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  1. John Adams' essential tremor.

    PubMed

    Louis, Elan D; Kavanagh, Patricia

    2005-12-01

    John Adams (1735-1826), one of the signers of the Declaration of Independence, was the second President of the United States. Adams had tremor for many years, about which little has been written. We examined John Adams' penmanship over a 62-year period and studied his correspondence and diaries. It is not clear when Adams' tremor began, although in a diary entry dated 6 December 1760, when Adams was 25 years old, there is evidence of low-amplitude kinetic tremor. The tremor continued in his written correspondence, becoming more persistent over time. Later in life, the clarity of his written correspondence diminished, with greater decomposition of characters and a reduction in the size of individual characters. This finding raises some speculation as to whether Adams could have been developing some parkinsonism, although the evidence in favor of this is not compelling. The most likely diagnosis was essential tremor.

  2. The ADAMS interactive interpreter

    SciTech Connect

    Rietscha, E.R.

    1990-12-17

    The ADAMS (Advanced DAta Management System) project is exploring next generation database technology. Database management does not follow the usual programming paradigm. Instead, the database dictionary provides an additional name space environment that should be interactively created and tested before writing application code. This document describes the implementation and operation of the ADAMS Interpreter, an interactive interface to the ADAMS data dictionary and runtime system. The Interpreter executes individual statements of the ADAMS Interface Language, providing a fast, interactive mechanism to define and access persistent databases. 5 refs.

  3. ADAM function in embryogenesis

    PubMed Central

    Alfandari, Dominique; McCusker, Catherine; Cousin, Hélène

    2009-01-01

    Cleavage of proteins inserted into the plasma membrane (shedding) is an essential process controlling many biological functions including cell signaling, cell adhesion and migration as well as proliferation and differentiation. ADAM surface metalloproteases have been shown to play an essential role in these processes. Gene inactivation during embryonic development have provided evidence of the central role of ADAM proteins in nematodes, flies, frogs, birds and mammals. The relative contribution of four subfamilies of ADAM proteins to developmental processes is the focus of this review. PMID:18935966

  4. Ansel Adams: early works

    NASA Astrophysics Data System (ADS)

    Throckmorton, Jodi

    2010-02-01

    Ansel Adams (1902-1984), photographer, musician, naturalist, explorer, critic, and teacher, was a giant in the field of landscape photography. In his images of the unspoiled Western landscape, he strove to capture the sublime: the transcendentalist concept that nature can generate the experience of awe for the viewer. Many viewers are familiar with the heroic, high-contrast prints on high-gloss paper that Adams made to order beginning in the 1970s; much less well known are the intimate prints that the artist crafted earlier in his career. This exhibition focuses on these masterful small prints from the 1920s into the 1950s. During this time period, Adams's printing style changed dramatically. The painterly, soft-focus, warm-toned style of the Parmelian Prints of the High Sierras from the 1920s evolved into the sharp-focus style of the f/64 school of photography that Adams co-founded in the 1930s with Edward Weston and Imogen Cunningham. After World War II, Adams opted for a cooler, higher-contrast look for his prints. Throughout the various styles in which he chose to work, Adams explored the power of nature and succeeded in establishing landscape photography as a legitimate form of modern art.

  5. Proceedings of the 1989 ADAM Workshop

    NASA Astrophysics Data System (ADS)

    Chipperfield, Alan

    ADAM is now a major software project; it provides a fully integrated environment for both data reduction and data acquisition. It is being used in Hawaii, Australia and the Canary Islands, as well as the UK, and has been adopted by Starlink as the environment in which Starlink data reduction software should run. One of the most remarkable things about ADAM is that it has been developed as a co-operative effort between groups that are spread across the world. Although the initial system came out of RGO, and ROE provided by far the major effort in designing and implementing the VAX version, various parts of what is now regarded as 'ADAM' have also come from other establishments. Co-ordinating a project being developed in this way is not an easy job, but the somewhat varied parentage of ADAM - although sometimes an administrative nightmare - is also one of its strengths; it is not a system developed in one place to serve the specific needs of that one place. One way in which this development is co-ordinated is by a series of workshops. These have taken place at about 18 month intervals since the first one in late 1985. The workshops are attended by people actively developing and/or making extensive use of ADAM, and provide a forum for detailed discussion of the problems in the current system and plans for its extension. The 1989 ADAM Workshop was held at Cosener's House, Abingdon from 3rd to 7th July 1989. An 'Open Meeting' was held on Friday 30th June at RAL to enable members of the Starlink community to provide input to the Workshop discussions. Before the previous workshop, in Hawaii, a trend had started to emerge for different establishments to plug the gaps in ADAM (which at the time was missing a number of important facilities) with local solutions. The Hawaii Workshop consolidated these local extensions, adopting some and rejecting others. As a result, ADAM, as reviewed by this third workshop, was a much more complete and uniform system, and it was possible to

  6. The ADAM workshops and meeting summary

    NASA Astrophysics Data System (ADS)

    Chipperfield, Alan J.

    1990-01-01

    ADAM is now a major software project; it provides a fully integrated environment for both data reduction and data acquisition. It is being used in Hawaii, Australia and the Canary Islands, as well as the UK, and has been adopted by Starlink as the environment in which Starlink data reduction software should run. One of the most remarkable things about ADAM is that it has been developed as a co-operative effort between groups that are spread across the world. Although the initial system came out of RGO, and ROE provided by far the major effort in designing and implementing the VAX version, various parts of what is now regarded as 'ADAM' have also come from other establishments. Co-ordinating a project being developed in this way is not an easy job, but the somewhat varied parentage of ADAM - although sometimes an administrative nightmare - is also one of its strengths; it is not a system developed in one place to serve the specific needs of that one place. One way in which this development is co-ordinated is by a series of workshops. These have taken place at about 18 month intervals since the first one in late 1985. The workshops are attended by people actively developing and/or making extensive use of ADAM, and provide a forum for detailed discussion of the problems in the current system and plans for its extension. The 1989 ADAM Workshop was held at Cosener's House, Abingdon from 3rd to 7th July 1989. An 'Open Meeting' was held on Friday 30th June at RAL to enable members of the Starlink community to provide input to the Workshop discussions. Before the previous workshop, in Hawaii, a trend had started to emerge for different establishments to plug the gaps in ADAM (which at the time was missing a number of important facilities) with local solutions. The Hawaii Workshop consolidated these local extensions, adopting some and rejecting others. As a result, ADAM, as reviewed by this third workshop, was a much more complete and uniform system, and it was possible to

  7. ADAM -- Interface Module Reference Manual

    NASA Astrophysics Data System (ADS)

    Chipperfield, A. J.; Kelly, B. D.; Wright, S. L.

    ADAM Interface Modules provide an interface between ADAM application programs and the rest of the system. This document describes in detail the facilities available with ADAM Interface Modules and the rules for using them. It is intended as a reference manual and should shed light on some of the finer points of the ADAM parameter system. Readers requiring an introduction to Interface Modules should read SG/4.

  8. Was Adam a Real Person?

    ERIC Educational Resources Information Center

    Lamoureux, Denis O.

    2011-01-01

    Belief in the historicity of Adam has been held firmly throughout the history of the church. In the light of modern biblical criticism and the evolutionary sciences, some conservative Christians are now questioning whether or not Adam was a real person. This paper argues that the existence of Adam in the opening chapters of scripture reflects an…

  9. All about Adam.

    ERIC Educational Resources Information Center

    Bradley, Ann

    1992-01-01

    Rochester Teachers Association President Adam Urbanski is kingpin of a new breed of union leaders who want to be partners, not adversaries, in the school improvement crusade. Despite his good intentions, many people in his hometown are disgruntled with him. The article describes his work over the past five years. (SM)

  10. The Adams Family

    ERIC Educational Resources Information Center

    Douven, Igor; Verbrugge, Sara

    2010-01-01

    According to Adams's Thesis, the acceptability of an indicative conditional sentence goes by the conditional probability of its consequent given its antecedent. We test, for the first time, whether this thesis is descriptively correct and show that it is not; in particular, we show that it yields the wrong predictions for people's judgments of the…

  11. Adams v. State.

    PubMed

    1998-01-01

    The Supreme Court of Georgia, on 4 May 1998, held that a state statute permitting a crime victim who is significantly exposed to HIV request an HIV blood test on the person charged with the crime and arrested does not violate the Fourth Amendment right against unreasonable searches, nor does it violate privacy or equal protection rights. Malik Adams attacked and struggled with police officers during arrest. In the struggle, Adams's and an officer's hands, on which there were bleeding wounds, came in contact. Even though Adams did not have any outward AIDS symptoms, the State filed a motion to compel HIV testing. The Supreme Court of Georgia held that, because the statute compelling HIV testing serves the compelling state interest of preventing the public's exposure to HIV, the search, in this case the taking and sampling of blood, was reasonable. The statute also did not violate Adams's right to privacy or state or federal equal protection clauses. The judgment of the Superior court was affirmed.

  12. Adams v. State.

    PubMed

    1998-01-01

    Court Decision: 498 South Eastern Reporter, 2d Series 268; 1998 May 4 (date of decision). The Supreme Court of Georgia held that a state statute permitting a crime victim who is significantly exposed to HIV request an HIV blood test on the person charged with the crime and arrested does not violate the Fourth Amendment right against unreasonable searches, nor does it violate privacy or equal protection rights. Malik Adams attacked and struggled with police officers during arrest. In the struggle, Adams's and an officer's hands, on which there were bleeding wounds, came in contact. Even though Adams did not have any outward AIDS symptoms, the State filed a motion to compel HIV testing. The Supreme Court of Georgia held that, because the statute compelling HIV testing serves the compelling state interest of preventing the public's exposure to HIV, the search, in this case the taking and sampling of blood, was reasonable. The statute also did not violate Adams's right to privacy or state or federal equal protection clauses.

  13. Simple, Scalable, Script-based, Science Processor for Measurements - Data Mining Edition (S4PM-DME)

    NASA Astrophysics Data System (ADS)

    Pham, L. B.; Eng, E. K.; Lynnes, C. S.; Berrick, S. W.; Vollmer, B. E.

    2005-12-01

    The S4PM-DME is the Goddard Earth Sciences Distributed Active Archive Center's (GES DAAC) web-based data mining environment. The S4PM-DME replaces the Near-line Archive Data Mining (NADM) system with a better web environment and a richer set of production rules. S4PM-DME enables registered users to submit and execute custom data mining algorithms. The S4PM-DME system uses the GES DAAC developed Simple Scalable Script-based Science Processor for Measurements (S4PM) to automate tasks and perform the actual data processing. A web interface allows the user to access the S4PM-DME system. The user first develops personalized data mining algorithm on his/her home platform and then uploads them to the S4PM-DME system. Algorithms in C and FORTRAN languages are currently supported. The user developed algorithm is automatically audited for any potential security problems before it is installed within the S4PM-DME system and made available to the user. Once the algorithm has been installed the user can promote the algorithm to the "operational" environment. From here the user can search and order the data available in the GES DAAC archive for his/her science algorithm. The user can also set up a processing subscription. The subscription will automatically process new data as it becomes available in the GES DAAC archive. The generated mined data products are then made available for FTP pickup. The benefits of using S4PM-DME are 1) to decrease the downloading time it typically takes a user to transfer the GES DAAC data to his/her system thus off-load the heavy network traffic, 2) to free-up the load on their system, and last 3) to utilize the rich and abundance ocean, atmosphere data from the MODIS and AIRS instruments available from the GES DAAC.

  14. New Mathematical Dimensions: Adam's Story

    ERIC Educational Resources Information Center

    Manizade, Agida

    2009-01-01

    Adam, an 11th grader, was identified as gifted and accepted into a two week summer enrichment program. He signed up for "Geometry with Flash Programming." He had no prior programming experience but had a strong and healthy self-image as mathematics student. Although Adam had a positive attitude toward mathematics and saw himself as a successful…

  15. The Adams family.

    PubMed

    Douven, Igor; Verbrugge, Sara

    2010-12-01

    According to Adams's Thesis, the acceptability of an indicative conditional sentence goes by the conditional probability of its consequent given its antecedent. We test, for the first time, whether this thesis is descriptively correct and show that it is not; in particular, we show that it yields the wrong predictions for people's judgments of the acceptability of important subclasses of the class of inferential conditionals. Experimental results are presented that reveal an interaction effect between, on the one hand, the type of inferential connection between a conditional's antecedent and its consequent and, on the other, the judged acceptability of the conditional in relation to the conditional probability of its consequent given its antecedent. Specifically, these results suggest a family of theses, each pertaining to a different type of conditional, about how conditionals relate to the relevant conditional probabilities.

  16. John Adams - an outstanding career.

    PubMed

    Lewin, David

    2016-12-07

    A distinguished nurse, teacher, researcher and historian, John Adams was educated at Aylesbury Grammar School and graduated from Selwyn College, Cambridge, with a degree in theological and religious studies.

  17. Evolution of Vertebrate Adam Genes; Duplication of Testicular Adams from Ancient Adam9/9-like Loci

    PubMed Central

    Wei, Shuo

    2015-01-01

    Members of the disintegrin metalloproteinase (ADAM) family have important functions in regulating cell-cell and cell-matrix interactions as well as cell signaling. There are two major types of ADAMs: the somatic ADAMs (sADAMs) that have a significant presence in somatic tissues, and the testicular ADAMs (tADAMs) that are expressed predominantly in the testis. Genes encoding tADAMs can be further divided into two groups: group I (intronless) and group II (intron-containing). To date, tAdams have only been reported in placental mammals, and their evolutionary origin and relationship to sAdams remain largely unknown. Using phylogenetic and syntenic tools, we analyzed the Adam genes in various vertebrates ranging from fishes to placental mammals. Our analyses reveal duplication and loss of some sAdams in certain vertebrate species. In particular, there exists an Adam9-like gene in non-mammalian vertebrates but not mammals. We also identified putative group I and group II tAdams in all amniote species that have been examined. These tAdam homologues are more closely related to Adams 9 and 9-like than to other sAdams. In all amniote species examined, group II tAdams lie in close vicinity to Adam9 and hence likely arose from tandem duplication, whereas group I tAdams likely originated through retroposition because of their lack of introns. Clusters of multiple group I tAdams are also common, suggesting tandem duplication after retroposition. Therefore, Adam9/9-like and some of the derived tAdam loci are likely preferred targets for tandem duplication and/or retroposition. Consistent with this hypothesis, we identified a young retroposed gene that duplicated recently from Adam9 in the opossum. As a result of gene duplication, some tAdams were pseudogenized in certain species, whereas others acquired new expression patterns and functions. The rapid duplication of Adam genes has a major contribution to the diversity of ADAMs in various vertebrate species. PMID:26308360

  18. Evolution of Vertebrate Adam Genes; Duplication of Testicular Adams from Ancient Adam9/9-like Loci.

    PubMed

    Bahudhanapati, Harinath; Bhattacharya, Shashwati; Wei, Shuo

    2015-01-01

    Members of the disintegrin metalloproteinase (ADAM) family have important functions in regulating cell-cell and cell-matrix interactions as well as cell signaling. There are two major types of ADAMs: the somatic ADAMs (sADAMs) that have a significant presence in somatic tissues, and the testicular ADAMs (tADAMs) that are expressed predominantly in the testis. Genes encoding tADAMs can be further divided into two groups: group I (intronless) and group II (intron-containing). To date, tAdams have only been reported in placental mammals, and their evolutionary origin and relationship to sAdams remain largely unknown. Using phylogenetic and syntenic tools, we analyzed the Adam genes in various vertebrates ranging from fishes to placental mammals. Our analyses reveal duplication and loss of some sAdams in certain vertebrate species. In particular, there exists an Adam9-like gene in non-mammalian vertebrates but not mammals. We also identified putative group I and group II tAdams in all amniote species that have been examined. These tAdam homologues are more closely related to Adams 9 and 9-like than to other sAdams. In all amniote species examined, group II tAdams lie in close vicinity to Adam9 and hence likely arose from tandem duplication, whereas group I tAdams likely originated through retroposition because of their lack of introns. Clusters of multiple group I tAdams are also common, suggesting tandem duplication after retroposition. Therefore, Adam9/9-like and some of the derived tAdam loci are likely preferred targets for tandem duplication and/or retroposition. Consistent with this hypothesis, we identified a young retroposed gene that duplicated recently from Adam9 in the opossum. As a result of gene duplication, some tAdams were pseudogenized in certain species, whereas others acquired new expression patterns and functions. The rapid duplication of Adam genes has a major contribution to the diversity of ADAMs in various vertebrate species.

  19. Adam Smith on population.

    PubMed

    Spengler, J J

    1970-11-01

    Abstract Adam Smith dealt with questions of population mainly in his Wealth of Nations. His discussion falls roughly under five heads and reflects in considerable measure his image of the English economy. (1) A country's population capacity, given the average level of consumption, was conditioned by the stock of land, the skill with which it was cultivated, and the degree to which division of labour could be increased and thereby augment output for domestic use and sale in external markets. (2) Growth of population was essentially in response to growth of the demand for labour and served to increase division of labour. (3) The social mechanisms underlying elevation of the scale of living are touched upon, and in an optimistic spirit. (4) The distribution of a country's population responded to its progress in opulence, with the rate of this progress conditioned by the degree to which inappropriate (e.g. mercantilist) policies were avoided. (5) Smith dealt briefly with such matters as colonies, education, size of economy, environmental influences, and public policy, all of which he recognized as significant for the quantity and quality of a country's numbers.

  20. Adam Smith and dependency.

    PubMed

    Ozler, Sule

    2012-06-01

    The focus of this paper is the works and life of Adam Smith, who is widely recognized as the father and founder of contemporary economics. Latent content analysis is applied to his seminal text in economics, An Inquiry into the Nature and Causes of the Wealth of Nations (1776). The results reveal that Smith considers dependence on others a problem and sees the solution to this problem in impersonalized interdependence. In addition, his views on social dependency and personal dependency, reflected in his Lectures on Jurisprudence (1963) and The Theory of Moral Sentiments (1759), are analyzed. This analysis suggests a central tension between dependence and independence in Smith's writings. The personal dependency patterns he exhibited in his life, which also suggest a tension between dependence and independence, are identified through a reading of his biographies. Based on insights from psychoanalytic literature, this paper proposes that developing the ideas in the Wealth of Nations was part of Smith's creative solution to this tension. In particular, his solution to one individual's dependence on another was through a system of impersonalized interdependence. In other words, Smith defended against his personal dependence through his economic theorizing.

  1. ADAM12 — EDRN Public Portal

    Cancer.gov

    ADAM12 is a member of the ADAM (a disintegrin and metalloprotease) protein family. ADAM family members are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions. ADAM12 has two alternatively spliced transcripts: a shorter secreted form and a longer membrane-bound form. The shorter form is found to stimulate myogenesis.

  2. What's an Adam's Apple? (For Kids)

    MedlinePlus

    ... Happens in the Operating Room? What's an Adam's Apple? KidsHealth > For Kids > What's an Adam's Apple? A A A You're at the high ... the throat. This is what's called an Adam's apple. Everyone's larynx grows during puberty, but a girl's ...

  3. ADAM 12: A Putative Marker of Oligodendrogliomas?

    PubMed Central

    Kanakis, Dimitrios; Lendeckel, Uwe; Theodosiou, Paraskevi; Dobrowolny, Henrik; Mawrin, Christian; Keilhoff, Gerburg; Bukowska, Alicia; Dietzmann, Knut; Bogerts, Bernhard; Bernstein, Hans-Gert

    2013-01-01

    ADAM 12 (meltrin alpha) belongs to a large family of molecules, consisting of members with both disintegrin and metalloproteinase properties. ADAMs have been implicated in several cell physiological processes including cell adhesion, cell fusion, proteolysis and signalling. ADAM 12 is widely expressed, including skeletal muscle, testis, bone, intestine, heart and kidney. In addition, a variety of tumours show elevated expression of ADAM12; among them being breast-, colon-, gastric- and lung-carcinoma. As to the brain, ADAM 12 has been shown previously to be expressed in rat and human oligodendrocytes. However, little is known about the expression of this protease in brain tumours. This study demonstrates the presence of ADAM 12 in non-neoplastic oligodendroglial cells of normal human brain as well as in neoplastic oligodendroglia and minigemistocytes arising from four pure oligodendrogliomas and three mixed oligoastrocytomas. Double stainings revealed a notable preference of ADAM 12 for the oligodendroglial over astroglial components. The results of immunohistochemistry are in accordance with the results obtained from the RT-PCR, which further demonstrated a mild difference concerning the mRNA concentration of ADAM 12 between similar grades of eight astrocytomas and eight oligodendrogliomas (namely four astrocytomas grade II versus four oligodendrogliomas grade II and four astrocytomas grade III versus four oligodendrogliomas grade III). Both cellular immunostaining for ADAM 12 and ADAM 12 mRNA content decrease with higher histologic grade of the tumour. Surprisingly, the latter parameter (ADAM12 mRNA) showed a significant opposite correlation to the degree of histologic tumour malignancy. From our data showing that ADAM 12 is highly expressed in, but not restricted to, oligodendrogliomas, we conclude that ADAM 12 immunohistochemistry may be a helpful tool in the diagnosis of brain tumours. PMID:23324579

  4. ADAM 12: a putative marker of oligodendrogliomas?

    PubMed

    Kanakis, Dimitrios; Lendeckel, Uwe; Theodosiou, Paraskevi; Dobrowolny, Henrik; Mawrin, Christian; Keilhoff, Gerburg; Bukowska, Alicia; Dietzmann, Knut; Bogerts, Bernhard; Bernstein, Hans-Gert

    2013-01-01

    ADAM 12 (meltrin alpha) belongs to a large family of molecules, consisting of members with both disintegrin and metalloproteinase properties. ADAMs have been implicated in several cell physiological processes including cell adhesion, cell fusion, proteolysis and signalling. ADAM 12 is widely expressed, including skeletal muscle, testis, bone, intestine, heart and kidney. In addition, a variety of tumours show elevated expression of ADAM12; among them being breast-, colon-, gastric- and lung-carcinoma. As to the brain, ADAM 12 has been shown previously to be expressed in rat and human oligodendrocytes. However, little is known about the expression of this protease in brain tumours. This study demonstrates the presence of ADAM 12 in non-neoplastic oligodendroglial cells of normal human brain as well as in neoplastic oligodendroglia and minigemistocytes arising from four pure oligodendrogliomas and three mixed oligoastrocytomas. Double stainings revealed a notable preference of ADAM 12 for the oligodendroglial over astroglial components. The results of immunohistochemistry are in accordance with the results obtained from the RT-PCR, which further demonstrated a mild difference concerning the mRNA concentration of ADAM 12 between similar grades of eight astrocytomas and eight oligodendrogliomas (namely four astrocytomas grade II versus four oligodendrogliomas grade II and four astrocytomas grade III versus four oligodendrogliomas grade III). Both cellular immunostaining for ADAM 12 and ADAM 12 mRNA content decrease with higher histologic grade of the tumour. Surprisingly, the latter parameter (ADAM12 mRNA) showed a significant opposite correlation to the degree of histologic tumour malignancy. From our data showing that ADAM 12 is highly expressed in, but not restricted to, oligodendrogliomas, we conclude that ADAM 12 immunohistochemistry may be a helpful tool in the diagnosis of brain tumours.

  5. Differential Surface Expression of ADAM10 and ADAM17 on Human T Lymphocytes and Tumor Cells

    PubMed Central

    Kabelitz, Dieter; Janssen, Ottmar

    2013-01-01

    A disintegrin and metalloproteases (ADAMs) have been implicated in many processes controlling organismic development and integrity. Important substrates of ADAM proteases include growth factors, cytokines and their receptors and adhesion proteins. The inducible but irreversible cleavage of their substrates alters cell-cell communication and signaling. The crucial role of ADAM proteases (e.g. ADAM10 and 17) for mammalian development became evident from respective knockout mice, that displayed pre- or perinatal lethality with severe defects in many organs and tissues. Although many substrates for these two ADAM proteases were identified over the last decade, the regulation of their surface appearance, their enzymatic activity and their substrate specificity are still not well understood. We therefore analyzed the constitutive and inducible surface expression of ADAM10 and ADAM17 on a variety of human T cell and tumor cell lines. We demonstrate that ADAM10 is constitutively present at comparably high levels on the majority of the tested cell types. Stimulation with phorbol ester and calcium ionophore does not significantly alter the amount of surface ADAM10, except for a slight down-regulation from T cell blasts. Using FasL shedding as a readout for ADAM10 activity, we show that PKC activation and calcium mobilization are both prerequisite for activation of ADAM10 resulting in a production of soluble FasL. In contrast to ADAM10, the close relative ADAM17 is detected at only low levels on unstimulated cells. ADAM17 surface expression on T cell blasts is rapidly induced by stimulation. Since this inducible mobilization of ADAM17 is sensitive to inhibitors of actin filament formation, we propose that ADAM17 but not ADAM10 is prestored in a subcellular compartment that is transported to the cell surface in an activation- and actin-dependent manner. PMID:24130797

  6. ADAMS: AIRLAB data management system user's guide

    NASA Technical Reports Server (NTRS)

    Conrad, C. L.; Ingogly, W. F.; Lauterbach, L. A.

    1986-01-01

    The AIRLAB Data Management System (ADAMS) is an online environment that supports research at NASA's AIRLAB. ADAMS provides an easy to use interactive interface that eases the task of documenting and managing information about experiments and improves communication among project members. Data managed by ADAMS includes information about experiments, data sets produced, software and hardware available in AIRLAB as well as that used in a particular experiment, and an on-line engineer's notebook. The User's Guide provides an overview of the ADAMS system as well as details of the operations available within ADAMS. A tutorial section takes the user step-by-step through a typical ADAMS session. ADAMS runs under the VAX/VMS operating system and uses the ORACLE database management system and DEC/FMS (the Forms Management System). ADAMS can be run from any VAX connected via DECnet to the ORACLE host VAX. The ADAMS system is designed for simplicity, so interactions within the underlying data management system and communications network are hidden from the user.

  7. Asteroid shape modelling with ADAM

    NASA Astrophysics Data System (ADS)

    Viikinkoski, Matti; Kaasalainen, Mikko; Durech, Josef

    2015-08-01

    Technological advancements have made it possible to obtain highly detailed images of asteroids, yet 3-D shape reconstruction remains a challenge. Shape inversion is an ill-posed inverse problem as systematic errors, shadowing effects due to non-convex features, and the limitations of the imaging systems render the direct inversion impossible. Moreover, the coverage of one observation session alone is seldom sufficient for 3-D reconstruction, necessitating a method for the integration of widely different, complementary data sources into a coherent shape solution.We present a new 3-D shape reconstruction method for asteroid models. ADAM, an acronym for all-data asteroid modelling, is a general procedure for combining disk-resolved observational data into a shape model. ADAM handles all disk-resolved data in a uniform manner via 2-D Fourier Transform. Almost all disk-resolved data sources are supported: adaptive optics and other images, range-Doppler radar data, and thermal infrared interferometry.As case studies, we examine the shape of (41) Daphne using the adaptive optics images and photometry, and create a model of the asteroid 2000 ET70 from the range-Doppler radar images. Finally, we combine ALMA science verification data, adaptive optics images, occultations, and lightcurve data to study the shape of the large main-belt asteroid (3) Juno.

  8. The Historical World of Henry Adams

    ERIC Educational Resources Information Center

    Blaser, Kent

    1976-01-01

    This paper examines Henry Adams' writings on history by considering four topics which comprise the basis of his thinking: politics, religion, sex, and science. Adam's main goal was to make history a means of exploring the most significant dimensions of human being. (Author/RM)

  9. ADAMs family and relatives in cardiovascular physiology and pathology.

    PubMed

    Zhang, Pu; Shen, Mengcheng; Fernandez-Patron, Carlos; Kassiri, Zamaneh

    2016-04-01

    A disintegrin and metalloproteinases (ADAMs) are a family of membrane-bound proteases. ADAM-TSs (ADAMs with thrombospondin domains) are a close relative of ADAMs that are present in soluble form in the extracellular space. Dysregulated production or function of these enzymes has been associated with pathologies such as cancer, asthma, Alzheimer's and cardiovascular diseases. ADAMs contribute to angiogenesis, hypertrophy and apoptosis in a stimulus- and cell type-dependent manner. Among the ADAMs identified so far (34 in mouse, 21 in human), ADAMs 8, 9, 10, 12, 17 and 19 have been shown to be involved in cardiovascular development or cardiomyopathies; and among the 19 ADAM-TSs, ADAM-TS1, 5, 7 and 9 are important in development of the cardiovascular system, while ADAM-TS13 can contribute to vascular disorders. Meanwhile, there remain a number of ADAMs and ADAM-TSs whose function in the cardiovascular system has not been yet explored. The current knowledge about the role of ADAMs and ADAM-TSs in the cardiovascular pathologies is still quite limited. The most detailed studies have been performed in other cell types (e.g. cancer cells) and organs (nervous system) which can provide valuable insight into the potential functions of ADAMs and ADAM-TSs, their mechanism of action and therapeutic potentials in cardiomyopathies. Here, we review what is currently known about the structure and function of ADAMs and ADAM-TSs, and their roles in development, physiology and pathology of the cardiovascular system.

  10. Molecular profiling of ADAM12 and ADAM17 genes in human malignant melanoma.

    PubMed

    Cireap, Natalia; Narita, Diana

    2013-10-01

    ADAM12 and ADAM17 proteins belong to a family of transmembrane disintegrin-containing metalloproteinases (ADAMs) involved in the proteins ectodomain shedding and cell-cell and cell-matrix interactions. However, the specific biological functions of ADAMs are still unclear and, until now, these proteins were not investigated yet in melanoma. The aim of this study was to analyze the splicing variants of ADAM12 (L and S) and ADAM17 gene expression in melanoma at transcriptional and translational level in comparison with control (non-tumor) tissues. Taking in account that ADAM17 sheddase is involved in the modulation of TNF-α (tumor necrosis factor alpha), we analyzed also this cytokine in the plasma of the same patients before any treatment, and we compared the results with healthy controls. Quantitative-RT-PCR and immunohistochemistry were used to analyze ADAM12 and ADAM17 genes expression and the analysis of TNF-α expression was carried out in the plasma using ELISA. We demonstrated that ADAM12L splicing variant together with ADAM17 gene are strongly overexpressed in melanomas, whereas ADAM12S, although up-regulated when compared with the non-tumor controls, the difference was not statistically significant. When we compared the levels of expression for the ADAMs genes according to the tumor stage, we observed that all three investigated genes were significantly overexpressed in advanced stage in comparison with early stage melanomas. In the plasma of the same patients, the expression of TNF-α was up-regulated and significantly correlated with the expression of ADAM17 and respectively, with the advanced tumor stage.

  11. The Attendance Nightmare.

    ERIC Educational Resources Information Center

    Phillips, John A., Jr.

    This paper describes a program intended to increase student attendance in a Savannah, Georgia, inner city high school. The author maintains that shifting the accountability for attendance to the students through peer pressure was perhaps the most significant reason for gains in attendance. He believes that a successful attendance increase program…

  12. Identification of ADAM10 and ADAM17 with potential roles in the spermatogenesis of the Chinese mitten crab, Eriocheir sinensis.

    PubMed

    Li, Qing; Xie, Jing; He, Lin; Wang, Yuanli; Duan, Zelin; Yang, Hongdan; Wang, Qun

    2015-05-10

    The ADAM (a disintegrin and metalloprotease) family plays an important role in sperm and egg fusion, development, inflammation, adhesion and migration. ADAM10 and ADAM17 are involved in the spermatogenesis. To better understand the role of ADAM10 and ADAM17 in the Chinese mitten crab, Eriocheir sinensis, the full-length cDNAs of ADAM10 and ADAM17 were cloned, and named Es-ADAM10 and Es-ADAM17, respectively. Sequence and structural analysis showed that Es-ADAM10 and Es-ADAM17 have the typical structure of the ADAM family. Quantitative real-time reverse transcription polymerase chain reaction analysis showed that Es-ADAM10 and Es-ADAM17 mRNAs were distributed in the heart, hepatopancreas, intestines, brain, muscle, thoracic ganglia, hemolymph, stomach, testis, ovary, gill and accessory gland. Both mRNAs were highly expressed in the muscles, and relatively high in the testis, ovary and accessory gland. In addition, the Es-ADAM17 mRNA level was detected in every stage of testis development, being relatively high from July to September, the lowest during October and November, increasing from December to January, and reached a peak in January. By contrast, the expression of Es-ADAM10 mRNA was constant during testis development. Immunofluorescence further showed that Es-ADAM10 and Es-ADAM17 proteins were present in the cytoplasm and cytomembrane of spermatocytes, and both detected in the sperm. Furthermore, etoposide induced upregulation of Es-ADAM17 and Es-ADAM10 at both the mRNA and protein levels. This study first showed that Es-ADAM10 and Es-ADAM17 were also involved in the spermatogenesis and mainly participated in the later germ cell apoptosis in E. sinensis.

  13. Cleavage Site Localization Differentially Controls Interleukin-6 Receptor Proteolysis by ADAM10 and ADAM17

    PubMed Central

    Riethmueller, Steffen; Ehlers, Johanna C.; Lokau, Juliane; Düsterhöft, Stefan; Knittler, Katharina; Dombrowsky, Gregor; Grötzinger, Joachim; Rabe, Björn; Rose-John, Stefan; Garbers, Christoph

    2016-01-01

    Limited proteolysis of the Interleukin-6 Receptor (IL-6R) leads to the release of the IL-6R ectodomain. Binding of the cytokine IL-6 to the soluble IL-6R (sIL-6R) results in an agonistic IL-6/sIL-6R complex, which activates cells via gp130 irrespective of whether the cells express the IL-6R itself. This signaling pathway has been termed trans-signaling and is thought to mainly account for the pro-inflammatory properties of IL-6. A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 are the major proteases that cleave the IL-6R. We have previously shown that deletion of a ten amino acid long stretch within the stalk region including the cleavage site prevents ADAM17-mediated cleavage, whereas the receptor retained its full biological activity. In the present study, we show that deletion of a triple serine (3S) motif (Ser-359 to Ser-361) adjacent to the cleavage site is sufficient to prevent IL-6R cleavage by ADAM17, but not ADAM10. We find that the impaired shedding is caused by the reduced distance between the cleavage site and the plasma membrane. Positioning of the cleavage site in greater distance towards the plasma membrane abrogates ADAM17-mediated shedding and reveals a novel cleavage site of ADAM10. Our findings underline functional differences in IL-6R proteolysis by ADAM10 and ADAM17. PMID:27151651

  14. John Quincy Adams's rhetorical crusade for astronomy.

    PubMed

    Portolano, M

    2000-09-01

    Astronomy thrived in Europe during the early nineteenth century, but in the United States a utilitarian mind-set opposed it. John Quincy Adams's oratory in support of American astronomical discovery reached its peak during congressional debate over the Smithsonian Institution (1838-1846). During this debate Adams countered proposals to found a university with plans for an observatory. His addresses to congressional and public audiences about observatories and astronomy were intended to foster interest in the science and encourage the growing astronomical community in America. Although the U.S. Naval Observatory in Washington, D.C., was established before the Smithsonian debate ended, many considered Adams its political father. Adams composed his speeches on astronomy in a systematic manner, following neoclassical principles of rhetoric that he had taught at Harvard University. His speeches both in and outside of Congress show evidence of the rhetorical principles he conscientiously used in the service of astronomy.

  15. Student Admission and Attendance.

    ERIC Educational Resources Information Center

    Majestic, Ann L.

    1988-01-01

    Considers the North Carolina statutes that define the process for admitting students to public schools and ensuring their attendance. Examines cases relating to issues of school admission and compulsory attendance. (MLF)

  16. A Conversation with Adam Heller.

    PubMed

    Heller, Adam; Cairns, Elton J

    2015-01-01

    Adam Heller, Ernest Cockrell Sr. Chair in Engineering Emeritus of the John J. McKetta Department of Chemical Engineering at The University of Texas at Austin, recalls his childhood in the Holocaust and his contributions to science and technology that earned him the US National Medal of Technology and Innovation in a conversation with Elton J. Cairns, Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley. Dr. Heller, born in 1933, describes the enslavement of his father by Hungarians in 1942; the confiscation of his family's home, business, and all its belongings in 1944; and his incarceration in a brick factory with 18,000 Jews who were shipped by the Hungarians to be gassed by Germans in Auschwitz. Dr. Heller and his immediate family survived the Holocaust and arrived in Israel in 1945. He studied under Ernst David Bergmann at the Hebrew University, and then worked at Bell Laboratories and GTE Laboratories, where he headed Bell Lab's Electronic Materials Research Department. At GTE Laboratories, he built in 1966 the first neodymium liquid lasers and in 1973 with Jim Auborn conceived and engineered the lithium thionyl chloride battery, one of the first to be manufactured lithium batteries, which is still in use. After joining the faculty of engineering of The University of Texas at Austin, he cofounded with his son Ephraim Heller TheraSense, now a major part of Abbott Diabetes Care, which produced a microcoulometer that made the monitoring of glucose painless by accurately measuring the blood glucose concentration in 300 nL of blood. He also describes the electrical wiring of enzymes, the basis for Abbott's state-of-the-art continuous glucose monitoring system. He discusses his perspective of reducing the risk of catastrophic global warming in a wealth-accumulating, more-energy-consuming world and provides advice for students entering careers in science or engineering.

  17. The Relationship between Undergraduate Attendance and Performance Revisited: Alignment of Student and Instructor Goals

    ERIC Educational Resources Information Center

    Westerman, James W.; Perez-Batres, Luis A.; Coffey, Betty S.; Pouder, Richard W.

    2011-01-01

    We revisit the relationship between attendance and performance in the undergraduate university setting and apply agency theory in the instructor-student context. Building on agency theory propositions in the educational setting advanced by Smith, Zsidisin, and Adams (2005), we propose that the student and instructor must align goals to promote the…

  18. ADAM: automated data management for research datasets

    PubMed Central

    Woodbridge, Mark; Tomlinson, Christopher D.; Butcher, Sarah A.

    2013-01-01

    Existing repositories for experimental datasets typically capture snapshots of data acquired using a single experimental technique and often require manual population and continual curation. We present a storage system for heterogeneous research data that performs dynamic automated indexing to provide powerful search, discovery and collaboration features without the restrictions of a structured repository. ADAM is able to index many commonly used file formats generated by laboratory assays and therefore offers specific advantages to the experimental biology community. However, it is not domain specific and can promote sharing and re-use of working data across scientific disciplines. Availability and implementation: ADAM is implemented using Java and supported on Linux. It is open source under the GNU General Public License v3.0. Installation instructions, binary code, a demo system and virtual machine image and are available at http://www.imperial.ac.uk/bioinfsupport/resources/software/adam. Contact: m.woodbridge@imperial.ac.uk PMID:23109181

  19. The Role of ADAM9 in Tumor-Stromal Interactions in Breast Cancer

    DTIC Science & Technology

    2010-04-01

    ADAM family members in cancer. ADAM12 is expressed in carcinoma and promotes breast cancer progression by inducing the apoptosis of surrounding...stromal cells (13). Consequently, ADAM12 protein levels correlate with advanced breast cancer (14, 15). In contrast, the disintegrin domain of ADAM15...subgroup of ADAMs that also contains ADAM12 and ADAM15 (18). The ADAM9 metalloprotease activity cleaves heparin-binding epidermal growth factor (HB

  20. Women in History--Abigail Adams: Life, Accomplishments, and Ideas

    ERIC Educational Resources Information Center

    Kenan, Sharon K.

    2008-01-01

    This article profiles the life, accomplishments, and ideas of Abigail Adams. Born in 1944, Adams lacked a formal education, but she more than made up for that shortcoming with her love of reading, especially literature, and her interests in politics and events surrounding the young colonies. Adams was supportive of the advancement of women. She…

  1. Adam Smith, Religion, and Tuition Tax Credits.

    ERIC Educational Resources Information Center

    Alexander, Kern

    1983-01-01

    Examines tuition tax credit programs in framework of Adam Smith's ideas on the economic impact of established churches. Finds that tuition tax credits would amount to state expenditures to relieve the financial burden of parochial school parents and would allow churches to invest commercially to maintain their charitable functions. (JW)

  2. Adam Smith and the Rhetoric of Style.

    ERIC Educational Resources Information Center

    Moran, Michael G.

    Historians of rhetoric have generally accepted the view that Adam Smith rejected the principles of classical rhetoric. However, while there can be no doubt that Smith greatly truncated the five classical arts of rhetoric (invention, arrangement, style, memory, and delivery) by reducing his concerns largely to style and arrangement, he did not…

  3. Paraprofessional of the Year 2009: Tina Adams

    ERIC Educational Resources Information Center

    Berry, John N., III

    2009-01-01

    There is no doubt among the staff and managers at North Carolina State University (NCSU) Libraries, Raleigh, that advanced library technician Tina Adams deserves to be the winner of the "Library Journal's "Paraprofessional of the Year Award for 2009." "Certainly this library has never seen anyone like her before, not in my nine…

  4. Propagandist of the Revolution: Samuel Adams.

    ERIC Educational Resources Information Center

    Scanlon, Thomas M.

    This paper explores Samuel Adam's role as perhaps the most important propagandist of the American Revolution and his efforts to exploit Great Britain's mistakes and to engender in the American colonists a love of liberty and a fear that Great Britain, if not resisted, would replace that liberty with tyranny. Suggesting that the Revolutionary War…

  5. Possible Binary Lightcurve for 3145 Walter Adams

    NASA Astrophysics Data System (ADS)

    Owings, Larry E.; Warner, Brian D.; Pravec, Petr; Kusnirak, Peter

    2011-01-01

    Lightcurve observations have yielded period determinations for asteroid 3145 Walter Adams. A primary period of 2.7113 ± 0.0001 hr, amplitude of 0.10 ± 0.05, and a possible secondary period of about 17.4 hr. The estimated diameter ratio is D2/D1 = 0.22 ± 0.02.

  6. Increased expression of ADAM12 and ADAM17 genes in laser-capture microdissected breast cancers and correlations with clinical and pathological characteristics.

    PubMed

    Narita, Diana; Seclaman, Edward; Ursoniu, Sorin; Anghel, Andrei

    2012-02-01

    ADAMs (a desintegrin and metalloprotease) are transmembrane glycoproteins involved in cell growth, differentiation, motility, and respectively, tumor growth and progression. Our aim was to evaluate ADAM12 spliced variants (ADAM12L - long membrane-bound and ADAM12S - secreted-short variant) and ADAM17 genes expression in breast cancers and to correlate their level of expression with clinical and pathological characteristics. Expression of ADAMs was analyzed using quantitative reverse-transcription polymerase chain reaction in laser-capture microdissected specimens of breast cancers and corresponding non-neoplastic breast tissues from 92 patients. The proteins' expression was confirmed by immunohistochemistry. Significantly elevated amounts of ADAM12L, ADAM12S and ADAM17 transcripts were found in malignant breast cells compared with normal breast tissue and both ADAMs proteins showed moderate to strong immunoexpression in tumor cells and peritumoral fibroblasts. ADAM12L and ADAM12S expressions were correlated with age, younger patients having higher expression of ADAM12L and ADAM12S; ductal cancers had higher expression of ADAM12L compared with lobular types, whereas ADAM12S was higher expressed in lobular cancers; higher expressions were found for both ADAM12 and ADAM17 in HER2/neu positive and highly proliferative cancers. High-grade cancers showed significantly increased expression of ADAM17. Our study on laser-capture microdissected specimens confers motivation for future work on development of ADAM-selective inhibitors for treatment of breast cancers.

  7. Exosome release of ADAM15 and the functional implications of human macrophage-derived ADAM15 exosomes.

    PubMed

    Lee, Hee Doo; Koo, Bon-Hun; Kim, Yeon Hyang; Jeon, Ok-Hee; Kim, Doo-Sik

    2012-07-01

    A disintegrin and metalloproteinase 15 (ADAM15), the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed membrane protein that is involved in tumor progression and suppression. However, the underlying mechanism of ADAM15-mediated tumor suppression is not clearly understood. This study demonstrates that ADAM15 is released as an exosomal component, and ADAM15 exosomes exert tumor suppressive activities. We found that exosomal ADAM15 release is stimulated by phorbol 12-myristate 13-acetate, a typical protein kinase C activator, in various tumor cell types, and this results in a corresponding decrease in plasma membrane-associated ADAM15. Exosomes rich in ADAM15 display enhanced binding affinity for integrin αvβ3 in an RGD-dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. Exosomal ADAM15 is released from human macrophages, and macrophage-derived ADAM15 exosomes have tumor inhibitory effects. This work suggests a primary role of ADAM15 for exosome-mediated tumor suppression, as well as functional significance of exosomal ADAM protein in antitumor immunity.

  8. ADAM12 is expressed by astrocytes during experimental demyelination.

    PubMed

    Baertling, Fabian; Kokozidou, Maria; Pufe, Thomas; Clarner, Tim; Windoffer, Reinhard; Wruck, Christoph J; Brandenburg, Lars-Ove; Beyer, Cordian; Kipp, Markus

    2010-04-22

    A disintegrin and metalloproteinase (ADAM) 12 represents a member of a large family of similarly structured multi-domain proteins. In the central nervous system (CNS), ADAM12 has been suggested to play a role in brain development, glioblastoma cell proliferation, and in experimental autoimmune encephalomyelitis. Furthermore, ADAM12 was reported to be almost exclusively expressed by oligodendrocytes and could, therefore, be considered as suitable marker for this cell type. In the present study, we investigated ADAM12 expression in the healthy and pathologically altered murine CNS. As pathological paradigm, we used the cuprizone demyelination model in which myelin loss during multiple sclerosis is imitated. Besides APC(+) oligodendrocytes, SMI311(+) neurons and GFAP(+) astrocytes express ADAM12 in the adult mouse brain. ADAM12 expression was further analyzed in vitro. After the induction of demyelination, we observed that activated astrocytes are the main source of ADAM12 in brain regions affected by oligodendrocyte loss. Exposure of astrocytes in vitro to either lipopolysaccharides (LPS), tumor necrosis factor alpha (TNFalpha), glutamate, or hydrogen peroxide revealed a highly stimulus-specific regulation of ADAM12 expression which was not seen in microglial BV2 cells. It appears that LPS- and TNFalpha-induced ADAM12 expression is mediated via the classic NFkappaB pathway. In summary, we demonstrated that ADAM12 is not a suitable marker for oligodendrocytes. Our results further suggest that ADAM12 might be implicated in the course of distinct CNS diseases such as demyelinating disorders.

  9. Heparan sulfate regulates ADAM12 through a molecular switch mechanism.

    PubMed

    Sørensen, Hans Peter; Vivès, Romain R; Manetopoulos, Christina; Albrechtsen, Reidar; Lydolph, Magnus C; Jacobsen, Jonas; Couchman, John R; Wewer, Ulla M

    2008-11-14

    The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM prodomains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes tumor progression and chondrocyte proliferation in osteoarthritic cartilage, is shown to possess a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate. Sheddase functions of ADAM12 are regulated by the switch, as are proteolytic functions in placental tissue and sera of pregnant women. Moreover, human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate. These data present a novel concept that might allow targeting of ADAM12 and suggest that other ADAMs may have specific regulatory activity embedded in their prodomain and catalytic domain structures.

  10. Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain

    PubMed Central

    Miller, Miles A.; Moss, Marcia L.; Powell, Gary; Petrovich, Robert; Edwards, Lori; Meyer, Aaron S.; Griffith, Linda G.; Lauffenburger, Douglas A.

    2015-01-01

    Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, “decoy” antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling. PMID:26477568

  11. Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain.

    PubMed

    Miller, Miles A; Moss, Marcia L; Powell, Gary; Petrovich, Robert; Edwards, Lori; Meyer, Aaron S; Griffith, Linda G; Lauffenburger, Douglas A

    2015-10-19

    Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, "decoy" antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling.

  12. Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain

    NASA Astrophysics Data System (ADS)

    Miller, Miles A.; Moss, Marcia L.; Powell, Gary; Petrovich, Robert; Edwards, Lori; Meyer, Aaron S.; Griffith, Linda G.; Lauffenburger, Douglas A.

    2015-10-01

    Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, “decoy” antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling.

  13. Cellular roles of ADAM12 in health and disease.

    PubMed

    Kveiborg, Marie; Albrechtsen, Reidar; Couchman, John R; Wewer, Ulla M

    2008-01-01

    ADAM12 belongs to the large family of ADAMs (a disintegrin and metalloproteases) and possesses extracellular metalloprotease and cell-binding functions, as well as intracellular signaling capacities. Interest in ADAM12 has increased recently because its expression is related to tumor progression and it is a potential biomarker for breast cancer. It is therefore important to understand ADAM12's functions. Many cellular roles for ADAM12 have been suggested. It is an active metalloprotease, and has been implicated in insulin-like growth factor (IGF) receptor signaling, through cleavage of IGF-binding proteins, and in epidermal growth factor receptor (EGFR) pathways, via ectodomain shedding of membrane-tethered EGFR ligands. These proteolytic events may regulate diverse cellular responses, such as altered cell differentiation, proliferation, migration, and invasion. ADAM12 may also regulate cell-cell and cell-extracellular matrix contacts through interactions with cell surface receptors - integrins and syndecans - potentially influencing the actin cytoskeleton. Moreover, ADAM12 interacts with several cytoplasmic signaling and adaptor molecules through its intracellular domain, thereby directly transmitting signals to or from the cell interior. These ADAM12-mediated cellular effects appear to be critical events in both biological and pathological processes. This review presents current knowledge on ADAM12 functions gained from in vitro and in vivo observations, describes ADAM12's role in both normal physiology and pathology, particularly in cancer, and discusses important areas for future investigation.

  14. Targeting ADAM12 in human disease: head, body or tail?

    PubMed

    Jacobsen, J; Wewer, U M

    2009-01-01

    ADAM12/meltrin alpha is a type I transmembrane multidomain protein involved in tumor progression and other severe diseases, including osteoarthritis, and as such could be considered as a potential drug target. In addition to protease activity, ADAM12 possesses cell binding and cell signaling properties. This functional trinity is reflected in the structure of ADAM12, which can be divided into head, body, and tail. The head of the protein (consisting of the pro and catalytic domains) mediates processing of growth factors and cytokines and has been implicated in epidermal growth factor (EGF) and insulin-like growth factor receptor signaling. The body of the protein (consisting of the disintegrin, cysteine-rich, and EGF-like domains) is involved in contacts with the extracellular matrix and other cells through interactions with integrins and syndecans. Finally, the tail of the protein (consisting of the cytoplasmic domain) is engaged in interactions with intracellular signaling molecules. In many studies, ADAM12 overexpression has been correlated with disease, and ADAM12 has been shown to promote tumor growth and progression in cancer. On the other hand, protective effects of ADAM12 in disease have also been reported. Future investigations should address the precise mechanisms of ADAM12 in disease and biology in order to counterbalance the benefits from targeting ADAM12 therapeutically with possible side effects. This review describes the biology of ADAM12, its association with disease, and evaluates the possible approaches to targeting ADAM12 in human disease.

  15. Iterative Mechanism Solutions with Scenario and ADAMS

    NASA Technical Reports Server (NTRS)

    Rhoades, Daren

    2006-01-01

    This slide presentation reviews the use of iterative solutions using Scenario for Motion (UG NX 2 Motion) to assist in designing the Mars Science Laboratory (MSL). The MSL will have very unique design requirements, and in order to meet these requirements the system must have the ability to design for static stability, simulate mechanism kinematics, simulate dynamic behaviour and be capable of reconfiguration, and iterations as designed. The legacy process used on the Mars Exploration rovers worked, but it was cumbersome using multiple tools, limited configuration control, with manual process and communication, and multiple steps. The aim is to develop a mechanism that would reduce turn around time, and make more reiterations possible, to improve the quality and quantity of data, and to enhance configuration control. Currently for NX Scenario for Motion uses are in the articulation studies, the simulations of traverse motions,and subsystem simulations. The design of the Rover landing model requires accurate results, flexible elements, such as beams, and the use of the full ADAMS solver has been used. In order to achieve this, when required, there has been a direct translation from Scenario to ADAMS, with additional data in ascii format. The process that has been designed to move from Scenario to ADAMS is reviewed.

  16. Catalytic properties of ADAM12 and its domain deletion mutants.

    PubMed

    Jacobsen, Jonas; Visse, Robert; Sørensen, Hans Peter; Enghild, Jan J; Brew, Keith; Wewer, Ulla M; Nagase, Hideaki

    2008-01-15

    Human ADAM12 (a disintegrin and metalloproteinase) is a multidomain zinc metalloproteinase expressed at high levels during development and in human tumors. ADAM12 exists as two splice variants: a classical type 1 membrane-anchored form (ADAM12-L) and a secreted splice variant (ADAM12-S) consisting of pro, catalytic, disintegrin, cysteine-rich, and EGF domains. Here we present a novel activity of recombinant ADAM12-S and its domain deletion mutants on S-carboxymethylated transferrin (Cm-Tf). Cleavage of Cm-Tf occurred at multiple sites, and N-terminal sequencing showed that the enzyme exhibits restricted specificity but a consensus sequence could not be defined as its subsite requirements are promiscuous. Kinetic analysis revealed that the noncatalytic C-terminal domains are important regulators of Cm-Tf activity and that ADAM12-PC consisting of the pro domain and catalytic domain is the most active on this substrate. It was also observed that NaCl inhibits ADAM12. Among the tissue inhibitors of metalloproteinases (TIMP) examined, the N-terminal domain of TIMP-3 (N-TIMP-3) inhibits ADAM12-S and ADAM12-PC with low nanomolar Ki(app) values while TIMP-2 inhibits them with a slightly lower affinity (9-44 nM). However, TIMP-1 is a much weaker inhibitor. N-TIMP-3 variants that lack MMP inhibitory activity but retained the ability to inhibit ADAM17/TACE failed to inhibit ADAM12. These results indicate unique enzymatic properties of ADAM12 among the members of the ADAM family of metalloproteinases.

  17. Internal architecture of the proximal femur--Adam's or Adams' arch? Historical mystery.

    PubMed

    Bartonícek, J

    2002-12-01

    The designation 'Adam Bogen' describing the thick medial cortex of the femoral neck is an incorrect term. This arch was described by Robert Adams (1795-1871), an outstanding Irish anatomist and surgeon. He was famous mainly for his book on gout and the description of disorders of cardiac rhythm, the so-called Adams-Stokes syndrome. He published his original description in the today unfortunately almost forgotten Cyclopaedia of Anatomy and Physiology, Vol. II (London, Longman, 1836-1839). The main editor of this monumental six-volume work was the famous anatomist and surgeon R.B.Todd. This book represents a significant source of information on diseases and injuries of the great joints (shoulder, elbow, wrist, knee, ankle).

  18. Shedding of Collagen XVII/BP180 in Skin Depends on Both ADAM10 and ADAM9*

    PubMed Central

    Franzke, Claus-Werner; Bruckner-Tuderman, Leena; Blobel, Carl P.

    2009-01-01

    Collagen XVII is a transmembrane collagen and the major autoantigen of the autoimmune skin blistering disease bullous pemphigoid. Collagen XVII is proteolytically released from the membrane, and the pathogenic epitope harbors the cleavage site for its ectodomain shedding, suggesting that proteolysis has an important role in regulating the function of collagen XVII in skin homeostasis. Previous studies identified ADAMs 9, 10, and 17 as candidate collagen XVII sheddases and suggested that ADAM17 is a major sheddase. Here we show that ADAM17 only indirectly affects collagen XVII shedding and that ADAMs 9 and 10 are the most prominent collagen XVII sheddases in primary keratinocytes because (a) collagen XVII shedding was not stimulated by phorbol esters, known activators of ADAM17, (b) constitutive and calcium influx-stimulated shedding was sensitive to the ADAM10-selective inhibitor GI254023X and was strongly reduced in Adam10−/− cells, (c) there was a 55% decrease in constitutive collagen XVII ectodomain shedding from Adam9−/− keratinocytes, and (d) H2O2 enhanced ADAM9 expression and stimulated collagen XVII shedding in skin and keratinocytes of wild type mice but not of Adam9−/− mice. We conclude that ADAM9 and ADAM10 can both contribute to collagen XVII shedding in skin with an enhanced relative contribution of ADAM9 in the presence of reactive oxygen species. These results provide critical new insights into the identity and regulation of the major sheddases for collagen XVII in keratinocytes and skin and have implications for the treatment of blistering diseases of the skin. PMID:19574220

  19. Shedding of collagen XVII/BP180 in skin depends on both ADAM10 and ADAM9.

    PubMed

    Franzke, Claus-Werner; Bruckner-Tuderman, Leena; Blobel, Carl P

    2009-08-28

    Collagen XVII is a transmembrane collagen and the major autoantigen of the autoimmune skin blistering disease bullous pemphigoid. Collagen XVII is proteolytically released from the membrane, and the pathogenic epitope harbors the cleavage site for its ectodomain shedding, suggesting that proteolysis has an important role in regulating the function of collagen XVII in skin homeostasis. Previous studies identified ADAMs 9, 10, and 17 as candidate collagen XVII sheddases and suggested that ADAM17 is a major sheddase. Here we show that ADAM17 only indirectly affects collagen XVII shedding and that ADAMs 9 and 10 are the most prominent collagen XVII sheddases in primary keratinocytes because (a) collagen XVII shedding was not stimulated by phorbol esters, known activators of ADAM17, (b) constitutive and calcium influx-stimulated shedding was sensitive to the ADAM10-selective inhibitor GI254023X and was strongly reduced in Adam10(-/-) cells, (c) there was a 55% decrease in constitutive collagen XVII ectodomain shedding from Adam9(-/-) keratinocytes, and (d) H(2)O(2) enhanced ADAM9 expression and stimulated collagen XVII shedding in skin and keratinocytes of wild type mice but not of Adam9(-/-) mice. We conclude that ADAM9 and ADAM10 can both contribute to collagen XVII shedding in skin with an enhanced relative contribution of ADAM9 in the presence of reactive oxygen species. These results provide critical new insights into the identity and regulation of the major sheddases for collagen XVII in keratinocytes and skin and have implications for the treatment of blistering diseases of the skin.

  20. Miscarriage Among Flight Attendants

    PubMed Central

    Grajewski, Barbara; Whelan, Elizabeth A.; Lawson, Christina C.; Hein, Misty J.; Waters, Martha A.; Anderson, Jeri L.; MacDonald, Leslie A.; Mertens, Christopher J.; Tseng, Chih-Yu; Cassinelli, Rick T.; Luo, Lian

    2015-01-01

    Background Cosmic radiation and circadian disruption are potential reproductive hazards for flight attendants. Methods Flight attendants from 3 US airlines in 3 cities were interviewed for pregnancy histories and lifestyle, medical, and occupational covariates. We assessed cosmic radiation and circadian disruption from company records of 2 million individual flights. Using Cox regression models, we compared respondents (1) by levels of flight exposures and (2) to teachers from the same cities, to evaluate whether these exposures were associated with miscarriage. Results Of 2654 women interviewed (2273 flight attendants and 381 teachers), 958 pregnancies among 764 women met study criteria. A hypothetical pregnant flight attendant with median firsttrimester exposures flew 130 hours in 53 flight segments, crossed 34 time zones, and flew 15 hours during her home-base sleep hours (10 pm–8 am), incurring 0.13 mGy absorbed dose (0.36 mSv effective dose) of cosmic radiation. About 2% of flight attendant pregnancies were likely exposed to a solar particle event, but doses varied widely. Analyses suggested that cosmic radiation exposure of 0.1 mGy or more may be associated with increased risk of miscarriage in weeks 9–13 (odds ratio = 1.7 [95% confidence interval = 0.95–3.2]). Risk of a first-trimester miscarriage with 15 hours or more of flying during home-base sleep hours was increased (1.5 [1.1–2.2]), as was risk with high physical job demands (2.5 [1.5–4.2]). Miscarriage risk was not increased among flight attendants compared with teachers. Conclusions Miscarriage was associated with flight attendant work during sleep hours and high physical job demands and may be associated with cosmic radiation exposure. PMID:25563432

  1. Adam12 plays a role during uterine decidualization in mice.

    PubMed

    Zhang, Li; Guo, Weixiang; Chen, Qi; Fan, Xiujun; Zhang, Ying; Duan, Enkui

    2009-12-01

    In mouse, decidualization is characterized by the proliferation of stromal cells and their differentiation into specialized type of cells (decidual cells) with polyploidy, surrounding the implanting blastocyst. However, the mechanisms involved in these processes remain poorly understood. Using multiple approaches, we have examined the role of Adam12 in decidualization during early pregnancy in mice. Adam12 is spatiotemporally expressed in decidualizing stromal cells in intact pregnant females and in pseudopregnant mice undergoing artificially induced decidualization. In the ovariectomized mouse uterus, the expression of Adam12 is upregulated after progesterone treatment, which is primarily mediated by nuclear progesterone receptor. In a stromal cell culture model, the expression of Adam12 gradually rises with the progression of stromal decidualization, whereas the attenuated expression of Adam12 after siRNA knockdown significantly blocks the progression of decidualization. Our study suggests that Adam12 is involved in promoting uterine decidualization during pregnancy.

