( P =0.31 ) but significant increase in serum autoantibody to desmoglein ΙΙΙ was found in patients with oral lichen planus ( P =0.00) . It seems that autoantibody against desmoglein III has a significant role in the pathogenesis of oral lichen planus.

Vesicular PtdIns(3,4,5)P3 and Rab7 are key effectors of sea urchin zygote nuclear membrane fusion.

Science.gov (United States)

Lete, Marta G; Byrne, Richard D; Alonso, Alicia; Poccia, Dominic; Larijani, Banafshé

2017-01-15

Regulation of nuclear envelope dynamics is an important example of the universal phenomena of membrane fusion. The signalling molecules involved in nuclear membrane fusion might also be conserved during the formation of both pronuclear and zygote nuclear envelopes in the fertilised egg. Here, we determine that class-I phosphoinositide 3-kinases (PI3Ks) are needed for in vitro nuclear envelope formation. We show that, in vivo, PtdIns(3,4,5)P 3 is transiently located in vesicles around the male pronucleus at the time of nuclear envelope formation, and around male and female pronuclei before membrane fusion. We illustrate that class-I PI3K activity is also necessary for fusion of the female and male pronuclear membranes. We demonstrate, using coincidence amplified Förster resonance energy transfer (FRET) monitored using fluorescence lifetime imaging microscopy (FLIM), a protein-lipid interaction of Rab7 GTPase and PtdIns(3,4,5)P 3 that occurs during pronuclear membrane fusion to create the zygote nuclear envelope. We present a working model, which includes several molecular steps in the pathways controlling fusion of nuclear envelope membranes. © 2017. Published by The Company of Biologists Ltd.

An autoantibody against N{sup {epsilon}}-(carboxyethyl)lysine (CEL): Possible involvement in the removal of CEL-modified proteins by macrophages

Energy Technology Data Exchange (ETDEWEB)

Mera, Katsumi [Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Nagai, Ryoji, E-mail: nagai-883@umin.ac.jp [Department of Food and Nutrition, Laboratory of Nutritional Science and Biochemistry, Japan Women' s University, Tokyo (Japan); Takeo, Kazuhiro; Izumi, Miyoko [Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Maruyama, Toru [Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Center for Clinical Pharmaceutical Science, Kumamoto University, Kumamoto (Japan); Otagiri, Masaki [Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto (Japan)

2011-04-08

Highlights: {yields} A higher amount of autoantibody against CEL than that of other AGEs was observed in human plasma. {yields} The purified human anti-CEL autoantibody specifically reacted with CEL. {yields} Anti-CEL antibody accelerated the uptake of {sup 125}I-CEL-HSA by macrophage in vitro. {yields} Endocytic uptake of {sup 125}I-CEL-HSA by mice liver was accelerated in the presence of anti-CEL antibody. -- Abstract: Advanced glycation end products (AGEs) are believed to play a significant role in the development of diabetic complications. In this study, we measured the levels of autoantibodies against several AGE structures in healthy human plasma and investigated the physiological role of the autoantibodies. A high titer of the autoantibody against N{sup {epsilon}}-(carboxyethyl)lysine (CEL) was detected in human plasma compared with other AGE structures such as CML and pentosidine. The purified human anti-CEL autoantibody reacted with CEL-modified human serum albumin (CEL-HSA), but not CML-HSA. A rabbit polyclonal anti-CEL antibody, used as a model autoantibody against CEL, accelerated the uptake of CEL-HSA by macrophages, but did not enhance the uptake of native HSA. Furthermore, when {sup 125}I-labeled CEL-HSA was injected into the tail vein of mice, accumulation of {sup 125}I-CEL-HSA in the liver was accelerated by co-injection of the rabbit anti-CEL antibody. These results demonstrate that the autoantibody against CEL in plasma may play a role in the macrophage uptake of CEL-modified proteins.

Prevalence of autoantibodies in the course of Gaucher disease type 1: A multicenter study comparing Gaucher disease patients to healthy subjects.

Science.gov (United States)

Serratrice, Christine; Bensalah, Nesma; Penaranda, Guillaume; Bardin, Nathalie; Belmatoug, Nadia; Masseau, Agathe; Rose, Christian; Lidove, Olivier; Camou, Fabrice; Maillot, François; Leguy, Vanessa; Magy-Bertrand, Nadine; Marie, Isabelle; Cherin, Patrick; Bengherbia, Monia; Carballo, Sebastian; Boucraut, José; Serratrice, Jacques; Berger, Marc; Verrot, Denis

2018-01-01

Type 1 Gaucher disease may be related to the presence of autoantibodies. Their clinical significance is questioned. Primary endpoint was to compare the prevalence of autoantibodies in type 1 Gaucher disease patients with healthy subjects, seeking correlations with autoimmune characteristics. Secondary endpoints were to determine whether patients with autoantibodies reported autoimmunity-related symptoms and if genotype, splenectomy or treatment influenced autoantibodies presence. Type 1 Gaucher disease patients and healthy volunteers were included in this national multicenter exploratory study. Autoantibodies presence was compared in both groups and assessed regarding to genotype, splenectomy, Gaucher disease treatment and autoimmunity-related symptoms. Twenty healthy subjects and 40 type 1 Gaucher disease patients were included. Of the studied group: 15 patients undergone splenectomy, 37 were treated either with enzyme replacement therapy (34) or with substrate reduction therapy (3), 25 were homozygous/heterozygous for the N370S mutation. In type 1 Gaucher disease group (studied group), 52% had positive autoantibodies versus 26% in control group. Antiphospholipid antibodies were more frequent in the studied group (30% vs. 5%), but without correlation to thrombosis, osteonecrosis or bone infarcts. In the studied group, antinuclear antibodies were more frequent (25% vs. 16%). None of the patients with autoantibodies had clinical manifestations of autoimmune diseases. Autoantibodies were not correlated with treatment, genotype, or splenectomy, except for anticardiolipid, more frequent in splenectomized patients. In type 1 Gaucher disease, autoantibodies were more frequent compared to a healthy population. However, they were not associated with an increased prevalence of clinical active autoimmune diseases. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

AUTOANTIBODIES TO GLUTAMIC ACID DECARBOXYLASE AS A PATHOGENETIC MARKER OF TYPE I DIABETES MELLITUS

OpenAIRE

N. V. Piven; L. N. Lukhverchyk; A. I. Burakovsky; N. V. Polegenkaya; M. V. Karpovich

2011-01-01

Abstract. A new method of enzyme-linked immunosorbent assay (in solid-phase ELISA format) has been developed to determine concentrations of autoantibodies to glutamic acid decarboxylase, as well as an evidencebased methodology is proposed for its medical implications, as a quantitative pathogenetic predictive marker of autoimmune diagnostics in type 1 diabetes mellitus. This technique could be implied for serial production of diagnostic reagent kits, aimed for detection of autoantibodies to g...

The measurement of TSH-receptor autoantibodies in human serum by radioreceptor assay

International Nuclear Information System (INIS)

Truong, T.X.

2002-01-01

TSH receptor autoantibodies (TRAB) are valuable in Graves' disease with a sensitivity of 85% and a specificity of 80%. Autoantibodies levels decrease progressively with antithyroid drugs treatment or after thyroidectomy. The predictive value of the level of TSH receptor autoantibodies is diversely appreciated. Nevertheless, the vast majority of the studies agrees on the fact that high levels of TSH receptor autoantibodies predict a relapse. The feto-placental transfer of these antibodies could explain congenital hyperthyroidism of newborns from mother affected by Graves' disease. These antibodies are present in certain cases of Hashimoto thyroiditis, subacute thyroiditis or silent thyroiditis in phase of thyrotoxicosis. In Vietnam, first time we have researched determination of TRAB levels in the non disease and the Graves' disease, after treatment of antithyroid drugs and after thyroidectomy. We imported TRAB - Kit from CIS bio international France. The principle of Radioreceptor assay (RRA ) is following: TR - Ab kit utilizes a principle of competition between TSH receptor autoantibodies present in the sample and bovine TSH radiolabelled with 125 -I, facing a fixed and limited amount of soluble porcine TSH receptors. The more TSH receptor autoantibodies are present in the sample, the less 125 -I- TSH is bound to the soluble TSH receptors. Free and bound fractions are separated in adding PEG solution followed by a centrifugation. Results are calculated from a calibration curve (U/l). The samples were counted by the multi crystal gamma counter Oakfield which was supplied from IAEA (Years 2000). This is the first study in Vietnam, the concentration of TSH receptor autoantibodies (TRAB) was determined by radioreceptor assay (RRA) on 30 normal subjects and 30 Grave's disease subjects. The normal range is 1,4 □ 0.6 U/l. Max of normal is 2.99U/l. Min of normal is 3.38U/l .There are 11 males and 29 females with age from 15 to 50 years old. Mean of Graves' disease is

[Hashimoto's encephalopathy and autoantibodies].

Science.gov (United States)

Yoneda, Makoto

2013-04-01

Encephalopathy occasionally occurs in association with thyroid disorders, but most of these are treatable. These encephalopathies include a neuropsychiatric disorder associated with hypothyroidism, called myxedema encephalopathy. Moreover, Hashimoto's encephalopathy (HE) has been recognized as a new clinical disease based on an autoimmune mechanism associated with Hashimoto's thyroiditis. Steroid treatment was successfully administered to these patients. Recently, we discovered that the serum autoantibodies against the NH2-terminal of α-enolase (NAE) are highly specific diagnostic biomarkers for HE. Further, we analyzed serum anti-NAE autoantibodies and the clinical features in many cases of HE from institutions throughout Japan and other countries. Approximately half of assessed HE patients carry anti-NAE antibodies. The age was widely distributed with 2 peaks (20-30 years and 50-70 years). Most HE patients were in euthyroid states, and all patients had anti-thyroid (TG) antibodies and anti-thyroid peroxidase (TPO) antibodies. Anti-TSH receptor (TSH-R) antibodies were observed in some cases. The common neuropsychiatry features are consciousness disturbance and psychosis, followed by cognitive dysfunction, involuntary movements, seizures, and ataxia. Abnormalities on electroencephalography (EEG) and decreased cerebral blood flow on brain SPECT were common findings, whereas abnormal findings on brain magnetic resonance imaging (MRI) were rare. HE patients have various clinical phenotypes such as the acute encephalopathy form, the chronic psychiatric form, and other particular clinical forms, including limbic encephalitis, progressive cerebellar ataxia, and Creutzfeldt-Jakob disease (CJD)-like form. The cerebellar ataxic form of HE clinically mimics spinocerebellar degeneration (SCD) and is characterized by the absence of nystagmus, absent or mild cerebellar atrophy, and lazy background activities on EEG. Taken together, these data suggest that the possibility of

Aquaporin-4 autoantibodies in neuromyelitis optica spectrum disorders: comparison between tissue-based and cell-based indirect immunofluorescence assays

Directory of Open Access Journals (Sweden)

Chan Koon H

2010-09-01

Full Text Available Abstract Background Neuromyelitis optica spectrum disorders (NMOSD are severe central nervous system inflammatory demyelinating disorders (CNS IDD characterized by monophasic or relapsing, longitudinally extensive transverse myelitis (LETM and/or optic neuritis (ON. A significant proportion of NMOSD patients are seropositive for aquaporin-4 (AQP4 autoantibodies. We compared the AQP4 autoantibody detection rates of tissue-based indirect immunofluorescence assay (IIFA and cell-based IIFA. Methods Serum of Chinese CNS IDD patients were assayed for AQP4 autoantibodies by tissue-based IIFA using monkey cerebellum and cell-based IIFA using transfected HEK293 cells which express human AQP4 on their cell membranes. Results In total, 128 CNS IDD patients were studied. We found that 78% of NMO patients were seropositive for AQP4 autoantibodies by cell-based IIFA versus 61% by tissue-based IFA (p = 0.250, 75% of patients having relapsing myelitis (RM with LETM were seropositive by cell-based IIFA versus 50% by tissue-based IIFA (p = 0.250, and 33% of relapsing ON patients were seropositive by cell-based IIFA versus 22% by tissue-based IIFA (p = 1.000; however the differences were not statistically significant. All patients seropositive by tissue-based IIFA were also seropositive for AQP4 autoantibodies by cell-based IIFA. Among 29 NMOSD patients seropositive for AQP4 autoantibodies by cell-based IIFA, 20 (69% were seropositive by tissue-based IIFA. The 9 patients seropositive by cell-based IIFA while seronegative by tissue-based IIFA had NMO (3, RM with LETM (3, a single attack of LETM (1, relapsing ON (1 and a single ON attack (1. Among 23 NMO or RM patients seropositive for AQP4 autoantibodies by cell-based IIFA, comparison between those seropositive (n = 17 and seronegative (n = 6 by tissue-based IIFA revealed no differences in clinical and neuroradiological characteristics between the two groups. Conclusion Cell-based IIFA is slightly more sensitive

All the Universe in an envelope

CERN Multimedia

2007-01-01

Do you know which force is hidden in an envelope or how many billions of years old are the atoms it contains? You will find the answers to these (curious) questions in a post office in the Pays de Gex. The French postal services of the Pays de Gex are again issuing pre-paid envelopes in collaboration with CERN (see Bulletin No. 24/2006). The new series presents some of the concepts of modern physics in an amazing way by showing what you can learn about the Universe with a single envelope. Packets of ten pre-stamped envelopes, each carrying a statement on fundamental physics, will be on sale from 7 July onwards. To learn more about the physics issues presented on the envelopes, people are invited to go to the CERN Web site where they will find the explanations. Five thousand envelopes will be put on sale in July and five thousand more during the French "Fête de la science" in October. They will be available from five post offices in the Pays de Gex (F...

Autoantibody detection in type 2 autoimmune hepatitis using a chimera recombinant protein.

Science.gov (United States)

Vitozzi, Susana; Lapierre, Pascal; Djilali-Saiah, Idriss; Alvarez, Fernando

2002-04-01

Autoantibodies against cytochrome P450 2D6 (CYP2D6), known as anti-liver/kidney microsome type 1 (LKM1) and/or anti-human formiminotransferase cyclodeaminase, formally known as anti-liver cytosol type 1 (LC1) define type 2 autoimmune hepatitis (AIH). The aims of this work are to develop a sensitive and specific test to detect anti-LKM1 and/or anti-LC1 autoantibodies and to establish the prevalence of anti-LC1. Sera from children with type 2 AIH (n=48) and those from a control group (n=100) were evaluated for anti-LKM1 and anti-LC1 by Enzyme-Linked Immunosorbent Assay (ELISA) and Western blotting. Each serum sample was assayed for reactivity against formiminotransferase cyclodeaminase and CYP2D6 alone or as part of a recombinant chimera protein. By ELISA with recombinant chimera protein, 50 serum samples were positive, 48 from patients with type 2 AIH and 2 from patients with chronic hepatitis C. Twenty-five of 48 (52%) patients studied were positive for both CYP2D6 and LC1 autoantibodies. Anti-LC1, either as the only marker or associated with anti-LKM1, was positive in 34/48 (71%). By Western blotting, anti-LC1 was found in 27/48 (56%) patients. This ELISA technique has proven to be antigen-specific and more sensitive than Western blot for the detection of anti-LC1 and anti-LKM1 autoantibodies. The prevalence of anti-LC1 (71%) confirms it as an important immunomarker in type 2 AIH.

The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope

Energy Technology Data Exchange (ETDEWEB)

Kind, Barbara, E-mail: barbara.kind@uniklinikum-dresden.de [Children' s Hospital, Technical University Dresden, D-01307 Dresden (Germany); Koehler, Katrin, E-mail: katrin.koehler@uniklinikum-dresden.de [Children' s Hospital, Technical University Dresden, D-01307 Dresden (Germany); Lorenz, Mike, E-mail: mlorenz@mpi-cbg.de [Max Planck Institute of Molecular Cell Biology and Genetics, D-01307 Dresden (Germany); Huebner, Angela, E-mail: angela.huebner@uniklinikum-dresden.de [Children' s Hospital, Technical University Dresden, D-01307 Dresden (Germany)

2009-12-11

The nuclear pore complex (NPC) consists of {approx}30 different proteins and provides the only sites for macromolecular transport between cytoplasm and nucleus. ALADIN was discovered as a new member of the NPC. Mutations in ALADIN are known to cause triple A syndrome, a rare autosomal recessive disorder characterized by adrenal insufficiency, alacrima, and achalasia. The function and exact location of the nucleoporin ALADIN within the NPC multiprotein complex is still unclear. Using a siRNA-based approach we downregulated the three known membrane integrated nucleoporins NDC1, GP210, and POM121 in stably expressing GFP-ALADIN HeLa cells. We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC. Solely the depletion of NDC1 caused mislocalization of ALADIN. Vice versa, the depletion of ALADIN led also to disappearance of NDC1 at the NPC. However, the downregulation of two further membrane-integral nucleoporins GP210 and POM121 had no effect on ALADIN localization. Furthermore, we could show a direct association of NDC1 and ALADIN in NPCs by fluorescence resonance energy transfer (FRET) measurements. Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated. The loss of integration of ALADIN in the NPC is a main pathogenetic aspect for the development of the triple A syndrome and suggests that the interaction between ALADIN and NDC1 may be involved in the pathogenesis of the disease.

The Use of Two-Photon FRET-FLIM to Study Protein Interactions During Nuclear Envelope Fusion In Vivo and In Vitro.

Science.gov (United States)

Byrne, Richard D; Larijani, Banafshé; Poccia, Dominic L

2016-01-01

FRET-FLIM techniques have wide application in the study of protein and protein-lipid interactions in cells. We have pioneered an imaging platform for accurate detection of functional states of proteins and their interactions in fixed cells. This platform, two-site-amplified Förster resonance energy transfer (a-FRET), allows greater signal generation while retaining minimal noise thus enabling application of fluorescence lifetime imaging microscopy (FLIM) to be routinely deployed in different types of cells and tissue. We have used the method described here, time-resolved FRET monitored by two-photon FLIM, to demonstrate the direct interaction of Phospholipase Cγ (PLCγ) by Src Family Kinase 1 (SFK1) during nuclear envelope formation and during male and female pronuclear membrane fusion in fertilized sea urchin eggs. We describe here a generic method that can be applied to monitor any proteins of interest.

Diabetes-related autoantibodies in cord blood from children of healthy mothers have disappeared by the time the child is one year old.

Science.gov (United States)

Ludvigsson, Johnny; Wahlberg, Jeanette

2002-04-01

Autoantibodies found in cord blood in children who later develop diabetes might be produced by the fetus. If so, continuous autoantibody production would still be expected in these children at one year of age. We decided to determine autoantibodies in cord blood and to see whether they persisted in these children at one year. Autoantibodies against GAD65 (glutamic acid decarboxylase) and IA-2 (tyrosine phosphatase) in cord blood were determined in 2,518 randomly selected children. Forty-nine (1.95%) were positive for GAD65 antibodies, 14 (0.56%) were positive for IA-2 antibodies, and 3 of them were positive for both GAD and IA-2. Four of the mothers of children with GAD65 autoantibodies in cord blood (8.2%) had type 1 diabetes as did 5 mothers of children with IA-2 antibodies (35.7 %), but only 0.4% of the mothers had type 1 diabetes in the autoantibody-negative group (P nobody of those with positive cord blood had GAD65 or IA-2 autoantibodies. We conclude that most autoantibodies found in cord blood samples of children are probably passively transferred from mother to child. Antibody screening of cord blood cannot be used to predict diabetes in the general population. Infections during pregnancy may initiate an immune process related to diabetes development.

Comparison of the prevalence of islet autoantibodies according to age and disease duration in patients with type 1 diabetes mellitus

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Young Hwa Kong

2013-06-01

Full Text Available PurposeThis study investigated the prevalence of islet autoantibodies in children and adults with T1DM according to their age and the duration of disease.MethodsWe measured the levels of islet autoantibodies, including antiglutamic acid decarboxylase antibody (anti-GAD Ab, and combined these with anthropometric measurements and laboratory tests of 137 patients newly diagnosed with T1DM during the last 20 years. The subjects were subdivided into four groups according to their age at the onset of the disease. We then compared the prevalence of islet autoantibodies in the different age groups with the duration of disease.ResultsAmong the 137 patients, 68.9% tested positive for islet autoantibodies (71.4% within 1 year; 67.7% after 1 year of the disease onset. Within 1 year of the onset of the disease, 66.3% of the patients were positive for the anti-GAD Ab, and 35.6% were positive for IAAs. The prevalence of islet autoantibodies was significantly higher in the prepubertal groups than in the postpubertal groups (80.0% vs. 58.3%. The rate of positive islet autoantibodies changed with the duration of disease, and it differed according to the type of autoantibody and the age of the patient.ConclusionThe rates of positive islet autoantibodies were significantly higher in younger than in older patients at the time of the diagnosis of the disease. The positive rates were significantly changed 1 year after the onset of the disease in the preschool and the children groups. So these findings suggest that we need to diagnose type 1B diabetes distinguished T2DM in aldolescent group, carefully.

Quantitation of autoantibodies in systemic autoimmune diseases : clinically useful?

NARCIS (Netherlands)

Kallenberg, C. G. M.; Stegeman, C. A.; Bootsma, H.; Biji, M.; Limburg, P. C.

2006-01-01

Serial assessment of levels of autoantibodies has been proposed as being clinically useful in certain systemic autoimmune diseases. In particular, attention has been given to anti-dsDNA antibodies in systemic lupus erythematosus (SLE) and ANCA in the ANCA-associated vasculitides (AAV). Much

Isotypes and antigenic profiles of pemphigus foliaceus and pemphigus vulgaris autoantibodies.

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Hacker, Mary K; Janson, Marleen; Fairley, Janet A; Lin, Mong-Shang

2002-10-01

In this study we systematically characterized isotype profiles and antigenic and tissue specificity of antidesmoglein autoantibodies from patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV) using enzyme-linked immunoabsorbent assays (ELISA), indirect immunofluorescence (IIF) staining, and immunoblotting (IB). In PF, we found that IgG1 antidesmoglein-1 (Dsg1) reacts with a linear epitope(s) on the ectodomain of Dsg1, while its IgG4 counterpart recognizes a conformational epitope(s). These two subclasses of anti-Dsg1 are both capable of recognizing tissues from monkey esophagus and adult human skin, but IgG1 is not able to react with mouse skin, which may explain why this isotype of anti-Dsg1 failed to induce PF-like lesions in the passive transfer animal model. In mucosal PV patients, we found that both IgG1 and IgG4 only recognized monkey esophagus tissue by IIF, except in one patient, indicating that these antibodies react with a unique conformational epitope(s) that is present in mucosal but not skin tissue. In generalized PV, IgG1 anti-Dsg3 autoantibodies appeared to recognize a linear epitope(s) on the Dsg3 ectodomain. In contrast, IgG4 anti-Dsg3 antibodies recognized both linear and conformational epitopes on the Dsg3 molecule. Interestingly, the IgG1 anti-Dsg3 antibodies failed to react with human and mouse skin tissues, suggesting that this subclass of autoantibodies may not play an essential role in the development of PV suprabasilar lesions. In summary, we conclude that this study further elucidates the pathological mechanisms of PF and PV autoantibodies by revealing their distinct isotype and antigenic profiles. This information may help us to better understand the autoimmune mechanisms underlying the development of pemphigus.

Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.

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Ramaekers, V T; Thöny, B; Sequeira, J M; Ansseau, M; Philippe, P; Boemer, F; Bours, V; Quadros, E V

2014-12-01

Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide. Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated. Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ(2)=21.6; pfolate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean±SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement. Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters

ECL-IAA and ECL-GADA Can Identify High-Risk Single Autoantibody-Positive Relatives in the TrialNet Pathway to Prevention Study.

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Steck, Andrea K; Fouts, Alexandra; Miao, Dongmei; Zhao, Zhiyuan; Dong, Fran; Sosenko, Jay; Gottlieb, Peter; Rewers, Marian J; Yu, Liping

2016-07-01

Relatives with single positive islet autoantibodies have a much lower risk of progression to diabetes than those with multiple autoantibodies. TrialNet subjects positive for single autoantibody to insulin (mIAA) (n = 50) or single autoantibody to glutamic acid decarboxylase (GADA) (n = 50) were analyzed using new electrochemiluminescence (ECL) assays (ECL-IAA and ECL-GADA, respectively) at their initial visit and longitudinally over time. Affinity assays were performed on a subset of single autoantibody-positive subjects at initial and most recent visits. After a mean follow-up of 5.3 years, 20 subjects developed type 1 diabetes. Among either single GADA or single mIAA subjects, those who were positive in the ECL assay showed higher affinity at the initial visit, and affinity results stayed consistent over time. No converting events from low to high or high to low affinity were seen over time. Confirmed positivity for ECL is associated with high affinity and can help staging of risk for type 1 diabetes in single autoantibody-positive subjects.

Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals.

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Martínez-Cerdeño, Verónica; Camacho, Jasmin; Fox, Elizabeth; Miller, Elaine; Ariza, Jeanelle; Kienzle, Devon; Plank, Kaela; Noctor, Stephen C; Van de Water, Judy

2016-01-01

Autism spectrum disorders (ASDs) affect up to 1 in 68 children. Autism-specific autoantibodies directed against fetal brain proteins have been found exclusively in a subpopulation of mothers whose children were diagnosed with ASD or maternal autoantibody-related autism. We tested the impact of autoantibodies on brain development in mice by transferring human antigen-specific IgG directly into the cerebral ventricles of embryonic mice during cortical neurogenesis. We show that autoantibodies recognize radial glial cells during development. We also show that prenatal exposure to autism-specific maternal autoantibodies increased stem cell proliferation in the subventricular zone (SVZ) of the embryonic neocortex, increased adult brain size and weight, and increased the size of adult cortical neurons. We propose that prenatal exposure to autism-specific maternal autoantibodies directly affects radial glial cell development and presents a viable pathologic mechanism for the maternal autoantibody-related prenatal ASD risk factor. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Radiative transfer in spherical circumstellar dust envelopes. III. Dust envelope models of some well known infrared stars

International Nuclear Information System (INIS)

Apruzese, J.P.

