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This report is based on the findings of an on-going plagiarism analysis (date: 2014-02-28). It is therefore not a final or conclusive report. It is recommended to visit the page http://de.vroniplag.wikia.com/wiki/Arc for the current state of the findings and further information.

A critical discussion of the thesis by Dr. Ana Catarina Ribeiro Carrão: A new insight on direct actions of Granulocyte-Colony Stimulating Factor in the myocardium

Submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin, in fulfillment of the requirements for the degree of Doctor rerum naturalium (Dr. rer. nat.), 1st reviewer: Prof. Dr. Petra Knaus, 2nd reviewer: PD Dr. Ivo Buschmann Date of defence: 4th June 2009 → Download DNB

The barcode displays a visualization of the pages that contain plagiarism, not the amount of plagiarism in the main text. Depending on the amount of plagiarized text there are three colors that are used:

  • black: up to 50 % of the lines on the page are plagiarized
  • dark red: between 50 % and 75 % of the lines on the page are plagiarized
  • light red: over 75 % of the lines on the page are plagiarized.

White pages have either not yet been investigated or nothing was found. Blue pages contain matter such as the title page, the table of contents, the reference section, empty pages and appendices. These are all not included in the calculations.

The barcode only shows the current state of the investigation. This is not the final result, as each case may continue to be worked on and added to by anyone as new sources turn up. Thus, a final state does not exist.

There are 32 pages containing plagiarism.

Pages with less than 50% plagiarism

16 pages: 015 016 017 018 020 030 031 032 033 036 037 038 042 043 046 050

Pages with between 50%-75% plagiarism

4 pages: 012 021 034 044

Pages with more than 75% plagiarism

12 pages: 013 014 019 022 023 024 028 029 040 041 047 049

Findings

  • Problematic text parallels can be found in the following chapters:
    • 1. Introduction
      • Chapter I: G-CSF and its biological actions (p. 12 [beginning]): page 12
        • I.1 Identification of G-CSF and its gene (p. 12-15): pages 12, 13, 14, 15 – [almost completely]
        • I.2 Production of G-CSF: cellular sources and physiological roles (p. 15-16): page 16
        • I.3 Granulocyte-Colony Stimulating Factor Receptor (p. 16-18): page 17
        • I.4 Signalling pathways activated by G-CSF and its receptor (p. 18-21): pages 18, 19, 20
        • I.5 Neutrophils and Reactive Oxygen Species (ROS) (p. 21-22): pages 21, 22 – [completely]
        • I.6 NADPH oxidase (p. 22-24): pages 22, 23, 24 – [almost completely]
      • Chapter II: Mechanisms of vascular growth (p. 28 [beginning]): page 28 – [completely]
        • II.1 Vasculogenesis and Angiogenesis (p. 28-31): pages 29, 30
        • II.2 Coronary Collateral Growth (CCG) (p. 31-32): pages 31, 32
        • II.3 Controversies on CCG (p. 32-35): pages 32, 33, 34
        • II.4 Redox-dependent signalling in CCG (p. 36-38): pages 36, 37, 38
    • 3. Methods
      • 3.1 Animal preparation for rat model of collateral growth (p. 40-41): pages 40, 41 – [completely]
      • 3.2 Mini-Pneumatic Snare Occluder for Rat Heart (p. 41): page 41 – [completely]
      • 3.2 [sic] Microsphere measurements of myocardial and collateral-dependent blood flow (p. 42-43): pages 42, 43 – [completely]
      • 3.4 Measurement of oxidative stress (p. 43-44): page 44
      • 3.9 Endothelial tube formation promoted by G-CSF cardiomyocyte stimulation media (p. 46-47): pages 46, 47
      • 3.9 [sic] Data analysis (p. 47): 47 – [completely]
    • 4. Results
      • 4.2 G-CSF induces Coronary Collateral Growth (CCG) (p. 49-50): pages 49, 50.
  • The images and tables in chapters 1-3 (without a single exception) have been copied from other publications without naming the source. In every single instance another source is given that however does not contain the copied material: Fig. 1, Fig. 2A, Fig. 2B, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig.7, Fig. 8A, Fig. 8B, Fig.9, Fig. 10, Fig. 11, Tab. 1

Prominent fragments

  • Fragment 019 01: An entire page including 9 references to the literature have been taken from a source that is only mentioned at the end of the page.
  • Fragment 021 11: Substantial text and two references to the literature have been copied without naming the source.
  • Fragment 032 11: This fragment is an example for an image that has been copied without naming the source.
  • Fragment 049 02: This fragment is remarkable because it documents a substantial text parallel in the chapter "4. Results". The source is not mentioned.

Prominent sources

Other observations

  • The section numbers 3.2, 3.3 and 3.9 have been assigned twice.

Statistic

  • Currently there are 41 reviewed fragments documented that are considered to be violations of citation rules. For 25 of them there is no reference given to the source used („Verschleierungen“ and „Komplettplagiate“). For 16 fragments the source is given, but the extent of the used text is not made clear („Bauernopfer“).
  • The publication has 51 pages that have been analyzed. On a total of 32 of these pages violations of citation rules have been documented. This represents a percentage of 62.7%. The 51 analyzed pages break down with respect to the amount of text parallels encountered as follows:
Percentage text parallels Number of pages
No text parallels documented 19
0%-50% text parallels 16
50%-75% text parallels 4
75%-100% text parallels 12
From these statistics an extrapolation of the amount of text of the publication under investigation that has been documented as problematic can be estimated (conservatively) as about 26% of the main part of the publication.


Illustration

The following chart illustrates the amount and the distribution of the text parallel findings. The colours show the type of plagiarism diagnosed:

  • grau="Komplettplagiat" (copy & paste): the source of the text parallel is not given, the copy is verbatim.
  • rot="Verschleierung" (disguised plagiarism): the source of the text parallel is not given, the copied text will be somewhat modified.
  • gelb="Bauernopfer" (pawn sacrifice): the source of the text parallel is mentioned, but the extent and/or the closeness of the copy to the source is not made clear by the reference.

Arc col.png

Definitions of plagiarism categories

The plagiarism categories used here are based on the discussion found at Wohnsdorf / Weber-Wulff: Strategien der Plagiatsbekämpfung, 2006. A complete description of the categories (in German) can be found at the VroniPlag-Wiki. In particular, the categories are:

Komplettplagiat (copy and paste)

The source of the text parallel is not given, the copy is verbatim.

Verschleierung (disguised plagiarism)

The source of the text parallel is not given, the copied text will be somewhat modified or disguised.

Bauernopfer (pawn sacrifice)

The source of the text parallel is mentioned, but the extent and/or closeness of the copying is not made clear by the reference.

Sources tabulated by plagiarism category

The following table lists all of the reviewed fragments by source (rows) and by plagiarism category (columns).