  2. ADAM10: a new player in breast cancer progression?

    PubMed Central

    Mullooly, Maeve; McGowan, Patricia M; Kennedy, Susan A; Madden, Stephen F; Crown, John; O' Donovan, Norma; Duffy, Michael J

    2015-01-01

    Background: The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. As cleavage of several of these proteins has been implicated in cancer formation and progression, we hypothesised that ADAM10 is also involved in these processes. Methods: ADAM10 expression was decreased by RNA interference and the effects of this on cell numbers, invasion and migration were determined. We also examined the effect of ADAM10 inhibition on breast cancer cell line invasion and migration. Results: Using the triple-negative (TN) breast cancer cell lines, BT20, MDA-MB-231 and the non-TN cell line MDA-MB-453, knockdown of ADAM10 expression significantly decreased in vitro migration (P<0.01; for each cell line). Similarly, treatment with the ADAM10-selective inhibitor GI254023X reduced migration in the three cell lines (for BT20, P<0.001; for MDA-MB-231, P=0.005; for MDA-MB-453, P=0.023). In contrast, neither knockdown of ADAM10 nor treatment with the ADAM10-selective inhibitor GI254023X significantly affected cell numbers. Using extracts of primary breast cancers, higher levels of ADAM10 were found more frequently in high-grade vs low-grade tumours (P<0.001) and in oestrogen receptor (ER)-negative compared with ER-positive tumours (P=0.005). Analysis of pooled publicly available data sets found that high levels of ADAM10 mRNA were associated with adverse outcome in patients with the basal subtype of breast cancer. Conclusions: Based on our combined cell line and breast cancer extract data, we conclude that ADAM10 is likely to be involved in breast cancer progression, especially in the basal subtype. PMID:26284334

  3. ADAM Proteases: Ligand Processing and Modulation of the Notch Pathway

    PubMed Central

    Zolkiewska, Anna

    2009-01-01

    ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step of the regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. PMID:18344021

  4. Making Connections: Attending Professional Conferences

    ERIC Educational Resources Information Center

    Cherrstrom, Catherine A.

    2012-01-01

    Attending a professional conference is an effective way to explore and advance knowledge, skills, and careers. For graduate students, attending a conference is an effective way to explore academic fields and new professions. However, attending a professional conference requires precious resources--time and money--so the decision to attend, or not,…

  5. From Adam Swift to Adam Smith: How the "Invisible Hand" Overcomes Middle Class Hypocrisy

    ERIC Educational Resources Information Center

    Tooley, James

    2007-01-01

    This paper challenges Richard Pring's suggestion that parents using private education may be undermining the desire for social justice and equality, using recent arguments of Adam Swift as a springboard. Swift's position on the banning of private schools, which uses a Rawlsian "veil of ignorance" argument, is explored, and it is suggested that, if…

  6. Connective tissue growth factor is a substrate of ADAM28

    SciTech Connect

    Mochizuki, Satsuki; Tanaka, Rena; Shimoda, Masayuki; Onuma, Junko; Fujii, Yutaka; Jinno, Hiromitsu; Okada, Yasunori

    2010-11-26

    Research highlights: {yields} The hyper-variable region in the cysteine-rich domain of ADAM28 binds to C-terminal domain of CTGF. {yields} ADAM28 cleaves CTGF alone and CTGF in the CTGF/VEGF{sub 165} complex. {yields} CTGF digestion by ADAM28 releases biologically active VEGF{sub 165} from the complex. {yields} ADAM28, CTGF and VEGF{sub 165} are commonly co-expressed by carcinoma cells in human breast carcinoma tissues. {yields} These suggest that ADAM28 promotes VEGF{sub 165}-induced angiogenesis in the breast carcinomas by selective CTGF digestion in the CTGF/VEGF{sub 165} complex. -- Abstract: ADAM28, a member of the ADAM (a disintegrin and metalloproteinase) gene family, is over-expressed by carcinoma cells and the expression correlates with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, information about substrates of ADAM28 is limited. We screened interacting molecules of ADAM28 in human lung cDNA library by yeast two-hybrid system and identified connective tissue growth factor (CTGF). Binding of CTGF to proADAM28 was demonstrated by yeast two-hybrid assay and protein binding assay. ADAM28 cleaved CTGF in dose- and time-dependent manners at the Ala{sup 181}-Tyr{sup 182} and Asp{sup 191}-Pro{sup 192} bonds in the hinge region of the molecule. ADAM28 selectively digested CTGF in the complex of CTGF and vascular endothelial growth factor{sub 165} (VEGF{sub 165}), releasing biologically active VEGF{sub 165} from the complex. RT-PCR and immunohistochemical analyses demonstrated that ADAM28, CTGF and VEGF are commonly co-expressed in the breast carcinoma tissues. These data provide the first evidence that CTGF is a novel substrate of ADAM28 and suggest that ADAM28 may promote VEGF{sub 165}-induced angiogenesis in the breast carcinomas by the CTGF digestion in the CTGF/VEGF{sub 165} complex.

  7. DEVELOP students attend conference

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Last month, Madeline Brozen and Jason Jones of the DEVELOP Program at John C. Stennis Space Center joined members from the program's national office at Langley Research Center to attend the Southern Growth Policies Board annual conference in Biloxi. Pictured are (l to r): Karen Allsbrook, Jonathan Gleason, Gov. Haley Barbour, Madeline Brozen, Lindsay Rogers and Tracey Silcox.

  8. School Counselors Improving Attendance

    ERIC Educational Resources Information Center

    Edwards, LaWanda

    2013-01-01

    This study examined the outcomes of interventions used to address attendance issues at a middle school located in the Southern United States. School-wide interventions were implemented to address absenteeism of all students and individual interventions were implemented to address absenteeism with targeted students. An explanation of each…

  9. Student Attendance Accounting Manual.

    ERIC Educational Resources Information Center

    Freitas, Joseph M.

    In response to state legislation authorizing procedures for changes in academic calendars and measurement of student workload in California community colleges, this manual from the Chancellor's Office provides guidelines for student attendance accounting. Chapter 1 explains general items such as the academic calendar, admissions policies, student…

  10. ADAM12 and ADAM17 gene expression in laser-capture microdissected and non-microdissected breast tumors.

    PubMed

    Narita, Diana; Seclaman, Edward; Ilina, Razvan; Cireap, Natalia; Ursoniu, Sorin; Anghel, Andrei

    2011-06-01

    ADAM (a disintegrin and metalloprotease)12 and ADAM17 are multidomain transmembrane proteins involved in ectodomain shedding of cytokines, growth factors and adhesion molecules, with pivotal activities in the tumor microenvironment. The aim of this study was to confirm the up-regulation of ADAM17 and ADAM12 gene splicing variants in breast tumors and to delineate their expression between laser-capture microdissected (LCM) and non-microdissected breast tumors. The gene expression was analyzed by quantitative-reverse transcription-PCR in a total sample of 109 breast tumors paired with corresponding non-neoplastic breast tissues. ADAM12 and 17 proteins expression for corresponding tissue samples was confirmed by immunohistochemistry. ADAM12S, 12L and 17 genes were significantly up-regulated in either malign or benign LCM samples when compared to non-tumor controls. For non-LCM samples, it was obtained also an increased expression for ADAM12 and 17 genes in cancers, while in benign tumors only ADAM12 variants were significantly up-regulated compared to controls. When benign versus malignant tumors were compared, in LCM samples all investigated genes displayed a higher expression in cancers, whereas in non-LCM, ADAM12 variants were overexpressed in benign samples. The increased expression of ADAM12 protein in the tumor cells and stroma of benign breast diseases was immunohistochemically confirmed. These differences between LCM and non-LCM samples were explained by the contribution of the stroma to the expression of this marker. This study underlines the accuracy conferred by homogenous LCM samples on gene expression profiles and confers further evidence regarding the role of ADAM12 and 17 in the breast tumorigenesis and progression.

  11. ADAM8 as a drug target in Pancreatic Cancer

    PubMed Central

    Schlomann, Uwe; Koller, Garrit; Conrad, Catharina; Ferdous, Taheera; Golfi, Panagiota; Garcia, Adolfo Molejon; Höfling, Sabrina; Parsons, Maddy; Costa, Patricia; Soper, Robin; Bossard, Maud; Hagemann, Thorsten; Roshani, Rozita; Sewald, Norbert; Ketchem, Randal R.; Moss, Marcia L.; Rasmussen, Fred H.; Miller, Miles A.; Lauffenburger, Douglas A.; Tuveson, David A.; Nimsky, Christopher; Bartsch, Jörg W.

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with less than 5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease-disintegrin, are correlated with poor clinical outcome. We show that ADAM8 expression is associated with increased migration and invasiveness of PDAC cells caused by activation of ERK 1/2 and higher MMP activities. For biological function, ADAM8 requires multimerisation and associates with β1-integrin on the cell surface. A peptidomimetic ADAM8 inhibitor, BK-1361, designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerisation. In PDAC cells, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK 1/2 and MMP activation. BK-1361 application in mice decreased tumour burden and metastasis of implanted pancreatic tumour cells and provides improved metrics of clinical symptoms and survival in a KrasG12D-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy. PMID:25629724

  12. The Failed Educations of John Stuart Mill and Henry Adams.

    ERIC Educational Resources Information Center

    Crossley, Robert

    1979-01-01

    Analyzes and contrasts Mill's "Autobiography" and Adams'"The Education of Henry Adams" in order to present two approaches to the nature of education and of failure. Maintains that their perspectives may serve as catalysts and cautions for contemporary theories of education and its utility and relevance. (CAM)

  13. Molecular profiling of ADAM12 gene in breast cancers.

    PubMed

    Nariţa, Diana; Anghel, A; Seclaman, E; Ilina, R; Cireap, Natalia; Ursoniu, S

    2010-01-01

    ADAMs (a disintegrin and metalloproteinase) family have been associated with the process of proteolytic "shedding" of membrane-associated proteins ectodomain and hence the rapid modulation of key cell signaling pathways in tissues microenvironment. A variety of cytokines, chemokines and growth factors which are initially produced as transmembrane proforms are activated by these sheddase activities. ADAM12 is highly expressed in rapidly growing tissues such as placenta and malignant tumors and it was found as one of the Candidate Cancer Genes in a comprehensive mutational analysis of human breast cancers. Our aim was to determine the gene expression profile of ADAM12 in breast cancers in comparison with normal breast and to correlate their level of expression with the clinical and pathological characteristics of breast cancers. Gene expression of ADAM12 spliced variants (12L and 12S) was evaluated using quantitative reverse-transcription PCR in samples obtained by laser capture microdissection from 38 patients with breast cancers and compared with adjacent healthy breast tissues. Both ADAM12L and 12S expression were significantly up-regulated in breast cancers, while in the normal breast, we found a very low expression. ADAM12L expression was significantly correlated with the histopathological types and, although not statistically significant, ADAM12 both variants were up-regulated in high-grade, highly-proliferative and HER2÷neu positive tumors. From these preliminary results, we found that ADAM12 could be an interesting marker and eventually a therapeutic target for breast cancer.

  14. ADAM17 Transactivates EGFR Signaling during Embryonic Eyelid Closure

    PubMed Central

    Hassemer, Eryn L.; Endres, Bradley; Toonen, Joseph A.; Ronchetti, Adam; Dubielzig, Richard; Sidjanin, Duska J.

    2013-01-01

    Purpose. During mammalian embryonic eyelid closure ADAM17 has been proposed to play a role as a transactivator of epidermal growth factor receptor (EGFR) signaling by shedding membrane bound EGFR ligands. However, ADAM17 also sheds numerous other ligands, thus implicating ADAM17 in additional molecular pathways. The goal of this study was to experimentally establish the role of ADAM17 and determine ADAM17-mediated pathways essential for the embryonic eyelid closure. Methods. Wild-type (WT) and woe mice, carrying a hypomorphic mutation in Adam17, were evaluated using H&E and scanning electron microscopy. Expressions of ADAM17, EGFR, and the phosphorylated form EGFR-P were evaluated using immunohistochemistry. BrdU and TUNEL assays were used to evaluate cell proliferation and apoptosis, respectively. In vitro scratch assays of primary cultures were used to evaluate cell migration. Clinical and histologic analyses established if the hypermorphic EgfrDsk5 allele can rescue the woe embryonic eyelid closure. Results. woe mice exhibited a failure to develop the leading edge of the eyelid and consequently failure of the embryonic eyelid closure. Expression of ADAM17 was identified in the eyelid epithelium in the cells of the leading edge. ADAM17 is essential for epithelial cell migration, but does not play a role in proliferation and apoptosis. EGFR was expressed in both WT and woe eyelid epithelium, but the phosphorylated EGFR-P form was detected only in WT. The EgfrDsk5 allele rescued woe eyelid closure defects, but also rescued woe anterior segment defects and the absence of meibomian glands. Conclusions. We provide in vivo genetic evidence that the role of ADAM17 during embryonic eyelid closure is to transactivate EGFR signaling. PMID:23211830

  15. Helping Eve overcome ADAM: G-quadruplexes in the ADAM-15 promoter as new molecular targets for breast cancer therapeutics.

    PubMed

    Brown, Robert V; Gaerig, Vanessa C; Simmons, Taesha; Brooks, Tracy A

    2013-12-05

    ADAM-15, with known zymogen, secretase, and disintegrin activities, is a catalytically active member of the ADAM family normally expressed in early embryonic development and aberrantly expressed in various cancers, including breast, prostate and lung. ADAM-15 promotes extracellular shedding of E-cadherin, a soluble ligand for the HER2/neu receptor, leading to activation, increased motility, and proliferation. Targeted downregulation of both ADAM-15 and HER2/neu function synergistically kills breast cancer cells, but to date there are no therapeutic options for decreasing ADAM-15 function or expression. In this vein, we have examined a unique string of guanine-rich DNA within the critical core promoter of ADAM-15. This region of DNA consists of seven contiguous runs of three or more consecutive guanines, which, under superhelical stress, can relax from duplex DNA to form an intrastrand secondary G-quadruplex (G4) structure. Using biophysical and biological techniques, we have examined the G4 formation within the entire and various truncated regions of the ADAM-15 promoter, and demonstrate strong intrastrand G4 formation serving to function as a biological silencer element. Characterization of the predominant G4 species formed within the ADAM-15 promoter will allow for specific drug targeting and stabilization, and the further development of novel, targeted therapeutics.

  16. A Disintegrin and Metalloproteinase10 (ADAM10) Regulates NOTCH Signaling during Early Retinal Development.

    PubMed

    Toonen, Joseph A; Ronchetti, Adam; Sidjanin, D J

    2016-01-01

    ADAM10 and ADAM17 are two closely related members of the ADAM (a disintegrin and metalloprotease) family of membrane-bound sheddases, which proteolytically cleave surface membrane proteins. Both ADAM10 and ADAM17 have been implicated in the proteolytic cleavage of NOTCH receptors and as such regulators of NOTCH signaling. During retinal development, NOTCH signaling facilitates retinal neurogenesis by maintaining progenitor cells in a proliferative state and by mediating retinal cell fates. However, the roles of ADAM10 and ADAM17 in the retina are not well defined. In this study, we set out to clarify the roles of ADAM10 and ADAM17 during early retinal development. The retinal phenotype of conditionally abated Adam17 retinae (Adam17 CKO) did not differ from the controls whereas conditionally ablated Adam10 retinae (Adam10 CKO) exhibited abnormal morphogenesis characterized by the formation of rosettes and a loss of retinal laminae phenotypically similar to morphological abnormalities identified in mice with retinal NOTCH signaling deficiency. Additionally, Adam10 CKO retinae exhibited abnormal neurogenesis characterized by fewer proliferating progenitor cells and greater differentiation of early photoreceptors and retinal ganglion cells. Moreover, constitutive activation of the NOTCH1-intracellular domain (N1-ICD) rescued Adam10 CKO abnormal neurogenesis, as well as abnormal retinal morphology by maintaining retinal cells in the progenitor state. Collectively these findings provide in vivo genetic evidence that ADAM10, and not ADAM17, is indispensable for proper retinal development as a regulator of NOTCH signaling.

  17. A Disintegrin and Metalloproteinase10 (ADAM10) Regulates NOTCH Signaling during Early Retinal Development

    PubMed Central

    Toonen, Joseph A.; Ronchetti, Adam; Sidjanin, D. J.

    2016-01-01

    ADAM10 and ADAM17 are two closely related members of the ADAM (a disintegrin and metalloprotease) family of membrane-bound sheddases, which proteolytically cleave surface membrane proteins. Both ADAM10 and ADAM17 have been implicated in the proteolytic cleavage of NOTCH receptors and as such regulators of NOTCH signaling. During retinal development, NOTCH signaling facilitates retinal neurogenesis by maintaining progenitor cells in a proliferative state and by mediating retinal cell fates. However, the roles of ADAM10 and ADAM17 in the retina are not well defined. In this study, we set out to clarify the roles of ADAM10 and ADAM17 during early retinal development. The retinal phenotype of conditionally abated Adam17 retinae (Adam17 CKO) did not differ from the controls whereas conditionally ablated Adam10 retinae (Adam10 CKO) exhibited abnormal morphogenesis characterized by the formation of rosettes and a loss of retinal laminae phenotypically similar to morphological abnormalities identified in mice with retinal NOTCH signaling deficiency. Additionally, Adam10 CKO retinae exhibited abnormal neurogenesis characterized by fewer proliferating progenitor cells and greater differentiation of early photoreceptors and retinal ganglion cells. Moreover, constitutive activation of the NOTCH1-intracellular domain (N1-ICD) rescued Adam10 CKO abnormal neurogenesis, as well as abnormal retinal morphology by maintaining retinal cells in the progenitor state. Collectively these findings provide in vivo genetic evidence that ADAM10, and not ADAM17, is indispensable for proper retinal development as a regulator of NOTCH signaling. PMID:27224017

  18. Adam Paulsen, a Pioneer in Auroral Research

    NASA Astrophysics Data System (ADS)

    Jørgensen, Torben S.; Rasmussen, Ole

    2006-02-01

    The 20 to 30 years following the first International Polar Year in 1882-1883 was a period of quickly advancing knowledge and understanding of auroral phenomena. This was the time when hypotheses of aurora being due to, for example, reflections of fires from the interior of the Earth or sunlight from ice particles were abandoned and replaced by the mechanism of precipitating electrons. One of the auroral researchers at that time was the Dane Adam Frederik Wivet Paulsen (1833-1907). However, when reading literature about auroral history, his ideas and work do not seem to have attracted much interest outside his own and neighboring countries. For example, in his sweeping historical account Majestic Lights: The Aurora in Science, History, and the Arts [1980], author Robert Eather only referred to Paulsen in a couple of lines.

  19. Species Specificity of ADAM10 and ADAM17 Proteins in Interleukin-6 (IL-6) Trans-signaling and Novel Role of ADAM10 in Inducible IL-6 Receptor Shedding*

    PubMed Central

    Garbers, Christoph; Jänner, Nathalie; Chalaris, Athena; Moss, Marcia L.; Floss, Doreen M.; Meyer, Dörte; Koch-Nolte, Friedrich; Rose-John, Stefan; Scheller, Jürgen

    2011-01-01

    Hypomorphic ADAM17ex/ex mice showed defects in mucosal regeneration due to inefficient enhanced GFR shedding. ADAM17 is the main sheddase of interleukin-6 receptor (IL-6R) to induce IL-6 trans-signaling. However, serum levels of soluble murine IL-6R were not reduced in ADAM17ex/ex mice, and murine ADAM17 was not the major sheddase of murine IL-6R. Shedding of murine IL-6R by murine ADAM17 was rescued in chimeric murine IL-6R proteins containing any extracellular domain but not the transmembrane and intracellular domain of human IL-6R. Apoptosis is a physiological stimulus of ADAM17-mediated shedding of human IL-6R. Even though apoptosis induced IL-6R shedding in mice, the responsible protease was identified as ADAM10. ADAM10 also was identified as protease responsible for ionomycin-induced shedding of murine and human IL-6R. However, in ADAM10-deficient murine embryonic fibroblasts, compensatory shedding of human IL-6R was mediated by ADAM17, but loss of ADAM10-mediated shedding of murine IL-6R was compensated by an as-yet-unidentified protease. Finally, we identified physiological purinergic P2X7 receptor stimulation as a novel inducer of murine and human IL-6R shedding solely mediated by ADAM10. In conclusion, we describe an unexpected species specificity of ADAM10 and ADAM17 and identified ADAM10 as novel inducible sheddase of IL-6R in mice and humans, which might have consequences for the interpretation of phenotypes from ADAM17- and ADAM10-deficient mice. PMID:21454673

  20. ADAM-17: The Enzyme That Does It All

    PubMed Central

    Gooz, Monika

    2010-01-01

    This review focuses on the role of ADAM-17 in disease. Since its debut as the tumor necrosis factor converting enzyme or TACE, ADAM-17 has been reported to be an indispensible regulator of almost every cellular event from proliferation to migration. The central role of ADAM-17 in cell regulation is rooted in its diverse array of substrates: cytokines, growth factors, and their receptors as well as adhesion molecules are activated or inactivated by their cleavage with ADAM-17. It is therefore not surprising that ADAM-17 is implicated in numerous human diseases including cancer, heart disease, diabetes, rheumatoid arthritis, kidney fibrosis, Alzheimer’s disease, and is a promising target for future treatments. The specific role of ADAM-17 in the pathophysiology of these diseases is very complex and depends on the cellular context. To exploit the therapeutic potential of ADAM-17, it is important to understand how its activity is regulated and how specific organs and cells can be targeted to inactivate or activate the enzyme. PMID:20184396

  1. Control design and simulation of systems modeled using ADAMS

    NASA Technical Reports Server (NTRS)

    Sohoni, Vikram N.

    1989-01-01

    A technique for control design and simulation using the ADAMS software and a control design software package is presented. For design of control systems ADAMS generates a minimum realization linear time invariant (LTI), state space representation of multi-body models. This LTI representation can be produced in formats for input to several commercial control design packages. The user can exercise various design strategies in the control design software to arrive at a suitable compensator. The resulting closed loop model can then be simulated using ADAMS. This procedure is illustrated with two examples.

  2. ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

    SciTech Connect

    Ungerer, Christopher; Doberstein, Kai; Boehm, Beate; Pfeilschifter, Josef; Mihic-Probst, Daniela; Gutwein, Paul

    2010-10-22

    Research highlights: {yields} Strong ADAM15 expression is found in normal melanocytes. {yields} ADAM15 expression is significantly downregulated in patients with melanoma metastasis. {yields} TGF-{beta} can downregulate ADAM15 expression in melanoma cells. {yields} Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. {yields} Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-{gamma} and TGF-{beta} downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.

  3. ADAM12 transmembrane and secreted isoforms promote breast tumor growth: a distinct role for ADAM12-S protein in tumor metastasis.

    PubMed

    Roy, Roopali; Rodig, Scott; Bielenberg, Diane; Zurakowski, David; Moses, Marsha A

    2011-06-10

    Increased levels of ADAM12 have been reported in a variety of human cancers. We have previously reported that urinary ADAM12 is predictive of disease status in breast cancer patients and that ADAM12 protein levels in urine increase with progression of disease. On the basis of these findings, the goal of this study was to elucidate the contribution of ADAM12 in breast tumor growth and progression. Overexpression of both the ADAM12-L (transmembrane) and ADAM12-S (secreted) isoforms in human breast tumor cells resulted in a significantly higher rate of tumor take and increased tumor size. Cells expressing the enzymatically inactive form of the secreted isoform, ADAM12-S, had tumor take rates and tumor volumes similar to those of wild-type cells, suggesting that the tumor-promoting activity of ADAM12-S was a function of its proteolytic activity. Of the two isoforms, only the secreted isoform, ADAM12-S, enhanced the ability of tumor cells to migrate and invade in vitro and resulted in a higher incidence of local and distant metastasis in vivo. This stimulatory effect of ADAM12-S on migration and invasion was dependent on its catalytic activity. Expression of both ADAM12 isoforms was found to be significantly elevated in human malignant breast tissue. Taken together, our results suggest that ADAM12 overexpression results in increased tumor take, tumor size, and metastasis in vivo. These findings suggest that ADAM12 may represent a potential therapeutic target in breast cancer.

  4. N-Glycosylation Regulates ADAM8 Processing and Activation*

    PubMed Central

    Srinivasan, Srimathi; Romagnoli, Mathilde; Bohm, Andrew; Sonenshein, Gail E.

    2014-01-01

    The transmembrane ADAM8 (A Disintegrin And Metalloproteinase 8) protein is abundantly expressed in human breast tumors and derived metastases compared with normal breast tissue, and plays critical roles in aggressive Triple-Negative breast cancers (TNBCs). During ADAM8 maturation, the inactive proform dimerizes or multimerizes and autocatalytically removes the prodomain leading to the formation of the active, processed form. ADAM8 is a glycoprotein; however, little was known about the structure or functional role of these sugar moieties. Here, we report that in estrogen receptor (ER)α-negative, but not -positive, breast cancer cells ADAM8 contains N-glycosylation, which is required for its correct processing and activation. Consistently ADAM8 dimers were detected on the surface of ERα-negative breast cancer cells but not on ERα-positive ones. Site-directed mutagenesis confirmed four N-glycosylazhytion sites (Asn-67, Asn-91, Asn-436, and Asn-612) in human ADAM8. The Asn-67 and Asn-91 prodomain sites contained high mannose, whereas complex type N-glycosylation was observed on Asn-436 and Asn-612 in the active and remnant forms. The Asn-91 and Asn-612 sites were essential for its correct processing and cell surface localization, in particular its exit from the Golgi and endoplasmic reticulum, respectively. The N436Q mutation led to decreased ADAM8 stability due to enhanced lysosomal degradation. In contrast, mutation of the Asn-67 site had only modest effects on enzyme stability and processing. Thus, N-glycosylation is essential for processing, localization, stability, and activity of ADAM8. PMID:25336660

  5. ADAM17 substrate release in proximal tubule drives kidney fibrosis

    PubMed Central

    Kefaloyianni, Eirini; Muthu, Muthu Lakshmi; Kaeppler, Jakob; Sun, Xiaoming; Sabbisetti, Venkata; Chalaris, Athena; Rose-John, Stefan; Wong, Eitan; Sagi, Irit; Waikar, Sushrut S.; Rennke, Helmut; Bonventre, Joseph V.

    2016-01-01

    Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates’ receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor–treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis. PMID:27642633

  6. Alternative mRNA splicing generates two distinct ADAM12 prodomain variants.

    PubMed

    Duhachek-Muggy, Sara; Li, Hui; Qi, Yue; Zolkiewska, Anna

    2013-01-01

    Human ADAM12, transcript variant 1 (later on referred to as Var-1b), present in publicly available databases contains the sequence 5'-GTAATTCTG-3' at the nucleotide positions 340-348 of the coding region, at the 3' end of exon 4. The translation product of this variant, ADAM12-Lb, includes the three amino acid motif (114)VIL(116) in the prodomain. This motif is not conserved in ADAM12 from different species and is not present in other human ADAMs. Currently, it is not clear whether a shorter variant, Var-1a, encoding the protein version without the (114)VIL(116) motif, ADAM12-La, is expressed in human. In this work, we have established that human mammary epithelial cells and breast cancer cells express both Var-1a and Var-1b transcripts. Importantly, the proteolytic processing and intracellular trafficking of the corresponding ADAM12-La and ADAM12-Lb proteins are different. While ADAM12-La is cleaved and trafficked to the cell surface in a manner similar to ADAM12 in other species, ADAM12-Lb is retained in the ER and is not proteolytically processed. Furthermore, the relative abundance of ADAM12-La and ADAM12-Lb proteins detected in several breast cancer cell lines varies significantly. We conclude that the canonical form of transmembrane ADAM12 is represented by Var-1a/ADAM12-La, rather than Var-1b/ADAM12-Lb currently featured in major sequence databases.

  7. TACE (ADAM17) inhibits Schwann cell myelination.

    PubMed

    La Marca, Rosa; Cerri, Federica; Horiuchi, Keisuke; Bachi, Angela; Feltri, M Laura; Wrabetz, Lawrence; Blobel, Carl P; Quattrini, Angelo; Salzer, James L; Taveggia, Carla

    2011-06-12

    Tumor necrosis factor-α-converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

  8. Adam Politzer-Father of Modern Otology.

    PubMed

    Dhungat, J V Pai; Gore, Geeta

    2015-09-01

    Adam Politzer (1835-1920) was born in Alberti near the city of Budapest in Hungary. He studied medicine at the University of Vienna and obtained his Doctorate degree in 1859. Some of his teachers belonged to the famous second "Vienna School" such as Joseph Skoda, Karl Rokitansky, Von Hebra, Josef Hyrtil, Johann Von Oppolzer and famous physiologist Carl Ludwig -who took special interest in him and was influential in his subsequent career. Politzer showed unusual interest in diseases of the ear and started to work in Carl Ludwig's laboratory. His interest at that time was mainly the physics of the auditory system. He studied the innervations of the intrinsic muscles of the ear There he was the first to demonstrate that the innervations of the tensor tympani muscle was by trigeminal nerve and that of the stapedial muscle was by facial nerve. He studied the air movement in the Eustachian tube and variation of air pressure in the tympanic cavity by connecting two manometers- one placed in the external auditory canal meatus, and another in the pharynx. He showed valve near the opening into the middle ear which controls the process. It is usually closed to keep the bacteria and other things away from the mouth and nose.

  9. ADAM12 induces estrogen-independence in breast cancer cells.

    PubMed

    Roy, Roopali; Moses, Marsha A

    2012-02-01

    Antiestrogen therapy has been used successfully to prolong disease-free and overall survival of ER positive breast cancer patients. However, 50% of patients with ER+ tumors fail to respond to such therapy or eventually acquire resistance to endocrine therapy, resulting in tumor progression and mortality. It is imperative, therefore, to understand the mechanisms that lead to hormone refractory breast cancer in order to develop therapeutics that can modulate the resistance to antiestrogen therapy. The protease, ADAM12, can be detected in the urine of breast cancer patients and its levels correlate with disease status, stage, and cancer risk. Within the context of this study, the authors have investigated the role of the two distinct isoforms of ADAM12 in breast tumor cell proliferation and as potential mediators of endocrine resistance. Using stable clones of ADAM12-overexpressing MCF-7 cells, the authors analyzed proliferation rates of these ER+ breast tumor cells both in estrogen-depleted medium and in the presence of the antiestrogens, tamoxifen, and ICI 182,780. Acquired estrogen resistance in these cells was analyzed using phospho-RTK analysis. Upregulation and phosphorylation of proteins were detected via immunoprecipitation and immunoblotting. EGFR and MAPK inhibitors were used to explore the mechanism of acquired estrogen resistance in breast tumor cells. It was observed that overexpression of the two isoforms, transmembrane ADAM12-L, and secreted ADAM12-S, in breast tumor cells promoted estrogen-independent proliferation. In ADAM12-L-expressing cells, estrogen-independence was a direct result of increased EGFR expression and MAPK activation, whereas, the mechanism in ADAM12-S-expressing cells may be enhanced IGF-1R signaling. The importance of the EGFR signaling pathway in the estrogen-independent growth of ADAM12-L expressing cells was highlighted by the effect of EGFR inhibitors AG1478 and PD15035 or MAPK inhibitor U0126, each of which abolished the

  10. Attendance Policies, Student Attendance, and Instructor Verbal Aggressiveness

    ERIC Educational Resources Information Center

    Snyder, Jason; Forbus, Robert; Cistulli, Mark

    2012-01-01

    The authors utilized an experimental design across six sections of a managerial communications course (N = 173) to test the impact of instructor verbal aggressiveness and class attendance policies on student class attendance. The experimental group received a policy based on the principle of social proof (R. B. Cialdini, 2001), which indicated…

  11. The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer?

    PubMed Central

    2011-01-01

    The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion. Forty gene members of the family have been identified, of which 21 are believed to be functional in humans. As proteases, their main substrates are the ectodomains of other transmembrane proteins. These substrates include precursor forms of growth factors, cytokines, growth factor receptors, cytokine receptors and several different types of adhesion molecules. Although altered expression of specific ADAMs has been implicated in different diseases, their best-documented role is in cancer formation and progression. ADAMs shown to play a role in cancer include ADAM9, ADAM10, ADAM12, ADAM15 and ADAM17. Two of the ADAMs, i.e., ADAM10 and 17 appear to promote cancer progression by releasing HER/EGFR ligands. The released ligands activate HER/EGFR signalling that culminates in increased cell proliferation, migration and survival. Consistent with a causative role in cancer, several ADAMs are emerging as potential cancer biomarkers for aiding cancer diagnosis and predicting patient outcome. Furthermore, a number of selective ADAM inhibitors, especially against ADAM10 and ADAM17, have been shown to have anti-cancer effects. At least one of these inhibitors is now undergoing clinical trials in patients with breast cancer. PMID:21906355

  12. Taking Charge: Walter Sydney Adams and the Mount Wilson Observatory

    NASA Astrophysics Data System (ADS)

    Brashear, R.

    2004-12-01

    The growing preeminence of American observational astronomy in the first half of the 20th century is a well-known story and much credit is given to George Ellery Hale and his skill as an observatory-building entrepreneur. But a key figure who has yet to be discussed in great detail is Walter Sydney Adams (1876-1956), Hale's Assistant Director at Mount Wilson Observatory. Due to Hale's illnesses, Adams was Acting Director for much of Hale's tenure, and he became the second Director of Mount Wilson from 1923 to 1946. Behind his New England reserve Adams was instrumental in the growth of Mount Wilson and thus American astronomy in general. Adams was hand-picked by Hale to take charge of stellar spectroscopy work at Yerkes and Mount Wilson and the younger astronomer showed tremendous loyalty to Hale and Hale's vision throughout his career. As Adams assumed the leadership role at Mount Wilson he concentrated on making the observatory a place where researchers worked with great freedom but maintain a high level of cooperation. This paper will concentrate on Adams's early years and look at his growing relationship with Hale and how he came to be the central figure in the early history of Mount Wilson as both a solar and stellar observatory. His education, his years at Dartmouth and Yerkes (including his unfortunate encounter with epsilon Leonis), and his formative years on Mount Wilson are all important in learning how he shaped the direction of Mount Wilson and the development of American astronomy in the first half of the 20th century. This latter history cannot be complete until we bring Adams into better focus.

  13. Characterization of Mammalian ADAM2 and Its Absence from Human Sperm

    PubMed Central

    Choi, Heejin; Jin, Sora; Kwon, Jun Tae; Kim, Jihye; Jeong, Juri; Kim, Jaehwan; Jeon, Suyeon; Park, Zee Yong; Jung, Kang-Jin; Park, Kwangsung; Cho, Chunghee

    2016-01-01

    The members of the ADAM (a disintegrin and metalloprotease) family are membrane-anchored multi-domain proteins that play prominent roles in male reproduction. ADAM2, which was one of the first identified ADAMs, is the best studied ADAM in reproduction. In the male germ cells of mice, ADAM2 and other ADAMs form complexes that contribute to sperm-sperm adhesion, sperm-egg interactions, and the migration of sperm in the female reproductive tract. Here, we generated specific antibodies against mouse and human ADAM2, and investigated various features of ADAM2 in mice, monkeys and humans. We found that the cytoplasmic domain of ADAM2 might enable the differential association of this protein with other ADAMs in mice. Western blot analysis with the anti-human ADAM2 antibodies showed that ADAM2 is present in the testis and sperm of monkeys. Monkey ADAM2 was found to associate with chaperone proteins in testis. In humans, we identified ADAM2 as a 100-kDa protein in the testis, but failed to detect it in sperm. This is surprising given the results in mice and monkeys, but it is consistent with the failure of ADAM2 identification in the previous proteomic analyses of human sperm. These findings suggest that the reproductive functions of ADAM2 differ between humans and mice. Our protein analysis showed the presence of potential ADAM2 complexes involving yet-unknown proteins in human testis. Taken together, our results provide new information regarding the characteristics of ADAM2 in mammalian species, including humans. PMID:27341348

  14. Student Attendance Accounting Manual, 1996.

    ERIC Educational Resources Information Center

    California Community Colleges, Sacramento. Office of the Chancellor.

    This report documents student attendance in California's community colleges. It begins by outlining the requirements for academic calendars as they relate to student attendance. It then defines who is admissible to community colleges in California and classifies all of the possible enrollment statuses one may take. The first chapter defines which…

  15. Phosphatidylserine exposure is required for ADAM17 sheddase function

    PubMed Central

    Sommer, Anselm; Kordowski, Felix; Büch, Joscha; Maretzky, Thorsten; Evers, Astrid; Andrä, Jörg; Düsterhöft, Stefan; Michalek, Matthias; Lorenzen, Inken; Somasundaram, Prasath; Tholey, Andreas; Sönnichsen, Frank D.; Kunzelmann, Karl; Heinbockel, Lena; Nehls, Christian; Gutsmann, Thomas; Grötzinger, Joachim; Bhakdi, Sucharit; Reiss, Karina

    2016-01-01

    ADAM17, a prominent member of the ‘Disintegrin and Metalloproteinase' (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Here we present evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase activity. PS exposure is tightly coupled to substrate shedding provoked by diverse ADAM17 activators. PS dependency is demonstrated in the following: (a) in Raji cells undergoing apoptosis; (b) in mutant PSA-3 cells with manipulatable PS content; and (c) in Scott syndrome lymphocytes genetically defunct in their capacity to externalize PS in response to intracellular Ca2+ elevation. Soluble phosphorylserine but not phosphorylcholine inhibits substrate cleavage. The isolated membrane proximal domain (MPD) of ADAM17 binds to PS but not to phosphatidylcholine liposomes. A cationic PS-binding motif is identified in this domain, replacement of which abrogates liposome-binding and renders the protease incapable of cleaving its substrates in cells. We speculate that surface-exposed PS directs the protease to its targets where it then executes its shedding function. PMID:27161080

  16. ADAM12: a genetic modifier of preclinical peripheral arterial disease

    PubMed Central

    Chen, Lingdan; Okutsu, Mitsuharu; Farber, Charles R.; Hazarika, Surovi; Jones, W. Schuyler; Craig, Damian; Marchuk, Douglas A.; Lye, R. John; Shah, Svati H.; Annex, Brian H.

    2015-01-01

    In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 (ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2. PMID:26163448

  17. Essential Role for ADAM19 in Cardiovascular Morphogenesis

    PubMed Central

    Zhou, Hong-Ming; Weskamp, Gisela; Chesneau, Valérie; Sahin, Umut; Vortkamp, Andrea; Horiuchi, Keisuke; Chiusaroli, Riccardo; Hahn, Rebecca; Wilkes, David; Fisher, Peter; Baron, Roland; Manova, Katia; Basson, Craig T.; Hempstead, Barbara; Blobel, Carl P.

    2004-01-01

    Congenital heart disease is the most common form of human birth defects, yet much remains to be learned about its underlying causes. Here we report that mice lacking functional ADAM19 (mnemonic for a disintegrin and metalloprotease 19) exhibit severe defects in cardiac morphogenesis, including a ventricular septal defect (VSD), abnormal formation of the aortic and pulmonic valves, leading to valvular stenosis, and abnormalities of the cardiac vasculature. During mouse development, ADAM19 is highly expressed in the conotruncus and the endocardial cushion, structures that give rise to the affected heart valves and the membranous ventricular septum. ADAM19 is also highly expressed in osteoblast-like cells in the bone, yet it does not appear to be essential for bone growth and skeletal development. Most adam19−/− animals die perinatally, likely as a result of their cardiac defects. These findings raise the possibility that mutations in ADAM19 may contribute to human congenital heart valve and septal defects. PMID:14673146

  18. ADAM12: a genetic modifier of preclinical peripheral arterial disease.

    PubMed

    Dokun, Ayotunde O; Chen, Lingdan; Okutsu, Mitsuharu; Farber, Charles R; Hazarika, Surovi; Jones, W Schuyler; Craig, Damian; Marchuk, Douglas A; Lye, R John; Shah, Svati H; Annex, Brian H

    2015-09-01

    In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 (ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.

  19. The Adam language: Ada extended with support for multiway activities

    NASA Technical Reports Server (NTRS)

    Charlesworth, Arthur

    1993-01-01

    The Adam language is an extension of Ada that supports multiway activities, which are cooperative activities involving two or more processes. This support is provided by three new constructs: diva procedures, meet statements, and multiway accept statements. Diva procedures are recursive generic procedures having a particular restrictive syntax that facilitates translation for parallel computers. Meet statements and multiway accept statements provide two ways to express a multiway rendezvous, which is an n-way rendezvous generalizing Ada's 2-way rendezvous. While meet statements tend to have simpler rules than multiway accept statements, the latter approach is a more straightforward extension of Ada. The only nonnull statements permitted within meet statements and multiway accept statements are calls on instantiated diva procedures. A call on an instantiated diva procedure is also permitted outside a multiway rendezvous; thus sequential Adam programs using diva procedures can be written. Adam programs are translated into Ada programs appropriate for use on parallel computers.

  20. ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function

    PubMed Central

    Cui, Dan; Arima, Mitsuru; Takubo, Keiyo; Kimura, Tokuhiro; Horiuchi, Keisuke; Minagawa, Takuya; Matsuda, Satoshi; Ikeda, Eiji

    2015-01-01

    Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases. PMID:26242473

  1. ADAM12 and ADAM17 are essential molecules for hypoxia-induced impairment of neural vascular barrier function.

    PubMed

    Cui, Dan; Arima, Mitsuru; Takubo, Keiyo; Kimura, Tokuhiro; Horiuchi, Keisuke; Minagawa, Takuya; Matsuda, Satoshi; Ikeda, Eiji

    2015-08-05

    Neural vascular barrier is essential for the life of multicellular organisms, and its impairment by tissue hypoxia is known to be a central of pathophysiology accelerating the progression of various intractable neural diseases. Therefore, the molecules involved in hypoxia-induced impairment of vascular barrier can be the targets to establish new therapies for intractable diseases. Here, we demonstrate that a disintegrin and metalloproteinases (ADAMs) 12 and 17 expressed in endothelial cells are the molecules responsible for the impairment of neural vascular barrier by hypoxia. Brain microvascular endothelial cells in vitro lost their barrier properties immediately after hypoxic stimulation through diminished localization of claudin-5, a tight junction molecule, on cell membranes. Hypoxic disappearance of claudin-5 from cell membranes and the consequent loss of barrier properties were completely suppressed by inhibition of the metalloproteinase activity which was found to be attributed to ADAM12 and ADAM17. Inhibition of either ADAM12 or ADAM17 was sufficient to rescue the in vivo neural vasculature under hypoxia from the loss of barrier function. This is the first report to specify the molecules which are responsible for hypoxia-induced impairment of neural vascular barrier and furthermore can be the targets of new therapeutic strategies for intractable neural diseases.

  2. Jefferson and Adams on the mind-body problem.

    PubMed

    Robinson, Daniel N

    2003-08-01

    Amidst the voluminous correspondence between Thomas Jefferson and John Adams are several letters pertaining to the material basis of mental life. These reveal in a most suggestive way the substantial differences between them. Well informed on prevailing scientific and philosophical perspectives, Jefferson and Adams used the issue to express their positions on the nature and limits of knowledge, the relative authority of scientific methods and speculations, and the larger question of human perfectibility. At the same time, their exchanges illuminate the prevailing and divergent perspectives on human psychology adopted by major leaders of thought in the New World.

  3. 75 FR 51519 - Regional Transportation District-Acquisition Exemption-Union Pacific Railroad Company in Adams...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-20

    ... Railroad Company in Adams, Denver, and Jefferson Counties, CO Regional Transportation District (RTD) \\1... Subdivision extending approximately 8.96 miles, from milepost 628.50, in Adams County, CO., to milepost...

  4. 77 FR 60004 - Culturally Significant Object Imported for Exhibition Determinations: “Wtewael's Adam and Eve”

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-01

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF STATE Culturally Significant Object Imported for Exhibition Determinations: ``Wtewael's Adam and Eve'' SUMMARY... object to be included in the exhibition ``Wtewael's Adam and Eve,'' imported from abroad for...

  5. The Role of ADAM9 in Tumor-Stromal Interactions in Breast Cancer

    DTIC Science & Technology

    2009-04-01

    endogenously express ADAM9-L and –S (Fig 1 ). Year two research focused on using isoform specific antibodies for immunocytochemistry in preparation for...migration. As outlined in the task 2 update, we have shown that the different isoforms of ADAM9 have opposing effects on breast cancer cell migration...both isoforms of ADAM-9, and our future work in this area will further define the relevant signaling pathways which participate in ADAM9 mediated

  6. Father Knows Best: Using Adam Smith to Teach Transactions Costs

    ERIC Educational Resources Information Center

    Dupont, Brandon

    2014-01-01

    Adam Smith's moral philosophy can be used to introduce economics students to the important idea of transactions costs. The author provides a brief background in this article to Smith's moral philosophy and connects it to the costs of transacting in a way that fits easily into the standard principles of microeconomics classroom. By doing…

  7. The ADaptation and Anticipation Model (ADAM) of sensorimotor synchronization

    PubMed Central

    van der Steen, M. C. (Marieke); Keller, Peter E.

    2013-01-01

    A constantly changing environment requires precise yet flexible timing of movements. Sensorimotor synchronization (SMS)—the temporal coordination of an action with events in a predictable external rhythm—is a fundamental human skill that contributes to optimal sensory-motor control in daily life. A large body of research related to SMS has focused on adaptive error correction mechanisms that support the synchronization of periodic movements (e.g., finger taps) with events in regular pacing sequences. The results of recent studies additionally highlight the importance of anticipatory mechanisms that support temporal prediction in the context of SMS with sequences that contain tempo changes. To investigate the role of adaptation and anticipatory mechanisms in SMS we introduce ADAM: an ADaptation and Anticipation Model. ADAM combines reactive error correction processes (adaptation) with predictive temporal extrapolation processes (anticipation) inspired by the computational neuroscience concept of internal models. The combination of simulations and experimental manipulations based on ADAM creates a novel and promising approach for exploring adaptation and anticipation in SMS. The current paper describes the conceptual basis and architecture of ADAM. PMID:23772211

  8. What Ever Happened to . . . John Adams High School?

    ERIC Educational Resources Information Center

    Doremus, Richard R.

    1981-01-01

    First in a series, this article describes the rise and fall of John Adams High School, an experimental school in Portland (Oregon) that was recently closed after 12 years of operation. The experiences of those who tried to make the experiment work may help others interested in educational innovation. (WD)

  9. "The Adams Chronicles" and the American History Survey

    ERIC Educational Resources Information Center

    Rollins, Richard M.

    1977-01-01

    Film documentaries can be a valuable addition to introductory American history courses. Using "The Adams Chronicles" as an example, the author identifies flaws in the film and then explains how careful planning and analysis of the video and printed programs enabled him to incorporate it effectively into a freshman-level survey course at Ohio State…

  10. Adam Smith and the Moral Economy of the Classroom System.

    ERIC Educational Resources Information Center

    Hamilton, D.

    1980-01-01

    Traces the development of mass schooling to its origins in 19th-century Glasgow. Its importance as an intellectual and economic center enabled Glasgow to invent a solution to the problem of urban schooling, while the association of scholars like Adam Smith with Glasgow University made Scottish educational theories acceptable around the world. (DB)

  11. Adam Smith and the Teaching of English Literature.

    ERIC Educational Resources Information Center

    Court, Franklin E.

    1985-01-01

    Adam Smith used selections from English literature in his classroom during the eighteenth century because he believed that vernacular literature could provide a ready context for the teaching of ideological, social, and moral lessons. He believed that higher education should prepare students for the real business of the real world. (RM)

  12. An Informal Report on Collegiate Successes with "The Adams Chronicles."

    ERIC Educational Resources Information Center

    Goldsberry, Gary G.

    In the spring of 1976, "The Adams Chronicles", a bicentennial television course developed by Coast Community College District and the University of California at San Diego, was distributed to colleges nationwide at no charge with the understanding that each college would return information regarding promotion, enrollment, and form of…

  13. 5. Aerial view west, Adams Dam Road bottom center, State ...

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

    5. Aerial view west, Adams Dam Road bottom center, State Route 100 center, duck pond and reservoir center, State Route 100 center right, State Route 92 below center right, Brandywine Creek State Park center bottom. - Winterthur Farms, Intersection State Routes 92 & 100, Intersection State Routes 92 & 100, Winterthur, New Castle County, DE

  14. 4. Aerial view southwest, Adams Dam Road bottom left, State ...

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

    4. Aerial view southwest, Adams Dam Road bottom left, State Route 100 center, back gates to Winterthur and Wilmington Country Club upper center, duck pond and reservoir bottom right and center, and State Route 92 center bottom. - Winterthur Farms, Intersection State Routes 92 & 100, Intersection State Routes 92 & 100, Winterthur, New Castle County, DE

  15. 3. Aerial view southeast, State Route 92 bottom left, Adams ...

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

    3. Aerial view southeast, State Route 92 bottom left, Adams Dam Road center, Brandywine Creek State Park and J. Chandler Farm in center left, duck pond bottom right and reservoir bottom left. - Winterthur Farms, Intersection State Routes 92 & 100, Intersection State Routes 92 & 100, Winterthur, New Castle County, DE

  16. Using Attendance Worksheets to Improve Student Attendance, Participation, and Learning

    NASA Astrophysics Data System (ADS)

    Rhoads, Edward

    2013-06-01

    As science instructors we are faced with two main barriers with respect to student learning. The first is motivating our students to attend class and the second is to make them active participants in the learning process once we have gotten them to class. As we head further into the internet age this problem only gets exacerbated as students have replaced newspapers with cell phones which can surf the web, check their emails, and play games. Quizzes can motivated the students to attend class but do not necessarily motivate them to pay attention. Active learning techniques work but we as instructors have been bombarded by the active learning message to the point that we either do it already or refuse to. I present another option which in my classroom has doubled the rate at which students learn my material. By using attendance worksheets instead of end of class quizzes I hold students accountable for not just their attendance but for when they show up and when they leave the class. In addition it makes the students an active participant in the class even without using active learning techniques as they are writing notes and answering the questions you have posed while the class is in progress. Therefore using attendance worksheets is an effective tool to use in order to guide student learning.

  17. 29 CFR 785.28 - Involuntary attendance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS HOURS WORKED Application of Principles Lectures, Meetings and Training Programs § 785.28 Involuntary attendance. Attendance is not voluntary,...

  18. 29 CFR 785.28 - Involuntary attendance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS HOURS WORKED Application of Principles Lectures, Meetings and Training Programs § 785.28 Involuntary attendance. Attendance is not voluntary,...

  19. 29 CFR 785.28 - Involuntary attendance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS HOURS WORKED Application of Principles Lectures, Meetings and Training Programs § 785.28 Involuntary attendance. Attendance is not voluntary,...

  20. 29 CFR 785.28 - Involuntary attendance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS HOURS WORKED Application of Principles Lectures, Meetings and Training Programs § 785.28 Involuntary attendance. Attendance is not voluntary,...

  1. 29 CFR 785.28 - Involuntary attendance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS HOURS WORKED Application of Principles Lectures, Meetings and Training Programs § 785.28 Involuntary attendance. Attendance is not voluntary,...

  2. Secretion-Positive LGI1 Mutations Linked to Lateral Temporal Epilepsy Impair Binding to ADAM22 and ADAM23 Receptors

    PubMed Central

    Dazzo, Emanuela; Belluzzi, Elisa; Malacrida, Sandro; Vitiello, Libero; Greggio, Elisa; Tosatto, Silvio C. E.

    2016-01-01

    Autosomal dominant lateral temporal epilepsy (ADTLE) is a focal epilepsy syndrome caused by mutations in the LGI1 gene, which encodes a secreted protein. Most ADLTE-causing mutations inhibit LGI1 protein secretion, and only a few secretion-positive missense mutations have been reported. Here we describe the effects of four disease-causing nonsynonymous LGI1 mutations, T380A, R407C, S473L, and R474Q, on protein secretion and extracellular interactions. Expression of LGI1 mutant proteins in cultured cells shows that these mutations do not inhibit protein secretion. This finding likely results from the lack of effects of these mutations on LGI1 protein folding, as suggested by 3D protein modelling. In addition, immunofluorescence and co-immunoprecipitation experiments reveal that all four mutations significantly impair interaction of LGI1 with the ADAM22 and ADAM23 receptors on the cell surface. These results support the existence of a second mechanism, alternative to inhibition of protein secretion, by which ADLTE-causing LGI1 mutations exert their loss-of-function effect extracellularly, and suggest that interactions of LGI1 with both ADAM22 and ADAM23 play an important role in the molecular mechanisms leading to ADLTE. PMID:27760137

  3. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules.

    PubMed

    Ludwig, Andreas; Hundhausen, Christian; Lambert, Millard H; Broadway, Neil; Andrews, Robert C; Bickett, D Mark; Leesnitzer, M Anthony; Becherer, J David

    2005-03-01

    The transmembrane metzinkin-proteases of the ADAM (a disintegrin and a metalloproteinase)-family ADAM10 and ADAM 17 are both implicated in the ectodomain shedding of various cell surface molecules including the IL6-receptor and the transmembrane chemokines CX3CL1 and CXCL16. These molecules are constitutively released from cultured cells, a process that can be rapidly enhanced by cell stimulation with phorbol esters such as PMA. Recent research supports the view that the constitutive cleavage predominantly involves ADAM10 while the inducible one is mediated to a large extent by ADAM17. We here describe the discovery of hydroxamate compounds with different potency against ADAM10 and ADAM17 and different ability to block constitutive and inducible cleavage of IL6R, CX3CL1 and CXCL16 by the two proteases. By screening a number of hydroxamate inhibitors for the inhibition of recombinant metalloproteinases, a compound was found inhibiting ADAM10 with more than 100-fold higher potency than ADAM17, which may be explained by an improved fit of the compound to the S1' specificity pocket of ADAM10 as compared to that of ADAM17. In cell-based cleavage experiments this compound (GI254023X) potently blocked the constitutive release of IL6R, CX3CL1 and CXCL16, which was in line with the reported involvement of ADAM10 but not ADAM17 in this process. By contrast, the compound did not affect the PMA-induced shedding, which was only blocked by GW280264X, a potent inhibitor of ADAM17. As expected, GI254023X did not further decrease the residual release of CX3CL1 and CXCL16 in ADAM10-deficient cells verifying that the compound's effect on the constitutive shedding of these molecules was exclusively due to the inhibition of ADAM10. Thus, GI254023X may by of use as a preferential inhibitor of constitutive shedding events without effecting the inducible shedding in response to agonists acting similar to PMA.

  4. ADAM17 silencing in mouse colon carcinoma cells: the effect on tumoricidal cytokines and angiogenesis.

    PubMed

    Das, Sudipta; Czarnek, Maria; Bzowska, Monika; Mężyk-Kopeć, Renata; Stalińska, Krystyna; Wyroba, Barbara; Sroka, Jolanta; Jucha, Jarosław; Deneka, Dawid; Stokłosa, Paulina; Ogonek, Justyna; Swartz, Melody A; Madeja, Zbigniew; Bereta, Joanna

    2012-01-01

    ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.

  5. A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis

    PubMed Central

    Köhn-Gaone, Julia; Chalupsky, Karel; Lüllmann-Rauch, Renate; Barikbin, Roja; Bergmann, Juri; Wöhner, Birte; Zbodakova, Olga; Leuschner, Ivo; Martin, Gregor; Tiegs, Gisa; Rose-John, Stefan; Sedlacek, Radislav; Tirnitz-Parker, Janina E.E.; Saftig, Paul; Schmidt-Arras, Dirk

    2016-01-01

    A Disintegrin And Metalloprotease (ADAM) 10 exerts essential roles during organ development and tissue integrity in different organs, mainly through activation of the Notch pathway. However, only little is known about its implication in liver tissue physiology. Here we show that in contrast to its role in other tissues, ADAM10 is dispensable for the Notch2-dependent biliary tree formation. However, we demonstrate that expression of bile acid transporters is dependent on ADAM10. Consequently, mice deficient for Adam10 in hepatocytes, cholangiocytes and liver progenitor cells develop spontaneous hepatocyte necrosis and concomitant liver fibrosis. We furthermore observed a strongly augmented ductular reaction in 15-week old ADAM10Δhep/Δch mice and demonstrate that c-Met dependent liver progenitor cell activation is enhanced. Additionally, liver progenitor cells are primed to hepatocyte differentiation in the absence of ADAM10. These findings show that ADAM10 is a novel central node controlling liver tissue homeostasis. Highlights: Loss of ADAM10 in murine liver results in hepatocyte necrosis and concomitant liver fibrosis. ADAM10 directly regulates expression of bile acid transporters but is dispensable for Notch2-dependent formation of the biliary system. Activation of liver progenitor cells is enhanced through increased c-Met signalling, in the absence of ADAM10. Differentiation of liver progenitor cells to hepatocytes is augmented in the absence of ADAM10. PMID:26942887

  6. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice.

    PubMed

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M; Schrøder, Henrik Daa

    2007-11-01

    Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed effect of ADAM12 was suggested to be mediated via a membrane-stabilizing up-regulation of utrophin, alpha7B integrin, and dystroglycans. Ectopic ADAM12 expression in normal mouse skeletal muscle also improved regeneration after freeze injury, presumably by the same mechanism. Hence, it was suggested that ADAM12 could be a candidate for nonreplacement gene therapy of Duchenne muscular dystrophy. We therefore evaluated the long-term effect of ADAM12 overexpression in muscle. Surprisingly, we observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically overexpressing ADAM12 (ADAM12(+)/mdx mice), even though their utrophin levels were mildly elevated compared with age-matched controls. Thus, membrane stabilization was not sufficient to provide protection during prolonged disease. Consequently, we reinvestigated skeletal muscle regeneration in ADAM12 transgenic mice (ADAM12(+)) after a knife cut lesion and observed that the regeneration process was significantly impaired. ADAM12 seemed to inhibit the satellite cell response and delay myoblast differentiation. These results discourage long-term therapeutic use of ADAM12. They also point to impaired regeneration as a possible factor in development of muscular dystrophy.

  7. Cell-surface metalloprotease ADAM12 is internalized by a clathrin- and Grb2-dependent mechanism.

    PubMed

    Stautz, Dorte; Leyme, Anthony; Grandal, Michael Vibo; Albrechtsen, Reidar; van Deurs, Bo; Wewer, Ulla; Kveiborg, Marie

    2012-11-01

    ADAM12 (A Disintegrin And Metalloprotease 12), a member of the ADAMs family of transmembrane proteins, is involved in ectodomain shedding, cell-adhesion and signaling, with important implications in cancer. Therefore, mechanisms that regulate the levels and activity of ADAM12 at the cell-surface are possibly crucial in these contexts. We here investigated internalization and subsequent recycling or degradation of ADAM12 as a potentially important regulatory mechanism. Our results show that ADAM12 is constitutively internalized primarily via the clathrin-dependent pathway and is subsequently detected in both early and recycling endosomes. The protease activity of ADAM12 does not influence this internalization mechanism. Analysis of essential elements for internalization established that proline-rich regions in the cytoplasmic domain of ADAM12, previously shown to interact with Src-homology 3 domains, were necessary for proper internalization. These sites in the ADAM12 cytoplasmic domain interacted with the adaptor protein growth factor receptor-bound protein 2 (Grb2) and knockdown of Grb2 markedly reduced ADAM12 internalization. These studies establish that internalization is indeed a mechanism that regulates ADAM cell surface levels and show that ADAM12 internalization involves the clathrin-dependent pathway and Grb2.

  8. Tetraspanin15 regulates cellular trafficking and activity of the ectodomain sheddase ADAM10.

    PubMed

    Prox, Johannes; Willenbrock, Michael; Weber, Silvio; Lehmann, Tobias; Schmidt-Arras, Dirk; Schwanbeck, Ralf; Saftig, Paul; Schwake, Michael

    2012-09-01

    A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well-documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10-TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10.