1975-01-01

The radiative transfer techniques described elsewhere by the author have been employed to construct dust envelope models of several well known infrared stars. The resulting calculations indicate that the infrared emissivity of circumstellar grains generally must be higher than that which many calculations of small nonsilicate grains yield. This conclusion is dependent to some degree on the (unknown) size of the stellar envelopes considered, but is quite firm in the case of the spatially resolved envelope of IRC+10216. Further observations of the spatial distribution of the infrared radiation from stellar envelopes will be invaluable in deciphering the properties of the circumstellar grains

Serum Autoantibody Measurement for the Detection of Hepatocellular Carcinoma

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Middleton, Catrin H.; Irving, William; Robertson, John F. R.; Murray, Andrea; Parsy-Kowalska, Celine B.; Macdonald, Isabel K.; McElveen, Jane; Allen, Jared; Healey, Graham F.; Thomson, Brian J.; Ryder, Stephen J.; Holdenrieder, Stefan; Chapman, Caroline J.

2014-01-01

Background Individuals with liver disease, and especially those with Hepatitis B or C, are at an increased risk of developing hepatocellular carcinoma (HCC) which is the third most common cause of cancer-related death worldwide. Inadequate screening tests largely account for presentation of advanced tumours and high mortality rates. Early detection of HCC amongst high-risk groups is paramount in improving prognosis. This research aimed to further characterise the previously described humoral immune response raised to tumour-associated antigens (TAAs) in the serum of patients with HCC. Methods Serum from 96 patients with confirmed HCC, 96 healthy controls matched for age and sex, 78 patients with confirmed liver cirrhosis and 91 patients with confirmed chronic liver disease were analysed for the presence of IgG autoantibodies raised to 41 recombinant TAAs/antigen fragments by ELISA. Results Varying autoantibody specificities (97–100%) and sensitivities (0–10%) were observed to individual TAAs. A 21-antigen panel achieved a specificity of 92% and sensitivity of 45% for the detection of HCC. This same panel identified 21% of 169 high-risk controls as having elevated autoantibody levels. A reproducible panel of 10 antigens achieved a specificity of 91% and sensitivity of 41% in HCC. 15% of 152 high-risk controls gave positive results with this panel. Conclusions This minimally invasive blood test has the potential to offer advantages over currently available tools for the identification of HCC amongst pre-disposed patients. Results are comparable to current gold standards in HCC (Ultrasonography) and to similar tests in other cancers (EarlyCDT-Lung). PMID:25093332

Serum autoantibody measurement for the detection of hepatocellular carcinoma.

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Catrin H Middleton

Full Text Available BACKGROUND: Individuals with liver disease, and especially those with Hepatitis B or C, are at an increased risk of developing hepatocellular carcinoma (HCC which is the third most common cause of cancer-related death worldwide. Inadequate screening tests largely account for presentation of advanced tumours and high mortality rates. Early detection of HCC amongst high-risk groups is paramount in improving prognosis. This research aimed to further characterise the previously described humoral immune response raised to tumour-associated antigens (TAAs in the serum of patients with HCC. METHODS: Serum from 96 patients with confirmed HCC, 96 healthy controls matched for age and sex, 78 patients with confirmed liver cirrhosis and 91 patients with confirmed chronic liver disease were analysed for the presence of IgG autoantibodies raised to 41 recombinant TAAs/antigen fragments by ELISA. RESULTS: Varying autoantibody specificities (97-100% and sensitivities (0-10% were observed to individual TAAs. A 21-antigen panel achieved a specificity of 92% and sensitivity of 45% for the detection of HCC. This same panel identified 21% of 169 high-risk controls as having elevated autoantibody levels. A reproducible panel of 10 antigens achieved a specificity of 91% and sensitivity of 41% in HCC. 15% of 152 high-risk controls gave positive results with this panel. CONCLUSIONS: This minimally invasive blood test has the potential to offer advantages over currently available tools for the identification of HCC amongst pre-disposed patients. Results are comparable to current gold standards in HCC (Ultrasonography and to similar tests in other cancers (EarlyCDT-Lung.

Clinical utility of autoantibodies and biologic markers in rheumatoid ...

African Journals Online (AJOL)

Objective: To review the current and emerging auto-antibodies and biologic markers in rheumatoid arthritis. Data source: Published original research work and reviews were searched in English related to pathophysiology, diagnosis and auto antibodies in rheumatoid arthritis. Study design: Only articles that emphasis on ...

Increased prevalence of autoimmune disorders and autoantibodies in parents of children with opsoclonus-myoclonus syndrome (OMS).

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Krasenbrink, I; Fühlhuber, V; Juhasz-Boess, I; Stolz, E; Hahn, A; Kaps, M; Hero, B; Blaes, F

2007-06-01

Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease in childhood which can be associated with neuroblastoma. Since autoantibodies have been detected in some patients with OMS, an autoimmune etiology is suspected. We compared the prevalence of autoimmune disorders and autoantibodies in parents of children with OMS and in a group of controls of same age and sex. Autoimmune diseases were found in 15.8% of the parents of OMS children, but only in 2.0% of the controls (pOMS parents (42.8% vs. 8.0%, pOMS parents also had significantly more autoantibodies against CNS structures than the controls (pOMS and may also hint to a genetic susceptibility for OMS.

Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors.

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Tao Cui

Full Text Available BACKGROUND: Small intestine neuroendocrine tumors (SI-NETs belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2 as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs. METHODOLOGY/PRINCIPAL FINDINGS: A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC, to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples. CONCLUSION: Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA for the risk of recurrence after radical operation of these tumors.

Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors.

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Cui, Tao; Hurtig, Monica; Elgue, Graciela; Li, Su-Chen; Veronesi, Giulia; Essaghir, Ahmed; Demoulin, Jean-Baptiste; Pelosi, Giuseppe; Alimohammadi, Mohammad; Öberg, Kjell; Giandomenico, Valeria

2010-12-30

Small intestine neuroendocrine tumors (SI-NETs) belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2) as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs. A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC), to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples. Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA) for the risk of recurrence after radical operation of these tumors.

[Efficacy of combination therapy with pegylated-interferon alfa-2a plus ribavirin in autoantibody-positive chronic hepatitis C patients].

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Li, Ya-xin; Yang, Yan-jia; Yang, Mei; Chen, Li-yu; Lu, Jia-jie; Ma, Yuan-ji; Liu, Kai; Lei, Xue-zhong; Tang, Hong

2013-05-01

To evaluate the therapeutic efficacy of antiviral combination therapy with pegylated-interferon alpha-2a plus ribavirin (RBV) in patients with autoantibody-positive chronic hepatitis C (CHC) and to investigate the impact of the presence of autoantibodies on the treatment outcome. Eighty-six consecutive CHC patients who underwent a 48-week treatment regimen composed of Peg-IFNa-2a (135 or 180 mug/wk) plus weight-based RBV ( less than or equal to 65 kg, 800 mg/d; 65 to 75 kg, 1000 mg/d; more than or equal to75 kg, 1200 mg/d ). Prior to treatment (baseline) and at end of treatment (EOT; week 48), levels of antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti liver/kidney microsomal antibody type 1 (LKM1), anti-La (SSB), and anti liver cytosolic-1 (LC-1) were detected by indirect immunofluorescence. At baseline, during treatment (weeks 4, 12, 24, and 36), EOT, and 24 weeks after EOT, levels of HCV RNA were assessed by real-time quantitative PCR. Rapid virological response (RVR) was defined as HCV RNA less than 10(3) copy/ml at week 4. Sustained virologic response (SVR) was defined as HCV RNA load below the lower limit of detection at 24 weeks after EOT. Correlation between autoantibodies and treatment-induced reduced HCV RNA load was assessed by univariate analysis of variance or chi-squared tests. Autoantibodies were detected in 24 patients, which included 14 ANA-positive patients, five SMA-positive patients, three LKM1-positive patients, one patient with double-positivity for ANA and SSB, and one patient with double-positivity for ANA and LC-1. The autoantibody-positive patients and autoantibody-negative patients showed similar rates of RVR (70.8% vs. 72.5%, P more than 0.05) and SVR (81.4% vs. 82.2%, P more than 0.05). Antiviral therapy with Peg-IFNa-2a RBV can effectively reduce the HCV RNA load in autoantibody-positive CHC patients; however, the presence of autoantibodies may not be an independent predictor of therapy outcome.

Paving the way to understand humoral autoantibody epilepsy on the molecular level

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Guiscard eSeebohm

2015-07-01

Full Text Available Correct function of neuronal networks is enabled by a delicate interplay among neurons communicating with each other. One of the keys is the communication at chemical synapses where neurotransmitters like glutamate, GABA and glycine enable signal transfer over the synaptic cleft. Thereby, the neurotransmitters are released from the presynapse and bind as ligands to specific receptors at the postsynaptic side to allow for modulation of the postsynaptic membrane potentials. The postsynaptic electrical signal, which is highly modulated by voltage gated ion channels, spreads over the dendritic tree and is thus integrated to allow for generation of action potentials at the axon hillock. This concert of receptors and voltage gated ion channels depends on correct function of all its components. Misfunction of receptors and/or voltage-gated potassium channels (VGKC leads to diverse adverse effects in patients. Such malfunctions can be the result of inherited genetic alterations or pharmacological side effects by drugs. Recently, auto-antibodies targeting receptor or channel complexes like NMDAR, AMPAR, GABA-receptors, glycine-receptors, LGI1 or CASPR2 (previously termed VGKC-complex antibodies have been discovered. The presence of specific auto-antibodies against these targets associates with severe forms of antibody-mediated encephalitis. Understanding the molecular details of auto-antibody actions on receptor and VGKC complexes is highly desirable and may open the path to develop specific therapies to treat humoral autoimmune encephalitis. Here, we summarize the current knowledge and discuss technical approaches to fill the gap of knowledge. These techniques include electrophysiology, biochemical approaches for epitope mapping and in silico modeling to simulate molecular interactions between autoantibody and its molecular target.

Creating a Lunar EVA Work Envelope

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Griffin, Brand N.; Howard, Robert; Rajulu, Sudhakar; Smitherman, David

2009-01-01

A work envelope has been defined for weightless Extravehicular Activity (EVA) based on the Space Shuttle Extravehicular Mobility Unit (EMU), but there is no equivalent for planetary operations. The weightless work envelope is essential for planning all EVA tasks because it determines the location of removable parts, making sure they are within reach and visibility of the suited crew member. In addition, using the envelope positions the structural hard points for foot restraints that allow placing both hands on the job and provides a load path for reacting forces. EVA operations are always constrained by time. Tasks are carefully planned to ensure the crew has enough breathing oxygen, cooling water, and battery power. Planning first involves computers using a virtual work envelope to model tasks, next suited crew members in a simulated environment refine the tasks. For weightless operations, this process is well developed, but planetary EVA is different and no work envelope has been defined. The primary difference between weightless and planetary work envelopes is gravity. It influences anthropometry, horizontal and vertical mobility, and reaction load paths and introduces effort into doing "overhead" work. Additionally, the use of spacesuits other than the EMU, and their impacts on range of motion, must be taken into account. This paper presents the analysis leading to a concept for a planetary EVA work envelope with emphasis on lunar operations. There is some urgency in creating this concept because NASA has begun building and testing development hardware for the lunar surface, including rovers, habitats and cargo off-loading equipment. Just as with microgravity operations, a lunar EVA work envelope is needed to guide designers in the formative stages of the program with the objective of avoiding difficult and costly rework.

Life-threatening bleeding in a case of autoantibody-induced factor VII deficiency.

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Okajima, K; Ishii, M

1999-02-01

A male patient presented with life-threatening bleeding induced by autoantibody-induced factor VII (F.VII) deficiency. This patient had macroscopic hematuria, skin ecchymosis, gastrointestinal bleeding, and a neck hematoma that was causing disturbed respiration. He developed acute renal failure and acute hepatic failure, probably due to obstruction of the ureters and the biliary tract, respectively. Although activated partial thromboplastin time was normal, prothrombin time (PT) was remarkably prolonged at 71.8 seconds compared to 14.0 seconds in a normal control. Both the immunoreactive level of F.VII antigen and the F.VII activity of the patient's plasma samples were VII activity. These findings suggested the presence of a plasma inhibitor for F.VII. After administration of large doses of methylprednisolone, PT was gradually shortened and plasma levels of F.VII increased over time. Bleeding, acute renal failure, and acute hepatic failure improved markedly following the steroid treatment. These observations suggest that life-threatening bleeding can be induced by autoantibody-induced F.VII deficiency and that immunosuppressive therapy using large doses of steroid can be successful in inhibiting the production of the autoantibody.

Production of Autoantibodies by Murine B-1a Cells Stimulated with Helicobacter pylori Urease through Toll-Like Receptor 2 Signaling ▿ †

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Kobayashi, Fumiko; Watanabe, Eri; Nakagawa, Yohko; Yamanishi, Shingo; Norose, Yoshihiko; Fukunaga, Yoshitaka; Takahashi, Hidemi

2011-01-01

Helicobacter pylori infection is associated with several autoimmune diseases, in which autoantibody-producing B cells must be activated. Among these B cells, CD5-positive B-1a cells from BALB/c mice were confirmed to secrete autoantibodies when cocultured with purified H. pylori urease in the absence of T cells. To determine the mechanisms for autoantibody production, CD5-positive B-1a cells were sorted from murine spleen cells and stimulated with either purified H. pylori urease or H. pylori coated onto plates (referred to hereafter as plate-coated H. pylori), and autoantibody production was measured by enzyme-linked immunosorbent assay (ELISA). Complete urease was not secreted from H. pylori but was visually expressed over the bacterium-like endotoxin. Urease-positive plated-coated H. pylori stimulated B-1a cells to produce autoantibodies, although urease-deficient isotype-matched H. pylori did not. Autoantibody secretion by B-1a cells was inhibited when bacteria were pretreated with anti-H. pylori urease-specific antibody having neutralizing ability against urease enzymatic activity but not with anti-H. pylori urease-specific antibody without neutralizing capacity. The B-1a cells externally express various Toll-like receptors (TLRs): TLR1, TLR2, TLR4, and TLR6. Among the TLRs, blocking of TLR2 on B-1a cells with a specific monoclonal antibody (MAb), T2.5, inhibited autoantibody secretion when B-1a cells were stimulated with plate-coated H. pylori or H. pylori urease. Moreover, B-1a cells from TLR2-knockout mice did not produce those autoantibodies. The present study provides evidence that functional urease expressed on the surface of H. pylori will directly stimulate B-1a cells via innate TLR2 to produce various autoantibodies and may induce autoimmune disorders. PMID:21947775

Autoantibodies in renal diseases – clinical significance and recent developments in serological detection

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Gianna eKirsztajn

2015-05-01

Full Text Available Autoimmune dysfunctions are the bête noire in a range of debilitating nephropathies. Autoimmune-mediated damage to the kidneys can be triggered by autoantibodies directed against specific proteins or renal structures, for example the phospholipase A2 receptor or the glomerular basement membrane, resulting in glomerular diseases such as primary membranous nephropathy or Goodpasture’s disease. Moreover, secondary damage to the kidney can be part of the wide-reaching effects of systemic autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE – the latter counts lupus nephritis among its most severe manifestations. Systemic autoimmune diseases are characterized by non-organ-specific autoantibodies, directed for example against neutrophil cytoplasmic antigens in systemic vasculitis and against double-stranded DNA and nucleosomes in SLE.A large variety of innovative and highly specific and sensitive autoantibody tests have been developed in the last years that are available to identify autoimmune kidney diseases at an early stage. Thus, serological in vitro diagnostics allow for appropriate interventional therapy in order to prevent disease progression often resulting in need of dialysis and transplantation.

Autoantibody response against NALP5/MATER in primary ovarian insufficiency and in autoimmune Addison's disease.

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Brozzetti, Annalisa; Alimohammadi, Mohammad; Morelli, Silvia; Minarelli, Viviana; Hallgren, Åsa; Giordano, Roberta; De Bellis, Annamaria; Perniola, Roberto; Kämpe, Olle; Falorni, Alberto

2015-05-01

NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. Autoantibodies against NALP5/MATER and inhibin chains-α and -βA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-α/βA autoantibodies. NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.

Effects of the thymic microenvironment on autoantibody production in (NZB X NZW)F1 mice

International Nuclear Information System (INIS)

Huston, D.P.; Smathers, P.A.; Reeves, J.P.; Steinberg, A.D.

1983-01-01

The effects of the thymic microenvironment on autoantibody production in (NZB X NZW)F1 mice were studied. Neonatally thymectomized male and female F1 mice reconstituted with a parental or F1-irradiated thymic lobe were compared to nonreconstituted and sham-thymectomized controls. While maleness retarded the spontaneous production of ss- and ds-DNA antibodies, thymic grafts did not suppress antibodies to ss-DNA in either sex, but did suppress the production of antibodies to ds-DNA in female mice. A unique property of NZB thymic grafts was the inability to suppress anti-RBC antibodies in male mice. Thus, (i) the gender of the F1 recipient was the most important determinant of production of antibodies to ss-DNA, (ii) either maleness or the thymic microenvironment could retard production of anti-ds-DNA antibodies, and (iii) both gender and the thymic microenvironment were important in the regulation of anti-RBC antibody production. Since the administration of thymosin did not suppress autoantibody production, the effects of the thymic grafts was not solely via thymic hormone production. These studies suggest that sex hormones and/or the thymic microenvironment can exert a suppressive effect on autoantibody production and that autoantibodies differ in their susceptibility to such suppression

14 CFR 29.87 - Height-velocity envelope.

Science.gov (United States)

2010-01-01

... Category A engine isolation requirements, the height-velocity envelope for complete power failure must be... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Height-velocity envelope. 29.87 Section 29... AIRWORTHINESS STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Flight Performance § 29.87 Height-velocity envelope. (a...

Label-free nanoplasmonic sensing of tumor-associate autoantibodies for early diagnosis of colorectal cancer.

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Soler, Maria; Estevez, M-Carmen; Villar-Vazquez, Roi; Casal, J Ignacio; Lechuga, Laura M

2016-08-03

Colorectal cancer is treatable and curable when detected at early stages. However there is a lack of less invasive and more specific screening and diagnosis methods which would facilitate its prompt identification. Blood circulating autoantibodies which are immediately produced by the immune system at tumor appearance have become valuable biomarkers for preclinical diagnosis of cancer. In this work, we present the rapid and label-free detection of colorectal cancer autoantibodies directly in blood serum or plasma using a recently developed nanoplasmonic biosensor. Our nanoplasmonic device offers sensitive and real-time quantification of autoantibodies with excellent selectivity and reproducibility, achieving limits of detection around 1 nM (150-160 ng mL(-1)). A preliminary evaluation of clinical samples of colorectal cancer patients has shown good correlation with ELISA. These results demonstrate the reliability of the nanobiosensor strategy and pave the way towards the achievement of a sensitive diagnostic tool for early detection of colorectal cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Identification of novel autoantibodies for detection of malignant mesothelioma.

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Xufei Zhang

Full Text Available The malignant mesothelioma (MM survival rate has been hampered by the lack of efficient and accurate early detection methods. The immune system may detect the early changes of tumor progression by responding with tumor-associated autoantibody production. Hence, in this study, we translated the humoral immune response to cancer proteins into a potential blood test for MM.A T7 phage MM cDNA library was constructed using MM tumor tissues and biopanned for tumor-associated antigens (TAAs using pooled MM patient and normal serum samples. About 1008 individual phage TAA clones from the biopanned library were subjected to protein microarray construction and tested with 53 MM and 52 control serum samples as a training group. Nine candidate autoantibody markers were selected from the training group using Tclass system and logistic regression statistical analysis, which achieved 94.3% sensitivity and 90.4% specificity with an AUC value of 0.89 in receiver operating characteristic analysis. The classifier was further evaluated with 50 patient and 50 normal serum samples as an independent blind validation, and the sensitivity of 86.0% and the specificity of 86.0% were obtained with an AUC of 0.82. Sequencing and BLASTN analysis of the classifier revealed that five of these nine candidate markers were found to have strong homology to cancer related proteins (PDIA6, MEG3, SDCCAG3, IGHG3, IGHG1.Our results indicated that using a panel of 9 autoantibody markers presented a promising accuracy for MM detection. Although the results need further validation in high-risk groups, they provided the potentials in developing a serum-based assay for MM diagnosis.

Thyroid Autoantibodies in the Cerebrospinal Fluid of Subjects with and without Thyroid Disease: Implications for Hashimoto’s Encephalopathy

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Ioannis Ilias

2015-01-01

Full Text Available Introduction. Plasma antithyroid peroxidase (anti-TPO and anti-thyroglobulin antibodies (anti-Tg are widely used in the diagnosis of autoimmune thyroiditis. No research has compared anti-TPO and anti-Tg both in plasma and cerebrospinal fluid (CSF of healthy individuals vis-à-vis patients with thyroid disease. Methods. We measured anti-TPO and anti-Tg antibodies in plasma and CSF in nine subjects (mean age ± SD: 73 ± 6 years with hypothyroidism and nine subjects (mean age ± SD: 73 ± 8 years without thyroid disease. Results. The concentration of anti-TPO autoantibodies in CSF was very low compared to plasma in both subjects with thyroid and without thyroid disease (P=0.007. CSF anti-Tg autoantibodies titers were very low compared to the plasma in subjects with thyroid disease (P=0.004, whereas, in subjects without thyroid disease, this difference did not reach statistical significance (P=0.063. Conclusions. Thyroid autoantibodies levels were low in plasma and CSF; we did not observe any transfer of thyroid autoantibodies from the peripheral blood to the CSF. Therefore, regarding Hashimoto’s encephalopathy, where elevated antithyroid autoantibodies are often measured in blood, it is more likely that thyroiditis and encephalopathy represent nonspecific, but distinct, events of an aggressive immune system.

Prevalence of autoantibodies against cellular antigens in patients with HIV and leprosy coinfection in the Amazon region.

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Bichara, Clea Nazaré Carneiro; Bichara, Carlos David Araújo; Tostes, Camila; Povoa, Marinete Marins; Quaresma, Juarez Antonio Simões; Xavier, Marília Brasil

2017-06-01

Infectious agents can activate self-reactive T cells. In general, infections trigger various mechanisms, including a lack of auto-tolerance, induction of costimulatory molecules on antigen presenting cells, and molecular simulation, in addition to cross-reactions between microbial antigens and self-antigens. HIV and leprosy coinfections lead to self-immunity with the production of autoantibodies. However, not enough data on the immune behaviour associated with this coinfection are available. Therefore, this study focused on the detection of autoantibodies against cellular antigens (AACA) in individuals with HIV and leprosy coinfection in the Amazon region. Patients were distributed into four groups according to their infections: (i) coinfection with HIV and leprosy (n = 23), (ii) infection with leprosy (n = 33), (iii) infection with HIV/AIDS (n = 25), and (iv) healthy blood donor controls (n = 100). AACA were identified by indirect immunofluorescence and the samples were tested using a commercial diagnosis kit containing the antinuclear antibody HEp-2. Morphologically, all stages of cell division were assessed in addition to the morphological features associated with the nuclear matrix, nucleolus, mitotic spindle, and cytoplasm. There was a high prevalence of AACA in the coinfection group (47.8%, n = 11) when compared with the control group of healthy blood donors (2.0%). The results showed predominantly cytoplasmic staining in all groups analysed, and no difference was observed between the presence or absence of AACA and the leprosy forms (paucibacillary and multibacillary) in the coinfection group. The results of this study show that despite the tendency of coinfected patients to have higher levels of autoantibodies, no correlation was observed between clinical and laboratorial variables and morbidity associated with HIV and leprosy coinfections or the levels of AACA in the serum of coinfected patients. These data are important to elucidate

Solitary Alfven wave envelopes and the modulational instability

International Nuclear Information System (INIS)

Kennel, C.F.

1987-06-01

The derivative nonlinear Schroedinger equation describes the modulational instability of circularly polarized dispersive Alfven wave envelopes. It also may be used to determine the properties of finite amplitude localized stationary wave envelopes. Such envelope solitons exist only in conditions of modulational stability. This leaves open the question of whether, and if so, how, the modulational instability produces envelope solitons. 12 refs

Pulmonary function and autoantibodies in a long-term follow-up of juvenile dermatomyositis patients

DEFF Research Database (Denmark)

Mathiesen, Pernille Raasthøj; Buchvald, Frederik Fouirnaies; Nielsen, Kim G

2014-01-01

outcome, and (iii) identify possible associations between pulmonary impairment and myositis-specific autoantibodies (MSAs).Methods. Fifty-one JDM patients performed conventional spirometry in a cross-sectional follow-up study. The scores of the Myositis Damage Index (MDI), Myositis Damage by visual...... analogue scale (MYODAM-VAS) and physician's global damage assessment were used to estimate JDM outcome. ANAs, MSAs and myositis-associated autoantibodies were analysed in all patients.Results. Forty-two patients (82%) (mean follow-up time 14.3 years) had normal lung function. Four patients (8%) were...