Table: Arc: Sources / Fragments
Source
Year ÜP
KP
VS
BO
KW
KeinP

To be reviewed
In progress
Arc
Avalos 1996 0 1 1 0 0 0 2 0 0
Basu et al 2002 0 0 0 0 0 0 0 1 0
Becker et al 1999 0 1 0 0 0 0 1 0 0
Bedard Krause 2007 0 0 2 3 0 0 5 0 0
Demetri and Griffin 1991 0 1 1 3 0 0 5 0 0
Fukunaga et al 1991 0 0 0 0 0 0 0 1 0
Haghighat et al 2007 0 0 0 0 0 0 0 1 0
Heil Schaper 2004 0 0 0 2 0 0 2 0 0
Koerselman et al 2003 0 1 0 1 0 0 2 0 0
Liu et al 2008 0 0 1 0 0 0 1 0 0
Maulik et al 1998 0 0 1 0 0 0 1 0 0
Nagata Fukunaga 1991 0 1 0 0 0 0 1 0 0
Quinn and Gauss 2004 0 0 1 1 0 0 2 0 0
Risau 1997 0 0 0 2 0 0 2 0 0
Rocic et al 2007 0 0 3 0 0 0 3 0 0
Sampson et al 2007 0 0 1 2 0 0 3 0 0
Simons Ware 2003 0 0 1 0 0 0 1 0 0
Ten Dijke Arthur 2007 0 0 1 0 0 0 1 0 0
Toyota et al 2005 0 1 5 1 0 0 7 0 0
Ushio-Fukai 2006 0 0 0 1 0 0 1 0 0
Ward et al 1999 0 0 1 0 0 0 1 0 0
- 0 6 19 16 0 0 41 3 0



Fragments

41 reviewed fragments

FragmentSeiteArbeitZeileArbeitQuelleSeiteQuelleZeileQuelleTypus
Arc/Fragment 012 03123-11Demetri and Griffin 19912791left col. 1-14Verschleierung
Arc/Fragment 012 191219-29Demetri and Griffin 19912791left col. 16-32BauernOpfer
Arc/Fragment 013 01131-6, 8-34Demetri and Griffin 19912791-27922791:left col. 29-32.34-37.39-43 - right col. 1-2.4-29.33-36 - 2791:left col. 1-2.26-30.32-35BauernOpfer
Arc/Fragment 014 01141-14, 17-29Demetri and Griffin 199127922792: left col. 32-35; right col. 17-25.39-43.48-55; 2793: left col. 13-22 - right col. 1-9BauernOpfer
Arc/Fragment 015 01151-1Demetri and Griffin 19912793figureKomplettPlagiat
Arc/Fragment 016 09169-16Avalos 1996761l.col: 20ffVerschleierung
Arc/Fragment 017 01171-6Ward et al 199914956r.col: 12-16,19-22Verschleierung
Arc/Fragment 017 161716-27Avalos 1996763figureKomplettPlagiat
Arc/Fragment 017 281728-37Nagata Fukunaga 199113716ffKomplettPlagiat
Arc/Fragment 018 251825-31Sampson et al 20071 (online source)-BauernOpfer
Arc/Fragment 019 01191-34Sampson et al 20071 (online source)-BauernOpfer
Arc/Fragment 020 03203-4Sampson et al 20071 (online source)figures sectionVerschleierung
Arc/Fragment 021 112111-21Quinn and Gauss 2004760r.col: 16ffVerschleierung
Arc/Fragment 021 222122-30Bedard Krause 2007246l.col: 9ffBauernOpfer
Arc/Fragment 022 01221-13Bedard Krause 2007246l.col: 21ffBauernOpfer
Arc/Fragment 022 152215-24Quinn and Gauss 2004761l.col: 23ffBauernOpfer
Arc/Fragment 023 01231-5Bedard Krause 2007248, 252248: 1ff; 252: 1ffVerschleierung
Arc/Fragment 024 06246-19Bedard Krause 2007249, 250249: l.col: 16ffBauernOpfer
Arc/Fragment 028 01281-15, legend to fig. 5Risau 19976711; left col. 1-12.17-22; legend to fig. 1BauernOpfer
Arc/Fragment 029 01291-17, legend to fig. 6Risau 1997671, 672671: left col. 22-29 - right col. 1-9.23-25; 672: legend to fig. 2; left col. 2-7BauernOpfer
Arc/Fragment 030 01301-5Ten Dijke Arthur 2007863figure captionVerschleierung
Arc/Fragment 031 223122-29Koerselman et al 20032507l.col: 24-29, r.col:23-27BauernOpfer
Arc/Fragment 032 103210-13Simons Ware 20032, 3, 42: r.col: last lines; 3: l.col: 1; 4: figureVerschleierung
Arc/Fragment 032 113210-10Koerselman et al 20032508top of pageKomplettPlagiat
Arc/Fragment 033 253325-29Heil Schaper 2004450r.col: 14ffBauernOpfer
Arc/Fragment 034 01341-11Heil Schaper 2004450, 451450: r.col: 1ff; 451: l.col: 1ffBauernOpfer
Arc/Fragment 036 123612-14Bedard Krause 200724629-33Verschleierung
Arc/Fragment 037 01370-1Ushio-Fukai 20062311ffBauernOpfer
Arc/Fragment 037 113711-16Maulik et al 1998365l.col: 33-40Verschleierung
Arc/Fragment 038 01381-11Liu et al 20081, 21: 33-39 - 2: 1-3,9-11Verschleierung
Arc/Fragment 040 03403-32Toyota et al 20052109l.col: 10-46BauernOpfer
Arc/Fragment 041 01411-22Toyota et al 20052109l.col: 46ffVerschleierung
Arc/Fragment 042 164216-29Toyota et al 20052109r.col: 13ffVerschleierung
Arc/Fragment 043 01431-5Toyota et al 20052109r.col: 40ffVerschleierung
Arc/Fragment 044 01441-6Becker et al 1999H2241l.col: 21-31KomplettPlagiat
Arc/Fragment 044 154415-25Rocic et al 2007H2730left col. 33-47Verschleierung
Arc/Fragment 046 254625-27Rocic et al 2007H2730right col. 3-8Verschleierung
Arc/Fragment 047 01471-5 (complete)Rocic et al 2007H2730right col. 3-8, 22-26Verschleierung
Arc/Fragment 049 02492-11Toyota et al 20052109, 21102109: r.col: last two lines; 2110: l.col: 1ffVerschleierung
Arc/Fragment 049 144914-19Toyota et al 20052109r.col: 36-42Verschleierung
Arc/Fragment 050 01501-2Toyota et al 20052109r.col: 42-44KomplettPlagiat

Fragments

Remark on the colouring

The colouring is automatically generated and shows text parallels. Its purpose is to facilitate the orientation of the reader, it does not, however, automatically diagnose plagiarism of any kind. In order to form a judgement about a certain text parallel one should consult the text itself.

Remark on the line numbering

When identifying a fragment with line numbers everything that contains text (except for the page header and/or footer) is counted, including headings. However, charts and tables, including their captions, are usually not counted.