  9. ADAM17 Silencing in Mouse Colon Carcinoma Cells: The Effect on Tumoricidal Cytokines and Angiogenesis

    PubMed Central

    Das, Sudipta; Czarnek, Maria; Bzowska, Monika; Mężyk-Kopeć, Renata; Stalińska, Krystyna; Wyroba, Barbara; Sroka, Jolanta; Jucha, Jarosław; Deneka, Dawid; Stokłosa, Paulina; Ogonek, Justyna; Swartz, Melody A.; Madeja, Zbigniew; Bereta, Joanna

    2012-01-01

    ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response. PMID:23251384

  10. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression.

    PubMed

    Fröhlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar; Kronqvist, Pauliina; Kveiborg, Marie; Sehara-Fujisawa, Atsuko; Mercurio, Arthur M; Wewer, Ulla M

    2011-11-01

    Expression of ADAM12 is low in most normal tissues but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In this study, we found that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 seems to be dispensable for its tumor-promoting effect. Interestingly, we show that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma, ADAM12 is almost exclusively located in tumor cells and, only rarely, seen in the tumor-associated stroma. We hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, on the basis of the fact that TGF-β1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-β1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12 synthesis, and growth of these cells in vivo induced more than 200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLU) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our hypothesis that tumor-associated stroma triggers ADAM12 expression.

  11. Adams-Based Rover Terramechanics and Mobility Simulator - ARTEMIS

    NASA Technical Reports Server (NTRS)

    Trease, Brian P.; Lindeman, Randel A.; Arvidson, Raymond E.; Bennett, Keith; VanDyke, Lauren P.; Zhou, Feng; Iagnemma, Karl; Senatore, Carmine

    2013-01-01

    The Mars Exploration Rovers (MERs), Spirit and Opportunity, far exceeded their original drive distance expectations and have traveled, at the time of this reporting, a combined 29 kilometers across the surface of Mars. The Rover Sequencing and Visualization Program (RSVP), the current program used to plan drives for MERs, is only a kinematic simulator of rover movement. Therefore, rover response to various terrains and soil types cannot be modeled. Although sandbox experiments attempt to model rover-terrain interaction, these experiments are time-intensive and costly, and they cannot be used within the tactical timeline of rover driving. Imaging techniques and hazard avoidance features on MER help to prevent the rover from traveling over dangerous terrains, but mobility issues have shown that these methods are not always sufficient. ARTEMIS, a dynamic modeling tool for MER, allows planned drives to be simulated before commands are sent to the rover. The deformable soils component of this model allows rover-terrain interactions to be simulated to determine if a particular drive path would take the rover over terrain that would induce hazardous levels of slip or sink. When used in the rover drive planning process, dynamic modeling reduces the likelihood of future mobility issues because high-risk areas could be identified before drive commands are sent to the rover, and drives planned over these areas could be rerouted. The ARTEMIS software consists of several components. These include a preprocessor, Digital Elevation Models (DEMs), Adams rover model, wheel and soil parameter files, MSC Adams GUI (commercial), MSC Adams dynamics solver (commercial), terramechanics subroutines (FORTRAN), a contact detection engine, a soil modification engine, and output DEMs of deformed soil. The preprocessor is used to define the terrain (from a DEM) and define the soil parameters for the terrain file. The Adams rover model is placed in this terrain. Wheel and soil parameter files

  12. Birthday Effects and Preschool Attendance

    ERIC Educational Resources Information Center

    Huang, Francis L.; Invernizzi, Marcia A.

    2013-01-01

    Young-for-grade students have been shown to receive lower grades and have a higher likelihood of retention compared to their oldest peers upon kindergarten entry. Our study of 1474 economically disadvantaged first-time kindergarteners investigates if preschool attendance may ameliorate some of the risks potentially associated with being…

  13. System Verification of MSL Skycrane Using an Integrated ADAMS Simulation

    NASA Technical Reports Server (NTRS)

    White, Christopher; Antoun, George; Brugarolas, Paul; Lih, Shyh-Shiuh; Peng, Chia-Yen; Phan, Linh; San Martin, Alejandro; Sell, Steven

    2012-01-01

    Mars Science Laboratory (MSL) will use the Skycrane architecture to execute final descent and landing maneuvers. The Skycrane phase uses closed-loop feedback control throughout the entire phase, starting with rover separation, through mobility deploy, and through touchdown, ending only when the bridles have completely slacked. The integrated ADAMS simulation described in this paper couples complex dynamical models created by the mechanical subsystem with actual GNC flight software algorithms that have been compiled and linked into ADAMS. These integrated simulations provide the project with the best means to verify key Skycrane requirements which have a tightly coupled GNC-Mechanical aspect to them. It also provides the best opportunity to validate the design of the algorithm that determines when to cut the bridles. The results of the simulations show the excellent performance of the Skycrane system.

  14. ADAM: An Axisymmetric Duct Aeroacoustic Modeling system. [aircraft turbofan engines

    NASA Technical Reports Server (NTRS)

    Abrahamson, A. L.

    1983-01-01

    An interconnected system of computer programs for analyzing the propagation and attenuation of sound in aeroengine ducts containing realistic compressible subsonic mean flows, ADAM was developed primarily for research directed towards the reduction of noise emitted from turbofan aircraft engines. The two basic components are a streamtube curvature program for determination of the mean flow, and a finite element code for solution of the acoustic propagation problem. The system, which has been specifically tailored for ease of use, is presently installed at NASA Langley Reseach Center on a Control Data Cyber 175 Computer under the NOS Operating system employing a Tektronix terminal for interactive graphics. The scope and organization of the ADAM system is described. A users guide, examples of input data, and results for selected cases are included.

  15. Empathy's purity, sympathy's complexities; De Waal, Darwin and Adam Smith.

    PubMed

    van der Weele, Cor

    2011-07-01

    Frans de Waal's view that empathy is at the basis of morality directly seems to build on Darwin, who considered sympathy as the crucial instinct. Yet when we look closer, their understanding of the central social instinct differs considerably. De Waal sees our deeply ingrained tendency to sympathize (or rather: empathize) with others as the good side of our morally dualistic nature. For Darwin, sympathizing was not the whole story of the "workings of sympathy"; the (selfish) need to receive sympathy played just as central a role in the complex roads from sympathy to morality. Darwin's understanding of sympathy stems from Adam Smith, who argued that the presence of morally impure motives should not be a reason for cynicism about morality. I suggest that De Waal's approach could benefit from a more thorough alignment with the analysis of the workings of sympathy in the work of Darwin and Adam Smith.

  16. Automatic Dynamic Aircraft Modeler (ADAM) for the Computer Program NASTRAN

    NASA Technical Reports Server (NTRS)

    Griffis, H.

    1985-01-01

    Large general purpose finite element programs require users to develop large quantities of input data. General purpose pre-processors are used to decrease the effort required to develop structural models. Further reduction of effort can be achieved by specific application pre-processors. Automatic Dynamic Aircraft Modeler (ADAM) is one such application specific pre-processor. General purpose pre-processors use points, lines and surfaces to describe geometric shapes. Specifying that ADAM is used only for aircraft structures allows generic structural sections, wing boxes and bodies, to be pre-defined. Hence with only gross dimensions, thicknesses, material properties and pre-defined boundary conditions a complete model of an aircraft can be created.

  17. Distal Limb Defects and Aplasia Cutis: Adams-Oliver Syndrome.

    PubMed

    Renfree, Kevin J; Dell, Paul C

    2016-07-01

    Adams-Oliver syndrome is a rare congenital condition that should be considered in persons with terminal transverse limb deficiencies and scalp defects (aplasia cutis congenita). Broad phenotypic variability exists in this condition. In its more severe forms, Adams-Oliver syndrome can involve the cardiovascular system, central nervous system, gastrointestinal tract, and genitourinary system and should require prompt evaluation by appropriate subspecialists. Extremity involvement is typically bilateral and asymmetrical, with lower extremities involved more than upper extremities. Brachydactyly is the most common limb defect, and severity ranges from hypoplastic nails to complete absence of the distal limb. The syndrome has been described as resulting from autosomal dominant and recessive modes of inheritance, but most cases are sporadic. No gene has been identified. Although the exact pathogenic mechanism is unknown, a common hypothesis is that a vascular disturbance occurs in watershed areas, such as cranial vertex and limbs, during fetal development.

  18. Application of the ADAMS program to deployable space truss structures

    NASA Technical Reports Server (NTRS)

    Calleson, R. E.

    1985-01-01

    The need for a computer program to perform kinematic and dynamic analyses of large truss structures while deploying from a packaged configuration in space led to the evaluation of several existing programs. ADAMS (automatic dynamic analysis of mechanical systems), a generalized program from performing the dynamic simulation of mechanical systems undergoing large displacements, is applied to two concepts of deployable space antenna units. One concept is a one cube folding unit of Martin Marietta's Box Truss Antenna and the other is a tetrahedral truss unit of a Tetrahedral Truss Antenna. Adequate evaluation of dynamic forces during member latch-up into the deployed configuration is not yet available from the present version of ADAMS since it is limited to the assembly of rigid bodies. Included is a method for estimating the maximum bending stress in a surface member at latch-up. Results include member displacement and velocity responses during extension and an example of member bending stresses at latch-up.

  19. Evaluation of ADAM/1 model for advanced coal extraction concepts

    NASA Technical Reports Server (NTRS)

    Deshpande, G. K.; Gangal, M. D.

    1982-01-01

    Several existing computer programs for estimating life cycle cost of mining systems were evaluated. A commercially available program, ADAM/1 was found to be satisfactory in relation to the needs of the advanced coal extraction project. Two test cases were run to confirm the ability of the program to handle nonconventional mining equipment and procedures. The results were satisfactory. The model, therefore, is recommended to the project team for evaluation of their conceptual designs.

  20. Control of ADAM17 activity by regulation of its cellular localisation

    PubMed Central

    Lorenzen, Inken; Lokau, Juliane; Korpys, Yvonne; Oldefest, Mirja; Flynn, Charlotte M.; Künzel, Ulrike; Garbers, Christoph; Freeman, Matthew; Grötzinger, Joachim; Düsterhöft, Stefan

    2016-01-01

    An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. This central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation. Most mature ADAM17 is localised intracellularly, with only a small amount at the cell surface. We found that ADAM17 is constitutively internalised by clathrin-coated pits and that physiological stimulators such as GPCR ligands induce ADAM17-mediated shedding, but do not alter the cell-surface abundance of the protease. In contrast, the PKC-activating phorbol ester PMA, often used as a strong inducer of ADAM17, causes not only proteolysis by ADAM17 but also a rapid increase of the mature protease at the cell surface. This is followed by internalisation and subsequent degradation of the protease. Eventually, this leads to a substantial downregulation of mature ADAM17. Our results therefore imply that physiological activation of ADAM17 does not rely on its relocalisation, but that PMA-induced PKC activity drastically dysregulates the localisation of ADAM17. PMID:27731361

  1. Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System.

    PubMed

    Meyer zu Horste, Gerd; Derksen, Angelika; Stassart, Ruth; Szepanowski, Fabian; Thanos, Melissa; Stettner, Mark; Boettcher, Christina; Lehmann, Helmar C; Hartung, Hans-Peter; Kieseier, Bernd C

    2015-11-01

    The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.

  2. Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

    PubMed

    Bertram, Anna; Lovric, Svjetlana; Engel, Alissa; Beese, Michaela; Wyss, Kristin; Hertel, Barbara; Park, Joon-Keun; Becker, Jan U; Kegel, Johanna; Haller, Hermann; Haubitz, Marion; Kirsch, Torsten

    2015-11-01

    ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

  3. Involvement of ADAM10 in axonal outgrowth and myelination of the peripheral nerve.

    PubMed

    Jangouk, Parastoo; Dehmel, Thomas; Meyer Zu Hörste, Gerd; Ludwig, Andreas; Lehmann, Helmar C; Kieseier, Bernd C

    2009-12-01

    The disintegrin and metalloproteinase 10 (ADAM10) is a membrane-anchored metalloproteinase with both proteolytic and disintegrin characteristics. Here, we investigate the expression, regulation, and functional role of ADAM10 in axonal outgrowth and myelination of the peripheral nerve. Expression pattern analysis of 11 ADAM family members in co-cultures of rat dorsal root ganglia (DRG) neurons and Schwann cells (SCs) demonstrated the most pronounced mRNA expression for ADAM10. In further studies, ADAM10 was found to be consistently upregulated in DRG-SC co-cultures before the induction of myelination. Neurons as well as SCs widely expressed ADAM10 at the protein level. In neurons, the expression of ADAM10 was exclusively limited to the axons before the induction of myelination. Inhibition of ADAM10 activity by the hydroxamate-based inhibitors GI254023X and GW280264X resulted in a significant decrease in the mean axonal length. These data suggest that ADAM10 represents a prerequisite for myelination, although its activity is not required during the process of myelination itself as demonstrated by expression analysis of myelin protein zero (P0) and Sudan black staining. Hence, during the process of myelin formation, ADAM10 is highly upregulated and appears to be critically involved in axonal outgrowth that is a requirement for myelination in the peripheral nerve.

  4. Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

    PubMed Central

    Bertram, Anna; Lovric, Svjetlana; Engel, Alissa; Beese, Michaela; Wyss, Kristin; Hertel, Barbara; Park, Joon-Keun; Becker, Jan U.; Kegel, Johanna; Haller, Hermann; Haubitz, Marion

    2015-01-01

    ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease. PMID:25788529

  5. Upregulated expression of ADAM12 is associated with progression of oral squamous cell carcinoma.

    PubMed

    Uehara, Erika; Shiiba, Masashi; Shinozuka, Keiji; Saito, Kengo; Kouzu, Yukinao; Koike, Hirofumi; Kasamatsu, Atsushi; Sakamoto, Yosuke; Ogawara, Katsunori; Uzawa, Katsuhiro; Tanzawa, Hideki

    2012-05-01

    ADAMs are a disintegrin and metalloproteinase family of membrane-associated metalloproteinases characterized by their multidomain structure, and have been reported to be associated with various malignant tumors. The aim of this study was to identify crucial members of the ADAM family in oral squamous cell carcinoma (OSCC), and to reveal their biological function and clinical significance. To clarify whether ADAM family genes are involved in OSCC, changes in the expression profile were investigated by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis and immunohistochemical analysis. Functional analysis was performed by comparing cellular proliferation of siADAM-transfected cell lines and parental cell lines. Real-time qRT-PCR analysis identified significantly upregulated expression of ADAM12 in OSCC-derived cell lines. This was validated in OSCC samples using real-time qRT-PCR and immuno-histochemical staining. ADAM12 expression was correlated with TNM classification; significantly greater expression of ADAM12 was observed in tumors with higher T classification and more advanced stages. Moreover, siADAM12-transfected cells showed both a suppressed proliferation rate and increased transforming growth factor (TGF)-β3 expression. Our data indicate that ADAM12 is overexpressed in OSCC and might accelerate cellular proliferation. Its function may be associated with TGF-β signaling. This study suggests that controlling the expression or activity of ADAM12 could be a useful strategy in the development of an effective cure for OSCC.

  6. Dr. Lytle Adams' incendiary "bat bomb" of World War II.

    PubMed

    Christen, Arden G; Christen, Joan A

    2004-11-01

    On December 7, 1941, a 60-year old dentist from Irwin, Pennsylvania, Dr. Lytle S. Adams, was driving home from a vacation at Carlsbad Caverns in New Mexico. Hours earlier, he had been gripped with amazement as he witnessed millions of bats exiting the caves of Carlsbad. Listening to his car radio on his return trip, he was shocked to hear that Japan had just attacked Pearl Harbor. Dr. Adams, outraged over this travesty, began to mentally construct a plan for U.S. retaliation. As his thoughts returned to the countless bats that had awed him, he formed a tentative plan: millions of these small, flying mammals could be connected to tiny, time-fused incendiary bombs, and then released to land on the flimsily constructed structures which dotted the cities of Japan. Within a few minutes, the bombs would explode and enflame the entire urban areas. He postulated that these immeasurable numbers of fires, spreading their devastation over such vast areas within Japanese cities would result in the enemy's speedy surrender. This article documents the futile efforts of Dr. Adams, his team and the U.S. government to develop and employ an effective, incendiary bat bomb. The recently developed atom bomb, a far more deadly weapon was used in its place.

  7. [The importance of ADAM family proteins in malignant tumors].

    PubMed

    Walkiewicz, Katarzyna; Gętek, Monika; Muc-Wierzgoń, Małgorzata; Kokot, Teresa; Nowakowska-Zajdel, Ewa

    2016-02-11

    Increasing numbers of reports about the role of adamalysins (ADAM) in malignant tumors are being published. To date, more than 30 representatives of this group, out of which about 20 occur in humans, have been described. The ADAM family is a homogeneous group of proteins which regulate, from the stage of embryogenesis, a series of processes such as cell migration, adhesion, and cell fusion. Half of them have proteolytic activity and are involved in the degradation of the extracellular matrix and the disintegration of certain protein complexes, thereby regulating the bioavailability of various growth factors. Many of these functions have a direct role in the processes of carcinogenesis and promoting the growth of tumor, which affect some signaling pathways, including those related to insulin-like growth factors (IGF1, IGF2), vascular growth factor (VEGF), tumor necrosis factor α (TNFα) and the EGFR/HER pathway. Another branch of studies is the evaluation of the possibility of using members of ADAM family proteins in the diagnosis, especially in breast, colon and non- small cell lung cancer. The detection of concentrations of adamalysin in serum, urine and pleural aspirates might contribute to the development of methods of early diagnosis of cancer and monitoring the therapy. However, both the role of adamalysins in the development and progression of tumors and their importance as a diagnostic and predictive further research still need to be checked on large groups of patients.

  8. ADAM8 Enhances Osteoclast Precursor Fusion and Osteoclast Formation In Vitro and In Vivo

    PubMed Central

    Ishizuka, Hisako; García-Palacios, Verónica; Lu, Ganwei; Subler, Mark A; Zhang, Heju; Boykin, Christina S; Choi, Sun Jin; Zhao, Liena; Patrene, Kenneth; Galson, Deborah L; Blair, Harry C; Hadi, Tamer M; Windle, Jolene J; Kurihara, Noriyoshi; Roodman, G David

    2011-01-01

    ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)–ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-κB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease. © 2011 American Society for Bone and Mineral Research. PMID:20683884

  9. iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

    PubMed Central

    Li, Xue; Maretzky, Thorsten; Weskamp, Gisela; Monette, Sébastien; Qing, Xiaoping; Issuree, Priya Darshinee A.; Crawford, Howard C.; McIlwain, David R.; Mak, Tak W.; Salmon, Jane E.; Blobel, Carl P.

    2015-01-01

    The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17−/− mice die perinatally with open eyes, like Egfr−/− mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain. This suggests that ADAM17 is regulated by other integral membrane proteins, although much remains to be learned about the underlying mechanism. Recently, inactive Rhomboid 2 (iRhom2), which has seven transmembrane domains, emerged as a molecule that controls the maturation and function of ADAM17 in myeloid cells. However, iRhom2−/− mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2−/− double knockout mice resemble Adam17−/− and Egfr−/− mice in that they die perinatally with open eyes, misshapen heart valves, and growth plate defects. Mechanistically, we show lack of mature ADAM17 and strongly reduced EGFR phosphorylation in iRhom1/2−/− tissues. Finally, we demonstrate that iRhom1 is not essential for mouse development but regulates ADAM17 maturation in the brain, except in microglia, where ADAM17 is controlled by iRhom2. These results provide genetic, cell biological, and biochemical evidence that a principal function of iRhoms1/2 during mouse development is to regulate ADAM17-dependent EGFR signaling, suggesting that iRhoms1/2 could emerge as novel targets for treatment of ADAM17/EGFR-dependent pathologies. PMID:25918388

  10. The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain.

    PubMed

    Saftig, Paul; Lichtenthaler, Stefan F

    2015-12-01

    Proteins belonging to the 'A Disintegrin And Metalloproteinase' (ADAM) family are membrane-anchored proteases that are able to cleave the extracellular domains of several membrane-bound proteins in a process known as 'ectodomain shedding'. In the central nervous system, ADAM10 has attracted the most attention, since it was described as the amyloid precursor protein α-secretase over ten years ago. Despite the excitement over the potential of ADAM10 as a novel drug target in Alzheimer disease, the physiological functions of ADAM10 in the brain are not yet well understood. This is largely because of the embryonic lethality of ADAM10-deficient mice, which results from the loss of cleavage and signaling of the Notch receptor, another ADAM10 substrate. However, the recent generation of conditional ADAM10-deficient mice and the identification of further ADAM10 substrates in the brain has revealed surprisingly numerous and fundamental functions of ADAM10 in the development of the embryonic brain and also in the homeostasis of adult neuronal networks. Mechanistically, ADAM10 controls these functions by utilizing unique postsynaptic substrates in the central nervous system, in particular synaptic cell adhesion molecules, such as neuroligin-1, N-cadherin, NCAM, Ephrin A2 and A5. Consequently, a dysregulation of ADAM10 activity is linked to psychiatric and neurological diseases, such as epilepsy, fragile X syndrome and Huntington disease. This review highlights the recent progress in understanding the substrates and function as well as the regulation and cell biology of ADAM10 in the central nervous system and discusses the value of ADAM10 as a drug target in brain diseases.

  11. Modulation of integrin α4β1 by ADAM28 promotes lymphocyte adhesion and transendothelial migration.

    PubMed

    McGinn, Owen J; English, William R; Roberts, Stephanie; Ager, Ann; Newham, Peter; Murphy, Gillian

    2011-10-01

    ADAMs (a disintegrin and metalloproteinase) are a family of type I transmembrane glycoproteins related to snake venom metalloproteases and disintegrins. They are regulatory proteins that modulate intercellular adhesion and the bioavailability of growth factors, and have been implicated in many disease states, including cancer, immunity and inflammation. One member of the ADAM family, ADAM28, has been reported to bind to the integrin α4β1 in humans; however, the distribution of ADAM28 and the biological consequences of ADAM28-α4β1 interactions are yet to be fully elucidated. The expression of ADAM28 in human and murine tissues was examined by multiple Affymetrix microarray analyses, real-time RT-PCR (reverse transcription-PCR) and immunohistochemical staining. We found that ADAM28 has a relatively restricted expression pattern in mouse and human and is highly expressed in the B-lymphocyte lineage, including chronic lymphocytic leukaemic B-cells. The murine B-lymphoma line L1-2 and recombinant soluble murine ADAM28 were used to investigate ADAM28-α4β1 interactions. Our data reveal that ADAM28 binding to α4β1 is typical of integrin-ligand interactions, since it is attenuated by anti-functional integrin antibodies, and is enhanced by Mn2+ and the integrin mAb (monoclonal antibody) 9EG7. However, a key finding was that soluble ADAM28 unexpectedly enhanced α4β1-dependent cell adhesion to VCAM-1 (vascular cell adhesion molecule-1). In so doing ADAM28 was able to influence lymphocyte adhesion to, and migration through, endothelial monolayers, suggesting a physiological role for ADAM28 in regulating the specific spatial and temporal transendothelial migration of lymphocytes.

  12. A Disintegrin and Metalloprotease (ADAM) 10 and ADAM17 Are Major Sheddases of T Cell Immunoglobulin and Mucin Domain 3 (Tim-3)*

    PubMed Central

    Möller-Hackbarth, Katja; Dewitz, Christin; Schweigert, Olga; Trad, Ahmad; Garbers, Christoph; Rose-John, Stefan; Scheller, Jürgen

    2013-01-01

    T cell immunoglobulin and mucin domain 3 (Tim-3) dampens the response of CD4+ and CD8+ effector T cells via induction of cell death and/or T cell exhaustion and enhances the ability of macrophages to clear pathogens via binding to galectin 9. Here we provide evidence that human Tim-3 is a target of A disintegrin and metalloprotease (ADAM)-mediated ectodomain shedding resulting in a soluble form of Tim-3. We identified ADAM10 and ADAM17 as major sheddases of Tim-3 as shown by ADAM-specific inhibitors and the ADAM10 pro-domain in HEK293 cells and ADAM10/ADAM17-deficient murine embryonic fibroblasts. PMA-induced shedding of Tim-3 was abrogated by deletion of amino acids Glu181–Asp190 of the stalk region and Tim-3 lacking the intracellular domain was not efficiently cleaved after PMA stimulation. Surprisingly, a single lysine residue within the intracellular domain rescues shedding of Tim-3. Shedding of endogenous Tim-3 was found in primary human CD14+ monocytes after PMA and ionomycin stimulation. Importantly, the recently described down-regulation of Tim-3 from Toll-like receptor-activated CD14+ monocytes was caused by ADAM10- and ADAM17-mediated shedding. Inhibition of Tim-3 shedding from lipopolysaccharide-induced monocytes did not influence lipopolysaccharide-induced TNFα and IL-6 but increases IL-12 expression. In summary, we describe Tim-3 as novel target for ADAM-mediated ectodomain shedding and suggest a role of Tim-3 shedding in TLR-mediated immune responses of CD14+ monocytes. PMID:24121505

  13. The inertia of sex: Henry Adams on family and the politics of unconditional love.

    PubMed

    Duff, Brian

    2010-01-01

    This article offers a reassessment of the contemporary relevance of the political thought of Henry Adams through a focus on his ideas about the relationship between family and politics. Adams' ideas have been dismissed by contemporary thinkers, like Richard Rorty, who rely on similar ideas about the role family should play in politics. The article traces the role of ideas about family as a unifying theme in Adams' history, fiction, and autobiography. It shows both why Adams believed familial sentiments, especially feminine and motherly love, were crucial to political unity, and why he thought these sentiments had become increasingly difficult to rely upon. In showing how Adams wrestled with the difficulties that emerge in putting familial sentiments to use for politics, the article suggests that Adams' ideas offer useful lessons for contemporary thinkers interested in the relationship between family and politics.

  14. A substrate-optimized electrophoretic mobility shift assay for ADAM12.

    PubMed

    Kotzsch, Alexander; Skovgaard, Tine; Buus, Uwe; Andersen, Simon; Devkota, Kanchan; Berthelsen, Jens

    2014-05-01

    ADAM12 belongs to the A disintegrin and metalloprotease (ADAM) family of secreted sheddases activating extracellular growth factors such as epidermal growth factor receptor (EGFR) ligands and tumor necrosis factor-alpha (TNF-α). ADAM proteases, most notably ADAM17 (TNF-α-converting enzyme), have long been investigated as pharmaceutical drug targets; however, due to lack of potency and in vivo side effects, none of the small-molecule inhibitors discovered so far has made it beyond clinical testing. Ongoing research on novel selective inhibitors of ADAMs requires reliable biochemical assays to validate molecular probes from large-scale screening efforts. Here we describe an electrophoretic mobility shift assay for ADAM12 based on the identification of an optimized peptide substrate that is characterized by excellent performance and reproducibility.

  15. ADAM12: a potential target for the treatment of chronic wounds.

    PubMed

    Harsha, Asheesh; Stojadinovic, Olivera; Brem, Harold; Sehara-Fujisawa, Atsuko; Wewer, Ulla; Loomis, Cynthia A; Blobel, Carl P; Tomic-Canic, Marjana

    2008-08-01

    Wound healing is a complex process involving multiple cellular events, including cell proliferation, migration, and tissue remodeling. A disintegrin and metalloprotease 12 (ADAM12) is a membrane-anchored metalloprotease, which has been implicated in activation-inactivation of growth factors that play an important role in wound healing, including heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) and insulin growth factor (IGF) binding proteins. Here, we report that expression of ADAM12 is fivefold upregulated in the nonhealing edge of chronic ulcers compared to healthy skin, based on microarrays of biopsies taken from five patients and from healthy controls (p = 0.013). The increase in ADAM12 expression in chronic ulcers was confirmed by quantitative real-time polymerase chain reaction (RT-PCR). Moreover, immunohistochemical analysis demonstrated a pronounced increase in the membranous and intracellular signal for ADAM12 in the epidermis of chronic wounds compared to healthy skin. These findings, coupled with our previous observations that lack of keratinocyte migration contributes to the pathogenesis of chronic ulcers, prompted us to evaluate how the absence of ADAM12 affects the migration of mouse keratinocytes. Skin explants from newborn ADAM12-/- or wild-type (WT) mice were used to quantify keratinocyte migration out of the explants over a period of 7 days. We found a statistically significant increase in the migration of ADAM12-/- keratinocytes compared to WT control (p = 0.0014) samples. Taken together, the upregulation of ADAM12 in chronic wounds and the increased migration of keratinocytes in the absence of ADAM12 suggest that ADAM12 is an important mediator of wound healing. We hypothesize that increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration and that topical ADAM12 inhibitors may therefore prove useful for the treatment of chronic wounds.

  16. A Disintegrin and Metalloproteinase-12 (ADAM12): Function, Roles in Disease Progression, and Clinical Implications

    PubMed Central

    Nyren-Erickson, Erin K.; Jones, Justin M.; Srivastava, D. K.

    2013-01-01

    Background A disintegrin and metalloproteinase-12 (ADAM12) is a member of the greater ADAM family of enzymes: these are multifunctional, generally membrane-bound, zinc proteases for which there are forty genes known (21 of these appearing in humans). ADAM12 has been implicated in the pathogenesis of various cancers, liver fibrogenesis, hypertension, and asthma, and its elevation or decrease in human serum has been linked to these and other physiological/pathological conditions. Scope In this review, we begin with a brief overview of the ADAM family of enzymes and protein structure. We then discuss the role of ADAM12 in the progression and/or diagnosis of various disease conditions, and we will conclude with an exploration of currently known natural and synthetic inhibitors. Major Conclusions ADAM12 has potential to emerge as a successful drug target, although targeting the metalloproteinase domain with any specificity will be difficult to achieve due to structural similarity between the members of the ADAM and MMP family of enzymes. Overall, more research is required to establish ADAM12 being as a highly desirable biomarker and drug target of different diseases, and their selective inhibitors as potential therapeutic agents. General Significance Given the appearance of elevated levels of ADAM12 in various diseases, particularly breast cancer, our understanding of this enzyme both as a biomarker and a potential drug target could help make significant inroads into both early diagnosis and treatment of disease. PMID:23680494

  17. John Adams's Montesquieuean Moment: Enlightened Historicism in the Discourses on Davila.

    PubMed

    Green, Jonathan

    2016-01-01

    At the outset of the French Revolution John Adams penned a series of Discourses of Davila, philosophical ruminations on the sixteenth-century French Wars of Religion. Recent historians have read these Discourses in terms of Adams's Machiavellianism-his conviction that men's passions lead to violence, if unrestrained. But this reading overlooks the extent to which Adams intended his Discourses as a particular investigation into the French nation's character, and into whether the revolutionaries could lay claim to a native, French tradition of mixed constitutional government. Situating the Discourses vis-à-vis Adams's contemporaneous reading of Montesquieu, this article argues for an underappreciated historicist dimension to his thought.

  18. ADAM10 Is Involved in Cell Junction Assembly in Early Porcine Embryo Development

    PubMed Central

    Kwon, Jeongwoo; Jeong, Sung-min; Choi, Inchul; Kim, Nam-Hyung

    2016-01-01

    ADAM10 (A Disintegrin and Metalloprotease domain-containing protein 10) is a cell surface protein with a unique structure possessing both potential adhesion and protease domains. However, the role of ADAM10 in preimplantation stage embryos is not clear. In this study, we examined the expression patterns and functional roles of ADAM10 in porcine parthenotes during preimplantation development. The transcription level of ADAM10 dramatically increased from the morula stage onward. Immunostaining revealed that ADAM10 was present in both the nucleus and cytoplasm in early cleavage stage embryos, and localized to the apical region of the outer cells in morula and blastocyst embryos. Knockdown (KD) of ADAM10 using double strand RNA did not alter preimplantation embryo development until morula stage, but resulted in significantly reduced development to blastocyst stage. Moreover, the KD blastocyst showed a decrease in gene expression of adherens and tight junction (AJ/TJ), and an increase in trophectoderm TJ permeability by disrupting TJ assembly. Treatment with an ADAM10 specific chemical inhibitor, GI254023X, at the morula stage also inhibited blastocyst development and led to disruption of TJ assembly. An in situ proximity ligation assay demonstrated direct interaction of ADAM10 with coxsackie virus and adenovirus receptor (CXADR), supporting the involvement of ADAM10 in TJ assembly. In conclusion, our findings strongly suggest that ADADM10 is important for blastocyst formation rather than compaction, particularly for TJ assembly and stabilization in preimplantation porcine parthenogenetic development. PMID:27043020

  19. Chemotherapy-induced activation of ADAM-17: a novel mechanism of drug resistance in colorectal cancer

    PubMed Central

    Kyula, Joan N.; Van Schaeybroeck, Sandra; Doherty, Joanne; Fenning, Catherine S.; Longley, Daniel B.; Johnston, Patrick G.

    2010-01-01

    Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor (HER) survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a desintegrin and metalloproteases) and soluble growth factors in this acute drug resistance mechanism. Experimental design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting. Results: Chemotherapy (5-Fluorouracil, 5-FU) treatment resulted in acute increases in TGF-α-, amphiregulin- and heregulin-ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. siRNA-mediated silencing and pharmacological inhibition confirmed that ADAM-17 was the principal ADAM involved in this pro-survival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumour growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of HERs, but also increased the activity of a number of other growth factor receptors, such as IGF-1R and VEGFR. Conclusions: Chemotherapy acutely activates ADAM-17 which results in growth factor shedding, growth factor receptor activation and drug resistance in CRC tumours. Thus, pharmacological inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC. PMID:20570921

  20. ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils

    PubMed Central

    Wang, Yue; Wu, Jianming; Newton, Robert; Bahaie, Nooshin S.; Long, Chunmei; Walcheck, Bruce

    2012-01-01

    CD16b (FcγRIIIb) is exclusively expressed by human neutrophils and binds IgG in immune complexes. Cell surface CD16b undergoes efficient ectodomain shedding upon neutrophil activation and apoptosis. Indeed, soluble CD16b is present at high levels in the plasma of healthy individuals, which appears to be maintained by the daily turnover of apoptotic neutrophils. At this time, the principal protease responsible for CD16b shedding is not known. We show that CD16b plasma levels were significantly decreased in patients administered a selective inhibitor targeting the metalloproteases ADAM10 and ADAM17. Additional analysis with inhibitors selective for ADAM10 or ADAM17 revealed that only inhibition of ADAM17 significantly blocked the cleavage of CD16b following neutrophil activation and apoptosis. CD16b shedding by ADAM17 was further demonstrated using a unique ADAM17 function-blocking mAb and a cell-based ADAM17 reconstitution assay. Unlike human CD16, however, mouse CD16 did not undergo efficient ectodomain shedding upon neutrophil stimulation or apoptosis, indicating that this mechanism cannot be modeled in normal mice. Taken together, our findings are the first to directly demonstrate that ADAM17 cleaves CD16 in human leukocytes. PMID:23228566

  1. ADAM10 Is Involved in Cell Junction Assembly in Early Porcine Embryo Development.

    PubMed

    Kwon, Jeongwoo; Jeong, Sung-min; Choi, Inchul; Kim, Nam-Hyung

    2016-01-01

    ADAM10 (A Disintegrin and Metalloprotease domain-containing protein 10) is a cell surface protein with a unique structure possessing both potential adhesion and protease domains. However, the role of ADAM10 in preimplantation stage embryos is not clear. In this study, we examined the expression patterns and functional roles of ADAM10 in porcine parthenotes during preimplantation development. The transcription level of ADAM10 dramatically increased from the morula stage onward. Immunostaining revealed that ADAM10 was present in both the nucleus and cytoplasm in early cleavage stage embryos, and localized to the apical region of the outer cells in morula and blastocyst embryos. Knockdown (KD) of ADAM10 using double strand RNA did not alter preimplantation embryo development until morula stage, but resulted in significantly reduced development to blastocyst stage. Moreover, the KD blastocyst showed a decrease in gene expression of adherens and tight junction (AJ/TJ), and an increase in trophectoderm TJ permeability by disrupting TJ assembly. Treatment with an ADAM10 specific chemical inhibitor, GI254023X, at the morula stage also inhibited blastocyst development and led to disruption of TJ assembly. An in situ proximity ligation assay demonstrated direct interaction of ADAM10 with coxsackie virus and adenovirus receptor (CXADR), supporting the involvement of ADAM10 in TJ assembly. In conclusion, our findings strongly suggest that ADADM10 is important for blastocyst formation rather than compaction, particularly for TJ assembly and stabilization in preimplantation porcine parthenogenetic development.

  2. Increase of α-Secretase ADAM10 in Platelets Along Cognitively Healthy Aging.

    PubMed

    Schuck, Florian; Wolf, Dominik; Fellgiebel, Andreas; Endres, Kristina

    2016-01-01

    ADAM10 is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (AβPP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological AβPP cleavage product generated by ADAM10, sAβPPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets.

  3. ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

    PubMed Central

    Weerasekera, Lakshini; Rudnicka, Caroline; Sang, Qing-Xiang; Johnson, Matthew P.; Moses, Eric K.; Göring, Harald H. H.; Blangero, John; Hricova, Jana; Schlaich, Markus

    2017-01-01

    Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D. PMID:28265178

  4. Molecular characterization and expression analysis of ADAM12 during chicken embryonic development.

    PubMed

    Lin, Juntang; Luo, Jiankai; Redies, Christoph

    2010-12-01

    ADAM12 is a member of the disintegrin and metalloprotease (ADAM) family of molecules, which consist of multiple domains. ADAM12 is involved in different physiological and pathological processes. In the present study, full-length sequences of two chicken ADAM12 isoforms were cloned and identified by reverse transcription-polymerase chain reaction (RT-PCR), rapid amplification of cDNA ends methods and bioinformatics analysis. The long isoform consists of all domains characteristic for ADAMs and is strongly expressed in different tissues, whereas the short isoform lacks large parts of the metalloprotease and disintegrin domains and is only expressed weakly. Results from semi-quantitative RT-PCR show that the complete ADAM12 is stably expressed throughout chicken embryonic development, while the short isoform is only regionally detectable in the lung and brain. Results from in situ hybridization show that chicken ADAM12 is expressed exclusively in tissues and organs derived from the neural tube, the neural crest or the mesoderm, with a highly regulated spatiotemporal expression pattern. Our data confirm and extend studies of ADAM12 in other species, and suggest that ADAM12 may play a role in the development of several organs, including the formation of feather buds.

  5. ADAM12-deficient zebrafish exhibit retardation in body growth at the juvenile stage without developmental defects.

    PubMed

    Tokumasu, Yudai; Iida, Atsuo; Wang, Zi; Ansai, Satoshi; Kinoshita, Masato; Sehara-Fujisawa, Atsuko

    2016-05-01

    ADAM (a disintegrin and metalloprotease) constitutes a family of multi-domain proteins that are involved in development, homeostasis, and disease. ADAM12 plays important roles in myogenesis and adipogenesis in mice; however, the precise physiological mechanisms are not known, and the function of this gene in other vertebrates has not been examined. In this study, we used a simple model vertebrate, the zebrafish, to investigate the functions of ADAM12 during development. Zebrafish adam12 is conserved with those of mammals in the synteny and the amino-acid sequence. We examined adam12 expression in zebrafish embryos by whole mount in situ hybridization and the promoter activity of the adam12 upstream sequence. We found that adam12 is strongly expressed in the cardiovascular system, erythroid progenitors, brain, and jaw cartilage during zebrafish development, and adam12-knockout zebrafish exhibited reduced body size in the juvenile stage without apparent morphological defects. Taken together, these results suggest that adam12 plays a significant role in the regulation of body growth during juvenile stage in zebrafish, although the precise molecular mechanisms await further study.

  6. Metalloprotease-disintegrin ADAM12 expression is regulated by Notch signaling via microRNA-29.

    PubMed

    Li, Hui; Solomon, Emilia; Duhachek Muggy, Sara; Sun, Danqiong; Zolkiewska, Anna

    2011-06-17

    Metalloprotease-disintegrin ADAM12 is overexpressed and frequently mutated in breast cancer. We report here that ADAM12 expression in cultured mammalian cells is up-regulated by Notch signals. Expression of a constitutively active form of Notch1 in murine fibroblasts, myoblasts, or mammary epithelial cells or activation of the endogenous Notch signaling by co-culture with ligand-expressing cells increases ADAM12 protein and mRNA levels. Up-regulation of ADAM12 expression by Notch requires new transcription, is activated in a CSL-dependent manner, and is abolished upon inhibition of IκB kinase. Expression of a constitutively active Notch1 in NIH3T3 cells increases the stability of Adam12 mRNA. We further show that the microRNA-29 family, which has a predicted conserved site in the 3'-untranslated region of mouse Adam12, plays a critical role in mediating the stimulatory effect of Notch on ADAM12 expression. In human cells, Notch up-regulates the expression of the long form, but not the short form, of ADAM12 containing a divergent 3'-untranslated mRNA region. These studies uncover a novel paradigm in Notch signaling and establish Adam12 as a Notch-related gene.

  7. Advice for Administrators: Writing the Attendance Policy.

    ERIC Educational Resources Information Center

    Rood, Robert E.

    1989-01-01

    Since the 1990s, truancy has become administrators' most persistent problem. This article examines student absenteeism trends, characteristics of nonattenders, and current attendance policies. While schools can encourage attendance, final responsibility rests with students and parents. Includes four references. (MLH)

  8. Attendance and Attainment in a Calculus Course

    ERIC Educational Resources Information Center

    Meulenbroek, Bernard; van den Bogaard, Maartje

    2013-01-01

    In this paper the relationship between attendance and attainment in a standard calculus course is investigated. Calculus could in principle be studied without attending lectures due to the wealth of material available (in hardcopy and online). However, in this study we will show that the pass rate of students attending classes regularly (>75%…

  9. Recent eruptions of Mount Adams, Washington Cascades, USA

    USGS Publications Warehouse

    Hildreth, Wes; Fierstein, Judy

    1997-01-01

    The postglacial eruption rate for the Mount Adams volcanic field is ∼0.1 km3/k.y., four to seven times smaller than the average rate for the past 520 k.y. Ten vents have been active since the last main deglaciation ∼15 ka. Seven high flank vents (at 2100-2600 m) and the central summit vent of the 3742-m stratocone produced varied andesites, and two peripheral vents (at 2100 and 1200 m) produced mildly alkalic basalt. Eruptive ages of most of these units are bracketed with respect to regional tephra layers from Mount Mazama and Mount St. Helens. The basaltic lavas and scoria cones north and south of Mount Adams and a 13-km-long andesitic lava flow on its east flank are of early postglacial age. The three most extensive andesitic lava-flow complexes were emplaced in the mid-Holocene (7-4 ka). Ages of three smaller Holocene andesite units are less well constrained. A phreatomagmatic ejecta cone and associated andesite lavas that together cap the summit may be of latest Pleistocene age. but a thin layer of mid-Holocene tephra appears to have erupted there as well. An alpine-meadow section on the southeast flank contains 24 locally derived Holocene andesitic ash layers intercalated with several silicic tephras from Mazama and St. Helens. Microprobe analyses of phenocrysts from the ash layers and postglacial lavas suggest a few correlations and refine some age constraints. Approximately 6 ka, a 0.07-km3 debris avalanche from the southwest face of Mount Adams gen-erated a clay-rich debris flow that devastated >30 km2 south of the volcano. A gravitationally metastable 2-to 3-km3 reservoir of hydrothermally altered fragmental andesite remains on the ice-capped summit and, towering 3 km above the surrounding lowlands, represents a greater hazard than an eruptive recurrence in the style of the last 15 k.y.

  10. Lance–Adams syndrome: A special case of a mother

    PubMed Central

    Nigam, Gaurav Bhaskar; Babu, Sachin Suresh; Peter, C. Sudhir; Peter, C. Shobhna

    2016-01-01

    Predicting the neurological outcome in survivors of cardiorespiratory arrest is difficult. A distinction has been made between acute and chronic posthypoxic myoclonus, called myoclonic status epilepticus and Lance–Adams syndrome (LAS), respectively, with the acute condition carrying a bad prognosis. Here, we report a case of a 37-year-old female who developed seizures after a successful cardiopulmonary resuscitation. The available literature on such cases is very rare and has generally mentioned a poor outcome. However, our patient was successfully managed and showed clinical features of LAS. Thus, making an early diagnosis and proper management of hypoxic brain insults is positively related to improving the patient's functional outcome. PMID:27688633

  11. Simulation of Naval Guns' Breechblock System Dynamics Based on ADAMS

    NASA Astrophysics Data System (ADS)

    Tan, Bo; Liu, Hui-Min; Liu, Kai

    In order to study the dynamical characteristics of the breechblock system during gun firing, a virtual prototype model was established based on ADAMS, in which motion and force transmission among mechanisms are realized by collision. By simulation, kinematics and dynamics properties of main components are obtained, and the relationships between the motion of breechblock and the position of breechblock opening plate are analyzed. According to the simulation results, the collision among the breechblock opening plate and the roller is discontinuous, which may make the breechblock system fail to hitch the breechblock reliably. And within allowable scope of the structure, the breechblock opening template should be installed near the upside as much as possible.

  12. Applying the Adams influence model in nurse executive practice.

    PubMed

    Adams, Jeffrey M; Erickson, Jeanette Ives

    2011-04-01

    The ability to influence others is a required competency for nurse executives trying to achieve positive patient/organizational outcomes. The Adams Influence Model (AIM) is a framework for understanding the factors, attributes, and process of influence. The AIM is grounded in nursing and organizational literature and provides nurse leaders with a road map for developing an effective strategy to achieve influence with individuals and/or groups. The authors describe the AIM and present a case study illustrating its application by a chief nurse executive.

  13. The "delivery" of Adam: a medical interpretation of Michelangelo.

    PubMed

    Di Bella, Stefano; Taglietti, Fabrizio; Iacobuzio, Andrea; Johnson, Emma; Baiocchini, Andrea; Petrosillo, Nicola

    2015-04-01

    This article describes what we believe to be the key to interpreting the concept represented by Michelangelo's painting the Creation of Adam. This fresco, one of his most famous masterpieces, is situated in the heart of the Sistine Chapel and is viewed by millions of people every year. A man of many talents, Michelangelo's proficiency in anatomical dissection is reflected in his artwork. As such, analyses of hidden meanings in this fresco have been ascribed, including the concept of the "Brain-God." However, we see a postpartum uterus and adjacent anatomy, justifying our interpretation that Michelangelo was depicting something far more fundamental: the birth of mankind.

  14. MOUNT ADAMS WILDERNESS AND CONTIGUOUS ROADLESS AREAS, WASHINGTON.

    USGS Publications Warehouse

    Hildreth, Wes; Miller, M.

    1984-01-01

    There is little likelihood for the occurrence of metallic mineral or energy resources based on a mineral survey in 1981-82 in the Mount Adams Wilderness and contiguous roadless areas, Washington. No mining claims exist in the study area, which is almost entirely a young andesitic stratovolcano. There is no indication of a shallow magma reservoir capable of supporting a convective geothermal system. Drilling in the lowland periphery of the volcano might be technically difficult, but 150 degree -200 degree F waters suitable for space heating would not be unexpected at depths of 5000-6000 ft.

  15. ADAM10 Is the Major Sheddase Responsible for the Release of Membrane-associated Meprin A*

    PubMed Central

    Herzog, Christian; Haun, Randy S.; Ludwig, Andreas; Shah, Sudhir V.; Kaushal, Gur P.

    2014-01-01

    Meprin A, composed of α and β subunits, is a membrane-bound metalloproteinase in renal proximal tubules. Meprin A plays an important role in tubular epithelial cell injury during acute kidney injury (AKI). The present study demonstrated that during ischemia-reperfusion-induced AKI, meprin A was shed from proximal tubule membranes, as evident from its redistribution toward the basolateral side, proteolytic processing in the membranes, and excretion in the urine. To identify the proteolytic enzyme responsible for shedding of meprin A, we generated stable HEK cell lines expressing meprin β alone and both meprin α and meprin β for the expression of meprin A. Phorbol 12-myristate 13-acetate and ionomycin stimulated ectodomain shedding of meprin β and meprin A. Among the inhibitors of various proteases, the broad spectrum inhibitor of the ADAM family of proteases, tumor necrosis factor-α protease inhibitor (TAPI-1), was most effective in preventing constitutive, phorbol 12-myristate 13-acetate-, and ionomycin-stimulated shedding of meprin β and meprin A in the medium of both transfectants. The use of differential inhibitors for ADAM10 and ADAM17 indicated that ADAM10 inhibition is sufficient to block shedding. In agreement with these results, small interfering RNA to ADAM10 but not to ADAM9 or ADAM17 inhibited meprin β and meprin A shedding. Furthermore, overexpression of ADAM10 resulted in enhanced shedding of meprin β from both transfectants. Our studies demonstrate that ADAM10 is the major ADAM metalloproteinase responsible for the constitutive and stimulated shedding of meprin β and meprin A. These studies further suggest that inhibiting ADAM 10 activity could be of therapeutic benefit in AKI. PMID:24662289

  16. Metalloproteinases ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas.

    PubMed

    Wang, Junwen; Voellger, Benjamin; Benzel, Julia; Schlomann, Uwe; Nimsky, Christopher; Bartsch, Jörg W; Carl, Barbara

    2016-09-15

    Invasion of tumor cells critically depends on cell-cell or cell-extracellular matrix interactions. Enzymes capable of modulating these interactions belong to the proteinase families of ADAM (a disintegrin and metalloprotease) and MMP (matrix metalloprotease) proteins. Our objective is to examine their expression levels and evaluate the relationship between expression levels and cavernous sinus invasion in pituitary adenomas. Tissue samples from 35 patients with pituitary adenomas were analyzed. Quantitative real-time polymerase chain reaction (qPCR) was employed to assess mRNA expression levels for ADAM and MMP genes. Protein levels were examined using immunohistochemistry and Western Blot. Correlation analyses between expression levels and clinical parameters were performed. By silencing ADAM12 and MMP-14 with siRNA in a mouse pituitary adenoma cell line (TtT/GF), their cellular effects were investigated. In our study, nine women and 26 men were included, with a mean age of 53.1 years (range 15-84 years) at the time of surgery. There were 19 cases with cavernous sinus invasion. The proteins ADAM12 and MMP-14 were significantly up-regulated in invasive adenomas compared to noninvasive adenomas. Both human isoforms of ADAM12 (ADAM12L and ADAM12s) were involved in tumor invasion; moreover, ADAM12L was found to correlate positively with Ki-67 proliferation index in pituitary adenomas. In TtT/GF pituitary adenoma cells, silencing of ADAM12 and MMP-14 significantly inhibited cell invasion and migration, respectively, whereas only silencing of ADAM12 suppressed cell proliferation. We conclude that ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas, which qualifies these proteins in diagnosis and therapy.

  17. RACK1, a new ADAM12 interacting protein. Contribution to liver fibrogenesis.

    PubMed

    Bourd-Boittin, Katia; Le Pabic, Hélène; Bonnier, Dominique; L'Helgoualc'h, Annie; Théret, Nathalie

    2008-09-19

    ADAM12 belongs to a disintegrin-like and metalloproteinase-containing protein family that possesses multidomain structures composed of a pro-domain, a metalloprotease, disintegrin-like, cysteine-rich, epidermal growth factor-like, and transmembrane domains, and a cytoplasmic tail. Overexpression of several ADAMs has been reported in human cancer, and we recently described the involvement of ADAM12 in liver injury (Le Pabic, H., Bonnier, D., Wewer, U. M., Coutand, A., Musso, O., Baffet, G., Clement, B., and Theret, N. (2003) Hepatology 37, 1056-1066). In this study, we used a yeast two-hybrid screening of a cDNA library from human hepatocellular carcinoma to analyze binding partners of ADAM12. We identify RACK1, a receptor for activated protein kinase C (PKC), as a new ADAM12 interacting protein. RACK1 is up-regulated in patients with hepatocellular carcinoma and is highly expressed by activated hepatic stellate cells. We demonstrate the involvement of RACK1 in mediating the PKC-dependent translocation of ADAM12 to membranes of activated hepatic stellate cells. In particular, treatment of cells with phorbol esters enhances ADAM12 immunostaining in the membrane fractions and the co-immunoprecipitation of ternary complexes containing RACK1, ADAM12, and PKC. By using RNA interference, we demonstrate that inhibition of RACK1 expression diminishes the phorbol 12-myristate 13-acetate-dependent translocation of ADAM12 to membranes of hepatic stellate cells. Finally, hepatic stellate cells cultured on coated type I collagen induces relocalization of ADAM12 in the membrane, suggesting that this major matrix component in liver cancer and fibrogenesis might stimulate ADAM12 translocation to the cell membrane where its shedding activity takes place.

  18. Swaziland's Traditional Birth Attendants Survey.

    PubMed

    Lech, M M; Mngadi, T P

    2005-12-01

    The Traditional Birth Attendants (TBAs) Survey in Swaziland was undertaken between March 27th 1996 and April 8th 1996. The objective of the survey was to generate reliable information regarding activities of TBAs in Swaziland. The survey was conducted in 25 Chiefdoms sampled out of a total of 206 Chiefdoms registered in Swaziland. The total number of sampled respondents in the 25 Chiefdoms was 721. From the survey, it is estimated that there were probably 3000 TBAs in the country, and in the majority of cases such TBAs would be a 51-year old woman who herself had delivered six children and had worked as a TBA for at least 10 years. Between 9,000 and 12,000 deliveries are estimated to take place out of health facilities. Of these many, nearly 43.5% are assisted by "TBAs"; 16.3% of woman interviewed deliver relative/family member and 15.1% are assisted by friends/neighbours, etc. Some of TBAs carry out procedures which are considered to be potentially harmful. Nearly 30% of TBAs have administered herbs; 45% attend to abnormal deliveries (breech and multiple pregnancies); 26.7% re-use their cord cutting tools and in the case of haemorrhage 23.4% do manual procedures within reproductive tract of delivering women.

  19. The futility of utility: how market dynamics marginalize Adam Smith

    NASA Astrophysics Data System (ADS)

    McCauley, Joseph L.

    2000-10-01

    Economic theorizing is based on the postulated, nonempiric notion of utility. Economists assume that prices, dynamics, and market equilibria are supposed to be derived from utility. The results are supposed to represent mathematically the stabilizing action of Adam Smith's invisible hand. In deterministic excess demand dynamics I show the following. A utility function generally does not exist mathematically due to nonintegrable dynamics when production/investment are accounted for, resolving Mirowski's thesis. Price as a function of demand does not exist mathematically either. All equilibria are unstable. I then explain how deterministic chaos can be distinguished from random noise at short times. In the generalization to liquid markets and finance theory described by stochastic excess demand dynamics, I also show the following. Market price distributions cannot be rescaled to describe price movements as ‘equilibrium’ fluctuations about a systematic drift in price. Utility maximization does not describe equilibrium. Maximization of the Gibbs entropy of the observed price distribution of an asset would describe equilibrium, if equilibrium could be achieved, but equilibrium does not describe real, liquid markets (stocks, bonds, foreign exchange). There are three inconsistent definitions of equilibrium used in economics and finance, only one of which is correct. Prices in unregulated free markets are unstable against both noise and rising or falling expectations: Adam Smith's stabilizing invisible hand does not exist, either in mathematical models of liquid market data, or in real market data.

  20. The shedding activity of ADAM17 is sequestered in lipid rafts

    SciTech Connect

    Tellier, Edwige; Canault, Matthias; Rebsomen, Laure; Bonardo, Bernadette; Juhan-Vague, Irene; Nalbone, Gilles; Peiretti, Franck . E-mail: Franck.Peiretti@medecine.univ-mrs.fr

    2006-12-10

    The tumor necrosis factor-alpha (TNF) converting enzyme (ADAM17) is a metalloprotease-disintegrin responsible for the cleavage of several biologically active transmembrane proteins. However, the substrate specificity of ADAM17 and the regulation of its shedding activity are still poorly understood. Here, we report that during its transport through the Golgi apparatus, ADAM17 is included in cholesterol-rich membrane microdomains (lipid rafts) where its prodomain is cleaved by furin. Consequently, ADAM17 shedding activity is sequestered in lipid rafts, which is confirmed by the fact that metalloproteinase inhibition increases the proportion of ADAM17 substrates (TNF and its receptors TNFR1 and TNFR2) in lipid rafts. Membrane cholesterol depletion increases the ADAM17-dependent shedding of these substrates demonstrating the importance of lipid rafts in the control of this process. Furthermore, ADAM17 substrates are present in different proportions in lipid rafts, suggesting that the entry of each of these substrates in these particular membrane microdomains is specifically regulated. Our data support the idea that one of the mechanisms regulating ADAM17 substrate cleavage involves protein partitioning in lipid rafts.

  1. ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis

    PubMed Central

    Romagnoli, Mathilde; Mineva, Nora D; Polmear, Michael; Conrad, Catharina; Srinivasan, Srimathi; Loussouarn, Delphine; Barillé-Nion, Sophie; Georgakoudi, Irene; Dagg, Áine; McDermott, Enda W; Duffy, Michael J; McGowan, Patricia M; Schlomann, Uwe; Parsons, Maddy; Bartsch, Jörg W; Sonenshein, Gail E

    2014-01-01

    The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination. Subject Category Cancer PMID:24375628

  2. Role of MicroRNA-103a Targeting ADAM10 in Abdominal Aortic Aneurysm

    PubMed Central

    Jiao, Tong; Yao, Ye; Zhang, Bo; Sun, Qing-Feng; Li, Jing-Bo; Yuan, Chao; Jing, Bao; Wang, Yun-Peng

    2017-01-01

    MicroRNAs (miRNAs) are deregulated in various vascular ailments including abdominal aortic aneurysm (AAA). MiR-103 is involved in vascular, metabolic, and malignant diseases, but whether it participates in the pathogenesis of AAA remains elusive. ADAM10 plays a vital role in the formation of aneurysm, but whether miRs modulate its activity during AAA formation is totally unknown. In this study, we detected the significantly increased protein expression of ADAM10 in angiotensin II induced murine AAA specimens, while the mRNA expression of ADAM10 was similar between AAA and control, suggesting the posttranscriptional regulation. The ADAM10 specific inhibitor GI254023X dramatically reduced the macrophage infiltration of murine abdominal aorta. Bioinformatic predictions suggest that ADAM10 is the target of miR-103a/107 but the binding site is exclusive. At the cellular level, miR-103a-1 suppressed the protein expression of ADAM10, while antisense miR-103a-1 increased its expression. Particularly, with the progression of murine AAA, the mRNA expression of miR-103a/107 substantially decreased and the protein expression of ADAM10 greatly increased. Together, our data afford the new insight that miR-103a inhibited AAA growth via targeting ADAM10, which might be a promising therapeutic strategy to alleviate AAA. PMID:28357407

  3. Role of MicroRNA-103a Targeting ADAM10 in Abdominal Aortic Aneurysm.

    PubMed

    Jiao, Tong; Yao, Ye; Zhang, Bo; Hao, Da-Cheng; Sun, Qing-Feng; Li, Jing-Bo; Yuan, Chao; Jing, Bao; Wang, Yun-Peng; Wang, Hai-Yang

    2017-01-01

    MicroRNAs (miRNAs) are deregulated in various vascular ailments including abdominal aortic aneurysm (AAA). MiR-103 is involved in vascular, metabolic, and malignant diseases, but whether it participates in the pathogenesis of AAA remains elusive. ADAM10 plays a vital role in the formation of aneurysm, but whether miRs modulate its activity during AAA formation is totally unknown. In this study, we detected the significantly increased protein expression of ADAM10 in angiotensin II induced murine AAA specimens, while the mRNA expression of ADAM10 was similar between AAA and control, suggesting the posttranscriptional regulation. The ADAM10 specific inhibitor GI254023X dramatically reduced the macrophage infiltration of murine abdominal aorta. Bioinformatic predictions suggest that ADAM10 is the target of miR-103a/107 but the binding site is exclusive. At the cellular level, miR-103a-1 suppressed the protein expression of ADAM10, while antisense miR-103a-1 increased its expression. Particularly, with the progression of murine AAA, the mRNA expression of miR-103a/107 substantially decreased and the protein expression of ADAM10 greatly increased. Together, our data afford the new insight that miR-103a inhibited AAA growth via targeting ADAM10, which might be a promising therapeutic strategy to alleviate AAA.

  4. DEVELOPMENT OF THE HUMAN LUNG MEASURED BY AEROSOL-DERIVED AIRWAY MORPHEMETRY (ADAM).

    EPA Science Inventory

    We measured, in vivo, the airspace calibers of the small airways and alveoli by ADAM in the lungs of children of ages 6 to 18 years and adults aged 18 to 80 years. ADAM utilizes the gravitational settling time of inhaled monodisperse particles to infer the vertical distance to th...

  5. ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis.