Unexpected T cell regulatory activity of anti-histone H1 autoantibody: Its mode of action in regulatory T cell-dependent and -independent manners

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Takaoka, Yuki [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Kawamoto, Seiji, E-mail: skawa@hiroshima-u.ac.jp [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Katayama, Akiko [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Nakano, Toshiaki [Liver Transplantation Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan (China); Yamanaka, Yasushi; Takahashi, Miki [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Shimada, Yayoi; Chiang, Kuei-Chen [Kazusa Institute for Drug Discovery, Josai International University, Kisarazu (Japan); Ohmori, Naoya [Kazusa Institute for Drug Discovery, Josai International University, Kisarazu (Japan); Faculty of Nursing, Josai International University, Togane (Japan); Aki, Tsunehiro [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan); Goto, Takeshi; Sato, Shuji [Kazusa Institute for Drug Discovery, Josai International University, Kisarazu (Japan); Faculty of Nursing, Josai International University, Togane (Japan); Goto, Shigeru [Liver Transplantation Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan (China); Iwao Hospital, Yufuin (Japan); Chen, Chao-Long [Liver Transplantation Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan (China); Ono, Kazuhisa [Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima (Japan)

2013-02-08

Highlights: ► Anti-histone H1 autoantibody (anti-H1) acts on T cells to inhibit their activation. ► Anti-H1 suppresses T cell activation in Treg cell-dependent and -independent manners. ► Suboptimal dose of anti-H1 enhances suppressor function of Treg cells. ► High dose of anti-H1 directly inhibits T cell receptor signaling. -- Abstract: Induction of anti-nuclear antibodies against DNA or histones is a hallmark of autoimmune disorders, but their actual contribution to disease predisposition remains to be clarified. We have previously reported that autoantibodies against histone H1 work as a critical graft survival factor in a rat model of tolerogeneic liver transplantation. Here we show that an immunosuppressive anti-histone H1 monoclonal antibody (anti-H1 mAb) acts directly on T cells to inhibit their activation in response to T cell receptor (TCR) ligation. Intriguingly, the T cell activation inhibitory activity of anti-H1 mAb under suboptimal dosages required regulatory T (Treg) cells, while high dose stimulation with anti-H1 mAb triggered a Treg cell-independent, direct negative regulation of T cell activation upon TCR cross-linking. In the Treg cell-dependent mode of immunosuppressive action, anti-H1 mAb did not induce the expansion of CD4{sup +}Foxp3{sup +} Treg cells, but rather potentiated their regulatory capacity. These results reveal a previously unappreciated T cell regulatory role of anti-H1 autoantibody, whose overproduction is generally thought to be pathogenic in the autoimmune settings.

Unexpected T cell regulatory activity of anti-histone H1 autoantibody: Its mode of action in regulatory T cell-dependent and -independent manners

International Nuclear Information System (INIS)

Takaoka, Yuki; Kawamoto, Seiji; Katayama, Akiko; Nakano, Toshiaki; Yamanaka, Yasushi; Takahashi, Miki; Shimada, Yayoi; Chiang, Kuei-Chen; Ohmori, Naoya; Aki, Tsunehiro; Goto, Takeshi; Sato, Shuji; Goto, Shigeru; Chen, Chao-Long; Ono, Kazuhisa

2013-01-01

Highlights: ► Anti-histone H1 autoantibody (anti-H1) acts on T cells to inhibit their activation. ► Anti-H1 suppresses T cell activation in Treg cell-dependent and -independent manners. ► Suboptimal dose of anti-H1 enhances suppressor function of Treg cells. ► High dose of anti-H1 directly inhibits T cell receptor signaling. -- Abstract: Induction of anti-nuclear antibodies against DNA or histones is a hallmark of autoimmune disorders, but their actual contribution to disease predisposition remains to be clarified. We have previously reported that autoantibodies against histone H1 work as a critical graft survival factor in a rat model of tolerogeneic liver transplantation. Here we show that an immunosuppressive anti-histone H1 monoclonal antibody (anti-H1 mAb) acts directly on T cells to inhibit their activation in response to T cell receptor (TCR) ligation. Intriguingly, the T cell activation inhibitory activity of anti-H1 mAb under suboptimal dosages required regulatory T (Treg) cells, while high dose stimulation with anti-H1 mAb triggered a Treg cell-independent, direct negative regulation of T cell activation upon TCR cross-linking. In the Treg cell-dependent mode of immunosuppressive action, anti-H1 mAb did not induce the expansion of CD4 + Foxp3 + Treg cells, but rather potentiated their regulatory capacity. These results reveal a previously unappreciated T cell regulatory role of anti-H1 autoantibody, whose overproduction is generally thought to be pathogenic in the autoimmune settings

Genetic Diversity of Koala Retroviral Envelopes

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Wenqin Xu

2015-03-01

Full Text Available Genetic diversity, attributable to the low fidelity of reverse transcription, recombination and mutation, is an important feature of infectious retroviruses. Under selective pressure, such as that imposed by superinfection interference, gammaretroviruses commonly adapt their envelope proteins to use alternative receptors to overcome this entry block. The first characterized koala retroviruses KoRV subgroup A (KoRV-A were remarkable in their absence of envelope genetic variability. Once it was determined that KoRV-A was present in all koalas in US zoos, regardless of their disease status, we sought to isolate a KoRV variant whose presence correlated with neoplastic malignancies. More than a decade after the identification of KoRV-A, we isolated a second subgroup of KoRV, KoRV-B from koalas with lymphomas. The envelope proteins of KoRV-A and KoRV-B are sufficiently divergent to confer the ability to bind and employ distinct receptors for infection. We have now obtained a number of additional KoRV envelope variants. In the present studies we report these variants, and show that they differ from KoRV-A and KoRV-B envelopes in their host range and superinfection interference properties. Thus, there appears to be considerable variation among KoRVs envelope genes suggesting genetic diversity is a factor following the KoRV-A infection process.

Tumour auto-antibody screening: performance of protein microarrays using SEREX derived antigens

International Nuclear Information System (INIS)

Stempfer, René; Weinhäusel, Andreas; Syed, Parvez; Vierlinger, Klemens; Pichler, Rudolf; Meese, Eckart; Leidinger, Petra; Ludwig, Nicole; Kriegner, Albert; Nöhammer, Christa

2010-01-01

The simplicity and potential of minimal invasive testing using serum from patients make auto-antibody based biomarkers a very promising tool for use in diagnostics of cancer and auto-immune disease. Although several methods exist for elucidating candidate-protein markers, immobilizing these onto membranes and generating so called macroarrays is of limited use for marker validation. Especially when several hundred samples have to be analysed, microarrays could serve as a good alternative since processing macro membranes is cumbersome and reproducibility of results is moderate. Candidate markers identified by SEREX (serological identification of antigens by recombinant expression cloning) screenings of brain and lung tumour were used for macroarray and microarray production. For microarray production recombinant proteins were expressed in E. coli by autoinduction and purified His-tag (histidine-tagged) proteins were then used for the production of protein microarrays. Protein arrays were hybridized with the serum samples from brain and lung tumour patients. Methods for the generation of microarrays were successfully established when using antigens derived from membrane-based selection. Signal patterns obtained by microarrays analysis of brain and lung tumour patients' sera were highly reproducible (R = 0.92-0.96). This provides the technical foundation for diagnostic applications on the basis of auto-antibody patterns. In this limited test set, the assay provided high reproducibility and a broad dynamic range to classify all brain and lung samples correctly. Protein microarray is an efficient means for auto-antibody-based detection when using SEREX-derived clones expressing antigenic proteins. Protein microarrays are preferred to macroarrays due to the easier handling and the high reproducibility of auto-antibody testing. Especially when using only a few microliters of patient samples protein microarrays are ideally suited for validation of auto-antibody

14 CFR 27.87 - Height-speed envelope.

Science.gov (United States)

2010-01-01

... applicable power failure condition in paragraph (b) of this section, a limiting height-speed envelope must be... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Height-speed envelope. 27.87 Section 27.87... STANDARDS: NORMAL CATEGORY ROTORCRAFT Flight Performance § 27.87 Height-speed envelope. (a) If there is any...

Thyroid profile and autoantibodies in Type 1 diabetes subjects: A perspective from Eastern India

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Debmalya Sanyal

2017-01-01

Full Text Available Context: There has been a rise in the incidence of type 1 diabetes mellitus (T1DM in India. The prevalence of thyroid autoantibodies and thyroid dysfunction is common in T1DM. Aims: The aim of this study is to determine the incidence of thyroid dysfunction and thyroid autoantibodies in T1DM subjects, without any history of thyroid disease, and the prevalence of glutamic acid decarboxylase (GAD antibody, Islet antigen-2 antibody (IA2, thyroid peroxidase (TPO, and thyroglobulin autoantibodies (Tg-AB in T1DM subjects. Settings and Design: This was a cross-sectional clinical-based study. Subjects and Methods: Fifty subjects (29 males, 31 females with T1DM and without any history of thyroid dysfunction were included in the study. All subjects were tested for GAD antibody, IA2 antibody, TPO antibody, thyroglobulin antibody, free thyroxine, and thyroid-stimulating hormone. Statistical Analysis Used: A Chi-square/pooled Chi-square test was used to assess the trends in the prevalence of hypothyroidism. A two-tailed P< 0.05 was considered statistically significant. Results: The mean age of the subjects was 23.50 years. 9.8% of subjects were below the age of 12 years, 27.45% of subjects were of age 12–18 years, 37.25% of subjects were of age 19–30 years, and 25.49% of subjects were above 30 years. 78% were positive autoantibody for GAD, 30% for IA-2, 24% for TPO, and 16% were positive for Tg-AB. A total of 6.0% of T1DM subjects had evidence of clinical hypothyroidism, but the prevalence of subclinical hyperthyroidism (SCH varied from 32% to 68.0% for we considered different definitions of SCH as advocated by different guidelines. All subjects with overt hypothyroidism had positive GAD and thyroid autoantibodies. One (2% subject had clinical hyperthyroidism with strongly positive GAD, TPO, and Tg-AB. Conclusions: We found a high prevalence of GAD, IA2, TPO, and Tg-AB in our T1DM subjects. A substantial proportion of our subjects had undiagnosed thyroid

Preferential recognition of auto-antibodies against 4-hydroxynonenal modified DNA in the cancer patients.

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Faisal, Mohammad; Shahab, Uzma; Alatar, Abdulrahman A; Ahmad, Saheem

2017-11-01

The structural perturbations in DNA molecule may be caused by a break in a strand, a missing base from the backbone, or a chemically changed base. These alterations in DNA that occurs naturally can result from metabolic or hydrolytic processes. DNA damage plays a major role in the mutagenesis, carcinogenesis, aging and various other patho-physiological conditions. DNA damage can be induced through hydrolysis, exposure to reactive oxygen species (ROS) and other reactive carbonyl metabolites including 4-hydroxynonenal (HNE). 4-HNE is an important lipid peroxidation product which has been implicated in the mutagenesis and carcinogenesis processes. The present study examines to probe the presence of auto-antibodies against 4-hydroxynonenal damaged DNA (HNE-DNA) in various cancer subjects. In this study, the purified calf thymus DNA was damaged by the action of 4-HNE. The DNA was incubated with 4-HNE for 24 h at 37°C temperature. The binding characteristics of cancer auto-antibodies were assessed by direct binding and competitive inhibition ELISA. DNA modifications produced hyperchromicity in UV spectrum and decreased fluorescence intensity. Cancer sera exhibited enhanced binding with the 4-HNE modified calf thymus DNA as compared to its native conformer. The 4-HNE modified DNA presents unique epitopes which may be one of the factors for the auto-antibody induction in cancer patients. The HNE modified DNA presents unique epitopes which may be one of the factors for the autoantibody induction in cancer patients. © 2017 Wiley Periodicals, Inc.

Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives.

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Bosi, Emanuele; Boulware, David C; Becker, Dorothy J; Buckner, Jane H; Geyer, Susan; Gottlieb, Peter A; Henderson, Courtney; Kinderman, Amanda; Sosenko, Jay M; Steck, Andrea K; Bingley, Polly J

2017-08-01

Islet autoantibodies are markers of type 1 diabetes, and an increase in number of autoantibodies detected during the preclinical phase predicts progression to overt disease. To refine the effect of age in relation to islet antibody type on progression from single to multiple autoantibodies in relatives of people with type 1 diabetes. We examined 994 relatives with normal glucose tolerance who were positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated antigen 2, and zinc transporter 8 and islet cell antibodies were tested every 6 to 12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8 years, 8 to 11 years, 12 to 17 years, and ≥18 years, and optimal age breakpoints were identified by recursive partitioning analysis. After median follow-up of 2 years, 141 relatives had developed at least one additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by antibody type: Relatives with GADA showed a gradual decrease in risk over the four age groups, whereas relatives with IAA showed a sharp decrease above age 8 years. Recursive partitioning analysis identified age breakpoints at 14 years in relatives with GADA and at 4 years in relatives with IAA. In relatives with IAA, spread of islet autoimmunity is largely limited to early childhood, whereas immune responses initially directed at glutamic acid decarboxylase can mature over a longer period. These differences have important implications for monitoring these patients and for designing prevention trials. Copyright © 2017 Endocrine Society

Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders

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Pilar eMartinez-Martinez

2013-09-01

Full Text Available Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the CNS, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand–activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.

Thyroid autoantibodies and differentiated thyroid cancer: revue of 662 cases

International Nuclear Information System (INIS)

Izembart, M.; Dagousset, F.; Chevalier, A.; Hassid, V.; Leger, A.; Barritault, L.; Clerc, J.

1999-01-01

The incidence of thyroid autoantibodies is clearly increased in patients with differentiated thyroid cancer. The aim of this study was to re-evaluate frequency and evolution of anti-thyroglobulin and anti-microsomal (anti-peroxidase) autoantibodies in 662 patients with thyroid carcinoma treated with 131 radioiodine. Ours results obtained with 'classical' methods confirmed others earlier reports. When using more sensitive methods to detect thyroglobulin antibodies we obtained an increase in positive results and a more frequent association with anti-microsomal antibodies. Antibodies became undetectable with a variable period, ranging from a few months to 13 years in one case. If we suppose that the disappearance of antibodies is linked to the thyroid tissue disappearance, thyroid cancer follow up ought to include anti-thyroglobulin and anti-peroxidase antibodies, both directed against thyroid antigens. A decrease of both antibodies seems to indicate a favorable prognostic factor whereas an increase may suggest relapse. (author)

Integrity of the Linker of Nucleoskeleton and Cytoskeleton Is Required for Efficient Herpesvirus Nuclear Egress.

Science.gov (United States)

Klupp, Barbara G; Hellberg, Teresa; Granzow, Harald; Franzke, Kati; Dominguez Gonzalez, Beatriz; Goodchild, Rose E; Mettenleiter, Thomas C

2017-10-01

Herpesvirus capsids assemble in the nucleus, while final virion maturation proceeds in the cytoplasm. This requires that newly formed nucleocapsids cross the nuclear envelope (NE), which occurs by budding at the inner nuclear membrane (INM), release of the primary enveloped virion into the perinuclear space (PNS), and subsequent rapid fusion with the outer nuclear membrane (ONM). During this process, the NE remains intact, even at late stages of infection. In addition, the spacing between the INM and ONM is maintained, as is that between the primary virion envelope and nuclear membranes. The linker of nucleoskeleton and cytoskeleton (LINC) complex consists of INM proteins with a luminal SUN (Sad1/UNC-84 homology) domain connected to ONM proteins with a KASH (Klarsicht, ANC-1, SYNE homology) domain and is thought to be responsible for spacing the nuclear membranes. To investigate the role of the LINC complex during herpesvirus infection, we generated cell lines constitutively expressing dominant negative (dn) forms of SUN1 and SUN2. Ultrastructural analyses revealed a significant expansion of the PNS and the contiguous intracytoplasmic lumen, most likely representing endoplasmic reticulum (ER), especially in cells expressing dn-SUN2. After infection, primary virions accumulated in these expanded luminal regions, also very distant from the nucleus. The importance of the LINC complex was also confirmed by reduced progeny virus titers in cells expressing dn-SUN2. These data show that the intact LINC complex is required for efficient nuclear egress of herpesviruses, likely acting to promote fusion of primary enveloped virions with the ONM. IMPORTANCE While the viral factors for primary envelopment of nucleocapsids at the inner nuclear membrane are known to the point of high-resolution structures, the roles of cellular components and regulators remain enigmatic. Furthermore, the machinery responsible for fusion with the outer nuclear membrane is unsolved. We show here

Role of Natural Autoantibodies in Ugandans With Rheumatic Heart Disease and HIV

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Daniel M. Huck

2016-03-01

Interpretation: We found that HIV and RHD are associated with alterations in natural autoantibody responses previously linked to an increased risk for atherosclerosis and autoimmune inflammatory disease.

AUTOANTIBODIES TO GLUTAMIC ACID DECARBOXYLASE AS A PATHOGENETIC MARKER OF TYPE I DIABETES MELLITUS

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N. V. Piven

2011-01-01

Full Text Available Abstract. A new method of enzyme-linked immunosorbent assay (in solid-phase ELISA format has been developed to determine concentrations of autoantibodies to glutamic acid decarboxylase, as well as an evidencebased methodology is proposed for its medical implications, as a quantitative pathogenetic predictive marker of autoimmune diagnostics in type 1 diabetes mellitus. This technique could be implied for serial production of diagnostic reagent kits, aimed for detection of autoantibodies to glutamic acid decarboxylase by means of ELISA approach. (Med. Immunol., 2011, vol. 13, N 2-3, pp 257-260

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.

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Tsai, Shang-Yi A; Chuang, Jian-Ying; Tsai, Meng-Shan; Wang, Xiao-Fei; Xi, Zheng-Xiong; Hung, Jan-Jong; Chang, Wen-Chang; Bonci, Antonello; Su, Tsung-Ping

2015-11-24

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.

Characterization of autoantibodies in autoimmune hemolytic anemia following treatment with interferon alfa

International Nuclear Information System (INIS)

Bencomo Hernandez, Antonio; Gutierrez Diaz, Adys; Avila Cabrera, Onel; Rodriguez, Luis Ramon

2012-01-01

We studied 13 patients with chronic myeloid leukemia and autoimmune hemolytic anemia induced by interferon alfa. They underwent tests for immune protein detection and characterization of IgG subclasses in RBCs by direct antiglobulin test (PAD) and the microplate technique. Also they were applied ELISA test for quantifying immunoglobulins in the red blood cells. It was detected the presence of IgG and C3 in 53.84 % of cases, IgG alone in 23.07 % and in 15.38 % were identified IgG and IgA autoantibodies. In 11 patients the presence of IgG1 was showed and also in one case the subclass IgG3 autoantibodies was identified. The ELISA detected antibodies at concentrations of 183 IgG molecules per erythrocyte in a patient with negative PAD. In high-grade hemolysis patients, it was found a concentration of autoantibodies between 1 500 and 3 180 molecules of IgG per erythrocyte, while in low-grade hemolysis patients it behaved between 183 and 1 000 molecules. There was a negative correlation between Hb and plasma haptoglobin values with the number of IgG molecules per erythrocyte and a positive correlation between the latter with the reticulocyte count

Serum auto-antibody testing for early diagnosis of breast cancer

International Nuclear Information System (INIS)

Parvez, S.

2012-01-01

The aim of this thesis is generate prototype-tests suitable for randomized prospective validation of auto-antibody based diagnostic testing using serum samples. Tumours can stimulate the production of auto-antibodies against autologous cellular proteins known as TAAs (tumour associated antigens). This discovery has lead to a possibility of using the auto-antibodies as serological tools for the early diagnosis and management of breast cancer. The recombinant proteins expressed by the SEREX clones, identified from screenings of brain and lung tumour, were used for the production of the protein microarrays and macroarrays. The protein microarrays showed better correlation between the replicates of the serum samples used. The optimized protocols were used for the subsequent experiments. A sizable panel of 642 clone-proteins was selected by marker-screening on protein macroarrays with 38000 clones. These 642 clone-proteins were used to generate protein microarrays that differentiated serum samples from breast cancer patients and controls. Antigenic peptide motifs were identified by in-silico analysis of 642 clone-proteins and peptide arrays were generated using synthetically generated peptides. Comparative studies between protein microarrays and peptide microarrays were done using breast cancer and healthy control samples. Simultaneously, SEREX strategy was used for the identification of the immunogenic TAAs. I identified 192 cDNA expression clones derived from breast cancer tissue samples and the selection was done using breast cancer sera. The genes corresponding to these clones were found over-represented for the pathways that are known to be associated with cancers. These genes showed typical features of TAAs, like over-expression, mutations and fusion genes. (author)

Multiplex autoantibody detection for autoimmune liver diseases and autoimmune gastritis.

Science.gov (United States)

Vanderlocht, Joris; van der Cruys, Mart; Stals, Frans; Bakker-Jonges, Liesbeth; Damoiseaux, Jan

2017-09-01

Autoantibody detection for autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and autoimmune gastritis (AIG) is traditionally performed by IIF on a combination of tissues. Multiplex line/dot blots (LIA/DIA) offer multiple advantages, i.e. automation, objective reading, no interfering reactivities, no coincidental findings. In the current study we evaluated automated DIA (D-Tek) for detecting autoantibodies related to autoimmune diseases of the gastrointestinal tract. We tested samples of the Dutch EQC program and compared the results with the consensus of the participating labs. For the autoimmune liver diseases and AIG, respectively, 64 and 36 samples were tested. For anti-mitochondrial and anti-smooth muscle antibodies a concordance rate of 97% and 88% was observed, respectively. The concordance rate for anti-parietal cell antibodies was 92% when samples without EQC consensus (n=15) were excluded. For antibodies against intrinsic factor a concordance of 96% was observed. For all these antibodies discrepancies were identified that relate to the different test characteristics and the preponderance of IIF utilizing labs in the EQC program. In conclusion, we observed good agreement of the tested DIA blots with the consensus results of the Dutch EQC program. Taken together with the logistic advantages these blots are a good alternative for autoantibody detection in the respective diseases. A large prospective multicenter study is warranted to position these novel tests further in the whole spectrum of assays for the detection of these antibodies in a routine autoimmune laboratory. Copyright © 2017 Elsevier B.V. All rights reserved.

Bronchus-associated lymphoid tissue in pulmonary hypertension produces pathologic autoantibodies.

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Colvin, Kelley L; Cripe, Patrick J; Ivy, D Dunbar; Stenmark, Kurt R; Yeager, Michael E

2013-11-01

Autoimmunity has long been associated with pulmonary hypertension. Bronchus-associated lymphoid tissue plays important roles in antigen sampling and self-tolerance during infection and inflammation. We reasoned that activated bronchus-associated lymphoid tissue would be evident in rats with pulmonary hypertension, and that loss of self-tolerance would result in production of pathologic autoantibodies that drive vascular remodeling. We used animal models, histology, and gene expression assays to evaluate the role of bronchus-associated lymphoid tissue in pulmonary hypertension. Bronchus-associated lymphoid tissue was more numerous, larger, and more active in pulmonary hypertension compared with control animals. We found dendritic cells in and around lymphoid tissue, which were composed of CD3(+) T cells over a core of CD45RA(+) B cells. Antirat IgG and plasma from rats with pulmonary hypertension decorated B cells in lymphoid tissue, resistance vessels, and adventitia of large vessels. Lymphoid tissue in diseased rats was vascularized by aquaporin-1(+) high endothelial venules and vascular cell adhesion molecule-positive vessels. Autoantibodies are produced in bronchus-associated lymphoid tissue and, when bound to pulmonary adventitial fibroblasts, change their phenotype to one that may promote inflammation. Passive transfer of autoantibodies into rats caused pulmonary vascular remodeling and pulmonary hypertension. Diminution of lymphoid tissue reversed pulmonary hypertension, whereas immunologic blockade of CCR7 worsened pulmonary hypertension and hastened its onset. Bronchus-associated lymphoid tissue expands in pulmonary hypertension and is autoimmunologically active. Loss of self-tolerance contributes to pulmonary vascular remodeling and pulmonary hypertension. Lymphoid tissue-directed therapies may be beneficial in treating pulmonary hypertension.

Shared Genetic Basis for Type 1 Diabetes, Islet Autoantibodies, and Autoantibodies Associated With Other Immune-Mediated Diseases in Families With Type 1 Diabetes

DEFF Research Database (Denmark)

Brorsson, Caroline Anna; Pociot, Flemming

2015-01-01

) in autoimmune gastritis, transglutaminase (TGA) in celiac disease, and 21-hydroxylase (21-OHA) in autoimmune hypoadrenalism. In addition to the MHC region, we identify SNPs in five susceptibility loci (IFIH1, PTPN22, SH2B3, BACH2, and CTLA4) as significantly associated with more than one autoantibody at a false...

Multi-layered nanoparticles for penetrating the endosome and nuclear membrane via a step-wise membrane fusion process.

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Akita, Hidetaka; Kudo, Asako; Minoura, Arisa; Yamaguti, Masaya; Khalil, Ikramy A; Moriguchi, Rumiko; Masuda, Tomoya; Danev, Radostin; Nagayama, Kuniaki; Kogure, Kentaro; Harashima, Hideyoshi

2009-05-01

Efficient targeting of DNA to the nucleus is a prerequisite for effective gene therapy. The gene-delivery vehicle must penetrate through the plasma membrane, and the DNA-impermeable double-membraned nuclear envelope, and deposit its DNA cargo in a form ready for transcription. Here we introduce a concept for overcoming intracellular membrane barriers that involves step-wise membrane fusion. To achieve this, a nanotechnology was developed that creates a multi-layered nanoparticle, which we refer to as a Tetra-lamellar Multi-functional Envelope-type Nano Device (T-MEND). The critical structural elements of the T-MEND are a DNA-polycation condensed core coated with two nuclear membrane-fusogenic inner envelopes and two endosome-fusogenic outer envelopes, which are shed in stepwise fashion. A double-lamellar membrane structure is required for nuclear delivery via the stepwise fusion of double layered nuclear membrane structure. Intracellular membrane fusions to endosomes and nuclear membranes were verified by spectral imaging of fluorescence resonance energy transfer (FRET) between donor and acceptor fluorophores that had been dually labeled on the liposome surface. Coating the core with the minimum number of nucleus-fusogenic lipid envelopes (i.e., 2) is essential to facilitate transcription. As a result, the T-MEND achieves dramatic levels of transgene expression in non-dividing cells.

Envelope as Climate Negotiator: Evaluating adaptive building envelope's capacity to moderate indoor climate and energy

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Erickson, James

Through manipulation of adaptable opportunities available within a given environment, individuals become active participants in managing personal comfort requirements, by exercising control over their comfort without the assistance of mechanical heating and cooling systems. Similarly, continuous manipulation of a building skin's form, insulation, porosity, and transmissivity qualities exerts control over the energy exchanged between indoor and outdoor environments. This research uses four adaptive response variables in a modified software algorithm to explore an adaptive building skin's potential in reacting to environmental stimuli with the purpose of minimizing energy use without sacrificing occupant comfort. Results illustrate that significant energy savings can be realized with adaptive envelopes over static building envelopes even under extreme summer and winter climate conditions; that the magnitude of these savings are dependent on climate and orientation; and that occupant thermal comfort can be improved consistently over comfort levels achieved by optimized static building envelopes. The resulting adaptive envelope's unique climate-specific behavior could inform designers in creating an intelligent kinetic aesthetic that helps facilitate adaptability and resiliency in architecture.