41 reviewed fragments

[1.] Arc/Fragment 012 03

Verschleierung
Untersuchte Arbeit:
Seite: 12, Zeilen: 3-11
Quelle: Demetri and Griffin 1991
Seite(n): 2791, Zeilen: left col. 1-14
Granulocyte-colony stimulating factor (G-CSF) is a polypeptide growth factor that regulates the production of neutrophilic granulocytes. This physiological process serves as the foundation for critical host defence systems and occurs on a large scale in vivo. An adult of average size will produce approximately 120 billion granulocytes per day simply to replace normal losses1. This enormous production capacity may be increased by at least 10-fold under stress conditions such as infection. G-CSF plays a pivotal role in the basal regulation of neutrophil production as well as functioning as a primary regulatory factor controlling the neutrophil response to inflammatory stimuli. Also, G-CSF exhibits other biological activities and G-CSF-induced hematopoietic stem cell mobilization is widely used clinically for peripheral blood stem cell transplantation.

1. Basu S, Dunn A, Ward A. G-CSF: function and modes of action (Review). Int J Mol Med. 2002;10:3-10.

GRANULOCYTE colony-stimulating factor (G-CSF) is a polypeptide growth factor that regulates the production of neutrophilic granulocytes. This physiologic process serves as the foundation for critical host defense systems and occurs on a large scale in vivo. An adult of average size will produce approximately 120 billion granulocytes per day simply to replace normal losses. This enormous production capacity may be increased by at least 10-fold under stress conditions such as infection. G-CSF is likely to play a role in the basal regulation of neutrophil production as well as to function as a primary regulatory factor controlling the neutrophil response to inflammatory stimuli. Further, G-CSF exhibits other biologic activities besides proliferative effects: [...]
Anmerkungen

This passage is not recognizable as a citation.


[2.] Arc/Fragment 012 19

BauernOpfer
Untersuchte Arbeit:
Seite: 12, Zeilen: 19-29
Quelle: Demetri and Griffin 1991
Seite(n): 2791, Zeilen: left col. 16-32
G-CSF possesses unique and interesting characteristics among the family of hematopoietic growth factors. This chapter will summarize the current state of knowledge of the structure and function of G-CSF and its receptor.

I.1 Identification of G-CSF and its gene

The identification of CSFs was made possible by cell culture assays for hematopoietic progenitor cells developed in the mid 1960s by Metcalf and his colleagues2. These in vitro systems showed that the survival, proliferation, and differentiation of immature hematopoietic cells were dependent on the continued presence of humoral factors, which was collectively termed “colony-stimulating activity” (CSA)3. Before the purification of individual factors, early sources of CSA [included media that was conditioned by stimulated cultures of normal blood or certain tumour cells.]


2. Bradley TR, Robinson W, Metcalf D. Colony production in vitro by normal polycythaemic and anaemic bone marrow. Nature. 1967;214:511.

3. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78:2791-2808.

G-CSF possesses unique and interesting characteristics among the family of hematopoietic growth factors. This review will summarize the current state of knowledge of the structure and function of G-CSF and its receptor.

IDENTIFICATION OF G-CSF

The identification of CSFs was made possible by the cell culture assays for hematopoietic progenitor cells, which were developed in the mid 1960s independently by Metcalf, Sachs, and their colleagues. These in vitro systems showed that the survival, proliferation, and differentiation of immature hematopoietic cells were dependent on the continued presence of humoral factors, which were collectively termed “colony-stimulating activity” (CSA). Before the purification of individual factors, early sources of CSA included media conditioned by culture with stimulated normal blood or splenic leukocytes, placenta, or certain tumor cells1-5.


1. Metcalf D: The granulocyte-macrophage colony-stimulating factors. Science 229:16, 1985

2. Metcalf D: The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature 339:27, 1989

3. Sachs L The molecular control of blood cell development. Science 238:1374, 1987

4. Quesenberry P, Levitt L Hematopoietic stem cells. N Engl J Med 301:755,1979

5. Golde D, Cline M: Regulation of granulopoiesis. N Engl J Med 291:1388,1974

Anmerkungen

At the end of the page the source is given. Nevertheless nothing has been marked as a citation and it is not clear to the reader that even the end of the previous section is taken verbatim from the source.


[3.] Arc/Fragment 013 01

BauernOpfer
Untersuchte Arbeit:
Seite: 13, Zeilen: 1-6, 8-34
Quelle: Demetri and Griffin 1991
Seite(n): 2791-2792, Zeilen: 2791:left col. 29-32.34-37.39-43 - right col. 1-2.4-29.33-36 - 2791:left col. 1-2.26-30.32-35
[Before the purification of individual factors, early sources of CSA] included media that was conditioned by stimulated cultures of normal blood or certain tumour cells. It was initially unclear whether these complex mixtures contained both individual factors specific for proliferation and/or separate factors that would specifically induce differentiation. Further investigation showed that many of these biological activities were attributable to the simultaneous presence of multiple factors in the crude medium. [In 1978, Byrne et al.4 reported that medium that was conditioned by mouse heart tissue was found to contain CSFs which produce in vitro colonies of granulocytes and/or macrophages.] Purification of these CSFs proved difficult and for many factors, expression, cloning and production of recombinant proteins were required to completely define the unique biological properties of individual CSFs. G-CSF was probably first identified as having a distinct activity by Burgess and Metcalf5, not by its ability to stimulate proliferation, but rather by the capacity of postendotoxin-treated mouse serum to induce differentiation in a murine leukemic cell line. Therefore, Metcalf initially termed G-CSF a granulocyte-macrophage differentiation factor (GM-DF) and he noted it to be related to (or being the same as) the so-called macrophage- and granulocyte-inducing proteins, reported by Lotem et al.6. GM-DF was shown to be separate from GM-CSF, which had been partially purified in the late 1970s. This distinction was experimentally determined by the generation of neutralizing antiserum that could block the effects of GM-CSF, but which failed to block the activity of GM-DF. GM-DF was then shown to co-purify with a novel medium that selectively stimulated the formation of granulocytic colonies from normal hematopoietic progenitor cells in vitro7 and, after further purification, this factor was ultimately renamed G-CSF8. Nicola et al.8 described the biochemical characteristics of murine G-CSF in 1983, as a hydrophobic glycoprotein with an apparent molecular weight of 24-25 Kd, containing a neuraminic acid moiety and at least one internal disulfide bond that was necessary for its biological activity. After the identification of the murine G-CSF, a human molecule with analogous activities was discovered9. Both the proliferation- and differentiation-inducing activities of the murine and human G-CSF molecules cross species boundaries, in contrast to other hematopoietic growth factors such as GM-CSF or interleukin-3 (IL-3) which are active in a species-specific manner on the neutrophilic cell lineage3. In 1986, Nomura et al.10 finally described G-CSF as a molecule that specifically induces growth of the neutrophilic granulocyte lineage of cells.

Further understanding of the biological and biochemical properties of G-CSF was greatly facilitated by cloning of the gene encoding G-CSF and the production of [recombinant protein for study11, 12.]


3. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78:2791-2808.