    PubMed

    Romagnoli, Mathilde; Mineva, Nora D; Polmear, Michael; Conrad, Catharina; Srinivasan, Srimathi; Loussouarn, Delphine; Barillé-Nion, Sophie; Georgakoudi, Irene; Dagg, Áine; McDermott, Enda W; Duffy, Michael J; McGowan, Patricia M; Schlomann, Uwe; Parsons, Maddy; Bartsch, Jörg W; Sonenshein, Gail E

    2014-02-01

    The transmembrane metalloprotease-disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple-negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. In vivo, treatment with an anti-ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non-essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.

  6. 77 FR 75207 - The Adams Express Company and Petroleum & Resources Corporation; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-19

    ... COMMISSION The Adams Express Company and Petroleum & Resources Corporation; Notice of Application December 13... and Petroleum & Resources Corporation (the ``Funds''). DATES: Filing Dates: The application was filed..., 2012, The Adams Express Company held approximately 8.5% of the outstanding shares of...

  7. The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling.

    PubMed

    Weber, Silvio; Niessen, Michaela T; Prox, Johannes; Lüllmann-Rauch, Renate; Schmitz, Annika; Schwanbeck, Ralf; Blobel, Carl P; Jorissen, Ellen; de Strooper, Bart; Niessen, Carien M; Saftig, Paul

    2011-02-01

    The disintegrin and metalloproteinase Adam10 has been implicated in the regulation of key signaling pathways that determine skin morphogenesis and homeostasis. To address the in vivo relevance of Adam10 in the epidermis, we have selectively disrupted Adam10 during skin morphogenesis and in adult skin. K14-Cre driven epidermal Adam10 deletion leads to perinatal lethality, barrier impairment and absence of sebaceous glands. A reduction of spinous layers, not associated with differences in either proliferation or apoptosis, indicates that loss of Adam10 triggers a premature differentiation of spinous keratinocytes. The few surviving K14-Adam10-deleted mice and mice in which Adam10 was deleted postnatally showed loss of hair, malformed vibrissae, epidermal hyperproliferation, cyst formation, thymic atrophy and upregulation of the cytokine thymic stromal lymphopoetin (TSLP), thus indicating non cell-autonomous multi-organ disease resulting from a compromised barrier. Together, these phenotypes closely resemble skin specific Notch pathway loss-of-function phenotypes. Notch processing is indeed strongly reduced resulting in decreased levels of Notch intracellular domain fragment and functional Notch signaling. The data identify Adam10 as the major Site-2 processing enzyme for Notch in the epidermis in vivo, and thus as a central regulator of skin development and maintenance.

  8. ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis

    SciTech Connect

    Goeoz, Pal Goeoz, Monika; Baldys, Aleksander; Hoffman, Stanley

    2009-02-27

    Modulation of angiogenesis is a promising approach for treating a wide variety of human diseases including ischemic heart disease and cancer. In this study, we show that ADAM-17 is an important regulator of several key steps during angiogenesis. Knocking down ADAM-17 expression using lentivirus-delivered siRNA in HUVECs inhibited cell proliferation and the ability of cells to form close contact in two-dimensional cultures. Similarly, ADAM-17 depletion inhibited the ability of HUVECs to form capillary-like networks on top of three-dimensional Matrigel as well as in co-culture with fibroblasts within a three-dimensional scaffold. In mechanistic studies, both baseline and VEGF-induced MMP-2 activation and Matrigel invasion were inhibited by ADAM-17 depletion. Based on our findings we propose that ADAM-17 is part of a novel pro-angiogenic pathway leading to MMP-2 activation and vessel formation.

  9. The role of CXCL16 and its processing metalloproteinases ADAM10 and ADAM17 in the proliferation and migration of human mesangial cells

    SciTech Connect

    Schramme, Anja; Abdel-Bakky, Mohamed Sadek; Kaempfer-Kolb, Nicole; Pfeilschifter, Josef

    2008-05-30

    In this study, we analyzed the regulation and functional role of CXCL16 in human mesangial cells (hMCs). We can show, that CXCL16 is constitutively expressed in hMCs and is further up-regulated by cytokine mix (IFN{gamma}, TNF{alpha}, and IL1{beta}). The constitutive release of CXCL16 from hMCs was rapidly induced by the stimulation with cytokines. We identified ADAM10 and ADAM17 as being responsible for the cytokine-induced shedding of CXCL16. Notably, targeting ADAM10 and ADAM17 in hMCs decreased the chemotaxis of T-Jurkat cells, whereas the inhibition of CXCL16 had no significant influence. This suggests that both proteases are important players in the recruitment of immune cells into the glomerulus, but other substrates than CXCL16 are involved in this process. Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. This finding could be important to develop novel diagnostic and therapeutic strategies to treat mesangial proliferative kidney diseases.

  10. TLR4-mediated galectin-1 production triggers epithelial-mesenchymal transition in colon cancer cells through ADAM10- and ADAM17-associated lactate production.

    PubMed

    Park, Ga Bin; Kim, Daejin

    2017-01-01

    Toll-like receptor 4 (TLR4) activation is a key contributor to the carcinogenesis of colon cancer. Overexpression of galectin-1 (Gal-1) also correlates with increased invasive activity of colorectal cancer. Lactate production is a critical predictive factor of risk of metastasis, but the functional relationship between intracellular lactate and Gal-1 expression in TLR4-activated colon cancer remains unknown. In this study, we investigated the underlying mechanism and role of Gal-1 in metastasis and invasion of colorectal cancer (CRC) cells after TLR4 stimulation. Exposure to the TLR4 ligand lipopolysaccharide (LPS) increased expression of Gal-1, induced EMT-related cytokines, triggered the activation of glycolysis-related enzymes, and promoted lactate production. Gene silencing of TLR4 and Gal-1 in CRC cells inhibited lactate-mediated epithelial-mesenchymal transition (EMT) after TLR4 stimulation. Gal-1-mediated activation of a disintegrin and metalloproteinase 10 (ADAM10) and ADAM 17 increased the invasion activity and expression of mesenchymal characteristics in LPS-activated CRC cells. Conversely, inhibition of ADAM10 or ADAM17 effectively blocked the generation of lactate and the migration capacity of LPS-treated CRC cells. Thus, the TLR4/Gal-1 signaling pathway regulates lactate-mediated EMT processes through the activation of ADAM10 and ADAM17 in CRC cells.

  11. Functional analysis of a breast cancer-associated mutation in the intracellular domain of the metalloprotease ADAM12.

    PubMed

    Stautz, Dorte; Wewer, Ulla M; Kveiborg, Marie

    2012-01-01

    A recently identified breast cancer-associated mutation in the metalloprotease ADAM12 alters a potential dileucine trafficking signal, which could affect protein processing and cellular localization. ADAM12 belongs to the group of A Disintegrin And Metalloproteases (ADAMs), which are typically membrane-associated proteins involved in ectodomain shedding, cell-adhesion, and signaling. ADAM12 as well as several members of the ADAM family are over-expressed in various cancers, correlating with disease stage. Three breast cancer-associated somatic mutations were previously identified in ADAM12, and two of these, one in the metalloprotease domain and another in the disintegrin domain, were investigated and found to result in protein misfolding, retention in the secretory pathway, and failure of zymogen maturation. The third mutation, p.L792F in the ADAM12 cytoplasmic tail, was not investigated, but is potentially significant given its location within a di-leucine motif, which is recognized as a potential cellular trafficking signal. The present study was motivated both by the potential relevance of this documented mutation to cancer, as well as for determining the role of the di-leucine motif in ADAM12 trafficking. Expression of ADAM12 p.L792F in mammalian cells demonstrated quantitatively similar expression levels and zymogen maturation as wild-type (WT) ADAM12, as well as comparable cellular localizations. A cell surface biotinylation assay demonstrated that cell surface levels of ADAM12 WT and ADAM12 p.L792F were similar and that internalization of the mutant occurred at the same rate and extent as for ADAM12 WT. Moreover, functional analysis revealed no differences in cell proliferation or ectodomain shedding of epidermal growth factor (EGF), a known ADAM12 substrate between WT and mutant ADAM12. These data suggest that the ADAM12 p.L792F mutation is unlikely to be a driver (cancer causing)-mutation in breast cancer.

  12. Who attends family planning clinics?

    PubMed

    Chick, P; Nixon, J

    1984-08-01

    Data were obtained from 1,810 consecutive women who attended a central metropolitan (Brisbane) Family Planning Clinic during a 5 week period in 1982. Young women in particular formed the major client group with 32% being under 20 years of age. The client population was skewed towards women of upper socioeconomic status (SES). There was no SES disproportion in the use of oral contraceptives or IUD's. However, diaphragm use occurred disproportionately in women of upper SES groups; postcoital contraception was sought by and limited to, women of SES classes A and B only. The clinic satisfied a need for women with a history of failed or absent contraception and 15% had already had a termination of pregnancy by the time they first presented at the clinic.

  13. Evaluation of Flight Attendant Technical Knowledge

    NASA Technical Reports Server (NTRS)

    Dunbar, Melisa G.; Chute, Rebecca D.; Rosekind, Mark (Technical Monitor)

    1997-01-01

    Accident and incident reports have indicated that flight attendants have numerous opportunities to provide the flight-deck crew with operational information that may prevent or lessen the severity of a potential problem. Additionally, as carrier fleets transition from three person to two person flight-deck crews, the reliance upon the cabin crew for the transfer of this information may increase further. Recent research indicates that flight attendants do not feel confident in their ability to describe mechanical parts or malfunctions of the aircraft, and the lack of flight attendant technical training has been referenced in a number of recent reports. Chute and Wiener describe five factors which may produce communication barriers between cockpit and cabin crews: the historical background of aviation, the physical separation of the two crews, psychosocial issues, regulatory factors, and organizational factors. By examining these areas of division we can identify possible bridges and address the implications of deficient cockpit/cabin communication on flight safety. Flight attendant operational knowledge may provide some mitigation of these barriers. The present study explored both flight attendant technical knowledge and flight attendant and pilot expectations of flight attendant technical knowledge. To assess the technical knowledge of cabin crewmembers, 177 current flight attendants from two U.S. carriers voluntarily completed a 13-item technical quiz. To investigate expectations of flight attendant technical knowledge, 181 pilots and a second sample of 96 flight attendants, from the same two airlines, completed surveys designed to capture each group's expectations of operational knowledge required of flight attendants. Analyses revealed several discrepancies between the present level of flight attendant operational knowledge and pilots' and flight attendants' expected and desired levels of technical knowledge. Implications for training will be discussed.

  14. Regulation of mature ADAM17 by redox agents for L-selectin shedding1

    PubMed Central

    Wang, Yue; Herrera, Amy H.; Li, Ying; Belani, Kiran K.; Walcheck, Bruce

    2008-01-01

    L-selectin is constitutively expressed by neutrophils and plays a key role in directing these cells to sites of inflammation. Upon neutrophil activation, L-selectin is rapidly and efficiently down-regulated from the cell surface by ectodomain shedding. We have directly shown that ADAM17 is a primary and non-redundant sheddase of L-selection by activated neutrophils in vivo. Following cell activation, intracellular signals lead to the induction of ADAM17's enzymatic activity; however, the target of this inducer mechanism remains unclear. Our study provides evidence of an activation mechanism that involves the extracellular region of the mature form of cell surface ADAM17 and not its intracellular region. We demonstrate that the catalytic activity of purified ADAM17 lacking a pro-domain and its intracellular region is diminished under mild reducing conditions by DTT and enhanced by H2O2 oxidation. Moreover, H2O2 reversed ADAM17 inhibition by DTT. The treatment of neutrophils with H2O2 also induced L-selectin shedding in an ADAM17-dependent manner. These findings suggest that thioldisulfide conversion occurring in the extracellular region of ADAM17 may be involved in its activation. An analysis of ADAM17 revealed that within its disintegrin/cysteine-rich region are two highly conserved, vicinal cysteine sulfhydryl motifs (cysteine-X-X-cysteine, CXXC), which are well characterized targets for thiol-disulfide exchange in various other proteins. Using a cell-based ADAM17 reconstitution assay, we demonstrate that the CXXC motifs are critical for L-selectin cleavage. Taken together, our findings suggest that redox modifications of cysteinyl sulfhydryl groups in mature ADAM17 may serve as a mechanism for regulating the shedding of L-selectin following neutrophil stimulation. PMID:19201900

  15. A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma

    PubMed Central

    Kanzaki, Hiroyuki; Shinohara, Fumiaki; Suzuki, Maiko; Wada, Satoshi; Miyamoto, Yutaka; Yamaguchi, Yuuki; Katsumata, Yuta; Makihira, Seicho; Kawai, Toshi; Taubman, Martin A.; Nakamura, Yoshiki

    2016-01-01

    Interferon-gamma (IFN-γ) is a pleiotropic cytokine that exerts anti-tumor and anti-osteoclastogenic effects. Although transcriptional and post-transcriptional regulation of IFN-γ is well understood, subsequent modifications of secreted IFN-γ are not fully elucidated. Previous research indicates that some cancer cells escape immune surveillance and metastasize into bone tissue by inducing osteoclastic bone resorption. Peptidases of the a-disintegrin and metalloproteinase (ADAM) family are implicated in cancer cell proliferation and tumor progression. We hypothesized that the ADAM enzymes expressed by cancer cells degrades IFN-γ and attenuates IFN-γ-mediated anti-tumorigenic and anti-osteoclastogenic effects. Recombinant ADAM17 degraded IFN-γ into small fragments. The addition of ADAM17 to the culture supernatant of stimulated mouse splenocytes decreased IFN-γ concentration. However, ADAM17 inhibition in the stimulated mouse T-cells prevented IFN-γ degradation. ADAM17-expressing human breast cancer cell lines MCF-7 and MDA-MB-453 also degraded recombinant IFN-γ, but this was attenuated by ADAM17 inhibition. Degraded IFN-γ lost the functionality including the inhibititory effect on osteoclastogenesis. This is the first study to demonstrate the extracellular proteolytic degradation of IFN-γ by ADAM17. These results suggest that ADAM17-mediated degradation of IFN-γ may block the anti-tumorigenic and anti-osteoclastogenic effects of IFN-γ. ADAM17 inhibition may be useful for the treatment of attenuated cancer immune surveillance and/or bone metastases. PMID:27573075

  16. Identification of Novel Interaction between ADAM17 (a Disintegrin and Metalloprotease 17) and Thioredoxin-1*

    PubMed Central

    Aragão, Annelize Z. B.; Nogueira, Maria Luiza C.; Granato, Daniela C.; Simabuco, Fernando M.; Honorato, Rodrigo V.; Hoffman, Zaira; Yokoo, Sami; Laurindo, Francisco R. M.; Squina, Fabio M.; Zeri, Ana Carolina M.; Oliveira, Paulo S. L.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2012-01-01

    ADAM17, which is also known as TNFα-converting enzyme, is the major sheddase for the EGF receptor ligands and is considered to be one of the main proteases responsible for the ectodomain shedding of surface proteins. How a membrane-anchored proteinase with an extracellular catalytic domain can be activated by inside-out regulation is not completely understood. We characterized thioredoxin-1 (Trx-1) as a partner of the ADAM17 cytoplasmic domain that could be involved in the regulation of ADAM17 activity. We induced the overexpression of the ADAM17 cytoplasmic domain in HEK293 cells, and ligands able to bind this domain were identified by MS after protein immunoprecipitation. Trx-1 was also validated as a ligand of the ADAM17 cytoplasmic domain and full-length ADAM17 recombinant proteins by immunoblotting, immunolocalization, and solid phase binding assay. In addition, using nuclear magnetic resonance, it was shown in vitro that the titration of the ADAM17 cytoplasmic domain promotes changes in the conformation of Trx-1. The MS analysis of the cross-linked complexes showed cross-linking between the two proteins by lysine residues. To further evaluate the functional role of Trx-1, we used a heparin-binding EGF shedding cell model and observed that the overexpression of Trx-1 in HEK293 cells could decrease the activity of ADAM17, activated by either phorbol 12-myristate 13-acetate or EGF. This study identifies Trx-1 as a novel interaction partner of the ADAM17 cytoplasmic domain and suggests that Trx-1 is a potential candidate that could be involved in ADAM17 activity regulation. PMID:23105116

  17. Identification of novel interaction between ADAM17 (a disintegrin and metalloprotease 17) and thioredoxin-1.

    PubMed

    Aragão, Annelize Z B; Nogueira, Maria Luiza C; Granato, Daniela C; Simabuco, Fernando M; Honorato, Rodrigo V; Hoffman, Zaira; Yokoo, Sami; Laurindo, Francisco R M; Squina, Fabio M; Zeri, Ana Carolina M; Oliveira, Paulo S L; Sherman, Nicholas E; Paes Leme, Adriana F

    2012-12-14

    ADAM17, which is also known as TNFα-converting enzyme, is the major sheddase for the EGF receptor ligands and is considered to be one of the main proteases responsible for the ectodomain shedding of surface proteins. How a membrane-anchored proteinase with an extracellular catalytic domain can be activated by inside-out regulation is not completely understood. We characterized thioredoxin-1 (Trx-1) as a partner of the ADAM17 cytoplasmic domain that could be involved in the regulation of ADAM17 activity. We induced the overexpression of the ADAM17 cytoplasmic domain in HEK293 cells, and ligands able to bind this domain were identified by MS after protein immunoprecipitation. Trx-1 was also validated as a ligand of the ADAM17 cytoplasmic domain and full-length ADAM17 recombinant proteins by immunoblotting, immunolocalization, and solid phase binding assay. In addition, using nuclear magnetic resonance, it was shown in vitro that the titration of the ADAM17 cytoplasmic domain promotes changes in the conformation of Trx-1. The MS analysis of the cross-linked complexes showed cross-linking between the two proteins by lysine residues. To further evaluate the functional role of Trx-1, we used a heparin-binding EGF shedding cell model and observed that the overexpression of Trx-1 in HEK293 cells could decrease the activity of ADAM17, activated by either phorbol 12-myristate 13-acetate or EGF. This study identifies Trx-1 as a novel interaction partner of the ADAM17 cytoplasmic domain and suggests that Trx-1 is a potential candidate that could be involved in ADAM17 activity regulation.

  18. Expression of ADAMs and their inhibitors in sputum from patients with asthma.

    PubMed

    Paulissen, Geneviève; Rocks, Natacha; Quesada-Calvo, Florence; Gosset, Philippe; Foidart, Jean-Michel; Noel, Agnès; Louis, Renaud; Cataldo, Didier D

    2006-01-01

    ADAMs (a disintegrin and metalloprotease) constitute a family of cell surface proteins containing disintegrin and metalloprotease domains which associate features of adhesion molecules and proteases. ADAMTSs (a disintegrin and metalloprotease with thrombospondin motifs) bear thrombospondin type I motifs in C-terminal extremity, and most of them are secreted proteins. Because genetic studies have shown that ADAM-33 gene polymorphisms are associated with asthma, we designed this study to assess mRNA expression profile of several ADAM and ADAMTS proteases in sputum from patients with asthma and to investigate the relationship between expression of these proteases and asthma-associated inflammation and airway obstruction. mRNA expression profile of selected ADAM and ADAMTS proteinases (ADAM-8, -9, -10, -12, -15, -17, and -33; ADAMTS-1, -2, -15, -16, -17, -18, and -19), their physiological inhibitors TIMP-1 and TIMP-3, and RECK, a membrane-anchored MMP activity regulator, was obtained by RT-PCR analysis performed on cells collected by sputum induction from 21 patients with mild to moderate asthma and 17 healthy individuals. mRNA levels of ADAM-8, ADAM-9, ADAM-12, TIMP-1, and TIMP-3 were significantly increased, whereas mRNA levels coding for ADAMTS-1, ADAMTS-15, and RECK were significantly decreased in patients with asthma compared with control patients. ADAM-8 expression was negatively correlated with the forced expiratory volume at the first second (FEV(1)) (r = -0.57, P < 0.01), whereas ADAMTS-1 and RECK expressions were positively correlated to FEV(1) (r = 0.45, P < 0.05, and r = 0.55, P = 0.01, respectively). We conclude that expression of ADAMs and ADAMTSs and their inhibitors is modulated in airways from patients with asthma and that these molecules may play a role in the pathogenesis of asthma.

  19. Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia.

    PubMed

    Cesaro, Annabelle; Abakar-Mahamat, Abakar; Brest, Patrick; Lassalle, Sandra; Selva, Eric; Filippi, Jérôme; Hébuterne, Xavier; Hugot, Jean-Pierre; Doglio, Alain; Galland, Franck; Naquet, Philippe; Vouret-Craviari, Valérie; Mograbi, Baharia; Hofman, Paul M

    2009-06-01

    The acute phase of Crohn's disease (CD) is characterized by a large afflux of polymorphonuclear leukocytes (PMNL) into the mucosa and by the release of TNF-alpha. Conversion of inactive TNF-alpha into an active form requires the cleavage of a transmembrane TNF-alpha precursor by the TNF-alpha-converting enzyme (ADAM17), a protease mainly regulated by the tissue inhibitor of metalloproteinase 3 (TIMP3). The aim of the present study was to investigate in an in vitro model of PMNL transepithelial migration and in the intestinal mucosa of patients with CD the expression and regulation of ADAM17 and TIMP3 in intestinal epithelial cells (IEC). ADAM17 and TIMP3 expression was analyzed by Western blotting, RT-PCR, confocal microscopy, and immunohistochemistry by using the T84 model and digestive biopsies. ADAM17 expression in IEC was increased at a posttranscriptional level during the early phase (from 2 to 4 h) of PMNL transepithelial migration whereas TIMP3 was only increased 24 h later. TNF-alpha induced an early upregulation of ADAM17 in T84 cells, whereas PMNL adhesion, H(2)O(2), or epithelial tight junction opening alone did not affect the amount of ADAM17. Immunohistochemistry of intestinal biopsies revealed that strong expression of ADAM17 was associated with a high activity of CD. In contrast, TIMP3 was very poorly expressed in these biopsies. ADAM17 and TIMP3 profiling did not correlated with the NOD2/CARD15 status. The ADAM17 activity was higher both in the early phase of PMNL transepithelial migration and in active CD. These results showed early posttranscriptional upregulation of ADAM17 in IEC linked to PMNL transepithelial migration and a high activity of CD.

  20. A new species of Spiroberotha Adams 1989 (Neuroptera: Berothidae) and the first record of the genus in Brazil.

    PubMed

    Machado, Renato Jose Pires; Krolow, Tiago Kütter

    2016-03-20

    The genus Spiroberotha Adams, 1989 is classified in Berothidae (Neuroptera) with two described species: S. fernandezi Adams, 1989 from Venezuela and S. sanctarosae Adams, 1989 from Colombia, Costa Rica and Venezuela. Here we describe a new species, S. tocantinensis n. sp., from Palmas, Tocantins, Brazil. This is the first record of the genus in Brazil, extending its geographical distribution.

  1. 77 FR 5291 - The Designation of Monir Chouka, also Known as Mounir Chouka, Also Known as Abu Adam, Also Known...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-02

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF STATE The Designation of Monir Chouka, also Known as Mounir Chouka, Also Known as Abu Adam, Also Known as Abu Adam From Germany, also Known as Abu Adam aus Deutschland, as a Specially Designated Global Terrorist Pursuant to Section 1(b) of Executive Order...

  2. Extending computer-based critiquing to a new domain: ATTENDING, ESSENTIAL-ATTENDING, and VQ-ATTENDING.

    PubMed

    Miller, P L

    1986-01-01

    The paper describes a research project which is developing expert computer systems to critique a physician's plan of medical management. In particular, the paper outlines the evolution of three computer systems: ATTENDING, a system designed to critique anesthetic management, ESSENTIAL-ATTENDING, a domain-independent system-building system, and VQ-ATTENDING, a prototype system implemented using ESSENTIAL-ATTENDING to critique aspects of ventilator management. The goals of the research project are to explore the critiquing approach in several different medical domains, to understand the design problems involved in implementing such systems, and to help other researchers build critiquing systems in further domains.

  3. Flight Attendant Injuries: 1971-1976

    DTIC Science & Technology

    1982-01-01

    fighting in- flight fires, and evacuating passengers from disabled aircraft. Any injury to a flight attendant may adversely influence the safety of the other...the aircraft was responsible for the injury is the second largest event followed by the category in which the flight attendants were injured because...Report No. 2. Government Accession Ne. 3. Recipientlo Catalog No. FAA-AM-82-8 ]A___________ 4. Title and Subtitle 5. Report Dote FLIGHT ATTENDANT

  4. Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain

    SciTech Connect

    Endsley, Mark A.; Somasunderam, Anoma D.; Li, Guangyu; Oezguen, Numan; Thiviyanathan, Varatharasa; Murray, James L.; Rubin, Donald H.; Hodge, Thomas W.; and others

    2014-04-15

    Previously, we showed that ADAM10 is necessary for HIV-1 replication in primary human macrophages and immortalized cell lines. Silencing ADAM10 expression interrupted the HIV-1 life cycle prior to nuclear translocation of viral cDNA. Furthermore, our data indicated that HIV-1 replication depends on the expression of ADAM15 and γ-secretase, which proteolytically processes ADAM10. Silencing ADAM15 or γ-secretase expression inhibits HIV-1 replication between reverse transcription and nuclear entry. Here, we show that ADAM10 expression also supports replication in CD4{sup +} T lymphocytes. The intracellular domain (ICD) of ADAM10 associates with the HIV-1 pre-integration complex (PIC) in the cytoplasm and immunoprecipitates and co-localizes with HIV-1 integrase, a key component of PIC. Taken together, our data support a model whereby ADAM15/γ-secretase processing of ADAM10 releases the ICD, which then incorporates into HIV-1 PIC to facilitate nuclear trafficking. Thus, these studies suggest ADAM10 as a novel therapeutic target for inhibiting HIV-1 prior to nuclear entry. - Highlights: • Nuclear trafficking of the HIV-1 pre-integration complex depends on ADAM10. • ADAM10 associates with HIV-1 integrase in the pre-integration complex. • HIV-1 replication depends on the expression of ADAM15 and γ-secretase. • Silencing ADAM15 or γ-secretase expression inhibits nuclear import of viral cDNA. • ADAM10 is important for HIV-1 replication in human macrophages and CD4{sup +} T lymphocytes.

  5. Econophysical visualization of Adam Smith’s invisible hand

    NASA Astrophysics Data System (ADS)

    Cohen, Morrel H.; Eliazar, Iddo I.

    2013-02-01

    Consider a complex system whose macrostate is statistically observable, but yet whose operating mechanism is an unknown black-box. In this paper we address the problem of inferring, from the system’s macrostate statistics, the system’s intrinsic force yielding the observed statistics. The inference is established via two diametrically opposite approaches which result in the very same intrinsic force: a top-down approach based on the notion of entropy, and a bottom-up approach based on the notion of Langevin dynamics. The general results established are applied to the problem of visualizing the intrinsic socioeconomic force-Adam Smith’s invisible hand-shaping the distribution of wealth in human societies. Our analysis yields quantitative econophysical representations of figurative socioeconomic forces, quantitative definitions of “poor” and “rich”, and a quantitative characterization of the “poor-get-poorer” and the “rich-get-richer” phenomena.

  6. Defenses and morality: Adam Smith, Sigmund Freud, and contemporary psychoanalysis.

    PubMed

    Gabrinetti, Paul A; Özler, Sule

    2014-10-01

    In this paper we follow the development and transmission of moral learning from Adam Smith's impartial spectator to Sigmund Freud's superego and then to contemporary psychoanalysis. We argue that defenses are an integral component in the acquisition of any moral system. Elaborating on this argument, we assert that there is a progression from defensive systems that are "closed" to defensive systems that are "open," as defined in a recent work by Novick and Novick. The former system is "static, avoids reality, and is characterized by power dynamics, sadomasochism, and omnipotent defense." The latter, on the other hand, is a system that allows for "joy, creativity, spontaneity, love and it is attuned to reality." Furthermore, while Smith and Freud's systems are more one-person systems of defense, contemporary psychoanalysis has moved to more of a two-person system.

  7. A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions

    PubMed Central

    Giebeler, Nives; Zigrino, Paola

    2016-01-01

    Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs’ function that have underscored the importance of these proteins in physiological and pathological processes over the years. PMID:27120619

  8. Neptune's Discovery: Le Verrier, Adams, and the Assignment of Credit

    NASA Astrophysics Data System (ADS)

    Sheehan, William

    2011-01-01

    As one of the most significant achievements of 19th century astronomy, the discovery of Neptune has been the subject of a vast literature. A large part of this literature--beginning with the period immediately after the optical discovery in Berlin--has been the obsession with assigning credit to the two men who attempted to calculate the planet's position (and initially this played out against the international rivalry between France and England). Le Verrier and Adams occupied much different positions in the Scientific Establishments of their respective countries; had markedly different personalities; and approached the investigation using different methods. A psychiatrist and historian of astronomy tries to provide some new contexts to the familiar story of the discovery of Neptune, and argues that the personalities of these two men played crucial roles in their approaches to the problem they set themselves and the way others reacted to their stimuli. Adams had features of high-functioning autism, while Le Verrier's domineering, obsessive, orderly personality--though it allowed him to be immensely productive--eventually led to serious difficulties with his peers (and an outright revolt). Though it took extraordinary smarts to calculate the position of Neptune, the discovery required social skills that these men lacked--and thus the process to discovery was more bumbling and adventitious than it might have been. The discovery of Neptune occurred at a moment when astronomy was changing from that of heroic individuals to team collaborations involving multiple experts, and remains an object lesson in the sociological aspects of scientific endeavor.

  9. Down regulation of ADAM33 as a Predictive Biomarker of Aggressive Breast Cancer

    PubMed Central

    Manica, Graciele C. M.; Ribeiro, Caroline F.; Oliveira, Marco A. S. de; Pereira, Isabela T.; Chequin, Andressa; Ramos, Edneia A. S.; Klassen, Liliane M. B.; Sebastião, Ana Paula M.; Alvarenga, Larissa M.; Zanata, Silvio M.; Noronha, Lucia De; Rabinovich, Iris; Costa, Fabricio F.; Souza, Emanuel M.; Klassen, Giseli

    2017-01-01

    Breast cancer is a heterogeneous disease with differences in its clinical, molecular and biological features. Traditionally, immunohistochemical markers together with clinicopathologic parameters are used to classify breast cancer and to predict disease outcome. Triple-negative breast cancer (TNBC) is a particular type of breast cancer that is defined by a lack of expression of hormonal receptors and the HER2 gene. Most cases of TNBC also have a basal-like phenotype (BLBC) with expression of cytokeratin 5/6 and/or EGFR. A basal marker alone is insufficient for a better understanding of the tumor biology of TNBC. In that regard, the ADAM33 gene is silenced by DNA hypermethylation in breast cancer, which suggests that ADAM33 might be useful as a molecular marker. In the present study, we have produced monoclonal antibodies against the ADAM33 protein and have investigated the role of ADAM33 protein in breast cancer. We used 212 breast tumor samples and lower levels of ADAM33 were correlated with TNBC and basal-like markers. A lower level of ADAM33 was also correlated with shorter overall survival and metastasis-free survival and was considered an independent prognostic factor suggesting that ADAM33 is a novel molecular biomarker of TNBC and BLBC that might be useful as a prognostic factor. PMID:28294120

  10. SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation

    PubMed Central

    Saraceno, C; Marcello, E; Di Marino, D; Borroni, B; Claeysen, S; Perroy, J; Padovani, A; Tramontano, A; Gardoni, F; Di Luca, M

    2014-01-01

    A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents amyloid formation. Its activity depends on correct intracellular trafficking and on synaptic membrane insertion. Here, we describe that in hippocampal neurons the synapse-associated protein-97 (SAP97), an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes. This process is mediated by a previously uncharacterized protein kinase C phosphosite in SAP97 SRC homology 3 domain that modulates SAP97 association with ADAM10. Such mechanism is essential for ADAM10 trafficking from the Golgi outposts to the synapse, but does not affect ADAM10 transport from the endoplasmic reticulum. Notably, this process is altered in Alzheimer's disease brains. These results help in understanding the mechanism responsible for the modulation of ADAM10 intracellular path, and can constitute an innovative therapeutic strategy to finely tune ADAM10 shedding activity towards APP. PMID:25429624

  11. ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes.

    PubMed

    Hall, Katherine C; Hill, Daniel; Otero, Miguel; Plumb, Darren A; Froemel, Dara; Dragomir, Cecilia L; Maretzky, Thorsten; Boskey, Adele; Crawford, Howard C; Selleri, Licia; Goldring, Mary B; Blobel, Carl P

    2013-08-01

    Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.

  12. Down regulation of ADAM33 as a Predictive Biomarker of Aggressive Breast Cancer.

    PubMed

    Manica, Graciele C M; Ribeiro, Caroline F; Oliveira, Marco A S de; Pereira, Isabela T; Chequin, Andressa; Ramos, Edneia A S; Klassen, Liliane M B; Sebastião, Ana Paula M; Alvarenga, Larissa M; Zanata, Silvio M; Noronha, Lucia De; Rabinovich, Iris; Costa, Fabricio F; Souza, Emanuel M; Klassen, Giseli

    2017-03-15

    Breast cancer is a heterogeneous disease with differences in its clinical, molecular and biological features. Traditionally, immunohistochemical markers together with clinicopathologic parameters are used to classify breast cancer and to predict disease outcome. Triple-negative breast cancer (TNBC) is a particular type of breast cancer that is defined by a lack of expression of hormonal receptors and the HER2 gene. Most cases of TNBC also have a basal-like phenotype (BLBC) with expression of cytokeratin 5/6 and/or EGFR. A basal marker alone is insufficient for a better understanding of the tumor biology of TNBC. In that regard, the ADAM33 gene is silenced by DNA hypermethylation in breast cancer, which suggests that ADAM33 might be useful as a molecular marker. In the present study, we have produced monoclonal antibodies against the ADAM33 protein and have investigated the role of ADAM33 protein in breast cancer. We used 212 breast tumor samples and lower levels of ADAM33 were correlated with TNBC and basal-like markers. A lower level of ADAM33 was also correlated with shorter overall survival and metastasis-free survival and was considered an independent prognostic factor suggesting that ADAM33 is a novel molecular biomarker of TNBC and BLBC that might be useful as a prognostic factor.

  13. Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

    PubMed Central

    Davies, Elizabeth R.; Kelly, Joanne F.C.; Howarth, Peter H.; Wilson, David I.; Holgate, Stephen T.; Davies, Donna E.; Whitsett, Jeffrey A.

    2016-01-01

    Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma. PMID:27489884

  14. ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion.

    PubMed

    Aghababaei, M; Hogg, K; Perdu, S; Robinson, W P; Beristain, A G

    2015-12-01

    Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development.

  15. Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.

    PubMed

    Rao, Velidi H; Vogel, Kristen; Yanagida, Jodi K; Marwaha, Nitin; Kandel, Amrit; Trempus, Carol; Repertinger, Susan K; Hansen, Laura A

    2015-10-01

    Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness.

  16. Recombinant disintegrin domain of ADAM15 inhibits the proliferation and migration of Bel-7402 cells

    SciTech Connect

    Hou, Y.; Chu, M.; Du, F.F.; Lei, J.Y.; Chen, Y.; Zhu, R.Y.; Gong, X.H.; Ma, X.; Jin, J.

    2013-06-14

    Highlights: •rhddADAM15 inhibited the proliferation and migration of Bel-7402 cells. •rhddADAM15 inhibited growth and metastasis of Bel-7402 cells in zebrafish xenograft. •rhddADAM15 induced apoptosis in Bel-7402 cells and somatic cells of zebrafish. •Cell-cycle in Bel-7402 cells showed a partial G{sub 2}/S arrest. •Activity of caspases 8, 9 and 3 was increased in rhddADAM15-treated Bel-7402 cells. -- Abstract: ADAM15 (A Disintegrin And Metalloproteinase 15), a transmembrane protein containing seven domains, interacts with some integrins via its disintegrin domain and overexpresses in many solid tumors. In this study, the effect of the recombinant human disintegrin domain (rhddADAM15) on the proliferation and migration of Bel-7402 cells was evaluated in vitro and in vivo in zebrafish xenografts. rhddADAM15 (4 μM) severely inhibited the proliferation and migration of Bel-7402 cells, inducing a partial G{sub 2}/S arrest and morphological nucleus changes of apoptosis. Moreover, the activity of caspases 8, 9 and 3 in Bel-7402 cells was increased. In addition, the zebrafish was used as a model for apoptosis-induction and tumor-xenograft. rhddADAM15 (1 pM) inhibited the growth and metastasis of Bel-7402 cell xenografts in zebrafish and a lower concentration (0.1 pM) induced severe apoptosis in the somatic cells of zebrafish. In conclusion, our data identified rhddADAM15 as a potent inhibitor of tumor growth and metastasis, making it a promising tool for use in anticancer treatment.

  17. EMMPRIN and ADAM12 in prostate cancer: preliminary results of a prospective study.

    PubMed

    Bilgin Doğru, Elif; Dizdar, Yavuz; Akşit, Ece; Ural, Feyyaz; Şanlı, Öner; Yasasever, Vildan

    2014-11-01

    Extracellular metalloproteinase inducer (EMMPRIN) and a disintegrin and metalloproteinase (ADAM12) play a major role in cancer invasion and metastasis owing to the fact that they are directly related to the cell microenvironment and extracellular matrix (ECM) degradation. The aim of this study was to search for an answer to the question "whether the determination of EMMPRIN and ADAM12 values especially in urine may be helpful for the early diagnosis of prostate cancer without employing invasive methods" and also to check whether they may be useful for the determination of the patients with high metastasis risk. Peripheral blood and urine from 66 prostate cancer patients (40 local, 20 locally advanced, 6 metastatic) and 14 healthy controls were evaluated by enzyme-linked immunosorbent assay (ELISA) method. Serum EMMPRIN and ADAM12 values of the patients were seen to be statistically higher than the serum EMMPRIN and ADAM12 values of the healthy controls (p=0.01 and p=0.001, respectively). The urine ADAM12 levels were significantly higher in patients (p=0.013). No significant relationships were found between urine EMMPRIN values of the patients and the healthy controls (p>0.05). Positive correlation between urine EMMPRIN-urine ADAM12 tests was found in total patients group (r=0.683, p=0.001). Our preliminary results revealed that serum EMMPRIN and ADAM12 values and urine ADAM12 values may be useful markers in prostate cancer therapy. Due to the high correlation between these two tests, we are of the opinion that the use of urine ADAM12 in clinic may be sufficient and favorable together with prostate-specific antigen (PSA) for treatment.

  18. Genomic organization and promoter analysis of the bovine ADAM12 gene.

    PubMed

    Taniguchi, Y; Doronbekov, K; Yamada, T; Sasaki, Y; Takano, A; Sugimoto, Y

    2008-01-01

    A disintegrin and metalloprotease (ADAM) 12 is a member of the ADAM family possessing a putative role in a variety of biological processes such as modulation of proteolytic processing, cell adhesion, cell fusion, and signaling. Recently, it has been suggested that ADAM12 is involved in regulation of adipogenesis as well as myogenesis. In this study, we have determined the genomic structure of 5'- and 3'-regions in the bovine ADAM12 gene. We could obtain characteristics of lower homology of its exon 2 with human counterpart. Human exon S19 encodes for the sequence specific to a shorter secreted form of ADAM12S. The bovine ADAM12 gene had no canonical 3'-splice acceptor site at 5'-side of the putative exon S19, suggesting that the cattle could not produce a ADAM12S counterpart. To identify the regulatory elements, a 12 kb 5'-flanking region of the gene was cloned and luciferase reporter assay was carried out. Reporter plasmids with different length of proximal promoter region indicated the similar patterns of promoter activities between 3T3-L1 preadipose and Cos-1 nonadipose cells. However, 2.0 and 0.2 kb fragments located at - 8 and - 4.5 kb upstream of the putative transcription start site, respectively, increased the ADAM12 promoter activity about 1.5- to 2-fold in 3T3-L1, but not in Cos-1. These results suggested that the two distal regions might contribute to the preadipocyte-specific expression of ADAM12 gene.

  19. Phenotypic diversity of breast cancer-related mutations in metalloproteinase-disintegrin ADAM12.

    PubMed

    Qi, Yue; Duhachek-Muggy, Sara; Li, Hui; Zolkiewska, Anna

    2014-01-01

    Six different somatic missense mutations in the human ADAM12 gene have been identified so far in breast cancer. Five of these mutations involve highly conserved residues in the extracellular domain of the transmembrane ADAM12-L protein. Two of these extracellular mutations, D301H and G479E, have been previously characterized in the context of mouse ADAM12. Three other mutations, T596A, R612Q, and G668A, have been reported more recently, and their effects on ADAM12-L protein structure/function are not known. Here, we show that ADAM12-L bearing the G668A mutation is largely retained in the endoplasmic reticulum in its nascent, full-length form, with an intact N-terminal pro-domain. The T596A and R612Q mutants are efficiently trafficked to the cell surface and proteolytically processed to remove their pro-domains. However, the T596A mutant shows decreased catalytic activity at the cell surface, while the R612Q mutant is fully active and comparable to the wild-type ADAM12-L. The D301H and G479E mutants, consistent with the corresponding D299H and G477E mutants of mouse ADAM12 described earlier, are not proteolytically processed and do not exhibit catalytic activity at the cell surface. Among all six breast cancer-associated mutations in ADAM12-L, mutations that preserve the activity--R612Q and L792F--occur in triple-negative breast cancers, while loss-of-function mutations--D301H, G479E, T596A, and G668A--are found in non-triple negative cancers. This apparent association between the catalytic activity of the mutants and the type of breast cancer supports a previously postulated role of an active ADAM12-L in the triple negative breast cancer disease.

  20. Factors Influencing Likelihood of Voice Therapy Attendance.

    PubMed

    Misono, Stephanie; Marmor, Schelomo; Roy, Nelson; Mau, Ted; Cohen, Seth M

    2017-03-01

    Objective To identify factors associated with the likelihood of attending voice therapy among patients referred for it in the CHEER (Creating Healthcare Excellence through Education and Research) practice-based research network infrastructure. Study Design Prospectively enrolled cross-sectional study. Setting CHEER network of community and academic sites. Methods Data were collected on patient-reported demographics, voice-related diagnoses, voice-related handicap (Voice Handicap Index-10), likelihood of attending voice therapy (VT), and opinions on factors influencing likelihood of attending VT. The relationships between patient characteristics/opinions and likelihood of attending VT were investigated. Results A total of 170 patients with various voice-related diagnoses reported receiving a recommendation for VT. Of those, 85% indicated that they were likely to attend it, regardless of voice-related handicap severity. The most common factors influencing likelihood of VT attendance were insurance/copay, relief that it was not cancer, and travel. Those who were not likely to attend VT identified, as important factors, unclear potential improvement, not understanding the purpose of therapy, and concern that it would be too hard. In multivariate analysis, factors associated with greater likelihood of attending VT included shorter travel distance, age (40-59 years), and being seen in an academic practice. Conclusions Most patients reported plans to attend VT as recommended. Patients who intended to attend VT reported different considerations in their decision making from those who did not plan to attend. These findings may inform patient counseling and efforts to increase access to voice care.

  1. The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12*

    PubMed Central

    Solomon, Emilia; Li, Hui; Duhachek Muggy, Sara; Syta, Emilia; Zolkiewska, Anna

    2010-01-01

    Increased expression of metalloprotease-disintegrin ADAM12 is a hallmark of several pathological conditions, including cancer, cardiovascular disease, and certain inflammatory diseases of the central nervous system or the muscoskeletal system. We show that transforming growth factor β1 (TGFβ1) is a potent inducer of ADAM12 mRNA and protein in mouse fibroblasts and in mouse and human mammary epithelial cells. Induction of ADAM12 is detected within 2 h of treatment with TGFβ1, is Smad2/Smad3-dependent, and is a result of derepression of the Adam12 gene. SnoN, a negative regulator of the TGFβ signaling pathway, is a master regulator of ADAM12 expression in response to TGFβ1 stimulation. Overexpression of SnoN in NIH3T3 cells reduces the magnitude of ADAM12 induction by TGFβ1 treatment. Down-regulation of SnoN expression by short hairpin RNA enhances TGFβ1-induced expression of ADAM12. In a panel of TGFβ1-responsive cancer cell lines with high expression of SnoN, induction of ADAM12 by TGFβ1 is significantly impaired, suggesting that the endogenous SnoN plays a role in regulating ADAM12 expression in response to TGFβ1. Identification of SnoN as a repressor of the ADAM12 gene should contribute to advances in the studies on the role of ADAM12 in tumor progression and in the development of other pathologies. PMID:20457602

  2. Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function

    PubMed Central

    Kuhn, Peer-Hendrik; Colombo, Alessio Vittorio; Schusser, Benjamin; Dreymueller, Daniela; Wetzel, Sebastian; Schepers, Ute; Herber, Julia; Ludwig, Andreas; Kremmer, Elisabeth; Montag, Dirk; Müller, Ulrike; Schweizer, Michaela; Saftig, Paul; Bräse, Stefan; Lichtenthaler, Stefan F

    2016-01-01

    Metzincin metalloproteases have major roles in intercellular communication by modulating the function of membrane proteins. One of the proteases is the a-disintegrin-and-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer's disease amyloid precursor protein. ADAM10 is also required for neuronal network functions in murine brain, but neuronal ADAM10 substrates are only partly known. With a proteomic analysis of Adam10-deficient neurons we identified 91, mostly novel ADAM10 substrate candidates, making ADAM10 a major protease for membrane proteins in the nervous system. Several novel substrates, including the neuronal cell adhesion protein NrCAM, are involved in brain development. Indeed, we detected mistargeted axons in the olfactory bulb of conditional ADAM10-/- mice, which correlate with reduced cleavage of NrCAM, NCAM and other ADAM10 substrates. In summary, the novel ADAM10 substrates provide a molecular basis for neuronal network dysfunctions in conditional ADAM10-/- mice and demonstrate a fundamental function of ADAM10 in the brain. DOI: http://dx.doi.org/10.7554/eLife.12748.001 PMID:26802628

  3. ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice

    PubMed Central

    Guaiquil, Victor H.; Swendeman, Steven; Zhou, Wenhui; Guaiquil, Patricio; Weskamp, Gisela; Bartsch, Jörg W.

    2010-01-01

    ADAM8 is a member of the “a disintegrin and metalloproteinase” (ADAM) family of membrane-anchored metalloproteinases. ADAM8-deficient mice have no evident spontaneous developmental or pathological defects, and little is currently known about the role of ADAM8 in disease. Here, we investigated the contribution of ADAM8 to pathological neovascularization in mice using an oxygen-induced retinopathy (OIR) model and heterotopical injection of tumor cells. We found an increase in retinal re-vascularization but fewer neovascular tufts in the OIR model and increased growth of heterotopically injected tumor cells in Adam8−/− mice compared with wild-type controls. These results suggest that ADAM8 functions to limit both of these processes in wild-type mice. In cell-based assays, overexpression of ADAM8 increased the ectodomain shedding of several co-expressed membrane proteins with roles in angiogenesis (CD31, Tie-2, Flk-1, Flt-1, EphrinB2, EphB4, VE-cadherin, KL-1, E-selectin, and neuregulin-1β2). Thus, dysregulated expression of ADAM8 in endothelial cells in vivo could potentially increase the processing of these and other substrate proteins. Taken together, our findings suggest that inhibiting ADAM8 could be useful for promoting re-vascularization and thereby preventing formation of neovascular tufts in proliferative retinopathies. On the other hand, blocking ADAM8 could be detrimental in the context of rapidly growing tumors. PMID:20119708

  4. The role of SnoN in transforming growth factor beta1-induced expression of metalloprotease-disintegrin ADAM12.

    PubMed

    Solomon, Emilia; Li, Hui; Duhachek Muggy, Sara; Syta, Emilia; Zolkiewska, Anna

    2010-07-16

    Increased expression of metalloprotease-disintegrin ADAM12 is a hallmark of several pathological conditions, including cancer, cardiovascular disease, and certain inflammatory diseases of the central nervous system or the muscoskeletal system. We show that transforming growth factor beta1 (TGFbeta1) is a potent inducer of ADAM12 mRNA and protein in mouse fibroblasts and in mouse and human mammary epithelial cells. Induction of ADAM12 is detected within 2 h of treatment with TGFbeta1, is Smad2/Smad3-dependent, and is a result of derepression of the Adam12 gene. SnoN, a negative regulator of the TGFbeta signaling pathway, is a master regulator of ADAM12 expression in response to TGFbeta1 stimulation. Overexpression of SnoN in NIH3T3 cells reduces the magnitude of ADAM12 induction by TGFbeta1 treatment. Down-regulation of SnoN expression by short hairpin RNA enhances TGFbeta1-induced expression of ADAM12. In a panel of TGFbeta1-responsive cancer cell lines with high expression of SnoN, induction of ADAM12 by TGFbeta1 is significantly impaired, suggesting that the endogenous SnoN plays a role in regulating ADAM12 expression in response to TGFbeta1. Identification of SnoN as a repressor of the ADAM12 gene should contribute to advances in the studies on the role of ADAM12 in tumor progression and in the development of other pathologies.

  5. Extravillous trophoblast-associated ADAM12 exerts pro-invasive properties, including induction of integrin beta 1-mediated cellular spreading.

    PubMed

    Biadasiewicz, Katarzyna; Fock, Valerie; Dekan, Sabine; Proestling, Katharina; Velicky, Philipp; Haider, Sandra; Knöfler, Martin; Fröhlich, Camilla; Pollheimer, Jürgen

    2014-05-01

    ADAM12, consisting of a membrane-bound (ADAM12L) and a secreted (ADAM12S) form, is expressed exclusively in regenerating and developing tissue as well as in certain cancer types. Strong ADAM12 expression levels have been noticed in the human placenta, and deregulated ADAM12S levels were associated with various pregnancy-related disorders including pre-eclampsia and intrauterine growth restriction. However, the role of ADAM12 in trophoblast motility has not been investigated so far. Hence, the present study aimed to investigate the specific function of the protease by using different primary trophoblast cell models. Immunofluorescence and Western blot analyses of first trimester placental tissue and differentiating primary first trimester cytotrophoblasts (CTBs) indicated strong upregulation of both of the ADAM12 isoforms during extravillous trophoblast differentiation. Functional assays involving short interfering RNA (siRNA)-mediated knockdown studies in primary CTBs and first trimester explant cultures revealed a significant repression of trophoblast motility upon partial loss of ADAM12. Conversely, isoform-specific overexpression in the ADAM12-negative trophoblast cell line SGHPL-5 enhanced the invasive capacity of these cells. We further confirmed proteolytic activity of trophoblast-derived ADAM12S by demonstrating its potential to degrade insulin-like growth factor-binding protein 3. Finally, we suggest that ADAM12S exerts its pro-migratory function in trophoblasts by inducing integrin beta 1-mediated cellular spreading.

  6. Legal Challenges to Compulsory Attendance Laws.

    ERIC Educational Resources Information Center

    Beckham, Joseph C.

    Legal challenges to state compulsory attendance laws have emphasized four interrelated constitutional claims. Under provisions of the free exercise clause of the First Amendment, parents have challenged the state's authority to require public school attendance in lieu of home instruction and private, religious organizations have refused to comply…

  7. Does Mandatory Attendance Improve Student Performance?

    ERIC Educational Resources Information Center

    Marburger, Daniel R.

    2006-01-01

    Previous empirical literature indicates that student performance is inversely correlated with absenteeism. The author investigates the impact of enforcing an attendance policy on absenteeism and student performance. The evidence suggests that an enforced mandatory attendance policy significantly reduces absenteeism and improves exam performance.

  8. 42 CFR 35.22 - Attendants.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Transfer of Patients § 35.22 Attendants. Patients shall be transferred by such means... nursing attendants shall be qualified to care for persons suffering from the type of disease or...

  9. 42 CFR 35.22 - Attendants.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Transfer of Patients § 35.22 Attendants. Patients shall be transferred by such means... nursing attendants shall be qualified to care for persons suffering from the type of disease or...

  10. 42 CFR 35.22 - Attendants.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Transfer of Patients § 35.22 Attendants. Patients shall be transferred by such means... nursing attendants shall be qualified to care for persons suffering from the type of disease or...

  11. Attending Behavior of Children Near a Child Who is Reinforced for Attending

    ERIC Educational Resources Information Center

    Okovita, Hymie Wolf; Bucher, Bradley

    1976-01-01

    The present study investigated effects of a token program for one child on the attending behavior of other children sitting near him. Results show the rewarded child's attending increased in the reinforcement conditions and the unrewarded children's attending increased when they were sitting on either side of the rewarded child. (Author)

  12. TspanC8 Tetraspanins and A Disintegrin and Metalloprotease 10 (ADAM10) Interact via Their Extracellular Regions

    PubMed Central

    Noy, Peter J.; Yang, Jing; Reyat, Jasmeet S.; Matthews, Alexandra L.; Charlton, Alice E.; Furmston, Joanna; Rogers, David A.; Rainger, G. Ed; Tomlinson, Michael G.

    2016-01-01

    A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitously expressed transmembrane metalloprotease that cleaves the extracellular regions from its transmembrane substrates. ADAM10 is essential for embryonic development and is implicated in cancer, Alzheimer, and inflammatory diseases. The tetraspanins are a superfamily of 33 four-transmembrane proteins in mammals, of which the TspanC8 subgroup (Tspan5, 10, 14, 15, 17, and 33) promote ADAM10 intracellular trafficking and enzymatic maturation. However, the interaction between TspanC8s and ADAM10 has only been demonstrated in overexpression systems and the interaction mechanism remains undefined. To address these issues, an antibody was developed to Tspan14, which was used to show co-immunoprecipitation of Tspan14 with ADAM10 in primary human cells. Chimeric Tspan14 constructs demonstrated that the large extracellular loop of Tspan14 mediated its co-immunoprecipitation with ADAM10, and promoted ADAM10 maturation and trafficking to the cell surface. Chimeric ADAM10 constructs showed that membrane-proximal stalk, cysteine-rich, and disintegrin domains of ADAM10 mediated its co-immunoprecipitation with Tspan14 and other TspanC8s. This TspanC8-interacting region was required for ADAM10 exit from the endoplasmic reticulum. Truncated ADAM10 constructs revealed differential TspanC8 binding requirements for the stalk, cysteine-rich, and disintegrin domains. Moreover, Tspan15was the only TspanC8 to promote cleavage of the ADAM10 substrate N-cadherin, whereas Tspan14 was unique in reducing cleavage of the platelet collagen receptor GPVI. These findings suggest that ADAM10 may adopt distinct conformations in complex with different TspanC8s, which could impact on substrate selectivity. Furthermore, this study identifies regions of TspanC8s and ADAM10 for potential interaction-disrupting therapeutic targeting. PMID:26668317

  13. Apparent reduction of ADAM10 in scrapie-infected cultured cells and in the brains of scrapie-infected rodents.

    PubMed

    Chen, Cao; Lv, Yan; Zhang, Bao-Yun; Zhang, Jin; Shi, Qi; Wang, Jing; Tian, Chan; Gao, Chen; Xiao, Kang; Ren, Ke; Zhou, Wei; Dong, Xiao-Ping

    2014-12-01

    It has been described that A disintegrin and metalloproteinase (ADAM10) may involve in the physiopathology of prion diseases, but the direct molecular basis still remains unsolved. In this study, we confirmed that ADAM10 was able to cleave recombinant human prion protein in vitro. Using immunoprecipitation tests (IP) and immunofluorescent assays (IFA), reliable molecular interaction between the native cellular form of PrP (PrP(C)) and ADAM10 was observed not only in various cultured neuronal cell lines but also in brain homogenates of healthy hamsters and mice. Only mature ADAM10 (after removal of its prodomain) molecules showed the binding activity with the native PrP(C). Remarkably more prion protein (PrP)-ADAM10 complexes were detected in the membrane fraction of cultured cells. In the scrapie-infected SMB cell model, the endogenous ADAM10 levels, especially the mature ADAM10, were significantly decreased in the fraction of cell membrane. IP and IFA tests of prion-infected SMB-S15 cells confirmed no detectable PrP-ADAM10 complex in the cellular lysates and PrP-ADAM10 co-localization on the cell surface. Furthermore, we demonstrated that the levels of ADAM10 in the brain homogenates of scrapie agent 263K-infected hamsters and agent ME7-infected mice were also almost diminished at the terminal stage, showing time-dependent decreases during the incubation period. Our data here provide the solid molecular basis for the endoproteolysis of ADAM10 on PrP molecules and interaction between ADAM10 and PrP(C). Obvious loss of ADAM10 during prion infection in vitro and in vivo highlights that ADAM10 may play essential pathophysiological roles in prion replication and accumulation.

  14. Selective inhibition of ADAM12 catalytic activity through engineering of tissue inhibitor of metalloproteinase 2 (TIMP-2).

    PubMed

    Kveiborg, Marie; Jacobsen, Jonas; Lee, Meng-Huee; Nagase, Hideaki; Wewer, Ulla M; Murphy, Gillian

    2010-08-15

    The disintegrin and metalloprotease ADAM12 has important functions in normal physiology as well as in diseases, such as cancer. Little is known about how ADAM12 confers its pro-tumorigenic effect; however, its proteolytic capacity is probably a key component. Thus selective inhibition of ADAM12 activity may be of great value therapeutically and as an investigative tool to elucidate its mechanisms of action. We have previously reported the inhibitory profile of TIMPs (tissue inhibitor of metalloproteinases) against ADAM12, demonstrating in addition to TIMP-3, a unique ADAM-inhibitory activity of TIMP-2. These findings strongly suggest that it is feasible to design a TIMP mutant selectively inhibiting ADAM12. With this purpose, we characterized the molecular determinants of the ADAM12-TIMP complex formation as compared with known molecular requirements for TIMP-mediated inhibition of ADAM17/TACE (tumour necrosis factor alpha-converting enzyme). Kinetic analysis using a fluorescent peptide substrate demonstrated that the molecular interactions of N-TIMPs (N-terminal domains of TIMPs) with ADAM12 and TACE are for the most part comparable, yet revealed strikingly unique features of TIMP-mediated ADAM12 inhibition. Intriguingly, we found that removal of the AB-loop in N-TIMP-2, which is known to impair its interaction with TACE, resulted in increased affinity to ADAM12. Importantly, using a cell-based epidermal growth factor-shedding assay, we demonstrated for the first time an inhibitory activity of TIMPs against the transmembrane ADAM12-L (full-length ADAM12), verifying the distinctive inhibitory abilities of N-TIMP-2 and engineered N-TIMP-2 mutants in a cellular environment. Taken together, our findings support the idea that a distinctive ADAM12 inhibitor with future therapeutic potential can be designed.

  15. The Fall of Adam Osborne: Why His Company Failed and What It Means for Personal Computing.

    ERIC Educational Resources Information Center

    Immel, A. Richard

    1984-01-01

    Discusses some of the reasons for the failure of the Osborne Computer Corporation, including Adam Osborne's personality and background, the people he selected to run the company, and lack of financial controls. (MBR)

  16. ADAM 10 expression in primary uveal melanoma as prognostic factor for risk of metastasis.

    PubMed

    Caltabiano, Rosario; Puzzo, Lidia; Barresi, Valeria; Ieni, Antonio; Loreto, Carla; Musumeci, Giuseppe; Castrogiovanni, Paola; Ragusa, Marco; Foti, Pietro; Russo, Andrea; Longo, Antonio; Reibaldi, Michele

    2016-11-01

    Uveal melanoma is the most frequent primary intraocular neoplasm in adults. Although malignant melanoma may be located at any point in the uveal tract, the choroid and ciliary body are more frequent locations than the iris. In the present study, we examined ADAM10 expression levels in primary uveal melanoma both with and without metastasis, and we evaluated their association with other high risk characteristics for metastasis in order to assess if ADAM10 can be used to predict metastasis. This study included a total of 52 patients, 23 men and 29 women, with uveal melanoma. A significantly high expression of ADAM-10 was seen in patients with metastasis (11/13, 84.6%), but not in patients without metastasis (15/39, 38.5%). In conclusion we found that ADAM10 expression was associated with a more rapid metastatic progression confirming its role in uveal melanoma metastasis.

  17. ISS Update: Adam Naids on Creating "€œNASA Johnson Style"

    NASA Video Gallery

    Public Affairs Officer Dan Huot talks to Adam Naids, Hardware Development Engineer, one of the creators of the successful "€œGangnam Style" parody video "€œNASA Johnson Style."€ Featured on NASAâ€...