Osteoprotegerin autoantibodies do not predict low bone mineral density in middle-aged women.

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Vaziri-Sani, Fariba; Brundin, Charlotte; Agardh, Daniel

2017-12-01

Autoantibodies against osteoprotegerin (OPG) have been associated with osteoporosis. The aim was to develop an immunoassay for OPG autoantibodies and test their diagnostic usefulness of identifying women general population with low bone mineral density. Included were 698 women at mean age 55.1 years (range 50.4-60.6) randomly selected from the general population. Measurement of wrist bone mineral density (g/cm 2 ) was performed of the non-dominant wrist by dual-energy X-ray absorptiometry (DXA). A T-score density. Measurements of OPG autoantibodies were carried by radiobinding assays. Cut-off levels for a positive value were determined from the deviation from normality in the distribution of 398 healthy blood donors representing the 99.7th percentile. Forty-five of the 698 (6.6%) women were IgG-OPG positive compared with 2 of 398 (0.5%) controls ( p  density between IgG-OPG positive (median 0.439 (range 0.315-0.547) g/cm 2 ) women and IgG-OPG negative (median 0.435 (range 0.176-0.652) g/cm 2 ) women ( p  = 0.3956). Furthermore, there was neither a correlation between IgG-OPG levels and bone mineral density (r s  = 0.1896; p  = 0.2068) nor T-score (r s  = 0.1889; p  = 0.2086). Diagnostic sensitivity and specificity of IgG-OPG for low bone mineral density were 5.7% and 92.9%, and positive and negative predictive values were 7.4% and 90.8%, respectively. Elevated OPG autoantibody levels do not predict low bone mineral density in middle-aged women selected from the general population.

Evaluation of a radioreceptor assay for TSH receptor autoantibodies

Energy Technology Data Exchange (ETDEWEB)

Rootwelt, K.

1988-02-01

A commercial radioreceptor assay for TSH receptor autoantibodies (TRAb), based on solubilized porcine receptor and purified radio-iodinated bovine TSH, was tested in 264 subjects with a variety of thyroid disorders. The sensitivity of the assay for the detection of hyperthyroid Graves' disease was 91%. The assay specificity for Graves' disease was 95%. With the exception of one patient with Hashimoto's disease and one patient with de Quervain's subacute thyroiditis no subjects other than Graves' patients had detectable TRAb. Thus purely blocking TSII receptor autoantibodies were not detected with the assay. One female with thyroxine-treated idiopathic primary hypothyroidism who had given birth to two children with transiently elevated TSH, was found to have a circulating TSH-binding substance that resulted in an abnormally negative TRAb value, and highly discrepant results when TSH was measured with a double antibody TSH radioimmunoassay and an immunoradiometric assay. The TSH-binding substance was precipitated like a protein, but was not IgG. Similar findings have not previously been reported.

Injection envelope matching in storage rings

International Nuclear Information System (INIS)

Minty, M.G.; Spence, W.L.

1995-05-01

The shape and size of the transverse phase space injected into a storage ring can be deduced from turn-by-turn measurements of the transient behavior of the beam envelope in the ring. Envelope oscillations at 2 x the β-tron frequency indicate the presence of a β-mismatch, while envelope oscillations at the β-tron frequency are the signature of a dispersion function mismatch. Experiments in injection optimization using synchrotron radiation imaging of the beam and a fast-gated camera at the SLC damping rings are reported

Envelope Protection for In-Flight Ice Contamination

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Gingras, David R.; Barnhart, Billy P.; Ranaudo, Richard J.; Ratvasky, Thomas P.; Morelli, Eugene A.

2010-01-01

Fatal loss-of-control (LOC) accidents have been directly related to in-flight airframe icing. The prototype system presented in this paper directly addresses the need for real-time onboard envelope protection in icing conditions. The combinations of a-priori information and realtime aerodynamic estimations are shown to provide sufficient input for determining safe limits of the flight envelope during in-flight icing encounters. The Icing Contamination Envelope Protection (ICEPro) system has been designed and implemented to identify degradations in airplane performance and flying qualities resulting from ice contamination and provide safe flight-envelope cues to the pilot. Components of ICEPro are described and results from preliminary tests are presented.

A sensitive radio-immunoassay for serum thyroglobulin -including a correct screening for thyroglobulin autoantibodies

International Nuclear Information System (INIS)

Laurberg, Peter; Pedersen, K.M.

1987-01-01

A new thyroglobulin (Tg) assay employing polyethylene glycol (PEG) for separation of free and antibody bound : 125 I:Tg is described. By choosing a suitable PEG concentration the non-specific precipitation of free [ 125 I]Tg was kept low while both [ 125 I]Tg bound to rabbit anti-Tg immunoglobulins and to human Tg autoantibodies were precipitated. For all sera a 'blank' incubation with no rabbit anti-Tg immunoglobulins was run in parallel with the assay tubes. Hence any interference of Tg autoantibodies would be detected. A two-phase incubation gave a very low detection limit of 0.2 μg/l. The inter-assay coefficient of variation was 9.4% and the intra-assay coefficient of variation was 5.6%. Dilution curves of normal sera were parallel to the standard curve and Tg standards added to normal sera were recovered quantitatively. Twelve out of 60 normal sera from the Randers area contained Tg autoantibodies. The average serum Tg in the 48 sera without antibody was 44.6 ± 5.2 μg/l. (author)

Maternal celiac disease autoantibodies bind directly to syncytiotrophoblast and inhibit placental tissue transglutaminase activity

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Robinson Nicola J

2009-02-01

Full Text Available Abstract Background Celiac disease (CD occurs in as many as 1 in 80 pregnant women and is associated with poor pregnancy outcome, but it is not known if this is an effect on maternal nutrient absorption or, alternatively, if the placenta is an autoimmune target. The major autoantigen, tissue transglutaminase (tTG, has previously been shown to be present in the maternal-facing syncytiotrophoblast plasma membrane of the placenta. Methods ELISA was used to demonstrate the presence of antibodies to tissue transglutaminase in a panel of CD sera. Immunohistochemistry was used to evaluate the binding of IgA autoantibodies from CD serum to term placenta. In addition, novel direct binding and activity assays were developed to mimic the in vivo exposure of the villous placenta to maternal autoantibody. Results and Discussion CD IgA autoantibodies located to the syncytial surface of the placenta significantly more than IgA antibodies in control sera (P Conclusion These data indicate that direct immune effects in untreated CD women may compromise placental function.

Thermal Activated Envelope

DEFF Research Database (Denmark)

Foged, Isak Worre; Pasold, Anke

2015-01-01

The research studies the making of a responsive architectural envelope based on bi-materials. The bi-materials are organized according to a method that combines different isotropic metals and plastic into an active composite structure that reacts to temperature variations. Through an evolutionary......, environmental dynamics and occupancy dynamics. Lastly, a physical prototype is created, which illustrates the physical expression of the bi-materials and the problems related to manufacturing of these composite structures.......The research studies the making of a responsive architectural envelope based on bi-materials. The bi-materials are organized according to a method that combines different isotropic metals and plastic into an active composite structure that reacts to temperature variations. Through an evolutionary...

Autoimmune gastro-pancreatitis with anti-protein disulfide isomerase-associated 2 autoantibody in Aire-deficient BALB/cAnN mice.

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Hironori Kurisaki

Full Text Available Although the autoimmune regulator (Aire knockout (KO mouse model has been reported to present various organ-specific autoimmune diseases depending on genetic background, autoimmune pancreatitis in mice of BALB/c background has not yet been reported. Here, we report that Aire KO mice with BALB/cAnN background showed significant lymphoid cell infiltration in the pancreas and stomach. To examine whether the phenotype in the pancreas and stomach is due to autoimmune reaction associated with autoantibody production, indirect immunofluorescence staining followed by Western blot analysis was performed. Consequently, the autoantibody against pancreas and stomach was detected in the sera of Aire KO mice, and the target antigen of the autoantibody was identified as protein disulfide isomerase-associated 2 (Pdia2, which was reported to be expressed preferentially in the pancreas and stomach. Thus, Aire KO mice of BALB/cAnN background can serve as a useful animal model for autoimmune gastro-pancreatitis with anti-Pdia2 autoantibody production.

Autoimmune gastro-pancreatitis with anti-protein disulfide isomerase-associated 2 autoantibody in Aire-deficient BALB/cAnN mice.

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Kurisaki, Hironori; Nagao, Yukihiro; Nagafuchi, Seiho; Mitsuyama, Masao

2013-01-01

Although the autoimmune regulator (Aire) knockout (KO) mouse model has been reported to present various organ-specific autoimmune diseases depending on genetic background, autoimmune pancreatitis in mice of BALB/c background has not yet been reported. Here, we report that Aire KO mice with BALB/cAnN background showed significant lymphoid cell infiltration in the pancreas and stomach. To examine whether the phenotype in the pancreas and stomach is due to autoimmune reaction associated with autoantibody production, indirect immunofluorescence staining followed by Western blot analysis was performed. Consequently, the autoantibody against pancreas and stomach was detected in the sera of Aire KO mice, and the target antigen of the autoantibody was identified as protein disulfide isomerase-associated 2 (Pdia2), which was reported to be expressed preferentially in the pancreas and stomach. Thus, Aire KO mice of BALB/cAnN background can serve as a useful animal model for autoimmune gastro-pancreatitis with anti-Pdia2 autoantibody production.

Analysis of Building Envelope Construction in 2003 CBECS

Energy Technology Data Exchange (ETDEWEB)

Winiarski, David W.; Halverson, Mark A.; Jiang, Wei

2007-06-01

The purpose of this analysis is to determine "typical" building envelope characteristics for buildings built after 1980. We address three envelope components in this paper - roofs, walls, and window area. These typical building envelope characteristics were used in the development of DOE’s Reference Buildings .

The South Carolina bridge-scour envelope curves

Science.gov (United States)

Benedict, Stephen T.; Feaster, Toby D.; Caldwell, Andral W.

2016-09-30

The U.S. Geological Survey, in cooperation with the South Carolina Department of Transportation, conducted a series of three field investigations to evaluate historical, riverine bridge scour in the Piedmont and Coastal Plain regions of South Carolina. These investigations included data collected at 231 riverine bridges, which lead to the development of bridge-scour envelope curves for clear-water and live-bed components of scour. The application and limitations of the South Carolina bridge-scour envelope curves were documented in four reports, each report addressing selected components of bridge scour. The current investigation (2016) synthesizes the findings of these previous reports into a guidance manual providing an integrated procedure for applying the envelope curves. Additionally, the investigation provides limited verification for selected bridge-scour envelope curves by comparing them to field data collected outside of South Carolina from previously published sources. Although the bridge-scour envelope curves have limitations, they are useful supplementary tools for assessing the potential for scour at riverine bridges in South Carolina.

Evolution of envelope solitons of ionization waves

International Nuclear Information System (INIS)

Ohe, K.; Hashimoto, M.

1985-01-01

The time evolution of a particle-like envelope soliton of ionization waves in plasma was investigated theoretically. The hydrodynamic equations of one spatial dimension were solved and the nonlinear dispersion relation was derived. For the amplitude of the wave the nonlinear Schroedinger equation was derived. Its soliton solution was interpreted as the envelope soliton which was experimentally found. The damping rate of the envelope soliton was estimated. (D.Gy.)

The influence of maternal islet beta-cell autoantibodies in conjunction with gestational hyperglycemia on neonatal outcomes.

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Zhe Li

Full Text Available To determine the predictive value of the presence of maternal islet beta-cell autoantibodies with respect to neonatal outcomes.A total of 311 pregnant women with abnormal 75 g oral glucose tolerance test (OGTT results were enrolled in this study. Maternal glutamic acid decarboxylase autoantibodies (GADA, islet cell autoantibodies (ICA and insulin autoantibodies (IAA were tested in fasting blood both on the day following the routine OGTT and before delivery. The birth weight, Apgar score, blood glucose and outcomes of each neonate were later evaluated and recorded.1. In this study, 33.9% of the pregnant women with gestational hyperglycemia had detectable levels of one or more types of anti-islet cell antibodies in the third trimester. The proportion of women who produced GADA and/or ICA was significantly higher in the group of women with gestational hyperglycemia than in the control group (P<0.05. The groups similarly differed in the proportion of women who tested positive for any anti-islet cell antibody (P<0.05. 2. Of the patients in our study, those who produced GADA exhibited an increase in uterine and umbilical arterial pulsatility indexes (PIs during the third trimesters compared with the control group (P˂0.05. Additionally, an increased frequency of fetal growth restriction (FGR was observed in the infants of women who produced IAA during pregnancy compared with those without autoantibodies (P˂0.05. 3. The rate of newborn admission to the neonatal intensive care unit (NICU was significantly associated with the presence of maternal ICA during the third trimester (OR, 6.36; 95% CI, 1.22-33.26. 4. The incidence of neonatal asphyxia was associated with the presence of maternal GADA in both the second (OR, 10.44; 95% CI, 1.46-74.92 and the third (OR, 8.33; 95% CI, 1.45-47.82 trimesters.Approximately one-third of the women with gestational hyperglycemia produced anti-islet cell antibodies. The incidence of FGR was higher in women with

Autoantibody levels in myositis patients correlate with clinical response during B cell depletion with rituximab.

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Aggarwal, Rohit; Oddis, Chester V; Goudeau, Danielle; Koontz, Diane; Qi, Zengbiao; Reed, Ann M; Ascherman, Dana P; Levesque, Marc C

2016-06-01

To determine the longitudinal trends in serum levels of four myositis-associated autoantibodies: anti-Jo-1, -transcription intermediary factor 1 γ (TIF1-γ), -signal recognition particle (SRP) and -Mi-2, after B cell depletion with rituximab, and to determine the longitudinal association of these autoantibody levels with disease activity as measured by myositis core-set measures (CSMs). Treatment-resistant adult and pediatric myositis subjects (n = 200) received rituximab in the 44-week Rituximab in Myositis Trial. CSMs [muscle enzymes, manual muscle testing (MMT), physician and patient global disease activity, HAQ, and extramuscular disease activity] were evaluated monthly and anti-Jo-1 (n = 28), -TIF1-γ (n = 23), -SRP (n = 25) and -Mi-2 (n = 26) serum levels were measured using validated quantitative ELISAs. Temporal trends and the longitudinal relationship between myositis-associated autoantibodies levels and CSM were estimated using linear mixed models. Following rituximab, anti-Jo-1 levels decreased over time (P myositis subjects decreased after B cell depletion and were correlated with changes in disease activity, whereas anti-SRP levels were only associated with longitudinal muscle enzyme levels. The strong association of anti-Jo-1 levels with clinical outcomes suggests that anti-Jo-1 autoantibodies may be a good biomarker for disease activity. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prognostic relevance of Bmi-1 expression and autoantibodies in esophageal squamous cell carcinoma

International Nuclear Information System (INIS)

Liu, Wan-li; Li, Man-zhi; Song, Li-bing; Zeng, Mu-sheng; Guo, Xian-zhi; Zhang, Lan-jun; Wang, Jun-ye; Zhang, Ge; Guan, Su; Chen, Yu-min; Kong, Qing-li; Xu, Li-hua

2010-01-01

Overexpression of Bmi-1 has been observed in a variety of cancers, and it has been suggested to be an independent prognostic marker for the patients. The objective of this study was to determine the level of Bmi-1 expression or its autoantibodies in human esophageal squamous cell carcinoma (ESCC) and to correlate it with clinicopathologic data. We first examined Bmi-1 expression in ESCC cell lines and tumor samples by RT-PCR and Western blot analysis. We then analyzed Bmi-1 protein expression in 171 clinicopathologically characterized ESCC cases by immunohistochemistry. In addition, we detected its autoantibodies in sera of patients with ESCC by ELISA. We found that Bmi-1 expression was higher in the immortalized cells, cancer cell lines and most cancer tissue than in non-tumorous control tissue at both mRNA and protein level. In addition, Bmi-1 expression was observed in 64.3% (110 of 171) archive ESCC specimen by immunohistochemistry analysis, and the location of Bmi-1 in ESCC was in the nuclei instead of cytoplasm of tumor cells. There was a significant difference of Bmi-1 expression in patients categorized according to stage (P = 0.003) and pN classification (P = 0.047). Multivariate analysis suggested that Bmi-1 expression was an independent prognostic marker for ESCC patients. A prognostic significance of Bmi-1 was also found in the subgroup of T3~T4 and N1 tumor classification. Bmi-1 autoantibodies were detected in sera of 39.0% (62 of 159) ESCC patients. The correlations between anti-Bmi-1 antibodies and tumor stage (P = 0.040), or lymph node status (P < 0.001) were significant. Our results suggest that Bmi-1 protein is a valuable marker of ESCC progression. The presence of Bmi-1 autoantibodies in sera from patients with ESCC may have clinical utility in esophageal cancer diagnosis

LKM1 autoantibodies in chronic hepatitis C infection: a case of molecular mimicry?

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Marceau, Gabriel; Lapierre, Pascal; Béland, Kathie; Soudeyns, Hugo; Alvarez, Fernando

2005-09-01

Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients chronically infected by hepatitis C virus (HCV). Molecular mimicry between HCV proteins and CYP2D6 has been proposed to explain the emergence of these autoantibodies. Anti-LKM1 autoantibodies from hepatitis C-infected patients were affinity-purified against immobilized CYP2D6 protein and used to screen a phage display library. CYP2D6 conformational epitopes were identified using phage display analysis and the identification of statistically significant pairs (SSPs). Cross-reactivity between CYP2D6 and HCV protein candidates was tested by immunoprecipitation. Nineteen different clones were isolated, and their sequencing resulted in the mapping of a conformational epitope to the region of amino acids 254-288 of CYP2D6. Candidate HCV proteins for molecular mimicry included: core, E2, NS3 and NS5a. Affinity-purified autoantibodies from HCV+/LKM1+ patients immunoprecipitated either NS3, NS5a, or both, and these reactivities were specifically inhibited by immobilized CYP2D6. In conclusion, HCV+/LKM1+ sera recognize a specific conformational epitope on CYP2D6 between amino acids 254 to 288, the region that contains the major linear epitope in type 2 autoimmune hepatitis patients. Cross-reactivity due to molecular mimicry at the B-cell level was shown between the CYP2D6 and the HCV NS3 and NS5a proteins and could explain the presence of anti-LKM1 in patients chronically infected with HCV. Further investigation of the role played by this molecular mimicry in HCV-infected patients may lead to more specific strategies for diagnosis and treatment.

Electrochemiluminescence assays for insulin and glutamic acid decarboxylase autoantibodies improve prediction of type 1 diabetes risk.

Science.gov (United States)

Miao, Dongmei; Steck, Andrea K; Zhang, Li; Guyer, K Michelle; Jiang, Ling; Armstrong, Taylor; Muller, Sarah M; Krischer, Jeffrey; Rewers, Marian; Yu, Liping

2015-02-01

We recently developed new electrochemiluminescence (ECL) insulin autoantibody (IAA) and glutamic acid decarboxylase 65 autoantibody (GADA) assays that discriminate high-affinity, high-risk diabetes-specific autoantibodies from low-affinity, low-risk islet autoantibodies (iAbs) detected by radioassay (RAD). Here, we report a further validation of the ECL-IAA and -GADA assays in 3,484 TrialNet study participants. The ECL assay and RAD were congruent in those with prediabetes and in subjects with multiple autoantibodies, but only 24% (P<0.0001) of single RAD-IAA-positive and 46% (P<0.0001) of single RAD-GADA-positive were confirmed by the ECL-IAA and -GADA assays, respectively. During a follow-up (mean, 2.4 years), 51% of RAD-IAA-positive and 63% of RAD-GADA-positive subjects not confirmed by ECL became iAb negative, compared with only 17% of RAD-IAA-positive (P<0.0001) and 15% of RAD-GADA-positive (P<0.0001) subjects confirmed by ECL assays. Among subjects with multiple iAbs, diabetes-free survival was significantly shorter if IAA or GADA was positive by ECL and negative by RAD than if IAA or GADA was negative by ECL and positive by RAD (P<0.019 and P<0.0001, respectively). Both positive and negative predictive values in terms of progression to type 1 diabetes mellitus were superior for ECL-IAA and ECL-GADA, compared with RADs. The prevalence of the high-risk human leukocyte antigen-DR3/4, DQB1*0302 genotype was significantly higher in subjects with RAD-IAA or RAD-GADA confirmed by ECL. In conclusion, both ECL-IAA and -GADA are more disease-specific and better able to predict the risk of progression to type 1 diabetes mellitus than the current standard RADs.

LEVELS OF NEUROSPECIFIC ENOLASE AND ENOLASE-SPECIFIC AUTOANTIBODIES IN BLOOD SERUM OF THE PATIENTS WITH AUTOIMMUNE THYROPATIES

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N. N. Tsybikov

2010-01-01

Full Text Available The patients with autoimmune thyroiditis and various functional states of thyroid gland, and diffuse toxic goiter with pronounced thyrotoxicosis were studied for neurospecific enolase and enolase-specific autoantibodies levels in blood serum. Increased concentrations of neurospecific enolase and specific autoantibodies were revealed in all groups of the patients. A conclusion was drawn that nervous system may be involved into pathological process during development of thyropaties.

The Analysis of the Value of the Thyroid Autoantibody Measured by Radioimmunoassay

International Nuclear Information System (INIS)

Chung, Jae Hoon; Lee, Myung Shik; Cho, Bo Youn; Lee, Hong Kyu; Koh, Chang Soon; Min, Hun Ki; Lee, Mun Ho

1987-01-01

To evaluate the values of the thyroid autoantibody measured by radioimmunoassay (RIA) and compare it with hemagglutination method (HA) in the normal and the thyroid disease, data were obtained from total 618 persons; 236 healthy persons, 217 patients with Graves disease (including 113 patients with undertreated Graves' disease), 100 Hashimoto's disease, 31 thyroid nodule, and 34 simple goiter. RSR kit made in England was used and could be detected at least 3 U/ml. The positive rates of normal group were antirnicrosomal antibody (AMA) 31.8%, antithyroglobulin antibody (ATA) 44.5% by RIA and there was no considerable change in sex and age distribution. In Graves disease, the positive rates of AMA and ATA were 90.4, 76.9% by RIA, 85, 39% by HA. In Hashimoto's disease, 94,91% by RIA, and 87,48% by HA, respectively. The autoantibody titer by RIA in thyroid autoimmune disease as welt as in normal group was more sensitive than that by HA, especially in ATA. There were linear relationships between the titer of RIA and that of HA in AMA of Graves disease and AMA and ATA of Hashimotos disease. There was no relationship among thyroid autoantibody, free T, index, TBII, and TSH. The titers of AMA and ATA were found to decrease in patients with Graves disease during the course of antithyroid drug therapy. Of the 236 normal subjects, thirty-seven (15.7%) had concentrations of above 7.5 U/ml in AMA, forty-four (18. 6%) above 9 U/ml in ATA. These values were considered as the upper limit for the normal range. In Graves disease, 82,7, 53.8% were above 7.5, 9 U/ml, respectively; In Hashimoto's disease, HZ, 79% were positive. We conclude that RIA was more sensitive than HA in measuring the thyroid autoantibody, but we will study further more for determining the normal range and its interpretation.

Celiac Disease-Specific TG2-Targeted Autoantibodies Inhibit Angiogenesis Ex Vivo and In Vivo in Mice by Interfering with Endothelial Cell Dynamics.

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Suvi Kalliokoski

Full Text Available A characteristic feature of celiac disease is the presence of circulating autoantibodies targeted against transglutaminase 2 (TG2, reputed to have a function in angiogenesis. In this study we investigated whether TG2-specific autoantibodies derived from celiac patients inhibit angiogenesis in both ex vivo and in vivo models and sought to clarify the mechanism behind this phenomenon. We used the ex vivo murine aorta-ring and the in vivo mouse matrigel-plug assays to address aforementioned issues. We found angiogenesis to be impaired as a result of celiac disease antibody supplementation in both systems. Our results also showed the dynamics of endothelial cells was affected in the presence of celiac antibodies. In the in vivo angiogenesis assays, the vessels formed were able to transport blood despite impairment of functionality after treatment with celiac autoantibodies, as revealed by positron emission tomography. We conclude that celiac autoantibodies inhibit angiogenesis ex vivo and in vivo and impair vascular functionality. Our data suggest that the anti-angiogenic mechanism of the celiac disease-specific autoantibodies involves extracellular TG2 and inhibited endothelial cell mobility.

Celiac Disease–Specific TG2-Targeted Autoantibodies Inhibit Angiogenesis Ex Vivo and In Vivo in Mice by Interfering with Endothelial Cell Dynamics

Science.gov (United States)

Kalliokoski, Suvi; Sulic, Ana-Marija; Korponay-Szabó, Ilma R.; Szondy, Zsuzsa; Frias, Rafael; Perez, Mileidys Alea; Martucciello, Stefania; Roivainen, Anne; Pelliniemi, Lauri J.; Esposito, Carla; Griffin, Martin; Sblattero, Daniele; Mäki, Markku; Kaukinen, Katri; Lindfors, Katri; Caja, Sergio

2013-01-01

A characteristic feature of celiac disease is the presence of circulating autoantibodies targeted against transglutaminase 2 (TG2), reputed to have a function in angiogenesis. In this study we investigated whether TG2-specific autoantibodies derived from celiac patients inhibit angiogenesis in both ex vivo and in vivo models and sought to clarify the mechanism behind this phenomenon. We used the ex vivo murine aorta-ring and the in vivo mouse matrigel-plug assays to address aforementioned issues. We found angiogenesis to be impaired as a result of celiac disease antibody supplementation in both systems. Our results also showed the dynamics of endothelial cells was affected in the presence of celiac antibodies. In the in vivo angiogenesis assays, the vessels formed were able to transport blood despite impairment of functionality after treatment with celiac autoantibodies, as revealed by positron emission tomography. We conclude that celiac autoantibodies inhibit angiogenesis ex vivo and in vivo and impair vascular functionality. Our data suggest that the anti-angiogenic mechanism of the celiac disease-specific autoantibodies involves extracellular TG2 and inhibited endothelial cell mobility. PMID:23824706

Recombinant protein to analyze autoantibodies to proteinase 3 in systemic vasculitis

NARCIS (Netherlands)

Rarok, AA; Huitema, MG; van der Leij, MJ; van der Geld, YM; Berthold, H; Schmitt, J; Stegeman, CA; Limburg, PC; Kallenberg, CGM

2003-01-01

The presence of antineutrophil cytoplasmic autoantibodies with specificity for proteinase 3 (PR3-ANCA) usually is detected by enzyme-linked immunosorbent assay (ELISA) with purified PR3 as a substrate. We studied the technical performance of direct and capture ELISA using a recombinant

Specificities of anti-neutrophil autoantibodies in patients with rheumatoid arthritis (RA)

DEFF Research Database (Denmark)

Brimnes, J; Halberg, P; Jacobsen, Søren

1997-01-01

The objective of this study was to characterize antigens recognized by neutrophil-specific autoantibodies from patients with RA. Sera from 62 RA patients were screened by indirect immunofluorescence (IIF). Positive sera were further tested by ELISAs for antibodies against various granule proteins...