4. Byrne PV, Heit W, Kubanek B. Stimulation of in vitro granulocyte--macrophage colony formation by mouse heart conditioned medium. Br J Haematol. 1978;40:197-204.

5. Burgess AW, Metcalf D. Characterization of a serum factor stimulating the differentiation of myelomonocytic leukemic cells. Int J Cancer. 1980;26:647-654.

6. Lotem J, Lipton JH, Sachs L. Separation of different molecular forms of macrophage- and granulocyte-inducing proteins for normal and leukemic myeloid cells. Int J Cancer. 1980;25:763-771.

7. Metcalf D. Clonal extinction of myelomonocytic leukemic cells by serum from mice injected with endotoxin. Int J Cancer. 1980;25:225-233.

8. Nicola NA, Metcalf D, Matsumoto M, Johnson GR. Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem. 1983;258:9017-9023.

9. Nicola NA, Begley CG, Metcalf D. Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells. Nature. 1985;314:625-628.

10. Nomura H, Imazeki I, Oheda M, Kubota N, Tamura M, Ono M, Ueyama Y, Asano S. Purification and characterization of human granulocyte colonystimulating factor (G-CSF). Embo J. 1986;5:871-876.

11. Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, Ono M. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature. 1986;319:415-418.

12. Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986;232:61-65.

[Page 2791]

Before the purification of individual factors, early sources of CSA included media conditioned by culture with stimulated normal blood or splenic leukocytes, placenta, or certain tumor cells1-5. [...] It was initially unclear whether the complex mixtures termed CSA contained individual factors specific for proliferation and separate factors that specifically induced differentiation. [...] Further investigation showed that many of these biologic activities were attributable to the simultaneous presence of multiple factors in the crude CSA. Purification of the CSFs proved difficult, and, for many factors, expression cloning and production of recombinant protein were required to completely define the unique biologic properties of individual CSFs.

[...] G-CSF was probably first identified as a distinct activity by Burgess and Metcalf, not by its ability to stimulate proliferation, but rather by the capacity of postendotoxin-treated mouse serum or conditioned media to induce differentiation of a murine myelomonocytic leukemia cell line, the differentiation-responsive (D+) subline of WEHI3B cells6,7. Therefore, G-CSF was initiaIly termed a granulocyte-macrophage differentiation factor (GM-DF) by Metcalf’ and was noted to be related to (or the same as) a differentiating activity named MGI-1G by Lotem et al.8 G-CSF was shown to be separate from GM-CSF, which had been partially purified in the late 1970s. This distinction was experimentally determined by the generation of neutralizing antisera that could block the effects of GM-CSF but which failed to block the activity of GM-DF. GM-DF was then shown to copurify with a novel activity that selectively stimulated the formation of granulocytic colonies by normal hematopoietic progenitor cells in vitro,’ and after further purification, this factor was ultimately renamed G-CSF.9 Nicola et al9 described the biochemical characteristics of murine G-CSF in 1983 as a hydrophobic glycoprotein with an apparent molecular weight of 24 or 25 Kd, containing a neuraminic acid moiety and at least one internal disulfide bond necessary for biologic activity.

After the identification of the murine G-CSF, a human molecule with analogous activities was discovered. [...] Both the proliferation- and differentiation-inducing activities of the murine and human G-CSF molecules crossed species boundaries, in contrast to other hematopoietic growth factors such as

[Page 2792]

GM-CSF or interleukin-3 (IL-3), which are active on the neutrophilic lineage in a species-specific manner. [...] Nomura et al15 purified native human G-CSF from culture medium conditioned by the tumor cell line CHU-2 and described its properties as a molecule that specifically induced the growth of cells of the neutrophilic granulocyte lineage.15

CLONING OF THE G-CSF GENE

Further understanding of the biologic and biochemical properties of G-CSF was greatly facilitated by cloning of the gene encoding G-CSF and the production of recombinant protein for study.


1. Metcalf D: The granulocyte-macrophage colony-stimulating factors. Science 229:16, 1985

2. Metcalf D: The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature 339:27, 1989

3. Sachs L The molecular control of blood cell development. Science 238:1374, 1987

4. Quesenberry P, Levitt L Hematopoietic stem cells. N Engl J Med 301:755,1979

5. Golde D, Cline M: Regulation of granulopoiesis. N Engl J Med 291:1388,1974

6. Burgess A, Metcalf D: Characterization of a serum factor stimulating the differentiation of myelomonocytic leukemia cells. Int J Cancer 26:647,1980

7. Metcalf D: Clonal extinction of myelomonocytic leukemia cells by serum from mice injected with endotoxin. Int J Cancer 25:225,1980

8. Lotem J, Lipton J, Sachs L Separation of different molecular forms of macrophage and granulocyte-inducing proteins for normal and leukemic myeloid cells. Int J Cancer 25:763,1980

9. Nicola NA, Metcalf D, Matsumoto M, Johnson G R Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem 258:9017,1983

10. Nicola NA, Begley CG, Metcalf D: Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells. Nature 314:625,1985

14. Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, Barendt J, Platzer E, Moore MAS, Mertelsmann R, Welte K Recombinant human granulocyte colony-stimulating factor: Effects on normal and leukemic myeloid cells. Science 232:61,1986

15. Nomura H, Imazeki I, Oheda M, Kubota N, Tamura M, Ono M, Ueyama Y, Asano S: Purification and characterization of human granulocyte colony-stimulating actor (G-CSF). EMBO J 5:871,1986

17. Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto 0, Hirata Y, Kubota N, Oheda M, Nomura H, Ono M: Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature 319:415,1986

Anmerkungen

Although in this page all but one sentence has been taken - mostly verbatim - from the source Demetri and Griffin (1991) nothing has been marked as a citation, and the source is only given in passing.


[4.] Arc/Fragment 014 01

BauernOpfer
Untersuchte Arbeit:
Seite: 14, Zeilen: 1-14, 17-29
Quelle: Demetri and Griffin 1991
Seite(n): 2792, Zeilen: 2792: left col. 32-35; right col. 17-25.39-43.48-55; 2793: left col. 13-22 - right col. 1-9
[Further understanding of the biological and biochemical properties of G-CSF was greatly facilitated by cloning of the gene encoding G-CSF and the production of] recombinant protein for study11, 12.

Southern blot analysis of genomic human DNA showed that G-CSF is encoded by a single gene11, 13, and further studies determined that this single gene is located on chromosome 17q11-2214, 15. The genomic structure of the human G-CSF gene was determined by Nagata et al13, revealing that G-CSF gene consists of 5 exons spread over a locus of approximately 2.3 kb (Fig. 1). At the 5’-terminus of the second intron, two donor splice sequences are present in the tandem, only 9 bp apart. The localization of human G-CSF on chromosome 17 differs from that of several other human hematopoietic growth factors such as GM-CSF, IL-3, IL-4 and IL-5, which are clustered on the long arm of the chromosome 516. Following the description of the cDNA for human G-CSF, the murine G-CSF was cloned by crosshybridization with a human G-CSF cDNA probe. The murine G-CSF gene is highly homologous with the human gene, with 69% nucleic acid sequence homology in both coding and non-coding regions, and a 73% sequence homology in the predicted amino acid sequence of the protein17.[...]