  18. Highlighting High Performance: Adam Joseph Lewis Center for Environmental Studies, Oberlin College, Oberlin, Ohio

    SciTech Connect

    2002-11-01

    Oberlin College’s Adam Joseph Lewis Center for Environmental Studies is a high-performance building featuring an expansive photovoltaic system and a closed-loop groundwater heat pump system. Designers incorporated energy-efficient components and materials

  19. Expression of ADAM12 is regulated by E2F1 in small cell lung cancer.

    PubMed

    Li, Zunling; Wang, Yaopeng; Kong, Lijun; Yue, Zhen; Ma, Ying; Chen, Xufang

    2015-12-01

    Our previous study reported that ADAM12 was highly expressed in small cell lung cancer (SCLC) and could be an effective marker for diagnosis and prognosis. Yet, the reason for the high expression of ADAM12 in SCLC requires further elucidation. Transcription factor E2F1 has been receiving increasing attention due to the complexity and diversity of its function in cancer. In the present study, the expression of ADAM12 was significantly decreased following silencing of E2F1 expression by siRNA, thus indicating that E2F1 may regulate the expression of ADAM12 at the level of transcription. Chromatin immunoprecipitation-to-sequence analysis identified three binding sites for E2F1 in the locus for ADAM12. They were Chr10: 128010444-128011026, located in the intron of ADAM12, named seq0; Chr10: 128076927‑128078127, located in the promoter of ADAM12, named seq1; and Chr10: 128086195‑128086876, located in the upstream 20 kb from the transcription start site of ADAM12, named: seq2. Dual‑luciferase reporter experiments revealed that seq1 not seq0 and seq2 was able to promote the expression of luciferase. Notably, co-transfection of E2F1 significantly increased the activity of seq1 not seq0 and seq2, but quantitative polymerase chain reaction results showed that seq0, seq1 and seq2 could recruit E2F1, indicating that the influence of E2F1 in regulating the expression of ADAM12 was complex. Sequence analysis clarified that seq1 was a part of the ADAM12 promoter, yet the functions of seq0 and seq2 were unknown. Fusion fragments containing seq0-seq1 or seq2-seq1 were analyzed in luciferase constructs. Compared with seq1 alone, the activities of these fusion fragments were non-significantly reduced. The activities of fusion fragments were significantly decreased following co-transfection with E2F1. Thus, the present findings support the conclusion that the E2F1 transcription factor regulates the expression of ADAM12 by binding differential cis-acting elements.

  20. Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.

    PubMed

    Salem, Esam S B; Grobe, Nadja; Elased, Khalid M

    2014-03-15

    Angiotensin-converting enzyme 2 (ACE2) is located in several tissues and is highly expressed in renal proximal tubules, where it degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1-7). Accumulating evidence supports protective roles of ACE2 in several disease states, including diabetic nephropathy. A disintegrin and metalloprotease (ADAM) 17 is involved in the shedding of several transmembrane proteins, including ACE2. Our previous studies showed increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2 diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M, Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1 diabetic Akita mice. Results demonstrate increased renal ACE2 and ADAM17 expression and increased urinary ACE2 fragments (≈70 kDa) and albumin excretion in diabetic Akita mice. Immunostaining revealed colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding into the media, confirming ADAM17-mediated shedding of ACE2. Treatment of Akita mice with insulin implants for 20 wk normalized hyperglycemia and decreased urinary ACE2 and albumin excretion. Insulin also normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor of metalloproteinase 3 (TIMP3) protein expression. There was a positive linear correlation between urinary ACE2 and albuminuria, blood glucose, plasma creatinine, glucagon, and triglycerides. This is the first report showing an association between hyperglycemia, cardiovascular risk factors, and increased shedding of urinary ACE2 in diabetic Akita mice. Urinary ACE2 could be used as a biomarker for diabetic nephropathy and as an index of intrarenal ACE2 status.

  1. ADAM17 Inhibitors Attenuate Corneal Epithelial Detachment Induced by Mustard Exposure

    PubMed Central

    DeSantis-Rodrigues, Andrea; Chang, Yoke-Chen; A. Hahn, Rita; P. Po, Iris; Zhou, Peihong; Lacey, C. Jeffrey; Pillai, Abhilash; C. Young, Sherri; A. Flowers II, Robert; A. Gallo, Michael; D. Laskin, Jeffrey; R. Gerecke, Donald; K. H. Svoboda, Kathy; D. Heindel, Ned; Gordon, Marion K.

    2016-01-01

    Purpose Sulfur mustard, nitrogen mustard (NM), and 2-chloroethyl ethyl sulfide all cause corneal injury with epithelial–stromal separation, differing only by degree. Injury can resolve in a few weeks or develop into chronic corneal problems. These vesicants induce microbullae at the epithelial–stromal junction, which is partially caused by cleavage of transmembranous hemidesmosomal collagen XVII, a component anchoring the epithelium to the stroma. ADAM17 is an enzyme involved in wound healing and is able to cleave collagen XVII. The activity of ADAM17 was inhibited in vesicant-exposed corneas by four different hydroxamates, to evaluate their therapeutic potential when applied 2 hours after exposure, thereby allowing ADAM17 to perform its early steps in wound healing. Methods Rabbit corneal organ cultures exposed to NM for 2 hours were washed, then incubated at 37°C for 22 hours, with or without one of the four hydroxamates (dose range, 0.3–100 nmol in 20 μL, applied four times). Corneas were analyzed by light and immunofluorescence microscopy, and ADAM17 activity assays. Results Nitrogen mustard–induced corneal injury showed significant activation of ADAM17 levels accompanying epithelial–stromal detachment. Corneas treated with hydroxamates starting 2 hours post exposure showed a dose-dependent ADAM17 activity inhibition up to concentrations of 3 nmol. Of the four hydroxamates, NDH4417 (N-octyl-N-hydroxy-2-[4-hydroxy-3-methoxyphenyl] acetamide) was most effective for inhibiting ADAM17 and retaining epithelial–stromal attachment. Conclusions Mustard exposure leads to corneal epithelial sloughing caused, in part, by the activation of ADAM17 at the epithelial–stromal junction. Select hydroxamate compounds applied 2 hours after NM exposure mitigated epithelial–stromal separation. PMID:27058125

  2. Engineering of Specific Tissue Inhibitors to Block ADAM Type Metalloprotease-Mediated Mammary Neoplasia

    DTIC Science & Technology

    2001-07-01

    ADAM9 cleaves the HB- EGF when PKCd is activated, but neither the wildtype, nor the dominant-negative ADAM9, affects the EGFR transactivation (Izumi et...S. V. Subramanian, M. L. Fitzgerald, M. Bernfield, J. Bi- that accounts for these observations re- not other TIMPs, induce apoptosis (19). e!. Chem...12. D. Pan and G. M. Rubin, Cell90, 271 (1997). fy the cytoplasmic domains of the pro- and induces apoptosis by binding to the Fas 13. C. Cho et a

  3. The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17

    PubMed Central

    Dombernowsky, Sarah Louise; Samsøe-Petersen, Jacob; Petersen, Camilla Hansson; Instrell, Rachael; Hedegaard, Anne-Mette Bornhardt; Thomas, Laurel; Atkins, Katelyn Mae; Auclair, Sylvain; Albrechtsen, Reidar; Mygind, Kasper Johansen; Fröhlich, Camilla; Howell, Michael; Parker, Peter; Thomas, Gary; Kveiborg, Marie

    2015-01-01

    The metalloproteinase ADAM17 activates ErbB signalling by releasing ligands from the cell surface, a key step underlying epithelial development, growth, and tumour progression. However, mechanisms acutely controlling ADAM17 cell-surface availability to modulate the extent of ErbB ligand release are poorly understood. Here, through a functional genome-wide siRNA screen, we identify the sorting protein PACS-2 as a regulator of ADAM17 trafficking and ErbB signalling. PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding, without apparent effects on related proteases. PACS-2 co-localizes with ADAM17 on early endosomes and PACS-2 knockdown decreases the recycling and stability of internalized ADAM17. Hence, PACS-2 sustains ADAM17 cell-surface activity by diverting ADAM17 away from degradative pathways. Interestingly, Pacs2-deficient mice display significantly reduced levels of phosphorylated EGFR and intestinal proliferation. We suggest that this mechanism controlling ADAM17 cell-surface availability and EGFR signalling may play a role in intestinal homeostasis, with potential implications for cancer biology. PMID:26108729

  4. Breast cancer-associated mutations in metalloprotease disintegrin ADAM12 interfere with the intracellular trafficking and processing of the protein.

    PubMed

    Dyczynska, Emilia; Syta, Emilia; Sun, Danqiong; Zolkiewska, Anna

    2008-06-01

    ADAM12 has recently emerged as a Candidate Cancer Gene in a comprehensive genetic analysis of human breast cancers. Three somatic mutations in ADAM12 were observed at significant frequencies in breast cancers: D301H, G479E and L792F. The first 2 of these mutations involve highly conserved residues in ADAM12, and our computational sequence analysis confirms that they may be cancer-related. We show that the corresponding mutations in mouse ADAM12 inhibit the proteolytic processing and activation of ADAM12 in NIH3T3, COS-7, CHO-K1 cells and in MCF-7 breast cancer cells. The D/H and G/E ADAM12 mutants exert a dominant-negative effect on the processing of the wild-type ADAM12. Immunofluorescence analysis and cell surface biotinylation experiments demonstrate that the D/H and G/E mutants are retained inside the cell and are not transported to the cell surface. Consequently, the D/H and G/E mutants, unlike the wild-type ADAM12, are not capable of shedding Delta-like l, a ligand for Notch receptor, at the cell surface, or of stimulating cell migration. Our results suggest that the breast cancer-associated mutations interfere with the intracellular trafficking of ADAM12 and result in loss of the functional ADAM12 at the cell surface.

  5. Geologic map and geothermal assessment of the Mount Adams volcanic field, Cascade Range of southern Washington

    USGS Publications Warehouse

    Hildreth, Wes; Fierstein, Judy

    1990-01-01

    More than 60 Quaternary vents make up the basalt-to-rhyodacite Mount Adams volcanic field and have erupted scoriae and lavas with a total volume of >370 km3. The Mount Adams andesite-dacite stratocone itself is a compound edifice that includes the high cone above 2300 m (20-10 ka), remnants of at least two earlier andesite-dacite cones as old as 0.5 Ma, and 7 Holocene flank vents. Four other Holocene vents and tens of vents contemporaneous with Mount Adams are peripheral to the stratocone. All of these vents, including Mount Adams, lie within a N-S eruptive zone 55 km long and 5 km wide. The age of all known Mount Adams silicic products (>100 ka) and the heterogeneous mafic compositions of the summit cone and Holocene lavas make it unlikely that the stratocone is underlain by an upper-crustal reservoir. Rather, the stratocone at the focus is built up of fractionated hybrid magmas that rise from MASH zones (melting-assimilation-storage-homogenization). The pyroclastic core of breccia and scoria at Mount Adams has undergone acid-sulfate leaching and deposition of alunite, kaolinite, silica, gypsum, sulfur, and Fe-oxides and has been a constant source of avalanches and debris flows. Most heat supplied from depth to the fumarolically altered core is dispersed by the high precipitation rate and high permeability of the rubbly lava flows so that a hydrothermal convection pattern is not maintained. Summit-restricted fumaroles are weak and diffuse.

  6. ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview

    PubMed Central

    Takeda, Soichi

    2016-01-01

    A disintegrin and metalloproteinase (ADAM) family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs) are major components in most viper venoms. SVMPs are primarily responsible for hemorrhagic activity and may also interfere with the hemostatic system in envenomed animals. SVMPs are phylogenetically most closely related to ADAMs and, together with ADAMs and related ADAM with thrombospondin motifs (ADAMTS) family proteinases, constitute adamalysins/reprolysins or the M12B clan (MEROPS database) of metalloproteinases. Although the catalytic domain structure is topologically similar to that of other metalloproteinases such as matrix metalloproteinases, the M12B proteinases have a modular structure with multiple non-catalytic ancillary domains that are not found in other proteinases. Notably, crystallographic studies revealed that, in addition to the conserved metalloproteinase domain, M12B members share a hallmark cysteine-rich domain designated as the “ADAM_CR” domain. Despite their name, ADAMTSs lack disintegrin-like structures and instead comprise two ADAM_CR domains. This review highlights the current state of our knowledge on the three-dimensional structures of M12B proteinases, focusing on their unique domains that may collaboratively participate in directing these proteinases to specific substrates. PMID:27196928

  7. ADAMS/WT advanced development - version 1.4 and beyond

    SciTech Connect

    Elliott, A.S.; Depauw, T.R.

    1996-12-31

    ADAMS/WT is an wind-turbine-specific shell for the general-purpose mechanical system simulation package ADAMS5. It was developed under the guidance of the National Renewable Energy Laboratory to give engineers and analysts in the wind turbine community access to the analytical power of ADAMS, without having to become expert in its particular technology. The 1.4 version of ADAMS/WT is the most recent upgrade to the package, incorporating the most up-to-date version of the AeroDyn aerodynamic forcing subroutines from the University of Utah. It is also the first version to be made available on the Windows/NT platform. In version 1.4, ADAMS/WT has been significantly improved throughout and runs much faster. Automatic generation of standardized output has been added. The documentation has been extensively augmented with more detailed descriptions, more figures and more examples. ADAMS/WT remains the most powerful analytical tool available for horizontal-axis wind turbine development. 10 figs.

  8. Dual functions of cell-autonomous and non-cell-autonomous ADAM10 activity in granulopoiesis.

    PubMed

    Yoda, Masaki; Kimura, Tokuhiro; Tohmonda, Takahide; Uchikawa, Shinichi; Koba, Takeshi; Takito, Jiro; Morioka, Hideo; Matsumoto, Morio; Link, Daniel C; Chiba, Kazuhiro; Okada, Yasunori; Toyama, Yoshiaki; Horiuchi, Keisuke

    2011-12-22

    Previous studies have revealed various extrinsic stimuli and factors involved in the regulation of hematopoiesis. Among these, Notch-mediated signaling has been suggested to be critically involved in this process. Herein, we show that conditional inactivation of ADAM10, a membrane-bound protease with a crucial role in Notch signaling (S2 cleavage), results in myeloproliferative disorder (MPD) highlighted by severe splenomegaly and increased populations of myeloid cells and hematopoietic stem cells. Reciprocal transfer of bone marrow cells between wild-type and ADAM10 mutant mice revealed that ADAM10 activity in both hematopoietic and nonhematopoietic cells is involved in the development of MPD. Notably, we found that MPD caused by lack of ADAM10 in nonhematopoietic cells was mediated by G-CSF, whereas MPD caused by ADAM10-deficient hematopoietic cells was not. Taken together, the present findings reveal previously undescribed nonredundant roles of cell-autonomous and non-cell-autonomous ADAM10 activity in the maintenance of hematopoiesis.

  9. Increased abundance of ADAM9 transcripts in the blood is associated with tissue damage

    PubMed Central

    Rinchai, Darawan; Kewcharoenwong, Chidchamai; Kessler, Bianca; Lertmemongkolchai, Ganjana; Chaussabel, Damien

    2016-01-01

    Background: Members of the ADAM (a disintegrin and metalloprotease domain) family have emerged as critical regulators of cell-cell signaling during development and homeostasis. ADAM9 is consistently overexpressed in various human cancers, and has been shown to play an important role in tumorigenesis. However, little is known about the involvement of ADAM9 during immune-mediated processes. Results: Mining of an extensive compendium of transcriptomic datasets identified important gaps in knowledge regarding the possible role of ADAM9 in immunological homeostasis and inflammation: 1) The abundance of ADAM9 transcripts in the blood was increased in patients with acute infection but, 2) changed very little after in vitro exposure to a wide range of pathogen-associated molecular patterns (PAMPs). 3) Furthermore it was found to increase significantly in subjects as a result of tissue injury or tissue remodeling, in absence of infectious processes. Conclusions: Our findings indicate that ADAM9 may constitute a valuable biomarker for the assessment of tissue damage, especially in clinical situations where other inflammatory markers are confounded by infectious processes. PMID:27990250

  10. Lack of ADAM10 in endothelial cells affects osteoclasts at the chondro-osseus junction.

    PubMed

    Zhao, Ren; Wang, Aimin; Hall, Katherine C; Otero, Miguel; Weskamp, Gisela; Zhao, Baohong; Hill, Daniel; Goldring, Mary B; Glomski, Krzysztof; Blobel, Carl P

    2014-02-01

    Mice lacking ADAM10 in endothelial cells (Adam10ΔEC mice) have shorter femurs, tibiae, and humeri than controls, raising questions about how endothelial cells could control long bone growth. We performed a histopathological evaluation of the femur and tibia growth plates at different postnatal stages, and assessed the distribution of TRAP-positive osteoclasts and endothelial cells at the growth plate. The growth plates in Adam10ΔEC mice appeared normal at P7 and P14, but a thickened zone of hypertrophic chondrocytes and increased trabecular bone density were apparent by P21 and later. The number of TRAP+ cells at the COJ was normal at P7 and P14, but was strongly reduced at P21 and later. Moreover, the density of endomucin-stained endothelial cells at the COJ was increased starting at P7. The defects in long bone growth in Adam10ΔEC mice could be caused by a lack of osteoclastogenesis at the COJ. Moreover, ADAM10 appears to regulate endothelial cell organization in the developing bone vasculature, perhaps in a similar manner as in the developing retinal vascular tree, where ADAM10 is thought to control Notch-dependent endothelial cell fate decisions. This study provides evidence for the regulation of osteoclast function by endothelial cells in vivo.

  11. The metalloprotease ADAM12 regulates the effector function of human Th17 cells.

    PubMed

    Zhou, Angela X; El Hed, Aimee; Mercer, Frances; Kozhaya, Lina; Unutmaz, Derya

    2013-01-01

    A key modulator of immune homeostasis, TGFβ has an important role in the differentiation of regulatory T cells (Tregs) and IL-17-secreting T cells (Th17). How TGFβ regulates these functionally opposing T cell subsets is not well understood. We determined that an ADAM family metalloprotease called ADAM12 is specifically and highly expressed in both Tregs and CCR6+ Th17 cells. ADAM12 is induced in vitro upon differentiation of naïve T cells to Th17 cells or IL-17-secreting Tregs. Remarkably, silencing ADAM12 expression in CCR6+ memory T cells enhances the production of Th17 cytokines, similar to suppressing TGFβ signaling. Further, ADAM12 knockdown in naïve human T cells polarized towards Th17/Treg cells, or ectopically expressing RORC, greatly enhances IL-17-secreting cell differentiation, more potently then inhibiting TGFβ signals. Together, our findings reveal a novel regulatory role for ADAM12 in Th17 cell differentiation or function and may have implications in regulating their aberrant responses during immune pathologies.

  12. Extracellular engagement of ADAM12 induces clusters of invadopodia with localized ectodomain shedding activity.

    PubMed

    Albrechtsen, Reidar; Stautz, Dorte; Sanjay, Archana; Kveiborg, Marie; Wewer, Ulla M

    2011-01-15

    Invadopodia are dynamic actin structures at the cell surface that degrade extracellular matrix and act as sites of signal transduction. The biogenesis of invadopodia, including the mechanisms regulating their formation, composition, and turnover is not entirely understood. Here, we demonstrate that antibody ligation of ADAM12, a transmembrane disintegrin and metalloprotease, resulted in the rapid accumulation of invadopodia with extracellular matrix-degrading capacity in epithelial cells expressing the αvβ3 integrin and active c-Src kinase. The induction of invadopodia clusters required an intact c-Src interaction site in the ADAM12 cytoplasmic domain, but was independent of the catalytic activity of ADAM12. Caveolin-1 and transmembrane protease MMP14/MT1-MMP were both present in the ADAM12-induced clusters of invadopodia, and cholesterol depletion prevented their formation, suggesting that lipid-raft microdomains are involved in the process. Importantly, our data demonstrate that ADAM12-mediated ectodomain shedding of epidermal growth factor receptor ligands can occur within these invadopodia. Such localized growth factor signalling offers an interesting novel biological concept highly relevant to the properties of carcinoma cells, which often show upregulated ADAM12 and β3 integrin expression, together with high levels of c-Src kinase activity.

  13. The Influence of Religious Attendance on Smoking

    PubMed Central

    Brown, Qiana L.; Linton, Sabriya L.; Harrell, Paul T.; Mancha, Brent Edward; Alexandre, Pierre K.; Chen, Kuan-Fu; Eaton, William W.

    2014-01-01

    Generalized linear models were used to assess the relationship between religious attendance and lifetime smoking status among middle-aged adults (n = 666) sampled from waves three (1993 to 1996) and four (2004 to 2005) of the Baltimore Epidemiologic Catchment Area (ECA) study. Religious attendance once per week or greater as compared to never was inversely associated with smoking status. Future research should explore potential mediating factors of the association between religious attendance and smoking among middle-aged adults in order to gain a greater understanding of the mechanisms underlying this relationship. Funding: NIMH grant DA026652; NIDA grant T32DA007292. PMID:24827865

  14. Dynamics of ADAM17-Mediated Shedding of ACE2 Applied to Pancreatic Islets of Male db/db Mice

    PubMed Central

    Pedersen, Kim Brint; Chodavarapu, Harshita; Porretta, Constance; Robinson, Leonie K.

    2015-01-01

    Angiotensin-converting enzyme 2 (ACE2) gene therapy aimed at counteracting pancreatic ACE2 depletion improves glucose regulation in two diabetic mouse models: db/db mice and angiotensin II-infused mice. A disintegrin and metalloproteinase 17 (ADAM17) can cause shedding of ACE2 from the cell membrane. The aim of our studies was to determine whether ADAM17 depletes ACE2 levels in pancreatic islets and β-cells. Dynamics of ADAM17-mediated ACE2 shedding were investigated in 832/13 insulinoma cells. Within a wide range of ACE2 expression levels, including the level observed in mouse pancreatic islets, overexpression of ADAM17 increases shed ACE2 and decreases cellular ACE2 levels. We provide a mathematical description of shed and cellular ACE2 activities as a function of the ADAM17 activity. The effect of ADAM17 on the cellular ACE2 content was relatively modest with an absolute control strength value less than 0.25 and approaching 0 at low ADAM17 activities. Although we found that ADAM17 and ACE2 are both expressed in pancreatic islets, the β-cell is not the major cell type expressing ACE2 in islets. During diabetes progression in 8-, 12-, and 15-week-old db/db mice, ACE2 mRNA and ACE2 activity levels in pancreatic islets were not decreased over time nor significantly decreased compared with nondiabetic db/m mice. Levels of ADAM17 mRNA and ADAM17 activity were also not significantly changed. Inhibiting basal ADAM17 activity in mouse islets failed to affect ACE2 levels. We conclude that whereas ADAM17 has the ability to shed ACE2, ADAM17 does not deplete ACE2 from pancreatic islets in diabetic db/db mice. PMID:26441236

  15. Training traditional birth attendants in southern Sudan.

    PubMed

    Haarsager, Mary

    2008-01-01

    Traditional birth attendants are currently the principal service providers to pregnant women in southern Sudan. A training program provides education to promote maternal and newborn health as well as birth preparedness and establishes mechanisms for supportive supervision.

  16. Maternal religious attendance and low birth weight.

    PubMed

    Burdette, Amy M; Weeks, Janet; Hill, Terrence D; Eberstein, Isaac W

    2012-06-01

    We use data from the U.S. Fragile Families and Child Wellbeing study to test whether maternal religious attendance is protective against low birth weight. Building on previous research, we also consider the mediating influence of mental health, cigarette use, alcohol use, illicit drug use, poor nutrition, and prenatal care. Our results indicate that maternal religious attendance is protective against low birth weight. In fact, each unit increase in the frequency of religious attendance reduces the odds of low birth weight by 15%. Religious attendance is also associated with lower odds of cigarette use and poor nutrition, but is unrelated to mental health, alcohol use, illicit drug use, and prenatal care. Although lower rates of cigarette use help to mediate or explain 11% of the association between maternal religious attendance and low birth weight, we find no evidence to substantiate the mediating influence of mental health, alcohol use, illicit drug use, poor nutrition, or prenatal care. Our results suggest that the health benefits of religious involvement may extend across generations (from mother to child); however, additional research is needed to fully explain the association between maternal religious attendance and low birth weight. It is also important for future research to consider the extent to which the apparent health advantages of religious adults might be attributed to health advantages in early life, especially those related to healthy birth weight.

  17. ADAM33 is not essential for growth and development and does not modulate allergic asthma in mice.

    PubMed

    Chen, Chun; Huang, Xiaozhu; Sheppard, Dean

    2006-09-01

    A disintegrin and metalloprotease 33 (ADAM33) is a transmembrane protease and integrin ligand that has been identified as an asthma susceptibility gene product. To determine whether ADAM33 plays important roles in mammalian development and the modulation of allergic airway dysfunction, we generated ADAM33-null mice by gene targeting. ADAM33-null mice were born at expected Mendelian ratios, and both male and females developed normally and were fertile. No anatomical or histological abnormalities were detected in any tissues. In an animal model of allergic asthma, ADAM33-null mice showed normal allergen-induced airway hyperreactivity, immunoglobulin E production, mucus metaplasia, and airway inflammation. Our results demonstrate that ADAM33 is not essential for growth or reproduction in the mouse and does not modulate baseline or allergen-induced airway responsiveness.

  18. Henry Adams’s Life of George Cabot Lodge: A Portrait of the Artist as an Alienated Man

    DTIC Science & Technology

    1994-07-20

    literary tradition, especially as had been handed down from Adams’s Puritan forebears. My aim is to present the most complete critical study of this...several critics have pointed to this book as evidence of Adams’s diminished talents--when a careful study of the book in fact demonstrates otherwise...critical studies have given more than cursory attention to the Life of Lodge: J. C. Levenson, The Mind and Art of Henry Adams (1957); George Hochfield

  19. A transforming Src mutant increases the bioavailability of EGFR-ligands via stimulation of the cell surface metalloproteinase ADAM17

    PubMed Central

    Maretzky, Thorsten; Zhou, Wenhui; Huang, Xin-Yun; Blobel, Carl P.

    2012-01-01

    ADAM17 (a disintegrin and metalloproteinase 17) is a cell-surface metalloproteinase that regulates signaling via the epidermal growth factor receptor (EGFR) and has important roles in diseases such as cancer and rheumatoid arthritis. ADAM17 can be activated by stimulation of several tyrosine kinase receptors, raising questions about whether oncogenic tyrosine kinases could also enhance EGFR signaling and activation of ERK via stimulation of ADAM17. The main goal of this study was to evaluate the role of Src in activating ADAM17. We provide evidence that a constitutively active transforming form of Src, the E378G mutant, as well as v-Src enhance ADAM17-mediated shedding of the EGFR-ligand TGFα. Moreover, we demonstrate that constitutive shedding of TGFα can be reduced by inhibition of Src in several cell lines, including COS7, MCF7, PAE and HaCaT cells. Src(E378G)-stimulated shedding of TGFα is abolished in Adam17−/− cells, but can be rescued by wild type ADAM17 and a mutant ADAM17 lacking its cytoplasmic domain. These findings demonstrate that ADAM17 is the principal TGFα sheddase that is activated by Src in a manner that does not require the cytoplasmic domain of ADAM17. Finally, we show that stimulation of ADAM17 by Src(E378G) leads to enhanced paracrine signaling via release of EGFR-ligands into the culture supernatant. These results raise the possibility that activation of ADAM17 by oncogenic forms of Src can aid in promoting tumorigenesis by enhancing signaling via the EGFR and ERK in an autocrine and paracrine manner. Enhanced autocrine signaling could further activate tumor cells expressing oncogenic mutants of Src, whereas paracrine signaling could stimulate EGFR and ERK signaling in surrounding non-transformed cells such as stromal cells, thereby contributing to crosstalk between tumor cells and stromal cells. PMID:20871631

  20. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.

    PubMed

    Hartmann, Dieter; de Strooper, Bart; Serneels, Lutgarde; Craessaerts, Katleen; Herreman, An; Annaert, Wim; Umans, Lieve; Lübke, Torben; Lena Illert, Anna; von Figura, Kurt; Saftig, Paul

    2002-10-01

    The metalloprotease ADAM 10 is an important APP alpha-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPs alpha generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative alpha-secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific 'teams' of different proteases exerting alpha-secretase activity.

  1. ADAM12 is a prognostic factor associated with an aggressive molecular subtype of high-grade serous ovarian carcinoma.

    PubMed

    Cheon, Dong-Joo; Li, Andrew J; Beach, Jessica A; Walts, Ann E; Tran, Hang; Lester, Jenny; Karlan, Beth Y; Orsulic, Sandra

    2015-07-01

    ADAM metallopeptidase domain 12 (ADAM12) is a promising biomarker because of its low expression in normal tissues and high expression in a variety of human cancers. However, ADAM12 levels in ovarian cancer have not been well characterized. We previously identified ADAM12 as one of the signature genes associated with poor survival in high-grade serous ovarian carcinoma (HGSOC). Here, we sought to determine if high levels of the ADAM12 protein and/or messenger RNA (mRNA) are associated with clinical variables in HGSOC. We show that high protein levels of ADAM12 in banked preoperative sera are associated with shorter progression-free and overall survival. Tumor levels of ADAM12 mRNA were also associated with shorter progression-free and overall survival as well as with lymphatic and vascular invasion, and residual tumor volume following cytoreductive surgery. The majority of genes co-expressed with ADAM12 in HGSOC were transforming growth factor (TGF)β signaling targets that function in collagen remodeling and cell-matrix adhesion. In tumor sections, the ADAM12 protein and mRNA were expressed in epithelial cancer cells and surrounding stromal cells. In vitro data showed that ADAM12 mRNA levels can be increased by TGFβ signaling and direct contact between epithelial and stromal cells. High tumor levels of ADAM12 mRNA were characteristic of the mesenchymal/desmoplastic molecular subtype of HGSOC, which is known to have the poorest prognosis. Thus, ADAM12 may be a useful biomarker of aggressive ovarian cancer for which standard treatment is not effective.

  2. Monocyte ADAM17 promotes diapedesis during transendothelial migration: identification of steps and substrates targeted by metalloproteinases.

    PubMed

    Tsubota, Yoshiaki; Frey, Jeremy M; Tai, Phillip W L; Welikson, Robert E; Raines, Elaine W

    2013-04-15

    Despite expanded definition of the leukocyte adhesion cascade and mechanisms underlying individual steps, very little is known about regulatory mechanisms controlling sequential shifts between steps. We tested the hypothesis that metalloproteinases provide a mechanism to rapidly transition monocytes between different steps. Our study identifies diapedesis as a step targeted by metalloproteinase activity. Time-lapse video microscopy shows that the presence of a metalloproteinase inhibitor results in a doubling of the time required for human monocytes to complete diapedesis on unactivated or inflamed human endothelium, under both static and physiological-flow conditions. Thus, diapedesis is promoted by metalloproteinase activity. In contrast, neither adhesion of monocytes nor their locomotion over the endothelium is altered by metalloproteinase inhibition. We further demonstrate that metalloproteinase inhibition significantly elevates monocyte cell surface levels of integrins CD11b/CD18 (Mac-1), specifically during transendothelial migration. Interestingly, such alterations are not detected for other endothelial- and monocyte-adhesion molecules that are presumed metalloproteinase substrates. Two major transmembrane metalloproteinases, a disintegrin and metalloproteinase (ADAM)17 and ADAM10, are identified as enzymes that control constitutive cleavage of Mac-1. We further establish that knockdown of monocyte ADAM17, but not endothelial ADAM10 or ADAM17 or monocyte ADAM10, reproduces the diapedesis delay observed with metalloproteinase inhibition. Therefore, we conclude that monocyte ADAM17 facilitates the completion of transendothelial migration by accelerating the rate of diapedesis. We propose that the progression of diapedesis may be regulated by spatial and temporal cleavage of Mac-1, which is triggered upon interaction with endothelium.

  3. The skilled attendance index: proposal for a new measure of skilled attendance at delivery.

    PubMed

    Hussein, Julia; Bell, Jacqueline; Nazzar, Alex; Abbey, Mercy; Adjei, Sam; Graham, Wendy

    2004-11-01

    Increasing the proportion of deliveries with skilled attendance is widely regarded as key to reducing maternal mortality and morbidity in developing countries. The percentage of deliveries with a health professional is commonly used to assess skilled attendance, but measures only the presence of an attendant, not the skills used or the enabling environment To supplement currently available information on the presence of an attendant at delivery, a method to measure the extent of skilled attendance at delivery through use of clinical records was devised. Data were collected from 416 delivery records in hospitals, government health centres and private non-hospital maternity facilities servicing Kintampo District, Ghana, using a case extraction form. Based on the defined criteria, summary measures of skilled attendance were calculated. Between 32.6% and 93.0% of the criteria for skilled attendance were met in the sample, with a mean of 65.5%. No delivery met all the criteria. A Skilled Attendance Index (SAI) was developed as a composite measure of delivery care. The SAI revealed that 26.9% of delivery records met at least three-quarters of the criteria for skilled attendance. Documentation of haemoglobin, current pregnancy complications, post-partum vital signs and completed partographs were amongst the criteria most poorly recorded. The purpose of applying these measures should be seen not as an end in itself but to advance improvements in delivery care.

  4. Analysis of mixed model in gear transmission based on ADAMS

    NASA Astrophysics Data System (ADS)

    Li, Xiufeng; Wang, Yabin

    2012-09-01

    The traditional method of mechanical gear driving simulation includes gear pair method and solid to solid contact method. The former has higher solving efficiency but lower results accuracy; the latter usually obtains higher precision of results while the calculation process is complex, also it is not easy to converge. Currently, most of the researches are focused on the description of geometric models and the definition of boundary conditions. However, none of them can solve the problems fundamentally. To improve the simulation efficiency while ensure the results with high accuracy, a mixed model method which uses gear tooth profiles to take the place of the solid gear to simulate gear movement is presented under these circumstances. In the process of modeling, build the solid models of the mechanism in the SolidWorks firstly; Then collect the point coordinates of outline curves of the gear using SolidWorks API and create fit curves in Adams based on the point coordinates; Next, adjust the position of those fitting curves according to the position of the contact area; Finally, define the loading conditions, boundary conditions and simulation parameters. The method provides gear shape information by tooth profile curves; simulates the mesh process through tooth profile curve to curve contact and offer mass as well as inertia data via solid gear models. This simulation process combines the two models to complete the gear driving analysis. In order to verify the validity of the method presented, both theoretical derivation and numerical simulation on a runaway escapement are conducted. The results show that the computational efficiency of the mixed model method is 1.4 times over the traditional method which contains solid to solid contact. Meanwhile, the simulation results are more closely to theoretical calculations. Consequently, mixed model method has a high application value regarding to the study of the dynamics of gear mechanism.

  5. TGF{beta} induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells

    SciTech Connect

    Ebi, Masahide; Kataoka, Hiromi; Shimura, Takaya; Kubota, Eiji; Hirata, Yoshikazu; Mizushima, Takashi; Mizoshita, Tsutomu; Tanaka, Mamoru; Mabuchi, Motoshi; Tsukamoto, Hironobu; Tanida, Satoshi; Kamiya, Takeshi; Higashiyama, Shigeki; Joh, Takashi

    2010-11-19

    Research highlights: {yields} TGF{beta} induces EGFR transactivation through proHB-EGF shedding by activated ADAM members in gastric cancer cells. {yields} TGF{beta} induces nuclear translocation of HB-EGF-CTF cleaved by ADAM members. {yields} TGF{beta} enhances cell growth by EGFR transactivation and HB-EGF-CTF nuclear translocation and ADAM inhibitors block these effects. {yields} Silencing of ADAM17 also blocks EGFR transactivation, HB-EGF-CTF nuclear translocation and cancer cell growth by TGF{beta}. {yields} ADAM17 may play a crucial role in this TGF{beta}-HB-EGF signal transduction. -- Abstract: Background and aims: Transforming growth factor-beta (TGF{beta}) is known to potently inhibit cell growth. Loss of responsiveness to TGF{beta} inhibition on cell growth is a hallmark of many types of cancer, yet its mechanism is not fully understood. Membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) ectodomain is cleaved by a disintegrin and metalloproteinase (ADAM) members and is implicated in epidermal growth factor receptor (EGFR) transactivation. Recently, nuclear translocation of the C-terminal fragment (CTF) of pro-HB-EGF was found to induce cell growth. We investigated the association between TGF{beta} and HB-EGF signal transduction via ADAM activation. Materials and methods: The CCK-8 assay in two gastric cancer cell lines was used to determine the effect for cell growth by TGF{beta}. The effect of two ADAM inhibitors was also evaluated. Induction of EGFR phosphorylation by TGF{beta} was analyzed and the effect of the ADAM inhibitors was also examined. Nuclear translocation of HB-EGF-CTF by shedding through ADAM activated by TGF{beta} was also analyzed. EGFR transactivation, HB-EGF-CTF nuclear translocation, and cell growth were examined under the condition of ADAM17 knockdown. Result: TGF{beta}-induced EGFR phosphorylation of which ADAM inhibitors were able to inhibit. TGF{beta} induced shedding of proHB-EGF allowing HB-EGF-CTF to

  6. Unsaturated Fatty Acids Drive Disintegrin and Metalloproteinase (ADAM)-dependent Cell Adhesion, Proliferation, and Migration by Modulating Membrane Fluidity*

    PubMed Central

    Reiss, Karina; Cornelsen, Isabell; Husmann, Matthias; Gimpl, Gerald; Bhakdi, Sucharit

    2011-01-01

    The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers. PMID:21642425

  7. Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity.

    PubMed

    Reiss, Karina; Cornelsen, Isabell; Husmann, Matthias; Gimpl, Gerald; Bhakdi, Sucharit

    2011-07-29

    The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers.

  8. ADAM10 is expressed in human podocytes and found in urinary vesicles of patients with glomerular kidney diseases

    PubMed Central

    2010-01-01

    Background The importance of the Notch signaling in the development of glomerular diseases has been recently described. Therefore we analyzed in podocytes the expression and activity of ADAM10, one important component of the Notch signaling complex. Methods By Western blot, immunofluorescence and immunohistochemistry analysis we characterized the expression of ADAM10 in human podocytes, human urine and human renal tissue. Results We present evidence, that differentiated human podocytes possessed increased amounts of mature ADAM10 and released elevated levels of L1 adhesion molecule, one well known substrate of ADAM10. By using specific siRNA and metalloproteinase inhibitors we demonstrate that ADAM10 is involved in the cleavage of L1 in human podocytes. Injury of podocytes enhanced the ADAM10 mediated cleavage of L1. In addition, we detected ADAM10 in urinary podocytes from patients with kidney diseases and in tissue sections of normal human kidney. Finally, we found elevated levels of ADAM10 in urinary vesicles of patients with glomerular kidney diseases. Conclusions The activity of ADAM10 in human podocytes may play an important role in the development of glomerular kidney diseases. PMID:20070888

  9. Comparative localization of ADAMs 10 and 15 in human cerebral cortex normal aging, Alzheimer disease and Down syndrome.

    PubMed

    Bernstein, Hans-Gert; Bukowska, Alicja; Krell, Dieter; Bogerts, Bernhard; Ansorge, Siegfried; Lendeckel, Uwe

    2003-02-01

    Using immunohistochemical techniques we studied the light microscopic localization of ADAMs (A Disintegrin And Metalloprotease) 10 and 15 in different neocortical areas of the human brain during normal aging, and also in patients with Alzheimer disease (AD) and Down syndrome (DS). ADAM 10, a putative alpha-secretase involved in Notch signaling, was found in neurons of the perinatal cortex. During aging there is an increase in intraneuronal staining intensity and in the number of cortical nerve cells that contain the enzyme. Furthermore, in AD and DS brains ADAM 10 immunoreactivity was associated with diffuse and neuritic plaques. ADAM 15 was detected in perinatal cortical pyramidal cells; during aging there was also an increase in intracellular staining and the number of stained cells per volume (cell density). In AD brains ADAM 15 was seen in a few diffuse plaques. Morphometric analysis revealed a significant reduction of ADAM 10 but not ADAM 15 immunoreactive neurons in AD brains in comparison to controls. Our findings support the idea that ADAM 10 is involved in the pathophysiology of AD and DS. ADAM 15 might be linked to AD via interaction with integrin and/or src protein tyrosine kinases.

  10. Liver protective effect of ursodeoxycholic acid includes regulation of ADAM17 activity

    PubMed Central

    2013-01-01

    Background Ursodeoxycholic acid (UDCA) is used to treat primary biliary cirrhosis, intrahepatic cholestasis, and other cholestatic conditions. Although much has been learned about the molecular basis of the disease pathophysiology, our understanding of the effects of UDCA remains unclear. Possibly underlying its cytoprotective, anti-apoptotic, anti-oxidative effects, UDCA was reported to regulate the expression of TNFα and other inflammatory cytokines. However, it is not known if this effect involves also modulation of ADAM family of metalloproteinases, which are responsible for release of ectodomains of inflammatory cytokines from the cell surface. We hypothesized that UDCA modulates ADAM17 activity, resulting in amelioration of cholestasis in a murine model of bile duct ligation (BDL). Methods The effect of UDCA on ADAM17 activity was studied using the human liver hepatocellular carcinoma cell line HepG2. Untransfected cells or cells ectopically expressing human ADAM17 were cultured with or without UDCA and further activated using phorbol-12-myristate-13-acetate (PMA). The expression and release of ADAM17 substrates, TNFα, TGFα, and c-Met receptor (or its soluble form, sMet) were evaluated using ELISA and quantitative real-time (qRT) PCR. Immunoblotting analyses were conducted to evaluate expression and activation of ADAM17 as well as the level of ERK1/2 phosphorylation after UDCA treatment. The regulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) by UDCA was studied using zymography and qRT-PCR. A mouse model of acute cholestasis was induced by common BDL technique, during which mice received daily orogastric gavage with either UDCA or vehicle only. Liver injury was quantified using alkaline phosphatase (ALP), relative liver weight, and confirmed by histological analysis. ADAM17 substrates in sera were assessed using a bead multiplex assay. Results UDCA decreases amount of shed TNFα, TGFα, and sMet in cell culture media and the phosphorylation of

  11. Father attendance in nurse home visitation.

    PubMed

    Holmberg, John R; Olds, David L

    2015-01-01

    Our aim was to examine the rates and predictors of father attendance at nurse home visits in replication sites of the Nurse-Family Partnership (NFP). Early childhood programs can facilitate father involvement in the lives of their children, but program improvements require an understanding of factors that predict father involvement. The sample consisted of 29,109 low-income, first-time mothers who received services from 694 nurses from 80 sites. We conducted mixed-model multiple regression analyses to identify population, implementation, site, and nurse influences on father attendance. Predictors of father attendance included a count of maternal visits (B = 0.12, SE = 0.01, F = 3101.77), frequent contact between parents (B = 0.61, SE = 0.02, F = 708.02), cohabitation (B = 1.41, SE = 0.07, F = 631.51), White maternal race (B = 0.77, SE = 0.06, F = 190.12), and marriage (B = 0.42, SE = 0.08, F = 30.08). Random effects for sites and nurses predicted father-visit participation (2.7 & 6.7% of the variance, respectively), even after controlling for population sociodemographic characteristics. These findings suggest that factors operating at the levels of sites and nurses influence father attendance at home visits, even after controlling for differences in populations served. Further inquiry about these influences on father visit attendance is likely to inform program-improvement efforts.

  12. ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway.

    PubMed

    Lin, Chen-Yuan; Chen, Hung-Jen; Huang, Cheng-Chung; Lai, Liang-Chuan; Lu, Tzu-Pin; Tseng, Guan-Chin; Kuo, Ting-Ting; Kuok, Qian-Yu; Hsu, Jennifer L; Sung, Shian-Ying; Hung, Mien-Chie; Sher, Yuh-Pyng

    2014-09-15

    The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease.

  13. 50th anniversary of the discovery of ibuprofen: an interview with Dr Stewart Adams.

    PubMed

    Halford, Gayle M; Lordkipanidzé, Marie; Watson, Steve P

    2012-01-01

    2011 marks the 50th anniversary of the discovery of ibuprofen. This article is a focus on the personal reflections and career of Dr Stewart Adams OBE, the scientist whose research lead to the discovery of the cyclooxygenase inhibitor. When Dr Adams discovered ibuprofen, he was working as a pharmacologist in the Research Department for the Boots Pure Drug Company Ltd. Dr Adams was assigned to work on rheumatoid arthritis (RA) and chose in 1953 to search for a drug that would be effective in RA but would not be a corticosteroid. He was one of the first workers in this field that later became known as NSAIDs (Non-Steroidal Anti Inflammatory Drugs). In 1961, Dr Adams with John Nicholson, the organic chemist, filed a patent for the compound 2-(4-isobutylphenyl) propionic acid, later to become one of the most successful NSAIDs in the modern world, ibuprofen. In this article, Dr Adams gives his modest insight into the early stages and initial observations which led to this world-wide success.

  14. Glioma-Derived ADAM10 Induces Regulatory B Cells to Suppress CD8+ T Cells

    PubMed Central

    Li, Wen-sheng; Luo, Lun; Huang, Zhen-chao; Guo, Ying

    2014-01-01

    CD8+ T cells play an important role in the anti-tumor activities of the body. The dysfunction of CD8+ T cells in glioma is unclear. This study aims to elucidate the glioma cell-derived ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in the suppression of CD8+ effector T cells by the induction of regulatory B cells. In this study, glioma cells were isolated from surgically removed glioma tissue and stimulated by Phorbol myristate acetage (PMA) in the culture. The levels of ADAM10 in the culture were determined by enzyme-linked immunosorbent assay. Immune cells were assessed by flow cytometry. The results showed that the isolated glioma cells express ADAM10, which was markedly up regulated after stimulated with PMA. The glioma-derived ADAM10 induced activated B cells to differentiate into regulatory B cells, the later suppressed CD8+ T cell proliferation as well as the induced regulatory T cells, which also showed the immune suppressor effect on CD8+ effector T cell proliferation. In conclusion, glioma cells produce ADAM10 to induce Bregs; the latter suppresses CD8+ T cells and induces Tregs. PMID:25127032

  15. ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands.

    PubMed

    Tanaka, Motonari; Nanba, Daisuke; Mori, Seiji; Shiba, Fumio; Ishiguro, Hiroshi; Yoshino, Koichiro; Matsuura, Nariaki; Higashiyama, Shigeki

    2004-10-01

    A disintegrin and metalloproteases (ADAMs) are implicated in the ectodomain shedding of epidermal growth factor receptor (EGFR) ligands in EGFR transactivation. However, the activation mechanisms of ADAMs remain elusive. To analyze the regulatory mechanisms of ADAM activation, we performed yeast two-hybrid screening using the cytoplasmic domain of ADAM12 as bait, and identified a protein that we designated Eve-1. Two cDNAs were cloned and characterized. They encode alternatively spliced isoforms of Eve-1, called Eve-1a and Eve-1b, that have four and five tandem Src homology 3 (SH3) domains in the carboxyl-terminal region, respectively, and seven proline-rich SH3 domain binding motifs in the amino-terminal region. The short forms of Eve-1, Eve-1c and Eve-1d, translated at Met-371 are human counterparts of mouse Sh3d19. Northern blot analysis demonstrated that Eve-1 is abundantly expressed in skeletal muscle and heart. Western blot analysis revealed the dominant production of Eve-1c in human cancer cell lines. Knockdown of Eve-1 by small interfering RNA in HT1080 cells reduced the shedding of proHB-EGF induced by angiotensin II and 12-O-tetradecanoylphorbol-13-acetate, as well as the shedding of pro-transforming growth factor-alpha, promphiregulin, and proepiregulin by 12-O-tetradecanoylphorbol-13-acetate, suggesting that Eve-1 plays a role in positively regulating the activity of ADAMs in the signaling of EGFR-ligand shedding.

  16. Pyrococcus Furiosus Genome Supplementary Data from the Adams Laboratory at the University of Georgia

    DOE Data Explorer

    Adams, Michael W.W.; Weinberg, Michael V.; Schut, Gerrit J.; Brehm, Scott; Datta, Susmitta; Zhou, J.

    The research in the Adams Laboratory focuses on the physiology of hyperthermophilic organisms with an emphasis on metal-containing enzymes in the hyperthermophilic marine archaeon Pyrococcus furiosus. Three of the many articles from this University of Georgia lab have supplementary materials that are available on the Adams Lab website. All three sets of data are Open Reading Frames (ORFs) used for DNA microarray experiments and the changes in signal intensities. The full citations for the three articles are: 1) Weinberg, M. V., Schut, G. J., Brehm, S., Datta, S. and Adams, M. W. W. (2005) Cold shock of a hyperthermophilic archaeon: Pyrococcus furiosus exhibits multiple responses to a suboptimal growth temperature with a key role for membrane-bound glycoproteins. J Bacteriol. 187, 336-348; 2) Schut, G. J., Brehm, S. D., Datta, S. and Adams, M. W. W. (2003) "Whole genome DNA microarray analysis of a hyperthermophile and an archaeon: Pyrococcus furiosus grown on carbohydrates or peptides" J. Bacteriol. 185, 3935-3947; Schut, G. J., Zhou, J. and Adams, M. W. W. (2001) "DNA microarray analysis of the hyperthermophilic archaeon Pyrococcus furiosus evidence for a new type of sulfur-reducing enzyme" J. Bacteriol. 183, 7027-7036. Note that these articles are copyrighted by the Journal of Bacteriology.

  17. Chromosomal mapping, sequence and transcription analysis of the porcine fertilin beta gene (ADAM2).

    PubMed

    Day, A E; Quilter, C R; Sargent, C A; Mileham, A J

    2003-10-01

    Fertilin beta (ADAM2) forms a part of the heterodimeric surface protein fertilin, found on the plasma membrane of mammalian sperm, and has been implicated in the process of sperm-egg fusion. Analysis of cDNA products obtained from adult porcine testis mRNA has presented a sequence corresponding to 2620 bp of the ADAM2 gene. This sequence contained an open reading frame encoding a 735-amino acid protein and homologous to ADAM2 genes known in other mammalian species. Polymerase chain reaction (PCR) analysis of genomic DNA showed that the 2620 bp of cDNA sequence comprises at least 21 exons and spans approximately 76 kb of genomic DNA, with its size and structure being relatively conserved between mouse, human and pig. Fluorescence in situ hybridization was used to map ADAM2 to chromosome 15 of the pig, using a bacterial artificial chromosome clone from the PigE BAC library. This finding is consistent with comparative mapping experiments performed between pig and human chromosomes. Analysis of nine mRNA samples, by reverse transcriptase-PCR, from different porcine tissues has also suggested that expression of ADAM2 is limited to the testis, a finding that is consistent with other mammalian species.

  18. A Guide for the Personal Care Attendant: Independent Living with Attendant Care.

    ERIC Educational Resources Information Center

    Board, Mary Ann; And Others

    The first of three booklets on attendant care of severely disabled persons is addressed to the personal care attendants (PCAs). An introductory section reviews the basic concepts of independent living, noting the role of PCAs in promoting independence. Discussions of congenital and acquired disability are followed by information on equipment and…

  19. An Analysis of Florida's School Districts' Attendance Policies and their Relationship to High School Attendance Rates

    ERIC Educational Resources Information Center

    Reardon, Ryan Turner

    2008-01-01

    The purpose of this non-experimental correlational study was to determine the relationship between the type of attendance policies in the high schools of the 67 Florida school districts, the size of the school district (number of high school students), the socioeconomic status SES) of the school district, and the average daily attendance rate of…

  20. School Attendance and Attainment: Poor Attenders' Perceptions of Schoolwork and Parental Involvement in Their Education

    ERIC Educational Resources Information Center

    Sheppard, Anne

    2009-01-01

    Because of established links with attainment, the UK government has, over the last ten years, developed policies to improve school attendance. Legislation now makes school attendance a parental responsibility. In the small-scale study reported in this article, Anne Sheppard, manager of an Education Welfare Service Team in North Yorkshire,…

  1. ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis and increased tumor growth.

    PubMed

    Albrechtsen, Reidar; Kveiborg, Marie; Stautz, Dorte; Vikeså, Jonas; Noer, Julie B; Kotzsh, Alexander; Nielsen, Finn Cilius; Wewer, Ulla M; Fröhlich, Camilla

    2013-10-15

    Matrix metalloproteinases (MMPs), in particular MMP-2, MMP-9 and MMP-14, play a key role in various aspects of cancer pathology. Likewise, ADAMs (a disintegrin and metalloproteinases), including ADAM12, are upregulated in malignant tumors and contribute to the pathology of cancers. Here, we show that there is a positive correlation between MMP-14 and ADAM12 expression in human breast cancer. We demonstrated that in 293-VnR and human breast cancer cells expressing ADAM12 at the cell surface, endogenous MMP-14 was recruited to the cell surface, resulting in its activation. Subsequent to this activation, gelatin degradation was stimulated and tumor cell apoptosis was decreased, with reduced expression of the pro-apoptotic proteins BCL2L11 and BIK. The effect on gelatin degradation was abrogated by inhibition of the MMP-14 activity and appeared to be dependent on cell surface αVβ3 integrin localization, but neither the catalytic activity of ADAM12 nor the cytoplasmic tail of ADAM12 were required. The significance of ADAM12-induced activation of MMP-14 was underscored by a reduction in MMP-14-mediated gelatin degradation and abolition of apoptosis-protective effects by specific monoclonal antibodies against ADAM12. Furthermore, orthotopic implantation of ADAM12-expressing MCF7 cells in nude mice produced tumors with increased levels of activated MMP-14 and confirmed that ADAM12 protects tumor cells against apoptosis, leading to increased tumor progression. In conclusion, our data suggest that a ternary protein complex composed of ADAM12, αVβ3 integrin and MMP-14 at the tumor cell surface regulates the function of MMP-14. This interaction might point to a novel concept for the development of MMP-14-targeting drugs in treating cancer.

  2. Association of ADAM12-S protein with radiographic features of knee osteoarthritis and bone and cartilage markers.

    PubMed

    Kerna, I; Kisand, K; Laitinen, P; Tamm, A E; Kumm, J; Lintrop, M; Tamm, A O

    2012-02-01

    ADAM12 (A disintegrin and metalloprotease) is one of the candidate genes demonstrating susceptibility to osteoarthritis. The purpose of this study was to investigate the relationship between ADAM12-S protein and radiographic knee osteoarthritis (KOA) and its correlation to several bone and cartilage biomarkers. The ADAM12-S protein was measured in 276 subjects (60% women, aged 32-60 years), including 181 individuals with and 95 without radiographic KOA features. The radiographs were obtained from both tibiofemoral (TF) and patellofemoral (PF) joints. The serum levels of ADAM12-S protein were measured by DELFIA1/AutoDELFIA research kit. The ADAM12-S protein was found in detectable ranges in 43 subjects (16 men), without statistical difference between the two genders. In the whole group, the ADAM12-S was related to radiographic KOA grades in TF (P = 0.004) as well in PF joint (P = 0.003). We also found a correlation between ADAM12-S protein and osteophytes in TF and/or PF joints (P = 0.003). No correlations were found between serum levels of S-CTx-I (C-terminal cross-linked telopeptides of type I collagen) or S-PINP (type I procollagen N-terminal propeptide) and ADAM12-S. Similarly, in the whole group, the ADAM12-S protein was not correlated with U-CTx-II (urinary C-telopeptide fragments of type II collagen); however, in the female group, trend to positive correlation between the investigated biomarkers (P = 0.019) was observed. The ADAM12-S protein could be elevated in some KOA cases, and this elevation correlates with the grades of the disease, mostly owning to development of osteophytes. This finding suggests the possible involvement of the ADAM12-S protein in the pathogenesis of KOA.

  3. The Disintegrin and Metalloprotease ADAM12 Is Associated with TGF-β-Induced Epithelial to Mesenchymal Transition.

    PubMed

    Ruff, Michaël; Leyme, Anthony; Le Cann, Fabienne; Bonnier, Dominique; Le Seyec, Jacques; Chesnel, Franck; Fattet, Laurent; Rimokh, Ruth; Baffet, Georges; Théret, Nathalie

    2015-01-01

    The increased expression of the Disintegrin and Metalloprotease ADAM12 has been associated with human cancers, however its role remain unclear. We have previously reported that ADAM12 expression is induced by the transforming growth factor, TGF-β and promotes TGF-β-dependent signaling through interaction with the type II receptor of TGF-β. Here we explore the implication of ADAM12 in TGF-β-mediated epithelial to mesenchymal transition (EMT), a key process in cancer progression. We show that ADAM12 expression is correlated with EMT markers in human breast cancer cell lines and biopsies. Using a non-malignant breast epithelial cell line (MCF10A), we demonstrate that TGF-β-induced EMT increases expression of the membrane-anchored ADAM12L long form. Importantly, ADAM12L overexpression in MCF10A is sufficient to induce loss of cell-cell contact, reorganization of actin cytoskeleton, up-regulation of EMT markers and chemoresistance. These effects are independent of the proteolytic activity but require the cytoplasmic tail and are specific of ADAM12L since overexpression of ADAM12S failed to induce similar changes. We further demonstrate that ADAM12L-dependent EMT is associated with increased phosphorylation of Smad3, Akt and ERK proteins. Conversely, inhibition of TGF-β receptors or ERK activities reverses ADAM12L-induced mesenchymal phenotype. Together our data demonstrate that ADAM12L is associated with EMT and contributes to TGF-β-dependent EMT by favoring both Smad-dependent and Smad-independent pathways.

  4. ADAM and ADAMTS family proteins and their role in the colorectal cancer etiopathogenesis

    PubMed Central

    Przemyslaw, Leszczynski; Boguslaw, Hendrich Andrzej; Elzbieta, Szmida; Malgorzata, Sasiadek Maria

    2013-01-01

    The ADAM and ADAMTS families, also called adamalysins belong to an important group of extracellular matrix proteins. The ADAMs family belong to both the transmembrane and secreted proteins, while ADAMTS family only contains secreted forms. Adamalysins play an important role in the cell phenotype regulation via their activities in signaling pathways, cell adhesion and migration. The human proteome contains 21 ADAM, and 19 ADAMTS proteins, which are involved in extracellular matrix remodeling, shedding of various substrates such as: adhesion ligands, growth factors, their receptors and diverse cytokines. Recent studies provide evidence that adamalysins play a crucial role in colorectal cancer (CRC) etiopathogenesis. It seems possible that adamalysins might be used as CRC prediction markers or potential pharmaceutical targets. [BMB Reports 2013; 46(3): 139-150] PMID:23527857

  5. Cloning and expression of ADAM-related metalloproteases in equine laminitis.

    PubMed

    Coyne, Michael J; Cousin, Hélène; Loftus, John P; Johnson, Philip J; Belknap, James K; Gradil, Carlos M; Black, Samuel J; Alfandari, Dominique

    2009-06-15

    Equine laminitis is a debilitating disease affecting the digital laminae that suspend the distal phalanx within the hoof. While the clinical progression of the disease has been well documented, the molecular events associated with its pathogenesis remain largely unknown. Using real time quantitative PCR (RT-qPCR), we have investigated the expression of genes coding for proteins containing a Disintegrin and Metalloprotease domain (ADAM), as well as genes encoding the natural inhibitors of these enzymes (tissue inhibitor of metalloprotease; TIMP) in horses with naturally-acquired (acute, chronic and aggravated chronic clinical cases) or experimentally-induced (black walnut extract (BWE) and starch gruel models) laminitis. Changes in expression of these enzymes and regulators may underlie the pathologic remodeling of lamellar tissue in laminitis. Genes encoding ADAMs involved in inflammation (ADAM-10 and ADAM-17), as well as those implicated in arthritis (ADAMTS-1, ADAMTS-4 and ADAMTS-5) were cloned, and the sequences used to generate specific oligonucleotide primers for the RT-qPCR experiments. Our results show that genes encoding ADAM-10 and ADAM-17 were not induced in most laminitic animals, whereas ADAMTS-4 gene expression was strongly upregulated in nearly all horses with experimentally-induced and naturally-acquired laminitis. The expression of matrix metalloproteases (MMP)-9 and ADAMTS-5 was also increased in many of the laminitic horses. In addition, TIMP-2 gene expression was decreased in most laminitic horses, whereas expression of genes encoding other TIMPs, namely TIMP-1 and TIMP-3, was randomly increased or decreased in the various models. We conclude that increased expression of lamellar ADAMTS-4 is a common feature of laminitis consistent with a central role of the gene product in the pathophysiology of the disease.

  6. Adam M. Reid: APA/APAGS Award for Distinguished Graduate Student in Professional Psychology.

    PubMed

    2015-11-01

    The APA/APAGS Award for Distinguished Graduate Student in Professional Psychology is awarded on an annual basis by the APA Board of Professional Affairs (BPA) and the American Psychological Association of Graduate Students (APAGS) to a graduate student who has demonstrated outstanding practice and application of psychology. One of the 2015 award winners is Adam M. Reid, who received this award "for his community service, in which he has integrated the highest standards of professional psychological clinical practice and science." Adam's award citation, biography, and a selected bibliography are presented here.