Plasma autoantibodies against heat shock protein 70, enolase 1 and ribonuclease/angiogenin inhibitor 1 as potential biomarkers for cholangiocarcinoma.

Directory of Open Access Journals (Sweden)

Rucksak Rucksaken

Full Text Available The diagnosis of cholangiocarcinoma (CCA is often challenging, leading to poor prognosis. CCA arises via chronic inflammation which may be associated with autoantibodies production. This study aims to identify IgG antibodies directed at self-proteins and tumor-associated antigens. Proteins derived from immortalized cholangiocyte cell line (MMNK1 and CCA cell lines (M055, M214 and M139 were separated using 2-dimensional electrophoresis and incubated with pooled plasma of patients with CCA and non-neoplastic controls by immunoblotting. Twenty five immunoreactive spots against all cell lines-derived proteins were observed on stained gels and studied by LC-MS/MS. Among these, heat shock protein 70 (HSP70, enolase 1 (ENO1 and ribonuclease/angiogenin inhibitor 1 (RNH1 obtained the highest matching scores and were thus selected for further validation. Western blot revealed immunoreactivity against HSP70 and RNH1 in the majority of CCA cases and weakly in healthy individuals. Further, ELISA showed that plasma HSP70 autoantibody level in CCA was significantly capable to discriminate CCA from healthy individuals with an area under the receiver operating characteristic curve of 0.9158 (cut-off 0.2630, 93.55% sensitivity and 73.91% specificity. Plasma levels of IgG autoantibodies against HSP70 were correlated with progression from healthy individuals to cholangitis to CCA (r = 0.679, P<0.001. In addition, circulating ENO1 and RNH1 autoantibodies levels were also significantly higher in cholangitis and CCA compared to healthy controls (P<0.05. Moreover, the combinations of HSP70, ENO1 or RNH1 autoantibodies positivity rates improved specificity to over 78%. In conclusion, plasma IgG autoantibodies against HSP70, ENO1 and RNH1 may represent new diagnostic markers for CCA.

Methodological Challenges in Protein Microarray and Immunohistochemistry for the Discovery of Novel Autoantibodies in Paediatric Acute Disseminated Encephalomyelitis

Science.gov (United States)

Peschl, Patrick; Ramberger, Melanie; Höftberger, Romana; Jöhrer, Karin; Baumann, Matthias; Rostásy, Kevin; Reindl, Markus

2017-01-01

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune-mediated demyelinating disease affecting mainly children and young adults. Differentiation to multiple sclerosis is not always possible, due to overlapping clinical symptoms and recurrent and multiphasic forms. Until now, immunoglobulins reactive to myelin oligodendrocyte glycoprotein (MOG antibodies) have been found in a subset of patients with ADEM. However, there are still patients lacking autoantibodies, necessitating the identification of new autoantibodies as biomarkers in those patients. Therefore, we aimed to identify novel autoantibody targets in ADEM patients. Sixteen ADEM patients (11 seronegative, 5 seropositive for MOG antibodies) were analysed for potential new biomarkers, using a protein microarray and immunohistochemistry on rat brain tissue to identify antibodies against intracellular and surface neuronal and glial antigens. Nine candidate antigens were identified in the protein microarray analysis in at least two patients per group. Immunohistochemistry on rat brain tissue did not reveal new target antigens. Although no new autoantibody targets could be found here, future studies should aim to identify new biomarkers for therapeutic and prognostic purposes. The microarray analysis and immunohistochemistry methods used here have several limitations, which should be considered in future searches for biomarkers. PMID:28327523

200 Area Deactivation Project Facilities Authorization Envelope Document

International Nuclear Information System (INIS)

DODD, E.N.

2000-01-01

Project facilities as required by HNF-PRO-2701, Authorization Envelope and Authorization Agreement. The Authorization Agreements (AA's) do not identify the specific set of environmental safety and health requirements that are applicable to the facility. Therefore, the facility Authorization Envelopes are defined here to identify the applicable requirements. This document identifies the authorization envelopes for the 200 Area Deactivation

Obstetric and vascular APS: same autoantibodies but different diseases?

Science.gov (United States)

Meroni, P L; Raschi, E; Grossi, C; Pregnolato, F; Trespidi, L; Acaia, B; Borghi, M O

2012-06-01

Beta2 glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPLs) are the main pathogenic autoantibody population and at the same time the laboratory diagnostic tool for the antiphospholipid syndrome (APS). These antibodies are responsible for both the vascular and the obstetric manifestations of the syndrome but the pathogenic mechanisms behind these manifestations are not the same. For example, thrombotic events do not appear to play a major role in APS miscarriages and a direct reactivity of β2GPI-dependent aPLs on decidual and trophoblast cells was reported. A local expression of β2GPI on these tissues was reported both in physiological conditions and in APS women, thus explaining the local tropism of the autoantibodies. The two hit hypothesis was suggested to explain why the vascular manifestations of APS may occur only occasionally in spite of the persistent presence of aPLs. This is not apparently the case for the obstetric variant of the syndrome, making the difference even more striking. A different pathogenesis may also provide the rationale for the well-known fact that the vascular and the obstetric manifestations may occur independently although in a minority of cases.

Cell cycle regulation of human immunodeficiency virus type 1 integration in T cells: antagonistic effects of nuclear envelope breakdown and chromatin condensation

International Nuclear Information System (INIS)

Mannioui, Abdelkrim; Schiffer, Cecile; Felix, Nathalie

2004-01-01

We examined the influence of mitosis on the kinetics of human immunodeficiency virus type 1 integration in T cells. Single-round infection of cells arrested in G1b or allowed to synchronously proceed through division showed that mitosis delays virus integration until 18-24 h postinfection, whereas integration reaches maximum levels by 15 h in G1b-arrested cells. Subcellular fractionation of metaphase-arrested cells indicated that, while nuclear envelope disassembly facilitates docking of viral DNA to chromatin, chromosome condensation directly antagonizes and therefore delays integration. As a result of the balance between the two effects, virus integration efficiency is eventually up to threefold greater in dividing cells. At the single-cell level, using a green fluorescent protein-expressing reporter virus, we found that passage through mitosis leads to prominent asymmetric segregation of the viral genome in daughter cells without interfering with provirus expression

Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years

DEFF Research Database (Denmark)

Sørensen, Jesper Sand; Vaziri-Sani, Fariba; Maziarz, M

2012-01-01

To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D.......To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D....

Detection and Characterization of Autoantibodies to Neuronal Cell-Surface Antigens in the Central Nervous System

Directory of Open Access Journals (Sweden)

Marleen eVan Coevorden-Hameete

2016-05-01

Full Text Available Autoimmune encephalitis (AIE is a group of disorders in which autoantibodies directed at antigens located on the plasma membrane of neurons induce severe neurological symptoms. In contrast to classical paraneoplastic disorders, AIE patients respond well to immunotherapy. The detection of neuronal surface autoantibodies in patients’ serum or CSF therefore has serious consequences for the patients’ treatment and follow-up and requires the availability of sensitive and specific diagnostic tests. This mini-review provides a guideline for both diagnostic and research laboratories that work on the detection of known surface autoantibodies and/or the identification of novel surface antigens. We discuss the strengths and pitfalls of different techniques for anti-neuronal antibody detection: 1 Immunohistochemistry and immunofluorescence on rat/ primate brain sections, 2 Immunocytochemistry of living cultured hippocampal neurons, 3 Cell Based Assay (CBA. In addition, we discuss the use of immunoprecipitation and mass spectrometry analysis for the detection of novel neuronal surface antigens, which is a crucial step in further disease classification and the development of novel CBAs.

Energetics of Transport through the Nuclear Pore Complex

NARCIS (Netherlands)

Ghavami, Ali; van der Giessen, Erik; Onck, Patrick R

2016-01-01

Molecular transport across the nuclear envelope in eukaryotic cells is solely controlled by the nuclear pore complex (NPC). The NPC provides two types of nucleocytoplasmic transport: passive diffusion of small molecules and active chaperon-mediated translocation of large molecules. It has been shown

Usefulness of antineutrophil cytoplasmic autoantibodies in diagnosing and managing systemic vasculitis

NARCIS (Netherlands)

Kallenberg, Cees G. M.

Purpose of reviewAntineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the work-up of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of

Lack of autoantibody induction by mercury exposure in artisanal gold mining settings in Colombia: Findings and a review of the epidemiology literature.

Science.gov (United States)

Sánchez Rodríguez, Luz Helena; Flórez-Vargas, Oscar; Rodríguez-Villamizar, Laura Andrea; Vargas Fiallo, Yolanda; Stashenko, Elena E; Ramírez, Gerardo

2015-01-01

Mercury (Hg) has been implicated as an immunotoxicant in experimental animal models, but its role in the induction of human autoimmunity remains unclear due to contradictory findings. Therefore, it has been claimed that it is important to examine other populations in order to clarify the role of Hg in these diseases. The aim of this study was to investigate whether occupational Hg exposure due to artisanal gold mining is associated with the prevalence of autoimmune biomarkers. A cross-sectional study was conducted comparing Hg-exposed gold miners (n = 164) with a control population (n = 127). Hair, blood, and 24-h urine samples were collected for measures of Hg levels, as well as of anti-nuclear antibodies (ANA) and rheumatoid factor (RF). Participants were clinically evaluated by a general practice physician, a rheumatologist, and a toxicologist. Statistically significant differences (p mining activities had a significant impact on autoantibodies as biomarkers of autoimmune diseases. In a review context, the epidemiological findings were interpreted in light of the conflicting data in the literature about how Hg exposure was linked to development of autoantibodies. Validation of these findings in prospective studies is needed to firmly establish the role of Hg in development of autoimmunity in human populations.

Simplified approaches for the development of an ELISA to detect circulating autoantibodies to p53 in cancer patients

Directory of Open Access Journals (Sweden)

Tayapiwatana Chatchai

2008-02-01

Full Text Available Abstract Background The recognition that human tumors stimulate the production of autoantibodies has initiated the use of this immune response as serological markers for the early diagnosis and management of cancer. The enzyme-linked immunosorbent assay (ELISA is the most common method used in detecting autoantibodies, which involves coating the microtiter plate with the tumor associated antigen (TAA of interest and allowing serum antibodies to bind. The patient's sample is directly in contact with the coating antigen so the protein used for coating must be pure to avoid non-specific binding. In this study, a simplified method to selectively and specifically immobilize TAAs onto microtiter plates in order to detect circulating autoantibodies in cancer patients without prior purification process was described. Wild type full-length p53 protein was produced in fusion with biotin carboxyl carrier peptide (BCCP or hexahistidine [(His6] using pAK400 and pET15b(+ vectors, respectively. The recombinant p53 fusion protein produced was then subjected to react with either a commercial p53 monoclonal antibody (mAb or sera from lung cancer patients and healthy volunteers in an enzyme-linked immunosorbent assay (ELISA format. Results Both of the immobilized p53 fusion proteins as well as the purified (His6-p53 fusion protein had a similar dose response of detection to a commercial p53 mAb (DO7. When the biotinylated p53-BCCP fusion protein was used as an antigen to detect p53 autoantibodies in clinical samples, the result showed that human serum reacted strongly to avidin-coated microwell even in the absence of the biotinylated p53-BCCP fusion protein, thus compromised its ability to differentiate weakly positive sera from those that were negative. In contrast, the (His6-p53 protein immobilized directly onto Ni+ coated microplate was able to identify the p53 autoantibody positive serum. In addition, its reactivity to clinical serum samples highly correlated

Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis

DEFF Research Database (Denmark)

Wichman, Johanna Eva Märta; Winther, Kristian Hillert; Bonnema, Steen Joop

2016-01-01

BACKGROUND: Selenium supplementation may decrease circulating thyroid autoantibodies in patients with chronic autoimmune thyroiditis (AIT), but the available trials are heterogenous. This study expands and critically reappraises the knowledge on this topic. METHODS: A literature search identified...... 3366 records. Controlled trials in adults (≥18 years of age) with AIT, comparing selenium with or without levothyroxine (LT4), versus placebo and/or LT4, were eligible. Assessed outcomes were serum thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) autoantibody levels, and immunomodulatory effects...... and LT4-untreated. Heterogeneity was estimated using I(2), and quality of evidence was assessed per outcome, using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: In LT4-treated populations, the selenium group had significantly lower TPOAb levels after...

Idiopathic factor VIII inhibitor autoantibody in a man presented after accident.

NARCIS (Netherlands)

Mansouritorghabeh, H.; Lak, M.; Heerde, W.L. van

2009-01-01

Acquired hemophilia A is a rare but severe autoimmune bleeding disorder caused by autoantibodies against factor VIII activity and is a potentially life-threatening hemorrhagic disorder. The incidence of acquired hemophilia A has been estimated as 1.48 cases per million per year. The overall rate of

Featured Image: Orbiting Stars Share an Envelope

Science.gov (United States)

Kohler, Susanna

2016-03-01

This beautiful series of snapshots from a simulation (click for a better look!) shows what happens when two stars in a binary system become enclosed in the same stellar envelope. In this binary system, one of the stars has exhausted its hydrogen fuel and become a red giant, complete with an expanding stellar envelope composed of hydrogen and helium. Eventually, the envelope expands so much that the companion star falls into it, where it releases gravitational potential energy into the common envelope. A team led by Sebastian Ohlmann (Heidelberg Institute for Theoretical Studies and University of Wrzburg) recently performed hydrodynamic simulations of this process. Ohlmann and collaborators discovered that the energy release eventually triggers large-scale flow instabilities, which leads to turbulence within the envelope. This process has important consequences for how these systems next evolve (for instance, determining whether or not a supernova occurs!). You can check out the authors video of their simulated stellar inspiral below, or see their paper for more images and results from their study.CitationSebastian T. Ohlmann et al 2016 ApJ 816 L9. doi:10.3847/2041-8205/816/1/L9

The performance of energy efficient residential building envelope systems

Energy Technology Data Exchange (ETDEWEB)

Proskiw, G.

1996-08-01

The adequacy and durability of residential building envelope systems under actual field conditions were evaluated. A building envelope offers protection from cold, heat, moisture, wind and noise. However, they are exposed to thermal, structural, and moisture stresses and their performance can degrade over time. Envelope performance was evaluated at 20 energy efficient and four conventional, detached modern homes in Winnipeg, Canada. The three complementary measurement tools were wood moisture content (WMC) of framing members, thermographic examinations, and airtightness tests. As expected, energy efficient building envelope systems performed better than the conventional systems. No evidence of envelope degradation was found in any of the energy efficient houses. The building envelopes using polyethylene air barriers performed slightly better than those which used the airtight drywall approach, although both were considered satisfactory. WMC levels were a bit lower in the polyethylene-clad house. 1 ref., 1 tab.

Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes?A Recursive Partitioning Analysis

OpenAIRE

Xu, Ping; Krischer, Jeffrey P.

2016-01-01

OBJECTIVE To define prognostic classification factors associated with the progression from single to multiple autoantibodies, multiple autoantibodies to dysglycemia, and dysglycemia to type 1 diabetes onset in relatives of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS Three distinct cohorts of subjects from the Type 1 Diabetes TrialNet Pathway to Prevention Study were investigated separately. A recursive partitioning analysis (RPA) was used to determine the risk classes. Clini...

Antinuclear human autoantibodies as markers in Nicotiana tabacum pollen tubes

Directory of Open Access Journals (Sweden)

C. Poggialini

2014-01-01

Full Text Available In the present paper we report on the use of antinuclear human autoantibodies as specific markers in Nicotiana tabacum pollen tubes. The antibodies have been tested by fluorescence techniques using a confocal laser scanning microscope. All the antibodies showed specifc labelling pattern and the results, although preliminary in nature, could open new perspectives of research.

Implementation of an Improved Safe Operating Envelope

International Nuclear Information System (INIS)

Prime, Robyn; McIntyre, Mark; Reeves, David

2008-01-01

This paper is a continuation of the paper presented at IYNC 2004 on 'The Definition of a Safe Operating Envelope'. The current paper concentrates on the implementation process of the Safe Operating Envelope employed at the Point Lepreau Generating Station. (authors)

Envelope enhancement increases cortical sensitivity to interaural envelope delays with acoustic and electric hearing.

Directory of Open Access Journals (Sweden)

Douglas E H Hartley

Full Text Available Evidence from human psychophysical and animal electrophysiological studies suggests that sensitivity to interaural time delay (ITD in the modulating envelope of a high-frequency carrier can be enhanced using half-wave rectified stimuli. Recent evidence has shown potential benefits of equivalent electrical stimuli to deaf individuals with bilateral cochlear implants (CIs. In the current study we assessed the effects of envelope shape on ITD sensitivity in the primary auditory cortex of normal-hearing ferrets, and profoundly-deaf animals with bilateral CIs. In normal-hearing animals, cortical sensitivity to ITDs (±1 ms in 0.1-ms steps was assessed in response to dichotically-presented i sinusoidal amplitude-modulated (SAM and ii half-wave rectified (HWR tones (100-ms duration; 70 dB SPL presented at the best-frequency of the unit over a range of modulation frequencies. In separate experiments, adult ferrets were deafened with neomycin administration and bilaterally-implanted with intra-cochlear electrode arrays. Electrically-evoked auditory brainstem responses (EABRs were recorded in response to bipolar electrical stimulation of the apical pair of electrodes with singe biphasic current pulses (40 µs per phase over a range of current levels to measure hearing thresholds. Subsequently, we recorded cortical sensitivity to ITDs (±800 µs in 80-µs steps within the envelope of SAM and HWR biphasic-pulse trains (40 µs per phase; 6000 pulses per second, 100-ms duration over a range of modulation frequencies. In normal-hearing animals, nearly a third of cortical neurons were sensitive to envelope-ITDs in response to SAM tones. In deaf animals with bilateral CI, the proportion of ITD-sensitive cortical neurons was approximately a fifth in response to SAM pulse trains. In normal-hearing and deaf animals with bilateral CI the proportion of ITD sensitive units and neural sensitivity to ITDs increased in response to HWR, compared with SAM stimuli

Parvoviral nuclear import: bypassing the host nuclear-transport machinery.

Science.gov (United States)

Cohen, Sarah; Behzad, Ali R; Carroll, Jeffrey B; Panté, Nelly

2006-11-01

The parvovirus Minute virus of mice (MVM) is a small DNA virus that replicates in the nucleus of its host cells. However, very little is known about the mechanisms underlying parvovirus' nuclear import. Recently, it was found that microinjection of MVM into the cytoplasm of Xenopus oocytes causes damage to the nuclear envelope (NE), suggesting that the nuclear-import mechanism of MVM involves disruption of the NE and import through the resulting breaks. Here, fluorescence microscopy and electron microscopy were used to examine the effect of MVM on host-cell nuclear structure during infection of mouse fibroblast cells. It was found that MVM caused dramatic changes in nuclear shape and morphology, alterations of nuclear lamin immunostaining and breaks in the NE of infected cells. Thus, it seems that the unusual nuclear-import mechanism observed in Xenopus oocytes is in fact used by MVM during infection of host cells.

Safeguards Envelope Progress FY08

Energy Technology Data Exchange (ETDEWEB)

Robert Bean; Richard Metcalf; Aaron Bevill

2008-09-01

The Safeguards Envelope Project met its milestones by creating a rudimentary safeguards envelope, proving the value of the approach on a small scale, and determining the most appropriate path forward. The Idaho Chemical Processing Plant’s large cache of reprocessing process monitoring data, dubbed UBER Data, was recovered and used in the analysis. A probabilistic Z test was used on a Markov Monte Carlo simulation of expected diversion data when compared with normal operating data. The data regarding a fully transient event in a tank was used to create a simple requirement, representative of a safeguards envelope, whose impact was a decrease in operating efficiency by 1.3% but an increase in material balance period of 26%. This approach is operator, state, and international safeguards friendly and should be applied to future reprocessing plants. Future requirements include tank-to-tank correlations in reprocessing facilities, detailed operations impact studies, simulation inclusion, automated optimization, advanced statistics analysis, and multi-attribute utility analysis.

Safeguards Envelope Progress FY08

International Nuclear Information System (INIS)

Bean, Robert; Metcalf, Richard; Bevill, Aaron

2008-01-01

The Safeguards Envelope Project met its milestones by creating a rudimentary safeguards envelope, proving the value of the approach on a small scale, and determining the most appropriate path forward. The Idaho Chemical Processing Plant's large cache of reprocessing process monitoring data, dubbed UBER Data, was recovered and used in the analysis. A probabilistic Z test was used on a Markov Monte Carlo simulation of expected diversion data when compared with normal operating data. The data regarding a fully transient event in a tank was used to create a simple requirement, representative of a safeguards envelope, whose impact was a decrease in operating efficiency by 1.3% but an increase in material balance period of 26%. This approach is operator, state, and international safeguards friendly and should be applied to future reprocessing plants. Future requirements include tank-to-tank correlations in reprocessing facilities, detailed operations impact studies, simulation inclusion, automated optimization, advanced statistics analysis, and multi-attribute utility analysis

Muller cell-specific autoantibodies in a patient with progressive loss of vision

NARCIS (Netherlands)

Peek, R.; Verbraak, F.; Coevoet, H. M.; Kijlstra, A.

1998-01-01

PURPOSE. To study the specificity of circulating retinal autoantibodies in a patient with progressive loss of vision resembling cancer-associated retinopathy in the absence of systemic malignancy. METHODS. Patient's serum was tested for the presence of antiretinal antibodies by Western blot

Physical properties of the red giant envelopes

Energy Technology Data Exchange (ETDEWEB)

Maciel, W J [Instituto de Astronomia e Geofisico da Universidade de Sao Paulo (Brazil)

1978-12-01

In this work, several model envelopes are calculated for cool giant stars with mass loss due to the action of stellar radiation pressure on molecules and grains. Molecular profiles as well as average values of some physical parameters of the envelopes are obtained.

Implementation of an Improved Safe Operating Envelope

Energy Technology Data Exchange (ETDEWEB)

Prime, Robyn; McIntyre, Mark [NB Power Nuclear, P.O. Box 600, Lepreau, NB (Canada); Reeves, David [Atlantic Nuclear Services Ltd., PO Box 1268 Fredericton, NB (Canada)

2008-07-01

This paper is a continuation of the paper presented at IYNC 2004 on 'The Definition of a Safe Operating Envelope'. The current paper concentrates on the implementation process of the Safe Operating Envelope employed at the Point Lepreau Generating Station. (authors)

The Role of GAD65 Autoantibody in Diabetes Mellitus and their First-Degree Relatives and Comparison with Healthy Persons

Directory of Open Access Journals (Sweden)

M Nakhjavani

2001-06-01

Full Text Available The diabetes is an autoimmune disease, in which the role of autoantibodies is of a specific importance. The appearance of these autoantibodies can be the first symptom in the serum of type I diabetic patients, which may appear ten years before onset of the disease. The most important autoantibodies include Glutamic acid decarboxylase autoantibodies (GAD65-Ab. This can be used as a good tool for prediction in screening tests in type I diabetic patients. In the present study with prosedure RIA, we investigated the level of GAD65-Ab in patients with diabetes type I and their close relatives, and compared them with healthy persons. From the type I diabetic patients who have been suffering from the disease for periods of one week to twenty years, 63.3% of them had positive Anti-GAD65. This ratio was 8% in their close trelatives, and 0% in healthy persons. The difference in Anti-GAD65 between the healthy persons and close relative of patients was significant. This test may be employed in diabetes type I, as a screening test, and confirms the results of studies which have been conducted so far outside this country.

Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.

OpenAIRE

Manns, M P; Johnson, E F; Griffin, K J; Tan, E M; Sullivan, K F

1989-01-01

Type 1, liver kidney microsomal autoantibodies (LKM-1) are associated with a subgroup of idiopathic autoimmune type, chronic active hepatitis (CAH). The antigenic specificity of LKM-1 autoantibodies from 13 patients was investigated by immunoblot analysis of human liver microsomal proteins. Polypeptides of 50, 55, and 64 kD were detected with these antisera. A high titer LKM-1 serum was selected to screen a human liver lambda gt11 cDNA expression library, resulting in the isolation of several...

β2-glycoprotein-1 autoantibodies from patients with antiphospholipid syndrome are sufficient to potentiate arterial thrombus formation in a mouse model

Science.gov (United States)

Arad, Ariela; Proulle, Valerie; Furie, Richard A.; Furie, Barbara C.