The human G-CSF gene is distantly related to the IL-6 gene. The number, location and size of the introns and exons that comprise these two genes are similar. Additionally, the amino acid sequences of G-CSF and IL-6 share some localized homology. Between amino acid residues 20 to 85 of G-CSF, the positions of 17 residues match with residues located between positions 28 to 91 of the IL-6 molecule, which yields a sequence homology for this region of 26%3. Additionally, the positions of four cysteine residues are precisely conserved between G-CSF and IL-6 in this region of relative homology. The tertiary structure of G-CSF may be quite similar to that of IL-6, particularly if intra-chain disulfide bridges are similarly located within these molecules. Thus, it is possible that the genes encoding G-CSF and IL-6 may have arisen from a gene duplication event after which they have subsequently diverged. There is no linkage of chromosomal localization between G-CSF and IL-6, because human IL-6 is located at chromosome 7p1519.


3. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78:2791-2808.

11. Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, Ono M. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature. 1986;319:415-418.

12. Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986;232:61-65.

13. Nagata S, Tsuchiya M, Asano S, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, Yamazaki T. The chromosomal gene structure and two mRNAs for human granulocyte colony-stimulating factor. Embo J. 1986;5:575-581.

14. Le Beau MM, Lemons RS, Carrino JJ, Pettenati MJ, Souza LM, Diaz MO, Rowley JD. Chromosomal localization of the human G-CSF gene to 17q11 proximal to the breakpoint of the t(15;17) in acute promyelocytic leukemia. Leukemia. 1987;1:795-799.

15. Simmers RN, Webber LM, Shannon MF, Garson OM, Wong G, Vadas MA, Sutherland GR. Localization of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia. Blood. 1987;70:330-332.

16. Nicola NA. Hemopoietic cell growth factors and their receptors. Annu Rev Biochem. 1989;58:45-77.

17. Tsuchiya M, Asano S, Kaziro Y, Nagata S. Isolation and characterization of the cDNA for murine granulocyte colony-stimulating factor. Proc Natl Acad Sci U S A. 1986;83:7633-7637.

19. Kishimoto T. The biology of interleukin-6. Blood. 1989;74:1-10.

[Page 2792]

Further understanding of the biologic and biochemical properties of G-CSF was greatly facilitated by cloning of the gene encoding G-CSF and the production of recombinant protein for study. [...]

Southern blot analysis of genomic human DNA showed that human G-CSF is encoded by a single gene,17,18 and further studies determined that this single gene is located on chromosome 17q11-22.20,21 The genomic structure of the human G-CSF gene was determined by Nagata et al.18 The G-CSF gene consists of 5 exons spread over a locus of approximately 2.3 kb. At the 5’-terminus of the second intron, two donor splice sequences are present in tandem, only 9 bp apart. [...]

[...] The localization of human G-CSF on chromosome 17 differs from that of several other human hematopoietic growth factors such as GM-CSF, IL-3, IL-4, and IL-5, which are clustered on the long arm of chromosome 5.22 [...]

Following the description of the cDNA for human G-CSF, the murine G-CSF gene was cloned by crosshybridization with a human G-CSF cDNA probe under low stringency conditions.23 The murine G-CSF gene is highly homologous with the human gene, with 69% nucleic acid sequence homology in both coding and noncoding regions, and a 73% sequence homology in the predicted amino acid sequence of the protein.23

[Page 2793]

The human G-CSF gene is distantly related to the IL-6 gene. The number, location, and size of the introns and exons that comprise these two genes are similar. Additionally, the amino acid sequences of G-CSF and IL-6 share some localized homology. Between amino acid residues 20 to 85 of G-CSF, the positions of 17 residues match with residues located between positions 28 to 91 of the IL-6 molecule, which yields a sequence homology for this region of 26%.26, 27 Additionally, the positions of four cysteine residues are precisely conserved between G-CSF and IL-6 in this region of relative homology. The tertiary structure of G-CSF may be quite similar to that of IL-6, particularly if intrachain disulfide bridges are similarly located within these molecules. Thus, it is possible that the genes encoding G-CSF and IL-6 may have arisen from a gene duplication event from which they have subsequently diverged. There is no linkage of chromosomal localization between G-CSF and IL-6 because the human IL-6 gene is located at chromosome 7p15.28


14. Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, Barendt J, Platzer E, Moore MAS, Mertelsmann R, Welte K Recombinant human granulocyte colony-stimulating factor: Effects on normal and leukemic myeloid cells. Science 232:61,1986

17. Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, Ono M: Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature 319:415,1986

18. Nagata S, Tsuchiya M, Asano S, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H, Yamazaki T: The chromosomal gene structure and two mRNAs for human granulocyte colony-stimulating factor. Embo J 5:575,1986

20. Le Beau M, Lemons R, Carrino J, Pettenati M, Souza L, Diaz M, Rowley J: Chromosomal localization of the human G-CSF gene to 17q11 proximal to the breakpoint of the t(15;17) in acute promyelocytic leukemia. Leukemia 1:795,1987

21. Simmers RN, Webber LM, Shannon MF, Garson OM, Wong G, Vadas MA, Sutherland GR: Localization of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia. Blood 70:330, 1987

22. Nicola N: Hemopoietic cell growth factors and their receptors. Annu Rev Biochem 58:45,1989

23. Tsuchiya M, Asano S, Kaziro Y, Nagata S: Isolation and characterization of the cDNA for murine granulocyte colony-stimulating factor. Proc Natl Acad Sci USA 83:7633,1986

26. Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A, Tsunasawa S, Sakiyama F, Matsui H, Takahara Y, Taniguchi T, Kishimoto T Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 32473,1986

27. Kishimoto T: The biology of interleukin-6. Blood 74:1, 1989

28. Sutherland GR, Baker E, Callen DF, Hyland VJ, Wong G, Clark S, Jones SS, Eglinton LK, Shannon MF, Lopez AF, Vadas MA Interleukin 4 is at 5q31 and interleukin 6 is at 7p15. Hum Genet 79:335,1988

Anmerkungen

Nothing has been marked as a citation. The source is only named once, and then only in passing.


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Fig. 1 – Molecular organization of the gene encoding human G-CSF, structure of the G-CSF RNA transcript, and secondary structure of the native human G-CSF protein.8


8. Nicola NA, Metcalf D, Matsumoto M, Johnson GR. Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem. 1983;258:9017-9023.

15a source.png

Fig 1. Molecular organization of the gene encoding human G-CSF, structure of the G-CSF RNA transcript, and secondary structure of the native human G-CSF protein.

Anmerkungen

The correct source is not given. Neither the image nor the caption can be found in the given source Nicola et al. (1983).