  7. George Adams Junior and his 1789 book An essay on vision.

    PubMed

    Goss, David A

    2009-04-01

    English instrument maker George Adams Junior (1750-1795) published An Essay on Vision in 1789, with a second edition appearing in 1792. The 153 page book (157 pages in the second edition) presented material on structure of the eye and the basic nature of vision and vision conditions, with an emphasis on the proper use and choice of spectacles for the "long sighted" and the "short-sighted." A brief biographical sketch of Adams is given, and the contents of the book are discussed, with presentation of excerpts relating to general optometric principles. The excerpts can serve to illustrate the state of optometric knowledge in the late eighteenth century.

  8. 77 FR 64847 - Union Pacific Railroad Company-Abandonment Exemption-in Adams, Weld and Boulder Counties, Colo.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-23

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF TRANSPORTATION Surface Transportation Board Union Pacific Railroad Company--Abandonment Exemption--in Adams, Weld... near Eastlake to the end of the line at milepost 33.17 near Valmont, in Adams, Weld and...

  9. Problems with McAdams and Pals's (2006) Proposal of a Framework for an Integrative Theory of Personality

    ERIC Educational Resources Information Center

    Epstein, Seymour

    2007-01-01

    Comments on the original article "A New Big Five: Fundamental Principles for an Integrative Science of Personality," by Dan P. McAdams and Jennifer L. Pals (see record 2006-03947-002). Here, the current author begins with a critique of McAdams and Pals's (April 2006) five principles for a framework for an integrative theory of personality. The…

  10. A Reader Response to File and Adams's "The Reality, Robustness, and Possible Superiority of Incidental Vocabulary Acquisition"

    ERIC Educational Resources Information Center

    Mason, Beniko; Krashen, Stephen

    2010-01-01

    File and Adams (2010) conclude that their data confirm the superiority of form-focused vocabulary instruction over incidental acquisition. The authors of this response argue that File and Adams's data actually confirm the reality, robustness, and possible superiority of incidental acquisition. Their subjects heard two passages read to them that…

  11. Polo-like Kinase 2, a Novel ADAM17 Signaling Component, Regulates Tumor Necrosis Factor α Ectodomain Shedding*

    PubMed Central

    Schwarz, Jeanette; Schmidt, Stefanie; Will, Olga; Koudelka, Tomas; Köhler, Kaja; Boss, Melanie; Rabe, Björn; Tholey, Andreas; Scheller, Jürgen; Schmidt-Arras, Dirk; Schwake, Michael; Rose-John, Stefan; Chalaris, Athena

    2014-01-01

    ADAM17 (a disintegrin and metalloprotease 17) controls pro- and anti-inflammatory signaling events by promoting ectodomain shedding of cytokine precursors and cytokine receptors. Despite the well documented substrate repertoire of ADAM17, little is known about regulatory mechanisms, leading to substrate recognition and catalytic activation. Here we report a direct interaction of the acidophilic kinase Polo-like kinase 2 (PLK2, also known as SNK) with the cytoplasmic portion of ADAM17 through the C-terminal noncatalytic region of PLK2 containing the Polo box domains. PLK2 activity leads to ADAM17 phosphorylation at serine 794, which represents a novel phosphorylation site. Activation of ADAM17 by PLK2 results in the release of pro-TNFα and TNF receptors from the cell surface, and pharmacological inhibition of PLK2 leads to down-regulation of LPS-induced ADAM17-mediated shedding on primary macrophages and dendritic cells. Importantly, PLK2 expression is up-regulated during inflammatory conditions increasing ADAM17-mediated proteolytic events. Our findings suggest a new role for PLK2 in the regulation of inflammatory diseases by modulating ADAM17 activity. PMID:24338472

  12. MicroRNA-145 Targets the Metalloprotease ADAM17 and Is Suppressed in Renal Cell Carcinoma Patients1

    PubMed Central

    Doberstein, Kai; Steinmeyer, Nico; Hartmetz, Ann-Kathrin; Eberhardt, Wolfgang; Mittelbronn, Michel; Harter, Patrick N; Juengel, Eva; Blaheta, Roman; Pfeilschifter, Josef; Gutwein, Paul

    2013-01-01

    A disintegrin and metalloproteinase 17 (ADAM17) is a metalloprotease that is overexpressed in many cancer types, including renal cancers. However, the regulatory mechanisms of ADAM17 in cancer development and progression are poorly understood. In the present work, we provide evidence using overexpression and inhibition of microRNA 145 (miR-145) that miR-145 negatively regulates ADAM17 expression. Furthermore, we show that ADAM17 negatively regulates miR-145 through tumor necrosis factor-α, resulting in a reciprocal negative feedback loop. In this study, the expression of ADAM17 and miR-145 correlated negatively in renal cancer tumor tissues and cell lines, suggesting an important regulatory mechanism. Additionally, we showed that the regulation of ADAM17 is partly involved in the effects of miR-145 on proliferation and migration, whereas no involvement in chemosensitivity was observed. Importantly, in the healthy kidney, miR-145 was detected in different cell types including tubular cells, which are considered the origin of renal cancer. In renal cancer cell lines, miR-145 expression was strongly suppressed by methylation. In summary, miR-145 is downregulated in renal cancer patients, which leads to the up-regulation of ADAM17 in renal cancer. Importantly, miR-145 and ADAM17 are regulated in a reciprocal negative feedback loop. PMID:23441135

  13. Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

    PubMed Central

    Endres, Kristina; Deller, Thomas

    2017-01-01

    ADAM10 (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological alpha-secretase in neurons, responsible for cleaving APP in a non-amyloidogenic manner. This cleavage results in the production of a neuroprotective APP-derived fragment, APPs-alpha, and an attenuated production of neurotoxic A-beta peptides. An increase in ADAM10 activity shifts the balance of APP processing toward APPs-alpha and protects the brain from amyloid deposition and disease. Thus, increasing ADAM10 activity has been proposed an attractive target for the treatment of neurodegenerative diseases and it appears to be timely to investigate the physiological mechanisms regulating ADAM10 expression. Therefore, in this article, we will (1) review reports on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or protein interactions, (2) describe conditions, which change ADAM10 expression in vitro and in vivo, (3) report how neuronal ADAM10 expression may be regulated in humans, and (4) discuss how this knowledge on the physiological and pathophysiological regulation of ADAM10 may help to preserve or restore brain function. PMID:28367112

  14. 77 FR 25229 - Adams-Warnock Railway, Inc.-Lease and Operation Exemption-Norfolk Southern Railway Company

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-27

    ... Surface Transportation Board Adams-Warnock Railway, Inc.--Lease and Operation Exemption-- Norfolk Southern Railway Company Adams--Warnock Railway, Inc. (AWRY), a noncarrier, has filed a verified notice of exemption under ] 49 CFR 1150.31 to lease from Norfolk Southern Railway Company (NSR), and to operate,...

  15. 38 CFR 3.667 - School attendance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... institution and a claim for such benefits is filed within 1 year from the child's 18th birthday. (2) Pension... child's 18th birthday, and if a claim for benefits is filed within 1 year from the child's 18th birthday... evidence of such school attendance is filed within 1 year from that date. (b) Vacation periods. A child...

  16. Does Attendance Enhance Political Science Grades?

    ERIC Educational Resources Information Center

    Tiruneh, Gizachew

    2007-01-01

    This article tests a relationship between class attendance and final grades in several political science courses that I taught at the University of Georgia, University of Vermont, and University of Central Arkansas between the Fall 2000 and Spring 2006 semesters. The study employs ordinary least square estimators to test the foregoing hypothesis.…

  17. Encouraging Faculty Attendance at Professional Development Events

    ERIC Educational Resources Information Center

    Burdick, Dakin; Doherty, Tim; Schoenfeld, Naomi

    2015-01-01

    For faculty development events to have the greatest impact on campus practice, faculty developers need to attract and include as many faculty members as possible at their events. This article describes the testing of a checklist regarding faculty attendance at professional development events through a survey of 238 faculty members at small…

  18. Service Station Attendant. Performance Objectives. Basic Course.

    ERIC Educational Resources Information Center

    Davis, John

    Several intermediate performance objectives and corresponding criterion measures are listed for each of 24 terminal objectives for a basic secondary level service station attendant course. The materials were developed for a two-semester course (2 and 3 hours daily). The specialized classroom and shop experiences are designed to enable the student…

  19. Attendance and Truancy Programs. Research Brief

    ERIC Educational Resources Information Center

    Walker, Karen

    2007-01-01

    According to the 2000 census, high school dropouts had a 52% employment rate, compared to 71% for high school graduates and 83% for college graduates. According to NCSE, the national dropout rate is 30% of which 80% had been chronically absent from school ("School attendance tracking: Challenges and effective practices"), which puts the…

  20. International Determinants of Private School Attendance

    ERIC Educational Resources Information Center

    Rutkowski, Leslie; Rutkowski, David; Plucker, Jonathan

    2012-01-01

    The current study uses Programme for International Student Assessment (PISA) 2006 data to investigate international determinants of private school attendance. In particular, we seek to understand whether student achievement and home background factors such as socioeconomic status (SES) or motivational and goal-oriented factors are more predictive…

  1. Automated Attendance Accounting System; Patent Application.

    ERIC Educational Resources Information Center

    Chapman, Carl P.; And Others

    An automated accounting system, useful for applying data to a computer from a multiplicity of terminals, has the potential of replacing the manual attendance accounting system now employed in schools. The inventors claim that such a sophisticated system with terminals in the classrooms would enable school administrators not only to monitor simple…

  2. Medical specialist attendance in nursing homes

    PubMed Central

    Balzer, Katrin; Butz, Stefanie; Bentzel, Jenny; Boulkhemair, Dalila; Lühmann, Dagmar

    2013-01-01

    The care in nursing homes was examined based on scientific studies. The analysis focuses on dementia and type II diabetes. There is evidence for deficits in the supply of medical specialist attendance to nursing home residents with these diseases in Germany. Compared with corresponding guidelines the medical care for nursing home residents may be too low or inadequate. PMID:23755088

  3. The Effects of Attending a Diverse College

    ERIC Educational Resources Information Center

    Hinrichs, Peter

    2011-01-01

    The question of whether there are benefits to be obtained from having a diverse student body is a key issue in the debate over affirmative action. This paper estimates the effects of college racial diversity on post-college earnings, civic behavior, and satisfaction with the college attended. I use the Beginning Postsecondary Students survey,…

  4. Earning and Learning: Reasons Students Attend College

    ERIC Educational Resources Information Center

    Arboleda, Ana; Chen, JingJing; Shelley, Mack C., II; Whalen, Donald F.

    2004-01-01

    Linear models of two of the most salient motivations for undergraduates to attend college--learning (intrinsic) and enhanced post-graduation earnings (extrinsic)--are estimated from a sample of 2,199 respondents to the 2000 Cooperative Institutional Research Program (CIRP) survey of first-year students, supplemented by institutional records. Model…

  5. 45 CFR 1305.8 - Attendance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Attendance. 1305.8 Section 1305.8 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF HUMAN DEVELOPMENT SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES THE ADMINISTRATION FOR CHILDREN, YOUTH AND FAMILIES, HEAD START PROGRAM...

  6. 45 CFR 1305.8 - Attendance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 4 2013-10-01 2013-10-01 false Attendance. 1305.8 Section 1305.8 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF HUMAN DEVELOPMENT SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES THE ADMINISTRATION FOR CHILDREN, YOUTH AND FAMILIES, HEAD START PROGRAM...

  7. 45 CFR 1305.8 - Attendance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false Attendance. 1305.8 Section 1305.8 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF HUMAN DEVELOPMENT SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES THE ADMINISTRATION FOR CHILDREN, YOUTH AND FAMILIES, HEAD START PROGRAM...

  8. 45 CFR 1305.8 - Attendance.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 4 2012-10-01 2012-10-01 false Attendance. 1305.8 Section 1305.8 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF HUMAN DEVELOPMENT SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES THE ADMINISTRATION FOR CHILDREN, YOUTH AND FAMILIES, HEAD START PROGRAM...

  9. 45 CFR 1305.8 - Attendance.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 4 2014-10-01 2014-10-01 false Attendance. 1305.8 Section 1305.8 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF HUMAN DEVELOPMENT SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES THE ADMINISTRATION FOR CHILDREN, YOUTH AND FAMILIES, HEAD START PROGRAM...

  10. 38 CFR 3.667 - School attendance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    .... (a) General. (1) Pension or compensation may be paid from a child's 18th birthday based upon school attendance if the child was at that time pursing a course of instruction at an approved educational institution and a claim for such benefits is filed within 1 year from the child's 18th birthday. (2)...

  11. 38 CFR 3.667 - School attendance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    .... (a) General. (1) Pension or compensation may be paid from a child's 18th birthday based upon school attendance if the child was at that time pursing a course of instruction at an approved educational institution and a claim for such benefits is filed within 1 year from the child's 18th birthday. (2)...

  12. 38 CFR 3.667 - School attendance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    .... (a) General. (1) Pension or compensation may be paid from a child's 18th birthday based upon school attendance if the child was at that time pursing a course of instruction at an approved educational institution and a claim for such benefits is filed within 1 year from the child's 18th birthday. (2)...

  13. ADAM17 is critical for multipolar exit and radial migration of neuronal intermediate progenitor cells in mice cerebral cortex.

    PubMed

    Li, Qingyu; Zhang, Zhengyu; Li, Zengmin; Zhou, Mei; Liu, Bin; Pan, Le; Ma, Zhixing; Zheng, Yufang

    2013-01-01

    The radial migration of neuronal progenitor cells is critical for the development of cerebral cortex layers. They go through a critical step transforming from multipolar to bipolar before outward migration. A Disintegrin and Metalloprotease 17 (ADAM17) is a transmembrane protease which can process many substrates involved in cell-cell interaction, including Notch, ligands of EGFR, and some cell adhesion molecules. In this study, we used in utero electroporation to knock down or overexpress ADAM17 at embryonic day 14.5 (E14.5) in neuronal progenitor cells to examine the role of ADAM17 in cortical embryonic neurogenesis. Our results showed that the radial migration of ADAM17-knocked down cells were normal till E16.5 and reached the intermediate zone (IZ). Then most transfected cells stopped migration and stayed at the IZ to inner cortical plate (CP) layer at E18.5, and there was higher percentage of multipolar cells at IZ layer in the ADAM17-knocked down group compared to the cells in control group. Marker staining revealed that those ADAM17-knocked down cells differentiated normally from neural stem cells (NSCs) to neuronal intermediate progenitor cells (nIPCs) but did not differentiate into mature neurons. The migration and multipolar exit defects caused by ADAM17 knockdown could be partially rescued by over-expressing an shRNA resistant ADAM17, while overexpressing ADAM17 alone did not affect the radial migration. Taken together, our results showed for the first time that, ADAM17 is critical in regulating the multipolar-stage exit and radial migration of the nIPCs during telencephalon cortex development in mice.

  14. ADAM8 is selectively upregulated in endothelial cells and is associated with angiogenesis after spinal cord injury in adult mice

    PubMed Central

    Mahoney, Edward T.; Benton, Richard L.; Maddie, Melissa A.; Whittemore, Scott R.; Hagg, Theo

    2009-01-01

    Endothelial cell (EC) loss and subsequent angiogenesis occurs over the first week after spinal cord injury (SCI). To identify molecular mechanisms that could be targeted with intravenous (i.v.) treatments we determined whether transmembrane A Disintegrin And Metalloprotease (ADAM) proteins are expressed in ECs of the injured spinal cord. ADAMs bind to integrins which are important for EC survival and angiogenesis. Female adult C57Bl/6 mice with a spinal cord contusion had progressively more ADAM8 (CD156) immunostaining in blood vessels and individual ECs between 1 and 28 days following injury. Uninjured spinal cords had little ADAM8 staining. The increase in ADAM8 mRNA and protein was confirmed in spinal cord lysates, and ADAM8 mRNA was present in FACS-enriched ECs. ADAM8 co-localized extensively and exclusively with the EC marker PECAM and also with i.v. injected lectins. I.v. injected isolectin B4 (IB4) labels a subpopulation of blood vessels at and within the injury epicenter 3-7 days after injury, coincident with angiogenesis. Both ADAM8 and the proliferation marker Ki-67 were present in IB4-positive microvessels. ADAM8-positive proliferating cells were seen at the leading end of IB4-positive blood vessels. Angiogenesis was confirmed by BrdU incorporation, binding of i.v. injected nucleolin antibodies, and MT1-MMP immunostaining in a subset of blood vessels. These data suggest that ADAM8 is vascular-selective and plays a role in proliferation and/or migration of ECs during angiogenesis following SCI. PMID:19003792

  15. Higher Education Financing in the Fifty States: Significance for the 'Adams' States.

    ERIC Educational Resources Information Center

    Budig, Jeanne E.; Khan, Anwar

    Findings of a study on higher education financing in the states are summarized with specific reference for the states covered by the 1977 Adams versus Richardson decision. The study, "Higher Education Financing in the Fifty States: Interstate Comparisons" (Marilyn McCoy, D. Kent Halstead), was jointly issued by the National Center for…

  16. Adam Smith and the Educative Critique: A Response to My Commentators

    ERIC Educational Resources Information Center

    Weinstein, Jack Russell

    2015-01-01

    This paper is both a response to the four reviewers in a special symposium on my book Adam Smith's Pluralism and a substantive discussion of philosophy of education. In it, I introduce what I call "the educative critique," a mode of analysis similar to Marxist, feminist, or postcolonial critiques, but focusing on the educative role of a…

  17. Tales of Hate and "Differance": A Narrative Analysis of Gayman's "The Book of Adam."

    ERIC Educational Resources Information Center

    Stroud, Scott R.

    This paper examines the Christian Identity artifact, "The Book of Adam," by Dan Gayman. Using narrative criticism, this artifact is shown to construct the white race as "progressing through time, as occupying sacred spatial locations, as essentially chosen by God, and as separate from other races." This narrative blurs the…

  18. Serendipity in the Theater: Maude Adams as James M. Barrie's American Muse.

    ERIC Educational Resources Information Center

    Diaz de Chumaceiro, Cora L.

    2003-01-01

    This essay discusses how Maude Adams influenced James M. Barrie's creative process and became his inspiration. Set change theory is underscored as a cognitive explanation for Barrie's illumination. The psychoanalytic theory of transference is proposed as an underlying mechanism for facilitating the change of mental set during the incubation stage.…

  19. ADAM10 localization in temporomandibular joint disk with internal derangement: an ex vivo immunohistochemical study.

    PubMed

    Loreto, Carla; Chiarenza, Giovanni Paolo Salvatore; Musumeci, Giuseppe; Castrogiovanni, Paola; Imbesi, Rosa; Ruggeri, Alessandra; Almeida, Luis Edoardo; Leonardi, Rosalia

    2016-04-01

    The purpose of this study was to determine the presence of ADAM10 in temporomandibular joint disk with internal derangement. Twenty-five paraffin blocks of displaced temporomandibular joint (TMJ) disk specimens from earlier investigations were retrieved from the archives of the University of Catania. Of these 16 had been removed from females and 9 from males; 11 with anterior disk displacement with reduction (ADDwR) and 14 with anterior disk displacement without reduction (ADDwoR). The sections were dehydrated, embedded in paraffin and cut. Then they were incubated in 0.3% H2O2/methanol and half of sections from each sample were incubated in diluted rabbit polyclonal anti-ADAM10 antibody. Then biotinylated anti-mouse/anti-rabbit IgG was applied to the sections, followed by avidin-biotin-perioxidase complex. The results were analyzed and the results were that ADAM10 was overexpressed in the posterior band of sections from patients with ADDwR compared to the other bands of both ADDwR and ADDwoR sections. Overexpression correlated with severe histopathological degeneration. We believe these results have the potential to provide insights into the pathogenesis of TMJ disk degeneration and to help design new therapeutic approaches targeting the proteolytic events that lead to tissue degeneration. Early therapeutic block of ADAM10 activity could succeed in limiting aggrecan-rich matrix breakdown without affecting normal physiology.

  20. Music for Elementary Teachers; Self-Help Guide (MUS 370). Adams State College.

    ERIC Educational Resources Information Center

    Stokes, Cloyce

    This self-help guide for the music teacher is one of a series of eight Teacher Education Modules developed by Adams State College Teacher Corps Program. The guide itself consists of 11 modules, the first five of which focus on the mathematical and scientific aspects of music--pitch, tempo, furation, time, and key. These five modules are…

  1. Highlighting High Performance Buildings: Adam Joseph Lewis Center for Environmental Studies

    SciTech Connect

    2002-11-01

    Oberlin College's Adam Joseph Lewis Center for Environmental Studies is a high-performance building featuring an expansive photovoltaic system and a closed-loop groundwater heat pump system. Designers incorporated energy-efficient components and materials that are local, non-toxic, and durable.

  2. Boundary Value Technique for Initial Value Problems Based on Adams-Type Second Derivative Methods

    ERIC Educational Resources Information Center

    Jator, S. N.; Sahi, R. K.

    2010-01-01

    In this article, we propose a family of second derivative Adams-type methods (SDAMs) of order up to 2k + 2 ("k" is the step number) for initial value problems. The methods are constructed through a continuous approximation of the SDAM which is obtained by multistep collocation. The continuous approximation is used to obtain initial value methods,…

  3. The emerging role of matrix metalloproteases of the ADAM family in male germ cell apoptosis

    PubMed Central

    Urriola-Muñoz, Paulina; Lagos-Cabré, Raúl

    2011-01-01

    Constitutive germ cell apoptosis during mammalian spermatogenesis is a key process for controlling sperm output and to eliminate damaged or unwanted cells. An increase or decrease in the apoptosis rate has deleterious consequences and leads to low sperm production. Apoptosis in spermatogenesis has been widely studied, but the mechanism by which it is induced under physiological or pathological conditions has not been clarified. We have recently identified the metalloprotease ADAM17 (TACE) as a putative physiological inducer of germ cell apoptosis. The mechanisms involved in regulating the shedding of the ADAM17 extracellular domain are still far from being understood, although they are important in order to understand cell-cell communications. Here, we review the available data regarding apoptosis during mammalian spermatogenesis and the localization of ADAM proteins in the male reproductive tract. We propose an integrative working model where ADAM17, p38 MAPK, protein kinase C (PKC) and the tyrosine kinase c-Abl participate in the physiological signalling cascade inducing apoptosis in germ cells. In our model, we also propose a role for the Sertoli cell in regulating the Fas/FasL system in order to induce the extrinsic pathway of apoptosis in germ cells. This working model could be applied to further understand constitutive apoptosis in spermatogenesis and in pathological conditions (e.g., varicocele) or following environmental toxicants exposure (e.g., genotoxicity or xenoestrogens). PMID:22319668

  4. Rethinking Equality of Opportunity: Comment on Adam Swift's "How Not to Be a Hypocrite"

    ERIC Educational Resources Information Center

    Anderson, Elizabeth

    2004-01-01

    Adam Swift objects to private schools on the grounds of equal opportunity and efficiency, and to both private and selective public schools on the grounds of solidarity and improving the academic achievement of less advantaged students. I argue that private schools are not inefficient, and that a meritocratic ideal of equality of opportunity in…

  5. 77 FR 2992 - Columbia National Wildlife Refuge, Adams and Grant Counties, WA; Final Comprehensive Conservation...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF THE INTERIOR Fish and Wildlife Service Columbia National Wildlife Refuge, Adams and Grant Counties, WA; Final Comprehensive Conservation Plan and Finding of No Significant Impact for Environmental Assessment AGENCY:...

  6. Award for Distinguished Scientific Early Career Contributions to Psychology: Adam K. Anderson

    ERIC Educational Resources Information Center

    American Psychologist, 2009

    2009-01-01

    Adam K. Anderson, recipient of the Award for Distinguished Scientific Early Career Contributions to Psychology, is cited for his outstanding contribution to understanding the representation of emotion and its influence on cognition. By combining psychological and neuroscience techniques with rigorous and creative experimental designs, Anderson has…

  7. Comparing Adam Smith's Wealth of Nations to James Madison's Federalist #10.

    ERIC Educational Resources Information Center

    Mundell, Jean

    1987-01-01

    Presents a lesson which calls upon students to compare Adam Smith's WEALTH OF NATIONS to James Madison's FEDERALIST #10 to see how the ancient concept of individual rights and liberties was used to describe both economic and governmental systems. Presents questions to provide the basis for comparison. (GEA)

  8. Back to Beginnings: Credentialism, Productivity, and Adam Smith's Division of Labour.

    ERIC Educational Resources Information Center

    Davis, Denis J.

    1981-01-01

    The foundation of factional pressures for upgrading educational credentials in the labor market is examined through a review of human capital and screening theories. The writings of Adam Smith are referenced to show that the claims of the beneficial effects of educational upgrading have been questioned for 200 years. (Author/MLW)

  9. Rhetorical Studies: A Reassessment of Adam Smith's Lectures on Rhetoric and Belles Lettres.

    ERIC Educational Resources Information Center

    Purcell, William M.

    1986-01-01

    Offers a dissenting interpretation of Adam Smith's Lectures on Rhetoric and Belles Lettres and a more conservative perspective on Smith's significance to the history of rhetorical theory. Views the lectures as an historical commentary on literature and rhetoric from the perspective of an eighteenth-century lecturer. (JD)

  10. Two Rival Conceptions of Vocational Education: Adam Smith and Friedrich List.

    ERIC Educational Resources Information Center

    Winch, Christopher

    1998-01-01

    Examines and discusses two views of political economy: (1) the classical model of Adam Smith; and (2) the social capitalist model associated with Friedrich List. Explores two varieties of vocational education and training that emerge from a comparison of Smith's and List's ideas. (CMK)

  11. How To Survive in Postindustrial Environments: Adam Smith's Advice for Today's Colleges and Universities.

    ERIC Educational Resources Information Center

    Ortmann, Andreas

    1997-01-01

    Adam Smith's discussion of the payment modes of teachers and resulting consequences for the quality of teaching and process of curricular innovation are reviewed through the conceptual lens of modern agency theory. Smith's analysis of higher education in his day (eighteenth century) sheds light on faculty incentive and assessment problems that…

  12. Springs, streams, and gas vent on and near Mount Adams volcano, Washington

    USGS Publications Warehouse

    Nathenson, Manuel; Mariner, Robert H.

    2013-01-01

    Springs and some streams on Mount Adams volcano have been sampled for chemistry and light stable isotopes of water. Spring temperatures are generally cooler than air temperatures from weather stations at the same elevation. Spring chemistry generally reflects weathering of volcanic rock from dissolved carbon dioxide. Water in some springs and streams has either dissolved hydrothermal minerals or has reacted with them to add sulfate to the water. Some samples appear to have obtained their sulfate from dissolution of gypsum while some probably involve reaction with sulfide minerals such as pyrite. Light stable isotope data for water from springs follow a local meteoric water line, and the variation of isotopes with elevation indicate that some springs have very local recharge and others have water from elevations a few hundred meters higher. No evidence was found for thermal or slightly thermal springs on Mount Adams. A sample from a seeping gas vent on Mount Adams was at ambient temperature, but the gas is similar to that found on other Cascade volcanoes. Helium isotopes are 4.4 times the value in air, indicating that there is a significant component of mantle helium. The lack of fumaroles on Mount Adams and the ambient temperature of the gas indicates that the gas is from a hydrothermal system that is no longer active.

  13. Time to Raise Cain? - A critique of the VAX ADAM system

    NASA Astrophysics Data System (ADS)

    Jones, Lewis

    1990-01-01

    The VAX ADAM system presently used by ROE, AAO, Starlink and others has been used to build the instrumentation systems for the William Herschel Telescope (WHT). Use of 'intelligent' microprocessor-based hardware within the WHT observing system, together with a fundamental requirement for increased efficiency in the observing process, has resulted in a new approach requiring sophisticated software in order to implement batch-oriented control. The result is that the WHT instrumentation system forms one of the largest and most complex implementations within the ADAM environment to date. During the design and implementation stages of the WHT instrumentation software, the ADAM environment has been found to be a less than satisfactory framework within which to construct a high-quality observing system to the original specification. This document is a distillation of specific problems which have been encountered by members of the La Palma Software Group, together with other general observations of shortcomings in the current implementation of the VAX ADAM environment.

  14. Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation.

    PubMed

    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-07-06

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent.

  15. Implementation of Distributed ADAMS Over Legion Using a Component DBMS Design. Final Report

    SciTech Connect

    Pfaltz, John L.; Orlandic, Ratko

    2002-11-26

    There were four primary research areas reported in the final report for the original funding period They are: implementation of high dimensional data spaces; knowledge discovery in scientific databases; and mismatch between implementing components; demonstrate the utility of ADAMS in a specific domain science.

  16. Making Socialists: Mary Bridges Adams and the Fight for Knowledge and Power, 1855-1939

    ERIC Educational Resources Information Center

    Weiler, Kathleen

    2012-01-01

    This article presents a review of "Making socialists: Mary Bridges Adams and the fight for knowledge and power, 1855-1939," by Jane Martin. Jane Martin has explored the history of late-nineteenth-century and early-twentieth century-British women educational activists in numerous publications over the past two decades. Her first book,…

  17. "Beginning To Read: Thinking and Learning about Print" by Marilyn Jager Adams. A Summary.

    ERIC Educational Resources Information Center

    Stahl, Steven A.; And Others

    Prepared for teachers, school administrators, parents, and other members of the interested public, this summary of Marilyn Jager Adams'"Beginning to Read: Thinking and Learning about Print" selects from the complex and extensive body of research in the book to present a more direct but much less detailed account of useful, research-based…

  18. Fractional Adams-Bashforth/Moulton methods: An application to the fractional Keller-Segel chemotaxis system

    NASA Astrophysics Data System (ADS)

    Zayernouri, Mohsen; Matzavinos, Anastasios

    2016-07-01

    We first formulate a fractional class of explicit Adams-Bashforth (A-B) and implicit Adams-Moulton (A-M) methods of first- and second-order accuracy for the time-integration of τ 0 CDt u (x , t) = g (t ; u), τ ∈ (0 , 1 ], where τ 0 CDt denotes the fractional derivative in the Caputo sense. In this fractional setting and in contrast to the standard Adams methods, an extra history load term emerges and the associated weight coefficients are τ-dependent. However when τ = 1, the developed schemes reduce to the well-known A-B and A-M methods with standard coefficients. Hence, in terms of scientific computing, our approach constitutes a minimal modification of the existing Adams libraries. Next, we develop an implicit-explicit (IMEX) splitting scheme for linear and nonlinear fractional PDEs of a general advection-reaction-diffusion type, and we apply our scheme to the time-space fractional Keller-Segel chemotaxis system. In this context, we evaluate the nonlinear advection term explicitly, employing the fractional A-B method in the prediction step, and we treat the corresponding diffusion term implicitly in the correction step using the fractional A-M scheme. Moreover, we perform the corresponding spatial discretization by employing an efficient and spectrally-accurate fractional spectral collocation method. Our numerical experiments exhibit the efficiency of the proposed IMEX scheme in solving nonlinear fractional PDEs.

  19. Cytoskeletal confinement of CX3CL1 limits its susceptibility to proteolytic cleavage by ADAM10

    PubMed Central

    Wong, Harikesh S.; Jaumouillé, Valentin; Heit, Bryan; Doodnauth, Sasha A.; Patel, Sajedabanu; Huang, Yi-Wei; Grinstein, Sergio; Robinson, Lisa A.

    2014-01-01

    CX3CL1 is a unique chemokine that acts both as a transmembrane endothelial adhesion molecule and, upon proteolytic cleavage, a soluble chemoattractant for circulating leukocytes. The constitutive release of soluble CX3CL1 requires the interaction of its transmembrane species with the integral membrane metalloprotease ADAM10, yet the mechanisms governing this process remain elusive. Using single-particle tracking and subdiffraction imaging, we studied how ADAM10 interacts with CX3CL1. We observed that the majority of cell surface CX3CL1 diffused within restricted confinement regions structured by the cortical actin cytoskeleton. These confinement regions sequestered CX3CL1 from ADAM10, precluding their association. Disruption of the actin cytoskeleton reduced CX3CL1 confinement and increased CX3CL1–ADAM10 interactions, promoting the release of soluble chemokine. Our results demonstrate a novel role for the cytoskeleton in limiting membrane protein proteolysis, thereby regulating both cell surface levels and the release of soluble ligand. PMID:25253723

  20. Urinary ADAM12 and MMP-9/NGAL complex detect the presence of gastric cancer.

    PubMed

    Shimura, Takaya; Dagher, Adelle; Sachdev, Monisha; Ebi, Masahide; Yamada, Tamaki; Yamada, Tomonori; Joh, Takashi; Moses, Marsha A

    2015-03-01

    Although the early diagnosis of gastric cancer provides the opportunity for curative endoscopic resection, comprehensive screening endoscopy would be invasive and expensive. To date, there is a complete absence of clinically useful gastric cancer biomarkers. With the goal of discovering noninvasive biomarkers for the early diagnosis of gastric cancer, we have conducted a case-control study using urine samples from individuals with gastric cancer versus healthy control samples. Of the enrolled 106 patients from September, 2012 to April, 2013, a cohort of 70 patients composed of 35 patients with gastric cancer and 35 age- and sex-matched healthy controls was analyzed. The gastric cancer group was composed of stage IA of 62.9% (22/35). The urinary levels of MMP-9/NGAL complex (uMMP-9/NGAL) and ADAM12 (uADAM12) were significantly higher in the gastric cancer group compared with the healthy control group as determined by monospecific ELISAs (uMMP-9/NGAL: median, 85 pg/mL vs. 0 pg/mL; P = 0.020; uADAM12: median, 3.35 ng/mL vs. 1.44 ng/mL; P < 0.001). Multivariate analysis demonstrated that both uMMP-9/NGAL and uADAM12 were significant, independent diagnostic biomarkers for gastric cancer. Moreover, MMP-9/NGAL activity was significantly elevated as determined by gelatin zymography. The combination of uMMP-9/NGAL with uADAM12 distinguished between control samples and gastric cancer samples with an AUC of 0.825 (P < 0.001) in an ROC analysis. Significantly, immunohistochemical analyses demonstrated a high coexpression of MMP-9 and NGAL (P < 0.001) and high expression of ADAM12 (P < 0.001) in gastric cancer tissues compared with adjacent normal tissues (N = 35). In summary, uMMP-9/NGAL and uADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease.

  1. Non-attendance at a difficult-asthma clinic.

    PubMed

    McDonough, Beverley; Mault, Susan

    Increasing demand for our weekly difficult-asthma clinic means routine appointments are at a premium. This led us to explore the reasons why patients failed to attend for appointments and whether contacting them by telephone within a week of their missed scheduled appointment increased attendance. Memory lapses were the most common reason for non-attendance. Telephoning non-attenders led to a two-fold increase in attendance at subsequent clinics. Non-attendance may be a reflection of poor concordance, which, in itself, may contribute to a patient's difficult asthma.

  2. Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy

    PubMed Central

    Muona, Mikko; Fukata, Yuko; Anttonen, Anna-Kaisa; Laari, Anni; Palotie, Aarno; Pihko, Helena; Lönnqvist, Tuula; Valanne, Leena; Somer, Mirja; Fukata, Masaki

    2016-01-01

    Objective: To identify the molecular genetic basis of a syndrome characterized by rapidly progressing cerebral atrophy, intractable seizures, and intellectual disability. Methods: We performed exome sequencing in the proband and whole-genome single nucleotide polymorphism genotyping (copy number variant analysis) in the proband-parent trio. We used heterologous expression systems to study the functional consequences of identified mutations. Results: The search for potentially deleterious recessive or de novo variants yielded compound heterozygous missense (c.1202G>A, p.Cys401Tyr) and frameshift deletion (c.2396delG, p.Ser799IlefsTer96) mutations in ADAM22, which encodes a postsynaptic receptor for LGI1. The deleterious effect of the mutations was observed in cell surface binding and immunoprecipitation assays, which revealed that both mutant proteins failed to bind to LGI1. Furthermore, immunoprecipitation assays showed that the frameshift mutant ADAM22 also did not bind to the postsynaptic scaffolding protein PSD-95. Conclusions: The mutations identified abolish the LGI1-ADAM22 ligand-receptor complex and are thus a likely primary cause of the proband's epilepsy syndrome, which is characterized by unusually rapidly progressing cortical atrophy starting at 3–4 months of age. These findings are in line with the implicated role of the LGI1-ADAM22 complex as a key player in nervous system development, specifically in functional maturation of postnatal synapses. Because the frameshift mutation affects an alternatively spliced exon with highest expression in postnatal brain, the combined effect of the mutations is likely to be hypomorphic rather than complete loss of function. This is compatible with the longer survival of the patient compared to Lgi1−/− and Adam22−/− mice, which develop lethal seizures during the first postnatal weeks. PMID:27066583

  3. Development of a High Fidelity Dynamic Module of the Advanced Resistive Exercise Device (ARED) Using Adams

    NASA Technical Reports Server (NTRS)

    Humphreys, B. T.; Thompson, W. K.; Lewandowski, B. E.; Cadwell, E. E.; Newby, N. J.; Fincke, R. S.; Sheehan, C.; Mulugeta, L.

    2012-01-01

    NASA's Digital Astronaut Project (DAP) implements well-vetted computational models to predict and assess spaceflight health and performance risks, and enhance countermeasure development. DAP provides expertise and computation tools to its research customers for model development, integration, or analysis. DAP is currently supporting the NASA Exercise Physiology and Countermeasures (ExPC) project by integrating their biomechanical models of specific exercise movements with dynamic models of the devices on which the exercises were performed. This presentation focuses on the development of a high fidelity dynamic module of the Advanced Resistive Exercise Device (ARED) on board the ISS. The ARED module, illustrated in the figure below, was developed using the Adams (MSC Santa Ana, California) simulation package. The Adams package provides the capabilities to perform multi rigid body, flexible body, and mixed dynamic analyses of complex mechanisms. These capabilities were applied to accurately simulate: Inertial and mass properties of the device such as the vibration isolation system (VIS) effects and other ARED components, Non-linear joint friction effects, The gas law dynamics of the vacuum cylinders and VIS components using custom written differential state equations, The ARED flywheel dynamics, including torque limiting clutch. Design data from the JSC ARED Engineering team was utilized in developing the model. This included solid modeling geometry files, component/system specifications, engineering reports and available data sets. The Adams ARED module is importable into LifeMOD (Life Modeler, Inc., San Clemente, CA) for biomechanical analyses of different resistive exercises such as squat and dead-lift. Using motion capture data from ground test subjects, the ExPC developed biomechanical exercise models in LifeMOD. The Adams ARED device module was then integrated with the exercise subject model into one integrated dynamic model. This presentation will describe the

  4. Comparison of different order Adams-Bashforth methods in an atmospheric general circulation model

    NASA Astrophysics Data System (ADS)

    Zhao, Bin; Zhang, Bo

    2011-12-01

    The Asselin-Robert time filter used in the leapfrog scheme does degrade the accuracy of calculations. As an attractive alternative to leapfrog time differencing, the second-order Adams-Bashforth method is not subject to time splitting instability and keeps excellent calculation accuracy. A second-order Adams-Bashforth model has been developed, which represents better stability, excellent convergence and improved simulation of prognostic variables. Based on these results, the higher-order Adams-Bashforth methods are developed on the basis of NCAR (National Center for Atmospheric Research) CAM 3.1 (Community Atmosphere Model 3.1) and the characteristics of dynamical cores are analyzed in this paper. By using Lorenz nonlinear convective equations, the filtered leapfrog scheme shows an excellent pattern for eliminating 2Δ t wave solutions after 20 steps but represents less computational solution accuracy. The fourth-order Adams-Bashforth method is closely converged to the exact solution and provides a reference against which other methods may be compared. Thus, the Adams-Bashforth methods produce more accurate and convergent solution with differencing order increasing. The Held-Suarez idealized test is carried out to demonstrate that all methods have similar climate states to the results of many other global models for long-term integration. Besides, higher-order methods perform better in mass conservation and exhibit improvement in simulating tropospheric westerly jets, which is likely equivalent to the advantages of increasing horizontal resolutions. Based on the idealized baroclinic wave test, a better capability of the higher-order method in maintaining simulation stability is convinced. Furthermore, after the baroclinic wave is triggered through overlaying the steady-state initial conditions with the zonal perturbation, the higher-order method has a better ability in the simulation of baroclinic wave perturbation.

  5. ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro.

    PubMed

    Eichenauer, Dennis A; Simhadri, Vijaya Lakshmi; von Strandmann, Elke Pogge; Ludwig, Andreas; Matthews, Vance; Reiners, Katrin S; von Tresckow, Bastian; Saftig, Paul; Rose-John, Stefan; Engert, Andreas; Hansen, Hinrich P

    2007-01-01

    CD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleavage of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)-expressing non-target cells. Because antibodies bind to sCD30, this results in unwanted antibody binding to these cells via sCD30 bridging. To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release. Shedding of CD30 can be enhanced by protein kinase C (PKC) activation, implicating the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. However, antibody-induced CD30 shedding is calcium dependent and PKC independent. This shedding involved the related metalloproteinase ADAM10 as shown by the use of the preferential ADAM10 inhibitor GI254023X and by an ADAM10-deficient cell line generated from embryonically lethal ADAM10(-/-) mouse. In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin's lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side effects of immunotherapy with monoclonal antibodies.

  6. Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin.

    PubMed

    Tippmann, Frank; Hundt, Jana; Schneider, Anja; Endres, Kristina; Fahrenholz, Falk

    2009-06-01

    Late-onset Alzheimer's disease is often connected with nutritional misbalance, such as enhanced cholesterol intake, deficiency in polyunsaturated fatty acids, or hypovitaminosis. The alpha-secretase ADAM10 has been found to be regulated by retinoic acid, the bioreactive metabolite of vitamin A. Here we show that retinoids induce gene expression of ADAM10 and alpha-secretase activity by nonpermissive retinoid acid receptor/retinoid X receptor (RAR/RXR) heterodimers, whereby alpha- and beta-isotypes of RAR play a major role. However, ligands of other RXR binding partners, such as the vitamin D receptor, do not stimulate alpha-secretase activity. On the basis of these findings, we examined the effect of synthetic retinoids and found a strong enhancement of nonamyloidogenic processing of the amyloid precursor protein by the vitamin A analog acitretin: it stimulated ADAM10 promoter activity with an EC(50) of 1.5 microM and led to an increase of mature ADAM10 protein that resulted in a two- to three-fold increase of the ratio between alpha- and beta-secretase activity in neuroblastoma cells. The alpha-secretase stimulation by acitretin was completely inhibited by the ADAM10-specific inhibitor GI254023X. Intracerebral injection of acitretin in APP/PS1-21 transgenic mice led to a reduction of Abeta(40) and Abeta(42). The results of this study may have clinical relevance because acitretin has been approved for the treatment of psoriasis since 1997 and found generally safe for long-term use in humans.

  7. Household Income and Preschool Attendance in China

    ERIC Educational Resources Information Center

    Gong, Xin; Xu, Di; Han, Wen-Jui

    2015-01-01

    This article draws upon the literature showing the benefits of high-quality preschools on child well-being to explore the role of household income on preschool attendance for a cohort of 3-to 6-year-olds in China using data from the China Health and Nutrition Survey, 1991-2006. Analyses are conducted separately for rural (N = 1,791) and urban…

  8. Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum.

    PubMed

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Duitman, Erwin; Brandt, Katja; Ludwig, Andreas; Hartmann, Dieter; Lemke, Greg; Saftig, Paul; Bulfone-Paus, Silvia

    2005-11-01

    Axl receptor tyrosine kinase exists as a transmembrane protein and as a soluble molecule. We show that constitutive and phorbol 12-myristate 13-acetate-induced generation of soluble Axl (sAxl) involves the activity of disintegrin-like metalloproteinase 10 (ADAM10). Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17. Furthermore, murine fibroblasts deficient in ADAM10 expression exhibited a significant reduction in constitutive and inducible Axl shedding, whereas reconstitution of ADAM10 restored sAxl production, suggesting that ADAM10-mediated proteolysis constitutes a major mechanism for sAxl generation in mice. Partially overlapping 14-amino-acid stretch deletions in the membrane-proximal region of Axl dramatically affected sAxl generation, indicating that these regions are involved in regulating the access of the protease to the cleavage site. Importantly, relatively high circulating levels of sAxl are present in mouse sera in a heterocomplex with Axl ligand Gas6. Conversely, two other family members, Tyro3 and Mer, were not detected in mouse sera and conditioned medium. sAxl is constitutively released by murine primary cells such as dendritic and transformed cell lines. Upon immobilization, sAxl promoted cell migration and induced the phosphorylation of Axl and phosphatidylinositol 3-kinase. Thus, ADAM10-mediated generation of sAxl might play an important role in diverse biological processes.

  9. Soluble Axl Is Generated by ADAM10-Dependent Cleavage and Associates with Gas6 in Mouse Serum†

    PubMed Central

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Duitman, Erwin; Brandt, Katja; Ludwig, Andreas; Hartmann, Dieter; Lemke, Greg; Saftig, Paul; Bulfone-Paus, Silvia

    2005-01-01

    Axl receptor tyrosine kinase exists as a transmembrane protein and as a soluble molecule. We show that constitutive and phorbol 12-myristate 13-acetate-induced generation of soluble Axl (sAxl) involves the activity of disintegrin-like metalloproteinase 10 (ADAM10). Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17. Furthermore, murine fibroblasts deficient in ADAM10 expression exhibited a significant reduction in constitutive and inducible Axl shedding, whereas reconstitution of ADAM10 restored sAxl production, suggesting that ADAM10-mediated proteolysis constitutes a major mechanism for sAxl generation in mice. Partially overlapping 14-amino-acid stretch deletions in the membrane-proximal region of Axl dramatically affected sAxl generation, indicating that these regions are involved in regulating the access of the protease to the cleavage site. Importantly, relatively high circulating levels of sAxl are present in mouse sera in a heterocomplex with Axl ligand Gas6. Conversely, two other family members, Tyro3 and Mer, were not detected in mouse sera and conditioned medium. sAxl is constitutively released by murine primary cells such as dendritic and transformed cell lines. Upon immobilization, sAxl promoted cell migration and induced the phosphorylation of Axl and phosphatidylinositol 3-kinase. Thus, ADAM10-mediated generation of sAxl might play an important role in diverse biological processes. PMID:16227584

  10. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

    PubMed Central

    Saha, Nayanendu; Eissman, Moritz F.; Xu, Kai; Llerena, Carmen; Kusebauch, Ulrike; Ding, Bi-Sen; Cao, Zhongwei; Rafii, Shahin; Ernst, Matthias; Scott, Andrew M.; Nikolov, Dimitar B.; Lackmann, Martin

    2016-01-01

    The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance. PMID:27503072

  11. A Staphylococcus aureus Pore-Forming Toxin Subverts the Activity of ADAM10 to Cause Lethal Infection

    PubMed Central

    Inoshima, Ichiro; Inoshima, Naoko; Wilke, Georgia; Powers, Michael; Frank, Karen; Wang, Yang; Wardenburg, Juliane Bubeck

    2011-01-01

    Staphylococcus aureus is a major cause of human disease, responsible for half a million infections and approximately 20,000 deaths per year in the United States alone 1,2. This pathogen secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia 3–5. α-hemolysin injures epithelial cells by interacting with its receptor, the zinc-dependent metalloprotease ADAM10 6. We show that mice harboring a conditional disruption of the Adam10 gene in lung epithelium are resistant to lethal pneumonia. Investigation of the molecular mechanism of toxin-receptor function revealed that α-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage is associated with disruption of epithelial barrier function, contributing to the pathogenesis of lethal acute lung injury. A metalloprotease inhibitor of ADAM10 prevents E-cadherin cleavage; similarly, E-cadherin proteolysis and barrier disruption is attenuated in ADAM10 knockout mice. Together, these data attest to the function of ADAM10 as the cellular receptor for α-hemolysin. The observation that Hla can usurp the metalloprotease activity of its receptor reveals a novel mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury, and defines ADAM10 inhibition as a strategy for disease modification. PMID:21926978

  12. ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site

    PubMed Central

    Le Gall, Sylvain M.; Maretzky, Thorsten; Issuree, Priya D. A.; Niu, Xiao-Da; Reiss, Karina; Saftig, Paul; Khokha, Rama; Lundell, Daniel; Blobel, Carl P.

    2010-01-01

    Protein ectodomain shedding is crucial for cell–cell interactions because it controls the bioavailability of soluble tumor necrosis factor-α (TNFα) and ligands of the epidermal growth factor (EGF) receptor, and the release of many other membrane proteins. Various stimuli can rapidly trigger ectodomain shedding, yet much remains to be learned about the identity of the enzymes that respond to these stimuli and the mechanisms underlying their activation. Here, we demonstrate that the membrane-anchored metalloproteinase ADAM17, but not ADAM10, is the sheddase that rapidly responds to the physiological signaling pathways stimulated by thrombin, EGF, lysophosphatidic acid and TNFα. Stimulation of ADAM17 is swift and quickly reversible, and does not depend on removal of its inhibitory pro-domain by pro-protein convertases, or on dissociation of an endogenous inhibitor, TIMP3. Moreover, activation of ADAM17 by physiological stimuli requires its transmembrane domain, but not its cytoplasmic domain, arguing against inside–out signaling via cytoplasmic phosphorylation as the underlying mechanism. Finally, experiments with the tight binding hydroxamate inhibitor DPC333, used here to probe the accessibility of the active site of ADAM17, demonstrate that this inhibitor can quickly bind to ADAM17 in stimulated, but not quiescent cells. These findings support the concept that activation of ADAM17 involves a rapid and reversible exposure of its catalytic site. PMID:20980382

  13. MiR-153 inhibits migration and invasion of human non-small-cell lung cancer by targeting ADAM19

    SciTech Connect

    Shan, Nianxi; Shen, Liangfang; Wang, Jun; He, Dan; Duan, Chaojun

    2015-01-02

    Highlights: • Decreased miR-153 and up-regulated ADAM19 are correlated with NSCLC pathology. • MiR-153 inhibits the proliferation and migration and invasion of NSCLC cells in vitro. • ADAM19 is a direct target of miR-153. • ADAM19 is involved in miR-153-suppressed migration and invasion of NSCLC cells. - Abstract: MiR-153 was reported to be dysregulated in some human cancers. However, the function and mechanism of miR-153 in lung cancer cells remains unknown. In this study, we investigated the role of miR-153 in human non-small-cell lung cancer (NSCLC). Using qRT-PCR, we demonstrated that miR-153 was significantly decreased in clinical NSCLC tissues and cell lines, and downregulation of miR-153 was significantly correlated with lymph node status. We further found that ectopic expression of miR-153 significantly inhibited the proliferation and migration and invasion of NSCLC cells in vitro, suggesting that miR-153 may be a novel tumor suppressor in NSCLC. Further integrated analysis revealed that ADAM19 is as a direct and functional target of miR-153. Luciferase reporter assay demonstrated that miR-153 directly targeted 3′UTR of ADAM19, and correlation analysis revealed an inverse correlation between miR-153 and ADAM19 mRNA levels in clinical NSCLC tissues. Knockdown of ADAM19 inhibited migration and invasion of NSCLC cells which was similar with effects of overexpression of miR-153, while overexpression of ADAM19 attenuated the function of miR-153 in NSCLC cells. Taken together, our results highlight the significance of miR-153 and ADAM19 in the development and progression of NSCLC.

  14. ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins.

    PubMed

    Fröhlich, Camilla; Klitgaard, Marie; Noer, Julie B; Kotzsch, Alexander; Nehammer, Camilla; Kronqvist, Pauliina; Berthelsen, Jens; Blobel, Carl; Kveiborg, Marie; Albrechtsen, Reidar; Wewer, Ulla M

    2013-05-15

    ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.

  15. A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion.

    PubMed

    Rao, V H; Kandel, A; Lynch, D; Pena, Z; Marwaha, N; Deng, C; Watson, P; Hansen, L A

    2012-06-07

    Increased activation of epidermal growth factor receptor (EGFR) family members such as HER2/Erbb2 can result in more aggressive disease, resistance to chemotherapy and reduced survival of head and neck squamous cell carcinoma (HNSCC) patients. In order to identify mechanisms through which these receptor tyrosine kinases accelerate tumor progression, the regulation of metalloprotease expression by EGFR family members was investigated in 11 squamous cell carcinoma (SCC) cell lines. HER2 expression was significantly correlated with ADAM12 (A Disintegrin And Metalloprotease 12) expression in these cell lines and was co-expressed in human head and neck cancers. Inhibition of HER2 or EGFR decreased ADAM12 transcripts whereas HER2 transfection upregulated ADAM12 expression. To understand the molecular mechanisms underlying HER2 regulation of ADAM12, we investigated the signaling pathways directing ADAM12 production in SCC cells. Inhibition of phosphatidyl inositol-3-kinase or mammalian target of rapamycin decreased ADAM12 transcripts in HER2-expressing SCC cells, whereas transfection with AKT increased ADAM12 mRNA. Experiments utilizing ADAM12 transfection or siRNA targeting of ADAM12 revealed that the protease increased both the migration and invasiveness of oral SCC cells. Surprisingly, ADAM12 also increased HER2 message, protein levels and activity through an Ets1-dependent mechanism. Collectively, these results reveal a novel positive activation loop between ADAM12 and HER2 that may contribute to HNSCC progression.

  16. ADAM12 localizes with c-Src to actin-rich structures at the cell periphery and regulates Src kinase activity.

    PubMed

    Stautz, Dorte; Sanjay, Archana; Hansen, Matilde Thye; Albrechtsen, Reidar; Wewer, Ulla M; Kveiborg, Marie

    2010-01-01

    ADAM12 is an active metalloprotease playing an important role in tumour progression. Human ADAM12 exists in two splice variants: a long transmembrane form, ADAM12-L, and a secreted form, ADAM12-S. The subcellular localization of ADAM12-L is tightly regulated and involves intracellular interaction partners and signalling proteins. We demonstrate here a c-Src-dependent redistribution of ADAM12-L from perinuclear areas to actin-rich Src-positive structures at the cell periphery, and identified two separate c-Src binding sites in the cytoplasmic tail of ADAM12-L that interact with the SH3 domain of c-Src with different binding affinities. The association between ADAM12-L and c-Src is transient, but greatly stabilized when the c-Src kinase activity is disrupted. In agreement with this observation, kinase-active forms of c-Src induce ADAM12-L tyrosine phosphorylation. Interestingly, ADAM12-L was also found to enhance Src kinase activity in response to external signals, such as integrin engagement. Thus, we suggest that activated c-Src binds, phosphorylates, and redistributes ADAM12-L to specific sites at the cell periphery, which may in turn promote signalling mechanisms regulating cellular processes with importance in cancer.

  17. Extraction and Separation Modeling of Orion Test Vehicles with ADAMS Simulation

    NASA Technical Reports Server (NTRS)

    Fraire, Usbaldo, Jr.; Anderson, Keith; Cuthbert, Peter A.

    2013-01-01

    The Capsule Parachute Assembly System (CPAS) project has increased efforts to demonstrate the performance of fully integrated parachute systems at both higher dynamic pressures and in the presence of wake fields using a Parachute Compartment Drop Test Vehicle (PCDTV) and a Parachute Test Vehicle (PTV), respectively. Modeling the extraction and separation events has proven challenging and an understanding of the physics is required to reduce the risk of separation malfunctions. The need for extraction and separation modeling is critical to a successful CPAS test campaign. Current PTV-alone simulations, such as Decelerator System Simulation (DSS), require accurate initial conditions (ICs) drawn from a separation model. Automatic Dynamic Analysis of Mechanical Systems (ADAMS), a Commercial off the Shelf (COTS) tool, was employed to provide insight into the multi-body six degree of freedom (DOF) interaction between parachute test hardware and external and internal forces. Components of the model include a composite extraction parachute, primary vehicle (PTV or PCDTV), platform cradle, a release mechanism, aircraft ramp, and a programmer parachute with attach points. Independent aerodynamic forces were applied to the mated test vehicle/platform cradle and the separated test vehicle and platform cradle. The aero coefficients were determined from real time lookup tables which were functions of both angle of attack ( ) and sideslip ( ). The atmospheric properties were also determined from a real time lookup table characteristic of the Yuma Proving Grounds (YPG) atmosphere relative to the planned test month. Representative geometries were constructed in ADAMS with measured mass properties generated for each independent vehicle. Derived smart separation parameters were included in ADAMS as sensors with defined pitch and pitch rate criteria used to refine inputs to analogous avionics systems for optimal separation conditions. Key design variables were dispersed in a Monte

  18. A disintegrin and metalloproteinase 12 (ADAM12) localizes to invasive trophoblast, promotes cell invasion and directs column outgrowth in early placental development.

    PubMed

    Aghababaei, M; Perdu, S; Irvine, K; Beristain, A G

    2014-03-01

    During pregnancy, stromal- and vascular-remodeling trophoblasts serve critical roles in directing placental development acquiring pro-invasive characteristics. The A Disintegrin and Metalloproteinase (ADAM) family of multifunctional proteins direct cellular processes across multiple organ systems via their intrinsic catalytic, cell adhesive and intracellular signaling properties. ADAM12, existing as two distinct splice variants (ADAM12L and ADAM12S), is highly expressed in the human placenta and promotes cell migration and invasion in several tumor cell lines; however, its role in trophoblast biology is unknown. In this study, ADAM12 was localized to anchoring trophoblast columns in first trimester placentas and to highly invasive extracellular matrix-degrading trophoblasts in placental villous explants. The importance of ADAM12 in directing trophoblast invasion was tested using loss-of and gain-of-function strategies, where siRNA-directed knockdown of ADAM12 inhibited trophoblast cell invasion while over-expression promoted migration and invasion in two trophoblastic cell models. In placental villous explant cultures, siRNA-directed loss of ADAM12 significantly dampened trophoblast column outgrowth. Additionally, we provide functional evidence for the ADAM12S variant in promoting trophoblast invasion and column outgrowth through a mechanism requiring its catalytic activity. This is the first study to assign a function for ADAM12 in trophoblast biology, where ADAM12 may play a central role regulating the behavior of invasive trophoblast subsets in early pregnancy. This study also underlines the importance of ADAM12L and ADAM12S in directing cell motility in normal developmental processes outside of cancer, specifically highlighting a potentially important function of ADAM12S in directing early placental development.

  19. Should We Bother Improving Students' Attendance at Seminars?

    ERIC Educational Resources Information Center

    Gbadamosi, Gbolahan

    2015-01-01

    This study uses action research intervention to improve students' attendance at seminars. Specifically, the study asks the question: will students' attendance improve if they drive their own learning by running their own seminars? Records of lecture and seminar attendance at a module and comparative ones were used. Focus group interviews provided…

  20. 38 CFR 21.374 - Authorization for travel of attendants.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2013-07-01 2013-07-01 false Authorization for travel... 38 U.S.C. Chapter 31 Interregional and Intraregional Travel of Veterans § 21.374 Authorization for travel of attendants. (a) Travel for attendants. The services of an attendant to accompany a...

  1. 38 CFR 21.374 - Authorization for travel of attendants.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2014-07-01 2014-07-01 false Authorization for travel... 38 U.S.C. Chapter 31 Interregional and Intraregional Travel of Veterans § 21.374 Authorization for travel of attendants. (a) Travel for attendants. The services of an attendant to accompany a...

  2. 38 CFR 21.374 - Authorization for travel of attendants.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Authorization for travel... 38 U.S.C. Chapter 31 Interregional and Intraregional Travel of Veterans § 21.374 Authorization for travel of attendants. (a) Travel for attendants. The services of an attendant to accompany a...

  3. 38 CFR 21.374 - Authorization for travel of attendants.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false Authorization for travel... 38 U.S.C. Chapter 31 Interregional and Intraregional Travel of Veterans § 21.374 Authorization for travel of attendants. (a) Travel for attendants. The services of an attendant to accompany a...

  4. 38 CFR 21.374 - Authorization for travel of attendants.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Authorization for travel... 38 U.S.C. Chapter 31 Interregional and Intraregional Travel of Veterans § 21.374 Authorization for travel of attendants. (a) Travel for attendants. The services of an attendant to accompany a...

  5. Interpreting the Influence of Community College Attendance upon Baccalaureate Attainment

    ERIC Educational Resources Information Center

    Townsend, Barbara K.