2011-01-01

Antiphospholipid syndrome is characterized by thrombosis, recurrent fetal loss, and the presence of the lupus anticoagulant, anticardiolipin antibodies, or anti–β2-glycoprotein-1 (anti–β2-GP1) antibodies. Although anti–β2-GP1 antibodies have been documented as a biomarker for diagnosis of antiphospholipid syndrome, their direct role in the pathogenesis of thrombosis is unknown. We have demonstrated using intravital microscopy that anti–β2-GP1 autoantibodies purified from the sera of patients with antiphospholipid syndrome complicated by thrombosis greatly amplify thrombus size after laser-induced vessel wall injury in live mice. Anti–β2-GP1 autoantibodies from 3 patients with antiphospholipid syndrome were affinity-purified using human β2-GP1 bound to agarose. The effects of purified anti–β2-GP1 IgG autoantibodies, of anti–β2-GP1–depleted IgG, and of IgG from normal human sera on thrombus formation were measured in mice after arterial injury in the cremaster muscle. Before injury, purified anti–β2-GP1 IgG autoantibodies, anti–β2-GP1 antibody–depleted IgG, or IgG from normal human sera were infused. Increasing amounts of purified anti–β2-GP1 autoantibodies increased thrombus size in a dose-dependent manner, whereas neither anti–β2-GP1 antibody-depleted IgG nor IgG from normal serum affected thrombus size. These results indicate that anti–β2-GP1 IgG autoantibodies in antiphospholipid syndrome patient sera are not only a marker of antiphospholipid syndrome but are directly involved in the pathogenesis of thrombosis. PMID:21245481

Physical properties of the red giant envelopes

International Nuclear Information System (INIS)

Maciel, W.J.

1978-01-01

In this work, several model envelopes are calculated for cool giant stars with mass loss due to the action of stellar radiation pressure on molecules and grains. Molecular profiles as well as average values of some physical parameters of the envelopes are obtained [pt

Full waveform inversion using envelope-based global correlation norm

Science.gov (United States)

Oh, Ju-Won; Alkhalifah, Tariq

2018-05-01

To increase the feasibility of full waveform inversion on real data, we suggest a new objective function, which is defined as the global correlation of the envelopes of modelled and observed data. The envelope-based global correlation norm has the advantage of the envelope inversion that generates artificial low-frequency information, which provides the possibility to recover long-wavelength structure in an early stage. In addition, the envelope-based global correlation norm maintains the advantage of the global correlation norm, which reduces the sensitivity of the misfit to amplitude errors so that the performance of inversion on real data can be enhanced when the exact source wavelet is not available and more complex physics are ignored. Through the synthetic example for 2-D SEG/EAGE overthrust model with inaccurate source wavelet, we compare the performance of four different approaches, which are the least-squares waveform inversion, least-squares envelope inversion, global correlation norm and envelope-based global correlation norm. Finally, we apply the envelope-based global correlation norm on the 3-D Ocean Bottom Cable (OBC) data from the North Sea. The envelope-based global correlation norm captures the strong reflections from the high-velocity caprock and generates artificial low-frequency reflection energy that helps us recover long-wavelength structure of the model domain in the early stages. From this long-wavelength model, the conventional global correlation norm is sequentially applied to invert for higher-resolution features of the model.

Dynamic changes and clinical significance of thyroid auto-antibodies before and after radioiodine treatment for Graves' disease

International Nuclear Information System (INIS)

Zhao Zhiying; Zhu Li; Wang Zhenghua

2005-01-01

To study the changes and their clinical effect of serum levels of thyroid globulin auto-antibodies (TGAb), thyroid peroxidase auto-antibodies (TPOAb) during radioiodine treatment of Graves' disease, and to investigate early therapeutic effect of radioiodine and influence factors for early hypothyroidism, 334 patients were divided into a positive group (TGAb>115IU/mL, TPOAb>34IU/mL) and a negative group (TGAb 131 I treatment. The levels of FT 3 , FT 4 , TSH, TGAb and TPOAb in serum were measured before 131 I therapy and at the 3rd, 6th, 9th, 12th month after the treatment respectively. Within one year after radioiodine treatment, 23.8% patients (48 out of 202) in the positive group and 11.4% (15 out of 132) in the negative group suffered from early hypothyroidism (P 131 I could reduce the level of thyroid auto-antibodies and promote the improvement and recovery of autoimmunity status. (authors)

Inhibition of enveloped viruses infectivity by curcumin.

Directory of Open Access Journals (Sweden)

Tzu-Yen Chen

Full Text Available Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter than for the pseudorabies virus (approximately 180 nm and the vaccinia virus (roughly 335 × 200 × 200 nm. These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses.

Inhibition of Enveloped Viruses Infectivity by Curcumin

Science.gov (United States)

Wen, Hsiao-Wei; Ou, Jun-Lin; Chiou, Shyan-Song; Chen, Jo-Mei; Wong, Min-Liang; Hsu, Wei-Li

2013-01-01

Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA) activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB)-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter) than for the pseudorabies virus (approximately 180 nm) and the vaccinia virus (roughly 335 × 200 × 200 nm). These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses. PMID:23658730

Natural (auto)antibodies in calves are affected by age and diet

NARCIS (Netherlands)

Khobondo, J.O.; Nieuwland, M.G.B.; Webb, L.E.; Bokkers, E.A.M.; Parmentier, H.K.

2015-01-01

Background: Natural autoantibodies (N(a)ab) were found in every species tested so far, and are likely important in maintaining homeostasis. Objectives: (1) To determine N(a)ab in Bos taurus calves, (2) evaluate effects of diet and age on N(a)ab binding repertoires in calves, and (3) delineate bovine

Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses

Directory of Open Access Journals (Sweden)

Wahyu eWulan

2015-06-01

Full Text Available Most viruses with non-segmented single stranded RNA genomes complete their life cycle in the cytoplasm of infected cells. However, despite undergoing replication in the cytoplasm, the structural proteins of some of these RNA viruses localize to the nucleus at specific times in the virus life cycle, primarily early in infection. Limited evidence suggests that this enhances successful viral replication by interfering with or inhibiting the host antiviral response. Nucleocapsid proteins of RNA viruses have a well-established, essential cytoplasmic role in virus replication and assembly. Intriguingly, nucleocapsid proteins of some RNA viruses also localize to the nucleus/nucleolus of infected cells. Their nuclear function is less well understood although significant advances have been made in recent years. This review will focus on the nucleocapsid protein of cytoplasmic enveloped RNA viruses, including their localization to the nucleus/nucleolus and function therein. A greater understanding of the nuclear localization of nucleocapsid proteins has the potential to enhance therapeutic strategies as it can be a target for the development of live-attenuated vaccines or antiviral drugs.

A digital processing method for the analysis of complex nuclear spectra

International Nuclear Information System (INIS)

Madan, V.K.; Abani, M.C.; Bairi, B.R.

1994-01-01

This paper describes a digital processing method using frequency power spectra for the analysis of complex nuclear spectra. The power spectra were estimated by employing modified discrete Fourier transform. The method was applied to observed spectral envelopes. The results for separating closely-spaced doublets in nuclear spectra of low statistical precision compared favorably with those obtained by using a popular peak fitting program SAMPO. The paper also describes limitations of the peak fitting methods. It describes the advantages of digital processing techniques for type II digital signals including nuclear spectra. A compact computer program occupying less than 2.5 kByte of memory space was written in BASIC for the processing of observed spectral envelopes. (orig.)

Correlation between imaging findings and autoantibody levels and prognosis in patients with neuropsychiatric systemic lupus erythematosus

International Nuclear Information System (INIS)

Zhou Guangyu; Han Xuemei; Jin Ling

2013-01-01

Objective: To investigate the correlation between cranial magnetic resonance imaging (MRI) findings and autoantibody levels in patients with neuropsychiatric systemic lupus erythematosus (NPSLE), and to elucidate the role of MRI findings in predicting the prognosis of NPSLE. Methods: In total, 36 well-documented cases of NPSLE diagnosed definitely were selected. All the patients were divided into survival group (n=27) and dead group (n=9). Anti-nuclear antibodies and anti-dsDNA antibodies in serum were detected by indirect immunofluorescence and colloidal gold spot penetration method, respectively. Immunoblotting method was used to detect anti-Sm, anti-SSA, anti-SSB, anti U1-RNP, and anti-ribosomal P protein antibodies. Anti-cardiolipin antibody (ACL) was detected byELISA method. The correlation between MRI findings of cerebral lesions and autoantibodies, and prognosis was analyzed. Results: Cranial MRI scans on admission were abnormal in 32 patients (88.9% ), among which 21 cases showed diffuse manifestations, 10 cases showed focal lesion in brain and 1 case showed brain atrophy. The diffuse lesion on MRI showed multiple spotty or patchy normal intensity signal on T 1 -weighted image (T 1 WI) and high-intensity signal changes on T 2 -weighted image (T 2 WI). The focal lesion showed single spotty or patchy normal intensity signal on T 1 WI and high-intensity signal changes on T 2 WI. The lesion sites included basal ganglia, subcortical white matter, anterior and posterior horn of lateral ventricle, semiovale center, cerebral cortex, brainstem and cerebellum. Of 9 patients in dead group, 6 cases presented with focal lesion and the percentage of focal lesion cases in dead group was significantly higher than that in survival group (P<0.01). The percentages of lesion number in brainstem and basal ganglia in dead group were 11.5% and 26.9% , respectively, which were significantly higher than those in survival group (P<0.05 or P<0.01). The positive rate of ACL in cases

Moisture accumulation in a building envelope

Energy Technology Data Exchange (ETDEWEB)

Forest, T.W.; Checkwitch, K.

1988-09-01

In a large number of cases, the failure of a building envelope can be traced to the accumulation of moisture. In a cold winter climate, characteristic of the Canadian prairies, moisture is deposited in the structure by the movement of warm, moist air through the envelope. Tests on the moisture accumulation in a building envelope were initiated in a test house at an Alberta research facility during the 1987/88 heating season. The indoor moisture generation rate was measured and compared with the value inferred from the measured air infiltration rate. With the flue open, the moisture generation rate was approximately 5.5 kg/d of which 0.7 kg/d entered the building envelope; the remainder was exhausted through the flue. With the flue blocked, the moisture generation rate decreased to 3.4 kg/d, while the amount of moisture migrating through the envelope increased to 4.0 kg/d. The moisture accumulation in wall panels located on the north and south face of the test house was also monitored. Moisture was allowed to enter the wall cavity via a hole in the drywall. The fiberglass insulation remained dry throughout the test period. The moisture content of the exterior sheathing of the north panel increased to a maximum of 18% wt in the vicinity of the hole, but quickly dried when the ambient temperatures increased towards the end of the season. The south panel showed very little moisture accumlation due to the effects of solar radiation. 14 refs., 9 figs.

Colostrum of Healthy Mothers Contains Broad Spectrum of Secretory IgA Autoantibodies

Czech Academy of Sciences Publication Activity Database

Přibylová, Jaroslava; Krausová, Klára; Kocourková, I.; Rossmann, Pavel; Klimešová, Klára; Kverka, Miloslav; Tlaskalová-Hogenová, Helena

2012-01-01

Roč. 32, č. 6 (2012), s. 1372-1380 ISSN 0271-9142 R&D Projects: GA ČR(CZ) GAP304/11/1252 Institutional support: RVO:61388971 Keywords : Autoantibodies * mucosal immunity * immunoglobulins Subject RIV: EC - Immunology Impact factor: 3.382, year: 2012

AtNEA1-identification and characterization of a novel plant nuclear ...

African Journals Online (AJOL)

In animal and yeast cells, a cross nuclear envelope structure linker of nucleoskeleton and cytoskeleton (LINC) is formed by outer nuclear membrane SUN proteins and inner nuclear membrane KASH proteins. However, little information was acquired about plant SUN-KASH structure until they were found in plant SUN ...

Neuromyelitis optica in a young child with positive serum autoantibody

OpenAIRE

Loma, Ingrid P.; Asato, Miya R.; Filipink, Robyn A.; Alper, Gulay

2008-01-01

Relapsing neuromyelitis optica is rare in children. The identification of highly specific serum autoantibody marker (neuromyelitis optica –immunoglobulin G) differentiates neuromyelitis optica from other demyelinating disorders particularly in clinically challenging cases. We present a child with multiple episodes of transverse myelitis and optic neuritis with positive neuromyelitis optica-immunoglobulin G titers consistent with a diagnosis of relapsing neuromyelitis optica. Serial titers of ...

Nuclear networking.

Science.gov (United States)

Xie, Wei; Burke, Brian

2017-07-04

Nuclear lamins are intermediate filament proteins that represent important structural components of metazoan nuclear envelopes (NEs). By combining proteomics and superresolution microscopy, we recently reported that both A- and B-type nuclear lamins form spatially distinct filament networks at the nuclear periphery of mouse fibroblasts. In particular, A-type lamins exhibit differential association with nuclear pore complexes (NPCs). Our studies reveal that the nuclear lamina network in mammalian somatic cells is less ordered and more complex than that of amphibian oocytes, the only other system in which the lamina has been visualized at high resolution. In addition, the NPC component Tpr likely links NPCs to the A-type lamin network, an association that appears to be regulated by C-terminal modification of various A-type lamin isoforms. Many questions remain, however, concerning the structure and assembly of lamin filaments, as well as with their mode of association with other nuclear components such as peripheral chromatin.

A Spectral Algorithm for Envelope Reduction of Sparse Matrices

Science.gov (United States)

Barnard, Stephen T.; Pothen, Alex; Simon, Horst D.

1993-01-01

The problem of reordering a sparse symmetric matrix to reduce its envelope size is considered. A new spectral algorithm for computing an envelope-reducing reordering is obtained by associating a Laplacian matrix with the given matrix and then sorting the components of a specified eigenvector of the Laplacian. This Laplacian eigenvector solves a continuous relaxation of a discrete problem related to envelope minimization called the minimum 2-sum problem. The permutation vector computed by the spectral algorithm is a closest permutation vector to the specified Laplacian eigenvector. Numerical results show that the new reordering algorithm usually computes smaller envelope sizes than those obtained from the current standard algorithms such as Gibbs-Poole-Stockmeyer (GPS) or SPARSPAK reverse Cuthill-McKee (RCM), in some cases reducing the envelope by more than a factor of two.

Transfer of the amino-terminal nuclear envelope targeting domain of human MX2 converts MX1 into an HIV-1 resistance factor.

Science.gov (United States)

Goujon, Caroline; Moncorgé, Olivier; Bauby, Hélène; Doyle, Tomas; Barclay, Wendy S; Malim, Michael H

2014-08-01

The myxovirus resistance 2 (MX2) protein of humans has been identified recently as an interferon (IFN)-inducible inhibitor of human immunodeficiency virus type 1 (HIV-1) that acts at a late postentry step of infection to prevent the nuclear accumulation of viral cDNA (C. Goujon et al., Nature 502:559-562, 2013, http://dx.doi.org/10.1038/nature12542; M. Kane et al., Nature 502:563-566, 2013, http://dx.doi.org/10.1038/nature12653; Z. Liu et al., Cell Host Microbe 14:398-410, 2013, http://dx.doi.org/10.1016/j.chom.2013.08.015). In contrast, the closely related human MX1 protein, which suppresses infection by a range of RNA and DNA viruses (such as influenza A virus [FluAV]), is ineffective against HIV-1. Using a panel of engineered chimeric MX1/2 proteins, we demonstrate that the amino-terminal 91-amino-acid domain of MX2 confers full anti-HIV-1 function when transferred to the amino terminus of MX1, and that this fusion protein retains full anti-FluAV activity. Confocal microscopy experiments further show that this MX1/2 fusion, similar to MX2 but not MX1, can localize to the nuclear envelope (NE), linking HIV-1 inhibition with MX accumulation at the NE. MX proteins are dynamin-like GTPases, and while MX1 antiviral function requires GTPase activity, neither MX2 nor MX1/2 chimeras require this attribute to inhibit HIV-1. This key discrepancy between the characteristics of MX1- and MX2-mediated viral resistance, together with previous observations showing that the L4 loop of the stalk domain of MX1 is a critical determinant of viral substrate specificity, presumably reflect fundamental differences in the mechanisms of antiviral suppression. Accordingly, we propose that further comparative studies of MX proteins will help illuminate the molecular basis and subcellular localization requirements for implementing the noted diversity of virus inhibition by MX proteins. Interferon (IFN) elicits an antiviral state in cells through the induction of hundreds of IFN

Solid phase radioimmunoassay for detection of serum autoantibodies in systemic lupus erythematosus

Energy Technology Data Exchange (ETDEWEB)

Smith, K O; Harrington, J T; Gehle, W D

1977-03-01

Solid phase radioimmunoassay (RIA) methods for measuring autoantibodies in systemic lupus erythematosus (SLE) patients' serum were developed to improve the sensitvity and quantitative precision of the determinations. Two mechanical systems were studied: (1) acetone fixed cell monolayers in glass tubes and (2) antigen coated plastic beads. Both systems were senssitive and reproducible. The most sensitive, versatile system involves the coating of the plastic beads with nuclear antigen(s), incubation overnight with sera and labelling with /sup 125/I conjugated antihuman globulin. Linear binding of this radioactive tag is obtained over a wide range of SLE serum dilutions and the slopes of the serum dilution titration curves are almost identical for all SLE patients' sera tested. Therefore, a standard titration curve can be constructed from the results with a positive serum, and end-point dilutions of unknown sera estimated from results obtained with a single serum dilution. Alternatively, binding ratios of unknown sera can be usefully compared at fixed dilutions with standard positive and negative sera. For example, high binding ratios (>3.0) were obtained with 19/20 SLE sera and 0/20 control sera. Antigens used in these systems include crude, whole-cell lysates and lysates from purified nuclei.

Moisture Dynamics in Building Envelopes

DEFF Research Database (Denmark)

Peuhkuri, Ruut Hannele

2003-01-01

The overall scope of this Thesis "Moisture dynamics in building envelopes" has been to characterise how the various porous insulation materials investigated performed hygrothermally under conditions similar to those in a typical building envelope. As a result of the changing temperature...... part of the Thesis consists of a theory and literature review on the moisture storage and transport processes (Chapter 2), on the non-Fickian moisture transport (Chapter 3)and on the methods for determining the moisture properties (Chapter 4). In the second part, the conducted experimental work...

Moisture dynamics in building envelopes

Energy Technology Data Exchange (ETDEWEB)

Peuhkuri, R.

2003-07-01

The overall scope of this Thesis 'Moisture dynamics in building envelopes' has been to characterise how the various porous insulation materials investigated performed hygro thermally under conditions similar to those in a typical building envelope. As a result of the changing temperature and moisture conditions in the exterior weather and indoor climate the materials dynamically absorb and release moisture. The complexity of the impact of these conditions on the resulting moisture transport and content of the materials has been studied in this Thesis with controlled laboratory tests. (au)

Common envelope evolution

NARCIS (Netherlands)

Taam, Ronald E.; Ricker, Paul M.

2010-01-01

The common envelope phase of binary star evolution plays a central role in many evolutionary pathways leading to the formation of compact objects in short period systems. Using three dimensional hydrodynamical computations, we review the major features of this evolutionary phase, focusing on the

Autoantibodies to MUC1 glycopeptides cannot be used as a screening assay for early detection of breast, ovarian, lung or pancreatic cancer

DEFF Research Database (Denmark)

Burford, B; Gentry-Maharaj, A; Graham, R

2013-01-01

Autoantibodies have been detected in sera before diagnosis of cancer leading to interest in their potential as screening/early detection biomarkers. As we have found autoantibodies to MUC1 glycopeptides to be elevated in early-stage breast cancer patients, in this study we analysed these autoanti...

Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes-A Recursive Partitioning Analysis.

Science.gov (United States)

Xu, Ping; Krischer, Jeffrey P

2016-06-01

To define prognostic classification factors associated with the progression from single to multiple autoantibodies, multiple autoantibodies to dysglycemia, and dysglycemia to type 1 diabetes onset in relatives of individuals with type 1 diabetes. Three distinct cohorts of subjects from the Type 1 Diabetes TrialNet Pathway to Prevention Study were investigated separately. A recursive partitioning analysis (RPA) was used to determine the risk classes. Clinical characteristics, including genotype, antibody titers, and metabolic markers were analyzed. Age and GAD65 autoantibody (GAD65Ab) titers defined three risk classes for progression from single to multiple autoantibodies. The 5-year risk was 11% for those subjects >16 years of age with low GAD65Ab titers, 29% for those ≤16 years of age with low GAD65Ab titers, and 45% for those subjects with high GAD65Ab titers regardless of age. Progression to dysglycemia was associated with islet antigen 2 Ab titers, and 2-h glucose and fasting C-peptide levels. The 5-year risk is 28%, 39%, and 51% for respective risk classes defined by the three predictors. Progression to type 1 diabetes was associated with the number of positive autoantibodies, peak C-peptide level, HbA1c level, and age. Four risk classes defined by RPA had a 5-year risk of 9%, 33%, 62%, and 80%, respectively. The use of RPA offered a new classification approach that could predict the timing of transitions from one preclinical stage to the next in the development of type 1 diabetes. Using these RPA classes, new prevention techniques can be tailored based on the individual prognostic risk characteristics at different preclinical stages. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes—A Recursive Partitioning Analysis

Science.gov (United States)

Krischer, Jeffrey P.

2016-01-01

OBJECTIVE To define prognostic classification factors associated with the progression from single to multiple autoantibodies, multiple autoantibodies to dysglycemia, and dysglycemia to type 1 diabetes onset in relatives of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS Three distinct cohorts of subjects from the Type 1 Diabetes TrialNet Pathway to Prevention Study were investigated separately. A recursive partitioning analysis (RPA) was used to determine the risk classes. Clinical characteristics, including genotype, antibody titers, and metabolic markers were analyzed. RESULTS Age and GAD65 autoantibody (GAD65Ab) titers defined three risk classes for progression from single to multiple autoantibodies. The 5-year risk was 11% for those subjects >16 years of age with low GAD65Ab titers, 29% for those ≤16 years of age with low GAD65Ab titers, and 45% for those subjects with high GAD65Ab titers regardless of age. Progression to dysglycemia was associated with islet antigen 2 Ab titers, and 2-h glucose and fasting C-peptide levels. The 5-year risk is 28%, 39%, and 51% for respective risk classes defined by the three predictors. Progression to type 1 diabetes was associated with the number of positive autoantibodies, peak C-peptide level, HbA1c level, and age. Four risk classes defined by RPA had a 5-year risk of 9%, 33%, 62%, and 80%, respectively. CONCLUSIONS The use of RPA offered a new classification approach that could predict the timing of transitions from one preclinical stage to the next in the development of type 1 diabetes. Using these RPA classes, new prevention techniques can be tailored based on the individual prognostic risk characteristics at different preclinical stages. PMID:27208341

MHTGR thermal performance envelopes: Reliability by design

International Nuclear Information System (INIS)

Etzel, K.T.; Howard, W.W.; Zgliczynski, J.B.

1992-05-01

This document discusses thermal performance envelopes which are used to specify steady-state design requirements for the systems of the Modular High Temperature Gas-Cooled Reactor to maximize plant performance reliability with optimized design. The thermal performance envelopes are constructed around the expected operating point accounting for uncertainties in actual plant as-built parameters and plant operation. The components are then designed to perform successfully at all points within the envelope. As a result, plant reliability is maximized by accounting for component thermal performance variation in the design. The design is optimized by providing a means to determine required margins in a disciplined and visible fashion

The limited role of recombination energy in common envelope removal

Science.gov (United States)

Grichener, Aldana; Sabach, Efrat; Soker, Noam

2018-05-01

We calculate the outward energy transport time by convection and photon diffusion in an inflated common envelope and find this time to be shorter than the envelope expansion time. We conclude therefore that most of the hydrogen recombination energy ends in radiation rather than in kinetic energy of the outflowing envelope. We use the stellar evolution code MESA and inject energy inside the envelope of an asymptotic giant branch star to mimic energy deposition by a spiraling-in stellar companion. During 1.7 years the envelope expands by a factor of more than 2. Along the entire evolution the convection can carry the energy very efficiently outwards, to the radius where radiative transfer becomes more efficient. The total energy transport time stays within several months, shorter than the dynamical time of the envelope. Had we included rapid mass loss, as is expected in the common envelope evolution, the energy transport time would have been even shorter. It seems that calculations that assume that most of the recombination energy ends in the outflowing gas might be inaccurate.

Control room habitability in Spanish Nuclear Power Plants

International Nuclear Information System (INIS)

Mediavilla, F.; Sierra, J. J.

2007-01-01

Since the NRC published in 2003 the Generic Letter 2003-01 Control room Habitability and the Regulatory guide 1.197 Demonstrating Control Room Envelope Integrity at Nuclear Power Reactors, where it is emphasized the importance of verifying the control room habitability by means of alternative methods, Spanish Nuclear Power Plants are undertaking the different necessary activities to fulfill the requirements of the regulatory commission. This paper describes the main mechanisms included in NEI 99-03 Nuclear Energy Institute publication Control room Habitability Assessment guidance, to demonstrate and maintain Control room Habitability. In addition, in this article it Ds shown the theoretical principle of the test used to quantify air in-leakage in a control room envelope by using tracer gas techniques. The necessary activities to perform the initial in leakage testing are also put forward. Since 2006 Tecnatom, S. A. has performed the baseline testing in four Spanish Units, all of them with successful results. The rest of the Plants are scheduled to perform the tests during the second half of this year. Finally, this document summarises the more important aspects to be taken into account in the development of control room Habitability Programs, which are expected to ensure the integral maintenance of the Control room Envelope during the life a plant. (Author)

Determination of auto-antibodies to native and oxidized low-density lipoproteins (LDL) in serum of patients underwent coronariography in the Medical-Surgical Research Center (MSRC)

International Nuclear Information System (INIS)

Conde CerdeiraI, Hector; Soto Lopez, Yosdel; Aroche Aportela, Ronald

2010-01-01

Low-density lipoprotein (LDL) oxidation is an important event in atherosclerosis development. The relationship between oxidized LDL (oxLDL) autoantibodies and coronary artery disease (CAD) remains controversial. IgM and IgG autoantibodies to oxLDL were measured in twenty patients undergoing clinically indicated coronary angiography, and in ten young healthy volunteers from the Center of Molecular Immunology. The levels of IgM autoantibodies to oxLDL did not differ between no CAD patients and healthy subjects, but the levels of IgM autoantibodies to oxLDL of these two groups were higher compared with the one of CAD patient group. Our results, although preliminary, supports the hypothesis that this kind of Abs might be inversely associated with the presence of atherosclerosis

Use of response envelopes for seismic margin assessment of reinforced concrete walls and slabs

Energy Technology Data Exchange (ETDEWEB)

Ile, Nicolas; Frau, Alberto, E-mail: alberto.frau@cea.fr

2017-04-01

Highlights: • Proposal of a method for application of the elliptical envelope to RC shell elements. • Proposal of new algorithms for the seismic margin evaluation for RC shell elements. • Verification of a RC wall 3D structure, using the proposed assessment approach. - Abstract: Seismic safety evaluations of existing nuclear facilities are usually based on the assumption of structural linearity. For the design basis earthquake (DBE), it is reasonable to apply a conventional evaluation of the seismic safety of building structures and carry out a linear elastic analysis to assess the load effects on structural elements. Estimating the seismic capacity of a structural element requires an estimation of the critical combination of responses acting in this structural element and compare this combination with the capacity of the element. By exploiting the response-spectrum-based procedure for predicting the response envelopes in linear structures formulated by Menun and Der Kiureghian (2000a), algorithms are developed for the seismic margin assessment of reinforced concrete shell finite elements. These algorithms facilitate the comparison of the response-spectrum-based envelopes to prescribed capacity surfaces for the purpose of assessing the safety margin of this kind of structures. The practical application of elliptical response envelopes in case of shell finite elements is based on the use of layer models such as those developed by Marti (1990), which transfer the generalized stress field to three layers under the assumption that the two outer layers carry membrane forces and the internal layer carries only the out-of-plane shears. The utility of the assessment approach is discussed with reference to a case study of a 3D structure made of reinforced concrete walls.