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The immature neutrophils that arise from bone marrow follow a process that involves proliferation, differentiation along the granulocyte lineage and terminal maturation into functional neutrophils. Many other hematopoietic growth factors like stem cell factor (SCF), IL-3, GM-CSF, IL-6, have been shown to be positive regulators of granulopoiesis and act at different stages of myeloid cell development. But, G-CSF is unique among the regulators of granulopoiesis, because it not only stimulates the proliferation but also potently induces the terminal maturation of myeloid progenitor cells to neutrophilic granulocytes1.

1. Basu S, Dunn A, Ward A. G-CSF: function and modes of action (Review). Int J Mol Med. 2002;10:3-10.

Mature neutrophils arise from bone marrow (BM) stem cells following a process involving proliferation, commitment to differentiation along the granulocyte lineage, and terminal maturation.5 Several hematopoietic growth factors including stem cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and G-CSF have been shown to be positive regulators of granulopoiesis and act at different stages of myeloid cell development.6,7 [...] G-CSF is unique among the regulators of granulopoiesis in that it not only stimulates the proliferation but also potently induces the terminal maturation of myeloid progenitor cells to neutrophilic granulocytes.

[...]

Anmerkungen

The source is given before this passage, but without any indication that the text after the reference is taken from it.


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The cytoplasmic region of the G-CSFR can be subdivided into a membrane-proximal domain, which contains two conserved sub-domains known as box 1 and box 2, and a membrane-distal domain, which contains a less conserved box 3 sequence18. In addition, there are four tyrosine residues in the cytoplasmic region of the G-CSFR at positions 704, 729, 744 and 764 of the human receptor, three of which lie in the membrane-distal domain30.

18. Fukunaga R, Ishizaka-Ikeda E, Seto Y, Nagata S. Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Cell Res. 1990;61:341-350.

30. Fukunaga R, Seto Y, Mizushima S, Nagata S. Three Different mRNAs Encoding Human Granulocyte Colony-Stimulating Factor Receptor. Proceedings of the National Academy of Sciences. 1990;87:8702-8706.

The cytoplasmic region of the G-CSF-R can be subdivided into a membrane-proximal domain, which contains two conserved subdomains known as box 1 and box 2, and a membrane- distal domain, which contains a less-conserved box 3 sequence (5). [...] In addition, there are four tyrosine (Tyr) residues in the cytoplasmic region of the G-CSF-R, at positions 704, 729, 744, and 764 of the human receptor, three of which lie in the membrane-distal domain (28).

5. Fukunaga, R., Ishizaka Ikeda, E., Seto, Y., and Nagata, S. (1990) Cell 61, 341–350

28. Fukunaga, R., Seto, Y., Mizushima, S., and Nagata, S. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 8702–8706

Anmerkungen

The source is not mentioned anywhere in the paper.

Fukunaga et al. (1990) does not contain the documented passage.


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Fig. 2 – A: Schematic diagram of the structure of the human G-CSFR. The extracellular region (EX) of the G-CSFR contains an Ig-like domain, a cytokine receptor homologous region (CRH) with conserved cysteine (C) residues and the WSXWS motif, and three fibronectin type III (Fn3) domains. The intracellular domain (ID) of the G-CSFR contains three subdomains, designated boxes 1,2, and 3. Numbers correspond to amino acid residues. TM, transmembrane domain; Y, tyrosine residues24.


24. Nagata S, Fukunaga R. Granulocyte colony-stimulating factor and its receptor. Prog Growth Factor Res. 1991;3:131-141.

17a source.png

Fig 1. Schematic diagram of the structure of the hG-CSFR. The extracellular region (EX) of the G-CSFR contains an Ig-like domain, a cytokine receptor homologous region (CRH) with conserved cysteine (C) residues and the WSXWS motif, and three fibronectin type III (Fn3) domains. The intracellular domain (ID) of the G-CSFR contains three subdomains designated boxes 1,2, and 3 [...]. Numbers correspond to amino acid residues. TM, transmembrane domain; Y, tyrosine residues.

Anmerkungen

The source is not given. The copied material cannot be found in Nagata & Fukunaga (1991)


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B: Schematic representation of the homo- and hetero-dimeric structures of functional receptors for IL-6, G-CSF, GM-CSF and IL-2. The CRH domains containing the conserved cysteine residues (thin bars) and the WSXWS motif (thick bar) are indicated by shaded boxes. The gp130 (the β-chain of the IL-6 receptor) has a remarkable similarity to the G-CSFR. The numbers indicate the percentage of identical amino acids in each subdomain23.


23. Basu S, Hodgson G, Katz M, Dunn AR. Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation. Blood. 2002;100:854-861.

17c source.png

FIGURE 4. Schematic representation of the homo- and hetero-dimeric structures of functional receptors for IL-6, G-CSF, GM-CSF and IL-2. The CRH domains containing the conserved cysteine residues (thin bars) and the 'WSXWS' motif (thick bar) are indicated by shaded boxes. The gp130 (the β-chain of the IL-6 receptor) has a remarkable similarity to the G-CSF receptor as shown in Fig. 3. The numbers indicate the percentage of identical amino acids in each subdomain.

Anmerkungen

The source is not given. None of the copied material can be found in Basu et al. (2002)


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G-CSF is an essential growth factor for the optimal production of neutrophils and their precursors. When either G-CSF or its cognate receptor are genetically ablated, the resulting mice are severely neutropenic and susceptible to opportunistic infections20, 40, 41. The loss of G-CSF signalling accounts for the defects on proliferation, differentiation and survival at the progenitor, precursor or terminally differentiated neutrophil stages. The structural functional analysis of the G-CSFR attributes proliferative signalling to the proximal domain (~60 amino acids proximal to the plasma [membrane) and differentiation signalling to the distal domain (~100 amino acids at the C-terminus)29.]

20. Lieschke GJ, Grail D, Hodgson G, Metcalf D, Stanley E, Cheers C, Fowler KJ, Basu S, Zhan YF, Dunn AR. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood. 1994;84:1737-1746.

29. Sampson M, Zhu QS, Corey SJ. Src kinases in G-CSF receptor signaling. Front Biosci. 2007;12:1463-1474.

40. Hermans MH, Ward AC, Antonissen C, Karis A, Lowenberg B, Touw IP. Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia. Blood. 1998;92:32-39.

41. Liu F, Poursine-Laurent J, Link DC. The granulocyte colony-stimulating factor receptor is required for the mobilization of murine hematopoietic progenitors into peripheral blood by cyclophosphamide or interleukin-8 but not flt-3 ligand. Blood. 1997;90:2522-2528.

2. INTRODUCTION

[...]

G-CSF is an essential growth factor for the optimal production of neutrophils and their precursors. When either G-CSF or its cognate receptor is genetically ablated, the resulting mice are severely neutropenic and susceptible to opportunistic infections (3-6). Loss of G-CSF signaling for proliferation, differentiation, and survival at the progenitor, precursor, or terminally differentiated neutrophil stages accounts for these defects. [...]