    2007-01-01

    National quantitative studies examining the impact of community college attendance upon educational attainment conclude that initial attendance at a community college (as opposed to a 4-year institution) reduces the likelihood of attaining a bachelor's degree. Yet these studies, which suggest that initial attendance at a community college is not a…

  6. Positively essential: traditional birth attendants in Malawi.

    PubMed

    Stronge, Shirley

    2011-06-01

    One of the biggest challenges for healthcare professionals working in developing countries is the lack of trained personnel to carry out much needed health care provision. Shirley Stronge worked as a nurse/midwife tutor in a rural area in the north of Malawi. Millennium Development Goals four and five have focused our attention on the care required by mothers and newborns. Shirley has chosen to reflect on the role of Traditional Birth Attendants in the north of Malawi and their positive impact on maternity services in this area.

  7. A Comparison of Sexual Minority Youth Who Attend Religiously Affiliated Schools and Their Nonreligious-School-Attending Counterparts

    ERIC Educational Resources Information Center

    Stewart, Brandon T.; Heck, Nicholas C.; Cochran, Bryan N.

    2015-01-01

    Sexual minority youth are an at-risk group for negative health outcomes. The present study compares descriptive characteristics and outness of sexual minority youth who attend religious schools to sexual minorities who do not attend religious schools, and also investigates if attending religiously affiliated schools is associated with levels of…

  8. Class Attendance in College: A Meta-Analytic Review of the Relationship of Class Attendance with Grades and Student Characteristics

    ERIC Educational Resources Information Center

    Crede, Marcus; Roch, Sylvia G.; Kieszczynka, Urszula M.

    2010-01-01

    A meta-analysis of the relationship between class attendance in college and college grades reveals that attendance has strong relationships with both class grades (k = 69, N = 21,195, p = 0.44) and GPA (k = 33, N = 9,243, p = 0.41). These relationships make class attendance a better predictor of college grades than any other known predictor of…

  9. Increasing Attendance for Psychotherapy: Implementation Intentions and the Self-Regulation of Attendance-Related Negative Affect

    ERIC Educational Resources Information Center

    Sheeran, Paschal; Aubrey, Richard; Kellett, Stephen

    2007-01-01

    The present study evaluated an implementation intention intervention that aimed to increase attendance at scheduled, initial appointments for psychotherapy by helping clients to manage negative feelings about attendance. Participants received a postal questionnaire that measured their views about attending psychotherapy. One half of the sample was…

  10. α-Lipoic acid reduces neurogenic hypertension by blunting oxidative stress-mediated increase in ADAM17

    PubMed Central

    de Queiroz, Thyago M.; Xia, Huijing; Filipeanu, Catalin M.; Braga, Valdir A.

    2015-01-01

    We previously reported that type 2 angiotensin-converting enzyme (ACE2) compensatory activity is impaired by the disintegrin and metalloprotease 17 (ADAM17), and lack of ACE2 is associated with oxidative stress in neurogenic hypertension. To investigate the relationship between ADAM17 and oxidative stress, Neuro2A cells were treated with ANG II (100 nM) 24 h after vehicle or α-lipoic acid (LA, 500 μM). ADAM17 expression was increased by ANG II (120.5 ± 9.1 vs. 100.2 ± 0.8%, P < 0.05) and decreased after LA (69.0 ± 0.3 vs. 120.5 ± 9.1%, P < 0.05). In another set of experiments, LA reduced ADAM17 (92.9 ± 5.3 vs. 100.0 ± 11.2%, P < 0.05) following its overexpression. Moreover, ADAM17 activity was reduced by LA in ADAM17-overexpressing cells [109.5 ± 19.8 vs. 158.0 ± 20.0 fluorescence units (FU)·min−1·μg protein−1, P < 0.05], in which ADAM17 overexpression increased oxidative stress (114.1 ± 2.5 vs. 101.0 ± 1.0%, P < 0.05). Conversely, LA-treated cells attenuated ADAM17 overexpression-induced oxidative stress (76.0 ± 9.1 vs. 114.1 ± 2.5%, P < 0.05). In deoxycorticosterone acetate (DOCA)-salt hypertensive mice, a model in which ADAM17 expression and activity are increased, hypertension was blunted by pretreatment with LA (119.0 ± 2.4 vs. 131.4 ± 2.2 mmHg, P < 0.05). In addition, LA improved dysautonomia and baroreflex sensitivity. Furthermore, LA blunted the increase in NADPH oxidase subunit expression, as well as the increase in ADAM17 and decrease in ACE2 activity in the hypothalamus of DOCA-salt hypertensive mice. Taken together, these data suggest that LA might preserve ACE2 compensatory activity by breaking the feedforward cycle between ADAM17 and oxidative stress, resulting in a reduction of neurogenic hypertension. PMID:26254330

  11. ADaM: augmenting existing approximate fast matching algorithms with efficient and exact range queries

    PubMed Central

    2014-01-01

    Background Drug discovery, disease detection, and personalized medicine are fast-growing areas of genomic research. With the advancement of next-generation sequencing techniques, researchers can obtain an abundance of data for many different biological assays in a short period of time. When this data is error-free, the result is a high-quality base-pair resolution picture of the genome. However, when the data is lossy the heuristic algorithms currently used when aligning next-generation sequences causes the corresponding accuracy to drop. Results This paper describes a program, ADaM (APF DNA Mapper) which significantly increases final alignment accuracy. ADaM works by first using an existing program to align "easy" sequences, and then using an algorithm with accuracy guarantees (the APF) to align the remaining sequences. The final result is a technique that increases the mapping accuracy from only 60% to over 90% for harder-to-align sequences. PMID:25079667

  12. ADAM10 Mediates Vascular Injury Induced by Staphylococcus aureus α-Hemolysin

    PubMed Central

    Powers, Michael E.; Kim, Hwan Keun; Wang, Yang

    2012-01-01

    Staphylococcus aureus is a leading cause of bacteremia and sepsis. The interaction of S. aureus with the endothelium is central to bloodstream infection pathophysiology yet remains ill-understood. We show herein that staphylococcal α-hemolysin, a pore-forming cytotoxin, is required for full virulence in a murine sepsis model. The α-hemolysin binding to its receptor A-disintegrin and metalloprotease 10 (ADAM10) upregulates the receptor’s metalloprotease activity on endothelial cells, causing vascular endothelial–cadherin cleavage and concomitant loss of endothelial barrier function. These cellular injuries and sepsis severity can be mitigated by ADAM10 inhibition. This study therefore provides mechanistic insight into toxin-mediated endothelial injury and suggests new therapeutic approaches for staphylococcal sepsis. PMID:22474035

  13. Adam M. Grant: Award for Distinguished Scientific Early Career Contributions to Psychology.

    PubMed

    2011-11-01

    Presents Adam M. Grant, the 2011 winner of the American Psychological Association Award for Distinguished Scientific Early Career Contributions to Psychology. "For extensive, elegant, and programmatic research on the power of relational job design in enhancing employee motivation, productivity, and satisfaction; for creative and rigorous studies documenting the profound and surprising effects of connecting employees to their impact on others; for highlighting prosocial motivation, not only extrinsic and intrinsic motivations, as a key force behind employee behavior; and for demonstrating by example the feasibility and benefits of conducting field experiments, yielding studies rich in internal validity, external validity, and practical impact. In addition to his accomplishments, Adam M. Grant is known for his generosity as a scholar, teacher, and colleague." (PsycINFO Database Record (c) 2011 APA, all rights reserved).

  14. Tetraspanin-8 promotes hepatocellular carcinoma metastasis by increasing ADAM12m expression

    PubMed Central

    Wang, Yanru; Chen, Guangnan; Huang, Jing; Chen, Jie; Zhao, Yan; Sun, Ruixia; Liang, Chunmin; Liu, Binbin

    2016-01-01

    Recent evidence indicates that tetraspanin-8 (TSPAN8) promotes tumor progression and metastasis. In this study, we explored the effects of TSPAN8 and the molecular mechanisms underlying hepatocellular carcinoma (HCC) metastasis using various HCC cell lines, tissues from 149 HCC patients, and animal models of HCC progression. We showed that elevated expression of TSPAN8 promoted HCC invasion in vitro and metastasis in vivo, but did not influence HCC cell proliferation in vitro. Increased TSPAN8 expression in human HCC was predictive of poor survival, and multivariate analyses indicated TSPAN8 expression to be an independent predictor for both postoperative overall survival and relapse-free survival. Importantly, TSPAN8 enhanced HCC invasion and metastasis by increasing ADAM12m expression. We therefore conclude that TSPAN8 and ADAM12m may be useful therapeutic targets for the prevention of HCC progression and metastasis. PMID:27270327

  15. Disintegrin Metalloprotease (ADAM) 10 Regulates Endothelial Permeability and T Cell Transmigration by Proteolysis of Vascular Endothelial Cadherin

    PubMed Central

    Schulz, Beate; Pruessmeyer, Jessica; Maretzky, Thorsten; Ludwig, Andreas; Blobel, Carl P.; Saftig, Paul; Reiss, Karina

    2009-01-01

    Vascular endothelial (VE)-cadherin is the major adhesion molecule of endothelial adherens junctions. It plays an essential role in controlling endothelial permeability, vascular integrity, leukocyte transmigration, and angiogenesis. Elevated levels of soluble VE-cadherin are associated with diseases like coronary atherosclerosis. Previous data showed that the extracellular domain of VE-cadherin is released by an unknown metalloprotease activity during apoptosis. In this study, we used gain of function analyses, inhibitor studies and RNA interference experiments to analyze the proteolytic release of VE-cadherin in human umbilical vein endothelial cells (HUVECs). We found that VE-cadherin is specifically cleaved by the disintegrin and metalloprotease ADAM10 in its ectodomain releasing a soluble fragment and generating a carboxyterminal membrane bound stub, which is a substrate for a subsequent γ-secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca2+-influx and staurosporine treatment, indicating that ADAM10-mediated VE-cadherin cleavage contributes to the dissolution of adherens junctions during endothelial cell activation and apoptosis, respectively. In contrast, protein kinase C activation or inhibition did not modulate VE-cadherin processing. Increased ADAM10 expression was functionally associated with an increase in endothelial permeability. Remarkably, our data indicate that ADAM10 activity also contributes to the thrombin-induced decrease of endothelial cell-cell adhesion. Moreover, knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impaired T cell transmigration. Taken together our data identify ADAM10 as a novel regulator of vascular permeability and demonstrate a hitherto unknown function of ADAM10 in the regulation of VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration. PMID:18420943

  16. Serological immune response against ADAM10 pro-domain is associated with favourable prognosis in stage III colorectal cancer patients

    PubMed Central

    Álvarez-Fernández, Sheila María; Barbariga, Marco; Cannizzaro, Luca; Cannistraci, Carlo Vittorio; Hurley, Laura; Zanardi, Alan; Conti, Antonio; Sanvito, Francesca; Innocenzi, Anna; Pecorelli, Nicolò; Braga, Marco; Alessio, Massimo

    2016-01-01

    A humoral immune response against aberrant tumor proteins can be elicited in cancer patients, resulting in the production of auto-antibodies (Abs). By serological proteome analysis we identified the surface membrane protein ADAM10, a metalloproteinase that has a role in epithelial-tumor progression and invasion, as a target of the immune response in colorectal cancer (Crc). A screening carried out on the purified protein using testing cohorts of sera (Crc patients n = 57; control subjects n = 39) and validation cohorts of sera (Crc patients n = 49; control subjects n = 52) indicated that anti-ADAM10 auto-Abs were significantly induced in a large group (74%) of colon cancer patients, in particular in patients at stage II and III of the disease. Interestingly, in Crc patients classified as stage III disease, the presence of anti-ADAM10 auto-Abs in the sera was associated with a favourable follow-up with a significant shifting of the recurrence-free survival median time from 23 to 55 months. Even though the ADAM10 protein was expressed in Crc regardless the presence of auto-Abs, the immature/non-functional isoform of ADAM10 was highly expressed in the tumor of anti-ADAM10-positive patients and was the isoform targeted by the auto-Abs. In conclusion, the presence of anti-ADAM10 auto-Abs seems to reflect the increased tumor expression of the immunogenic immature-ADAM10 in a group of Crc patients, and is associated with a favourable prognosis in patients at stage III of the disease. PMID:27517630

  17. Lysophosphatidic acid-induced ADAM12 expression mediates human adipose tissue-derived mesenchymal stem cell-stimulated tumor growth.

    PubMed

    Do, Eun Kyoung; Kim, Young Mi; Heo, Soon Chul; Kwon, Yang Woo; Shin, Sang Hun; Suh, Dong-Soo; Kim, Ki-Hyung; Yoon, Man-Soo; Kim, Jae Ho

    2012-11-01

    Lysophosphatidic acid (LPA) is involved in mesenchymal stem cell-stimulated tumor growth in vivo. However, the molecular mechanism by which mesenchymal stem cells promote tumorigenesis remains elusive. In the present study, we demonstrate that conditioned medium from A549 human lung adenocarcinoma cells (A549 CM) induced the expression of ADAM12, a disintegrin and metalloproteases family member, in human adipose tissue-derived mesenchymal stem cells (hASCs). A549 CM-stimulated ADAM12 expression was abrogated by pretreatment of hASCs with the LPA receptor 1 inhibitor Ki16425 or by small interfering RNA-mediated silencing of LPA receptor 1, suggesting a key role for the LPA-LPA receptor 1 signaling axis in A549 CM-stimulated ADAM12 expression. Silencing of ADAM12 expression using small interfering RNA or short hairpin RNA abrogated LPA-induced expression of both α-smooth muscle actin, a marker of carcinoma-associated fibroblasts, and ADAM12 in hASCs. Using a xenograft transplantation model of A549 cells, we demonstrated that silencing of ADAM12 inhibited the hASC-stimulated in vivo growth of A549 xenograft tumors and the differentiation of transplanted hASCs to α-smooth muscle actin-positive carcinoma-associated fibroblasts. LPA-conditioned medium from hASCs induced the adhesion of A549 cells and silencing of ADAM12 inhibited LPA-induced expression of extracellular matrix proteins, periostin and βig-h3, in hASCs and LPA-conditioned medium-stimulated adhesion of A549 cells. These results suggest a pivotal role for LPA-stimulated ADAM12 expression in tumor growth and the differentiation of hASCs to carcinoma-associated fibroblasts expressing α-smooth muscle actin, periostin, and βig-h3.

  18. Rival ecologies of global commerce: Adam Smith and the natural historians.

    PubMed

    Jonsson, Fredrik Albritton

    2010-01-01

    This essay explores how the defense of global commerce pioneered in the Enlightenment was tied to the improvement of the natural order. Two rival ecologies, one made by natural historians and the other developed by Adam Smith and his liberal successors, vied for intellectual precedence as well as for practical application in the metropole and the colonies. Together they constitute the beginnings of an ongoing quarrel over the environmental foundation of capitalism.

  19. Geochemical survey of the Adams Gap and Shinbone Creek Roadless Areas, Clay County, Alabama

    USGS Publications Warehouse

    Robinson, G.R.; Klein, T.L.; Lesure, F.G.; Hanley, J.T.

    1984-01-01

    Reports covering the mineral resources of Clay County and vicinity include Brewer (1896) and Adams (1930) on gold, Prouty (1923) on graphite, and Heinrich and Olson (1953) on mica. The mineral resources of the Talladega National Forest were evaluated by Gilbert and Smith (1973). The mineral resource potential of the two roadless areas is detailed in Robinson and others (1983) and an accompanying geologic report is given in Robinson and others (in press).

  20. Museum Quality: A New Museum and Recharged College Bring Creative Energy to North Adams, Massachusetts

    ERIC Educational Resources Information Center

    Grant, Mary

    2005-01-01

    Nestled in the valley between the Berkshire hills and the Taconic range, North Adams, Massachusetts, in many ways is typical of old New England mill towns working hard to create a new identity in the global economy. When Sprague Electric left town in 1985, the city of 16,000 reeled from the loss of 4,000 blue-collar jobs. This article describes…

  1. Melittin Modulates Keratinocyte Function through P2 Receptor-dependent ADAM Activation*

    PubMed Central

    Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch-Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina

    2012-01-01

    Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-α, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent. PMID:22613720

  2. IL-1β and ADAM17 are central regulators of β-defensin expression in Candida esophagitis.

    PubMed

    Pahl, Rene; Brunke, Gabriele; Steubesand, Nadine; Schubert, Sabine; Böttner, Martina; Wedel, Thilo; Jürgensen, Christian; Hampe, Jochen; Schäfer, Heiner; Zeissig, Sebastian; Schreiber, Stefan; Rosenstiel, Philip; Reiss, Karina; Arlt, Alexander

    2011-04-01

    Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions, it may cause life-threatening infections, including Candida sepsis. We have recently shown that human β-defensins (hBDs) hBD-2 and hBD-3 are upregulated in Candida esophagitis and that this antifungal host response is distinctly regulated by NF-κB and MAPK/activator protein-1 (AP-1) pathways. Here, we show that C. albicans induces hBD-2 through an autocrine IL-1β loop and that activation of the epidermal growth factor receptor (EGFR) by endogenous transforming growth factor-α (TGF-α) is a crucial event in the induction of hBD-3. To further dissect upstream signaling events, we investigated expression of the central sheddases for EGFR ligands ADAM10 and ADAM17 in the healthy and infected esophagus. Next, we used pharmaceutical inhibitors and small-interfering RNA-mediated knock down of ADAM10 and ADAM17 to reveal that ADAM17-induced shedding of TGF-α is a crucial step in the induction of hBD-3 expression in response to Candida infection. In conclusion, we describe for the first time an autocrine IL-1β loop responsible for the induction of hBD-2 expression and an ADAM17-TGF-α-EGFR-MAPK/AP-1 pathway leading to hBD-3 upregulation in the course of a Candida infection of the esophagus.

  3. Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

    PubMed Central

    Wang, Xiang; Bosonea, Ana-Maria; Odenbach, Jeffrey; Fernandez-Patron, Carlos

    2014-01-01

    Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists. Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca2+ release from intracellular stores, Ca2+ uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and ‘a disintegrin and metalloproteinases’ (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease. PMID:24976815

  4. Recombinant disintegrin domain of human ADAM9 inhibits migration and invasion of DU145 prostate tumor cells

    PubMed Central

    Martin, Ana Carolina Baptista Moreno; Cardoso, Ana Carolina Ferreira; Selistre-de-Araujo, Heloisa Sobreiro; Cominetti, Márcia Regina

    2015-01-01

    One of the most important features of malignant cells is their capacity to invade adjacent tissues and metastasize to distant organs. This process involves the creation, by tumor and stroma cells, of a specific microenvironment, suitable for proliferation, migration and invasion of tumor cells. The ADAM family of proteins has been involved in these processes. This work aimed to investigate the role of the recombinant disintegrin domain of the human ADAM9 (rADAM9D) on the adhesive and mobility properties of DU145 prostate tumor cells. rADAM9D was able to support DU145 cell adhesion, inhibit the migration of DU145 cells, as well as the invasion of this cell line through matrigel in vitro. Overall this work demonstrates that rADAM9D induces specific cellular migratory properties when compared with different constructs having additional domains, specially those of metalloproteinase and cysteine-rich domains. Furthermore, we showed that rADAM9D was able to inhibit cell adhesion, migration and invasion mainly through interacting with α6β1 in DU145 tumor cell line. These results may contribute to the development of new therapeutic strategies for prostate cancer. PMID:26211476

  5. ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor α

    PubMed Central

    Le Gall, Sylvain M.; Bobé, Pierre; Reiss, Karina; Horiuchi, Keisuke; Niu, Xiao-Da; Lundell, Daniel; Gibb, David R.; Conrad, Daniel; Saftig, Paul

    2009-01-01

    Protein ectodomain shedding is a critical regulator of many membrane proteins, including epidermal growth factor receptor-ligands and tumor necrosis factor (TNF)-α, providing a strong incentive to define the responsible sheddases. Previous studies identified ADAM17 as principal sheddase for transforming growth factor (TGF)-α and heparin-binding epidermal growth factor, but Ca++ influx activated an additional sheddase for these epidermal growth factor receptor ligands in Adam17−/− cells. Here, we show that Ca++ influx and stimulation of the P2X7R signaling pathway activate ADAM10 as sheddase of many ADAM17 substrates in Adam17−/− fibroblasts and primary B cells. Importantly, although ADAM10 can shed all substrates of ADAM17 tested here in Adam17−/− cells, acute treatment of wild-type cells with a highly selective ADAM17 inhibitor (SP26) showed that ADAM17 is nevertheless the principal sheddase when both ADAMs 10 and 17 are present. However, chronic treatment of wild-type cells with SP26 promoted processing of ADAM17 substrates by ADAM10, thus generating conditions such as in Adam17−/− cells. These results have general implications for understanding the substrate selectivity of two major cellular sheddases, ADAMs 10 and 17. PMID:19158376

  6. The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function.

    PubMed

    Lovero, Kathryn L; Fukata, Yuko; Granger, Adam J; Fukata, Masaki; Nicoll, Roger A

    2015-07-28

    Synapse development is coordinated by a number of transmembrane and secreted proteins that come together to form synaptic organizing complexes. Whereas a variety of synaptogenic proteins have been characterized, much less is understood about the molecular networks that support the maintenance and functional maturation of nascent synapses. Here, we demonstrate that leucine-rich, glioma-inactivated protein 1 (LGI1), a secreted protein previously shown to modulate synaptic AMPA receptors, is a paracrine signal released from pre- and postsynaptic neurons that acts specifically through a disintegrin and metalloproteinase protein 22 (ADAM22) to set postsynaptic strength. We go on to describe a novel role for ADAM22 in maintaining excitatory synapses through PSD-95/Dlg1/zo-1 (PDZ) domain interactions. Finally, we show that in the absence of LGI1, the mature synapse scaffolding protein PSD-95, but not the immature synapse scaffolding protein SAP102, is unable to modulate synaptic transmission. These results indicate that LGI1 and ADAM22 form an essential synaptic organizing complex that coordinates the maturation of excitatory synapses by regulating the functional incorporation of PSD-95.

  7. ADAM33 polymorphisms are associated with asthma and a distinctive palm dermatoglyphic pattern

    PubMed Central

    XUE, WEILIN; HAN, WEI; ZHOU, ZHAO-SHAN

    2013-01-01

    A close correlation between asthma and palm dermatoglyphic patterns has been observed in previous studies, but the underlying genetic mechanisms have not been investigated. A disintegrin and metalloprotein-33 (ADAM33) polymorphisms are important in the development of asthma and other atopic diseases. To investigate the underlying mechanisms of the association between asthma and distinctive palm dermatoglyphic patterns, thirteen ADAM33 single-nucleotide polymorphisms (SNPs) were analyzed for the association between asthma and palm dermatoglyphic patterns in a population of 400 asthmatic patients and 200 healthy controls. Based on the results, five SNPs, rs44707 (codominant model, P=0.031; log-additive model, P=0.0084), rs2787094 (overdominant model, P=0.049), rs678881 (codominant model, P=0.028; overdominant model, P=0.0083), rs677044 (codominant model, P=0.013; log-additive model, P=0.0033) and rs512625 (dominant model, P=0.033), were associated with asthma in this population. Two SNPs, rs44707 (dominant model, P=0.042) and rs2787094 (codominant model, P=0.014; recessive model, P=0.0038), were observed in the asthma patients with the distinctive palm pattern. As rs44707 and rs2787094 are associated with asthma and a distinctive palm pattern, the data suggest that ADAM33 polymorphisms are correlated with asthma and may be the underlying genetic basis of the association between asthma and palm dermatoglyphic patterns. PMID:24141861

  8. Validation of the advanced dynamic anthropomorphic manikin (ADAM) database: horizontal sled test.

    PubMed

    Banks, D; Obergefell, L; Rizer, A

    1997-01-01

    As the U.S. Air Force (USAF) continues to introduce advanced technology to make its planes more dynamic, it is becoming increasingly more difficult to adequately test the systems to ensure pilot safety. A cost effective solution to this problem is the use of computer modeling to augment testing. The accuracy of such computer modeling depends on the validity of the analytical formulation, and the correctness of the database characterizing the systems being modeled. One such database is for the large Advanced Dynamic Anthropomorphic Manikin (ADAM); a human surrogate developed by the USAF for high speed ejection testing. The database is used in the Articulated Total Body (ATB) computer model utilized by the Armstrong Laboratories to predict human body dynamics during aircraft crashes and emergency escapes. The large ADAM database, and the parameters from a horizontal sled test were used in an ATB sled simulation. The results of the ATB simulation are compared with actual sled test data. These results include head, chest, and pelvis accelerations; neck and lumbar loads; and elbow, knee, hip and shoulder angular motion. The comparisons are the basis for validating the ADAM database for future predictive simulations.

  9. An evolutionary recent neuroepithelial cell adhesion function of huntingtin implicates ADAM10-Ncadherin.

    PubMed

    Lo Sardo, Valentina; Zuccato, Chiara; Gaudenzi, Germano; Vitali, Barbara; Ramos, Catarina; Tartari, Marzia; Myre, Michael A; Walker, James A; Pistocchi, Anna; Conti, Luciano; Valenza, Marta; Drung, Binia; Schmidt, Boris; Gusella, James; Zeitlin, Scott; Cotelli, Franco; Cattaneo, Elena

    2012-05-01

    The Huntington's disease gene product, huntingtin, is indispensable for neural tube formation, but its role is obscure. We studied neurulation in htt-null embryonic stem cells and htt-morpholino zebrafish embryos and found a previously unknown, evolutionarily recent function for this ancient protein. We found that htt was essential for homotypic interactions between neuroepithelial cells; it permitted neurulation and rosette formation by regulating metalloprotease ADAM10 activity and Ncadherin cleavage. This function was embedded in the N terminus of htt and was phenocopied by treatment of htt knockdown zebrafish with an ADAM10 inhibitor. Notably, in htt-null cells, reversion of the rosetteless phenotype occurred only with expression of evolutionarily recent htt heterologues from deuterostome organisms. Conversely, all of the heterologues that we tested, including htt from Drosophila melanogaster and Dictyostelium discoideum, exhibited anti-apoptotic activity. Thus, anti-apoptosis may have been one of htt’s ancestral function(s), but, in deuterostomes, htt evolved to acquire a unique regulatory activity for controlling neural adhesion via ADAM10-Ncadherin, with implications for brain evolution and development.

  10. iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.

    PubMed

    Brooke, Matthew A; Etheridge, Sarah L; Kaplan, Nihal; Simpson, Charlotte; O'Toole, Edel A; Ishida-Yamamoto, Akemi; Marches, Olivier; Getsios, Spiro; Kelsell, David P

    2014-08-01

    iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.

  11. Overexpression of the A Disintegrin and Metalloproteinase ADAM15 is linked to a Small but Highly Aggressive Subset of Prostate Cancers.

    PubMed

    Burdelski, Christoph; Fitzner, Michael; Hube-Magg, Claudia; Kluth, Martina; Heumann, Asmus; Simon, Ronald; Krech, Till; Clauditz, Till; Büscheck, Franziska; Steurer, Stefan; Wittmer, Corinna; Hinsch, Andrea; Luebke, Andreas M; Jacobsen, Frank; Minner, Sarah; Tsourlakis, Maria Christina; Beyer, Burkhard; Steuber, Thomas; Thederan, Imke; Sauter, Guido; Izbicki, Jakob; Schlomm, Thorsten; Wilczak, Waldemar

    2017-04-01

    The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions (P<.0001) but unrelated to deletions of 3p, 5q and 6q. In univariate analysis, high ADAM15 expression was strongly linked to PSA recurrence (P<.0001). However, in multivariate analyses this association was only maintained if the analysis was limited to preoperatively available parameters in ERG-negative cancers. The results of our study demonstrate that ADAM15 is strongly up regulated in a small but highly aggressive fraction of prostate cancers. In these tumors, ADAM15 may represent a suitable drug target. In a preoperative scenario, ADAM15 expression measurement may assist prognosis assessment, either alone or in combination with other markers.

  12. ADAM10 new selective inhibitors reduce NKG2D ligand release sensitizing Hodgkin lymphoma cells to NKG2D-mediated killing

    PubMed Central

    Zocchi, Maria Raffaella; Camodeca, Caterina; Nuti, Elisa; Rossello, Armando; Venè, Roberta; Tosetti, Francesca; Dapino, Irene; Costa, Delfina; Musso, Alessandra; Poggi, Alessandro

    2016-01-01

    ABSTRACT Hodgkin lymphoma (HL) resistant to conventional therapies is increasing, making of interest the search for new schemes of treatment. Members of the “A Disintegrin And Metalloproteases” (ADAMs) family, mainly ADAM10 or ADAM17, have been proposed as therapeutic targets in solid tumors and some ADAMs inhibitors have been shown to exert antitumor effects. We have previously described an overexpression of ADAM10 in HL, together with increased release of NKG2D ligands (NKG2D-L) and reduced activation of effector T lymphocytes with anti-lymphoma capacity. Aim of the present work was to verify whether inhibition of ADAM10 in HL cells could restore the triggering of NKG2D-dependent anti-lymphoma T cell response. As no selective ADAM10 blockers have been reported so far, we synthesized the two hydroxamate compounds LT4 and MN8 with selectivity for ADAM10 over metalloproteases (MMPs), LT4 showing higher specificity for ADAM10 over ADAM17. We show that (i) HL lymph nodes (LN) and cultured HL cells express high levels of the mature active membrane form of ADAM10; (ii) ADAM10 is the major sheddase for the NKG2D-L in HL cells; (iii) the new LT4 and MN8 compounds strongly reduce the shedding of NKG2D-L by HL cell lines and enhance the binding of NKG2D receptor; (iv) of note, these new ADAM10 inhibitors increase the sensitivity of HL cell lines to NKG2D-dependent cell killing exerted by natural killer and γδ T cells. Overall, the biologic activity of LT4 and MN8 appears to be more potent than that of the commercial inhibitor GI254023X. PMID:27467923

  13. ADAM10 new selective inhibitors reduce NKG2D ligand release sensitizing Hodgkin lymphoma cells to NKG2D-mediated killing.

    PubMed

    Zocchi, Maria Raffaella; Camodeca, Caterina; Nuti, Elisa; Rossello, Armando; Venè, Roberta; Tosetti, Francesca; Dapino, Irene; Costa, Delfina; Musso, Alessandra; Poggi, Alessandro

    2016-05-01

    Hodgkin lymphoma (HL) resistant to conventional therapies is increasing, making of interest the search for new schemes of treatment. Members of the "A Disintegrin And Metalloproteases" (ADAMs) family, mainly ADAM10 or ADAM17, have been proposed as therapeutic targets in solid tumors and some ADAMs inhibitors have been shown to exert antitumor effects. We have previously described an overexpression of ADAM10 in HL, together with increased release of NKG2D ligands (NKG2D-L) and reduced activation of effector T lymphocytes with anti-lymphoma capacity. Aim of the present work was to verify whether inhibition of ADAM10 in HL cells could restore the triggering of NKG2D-dependent anti-lymphoma T cell response. As no selective ADAM10 blockers have been reported so far, we synthesized the two hydroxamate compounds LT4 and MN8 with selectivity for ADAM10 over metalloproteases (MMPs), LT4 showing higher specificity for ADAM10 over ADAM17. We show that (i) HL lymph nodes (LN) and cultured HL cells express high levels of the mature active membrane form of ADAM10; (ii) ADAM10 is the major sheddase for the NKG2D-L in HL cells; (iii) the new LT4 and MN8 compounds strongly reduce the shedding of NKG2D-L by HL cell lines and enhance the binding of NKG2D receptor; (iv) of note, these new ADAM10 inhibitors increase the sensitivity of HL cell lines to NKG2D-dependent cell killing exerted by natural killer and γδ T cells. Overall, the biologic activity of LT4 and MN8 appears to be more potent than that of the commercial inhibitor GI254023X.

  14. Taiwan cobra phospholipase A2 suppresses ERK-mediated ADAM17 maturation, thus reducing secreted TNF-α production in human leukemia U937 cells.

    PubMed

    Chen, Ying-Jung; Lin, Hui-Chen; Chen, Ku-Chung; Lin, Shinne-Ren; Cheng, Tian-Lu; Chang, Long-Sen

    2014-08-01

    The goal of this study was to explore the signaling pathway regulating the processing of proADAM17 into ADAM17 in Taiwan cobra phospholipase A2 (PLA2)-treated human leukemia U937 cells. PLA2 induced reactive oxygen species (ROS)-elicited p38 MAPK activation and ERK inactivation in U937 cells. Catalytically inactive bromophenacylated PLA2 (BPB-PLA2) and PLA2 mutants evoked Ca(2+)-mediated p38 MAPK activation, and the level of phosphorylated ERK remained unchanged. PLA2 treatment reduced mature ADAM17 expression and secreted TNF-α (sTNF-α) production. Co-treatment of SB202190 (p38 MAPK inhibitor) and catalytically inactive PLA2 increased ERK phosphorylation, ADAM17 maturation and sTNF-α production. Nevertheless, mRNA levels of ADAM17 and TNF-α were insignificantly altered after PLA2 and SB202190/BPB-PLA2 treatment. ADAM17 activity assay and knock-down of ADAM17 revealed that ADAM17 was involved in sTNF-α production. Restoration of ERK activation increased the processing of proADAM17 into ADAM17 in PLA2-treated cells, while inactivation of ERK reduced ADAM17 maturation in untreated and SB202190/BPB-PLA2-treated cells. Removal of cell surface heparan sulfate abrogated PLA2 and SB202190/BPB-PLA2 effect on ADAM17 maturation. Taken together, the present data reveal that PLA2 suppresses ERK-mediated ADAM17 maturation, thus reducing sTNF-α production in U937 cells. Moreover, the binding with heparan sulfate is crucial for the PLA2 effect.

  15. To Attend or Not To Attend: Guiding All Students in the Right Direction.

    ERIC Educational Resources Information Center

    Smith, Irving; Johnson, Robert E.

    2003-01-01

    Argues that a perpetual cycle of education deprivation is embedded in our educational system that forces some of the best students into a vocational education path that may not include attending college. Proposes that students must be educated early about the value of a college education and must be aware that they are making decisions with…

  16. [Association between polymorphism of ADAM33 gene and bronchial asthma in Mongolian population].

    PubMed

    Zhu, S F; Li, J G

    2016-09-20

    Objective: To investigate the different genotype and allele frequency distribution of ADAM33 gene T1, T2, V4, S2 sites Mongolian population, and discuss the relationship between ADAM33 gene polymorphism and bronchial asthma. Methods: From January 2014 to December 2015, a total of 180 cases of Mongolian patients with asthma were detected, compared with 186 cases of healthy Mongolian as controled and screening significant genes.Selected restriction fragment length polymorphism (PCR-RFLP) method to detected ADAM33 gene polymorphism.According to condition , the asthma group was divided into mild(n=83), medium group(n=47)and severe group(n=50). The distribution difference of different genotype and every genotype of V4 FEV1, eosinophils, IgE comparison were compared , and analysis their correlation. Results: In ADAM33 , the distribution of T1 sites (AA and AG genotypes) had statistical significance compared asthma group with control group(χ(2)=8.810, 8.294, P<0.05, OR=1.983, 0.500). The OR value of G allele was 0.580.The distribution of S2 site(CC genotype) had statistical significance(χ(2)=4.277, P<0.05), the OR value of G allele was 1.423.the distribution of V4 sites (GC and GG genotypes) had statistical significance between the two groups (χ(2)=7.880, 10.313, P<0.05), OR value was 0.459, 2.130, G allele OR value was 1.496.The distribution frequency difference of each genotype in V4 sites in mild, medium and severe group was statistically significant (χ(2)=16.049, P<0.05), and compared various genotypes of FEV1, IgE, the difference was statistically significant (P<0.05), for each genotype of T2 site in asthma group and the control group there was no statistically significant in the distribution (χ(2)=1.218, 0.248, 1.287, P>0.05). Conclusions: T1, V4, S2 locus polymorphism of ADAM33 gene may play a role in the Mongolian asthma population, and T2 locus polymorphism may has no relationship with Mongolian asthma patients.And the genotype polymorphism of V4 sites may

  17. Reliability evaluation of I-123 ADAM SPECT imaging using SPM software and AAL ROI methods

    NASA Astrophysics Data System (ADS)

    Yang, Bang-Hung; Tsai, Sung-Yi; Wang, Shyh-Jen; Su, Tung-Ping; Chou, Yuan-Hwa; Chen, Chia-Chieh; Chen, Jyh-Cheng

    2011-08-01

    The level of serotonin was regulated by serotonin transporter (SERT), which is a decisive protein in regulation of serotonin neurotransmission system. Many psychiatric disorders and therapies were also related to concentration of cerebral serotonin. I-123 ADAM was the novel radiopharmaceutical to image SERT in brain. The aim of this study was to measure reliability of SERT densities of healthy volunteers by automated anatomical labeling (AAL) method. Furthermore, we also used statistic parametric mapping (SPM) on a voxel by voxel analysis to find difference of cortex between test and retest of I-123 ADAM single photon emission computed tomography (SPECT) images.Twenty-one healthy volunteers were scanned twice with SPECT at 4 h after intravenous administration of 185 MBq of 123I-ADAM. The image matrix size was 128×128 and pixel size was 3.9 mm. All images were obtained through filtered back-projection (FBP) reconstruction algorithm. Region of interest (ROI) definition was performed based on the AAL brain template in PMOD version 2.95 software package. ROI demarcations were placed on midbrain, pons, striatum, and cerebellum. All images were spatially normalized to the SPECT MNI (Montreal Neurological Institute) templates supplied with SPM2. And each image was transformed into standard stereotactic space, which was matched to the Talairach and Tournoux atlas. Then differences across scans were statistically estimated on a voxel by voxel analysis using paired t-test (population main effect: 2 cond's, 1 scan/cond.), which was applied to compare concentration of SERT between the test and retest cerebral scans.The average of specific uptake ratio (SUR: target/cerebellum-1) of 123I-ADAM binding to SERT in midbrain was 1.78±0.27, pons was 1.21±0.53, and striatum was 0.79±0.13. The cronbach's α of intra-class correlation coefficient (ICC) was 0.92. Besides, there was also no significant statistical finding in cerebral area using SPM2 analysis. This finding might help us

  18. Modelling the distance impedance of protest attendance

    NASA Astrophysics Data System (ADS)

    Traag, V. A.; Quax, R.; Sloot, P. M. A.

    2017-02-01

    Protesters are usually young, relatively well educated, middle class people that are politically engaged. But where do protesters come from? We here show, based on mobile phone data, that distance is an important impedance to protest attendance. Most protesters come from nearby regions, suggesting distance forms an obstacle to participation. Although this effect can be partly explained by social network effects, which show similar spatial dependencies, an effect of distance remains. This suggests distance still acts as an obstacle to participation, although it may also be that long-range contacts are less effective for recruitment. Face-to-face contacts seem more important in spreading protests through earlier participants, whereas central recruitment works better by telephone. Our results are important for understanding processes of recruitment.

  19. Attending to music decreases inattentional blindness.

    PubMed

    Beanland, Vanessa; Allen, Rosemary A; Pammer, Kristen

    2011-12-01

    This article investigates how auditory attention affects inattentional blindness (IB), a failure of conscious awareness in which an observer does not notice an unexpected event because their attention is engaged elsewhere. Previous research using the attentional blink paradigm has indicated that listening to music can reduce failures of conscious awareness. It was proposed that listening to music would decrease IB by reducing observers' frequency of task-unrelated thoughts (TUTs). Observers completed an IB task that varied both visual and auditory demands. Listening to music was associated with significantly lower IB, but only when observers actively attended to the music. Follow-up experiments suggest this was due to the distracting qualities of the audio task. The results also suggest a complex relationship between IB and TUTs: during demanding tasks, as predicted, noticers of the unexpected stimulus reported fewer TUTs than non-noticers. During less demanding tasks, however, noticers reported more TUTs than non-noticers.

  20. Lipoid Pneumonia in a Gas Station Attendant

    PubMed Central

    Yampara Guarachi, Gladis Isabel; Barbosa Moreira, Valeria; Santos Ferreira, Angela; Sias, Selma M. De A.; Rodrigues, Cristovão C.; Teixeira, Graça Helena M. do C.

    2014-01-01

    The exogenous lipoid pneumonia, uncommon in adults, is the result of the inhalation and/or aspiration of lipid material into the tracheobronchial tree. This is often confused with bacterial pneumonia and pulmonary tuberculosis due to a nonspecific clinical and radiologic picture. It presents acutely or chronically and may result in pulmonary fibrosis. We describe here a case of lipoid pneumonia in a gas station attendant who siphoned gasoline to fill motorcycles; he was hospitalized due to presenting with a respiratory infection that was hard to resolve. The patient underwent bronchoscopy with bronchoalveolar lavage, which, on cytochemical (oil red O) evaluation, was slightly positive for lipid material in the foamy cytoplasm of alveolar macrophages. Due to his occupational history and radiographic abnormalities suggestive of lipoid pneumonia, a lung biopsy was performed to confirm the diagnosis. The patient was serially treated with segmental lung lavage and showed clinical, functional, and radiological improvement. PMID:25374742

  1. Springs, streams, and gas vent on and near Mount Adams volcano, Washington

    NASA Astrophysics Data System (ADS)

    Nathenson, M.; Mariner, R. H.

    2013-12-01

    The construction of the Mount Adams stratovolcano in southwestern Washington started at about 520 ka (see review in Nathenson and Mariner, 2013). The volume rate of eruption has varied episodically, with the most recent period of high production having built the current central edifice during the period 35 to 10 ka. Eruptions have continued into the Holocene, but the rate of eruption has not been large. An extensive area and volume of hydrothermal alteration estimated from geologic and geophysical mapping indicates that there has been a significant hydrothermal system in the past. Oxidation of hydrogen sulfide produced elemental sulfur and sulfuric acid that interacted with andesite to produce kaolinite, alunite, gypsum, and silica. Springs and some streams on Mount Adams volcano have been sampled for chemistry and light stable isotopes of water (Nathenson and Mariner, 2013). No evidence was found for thermal or slightly thermal springs on Mount Adams. Spring temperatures are generally cooler than air temperatures from weather stations at the same elevation. Spring chemistry generally reflects weathering of volcanic rock from dissolved carbon dioxide. Water in some springs and streams has either dissolved hydrothermal minerals or has reacted with them to add sulfate to the water. Some samples appear to have obtained their sulfate from dissolution of gypsum while some probably involve reaction with sulfide minerals such as pyrite. Light stable isotope data for water from springs follow a local meteoric water line, and the variation of isotopes with elevation indicates that some springs have very local recharge and others have water from elevations a few hundred meters higher. A sample from a seeping gas vent on Mount Adams at an elevation of 3,609 m was at ambient temperature, but the gas is similar to that found on other Cascade volcanoes and appears to originate from a high-temperature (200°-300 °C) hydrothermal system. Helium isotopes are 4.4 times the value in

  2. ADAM-9 is a novel mediator of tenascin-C-stimulated invasiveness of brain tumor–initiating cells

    PubMed Central

    Sarkar, Susobhan; Zemp, Franz J.; Senger, Donna; Robbins, Stephen M.; Yong, V. Wee

    2015-01-01

    Background Tenascin-C (TNC), an extracellular matrix protein overexpressed in malignant gliomas, stimulates invasion of conventional glioma cell lines (U251, U87). However, there is a dearth of such information on glioma stemlike cells. Here, we have addressed whether and how TNC may regulate the invasiveness of brain tumor–initiating cells (BTICs) that give rise to glioma progenies. Methods Transwell inserts coated with extracellular matrix proteins were used to determine the role of TNC in BTIC invasion. Microarray analysis, lentiviral constructs, RNA interference-mediated knockdown, and activity assay ascertained the role of proteases in TNC-stimulated BTIC invasion in culture. Involvement of proteases was validated using orthotopic brain xenografts in mice. Results TNC stimulated BTIC invasiveness in a metalloproteinase-dependent manner. A global gene expression screen identified the metalloproteinase ADAM-9 as a potential regulator of TNC-stimulated BTIC invasiveness, and this was corroborated by an increase of ADAM-9 protein in 4 glioma patient–derived BTIC lines. Notably, RNA interference to ADAM-9, as well as inhibition of mitogen-activated protein kinase 8 (c-Jun NH2-terminal kinase), attenuated TNC-stimulated ADAM-9 expression, proteolytic activity, and BTIC invasiveness. The relevance of ADAM-9 to tumor invasiveness was validated using resected human glioblastoma specimens and orthotopic xenografts where elevation of ADAM-9 and TNC expression was prominent at the invasive front of the tumor. Conclusions This study has identified TNC as a promoter of the invasiveness of BTICs through a mechanism involving ADAM-9 proteolysis via the c-Jun NH2-terminal kinase pathway. PMID:25646025

  3. The Tracking of Referents in Discourse: Automated versus Attended Processes.

    DTIC Science & Technology

    2014-09-26

    DA17583 THE TRACKING OF REFERENTS IN DISCOURSE : AUTOHATED 1/1 VERSUS ATTENDED PROCESSES(U) OREGON UNIV EUGENE DEPT OF PSYCHOLOGY T GIVON ET AL. 0 MAY...8217; . ’-, .. " . ’,,: ’, """": -. ,. Ln NCognitive Science Program II THE TRACKING OF REFERENTS IN DISCOURSE : AUTOMATED VS. ATTENDED PROCESSES by T. Givon, W. Kellogg, MI...PERIOD COVERED The Tracking of Referents in Discourse : Final Report Automated vs. Attended Processes S. PERFORMING ORG. REPORT NUMBER 7. AUTHOR(#) S

  4. Flight Attendant Fatigue. Part IV. Analysis of Incident Reports

    DTIC Science & Technology

    2009-12-01

    combination of flight attendant(s), flight crew(s), or gate agent (s) Crew Illness/Injury Flight attendant or flight crew becomes sick or injured...possible hypoglycemia. I drank orange juice, had some sugar and water. nothing helped. From my first aid training, I deduced that I might be having...became ill and flight crew diverted to alternate to get medical assistance. 432684 Narrative: A cleaning agent was used on ovens that became toxic with

  5. Attending patient funerals: Practices and attitudes of Australian medical practitioners.

    PubMed

    Zambrano, Sofía C; Chur-Hansen, Anna; Crawford, Gregory B

    2017-02-01

    The appropriateness of attending a patient's funeral is a medical dilemma. This article focuses on 437 doctors who participated in an online survey. Seventy-one percent of general practitioners, 67% of oncologists, 67% of psychiatrists, 63% of palliative medicine specialists, 52% of surgeons, and 22% of intensive care specialists had attended patient funerals. Significant differences in demographics and between specialties were identified in terms of barriers and benefits associated with attendance. Although attendance is a personal decision, there is a need for open discussions in medical education and professional development concerning death and the role of doctors after a patient dies.

  6. IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17

    PubMed Central

    Booth, Brian W; Sandifer, Tracy; Martin, Erika L; Martin, Linda D

    2007-01-01

    Background The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-α (TGFα) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFα exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase (ADAM)17 responsible for this processing in a variety of tissues. Methods In this study, normal human bronchial epithelial (NHBE) cells grown in air/liquid interface (ALI) culture were used to examine the mechanisms whereby IL-13 induces release of TGFα and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFα and ADAM17 were visualized by confocal microscopy. Results IL-13 was found to induce proliferation of NHBE cells, and release of TGFα, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFα expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation. Conclusion Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFα shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine (IL-13) induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGFα to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated

  7. Helicopter magnetic and electromagnetic surveys at Mounts Adams, Baker and Rainier, Washington: implications for debris flow hazards and volcano hydrology

    USGS Publications Warehouse

    Finn, Carol A.; Deszcz-Pan, Maria

    2011-01-01

    High‐resolution helicopter magnetic and electromagnetic (HEM) data flown over the rugged, ice‐covered Mt. Adams, Mt. Baker and Mt. Rainier volcanoes (Washington), reveal the distribution of alteration, water and ice thickness essential to evaluating volcanic landslide hazards. These data, combined with geological mapping and rock property measurements, indicate the presence of appreciable thicknesses (>500 m) of water‐saturated hydrothermally altered rock west of the modern summit of Mount Rainier in the Sunset Amphitheater region and in the central core of Mount Adams north of the summit. Alteration at Mount Baker is restricted to thinner (<300 m) zones beneath Sherman Crater and the Dorr Fumarole Fields. The EM data identified water‐saturated rocks from the surface to the detection limit (100–200 m) in discreet zones at Mt. Rainier and Mt Adams and over the entire summit region at Mt. Baker. The best estimates for ice thickness are obtained over relatively low resistivity (<800 ohm‐m) ground for the main ice cap on Mt. Adams and over most of the summit of Mt. Baker. The modeled distribution of alteration, pore fluids and partial ice volumes on the volcanoes helps identify likely sources for future alteration‐related debris flows, including the Sunset Amphitheater region at Mt. Rainier, steep cliffs at the western edge of the central altered zone at Mount Adams and eastern flanks of Mt. Baker.

  8. A Disintegrin and Metalloproteinase-10 (ADAM-10) Mediates DN30 Antibody-induced Shedding of the Met Surface Receptor*

    PubMed Central

    Schelter, Florian; Kobuch, Julia; Moss, Marcia L.; Becherer, J. David; Comoglio, Paolo M.; Boccaccio, Carla; Krüger, Achim

    2010-01-01

    Met, the tyrosine kinase receptor for the hepatocyte growth factor is a prominent regulator of cancer cell invasiveness and has emerged as a promising therapeutic target. Binding of the anti-Met monoclonal antibody DN30 to its epitope induces the proteolytic cleavage of Met, thereby impairing the invasive growth of tumors. The molecular mechanism controlling this therapeutic shedding process has so far been unknown. Here, we report that A Disintegrin And Metalloproteinase (ADAM)-10, but not ADAM-17, is required for DN30-induced Met shedding. Knockdown of ADAM-10 in different tumor cell lines or abrogation of its proteolytic activity by natural or synthetic inhibitors abolished Met down-regulation on the cell surface as well as reduction of Met activation. Moreover, hepatocyte growth factor-induced tumor cell migration and invasion were impaired upon ADAM-10 knockdown. Thus, the therapeutic effect of DN30 involves ADAM-10-dependent Met shedding, linking for the first time a specific metalloprotease to target therapy against a receptor tyrosine kinase. PMID:20554517

  9. ADAM-10-Mediated N-cadherin Cleavage is Protein Kinase C-α–Dependent and Promotes Glioblastoma Cell Migration

    PubMed Central

    Kohutek, Zachary A.; diPierro, Charles G.; Redpath, Gerard T.; Hussaini, Isa M.

    2009-01-01

    Matrix metalloproteinases (MMPs) and the related ‘a disintegrin and metalloproteinases’ (ADAMs) promote tumorigenesis by cleaving extracellular matrix and protein substrates, including N-cadherin. While N-cadherin is thought to regulate cell adhesion, migration and invasion, its role has not been characterized in glioblastomas (GBMs). In this study, we investigated the expression and function of post-translational N-cadherin cleavage in GBM cells as well as its regulation by protein kinase C (PKC). N-cadherin cleavage occurred at a higher level in glioblastoma cells than in non-neoplastic astrocytes. Treatment with the PKC-activator phorbol 12-myristate 13-acetate (PMA) increased N-cadherin cleavage, which was reduced by pharmacological inhibitors and siRNA specific for ADAM-10 or PKC-α. Furthermore, treatment of GBM cells with PMA induced the translocation of ADAM-10 to the cell membrane, the site where N-cadherin was cleaved, and this translocation was significantly reduced by the PKC-α inhibitor Gö6976 or PKC-α shRNA. In functional studies, N-cadherin cleavage was required for GBM cell migration, as depletion of N-cadherin cleavage by N-cadherin siRNA, ADAM-10 siRNA, or a cleavage-site mutant N-cadherin, decreased GBM cell migration. Taken together, these results suggest that N-cadherin cleavage is regulated by a PKC-α-ADAM-10 cascade in GBM cells and may be involved in mediating GBM cell migration. PMID:19357285

  10. Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation

    PubMed Central

    Hong, Sung Woo; Hur, Wonhee; Choi, Jung Eun; Kim, Jung-Hee; Hwang, Daehee; Yoon, Seung Kew

    2016-01-01

    We investigated the biological role of CD133-expressing liver cancer stem cells (CSCs) enriched after irradiation of Huh7 cells in cell invasion and migration. We also explored whether a disintegrin and metalloproteinase-17 (ADAM17) influences the metastatic potential of CSC-enriched hepatocellular carcinoma (HCC) cells after irradiation. A CD133-expressing Huh7 cell subpopulation showed greater resistance to sublethal irradiation and specifically enhanced cell invasion and migration capabilities. We also demonstrated that the radiation-induced MMP-2 and MMP-9 enzyme activities as well as the secretion of vascular endothelial growth factor were increased more predominantly in Huh7CD133+ cell subpopulations than Huh7CD133− cell subpopulations. Furthermore, we showed that silencing ADAM17 significantly inhibited the migration and invasiveness of enriched Huh7CD133+ cells after irradiation; moreover, Notch signaling was significantly reduced in irradiated CD133-expressing liver CSCs following stable knockdown of the ADAM17 gene. In conclusion, our findings indicate that CD133-expressing liver CSCs have considerable metastatic capabilities after irradiation of HCC cells, and their metastatic capabilities might be maintained by ADAM17. Therefore, suppression of ADAM17 shows promise for improving the efficiency of current radiotherapies and reducing the metastatic potential of liver CSCs during HCC treatment. PMID:26993601

  11. Poor interoperability of the Adams-Harbertson method for analysis of anthocyanins: comparison with AOAC pH differential method.

    PubMed

    Brooks, Larry M; Kuhlman, Benjamin J; McKesson, Doug W; McCloskey, Leo

    2013-01-01

    The poor interoperability of anthocyanin glycosides measurements by two pH differential methods is documented. Adams-Harbertson, which was proposed for commercial winemaking, was compared to AOAC Official Method 2005.02 for wine. California bottled wines (Pinot Noir, Merlot, and Cabernet Sauvignon) were assayed in a collaborative study (n=105), which found mean precision of Adams-Harbertson winery versus reference measurements to be 77 +/- 20%. Maximum error is expected to be 48% for Pinot Noir, 42% for Merlot, and 34% for Cabernet Sauvignon from reproducibility RSD. Range of measurements was actually 30 to 91% for Pinot Noir. An interoperability study (n=30) found Adams-Harbertson produces measurements that are nominally 150% of the AOAC pH differential method. Large analytical chemistry differences are: AOAC method uses Beer-Lambert equation and measures absorbance at pH 1.0 and 4.5, proposed a priori by Flueki and Francis; whereas Adams-Harbertson uses "universal" standard curve and measures absorbance ad hoc at pH 1.8 and 4.9 to reduce the effects of so-called co-pigmentation. Errors relative to AOAC are produced by Adams-Harbertson standard curve over Beer-Lambert and pH 1.8 over pH 1.0. The study recommends using AOAC Official Method 2005.02 for analysis of wine anthocyanin glycosides.

  12. TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals

    PubMed Central

    Dornier, Emmanuel; Coumailleau, Franck; Ottavi, Jean-François; Moretti, Julien; Boucheix, Claude; Mauduit, Philippe

    2012-01-01

    The metalloprotease ADAM10/Kuzbanian catalyzes the ligand-dependent ectodomain shedding of Notch receptors and activates Notch. Here, we show that the human tetraspanins of the evolutionary conserved TspanC8 subfamily (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33) directly interact with ADAM10, regulate its exit from the endoplasmic reticulum, and that four of them regulate ADAM10 surface expression levels. In an independent RNAi screen in Drosophila, two TspanC8 genes were identified as Notch regulators. Functional analysis of the three Drosophila TspanC8 genes (Tsp3A, Tsp86D, and Tsp26D) indicated that these genes act redundantly to promote Notch signaling. During oogenesis, TspanC8 genes were up-regulated in border cells and regulated Kuzbanian distribution, Notch activity, and cell migration. Furthermore, the human TspanC8 tetraspanins Tspan5 and Tspan14 positively regulated ligand-induced ADAM10-dependent Notch1 signaling. We conclude that TspanC8 tetraspanins have a conserved function in the regulation of ADAM10 trafficking and activity, thereby positively regulating Notch receptor activation. PMID:23091066

  13. ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts.

    PubMed

    Christians, Julian K; Beristain, Alexander G

    2016-03-03

    Proper placental development and function is crucial for a healthy pregnancy, and there has been substantial research to identify markers of placental dysfunction for the early detection of pregnancy complications. Low first-trimester levels of a disintegrin and metalloproteinase 12 (ADAM12) and pregnancy-associated plasma protein-A (PAPP-A) have been consistently associated with the subsequent development of preeclampsia and fetal growth restriction. These molecules are both metalloproteinases secreted by the placenta that cleave insulin-like growth factor binding proteins (IGFBPs), although ADAM12 also has numerous other substrates. Recent work has identified ADAM12, and particularly its shorter variant, ADAM12S, as a regulator of the migration and invasion of trophoblasts into the lining of the uterus, a critical step in normal placental development. While the mechanisms underlying this regulation are not yet clear, they may involve the liberation of heparin-binding EGF-like growth factor (HB-EGF) and/or IGFs from IGFBPs. In contrast, there has been relatively little functional work examining PAPP-A or the IGFBP substrates of ADAM12 and PAPP-A. Understanding the functions of these markers and the mechanisms underlying their association with disease could improve screening strategies and enable the development of new therapeutic interventions.

  14. [Liu Jie attends Henan planned parenthood meeting].

    PubMed

    1981-03-03

    Henan scored excellent results in planned parenthood work last year. The natural population growth rate fell to 9.53/1000, a fall of 3.35/1000 from the 1979 level. The province victoriously fulfilled the population plan assigned by the state. Some 320,000 couples with 1 child have taken out single-child certificates. The provincial CCP Committee recently convened a planned parenthood meeting. Provincial CCP Committee 1st Secretary Liu Jie and Secretaries Dai Suli and Zhang Shude spoke at the meeting. Li Xiuzhen, deputy director of the State Council's planned parenthood leading group and director of its administrative office, also attended and spoke at the meeting. The speakers stressed: Party committees and government at all levels must strengthen leadership over planned parenthood, put this work in an important place on their agenda, resolve to promote this work, and succeed in grasping the 2 items of production together. We must further publicize and implement the Central Committee's open letter, vigorously advocate that each couple should have only 1 child, strictly control the birth of a 2nd child, and take resolute measures to prevent the birth of more than 2. We must put ideological education in the primary position. CCP and CYL members and cadres at all levels must take the lead in practicing planned parenthood.

  15. Hazard Zonation at Mount Adams, Washington based on Edifice and Flank Stability Modeling

    NASA Astrophysics Data System (ADS)

    Bowman, S. D.; Watters, R. J.

    2002-12-01

    Collapse of the edifice [summit] and flanks of volcanoes is common worldwide, including the Cascade Range. Many of these failures have transformed into devastating debris flows that may travel hundreds of miles from their source area and have killed or injured hundreds of thousands of people. Despite the danger posed by these failures and the incipient debris flows, limited geotechnical data exists to quantify hazards from edifice and flank failure. Recent field work and investigation at Mount Adams, Washington focused on developing and refining a methodology for characterizing volcanic stability for geologic hazard analysis. This methodology may be applied at other volcanoes worldwide. Geotechnical data, including discontinuity and strength characteristics, Rock Mass Rating (RMR), point load index, direct shear, unconfined compression, and triaxial data were used to identify sectors based upon common geotechnical and geologic characteristics. The geotechnical information collected at Mount Adams adds to the limited data available worldwide and provides general strength ranges for use in initial stability studies at other volcanoes. In addition, a new point load index device was developed for use at high elevation and remote locations. Stability of each identified sector was analyzed using limit equilibrium methods, based upon collected geotechnical and geologic data. Three previous failures were backanalysed to determine strength characteristics at the time of failure. Areas of immediate instability include The Castle and the Avalanche Glacier Headwall. Backanalysis of the Trout Lake Mudflow, which formed the Avalanche Glacier Headwall, suggests a seismic or eruption triggering mechanism. Stability analysis resulted in a failure hazard map quantifying the hazard in each sector from slope failure. This hazard map in combination with other data may be used by agencies and organizations involved in land-use planning in the Mount Adams area to protect lives and

  16. ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

    PubMed Central

    2011-01-01

    Background Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, Petri nets, and agent-based models, to gain a better understanding of them. The computational complexity to analyze the complete dynamics of these models grows exponentially in the number of variables, which impedes working with complex models. There exist software tools to analyze discrete models, but they either lack the algorithmic functionality to analyze complex models deterministically or they are inaccessible to many users as they require understanding the underlying algorithm and implementation, do not have a graphical user interface, or are hard to install. Efficient analysis methods that are accessible to modelers and easy to use are needed. Results We propose a method for efficiently identifying attractors and introduce the web-based tool Analysis of Dynamic Algebraic Models (ADAM), which provides this and other analysis methods for discrete models. ADAM converts several discrete model types automatically into polynomial dynamical systems and analyzes their dynamics using tools from computer algebra. Specifically, we propose a method to identify attractors of a discrete model that is equivalent to solving a system of polynomial equations, a long-studied problem in computer algebra. Based on extensive experimentation with both discrete models arising in systems biology and randomly generated networks, we found that the algebraic algorithms presented in this manuscript are fast for systems with the structure maintained by most biological systems, namely sparseness and robustness. For a large set of published complex discrete models, ADAM identified the attractors in less than one second. Conclusions Discrete modeling techniques are a useful tool for analyzing complex biological systems and there is a need in the biological community for accessible efficient analysis tools. ADAM provides analysis methods based on

  17. [Influence of Adam Schall's changing calendar on Yun - qi theory in the early Qing Dynasty].