Use of response envelopes for seismic margin assessment of reinforced concrete walls and slabs

International Nuclear Information System (INIS)

Ile, Nicolas; Frau, Alberto

2017-01-01

Highlights: • Proposal of a method for application of the elliptical envelope to RC shell elements. • Proposal of new algorithms for the seismic margin evaluation for RC shell elements. • Verification of a RC wall 3D structure, using the proposed assessment approach. - Abstract: Seismic safety evaluations of existing nuclear facilities are usually based on the assumption of structural linearity. For the design basis earthquake (DBE), it is reasonable to apply a conventional evaluation of the seismic safety of building structures and carry out a linear elastic analysis to assess the load effects on structural elements. Estimating the seismic capacity of a structural element requires an estimation of the critical combination of responses acting in this structural element and compare this combination with the capacity of the element. By exploiting the response-spectrum-based procedure for predicting the response envelopes in linear structures formulated by Menun and Der Kiureghian (2000a), algorithms are developed for the seismic margin assessment of reinforced concrete shell finite elements. These algorithms facilitate the comparison of the response-spectrum-based envelopes to prescribed capacity surfaces for the purpose of assessing the safety margin of this kind of structures. The practical application of elliptical response envelopes in case of shell finite elements is based on the use of layer models such as those developed by Marti (1990), which transfer the generalized stress field to three layers under the assumption that the two outer layers carry membrane forces and the internal layer carries only the out-of-plane shears. The utility of the assessment approach is discussed with reference to a case study of a 3D structure made of reinforced concrete walls.

Catalytic activity of autoantibodies toward myelin basic protein correlates with the scores on the multiple sclerosis expanded disability status scale.

Science.gov (United States)

Ponomarenko, Natalia A; Durova, Oxana M; Vorobiev, Ivan I; Belogurov, Alexey A; Telegin, Georgy B; Suchkov, Sergey V; Misikov, Victor K; Morse, Herbert C; Gabibov, Alexander G

2006-02-28

Autoantibodies toward myelin basic protein (MBP) evidently emerge in sera and cerebrospinal fluid of the patients with multiple sclerosis (MS), as well as in a MS rodent model, i.e., experimental autoimmune encephalomyelitis (EAE). The studies of the last two decades have unveiled somewhat controversial data on the diagnostic applicability of anti-MBP autoantibodies as a disease' marker. Here, we present the results of new functional analysis of the anti-MBP autoantibodies isolated from MS (in patients) and EAE (in mice) sera, based on their proteolytic activity against the targeted autoantigen. The activity was shown to be the intrinsic property of the IgG molecule. No activity was found in the sera-derived antibody fraction of healthy donors and control mice. Sera of 24 patients with clinically proven MS at different stages of the disease, and 20 healthy controls were screened for the anti-MBP antibody-mediated proteolytic activity. The activity correlated with the scores on the MS expanded disability status scale (EDSS) (r(2)=0.85, P<0.001). Thus, the anti-MBP autoantibody-mediated proteolysis may be regarded as an additional marker of the disease progression.

[Autoantibody profile among Kaingang and Guarani tribe Indians in Southern Brazil].

Science.gov (United States)

Utiyama, S R; Guardiano, J; Petzl-Erler, M L; Mocelim, V; de Messias-Reason, I J

2000-06-01

This study investigated the autoantibody profile of 241 blood samples from 176 Kaingang and 65 Guarani Indians from three populations living on the Rio das Cobras and Ivaí reservations, in the state of Paraná, in southern Brazil. The presence of antimitochondrial, anti-smooth muscle, antinuclear, anti-parietal cell, and anti-liver-kidney microsome antibodies was determined by indirect immunofluorescence. These results were compared with samples from 100 healthy Caucasian individuals from the general population of the state. Total positivity was 9% for the indigenous population and 4% for the control population. The prevalence of anti-smooth muscle antibodies was significantly higher among the Guarani and Kaingang individuals from the Rio das Cobras reservation (P = 0.03). It is likely that the increased exposure that these indigenous Brazilians have to infectious diseases that were previously unknown to them comes from more contact with non-native populations, growing acculturation, and cultural practices that include scarification and tattooing. The presence of auto-antibodies in these Brazilian Indians may be related to mechanisms of molecular mimicry with viral or bacterial antigens.

Redirecting the Cyanobacterial Bicarbonate Transporters BicA and SbtA to the Chloroplast Envelope: Soluble and Membrane Cargos Need Different Chloroplast Targeting Signals in Plants.

Directory of Open Access Journals (Sweden)

Vivien eRolland

2016-02-01

Full Text Available Most major crops used for human consumption are C3 plants, which yields are limited by photosynthetic inefficiency. To circumvent this, it has been proposed to implement the cyanobacterial CO2-concentrating mechanism (CCM, principally consisting of bicarbonate transporters and carboxysomes, into plant chloroplasts. As it is currently not possible to recover homoplasmic transplastomic monocots, foreign genes must be introduced in these plants via nuclear transformation. Consequently, it is paramount to ensure that resulting proteins reach the appropriate sub-cellular compartment, which for cyanobacterial transporters BicA and SbtA, is the chloroplast inner-envelope membrane (IEM. At present, targeting signals to redirect large transmembrane proteins from non-chloroplastic organisms to plant chloroplast envelopes are unknown. The goal of this study was to identify such signals, using agrobacteria-mediated transient expression and confocal microscopy to determine the sub-cellular localization of ~37 GFP-tagged chimeras. Initially, fragments of chloroplast proteins known to target soluble cargos to the stroma were tested for their ability to redirect BicA, but they proved ineffective. Next, different N-terminal regions from Arabidopsis IEM transporters were tested. We demonstrated that the N-terminus of AtHP59, AtPLGG1 or AtNTT1 (92-115 amino acids, containing a cleavable chloroplast transit peptide (cTP and a membrane protein leader (MPL, was sufficient to redirect BicA or SbtA to the chloroplast envelope. This constitutes the first evidence that nuclear-encoded transmembrane proteins from non-chloroplastic organisms can be targeted to the envelope of plant chloroplasts; a finding which represents an important advance in chloroplast engineering by opening up the door to further manipulation of the chloroplastic envelope.

Myositis-specific autoantibodies and their association with malignancy in Italian patients with polymyositis and dermatomyositis.

Science.gov (United States)

Ceribelli, Angela; Isailovic, Natasa; De Santis, Maria; Generali, Elena; Fredi, Micaela; Cavazzana, Ilaria; Franceschini, Franco; Cantarini, Luca; Satoh, Minoru; Selmi, Carlo

2017-02-01

This study aims to characterize myositis-specific antibodies in a well-defined cohort of patients with idiopathic inflammatory myopathy and to determine their association with cancer. Sera from 40 patients with polymyositis, dermatomyositis, and controls were tested by protein and RNA immunoprecipitation to detect autoantibodies, and immunoprecipitation-Western blot was used for anti-MJ/NXP-2, anti-MDA5, and anti-TIF1γ/α identification. Medical records were re-evaluated with specific focus on cancer. Anti-MJ/NXP-2 and anti-TIF1γ/α were the most common antibodies in dermatomyositis. In six dermatomyositis cases, we found five solid forms of cancer and one Hodgkin's lymphoma in long-term remission. Among patients with cancer-associated dermatomyositis, three were positive for anti-TIF1γ/α, two for anti-Mi-2, and one for anti-MJ/NXP-2. The strongest positivity of anti-TIF1γ was seen in two active forms of cancer, and this antibody was either negative or positive at low titers in the absence of cancer or in the 7-year remission Hodgkin's lymphoma. Four out of twenty (20 %) patients with polymyositis had solid cancer, but no specific association with autoantibodies was identified; further, none of the four cases of antisynthetase syndrome had a history of cancer. No serum myositis-associated autoantibody was observed in control sera, resulting in positive predictive value 75 %, negative predictive value 78.5 %, sensitivity 50 %, specificity 92 %, and area under the ROC curve 0.7083 for the risk of paraneoplastic DM in anti-TIF1γ/α (+) patients. Myositis-specific autoantibodies can be identified thanks to the use of immunoprecipitation, and their association with cancer is particularly clear for anti-TIF1γ/α in dermatomyositis. This association should be evaluated in a prospective study by immunoprecipitation in clinical practice.

Immunofluorescence pattern of antinuclear antibody and its association with autoantibody profile in systemic lupus erythematosus

Directory of Open Access Journals (Sweden)

Sadia Sharmin

2016-08-01

Full Text Available Background: Antinuclear antibody (ANA is useful in the diagnosis of systemic lupus erythematosus (SLE. Association of specific autoantibodies with the immunofluorescence pattern of ANA in SLE as noted in Western literature has been taken as reference in all over the world. However, in Bangladesh such research work or data correlating the autoantibodies and their ANA patterns is inadequate. Objective: To identify an association between immunofluorescence patterns of antinuclear antibody on HEp-2 cell and more specific antinuclear reactivities (e.g. anti-dsDNA and anti-extractable nuclear antigen in the serum samples of SLE patients.Methods: Serum samples of 37 SLE patients who were diagnosed by ARA (American Rheumatism Association classification criteria and laboratory tests, attending at lupus clinic of Bangabandhu Sheikh Mujib Medical University (BSMMU during the study period of six months were subjected for ANA testing by Indirect Imrnunofluorescence (IIF on HEp-2 cell, anti-dsDNA by ELISA and anti- extractable nuclear antigen (anti-ENA by Dot Immunoblot. Dot blot strips were tested for anti-Sm, anti-RNP, anti-SSA/Ro, and anti-SSB/La. Results: Out of 37 SLE patients 32 (86.5% cases were ANA positive by IIF on HEp-2 cell. ANA positive sera exhibited three fluorescence patterns such as speckled (43.7%, peripheral (34.3% and homogenous pattern (21.8%. Peripheral pattern (100% was strongly associated with anti-dsDNA (p<0.05 and homogenous pattern (85.7% was also predominantly associated with anti-dsDNA (p<0.05. Speckled pattern (85.6% was significantly associated with anti-ENA (p<0.05. Anti-dsDNA was positive in 75% of SLE cases and majority (45.8% of which showed peripheral pattern whereas anti-ENA was positive in 48.6% cases and majority (70.5% of which showed speckled pattern. The most commonly identified antinuclear autoreactivity was directed towards anti-RNP (22.2% then anti-Sm (16.6%, anti-SSA (16.6% and anti-SSB (11.1 %. Multiple anti

Early localization of NPA58, a rat nuclear pore-associated protein, to ...

Indian Academy of Sciences (India)

Unknown

Mitotic reassembly; nuclear envelope assembly; nuclear pore complex ... A consensus model for the vertebrate NPC based on ... A mouse monoclonal antibody to PCNA (PC10) a protein associ- ated with DNA replication centres during S ...

Enhanced insight into the autoimmune component of glaucoma: IgG autoantibody accumulation and pro-inflammatory conditions in human glaucomatous retina.

Science.gov (United States)

Gramlich, Oliver W; Beck, Sabine; von Thun Und Hohenstein-Blaul, Nadine; Boehm, Nils; Ziegler, Anika; Vetter, Jan M; Pfeiffer, Norbert; Grus, Franz H

2013-01-01

There is accumulating evidence that autoimmune components, such as autoantibodies and autoantibody depositions, play a role in the pathogenesis of neurodegenerative diseases like Alzheimeŕs disease or Multiple Sclerosis. Due to alterations of autoantibody patterns in sera and aqueous humor, an autoimmune component is also assumed in the pathogenesis of glaucoma, a common reason for irreversible blindness worldwide. So far there has been no convincing evidence that autoantibodies are accumulated in the retina of glaucoma patients and that the local immune homeostasis might be affected. Six human glaucomatous donor eyes and nine samples from donors with no recorded ocular disease were included. Antibody microarrays were used to examine the patterns of pro-inflammatory proteins and complement proteins. Analysis of TNF-α and interleukin levels revealed a slight up-regulation exclusively in the glaucomatous group, while complement protein levels were not altered. IgG autoantibody accumulations and/or cellular components were determined by immunohistology (n = 4 per group). A significantly reduced number of retinal ganglion cells was found in the glaucomatous group (healthy: 104±7 nuclei/mm, glaucoma: 67±9 nuclei/mm; p = 0.0007). Cell loss was accompanied by strong retinal IgG autoantibody accumulations, which were at least twice as high as in healthy subjects (healthy: 5.0±0.5 IgG deposits/100 cells, glaucoma: 9.4±1.9 IgG deposits/100 cells; p = 0.004). CD27(+) cells and CD27(+)/IgG(+) plasma cells were observed in all glaucomatous subjects, but not in controls. This work provides serious evidence for the occurrence of IgG antibody deposition and plasma cells in human glaucomatous retina. Moreover, the results suggest that these IgG deposits occurred in a pro-inflammatory environment which seems to be maintained locally by immune-competent cells like microglia. Thereby, glaucoma features an immunological involvement comparable to other

Spectral Envelopes and Additive + Residual Analysis/Synthesis

Science.gov (United States)

Rodet, Xavier; Schwarz, Diemo

The subject of this chapter is the estimation, representation, modification, and use of spectral envelopes in the context of sinusoidal-additive-plus-residual analysis/synthesis. A spectral envelope is an amplitude-vs-frequency function, which may be obtained from the envelope of a short-time spectrum (Rodet et al., 1987; Schwarz, 1998). [Precise definitions of such an envelope and short-time spectrum (STS) are given in Section 2.] The additive-plus-residual analysis/synthesis method is based on a representation of signals in terms of a sum of time-varying sinusoids and of a non-sinusoidal residual signal [e.g., see Serra (1989), Laroche et al. (1993), McAulay and Quatieri (1995), and Ding and Qian (1997)]. Many musical sound signals may be described as a combination of a nearly periodic waveform and colored noise. The nearly periodic part of the signal can be viewed as a sum of sinusoidal components, called partials, with time-varying frequency and amplitude. Such sinusoidal components are easily observed on a spectral analysis display (Fig. 5.1) as obtained, for instance, from a discrete Fourier transform.

Preserving Envelope Efficiency in Performance Based Code Compliance

Energy Technology Data Exchange (ETDEWEB)

Thornton, Brian A. [Thornton Energy Consulting (United States); Sullivan, Greg P. [Efficiency Solutions (United States); Rosenberg, Michael I. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Baechler, Michael C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

2015-06-20

The City of Seattle 2012 Energy Code (Seattle 2014), one of the most progressive in the country, is under revision for its 2015 edition. Additionally, city personnel participate in the development of the next generation of the Washington State Energy Code and the International Energy Code. Seattle has pledged carbon neutrality by 2050 including buildings, transportation and other sectors. The United States Department of Energy (DOE), through Pacific Northwest National Laboratory (PNNL) provided technical assistance to Seattle in order to understand the implications of one potential direction for its code development, limiting trade-offs of long-lived building envelope components less stringent than the prescriptive code envelope requirements by using better-than-code but shorter-lived lighting and heating, ventilation, and air-conditioning (HVAC) components through the total building performance modeled energy compliance path. Weaker building envelopes can permanently limit building energy performance even as lighting and HVAC components are upgraded over time, because retrofitting the envelope is less likely and more expensive. Weaker building envelopes may also increase the required size, cost and complexity of HVAC systems and may adversely affect occupant comfort. This report presents the results of this technical assistance. The use of modeled energy code compliance to trade-off envelope components with shorter-lived building components is not unique to Seattle and the lessons and possible solutions described in this report have implications for other jurisdictions and energy codes.

Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study.

Science.gov (United States)

Raab, Jennifer; Haupt, Florian; Scholz, Marlon; Matzke, Claudia; Warncke, Katharina; Lange, Karin; Assfalg, Robin; Weininger, Katharina; Wittich, Susanne; Löbner, Stephanie; Beyerlein, Andreas; Nennstiel-Ratzel, Uta; Lang, Martin; Laub, Otto; Dunstheimer, Desiree; Bonifacio, Ezio; Achenbach, Peter; Winkler, Christiane; Ziegler, Anette-G

2016-05-18

Type 1 diabetes can be diagnosed at an early presymptomatic stage by the detection of islet autoantibodies. The Fr1da study aims to assess whether early staging of type 1 diabetes (1) is feasible at a population-based level, (2) prevents severe metabolic decompensation observed at the clinical manifestation of type 1 diabetes and (3) reduces psychological distress through preventive teaching and care. Children aged 2-5 years in Bavaria, Germany, will be tested for the presence of multiple islet autoantibodies. Between February 2015 and December 2016, 100 000 children will be screened by primary care paediatricians. Islet autoantibodies are measured in capillary blood samples using a multiplex three-screen ELISA. Samples with ELISA results >97.5th centile are retested using reference radiobinding assays. A venous blood sample is also obtained to confirm the autoantibody status of children with at least two autoantibodies. Children with confirmed multiple islet autoantibodies are diagnosed with pre-type 1 diabetes. These children and their parents are invited to participate in an education and counselling programme at a local diabetes centre. Depression and anxiety, and burden of early diagnosis are also assessed. Of the 1027 Bavarian paediatricians, 39.3% are participating in the study. Overall, 26 760 children have been screened between February 2015 and November 2015. Capillary blood collection was sufficient in volume for islet autoantibody detection in 99.46% of the children. The remaining 0.54% had insufficient blood volume collected. Of the 26 760 capillary samples tested, 0.39% were positive for at least two islet autoantibodies. Staging for early type 1 diabetes within a public health setting appears to be feasible. The study may set new standards for the early diagnosis of type 1 diabetes and education. The study was approved by the ethics committee of Technische Universität München (Nr. 70/14). Published by the BMJ Publishing Group Limited. For

Evaluation of classical and novel autoantibodies for the diagnosis of Primary Biliary Cholangitis-Autoimmune Hepatitis Overlap Syndrome (PBC-AIH OS).

Science.gov (United States)

Nguyen, Henry H; Shaheen, Abdel Aziz; Baeza, Natalia; Lytvyak, Ellina; Urbanski, Stefan J; Mason, Andrew L; Norman, Gary L; Fritzler, Marvin J; Swain, Mark G

2018-01-01

Up to 20% of Primary Biliary Cholangitis (PBC) patients are estimated to have features that overlap with Autoimmune Hepatitis (AIH). Patients with PBC-AIH overlap syndrome (PBC-AIH OS) have been reported to exhibit suboptimal responses to ursodeoxycholic acid therapy, and are more likely to progress to cirrhosis. Anti-double stranded DNA (anti-dsDNA) and anti-p53 have been previously suggested to be potential autoantibodies for identifying patients with PBC-AIH OS. In our well defined PBC patient cohorts, a comprehensive assessment of various classical and novel autoantibodies was evaluated for their utility in identifying PBC-AIH OS patients. PBC-AIH OS was classified according to the Paris criteria and PBC as per the European Association for the Study of the Liver guidelines. Biobanked serum samples from 197 patients at the University of Calgary Liver Unit and the University of Alberta were analyzed for classical and novel autoantibodies. Anti-dsDNA was measured by the Crithidia luciliae immunofluorescence (CLIFT) assay (1:20 dilution) and chemiluminescence (CIA: QUANTA Flash®, Inova Diagnostics, San Diego). Anti-p53, anti-Ro52/TRIM21, anti-YB 1, anti-GW182, anti-Ge-1, and anti-Ago 2 were measured by either an addressable laser bead immunoassay (ALBIA) or line immunoassay (LIA). Autoantibodies against MIT3, gp210, sp100, LKM1, SLA, and the novel autoantibodies Hexokinase-1 (HK-1), and Kelch like protein 12 (KLHL-12) were measured using QUANTA Lite® ELISA assays. We applied non-parametric methods to compare the biomarkers frequencies between study groups. We used multivariate adjusted models and AUROC to compare the diagnostic accuracy of the different autoantibodies alone or in combination with serum biochemistry. 16 out of 197 PBC patients (8.1%) were classified as PBC-AIH OS. Compared to PBC patients, PBC-AIH OS patients were similar in age (median: 59 vs. 63, P = 0.21) and female predominance (94% vs. 89%, P = 1.00). Anti-dsDNA-by CLIFT (37.5% in PBC-AIH OS

Genotoxic effect and antigen binding characteristics of SLE auto-antibodies to peroxynitrite-modified human DNA.

Science.gov (United States)

Khan, Md Asad; Alam, Khursheed; Mehdi, Syed Hassan; Rizvi, M Moshahid A

2017-12-01

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by auto-antibodies against native deoxyribonucleic acid after modification and is one of the reasons for the development of SLE. Here, we have evaluated the structural perturbations in human placental DNA by peroxynitrite using spectroscopy, thermal denaturation and high-performance liquid chromatography (HPLC). Peroxynitrite is a powerful potent bi-functional oxidative/nitrative agent that is produced both endogenously and exogenously. In experimental animals, the peroxynitrite-modified DNA was found to be highly immunogenic. The induced antibodies showed cross-reactions with different types of DNA and nitrogen bases that were modified with peroxynitrite by inhibition ELISA. The antibody activity was inhibited by approximately 89% with its immunogen as the inhibitor. The antigen-antibodies interaction between induced antibodies with peroxynitrite-modified DNA showed retarded mobility as compared to the native form. Furthermore, significantly increased binding was also observed in SLE autoantibodies with peroxynitrite-modified DNA than native form. Moreover, DNA isolated from lymphocyte of SLE patients revealed significant recognition of anti-peroxynitrite-modified DNA immunoglobulin G (IgG). Our data indicates that DNA modified with peroxynitrite presents unique antigenic determinants that may induce autoantibody response in SLE. Copyright © 2017 Elsevier Inc. All rights reserved.

DATA ENVELOPMENT ANALYSIS OF BANKING SECTOR IN BANGLADESH

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Md. Rashedul Hoque

2012-05-01

Full Text Available Banking sector of Bangladesh is flourishing and contributing to its economy. In this aspect measuring efficiency is important. Data Envelopment Analysis technique is used for this purpose. The data are collected from the annual reports of twenty four different banks in Bangladesh. Data Envelopment Analysis is mainly of two types - constant returns to scale and variable returns to scale. Since this study attempts to maximize output, so the output oriented Data Envelopment Analysis is used. The most efficient bank is one that obtains the highest efficiency score.

Early localization of NPA58, a rat nuclear pore-associated protein

Indian Academy of Sciences (India)

We have studied the mitotic reassembly of the nuclear envelope, using antibodies to nuclear marker proteins and NPA58 in F-111 rat fibroblast cells. In earlier studies we have proposed that NPA58, a 58 kDa rat nuclear protein, is involved in nuclear protein import. In this report, NPA58 is shown to be localized on the ...

Validating predictions from climate envelope models

Science.gov (United States)

Watling, J.; Bucklin, D.; Speroterra, C.; Brandt, L.; Cabal, C.; Romañach, Stephanie S.; Mazzotti, Frank J.

2013-01-01

Climate envelope models are a potentially important conservation tool, but their ability to accurately forecast species’ distributional shifts using independent survey data has not been fully evaluated. We created climate envelope models for 12 species of North American breeding birds previously shown to have experienced poleward range shifts. For each species, we evaluated three different approaches to climate envelope modeling that differed in the way they treated climate-induced range expansion and contraction, using random forests and maximum entropy modeling algorithms. All models were calibrated using occurrence data from 1967–1971 (t1) and evaluated using occurrence data from 1998–2002 (t2). Model sensitivity (the ability to correctly classify species presences) was greater using the maximum entropy algorithm than the random forest algorithm. Although sensitivity did not differ significantly among approaches, for many species, sensitivity was maximized using a hybrid approach that assumed range expansion, but not contraction, in t2. Species for which the hybrid approach resulted in the greatest improvement in sensitivity have been reported from more land cover types than species for which there was little difference in sensitivity between hybrid and dynamic approaches, suggesting that habitat generalists may be buffered somewhat against climate-induced range contractions. Specificity (the ability to correctly classify species absences) was maximized using the random forest algorithm and was lowest using the hybrid approach. Overall, our results suggest cautious optimism for the use of climate envelope models to forecast range shifts, but also underscore the importance of considering non-climate drivers of species range limits. The use of alternative climate envelope models that make different assumptions about range expansion and contraction is a new and potentially useful way to help inform our understanding of climate change effects on species.

Validating predictions from climate envelope models.