6. TYROSINE PHOSPHORYLATION OF THE G-CSF RECEPTOR

Structural functional analysis of the G-CSF Receptor attributes proliferative signaling to the proximal domain (~60 amino acids proximal to the plasma membrane) and differentiation to the distal domain (~100 amino acids at the C-terminus) (Figure 1).


3. Hermans, M. H., A. C. Ward, C. Antonissen, A. Karis, B. Lowenberg & I. P. Touw: Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia. Blood, 92, 32-9 (1998)


4. Lieschke, G. J., D. Grail, G. Hodgson, D. Metcalf, E. Stanley, C. Cheers, K. J. Fowler, S. Basu, Y. F. Zhan & A. R. Dunn: Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood, 84, 1737-46 (1994)


5. Liu, F., J. Poursine-Laurent & D. C. Link: The granulocyte colony-stimulating factor receptor is required for the mobilization of murine hematopoietic progenitors into peripheral blood by cyclophosphamide or interleukin-8 but not flt-3 ligand. Blood, 90, 2522-8 (1997)


6. Liu, F., H. Y. Wu, R. Wesselschmidt, T. Kornaga & D. C. Link: Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity, 5, 491-501 (1996) 10.1016/S1074-7613 (00)80504-X

Anmerkungen

Though the source is named in the end nothing has been marked as a citation.

Also the references to the literature have been taken from the source.


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[The structural functional analysis of the G-CSFR attributes proliferative signalling to the proximal domain (~60 amino acids proximal to the plasma] membrane) and differentiation signalling to the distal domain (~100 amino acids at the C-terminus)29.

Current models of cytokine receptor signalling, including that for G-CSFR, assign a critical signal transduction role to Janus kinases (Jak). Although Jak2-deficient mice display major defects in IL-3 and GM-CSF signalling, mice deficient in either Jak1 or Jak2 have intact G-CSFR signalling42, 43. The Src family of proto-oncogenic tyrosine kinases seems to have a more important role in transducing G-CSF-induced cell cycle progression. Since Src kinases have a wider range of physiological substrates than do the Jaks, which primarily affect the STAT proteins, Src kinases may play a more important role in G-CSF-mediated cell survival and metabolism. These pathways that involve Erk1/2 or PI3-kinase may contribute to G-CSF-induced proliferation, differentiation, survival and cytoskeletal reorganization29. Multiple protein tyrosine kinases (PTK) (e.g., Jak2 and Src) probably phosphorylate the tyrosine residues (tyr704, tyr729, tyr744 and tyr764) of the G-CSFR44. When phosphorylated, the phosphotyrosine residues serve as docking sites for signalling proteins containing phosphotyrosine binding domains (e.g., SH2 or PTB). Recruitment of these signalling proteins serves to diversify and inactivate G-CSFR signal. Diversification involves recruitment of the STAT transcription factors and Ras/Erk1/2 and PI3-kinase pathways (Fig. 3). Tyr704 can be phosphorylated by the Jaks and then serve as a docking site for the SH2 domains of STAT proteins45. Resembling that site, when phosphorylated, tyr729 may also serve as a docking site for the SH2 domain of STAT. Tyr764 favours the Src kinase and the Src SH2 domain46. This site is also the preferred binding site for the SH2 domains of Grb2 and is functionally coupled to Shc and the SH2-containing tyrosine phosphatise-2 (Shp-2)47. Grb2 also interacts with Gab2, which leads to PI3-kinase activity48. Tyr764 is also functionally coupled to Ras activation and Jun kinase49. Thus, phosphor-tyr764 can transduce several different signals, with both positive and negative effects on growth. Substrate availability and sustained activation may determine functional outcome. In their phosphorylated states, tyr 744 and tyr 729 may serve as docking sites for cytokine inducible SH2 protein/suppressor of cytokine signalling (SOCS) and SH2-containing inositol phosphatese (SHIP)50. Both molecules are negative regulators of Jak-STAT and PI3-kinase, respectively. The C-terminal domain also recruits SH2-containing tyrosine phosphatise-1 (Shp-1), which dephosphorylates positive signalling molecules such as Lyn and STAT51. According to what was said, while there may be a crosstalk between Src and Jak signalling pathways, [each kinase can trigger a stereotyped response, e.g., Jak-STAT and Src-Ras/Pi3-kinase29.]


29. Sampson M, Zhu QS, Corey SJ. Src kinases in G-CSF receptor signaling. Front Biosci. 2007;12:1463-1474.

42. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93:385-395.

43. Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM, Jr., Schreiber RD. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93:373-383.

44. Corey SJ, Dombrosky-Ferlan PM, Zuo S, Krohn E, Donnenberg AD, Zorich P, Romero G, Takata M, Kurosaki T. Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor. J Biol Chem. 1998;273:3230-3235.

45. de Koning JP, Dong F, Smith L, Schelen AM, Barge RM, van der Plas DC, Hoefsloot LH, Lowenberg B, Touw IP. The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation. Blood. 1996;87:1335-1342.

46. Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, et al. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993;72:767-778.

47. de Koning JP, Schelen AM, Dong F, van Buitenen C, Burgering BM, Bos JL, Lowenberg B, Touw IP. Specific involvement of tyrosine 764 of human granulocyte colony-stimulating factor receptor in signal transduction mediated by p145/Shc/GRB2 or p90/GRB2 complexes. Blood. 1996;87:132-140.

48. Zhu QS, Robinson LJ, Roginskaya V, Corey SJ. G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses. Blood. 2004;103:3305-3312.

49. Rausch O, Marshall CJ. Tyrosine 763 of the murine granulocyte colony-stimulating factor receptor mediates Ras-dependent activation of the JNK/SAPK mitogen-activated protein kinase pathway. Mol Cell Biol. 1997;17:1170-1179.

50. Hunter MG, Jacob A, O'Donnell L C, Agler A, Druhan LJ, Coggeshall KM, Avalos BR. Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia. J Immunol. 2004;173:5036-5045.

3. THE G-CSF RECEPTOR

[...]

Current models of cytokine receptor signaling, including that for the G-CSF Receptor, assign the critical signal transduction role to the Janus kinases. [...] In distinction to Jak2-deficient mice that display major defects in IL-3, GM-CSF, Epo, and TPO signaling, mice deficient in either Jak1 or Jak2 have intact G-CSF Receptor signaling (22-24). As discussed below, Src kinases have a non-redundant function in transducing G-CSF-induced cell cycle progression. Src kinases have a wider range of physiological substrates than do the Jaks, which primarily affect the STAT proteins (Figure 1). Src kinases may also play a role in G-CSF-mediated survival and metabolism. These pathways that involve the Erk1/2 or PI 3-kinase may contribute to G-CSF-induced differential and cytoskeletal reorganization.

[...]

6. TYROSINE PHOSPHORYLATION OF THE G-CSF RECEPTOR

Structural functional analysis of the G-CSF Receptor attributes proliferative signaling to the proximal domain (~60 amino acids proximal to the plasma membrane) and differentiation to the distal domain (~100 amino acids at the C-terminus) (Figure 1). [...]