    PubMed

    Yang, S; Zhng, H

    2001-07-01

    The Yun - qi theory is closely related to the calendar system. In Chinese history, the change of the calendar system by Adam Schall von Bell in early Qing Dynasty was a disputable event. Studying its effect on Yun - qi theory, we find out the issue of changing the order of Zi and Shen lunar mansions, which annoyed many Chinese astronomers and scholars, had no significant influence on Yun - qi theory. As for the new calculation system of clepsydra and solar terms, these changes increased the accuracy of the Yun - qi calendar.

  18. ADAM10 mediates N-cadherin ectodomain shedding during retinal ganglion cell differentiation in primary cultured retinal cells from the developing chick retina.

    PubMed

    Paudel, Sharada; Kim, Yeoun-Hee; Huh, Man-Il; Kim, Song-Ja; Chang, Yongmin; Park, Young Jeung; Lee, Kyoo Won; Jung, Jae-Chang

    2013-04-01

    Here, we examined the role of ADAM10 during retinal cell differentiation in retinal sections and in vitro cultures of developing chick retinal cells from embryonic day 6 (ED6). Immunohistochemistry showed that ADAM10 is abundantly expressed in the inner zone of neuroblastic layer at ED5, and it becomes more highly expressed in the ganglion cell layer at ED7 and ED9. Western blotting confirmed that ADAM10 was expressed as an inactive pro-form that was processed to a shorter, active form in control cultured cells, but in cultures treated with an ADAM10 inhibitor (GI254023X) and ADAM10-specific siRNA, the level of mature ADAM10 decreased. Phase-contrast microscopy showed that long neurite extensions were present in untreated cultures 24 h after plating, whereas cultures treated with GI254023X showed significant decreases in neurite extension. Immunofluorescence staining revealed that there were far fewer differentiated ganglion cells in ADAM10 siRNA and GI254023X-treated cultures compared to controls, whereas the photoreceptor cells were unaltered. The Pax6 protein was more strongly detected in the differentiated ganglion cells of control cultures compared to ADAM10 siRNA and GI254023X-treated cultures. N-cadherin ectodomain shedding was apparent in control cultures after 24 h, when ganglion cell differentiation was observed, but ADAM10 siRNA and GI254023X treatment inhibited these processes. In contrast, N-cadherin staining was strongly detected in photoreceptor cells regardless of ADAM10 siRNA and GI254023X treatment. Taken together, these data indicate that the inhibition of ADAM10 can inhibit Pax6 expression and N-cadherin ectodomain shedding in retinal cells, possibly affecting neurite outgrowth and ganglion cell differentiation.

  19. A Mechanism of Male Germ Cell Apoptosis Induced by Bisphenol-A and Nonylphenol Involving ADAM17 and p38 MAPK Activation

    PubMed Central

    Moreno, Ricardo D.

    2014-01-01

    Germ cell apoptosis regulation is pivotal in order to maintain proper daily sperm production. Several reports have shown that endocrine disruptors such as Bisphenol-A (BPA) and Nonylphenol (NP) induce germ cell apoptosis along with a decrease in sperm production. Given their ubiquitous distribution in plastic products used by humans it is important to clarify their mechanism of action. TACE/ADAM17 is a widely distributed extracellular metalloprotease and participates in the physiological apoptosis of germ cells during spermatogenesis. The aims of this work were: 1) to determine whether BPA and NP induce ADAM17 activation; and 2) to study whether ADAM17 and/or ADAM10 are involved in germ cell apoptosis induced by BPA and NP in the pubertal rat testis. A single dose of BPA or NP (50 mg/kg) induces germ cell apoptosis in 21-day-old male rats, which was prevented by a pharmacological inhibitor of ADAM17, but not by an inhibitor of ADAM10. In vitro, we showed that BPA and NP, at similar concentrations to those found in human samples, induce the shedding of exogenous and endogenous (TNF-α) ADAM17 substrates in primary rat Sertoli cell cultures and TM4 cell line. In addition, pharmacological inhibitors of metalloproteases and genetic silencing of ADAM17 prevent the shedding induced in vitro by BPA and NP. Finally, we showed that in vivo BPA and NP induced early activation (phosphorylation) of p38 MAPK and translocation of ADAM17 to the cell surface. Interestingly, the inhibition of p38 MAPK prevents germ cell apoptosis and translocation of ADAM17 to the cell surface. These results show for the first time that xenoestrogens can induce activation of ADAM17 at concentrations similar to those found in human samples, suggesting a mechanism by which they could imbalance para/juxtacrine cell-to-cell-communication and induce germ cell apoptosis. PMID:25474107

  20. 10 CFR 36.65 - Attendance during operation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Attendance during operation. 36.65 Section 36.65 Energy NUCLEAR REGULATORY COMMISSION LICENSES AND RADIATION SAFETY REQUIREMENTS FOR IRRADIATORS Operation of Irradiators § 36.65 Attendance during operation. (a) Both an irradiator operator and at least one...

  1. Attendance Feedback in An Academic Setting: Preliminary Results

    ERIC Educational Resources Information Center

    Broucek, Willard G.; Bass, William

    2008-01-01

    In the fall of 2005, the attendance behavior of 118 business students at Northern State University (NSU) was monitored in 4 classes. After 10 weeks of classes Absenteeism Feedback was given to these students. Examination of the data indicated a strong correlation between attendance and subsequent course grade. (Contains 1 table.)

  2. 22 CFR 224.23 - Subpoenas for attendance at hearing.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Subpoenas for attendance at hearing. 224.23 Section 224.23 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT IMPLEMENTATION OF THE PROGRAM FRAUD CIVIL REMEDIES ACT § 224.23 Subpoenas for attendance at hearing. (a) A party wishing to procure...

  3. 14 CFR 135.107 - Flight attendant crewmember requirement.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... is a flight attendant crewmember on board the aircraft. ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false Flight attendant crewmember requirement... OPERATING REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH...

  4. 14 CFR 135.107 - Flight attendant crewmember requirement.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... is a flight attendant crewmember on board the aircraft. ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Flight attendant crewmember requirement... OPERATING REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH...

  5. 14 CFR 135.107 - Flight attendant crewmember requirement.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... is a flight attendant crewmember on board the aircraft. ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Flight attendant crewmember requirement... OPERATING REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH...

  6. 14 CFR 135.107 - Flight attendant crewmember requirement.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... is a flight attendant crewmember on board the aircraft. ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Flight attendant crewmember requirement... OPERATING REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH...

  7. 14 CFR 135.107 - Flight attendant crewmember requirement.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... is a flight attendant crewmember on board the aircraft. ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Flight attendant crewmember requirement... OPERATING REQUIREMENTS: COMMUTER AND ON DEMAND OPERATIONS AND RULES GOVERNING PERSONS ON BOARD SUCH...

  8. Point-Counterpoint: Should Attendance Be Required in Collegiate Classrooms?

    ERIC Educational Resources Information Center

    Pinto, Jo Ann M.; Lohrey, Peter

    2016-01-01

    This paper examines two divergent viewpoints about whether or not class attendance should be mandatory in higher education. The authors, both accounting professors at the same institution, delineate their respective viewpoints citing school policy, federal regulations and academic freedom as factors which motivate their attendance policy.

  9. 9 CFR 3.108 - Employees or attendants.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Transportation of Marine Mammals Animal Health and Husbandry Standards § 3.108 Employees or attendants. (a) A... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Employees or attendants. 3.108 Section 3.108 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...

  10. 9 CFR 3.108 - Employees or attendants.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Transportation of Marine Mammals Animal Health and Husbandry Standards § 3.108 Employees or attendants. (a) A... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Employees or attendants. 3.108 Section 3.108 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...

  11. 9 CFR 3.108 - Employees or attendants.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Transportation of Marine Mammals Animal Health and Husbandry Standards § 3.108 Employees or attendants. (a) A... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Employees or attendants. 3.108 Section 3.108 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...

  12. 9 CFR 3.108 - Employees or attendants.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Transportation of Marine Mammals Animal Health and Husbandry Standards § 3.108 Employees or attendants. (a) A... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Employees or attendants. 3.108 Section 3.108 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT...

  13. Boosting Student Attendance: Beyond Stickers, Stars, and Candy Bars

    ERIC Educational Resources Information Center

    Dill, Vicky; Lopez, Patrick; Stahlke, Tim; Stamp, Jeanne

    2016-01-01

    We know that students cannot learn if they are not in school, and that students with economic challenges miss school more frequently than other students. What obstacles create this attendance gap, and how can school districts provide the supports to improve attendance for these students? The authors of this article, who work with the Texas…

  14. 10 CFR 13.23 - Subpoenas for attendance at hearing.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Subpoenas for attendance at hearing. 13.23 Section 13.23 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.23 Subpoenas for attendance at hearing. (a) A party wishing to procure the appearance and testimony of any individual at the hearing...

  15. Improving Attendance of Kindergarten Students through Behavior Modification Techniques.

    ERIC Educational Resources Information Center

    Schofield, Betty D.

    A behavior modification program was implemented to improve attendance and punctuality patterns of kindergarten students attending a small, rural elementary school. Also incorporated into the intervention were self-esteem and parent involvement components. Motivational strategies used were: a token economy; group-oriented behavior management…

  16. Why September Matters: Improving Student Attendance. Policy Brief

    ERIC Educational Resources Information Center

    Olsen, Linda S.

    2014-01-01

    This brief examines absences in September and students' attendance over the rest of the year. Attendance should be addressed before it becomes problematic. Chronic absenteeism, missing more than 20 days of a school year, is an early indicator of disengagement. High absence rates have negative consequences not only for individual students, but also…

  17. Teacher Attendance Improvement Program. A Joint Business-Educator Project.

    ERIC Educational Resources Information Center

    Greater Newark Chamber of Commerce, NJ.

    This report reviews the experiences of two New Jersey school districts that have initiated Attendance Improvement Plans (AIP) for professional school personnel. It is intended to summarize a 1974 report entitled "Program to Improve Teacher Attendance." The districts that participated in the pilot project were Newark, with approximately…

  18. States Mull Obama's Call to Raise Compulsory-Attendance Age

    ERIC Educational Resources Information Center

    Maxwell, Lesli A.

    2012-01-01

    President Barack Obama's call for every state to require school attendance until age 18 may spark a flurry of action in some statehouses, but changing attendance laws will do little by itself to drive down the nation's dropout rates, experts on the issue say. In his State of the Union address last month, President Obama said states should require…

  19. Strategies to Increase Student Attendance at an Elementary School

    ERIC Educational Resources Information Center

    Fitzpatrick-Doria, Geraldine Ann

    2013-01-01

    This action research study addressed the need to increase student attendance at an elementary school. Previously, this school's Average Daily Attendance (ADA) has been 92%. With having nearly 900 students, there are approximately 70 daily absences, 1,400 monthly absences, and 13,000 yearly absences. To address the challenge, the researcher…

  20. Children's Economic Activities and Primary School Attendance in Rural Guatemala.

    ERIC Educational Resources Information Center

    Clark, Carol A. M.

    To investigate whether low school attendance rates in Guatemala (about 35% of primary school aged children do not attend) are due primarily to the need for children in low income families to contribute to family income or child care and other housekeeping tasks, time use data were collected in 4 rural villages from mothers of 369 children, aged…

  1. 45 CFR 2102.4 - Public attendance and participation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false Public attendance and participation. 2102.4 Section 2102.4 Public Welfare Regulations Relating to Public Welfare (Continued) COMMISSION OF FINE ARTS MEETINGS AND PROCEDURES OF THE COMMISSION Commission Meetings § 2102.4 Public attendance and...

  2. 45 CFR 2102.4 - Public attendance and participation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 4 2014-10-01 2014-10-01 false Public attendance and participation. 2102.4 Section 2102.4 Public Welfare Regulations Relating to Public Welfare (Continued) COMMISSION OF FINE ARTS MEETINGS AND PROCEDURES OF THE COMMISSION Commission Meetings § 2102.4 Public attendance and...

  3. 38 CFR 3.504 - Parents; aid and attendance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Parents; aid and... § 3.504 Parents; aid and attendance. The effective date of discontinuance of an increased award because of the parent's need for aid and attendance will be the day of last payment if need for aid...

  4. 38 CFR 3.504 - Parents; aid and attendance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Parents; aid and... § 3.504 Parents; aid and attendance. The effective date of discontinuance of an increased award because of the parent's need for aid and attendance will be the day of last payment if need for aid...

  5. 38 CFR 3.504 - Parents; aid and attendance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Parents; aid and... § 3.504 Parents; aid and attendance. The effective date of discontinuance of an increased award because of the parent's need for aid and attendance will be the day of last payment if need for aid...

  6. 38 CFR 3.504 - Parents; aid and attendance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Parents; aid and... § 3.504 Parents; aid and attendance. The effective date of discontinuance of an increased award because of the parent's need for aid and attendance will be the day of last payment if need for aid...

  7. 38 CFR 3.504 - Parents; aid and attendance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Parents; aid and... § 3.504 Parents; aid and attendance. The effective date of discontinuance of an increased award because of the parent's need for aid and attendance will be the day of last payment if need for aid...

  8. Researching Pupil Attending Behavior within Naturalistic Classroom Settings.

    ERIC Educational Resources Information Center

    Brooks, Douglas M.; Rogers, Constance J.

    1981-01-01

    Examines the relationship between teacher attitudes toward students and visual attending behavior in the classroom. Thirty-two students were identified in four categories, subsequently labeled accepted, indifferent, concerned and rejected. Results indicated significant differences in visual attending behavior and a two-way interaction with pupil…

  9. Child labour or school attendance? Evidence from Zambia.

    PubMed

    Jensen, P; Nielsen, H S

    1997-01-01

    "In this paper we investigate what affects school attendance and child labour in an LDC, using data for Zambia.... The empirical analysis suggests that both economic and sociological variables are important determinants for the choice between school attendance and child labour. In particular, we find some support for the hypothesis that poverty forces households to keep their children away from school."

  10. 10 CFR 13.23 - Subpoenas for attendance at hearing.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Subpoenas for attendance at hearing. 13.23 Section 13.23 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.23 Subpoenas for attendance at... the subpoena is directed may file with the ALJ a motion to quash the subpoena within ten days...

  11. Extended School Non-Attenders' Views: Developing Best Practice

    ERIC Educational Resources Information Center

    Gregory, Isabel Rose; Purcell, Anita

    2014-01-01

    Despite the abundance of legislation and research initiatives concerning children's participation in decision-making, there is less research in this area with regard to extended school non-attenders. Using semi-structured interviews, this research explores how the views of children and their families who have experienced school non-attendance can…

  12. Implementing Nunavut Education Act: Compulsory School Attendance Policy

    ERIC Educational Resources Information Center

    Kwarteng, E. Fredua

    2006-01-01

    This paper discusses the implementation of Nunavut compulsory school attendance policy as part of the Nunavut Education Act (2002). Using a bottom-up approach to policy implementation in the literature and the author's six years teaching experience in Nunavut, the paper argues that the compulsory school attendance policy may not achieve its…

  13. 39 CFR 6.4 - Attendance by conference telephone call.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Attendance by conference telephone call. 6.4 Section 6.4 Postal Service UNITED STATES POSTAL SERVICE THE BOARD OF GOVERNORS OF THE U.S. POSTAL SERVICE MEETINGS (ARTICLE VI) § 6.4 Attendance by conference telephone call. For regularly scheduled meetings...

  14. The use of positive reinforcement in conditioning attending behavior.

    PubMed

    Walker, H M; Buckley, N K

    1968-01-01

    Individual conditioning techniques were applied in a controlled setting to increase attending behavior of an underachieving 9-yr-old male subject. The procedure involved: (1) determining a stable response pattern, (2) introducing a treatment variable to establish a high rate of task-attending behavior, (3) measuring the effect of withdrawal of the treatment variable after attaining criterion performance, and (4) transferring control to the classroom. The interval of attending behavior required for reinforcement was systematically increased from 30 sec to 600 sec as the behavior came under experimental control. Manipulating the reinforcing contingencies measurably changed the proportion of attending behavior and the frequency and duration of non-attending events. Once the behaviors were under experimental control, procedures were established to program generalization and to maintain the behavior outside the experimental setting.

  15. The Dynamics and Correlates of Religious Service Attendance in Adolescence.

    PubMed

    Hardie, Jessica Halliday; Pearce, Lisa D; Denton, Melinda Lundquist

    2016-03-01

    This study examines changes in religious service attendance over time for a contemporary cohort of adolescents moving from middle to late adolescence. We use two waves of a nationally representative panel survey of youth from the National Study of Youth and Religion (NSYR) to examine the dynamics of religious involvement during adolescence. We then follow with an analysis of how demographic characteristics, family background, and life course transitions relate to changes in religious service attendance during adolescence. Our findings suggest that, on average, adolescent religious service attendance declines over time, related to major life course transitions such as becoming employed, leaving home, and initiating sexual activity. Parents' affiliation and attendance, on the other hand, are protective factors against decreasing attendance.

  16. Computer program for the automated attendance accounting system

    NASA Technical Reports Server (NTRS)

    Poulson, P.; Rasmusson, C.

    1971-01-01

    The automated attendance accounting system (AAAS) was developed under the auspices of the Space Technology Applications Program. The task is basically the adaptation of a small digital computer, coupled with specially developed pushbutton terminals located in school classrooms and offices for the purpose of taking daily attendance, maintaining complete attendance records, and producing partial and summary reports. Especially developed for high schools, the system is intended to relieve both teachers and office personnel from the time-consuming and dreary task of recording and analyzing the myriad classroom attendance data collected throughout the semester. In addition, since many school district budgets are related to student attendance, the increase in accounting accuracy is expected to augment district income. A major component of this system is the real-time AAAS software system, which is described.

  17. The use of positive reinforcement in conditioning attending behavior1

    PubMed Central

    Walker, Hill M.; Buckley, Nancy K.

    1968-01-01

    Individual conditioning techniques were applied in a controlled setting to increase attending behavior of an underachieving 9-yr-old male subject. The procedure involved: (1) determining a stable response pattern, (2) introducing a treatment variable to establish a high rate of task-attending behavior, (3) measuring the effect of withdrawal of the treatment variable after attaining criterion performance, and (4) transferring control to the classroom. The interval of attending behavior required for reinforcement was systematically increased from 30 sec to 600 sec as the behavior came under experimental control. Manipulating the reinforcing contingencies measurably changed the proportion of attending behavior and the frequency and duration of non-attending events. Once the behaviors were under experimental control, procedures were established to program generalization and to maintain the behavior outside the experimental setting. PMID:16795182

  18. Rural/Nonrural Differences in College Attendance Patterns

    PubMed Central

    Byun, Soo-yong; Irvin, Matthew J.; Meece, Judith L.

    2014-01-01

    Using data from the National Education Longitudinal Study of 1988, this study documented college attendance patterns of rural youth in terms of the selectivity of first postsecondary institution of attendance, the timing of transition to postsecondary education, and the continuity of enrollment. The study also examined how these college attendance patterns among rural students differed from those among their non-rural counterparts and which factors explained these rural/nonrural differences. Results showed that rural youth were less likely than their nonrural counterparts to attend a selective institution. In addition, rural youth were more likely to delay entry to postsecondary education, compared to their urban counterparts. Finally, rural students were less likely than their urban counterparts to be continuously enrolled in college. Much of these rural/nonrural disparities in college attendance patterns were explained by rural/nonrural differences in socioeconomic status and high school preparation. Policy implications, limitations of the study, and future research directions are also discussed. PMID:25983357

  19. Adam's Dream

    ERIC Educational Resources Information Center

    Piacenti, Alexandria

    2011-01-01

    Growing up as a young girl, summer camp was a typical affair. Packed lunches kept cold with frozen freezer packs, seemingly endless slip n' slides, activities, games, contests. Every morning, the author was eager to wake up and head off to hours and hours of fun with friends and counselors. However, one may think the camping experience could not…

  20. Teacher and Staff Attendance Improvement Programs: Attendance Improvement Guide for Superintendents. How to Improve Staff Illness Absence.

    ERIC Educational Resources Information Center

    Harclerode, Richard

    A successful program to improve personnel attendance has reduced sick leave in 40 New Jersey school districts without increasing dismissals, grievances, or costs. The author describes the five steps in this Attendance Improvement Program (AIP), including (1) analysis of data on staff absences due to illness; (2) preparation of operating guidelines…

  1. SuperADAM: Upgraded polarized neutron reflectometer at the Institut Laue-Langevin

    SciTech Connect

    Devishvili, A.; Zhernenkov, K.; Dennison, A. J. C.; Toperverg, B. P.; Wolff, M.; Hjoervarsson, B.; Zabel, H.

    2013-02-15

    A new neutron reflectometer SuperADAM has recently been built and commissioned at the Institut Laue-Langevin, Grenoble, France. It replaces the previous neutron reflectometer ADAM. The new instrument uses a solid state polarizer/wavelength filter providing a highly polarized (up to 98.6%) monochromatic neutron flux of 8 Multiplication-Sign 10{sup 4} n cm{sup -2} s{sup -1} with monochromatization {Delta}{lambda}/{lambda}= 0.7% and angular divergence {Delta}{alpha}= 0.2 mrad. The instrument includes both single and position sensitive detectors. The position sensitive detector allows simultaneous measurement of specular reflection and off-specular scattering. Polarization analysis for both specular reflection and off-specular scattering is achieved using either mirror analyzers or a {sup 3}He spin filter cell. High efficiency detectors, low background, and high flux provides a dynamic range of up to seven decades in reflectivity. Detailed specifications and the instrument capabilities are illustrated with examples of recently collected data in the fields of thin film magnetism and thin polymer films.

  2. John G.C. Adams: father of Dental Public Health in Canada.

    PubMed

    Kenny, David J; Dale, Anne C; Wencer, David G

    2014-01-01

    John Gennings Curtis Adams (1839-1922), Canada's first resident dental missionary, was the father of Dental Public Health in Canada. He established, personally funded and operated the first free dental hospital in North America for poor children and their mothers in Toronto from 1872, three years before the founding of The Hospital for Sick Children; he later became their first dentist of record. He was a visionary zealot for prevention of decay, dental education, and treatment over extraction. Dr. Adams understood that neither parents (rich or poor) nor physicians were aware of the extent of pathosis present in children's mouths. He petitioned individuals, lobbied politicians and unions and pressured dental organizations on the importance of twice-annual school inspections to demonstrate disease so that parents would seek care for their children. He wanted government-funded dental hospitals like his own to treat those who could not afford care. He realized his objectives and his reforms to prevent suffering, as Toronto school inspections began in 1911 and Toronto's first publicly-funded free dental clinic opened in 1913. He was Canada's first dental philanthropist and a visionary for preventive dentistry.

  3. Rationale and initial experience with the Tri-Ad Adams tricuspid annuloplasty ring.

    PubMed

    Milla, Federico; Castillo, Javier G; Varghese, Robin; Chikwe, Joanna; Anyanwu, Anelechi C; Adams, David H

    2012-04-01

    Controversy exists regarding the indication and method of repair of functional tricuspid regurgitation (TR) in patients undergoing mitral valve surgery. Whereas the American College of Cardiology/American Heart Association guidelines recommend tricuspid repair in the setting of severe TR, tricuspid repair is advised for less than severe TR in the setting of annular dilation or pulmonary hypertension. Although multiple repair strategies exist, the use of a ring annuloplasty (semirigid remodeling rings vs flexible bands) is the preferred method of therapy to avoid short- and long-term recurrence of TR. The new Tri-Ad Adams annuloplasty ring combines elements of semirigid and flexible bands that will not only allow for annular remodeling in the region of the right ventricular free wall but also potentially reduce injury to the conduction system with its flexible and "open" ends. In this article, we discuss the rational for an aggressive approach to functional tricuspid regurgitation, and show our initial clinical experience with the Tri-Ad Adams annuloplasty ring.

  4. Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage*

    PubMed Central

    van Tetering, Geert; van Diest, Paul; Verlaan, Ingrid; van der Wall, Elsken; Kopan, Raphael; Vooijs, Marc

    2009-01-01

    Notch signaling is controlled by ligand binding, which unfolds a negative control region to induce proteolytic cleavage of the receptor. First, a membrane-proximal cleavage is executed by a metalloprotease, removing the extracellular domain. This allows γ-secretase to execute a second cleavage within the Notch transmembrane domain, which releases the intracellular domain to enter the nucleus. Here we show that the ADAM10 metalloprotease Kuzbanian, but not ADAM17/tumor necrosis factor α-converting enzyme, plays an essential role in executing ligand-induced extracellular cleavage at site 2 (S2) in cells and localizes this step to the plasma membrane. Importantly, genetic or pharmacological inhibition of metalloproteases still allowed extracellular cleavage of Notch, indicating the presence of unknown proteases with the ability to cleave at S2. Gain of function mutations identified in human cancers and in model organisms that map to the negative control region alleviate the requirement for ligand binding for extracellular cleavage to occur. Because cancer-causing Notch1 mutations also depend on (rate-limiting) S2 proteolysis, the identity of these alternative proteases has important implications for understanding Notch activation in normal and cancer cells. PMID:19726682

  5. ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas.

    PubMed

    Wright, Casey M; Larsen, Jill E; Hayward, Nicholas K; Martins, Maria U; Tan, Maxine E; Davidson, Morgan R; Savarimuthu, Santiyagu M; McLachlan, Rebecca E; Passmore, Linda H; Windsor, Morgan N; Clarke, Belinda E; Duhig, Edwina E; Yang, Ian A; Bowman, Rayleen V; Fong, Kwun M

    2010-08-01

    Asbestos-related lung cancer accounts for 4-12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos-related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC-AC: asbestos-related lung cancer-adenocarcinoma) with 24 patients with no asbestos bodies (NARLC-AC: non-asbestos related lung cancer-adenocarcinoma). Genes differentially expressed between ARLC-AC and NARLC-AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT-PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons.

  6. ADAM12-cleaved ephrin-A1 contributes to lung metastasis.

    PubMed

    Ieguchi, K; Tomita, T; Omori, T; Komatsu, A; Deguchi, A; Masuda, J; Duffy, S L; Coulthard, M G; Boyd, A; Maru, Y

    2014-04-24

    Eph receptor tyrosine kinases and their ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced ephrin-A1 cleavage in response to transforming growth factor-β1 in primary tumors. Released soluble ephrin-A1 in the serum deteriorated the EphA1/ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis.

  7. Isotopic and trace element constraints on the petrogenesis of lavas from the Mount Adams volcanic field, Washington

    USGS Publications Warehouse

    Jicha, B.R.; Hart, G.L.; Johnson, C.M.; Hildreth, W.; Beard, B.L.; Shirey, S.B.; Valley, J.W.

    2009-01-01

    Strontium, Nd, Pb, Hf, Os, and O isotope compositions for 30 Quaternary lava flows from the Mount Adams stratovolcano and its basaltic periphery in the Cascade arc, southern Washington, USA indicate a major component from intraplate mantle sources, a relatively small subduction component, and interaction with young mafic crust at depth. Major- and trace-element patterns for Mount Adams lavas are distinct from the rear-arc Simcoe volcanic field and other nearby volcanic centers in the Cascade arc such as Mount St. Helens. Radiogenic isotope (Sr, Nd, Pb, and Hf) compositions do not correlate with geochemical indicators of slab-fluids such as (Sr/P)n and Ba/Nb. Mass-balance modeling calculations, coupled with trace-element and isotopic data, indicate that although the mantle source for the calc-alkaline Adams basalts has been modified with a fluid derived from subducted sediment, the extent of modification is significantly less than what is documented in the southern Cascades. The isotopic and trace-element compositions of most Mount Adams lavas require the presence of enriched and depleted mantle sources, and based on volume-weighted chemical and isotopic compositions for Mount Adams lavas through time, an intraplate mantle source contributed the major magmatic mass of the system. Generation of basaltic andesites to dacites at Mount Adams occurred by assimilation and fractional crystallization in the lower crust, but wholesale crustal melting did not occur. Most lavas have Tb/Yb ratios that are significantly higher than those of MORB, which is consistent with partial melting of the mantle in the presence of residual garnet. ??18O values for olivine phenocrysts in Mount Adams lavas are within the range of typical upper mantle peridotites, precluding involvement of upper crustal sedimentary material or accreted terrane during magma ascent. The restricted Nd and Hf isotope compositions of Mount Adams lavas indicate that these isotope systems are insensitive to crustal

  8. ADAM10 Cell Surface Expression but Not Activity Is Critical for Staphylococcus aureus α-Hemolysin-Mediated Activation of the NLRP3 Inflammasome in Human Monocytes.

    PubMed

    Ezekwe, Ejiofor A D; Weng, Chengyu; Duncan, Joseph A

    2016-03-30

    The Staphylococcus aureus toxin, α-hemolysin, is an important and well-studied virulence factor in staphylococcal infection. It is a soluble monomeric protein that, once secreted by the bacterium, forms a heptameric pore in the membrane of a broad range of host cell types. Hemolysin was recently discovered to bind and activate a disintegrin and metalloprotease 10 (ADAM10). In epithelial and endothelial cells, ADAM10 activation is required for the toxin's activity against these cells. In host monocytic cells, α-hemolysin activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome leading to production of pro-inflammatory cytokines and cell death. We now show that ADAM10 is critical for α-hemolysin-mediated activation of the NLRP3 inflammasome in human monocytes as siRNA knockdown or chemical blockade of ADAM10-α-hemolysin interaction leads to diminished inflammasome activation and cell death by reducing the available ADAM10 on the cell surface. Unlike epithelial cell and endothelial cell damage, which requires α-hemolysin induced ADAM10 activation, ADAM10 protease activity was not required for NLRP3 inflammasome activation. This work confirms the importance of ADAM10 in immune activation by α-hemolysin, but indicates that host cell signal induction by the toxin is different between host cell types.

  9. A1 adenosine receptor–stimulated exocytosis in bladder umbrella cells requires phosphorylation of ADAM17 Ser-811 and EGF receptor transactivation

    PubMed Central

    Prakasam, H. Sandeep; Gallo, Luciana I.; Li, Hui; Ruiz, Wily G.; Hallows, Kenneth R.; Apodaca, Gerard

    2014-01-01

    Despite the importance of ADAM17-dependent cleavage in normal biology and disease, the physiological cues that trigger its activity, the effector pathways that promote its function, and the mechanisms that control its activity, particularly the role of phosphorylation, remain unresolved. Using native bladder epithelium, in some cases transduced with adenoviruses encoding small interfering RNA, we observe that stimulation of apically localized A1 adenosine receptors (A1ARs) triggers a Gi-Gβγ-phospholipase C-protein kinase C (PKC) cascade that promotes ADAM17-dependent HB-EGF cleavage, EGFR transactivation, and apical exocytosis. We further show that the cytoplasmic tail of rat ADAM17 contains a conserved serine residue at position 811, which resides in a canonical PKC phosphorylation site, and is phosphorylated in response to A1AR activation. Preventing this phosphorylation event by expression of a nonphosphorylatable ADAM17S811A mutant or expression of a tail-minus construct inhibits A1AR-stimulated, ADAM17-dependent HB-EGF cleavage. Furthermore, expression of ADAM17S811A in bladder tissues impairs A1AR-induced apical exocytosis. We conclude that adenosine-stimulated exocytosis requires PKC- and ADAM17-dependent EGFR transactivation and that the function of ADAM17 in this pathway depends on the phosphorylation state of Ser-811 in its cytoplasmic domain. PMID:25232008

  10. ADAM10 Cell Surface Expression but Not Activity Is Critical for Staphylococcus aureus α-Hemolysin-Mediated Activation of the NLRP3 Inflammasome in Human Monocytes

    PubMed Central

    Ezekwe, Ejiofor A.D.; Weng, Chengyu; Duncan, Joseph A.

    2016-01-01

    The Staphylococcus aureus toxin, α-hemolysin, is an important and well-studied virulence factor in staphylococcal infection. It is a soluble monomeric protein that, once secreted by the bacterium, forms a heptameric pore in the membrane of a broad range of host cell types. Hemolysin was recently discovered to bind and activate a disintegrin and metalloprotease 10 (ADAM10). In epithelial and endothelial cells, ADAM10 activation is required for the toxin’s activity against these cells. In host monocytic cells, α-hemolysin activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome leading to production of pro-inflammatory cytokines and cell death. We now show that ADAM10 is critical for α-hemolysin-mediated activation of the NLRP3 inflammasome in human monocytes as siRNA knockdown or chemical blockade of ADAM10-α-hemolysin interaction leads to diminished inflammasome activation and cell death by reducing the available ADAM10 on the cell surface. Unlike epithelial cell and endothelial cell damage, which requires α-hemolysin induced ADAM10 activation, ADAM10 protease activity was not required for NLRP3 inflammasome activation. This work confirms the importance of ADAM10 in immune activation by α-hemolysin, but indicates that host cell signal induction by the toxin is different between host cell types. PMID:27043625

  11. Community-based skilled birth attendants in Bangladesh: attending deliveries at home.

    PubMed

    Ahmed, Tahera; Jakaria, S M

    2009-05-01

    Only 15% of births in Bangladesh in 2007 were delivered at health facilities, but the increase over previous years has been significant, and treatment-seeking from a medically trained provider for obstetric complications has also increased. A programme to create a cadre of skilled birth attendants for home births was launched by the Government of Bangladesh in 2004. The training, for community-based health and family planning fieldworkers, covers 74 essential midwifery skills and danger signs for referral. Training of trainers and supervisors for the fieldworkers was also initiated. By the end of 2008 an estimated 4,000 out of a proposed 13,500 skilled birth attendants and 50 of 4,000 proposed supervisors had been trained and were working in 56 districts. There needs to be a full evaluation of the programme and whether it has reduced maternal deaths. Bangladesh now needs to decide how long to invest in this programme and/or whether to train a new cadre of fully qualified midwives, as proposed by the Nursing Council. We believe this programme can only be an interim measure, not a long-term solution, as more women decide to seek institutional delivery and professional midwifery care. For the moment, though, task-shifting seems to have yielded beneficial results and important insights into human resources planning for safe motherhood in Bangladesh.

  12. Transition to skilled birth attendance: is there a future role for trained traditional birth attendants?

    PubMed

    Sibley, Lynn M; Sipe, Theresa Ann

    2006-12-01

    A brief history of training of traditional birth attendants (TBAs), summary of evidence for effectiveness of TBA training, and consideration of the future role of trained TBAs in an environment that emphasizes transition to skilled birth attendance are provided. Evidence of the effectiveness of TBA training, based on 60 studies and standard meta-analytic procedures, includes moderate-to-large improvements in behaviours of TBAs relating to selected intrapartum and postnatal care practices, small significant increases in women's use of antenatal care and emergency obstetric care, and small significant decreases in perinatal mortality and neonatal mortality due to birth asphyxia and pneumonia. Such findings are consistent with the historical focus of TBA training on extending the reach of primary healthcare and a few programmes that have included home-based management of complications of births and the newborns, such as birth asphyxia and pneumonia. Evidence suggests that, in settings characterized by high mortality and weak health systems, trained TBAs can contribute to the Millennium Development Goal 4--a two-thirds reduction in the rate of mortality of children aged less than 14 years by 2015--through participation in key evidence-based interventions.

  13. Hemispheric balance in processing attended and non-attended vowels and complex tones.

    PubMed

    Vihla, Minna; Salmelin, Riitta

    2003-04-01

    We compared cortical processing of attended and non-attended vowels and complex tones, using a whole-head neuromagnetometer, to test for possible hemispheric differences. Stimuli included vowels [a] and [i], spoken by two female Finnish speakers, and two complex tones, each with two pure tone components corresponding to the first and second formant frequencies (F1-F2) of the vowels spoken by speaker 1. Sequences including both vowels and complex tones were presented to eight Finnish males during passive and active (phoneme/speaker/complex tone identification) listening. Sequences including only vowels were presented to five of the subjects during passive listening and during a phoneme identification task. The vowel [i] spoken by speaker 1 and the corresponding complex tone were frequent, non-target stimuli. Responses evoked by these frequent stimuli were analyzed. Cortical activation at approximately 100 ms was stronger for the complex tone than the vowel in the right hemisphere (RH). Responses were similar during active and passive listening. Hemispheric balance remained the same when the vowel was presented in sequences including only vowels. The reduction of RH activation for vowels as compared with complex tones indicates a relative increase of left hemisphere involvement, possibly reflecting a shift towards more language-specific processing.

  14. ADAM28 is expressed by epithelial cells in human normal tissues and protects from C1q-induced cell death.

    PubMed

    Miyamae, Yuka; Mochizuki, Satsuki; Shimoda, Masayuki; Ohara, Kentaro; Abe, Hitoshi; Yamashita, Shuji; Kazuno, Saiko; Ohtsuka, Takashi; Ochiai, Hiroki; Kitagawa, Yuko; Okada, Yasunori

    2016-05-01

    ADAM28 (disintegrin and metalloproteinase 28), which was originally reported to be lymphocyte-specific, is over-expressed by carcinoma cells and plays a key role in cell proliferation and progression in human lung and breast carcinomas. We studied ADAM28 expression in human normal tissues and examined its biological function. By using antibodies specific to ADAM28, ADAM28 was immunolocalized mainly to epithelial cells in several tissues, including epididymis, bronchus and stomach, whereas lymphocytes in lymph nodes and spleen were negligibly immunostained. RT-PCR, immunoblotting and ELISA analyses confirmed the expression in these tissues, and low or negligible expression by lymphocytes was found in the lymph node and spleen. C1q was identified as a candidate ADAM28-binding protein from a human lung cDNA library by yeast two-hybrid system, and specific binding was demonstrated by binding assays, immunoprecipitation and surface plasmon resonance. C1q treatment of normal bronchial epithelial BEAS-2B and NHBE cells, both of which showed low-level expression of ADAM28, caused apoptosis through activation of p38 and caspase-3, and cell death with autophagy through accumulation of LC3-II and autophagosomes, respectively. C1q-induced cell death was attenuated by treatment of the cells with antibodies against the C1q receptor gC1qR/p33 or cC1qR/calreticulin. Treatment of C1q with recombinant ADAM28 prior to addition to culture media reduced C1q-induced cell death, and knockdown of ADAM28 using siRNAs increased cell death. These data demonstrate that ADAM28 is expressed by epithelial cells of several normal organs, and suggest that ADAM28 plays a role in cell survival by suppression of C1q-induced cytotoxicity in bronchial epithelial cells.

  15. Occupational injuries suffered by flight attendants while on board.

    PubMed

    Iglesias, R; Gonzalez, G; Morales, S T

    1989-11-01

    Inflight occupational injuries suffered by flight attendants are an important cause of medical disabilities. Mexicana Airlines has made an evaluation of this problem from 1983 to 1987. The injuries most frequently observed were contusions, skin cuts, sprains, fractures, spine disorders, and severe barotitis. The anatomic regions commonly affected were the hands, feet, and spine. These injuries are responsible for 15,573 work days lost for the average of 1,631 flight attendants. This study identified some unsafe actions and conditions in the flight attendants' working environment. The company has initiated an extensive training program to avoid unsafe actions and to eliminate certain unsafe conditions where possible.

  16. The effects of attending selective college tiers in China.

    PubMed

    Loyalka, Prashant; Song, Yingquan; Wei, Jianguo

    2012-03-01

    We estimate the effects of attending the first versus second-tier of higher education institutions on Chinese students' at-college and expected post-college outcomes using various quasi-experimental methods such as regression discontinuity, genetic matching, and regression discontinuity controlling for covariates. Overall we find that just attending the first versus second-tier makes little difference in terms of students' class ranking, net tuition, expected wages, or likelihood of applying for graduate school. The results do show, however, that just attending the first versus second tier makes it less likely that students will get their preferred major choice.

  17. Wanting to attend isn’t just wanting to quit: why some disadvantaged smokers regularly attend smoking cessation behavioural therapy while others do not: a qualitative study

    PubMed Central

    2014-01-01

    Background Attendance of a behavioural support programme facilitates smoking cessation. Disadvantaged smokers have been shown to attend less than their more affluent peers. We need to gain in-depth insight into underlying reasons for differing attendance behaviour in disadvantaged smokers, to better address this issue. This study aims to explore the underlying motivations, barriers and social support of smokers exhibiting different patterns of attendance at a free smoking cessation behavioural support programme in a disadvantaged neighbourhood of The Netherlands. Methods In 29 smokers undertaking smoking cessation group therapy or telephone counselling in a disadvantaged neighbourhood, qualitative interviews were completed, coded and analysed. Major themes were motivations, barriers to attend and social support. Motivations and social support were analysed with reference to the self-determination theory. Results Two distinct patterns of attendance emerged: those who missed up to two sessions (“frequent attenders”), and those who missed more than two sessions (“infrequent attenders”). The groups differed in their motivations to attend, barriers to attendance, and in the level of social support they received. In comparison with the infrequent attenders, frequent attenders more often had intrinsic motivation to attend (e.g. enjoyed attending), and named more self-determined extrinsic motivations to attend, such as commitment to attendance and wanting to quit. Most of those mentioning intrinsic motivation did not mention a desire to quit as a motivation for attendance. No organizational barriers to attendance were mentioned by frequent attenders, such as misunderstandings around details of appointments. Frequent attenders experienced more social support within and outside the course. Conclusion Motivation to attend behavioural support, as distinct from motivation to quit smoking, is an important factor in attendance of smoking cessation courses in disadvantaged

  18. Lightweight robotic mobility: template-based modeling for dynamics and controls using ADAMS/car and MATLAB

    NASA Astrophysics Data System (ADS)

    Adamczyk, Peter G.; Gorsich, David J.; Hudas, Greg R.; Overholt, James

    2003-09-01

    The U.S. Army is seeking to develop autonomous off-road mobile robots to perform tasks in the field such as supply delivery and reconnaissance in dangerous territory. A key problem to be solved with these robots is off-road mobility, to ensure that the robots can accomplish their tasks without loss or damage. We have developed a computer model of one such concept robot, the small-scale "T-1" omnidirectional vehicle (ODV), to study the effects of different control strategies on the robot's mobility in off-road settings. We built the dynamic model in ADAMS/Car and the control system in Matlab/Simulink. This paper presents the template-based method used to construct the ADAMS model of the T-1 ODV. It discusses the strengths and weaknesses of ADAMS/Car software in such an application, and describes the benefits and challenges of the approach as a whole. The paper also addresses effective linking of ADAMS/Car and Matlab for complete control system development. Finally, this paper includes a section describing the extension of the T-1 templates to other similar ODV concepts for rapid development.

  19. Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.

    PubMed

    Parry, David A; Toomes, Carmel; Bida, Lina; Danciger, Michael; Towns, Katherine V; McKibbin, Martin; Jacobson, Samuel G; Logan, Clare V; Ali, Manir; Bond, Jacquelyn; Chance, Rebecca; Swendeman, Steven; Daniele, Lauren L; Springell, Kelly; Adams, Matthew; Johnson, Colin A; Booth, Adam P; Jafri, Hussain; Rashid, Yasmin; Banin, Eyal; Strom, Tim M; Farber, Debora B; Sharon, Dror; Blobel, Carl P; Pugh, Edward N; Pierce, Eric A; Inglehearn, Chris F

    2009-05-01

    Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction.

  20. Loss of the Metalloprotease ADAM9 Leads to Cone-Rod Dystrophy in Humans and Retinal Degeneration in Mice

    PubMed Central

    Parry, David A.; Toomes, Carmel; Bida, Lina; Danciger, Michael; Towns, Katherine V.; McKibbin, Martin; Jacobson, Samuel G.; Logan, Clare V.; Ali, Manir; Bond, Jacquelyn; Chance, Rebecca; Swendeman, Steven; Daniele, Lauren L.; Springell, Kelly; Adams, Matthew; Johnson, Colin A.; Booth, Adam P.; Jafri, Hussain; Rashid, Yasmin; Banin, Eyal; Strom, Tim M.; Farber, Debora B.; Sharon, Dror; Blobel, Carl P.; Pugh, Edward N.; Pierce, Eric A.; Inglehearn, Chris F.

    2009-01-01

    Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction. PMID:19409519

  1. A bivariate genome-wide association study identifies ADAM12 as a novel susceptibility gene for Kashin-Beck disease

    PubMed Central

    Hao, Jingcan; Wang, Wenyu; Wen, Yan; Xiao, Xiao; He, Awen; Guo, Xiong; Yang, Tielin; Liu, Xiaogang; Shen, Hui; Chen, Xiangding; Tian, Qing; Deng, Hong-Wen; Zhang, Feng

    2016-01-01

    Kashin-Beck disease (KBD) is a chronic osteoarthropathy, which manifests as joint deformities and growth retardation. Only a few genetic studies of growth retardation associated with the KBD have been carried out by now. In this study, we conducted a two-stage bivariate genome-wide association study (BGWAS) of the KBD using joint deformities and body height as study phenotypes, totally involving 2,417 study subjects. Articular cartilage specimens from 8 subjects were collected for immunohistochemistry. In the BGWAS, ADAM12 gene achieved the most significant association (rs1278300 p-value = 9.25 × 10−9) with the KBD. Replication study observed significant association signal at rs1278300 (p-value = 0.007) and rs1710287 (p-value = 0.002) of ADAM12 after Bonferroni correction. Immunohistochemistry revealed significantly decreased expression level of ADAM12 protein in the KBD articular cartilage (average positive chondrocyte rate = 47.59 ± 7.79%) compared to healthy articular cartilage (average positive chondrocyte rate = 64.73 ± 5.05%). Our results suggest that ADAM12 gene is a novel susceptibility gene underlying both joint destruction and growth retardation of the KBD. PMID:27545300

  2. A bivariate genome-wide association study identifies ADAM12 as a novel susceptibility gene for Kashin-Beck disease.

    PubMed

    Hao, Jingcan; Wang, Wenyu; Wen, Yan; Xiao, Xiao; He, Awen; Guo, Xiong; Yang, Tielin; Liu, Xiaogang; Shen, Hui; Chen, Xiangding; Tian, Qing; Deng, Hong-Wen; Zhang, Feng

    2016-08-22

    Kashin-Beck disease (KBD) is a chronic osteoarthropathy, which manifests as joint deformities and growth retardation. Only a few genetic studies of growth retardation associated with the KBD have been carried out by now. In this study, we conducted a two-stage bivariate genome-wide association study (BGWAS) of the KBD using joint deformities and body height as study phenotypes, totally involving 2,417 study subjects. Articular cartilage specimens from 8 subjects were collected for immunohistochemistry. In the BGWAS, ADAM12 gene achieved the most significant association (rs1278300 p-value = 9.25 × 10(-9)) with the KBD. Replication study observed significant association signal at rs1278300 (p-value = 0.007) and rs1710287 (p-value = 0.002) of ADAM12 after Bonferroni correction. Immunohistochemistry revealed significantly decreased expression level of ADAM12 protein in the KBD articular cartilage (average positive chondrocyte rate = 47.59 ± 7.79%) compared to healthy articular cartilage (average positive chondrocyte rate = 64.73 ± 5.05%). Our results suggest that ADAM12 gene is a novel susceptibility gene underlying both joint destruction and growth retardation of the KBD.

  3. 29 CFR 452.38 - Meeting attendance requirements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., where over 97 percent of the members were ineligible (Wirtz v. Local 153, Glass Bottle Blowers Ass'n... Blowers Ass'n., 290 F. Supp. 965 (N.D. Cal., 1968)); attendance at each of eight meetings in the...

  4. 77 FR 69450 - Notice of FERC Staff Attendance

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-19

    ... ER13-105-000 Cheyenne Light, Fuel and Power Company. ER13-120-000 Avista Corporation ER13-93-000 Avista... staff will attend a meeting conducted by representatives of WestConnect, ColumbiaGrid, Northern...

  5. 29 CFR 452.38 - Meeting attendance requirements.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., where over 97 percent of the members were ineligible (Wirtz v. Local 153, Glass Bottle Blowers Ass'n... Blowers Ass'n., 290 F. Supp. 965 (N.D. Cal., 1968)); attendance at each of eight meetings in the...

  6. 29 CFR 452.38 - Meeting attendance requirements.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., where over 97 percent of the members were ineligible (Wirtz v. Local 153, Glass Bottle Blowers Ass'n... Blowers Ass'n., 290 F. Supp. 965 (N.D. Cal., 1968)); attendance at each of eight meetings in the...

  7. 29 CFR 452.38 - Meeting attendance requirements.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., where over 97 percent of the members were ineligible (Wirtz v. Local 153, Glass Bottle Blowers Ass'n... Blowers Ass'n., 290 F. Supp. 965 (N.D. Cal., 1968)); attendance at each of eight meetings in the...

  8. 29 CFR 452.38 - Meeting attendance requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., where over 97 percent of the members were ineligible (Wirtz v. Local 153, Glass Bottle Blowers Ass'n... Blowers Ass'n., 290 F. Supp. 965 (N.D. Cal., 1968)); attendance at each of eight meetings in the...

  9. A new approach to sharp Moser-Trudinger and Adams type inequalities: A rearrangement-free argument

    NASA Astrophysics Data System (ADS)

    Lam, Nguyen; Lu, Guozhen

    The main purpose of this paper is two-fold. On the one hand, we will develop a new approach to establish sharp singular Moser-Trudinger and Adams type inequalities in unbounded domains of Euclidean spaces without using the standard symmetrization. On the other hand, we will prove the sharp singular Adams type inequality on high order Sobolev spaces W(Rn) of arbitrary integer order m (Theorem 1.1) which improves the results of Ruf and Sani (2013) [48] where sharp Adams inequalities were established for even m and those of the authors (Lam and Lu, 2012 [28,29]) for odd m but with different and more restricted norms. We first establish the sharp local singular Adams inequality on domains Ω in Rn of finite measure (Theorem 1.4). We take a perspective that any function in the high order Sobolev spaces W(Rn) can be represented as a Bessel potential. Thus, we can fully use the tools from harmonic analysis and the kernel properties of the polyharmonic operators (. Once we have established this sharp local Adams inequality, then we can adapt the rearrangement-free method we will develop in this paper to derive a global sharp Adams inequality from a local one. Our argument substantially simplifies those in Ruf and Sani (2013) [48] and Lam and Lu (2012) [28,29] and avoids the use of rather deep and complicated comparison principle of solutions to polyharmonic operators used in Ruf and Sani (2013) [48], Lam and Lu (2012) [28,29]. Moreover, our theorem holds on Sobolev spaces W(Rn) of any positive fractional order αAdams inequalities with less restrictions on the Sobolev norms (see Theorems 1.2, 1.3 and 1.5). Our approach is surprisingly simple and general and can be easily applied to scenarios such as Riemannian and sub-Riemannian manifolds where symmetrization argument does not work (see, e.g., on the Heisenberg group Lam and Lu (2012) [30]).

  10. True Color of Mars - Pathfinder Sol 24 at 4 PM

    NASA Technical Reports Server (NTRS)

    1999-01-01

    The brownish gray sky as it would be seen by an observer on Mars in this four-frame, true color mosaic taken on sol 24 (at approximately 1610 LST). The twin peaks can be seen on the horizon. The sky near the sun is a pale blue color. Azimuth extent is 60o and elevation extent is approximately 12odegrees. A description of the techniques used to generate this color image from IMP data can be found in Maki et al., 1999 (see full reference in Image Note). Note: a calibrated output device is required accurately reproduce the correct colors.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal investigator.

  11. Adam Smith's invisible hand is unstable: physics and dynamics reasoning applied to economic theorizing

    NASA Astrophysics Data System (ADS)

    McCauley, Joseph L.

    2002-11-01

    Neo-classical economic theory is based on the postulated, nonempiric notion of utility. Neo-classical economists assume that prices, dynamics, and market equilibria are supposed to be derived from utility. The results are supposed to represent mathematically the stabilizing action of Adam Smith's invisible hand. In deterministic excess demand dynamics, however, a utility function generally does not exist mathematically due to nonintegrability. Price as a function of demand does not exist and all equilibria are unstable. Qualitatively, and empirically, the neo-classical prediction of price as a function of demand describes neither consumer nor trader demand. We also discuss five inconsistent definitions of equilibrium used in economics and finance, only one of which is correct, and then explain the fallacy in the economists’ notion of ‘temporary price equilibria’.

  12. Cost-effectiveness of Project ADAM: a project to prevent sudden cardiac death in high school students.

    PubMed

    Berger, S; Whitstone, B N; Frisbee, S J; Miner, J T; Dhala, A; Pirrallo, R G; Utech, L M; Sachdeva, R C

    2004-01-01

    Public access defibrillation (PAD) in the adult population is thought to be both efficacious and cost-effective. Similar programs aimed at children and adolescents have not been evaluated for their cost-effectiveness. This study evaluates the potential cost-effectiveness of implementing Project ADAM, a program targeting children and adolescents in high schools in the Milwaukee Public School System. Project ADAM provides education about cardiopulmonary resuscitation (CPR) and the warning signs of sudden cardiac death (SCD) and training in the use and placement of automated external defibrillators (AEDs) in high schools. We developed decision analysis models to evaluate the cost-effectiveness of the decision to implement Project ADAM in public high schools in Milwaukee. We examined clinical model and public policy applications. Data on costs included estimates of hospital-based charges derived from a pediatric medical center where a series of patients were treated for SCD, educational programming, and the direct costs of one AED and training for 15 personnel per school. We performed sensitivity analyses to assess the variation in outputs with respect to changes to input data. The main outcome measures were Life years saved and incremental cost-effectiveness ratios. At an arbitrary societal willingness to pay $100,000 per life year saved, the policy to implement Project ADAM in schools is a cost-effective strategy at a threshold of approximately 5 patients over 5 years for the clinical model and approximately 8 patients over 5 years for the public policy model. Implementation of Project ADAM in high schools in the United States is potentially associated with an incremental cost-effectiveness ratio that is favorable.

  13. Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE

    PubMed Central

    Orme, Jacob J.; Du, Yong; Vanarsa, Kamala; Mayeux, Jessica; Li, Li; Mutwally, Azza; Arriens, Cristina; Min, Soyoun; Hutcheson, Jack; Davis, Laurie S.; Chong, Benjamin F.; Satterthwaite, Anne B.; Wu, Tianfu; Mohan, Chandra

    2016-01-01

    Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE. PMID:27237127

  14. Anxiety as a risk factor for school absenteeism: what differentiates anxious school attenders from non-attenders?

    PubMed Central

    2013-01-01

    Background Anxiety is a major risk factor for problematic school absenteeism. However, most anxious students attend school. What differentiates anxious attenders from non-attenders? Method High school students (N = 865) were assigned to groups based on anxiety and absenteeism scores. These groups were then tested for differences in risk factor profiles using discriminant analysis. Results Anxious school attenders were less affected by negative personality traits, total number of risk factors, social anxiety, panic, and behavioural and family problems. They also displayed greater resilience. Conclusions This study indicates that the risk for problematic school absenteeism increases as the number of risk factors aggregate and that treatment for anxious school refusal should be based on a profile of the individual's risk factors. PMID:23886245

  15. Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury.

    PubMed

    Dulauroy, Sophie; Di Carlo, Selene E; Langa, Francina; Eberl, Gérard; Peduto, Lucie

    2012-08-01

    Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α-positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12(+) cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12(+) cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12(+) cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12(+) cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.

  16. Mobile Attendance Checking System on Android Platform for Kazakhstani University

    NASA Astrophysics Data System (ADS)

    Saparkhojayev, N.; Shakhov, E.; Mailybayev, Y.

    2016-04-01

    In the 21st century-the century of Information Technology, it is difficult to imagine life without any gadgets: phones, tablets, computers, laptops, and so on. Today, smartphones and tablets are becoming popular, and thus their operating systems become popular too. Android is designed for low-power devices that run on battery power at full capacity, using all of its services, such as cameras, lights, GPS navigation, Wi-Fi, etc. In Kazakhstani universities, the process of checking students’ attendance is one of the important issues, because final grade evaluation of students is based on their total number of appearances and their grades during the whole semester. This raises the question of having some tool to control students’ attendance. There are many possible ways of controlling attendance: there are many examples when universities prefer to control attendance by the use of paper sheet, and some universities prefer to use two-stage way of controlling attendance: firstly, teachers and professors use paper sheet for checking students’ attendance and after this, they fill out these information into a system manually. However, this is not an efficient way since there will be spent much of time for calling students names and putting marks like “presence” or “absence” if the class is a lecture class, and in this class at least 5 groups are presented. Furthermore, some students may call his/her friend as “presence” nevertheless to the fact that this student is currently absent. After taking into consideration all these issues and the fact that many gadgets use Android platform, authors of the following research paper decided to create a mobile system that makes easier to check students’ attendance automatically, and this system is implemented in Almaty Management University, Kazakhstan. The system is based on Android platform, and in this paper, details of this system are presented.

  17. Evaluation of School Uniform Policy at John Adams and Truman Middle Schools for Albuquerque Public Schools.

    ERIC Educational Resources Information Center

    Elder, Deborah L.

    A uniform policy at two Albuquerque middle schools became a reality as a result of parent initiative. Parents provided input through attending meetings and a fashion show, serving on the uniform task force, completing surveys, voting, and revisiting the policy. Parents not only initiated the development of the policy, but were active participants…

  18. Predicting Scheduling and Attending for an Oral Cancer Examination

    PubMed Central

    Shepperd, James A.; Emanuel, Amber S.; Howell, Jennifer L.; Logan, Henrietta L.

    2015-01-01

    Background Oral and pharyngeal cancer is highly treatable if diagnosed early, yet late diagnosis is commonplace apparently because of delays in undergoing an oral cancer examination. Purpose We explored predictors of scheduling and attending an oral cancer examination among a sample of Black and White men who were at high risk for oral cancer because they smoked. Methods During an in-person interview, participants (N = 315) from rural Florida learned about oral and pharyngeal cancer, completed survey measures, and were offered a free examination in the next week. Later, participants received a follow-up phone call to explore why they did or did not attend their examination. Results Consistent with the notion that scheduling and attending an oral cancer exam represent distinct decisions, we found that the two outcomes had different predictors. Defensive avoidance and exam efficacy predicted scheduling an examination; exam efficacy and having coping resources, time, and transportation predicted attending the examination. Open-ended responses revealed that the dominant reasons participants offered for missing a scheduled examination was conflicting obligations, forgetting, and confusion or misunderstanding about the examination. Conclusions The results suggest interventions to increase scheduling and attending an oral cancer examination. PMID:26152644

  19. Migrant home attendants: regulation and practice in 7 countries.

    PubMed

    Cohen-Mansfield, Jiska; Garms-Homolová, Vjenka; Bentwich, Miriam

    2013-12-01

    We compared regulation and working and living conditions of foreign home attendants in 7 countries (Canada, Germany, Israel, Singapore, Spain, United Kingdom, United States). We conducted a literature search in the PSYCinfo, MEDLINE, and Google Scholar databases for 2002 to 2012. We found substantial between-country differences in the legal status of migrant caregivers and regulations regarding working and living conditions and drew 3 conclusions. Improving regulations will likely improve not only the well-being of foreign home attendants but also the care they provide. Countries in which many foreign home attendants work without specific legal entry programs should rethink their policies. Finally, requiring an employer's recommendation to obtain permanent residency may constrain foreign workers from registering complaints or leaving suboptimal employment situations.

  20. Skilled attendants for pregnancy, childbirth and postnatal care.

    PubMed

    de Bernis, Luc; Sherratt, Della R; AbouZahr, Carla; Van Lerberghe, Wim

    2003-01-01

    This paper sets out the rationale for ensuring that all pregnant women have access to skilled health care practitioners during pregnancy and childbirth. It describes why increasing access to a skilled attendant, especially at birth, is not only based on legitimate demand and clinical common sense, but is also cost-effective and feasible in resource-poor countries. Skilled attendants need to be supported by a health system providing a legal and policy infrastructure, an effective referral system and the supplies that are necessary for effective care. A skilled attendant providing skilled care will help achieve the goals of reducing both maternal and child mortality. Health care professionals as individual practitioners, leaders and informers have an important role in making this a reality.