Directory of Open Access Journals (Sweden)

James I Watling

Full Text Available Climate envelope models are a potentially important conservation tool, but their ability to accurately forecast species' distributional shifts using independent survey data has not been fully evaluated. We created climate envelope models for 12 species of North American breeding birds previously shown to have experienced poleward range shifts. For each species, we evaluated three different approaches to climate envelope modeling that differed in the way they treated climate-induced range expansion and contraction, using random forests and maximum entropy modeling algorithms. All models were calibrated using occurrence data from 1967-1971 (t1 and evaluated using occurrence data from 1998-2002 (t2. Model sensitivity (the ability to correctly classify species presences was greater using the maximum entropy algorithm than the random forest algorithm. Although sensitivity did not differ significantly among approaches, for many species, sensitivity was maximized using a hybrid approach that assumed range expansion, but not contraction, in t2. Species for which the hybrid approach resulted in the greatest improvement in sensitivity have been reported from more land cover types than species for which there was little difference in sensitivity between hybrid and dynamic approaches, suggesting that habitat generalists may be buffered somewhat against climate-induced range contractions. Specificity (the ability to correctly classify species absences was maximized using the random forest algorithm and was lowest using the hybrid approach. Overall, our results suggest cautious optimism for the use of climate envelope models to forecast range shifts, but also underscore the importance of considering non-climate drivers of species range limits. The use of alternative climate envelope models that make different assumptions about range expansion and contraction is a new and potentially useful way to help inform our understanding of climate change effects on

Erionite induces production of autoantibodies and IL-17 in C57BL/6 mice

Energy Technology Data Exchange (ETDEWEB)

Zebedeo, Christian Nash; Davis, Chad [Department of Biological Sciences, Idaho State University, Pocatello, ID (United States); Peña, Cecelia [Northwest Nazarene University, Nampa, ID (United States); Ng, Kok Wei [Department of Biological Sciences, Idaho State University, Pocatello, ID (United States); Pfau, Jean C., E-mail: pfaujean@isu.edu [Department of Biological Sciences, Idaho State University, Pocatello, ID (United States)

2014-03-15

Background: Erionite has similar chemical and physical properties to amphibole asbestos, which induces autoantibodies in mice. Current exposures are occurring in North Dakota due to the use of erionite-contaminated gravel. While erionite is known to cause mesothelioma and other diseases associated with asbestos, there is little known about its effects on the immune system. Objectives: We performed this study to determine whether erionite evokes autoimmune reactions in mice. Methods: Bone marrow derived macrophages (BMDM) were used to measure toxicity induced by erionite. Cytokine production by BMDM and splenocytes of C57BL/6 mice was examined by bead arrays and ELISA following exposure to erionite, amphiboles and chrysotile. Wild type C57BL/6 mice were exposed to saline, erionite, amphibole asbestos (Libby 6-Mix) or chrysotile through intratracheal instillations at equal mass (60 μg/mouse). Seven months after exposure, sera were examined for anti-nuclear antibodies (ANA) and IL-17. Immunohistochemistry was used to detect immune complex deposition in the kidneys. Results: Erionite and tremolite caused increased cytokine production belonging to the T{sub H}17 profile including IL-17, IL-6, TGF-β, and TNF-α. The frequency of ANA was increased in mice treated with erionite or amphibole compared to saline-treated mice. IL-17 and TNF-α were elevated in the sera of mice treated with erionite. The frequency of immune complex deposition in the kidneys increased from 33% in saline-treated mice to 90% with erionite. Conclusions: These data demonstrate that both erionite and amphibole asbestos induce autoimmune responses in mice, suggesting a potential for adverse effects in exposed communities. - Highlights: • Erionite, a fibrous mineral, is a current public health concern in the western USA. • Erionite exposure induces antinuclear autoantibodies in exposed mice. • Erionite induces a clear Th17 cytokine response in vitro and in vivo. • These responses were

Erionite induces production of autoantibodies and IL-17 in C57BL/6 mice

International Nuclear Information System (INIS)

Zebedeo, Christian Nash; Davis, Chad; Peña, Cecelia; Ng, Kok Wei; Pfau, Jean C.

2014-01-01

Background: Erionite has similar chemical and physical properties to amphibole asbestos, which induces autoantibodies in mice. Current exposures are occurring in North Dakota due to the use of erionite-contaminated gravel. While erionite is known to cause mesothelioma and other diseases associated with asbestos, there is little known about its effects on the immune system. Objectives: We performed this study to determine whether erionite evokes autoimmune reactions in mice. Methods: Bone marrow derived macrophages (BMDM) were used to measure toxicity induced by erionite. Cytokine production by BMDM and splenocytes of C57BL/6 mice was examined by bead arrays and ELISA following exposure to erionite, amphiboles and chrysotile. Wild type C57BL/6 mice were exposed to saline, erionite, amphibole asbestos (Libby 6-Mix) or chrysotile through intratracheal instillations at equal mass (60 μg/mouse). Seven months after exposure, sera were examined for anti-nuclear antibodies (ANA) and IL-17. Immunohistochemistry was used to detect immune complex deposition in the kidneys. Results: Erionite and tremolite caused increased cytokine production belonging to the T H 17 profile including IL-17, IL-6, TGF-β, and TNF-α. The frequency of ANA was increased in mice treated with erionite or amphibole compared to saline-treated mice. IL-17 and TNF-α were elevated in the sera of mice treated with erionite. The frequency of immune complex deposition in the kidneys increased from 33% in saline-treated mice to 90% with erionite. Conclusions: These data demonstrate that both erionite and amphibole asbestos induce autoimmune responses in mice, suggesting a potential for adverse effects in exposed communities. - Highlights: • Erionite, a fibrous mineral, is a current public health concern in the western USA. • Erionite exposure induces antinuclear autoantibodies in exposed mice. • Erionite induces a clear Th17 cytokine response in vitro and in vivo. • These responses were distinct

Quantification of the spatial organization of the nuclear lamina as a tool for cell classification

NARCIS (Netherlands)

Righolt, C.H.; Zatreanu, D.A.; Raz, V.

2013-01-01

The nuclear lamina is the structural scaffold of the nuclear envelope that plays multiple regulatory roles in chromatin organization and gene expression as well as a structural role in nuclear stability. The lamina proteins, also referred to as lamins, determine nuclear lamina organization and

Autoantibodies against Cytochrome P450 Side-Chain Cleavage Enzyme in Dogs (Canis lupus familiaris) Affected with Hypoadrenocorticism (Addison's Disease).

Science.gov (United States)

Boag, Alisdair M; Christie, Michael R; McLaughlin, Kerry A; Syme, Harriet M; Graham, Peter; Catchpole, Brian

2015-01-01

Canine hypoadrenocorticism likely arises from immune-mediated destruction of adrenocortical tissue, leading to glucocorticoid and mineralocorticoid deficiency. In humans with autoimmune Addison's disease (AAD) or autoimmune polyendocrine syndrome (APS), circulating autoantibodies have been demonstrated against enzymes associated with adrenal steroid synthesis. The current study investigates autoantibodies against steroid synthesis enzymes in dogs with spontaneous hypoadrenocorticism. Coding regions of canine CYP21A2 (21-hydroxylase; 21-OH), CYP17A1 (17-hydroxylase; 17-OH), CYP11A1 (P450 side-chain cleavage enzyme; P450scc) and HSD3B2 (3β hydroxysteroid dehydrogenase; 3βHSD) were amplified, cloned and expressed as 35S-methionine radiolabelled recombinant protein. In a pilot study, serum samples from 20 dogs with hypoadrenocorticism and four unaffected control dogs were screened by radio-immunoprecipitation assay. There was no evidence of reactivity against 21-OH, 17-OH or 3βHSD, but five dogs with hypoadrenocorticism showed immunoreactivity to P450scc compared with controls. Serum samples were subsequently obtained from 213 dogs diagnosed with hypoadrenocorticism and 110 dogs from a hospital control population. Thirty control dogs were randomly selected to establish a threshold for antibody positivity (mean + 3 × standard deviation). Dogs with hypoadrenocorticism were more likely to be P450scc autoantibody positive than hospital controls (24% vs. 1.2%, respectively; p = 0.0016). Sex was significantly associated with the presence of P450scc autoantibodies in the case population, with 30% of females testing positive compared with 17% of males (p = 0.037). Significant associations with breed (p = 0.015) and DLA-type (DQA1*006:01 allele; p = 0.017) were also found. This cross-sectional study indicates that P450scc autoantibodies are present in a proportion of dogs affected with hypoadrenocorticism.

Autoantibodies against Cytochrome P450 Side-Chain Cleavage Enzyme in Dogs (Canis lupus familiaris Affected with Hypoadrenocorticism (Addison's Disease.

Directory of Open Access Journals (Sweden)

Alisdair M Boag

Full Text Available Canine hypoadrenocorticism likely arises from immune-mediated destruction of adrenocortical tissue, leading to glucocorticoid and mineralocorticoid deficiency. In humans with autoimmune Addison's disease (AAD or autoimmune polyendocrine syndrome (APS, circulating autoantibodies have been demonstrated against enzymes associated with adrenal steroid synthesis. The current study investigates autoantibodies against steroid synthesis enzymes in dogs with spontaneous hypoadrenocorticism. Coding regions of canine CYP21A2 (21-hydroxylase; 21-OH, CYP17A1 (17-hydroxylase; 17-OH, CYP11A1 (P450 side-chain cleavage enzyme; P450scc and HSD3B2 (3β hydroxysteroid dehydrogenase; 3βHSD were amplified, cloned and expressed as 35S-methionine radiolabelled recombinant protein. In a pilot study, serum samples from 20 dogs with hypoadrenocorticism and four unaffected control dogs were screened by radio-immunoprecipitation assay. There was no evidence of reactivity against 21-OH, 17-OH or 3βHSD, but five dogs with hypoadrenocorticism showed immunoreactivity to P450scc compared with controls. Serum samples were subsequently obtained from 213 dogs diagnosed with hypoadrenocorticism and 110 dogs from a hospital control population. Thirty control dogs were randomly selected to establish a threshold for antibody positivity (mean + 3 × standard deviation. Dogs with hypoadrenocorticism were more likely to be P450scc autoantibody positive than hospital controls (24% vs. 1.2%, respectively; p = 0.0016. Sex was significantly associated with the presence of P450scc autoantibodies in the case population, with 30% of females testing positive compared with 17% of males (p = 0.037. Significant associations with breed (p = 0.015 and DLA-type (DQA1*006:01 allele; p = 0.017 were also found. This cross-sectional study indicates that P450scc autoantibodies are present in a proportion of dogs affected with hypoadrenocorticism.

Original paper Prevalence of selected organ-specific autoantibodies in rheumatoid arthritis and primary Sjögren’s syndrome patients

Directory of Open Access Journals (Sweden)

Arkadiusz Koszarny

2015-05-01

Full Text Available Objectives : The aim of the study was to investigate the prevalence of selected organ-specific autoantibodies in rheumatoid arthritis (RA and primary Sjögren’s syndrome (pSS patients, and discuss their clinical significance. Material and methods : The study included 121 RA and 30 pSS patients. Sera were tested for the presence of autoantibodies to thyroid peroxidase (anti-TPO, thyroglobulin (anti-TG, TSH receptor (TRAbs, mitochondrial antigen M2 (AMA-M2-3E and gliadin-analogous fusion peptides (anti-GAF(3X using the ELISA method. Non-organ-specific antibodies were determined: rheumatoid factor in IgM class, anti-citrullinated peptide antibodies and antinuclear antibodies. The occurrence of antibodies was also examined with regards to RA activity. Results : The following autoantibodies were detected in RA patients: anti-TPO – 13 (10.7%, anti-TG – 6 (5%, AMA-M2-3E – 3 (2.5%, anti-GAF(3X – 5 (4.1%. The respective levels of these autoantibodies in pSS patients were 3 (10%, 2 (6.7%, 4 (13.3% and 2 (6.7%. Polyautoimmunity was confirmed in 34 RA patients (including 20 cases of autoimmune thyroid disease [AITD] and in 6 pSS patients (6 cases of AITD. When RA patients were divided into anti-TPO positive and anti-TPO negative groups, we found a statistically significant relationship between groups regarding age and hemoglobin concentration. In pSS patients the anti-TPO positive group was less likely to use immunosuppressive drugs as compared with the anti-TPO negative group. Anti-TPO was significantly more frequently detected in RA + AITD vs. RA, RA + SS + AITD vs. RA and in pSS + AITD vs. pSS patients. Conclusions : Organ-specific autoantibodies are relatively frequently observed in patients with RA and pSS. Their presence is connected with the clinical picture of the diseases.

Transparent ceramic lamp envelope materials

Energy Technology Data Exchange (ETDEWEB)

Wei, G C [OSRAM SYLVANIA, 71 Cherry Hill Drive, Beverly, MA 01915 (United States)

2005-09-07

Transparent ceramic materials with optical qualities comparable to single crystals of similar compositions have been developed in recent years, as a result of the improved understanding of powder-processing-fabrication- sintering-property inter-relationships. These high-temperature materials with a range of thermal and mechanical properties are candidate envelopes for focused-beam, short-arc lamps containing various fills operating at temperatures higher than quartz. This paper reviews the composition, structure and properties of transparent ceramic lamp envelope materials including sapphire, small-grained polycrystalline alumina, aluminium oxynitride, yttrium aluminate garnet, magnesium aluminate spinel and yttria-lanthana. A satisfactory thermal shock resistance is required for the ceramic tube to withstand the rapid heating and cooling cycles encountered in lamps. Thermophysical properties, along with the geometry, size and thickness of a transparent ceramic tube, are important parameters in the assessment of its resistance to fracture arising from thermal stresses in lamps during service. The corrosive nature of lamp-fill liquid and vapour at high temperatures requires that all lamp components be carefully chosen to meet the target life. The wide range of new transparent ceramics represents flexibility in pushing the limit of envelope materials for improved beamer lamps.

Gravitational Waves from Accreting Neutron Stars Undergoing Common-envelope Inspiral

Science.gov (United States)

Holgado, A. Miguel; Ricker, Paul M.; Huerta, E. A.

2018-04-01

The common-envelope phase is a likely formation channel for close binary systems containing compact objects. Neutron stars in common envelopes accrete at a fraction of the Bondi–Hoyle–Lyttleton accretion rate, since the stellar envelope is inhomogeneous, but they may still be able to accrete at hypercritical rates (though not enough to become black holes). We show that common-envelope systems consisting of a neutron star with a massive primary may be gravitational-wave (GW) sources detectable in the Advanced LIGO band as far away as the Magellanic Clouds. To characterize their evolution, we perform orbital integrations using 1D models of 12 M ⊙ and 20 M ⊙ primaries, considering the effects of density gradient on the accretion onto the NS and spin evolution. From the range of possible accretion rates relevant to common-envelope evolution, we find that these systems may be louder GW sources than low-mass X-ray binaries like Sco X-1, which are currently the target of directed searches for continuous GWs. We also find that their strain amplitude signal may allow for novel constraints on the orbital separation and inspiral timescale in common envelopes when combined with pre-common-envelope electromagnetic observations.

Autoantibody signatures as biomarkers to distinguish prostate cancer from benign prostatic hyperplasia in patients with increased serum prostate specific antigen.

Science.gov (United States)

O'Rourke, Dennis J; DiJohnson, Daniel A; Caiazzo, Robert J; Nelson, James C; Ure, David; O'Leary, Michael P; Richie, Jerome P; Liu, Brian C-S

2012-03-22

Serum prostate specific antigen (PSA) concentrations lack the specificity to differentiate prostate cancer from benign prostate hyperplasia (BPH), resulting in unnecessary biopsies. We identified 5 autoantibody signatures to specific cancer targets which might be able to differentiate prostate cancer from BPH in patients with increased serum PSA. To identify autoantibody signatures as biomarkers, a native antigen reverse capture microarray platform was used. Briefly, well-characterized monoclonal antibodies were arrayed onto nanoparticle slides to capture native antigens from prostate cancer cells. Prostate cancer patient serum samples (n=41) and BPH patient samples (collected starting at the time of initial diagnosis) with a mean follow-up of 6.56 y without the diagnosis of cancer (n=39) were obtained. One hundred micrograms of IgGs were purified and labeled with a Cy3 dye and incubated on the arrays. The arrays were scanned for fluorescence and the intensity was quantified. Receiver operating characteristic curves were produced and the area under the curve (AUC) was determined. Using our microarray platform, we identified autoantibody signatures capable of distinguishing between prostate cancer and BPH. The top 5 autoantibody signatures were TARDBP, TLN1, PARK7, LEDGF/PSIP1, and CALD1. Combining these signatures resulted in an AUC of 0.95 (sensitivity of 95% at 80% specificity) compared to AUC of 0.5 for serum concentration PSA (sensitivity of 12.2% at 80% specificity). Our preliminary results showed that we were able to identify specific autoantibody signatures that can differentiate prostate cancer from BPH, and may result in the reduction of unnecessary biopsies in patients with increased serum PSA. Copyright © 2011 Elsevier B.V. All rights reserved.

Muscle ischaemia associated with NXP2 autoantibodies: a severe subtype of juvenile dermatomyositis.

Science.gov (United States)

Aouizerate, Jessie; De Antonio, Marie; Bader-Meunier, Brigitte; Barnerias, Christine; Bodemer, Christine; Isapof, Arnaud; Quartier, Pierre; Melki, Isabelle; Charuel, Jean-Luc; Bassez, Guillaume; Desguerre, Isabelle; Gherardi, Romain K; Authier, François-Jérôme; Gitiaux, Cyril

2018-05-01

Myositis-specific autoantibodies (MSAs) are increasingly used to delineate distinct subgroups of JDM. The aim of our study was to explore without a priori hypotheses whether MSAs are associated with distinct clinical-pathological changes and severity in a monocentric JDM cohort. Clinical, biological and histological findings from 23 JDM patients were assessed. Twenty-six histopathological parameters were subjected to multivariate analysis. Autoantibodies included anti-NXP2 (9/23), anti-TIF1γ (4/23), anti-MDA5 (2/23), no MSAs (8/23). Multivariate analysis yielded two histopathological clusters. Cluster 1 (n = 11) showed a more severe and ischaemic pattern than cluster 2 (n = 12) assessed by: total score severity ⩾ 20 (100.0% vs 25.0%); visual analogic score ⩾6 (100.0% vs 25.0%); the vascular domain score >1 (100.0% vs 41.7%); microinfarcts (100% vs 58.3%); ischaemic myofibrillary loss (focal punched-out vacuoles) (90.9 vs 25%); and obvious capillary loss (81.8% vs 16.7). Compared with cluster 2, patients in cluster 1 had strikingly more often anti-NXP2 antibodies (7/11 vs 2/12), more pronounced muscle weakness, more gastrointestinal involvement and required more aggressive treatment. Furthermore, patients with anti-NXP2 antibodies, mostly assigned in the first cluster, also displayed more severe muscular disease, requiring more aggressive treatment and having a lower remission rate during the follow-up period. Marked muscle ischaemic involvement and the presence of anti-NXP2 autoantibodies are associated with more severe forms of JDM.

Novel Real-Time Flight Envelope Monitoring System, Phase II

Data.gov (United States)

National Aeronautics and Space Administration — The proposed innovation is an aircraft flight envelope monitoring system that will provide real-time in-cockpit estimations of aircraft flight envelope boundaries....

Pre-paid envelopes commemorating the 2013 Open Days

CERN Multimedia

2013-01-01

The post office on CERN's Prévessin site is still selling pre-paid envelopes commemorating the 2013 Open Days. Hurry while stocks last!   The special envelopes, which are valid in France for non-priority letters weighing up to 20 grams, are ideal for your Christmas and New Year correspondence. A set of ten envelopes, each featuring a different image, costs € 8.70 or 10 CHF. The post office is located in Building 866 on the Prévessin site and is open Mondays to Thursdays from 9.30 a.m. to 12.30 p.m.

Use of Autoantibodies to Detect the Onset of Breast Cancer

Directory of Open Access Journals (Sweden)

Jérôme Lacombe

2014-01-01

Full Text Available The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, particularly for in situ carcinoma and early-stage breast cancer. However, the majority of women with abnormalities noted on screening mammograms are not diagnosed with cancer because of several factors, including radiologist assessment, patient age, breast density, malpractice concerns, and quality control procedures. Although magnetic resonance imaging is a highly sensitive detection tool that has become standard for women at very high risk of developing breast cancer, it lacks sufficient specificity and costeffectiveness for use as a general screening tool. Therefore, there is an important need to improve screening and diagnosis of early-invasive and noninvasive tumors, that is, in situ carcinoma. The great potential for molecular tools to improve breast cancer outcomes based on early diagnosis has driven the search for diagnostic biomarkers. Identification of tumor-specific markers capable of eliciting an immune response in the early stages of tumor development seems to provide an effective approach for early diagnosis. The aim of this review is to describe several autoantibodies identified during breast cancer diagnosis. We will focus on these molecules highlighted in the past two years and discuss the potential future use of autoantibodies as biomarkers of early-stage breast cancer.

Managing nuclear safety at Point Lepreau

Energy Technology Data Exchange (ETDEWEB)

Paciga, J [New Brunswick Power, Point Lepreau NGS, PQ (Canada)

1997-12-01

Managing nuclear safety at Point Lepreau nuclear power plant is described, including technical issues (station aging, definition of the safe operating envelope, design configuration management, code validation, safety analysis and engineering standards); regulatory issues (action items, probabilistic safety assessment, event investigation, periodic safety review, prioritization of regulatory issues, cost benefit assessment); human performance issues (goals and measures, expectations and accountability, supervisory training, safety culture, configuration management, quality of operations and maintenance).

Managing nuclear safety at Point Lepreau

International Nuclear Information System (INIS)

Paciga, J.

1997-01-01

Managing nuclear safety at Point Lepreau nuclear power plant is described, including technical issues (station aging, definition of the safe operating envelope, design configuration management, code validation, safety analysis and engineering standards); regulatory issues (action items, probabilistic safety assessment, event investigation, periodic safety review, prioritization of regulatory issues, cost benefit assessment); human performance issues (goals and measures, expectations and accountability, supervisory training, safety culture, configuration management, quality of operations and maintenance)

Combining EL4-B5-based B-cell stimulation and phage display technology for the successful isolation of human anti-Scl-70 autoantibody fragments.

Science.gov (United States)

Weber, Malte; Weiss, Etienne; Engel, Alfred M

2003-07-01

Scl-70 is the major antigen recognised by autoantibodies in the sera of patients with systemic sclerosis (SSc). The autoantibodies that specifically react with Scl-70 are highly characteristic of the disease and represent valuable markers for the diagnosis of SSc. We describe a novel strategy for cloning autoantibody fragments starting with a small blood sample from an SSc patient. B cells isolated from the collected peripheral blood mononuclear cells (PBMCs) were cultured in vitro using the EL4-B5 system. Anti-Scl-70 IgG-producing cells were pooled for RNA preparation followed by the generation of phagemid libraries of approximately 10(7) independent single-chain Fvs (scFvs). The screening of these libraries by phage display allowed us to isolate four anti-Scl-70 scFvs following three rounds of biopanning. About 10 times more starting blood material was needed to generate scFv libraries of similar size from PBMCs of an SSc patient and only two anti-Scl-70 scFvs were isolated after three rounds of phage selection. Together, this work shows that functional autoantibody fragments can be advantageously cloned after in vitro expansion of B cells. The isolated anti-Scl-70 autoantibody fragments represent useful tools for calibrating SSc diagnostic assays.

No neuronal autoantibodies detected in plasma of patients with a bipolar I disorder

NARCIS (Netherlands)

Snijders, Gijsje; Titulaer, Maarten J.; Bergink, Veerle; Bastiaansen, Anna E.; Schreurs, Marco W.J.; Ophoff, Roel A.; Boks, Marco P.; Kahn, René S.; de Witte, Lot D.

2018-01-01

A subpopulation of patients with bipolar disorder type I (BD-I) might suffer from undiagnosed autoimmune encephalitis. We tested plasma of 104 BD-I patients with a current or recent manic episode in the past 2 years for the presence of neuronal autoantibodies using immunohistochemistry,

Natural autoantibodies in Bos taurus calves during the first twelve weeks of life

NARCIS (Netherlands)

Mayasari, N.; Knegsel, van A.T.M.; Vries Reilingh, de G.; Kemp, B.; Parmentier, H.K.

2016-01-01

Natural autoantibodies (NAAb) have a role in maintaining physiological homeostasis and prevention of infections, and have been found in mammalian species tested so far. Albeit NAAb levels rise with age, little is known about the origin, function, regulation and initiation of NAAb in young

Decrease in TSH Receptor Autoantibodies during Antithyroid Treatment

DEFF Research Database (Denmark)

Christensen, Niels Juel; Habekost, Gurli; Bratholm, Palle

2011-01-01

We have previously shown that a long noncoding RNA transcript Heg is negatively correlated with TSH receptor autoantibodies (TRAb) in patients with untreated Graves' disease and with CD14 mRNA in treated patients and controls. Thus patients with high concentrations of Heg RNA have low levels...... of TRAb or CD14 mRNA, respectively. Here we show that an additional factor, gene expression of Cdk1 in mononuclear cells, is positively related to concentrations of TRAb in patients with untreated Graves' disease. Cdk1 mRNA is very important for regulation of cell cycle activity. It is well known...

Global Envelope Tests for Spatial Processes

DEFF Research Database (Denmark)

Myllymäki, Mari; Mrkvička, Tomáš; Grabarnik, Pavel

2017-01-01

Envelope tests are a popular tool in spatial statistics, where they are used in goodness-of-fit testing. These tests graphically compare an empirical function T(r) with its simulated counterparts from the null model. However, the type I error probability α is conventionally controlled for a fixed d......) the construction of envelopes for a deviation test. These new tests allow the a priori selection of the global α and they yield p-values. We illustrate these tests using simulated and real point pattern data....

Global envelope tests for spatial processes

DEFF Research Database (Denmark)

Myllymäki, Mari; Mrkvička, Tomáš; Grabarnik, Pavel

Envelope tests are a popular tool in spatial statistics, where they are used in goodness-of-fit testing. These tests graphically compare an empirical function T(r) with its simulated counterparts from the null model. However, the type I error probability α is conventionally controlled for a fixed......) the construction of envelopes for a deviation test. These new tests allow the a priori selection of the global α and they yield p-values. We illustrate these tests using simulated and real point pattern data....

Characteristics between the meshing pairs with different envelope profile in single screw compressors