Multiple PTK (e.g. Jak2 and Src) probably phosphorylate the tyrosine residues (Tyr704, Tyr729, Tyr744, and Tyr764) of the G-CSF Receptor (16). [...]

When phosphorylated, the phosphotyrosine residues serve as docking sites for signaling proteins containing a phosphotyrosine binding domains (e.g. SH2 or PTB). Recruitment of these signaling proteins serves to diversify and inactivate G-CSF Receptor's signal. Diversification involves recruitment of the STAT transcription factors and Ras/Erk1/2 and PI 3'kinase pathways (Figure 3). Y704VLQ fits the YXXQ motif, which can be phosphorylated by the Jaks and then serve as a docking site for the SH2 domains of STAT proteins (17). Resembling that site, when phosphorylated, Y729GQL may also serve as a docking site for the SH2 domain of STAT. Y764ENL best approximates the YEEI/L motif favored by both the Src kinase and the Src SH2 domain (56, 60). This site is also the preferred binding site (i.e. YpEN) for the SH2 domain of Grb2 and is functionally coupled to Shc and the SH2-containing tyrosine phosphatase-2 (Shp-2)(18). Grb2 also interacts with Gab2, which leads to PI 3'-kinase activity (61). Tyr764 is also functionally coupled to Ras activation and Jun kinase (62). Thus, phospho-Tyr764 can transduce several different signals with both positive and negative effects on growth. Substrate availability and sustained activation may determine functional outcome. In their phosphorylated states, Y744LRC and Y729GQL may serve as docking sites for cytokine inducible SH2 protein (CIS)/suppressor of cytokine signaling (SOCS) and SH2-containing inositol phosphatase (SHIP) (63-66). Both molecules are negative regulators of Jak-STAT and PI 3'-kinase, respectively. The C-terminal domain also recruits SH2-containing tyrosine phosphatase-1 (Shp-1), which desphosphorylates positive signaling molecules such as Lyn and STAT (67).

7. INTRACELLULAR SIGNALING IN MYELOID CELLS

[...]

[...] While there may be cross-talk between Src and Jak signaling pathways, each kinase can trigger a stereotyped response, e.g. Jak-STAT and Src-Ras/PI 3-kinase.


16. Corey, S. J., P. M. Dombrosky-Ferlan, S. Zuo, E. Krohn, A. D. Donnenberg, P. Zorich, G. Romero, M. Takata & T. Kurosaki: Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor. J Biol Chem, 273, 3230-5 (1998) 10.1074/jbc.273.6.3230

17. de Koning, J. P., F. Dong, L. Smith, A. M. Schelen, R. M. Barge, D. C. van der Plas, L. H. Hoefsloot, B. Lowenberg & I. P. Touw: The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation. Blood, 87, 1335-42 (1996)

18. de Koning, J. P., A. M. Schelen, F. Dong, C. van Buitenen, B. M. Burgering, J. L. Bos, B. Lowenberg & I. P. Touw: Specific involvement of tyrosine 764 of human granulocyte colony-stimulating factor receptor in signal transduction mediated by p145/Shc/GRB2 or p90/GRB2 complexes. Blood, 87, 132-40 (1996)

22. Parganas, E., D. Wang, D. Stravopodis, D. J. Topham, J. C. Marine, S. Teglund, E. F. Vanin, S. Bodner, O. R. Colamonici, J. M. van Deursen, G. Grosveld & J. N. Ihle: Jak2 is essential for signaling through a variety of cytokine receptors. Cell, 93, 385-95 (1998) 10.1016/S0092-8674 (00)81167-8

23. Rodig, S. J., M. A. Meraz, J. M. White, P. A. Lampe, J. K. Riley, C. D. Arthur, K. L. King, K. C. Sheehan, L. Yin, D. Pennica, E. M. Johnson, Jr. & R. D. Schreiber: Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell, 93, 373-83 (1998) 10.1016/S0092-8674 (00)81166-6

24. Neubauer, H., A. Cumano, M. Muller, H. Wu, U. Huffstadt & K. Pfeffer: Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell, 93, 397-409 (1998) 10.1016/S0092-8674 (00)81168-X

56. Songyang, Z., S. E. Shoelson, M. Chaudhuri, G. Gish, T. Pawson, W. G. Haser, F. King, T. Roberts, S. Ratnofsky, R. J. Lechleider & et al.: SH2 domains recognize specific phosphopeptide sequences. Cell, 72, 767-78 (1993)

61. Zhu, Q. S., L. J. Robinson, V. Roginskaya & S. J. Corey: G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses. Blood, 103, 3305-12 (2004)

62. Rausch, O. & C. J. Marshall: Tyrosine 763 of the murine granulocyte colony-stimulating factor receptor mediates Ras-dependent activation of the JNK/SAPK mitogen-activated protein kinase pathway. Mol Cell Biol, 17, 1170-9 (1997)

63. Hunter, M. G., A. Jacob, C. O'Donnell L, A. Agler, L. J. Druhan, K. M. Coggeshall & B. R. Avalos: Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia. J Immunol, 173, 5036-45 (2004)

64. van de Geijn, G. J., J. Gits, L. H. Aarts, C. Heijmans-Antonissen & I. P. Touw: G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact. Blood, 104, 667-74 (2004)

65. Hermans, M. H., G. J. van de Geijn, C. Antonissen, J. Gits, D. van Leeuwen, A. C. Ward & I. P. Touw: Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. Blood, 101, 2584-90 (2003)

66. van de Geijn, G. J., J. Gits & I. P. Touw: Distinct activities of suppressor of cytokine signaling (SOCS) proteins and involvement of the SOCS box in controlling G-CSF signaling. J Leukoc Biol, 76, 237-44 (2004)

Anmerkungen

Though the source is named in passing nothing has been marked as a citation.

Note that also all the references to the literature have been taken from the source.


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Fig. 3 – Diverse intracellular signalling pathways of the G-CSF Receptor. The cytoplasmic domain of the receptor contains Box 1 and Box 2 and Tyr704 in the proximal domain, necessary for mitogenesis. When phosphorylated, the four tyrosine residues serve as docking sites for SH2-containing proteins. Neither the structural basis of how cytosolic PTKs, such as Jak and Lyn, associate with the receptor, nor the specificity or redundancy of each tyrosine residue’s kinase are known28.


28. Basu S, Hodgson G, Zhang H-H, Katz M, Quilici C, Dunn AR. "Emergency" granulopoiesis in G-CSF-deficient mice in response to Candida albicans infection. Blood. 2000;95:3725-3733.

20a source.png

Figure 1. Intracellular signaling pathways of the G-CSF Receptor. [...] The cytoplasmic domain of the receptor contains Box 1 and Box 2 and Tyr704 in the proximal domain, which is necessary for mitogenesis. [...] When phosphorylated, the four tyrosine residues serve as docking sites for SH2-containing proteins. [...] Neither the structural basis of how cytosolic PTKs, such as Jak and Lyn, associate with the receptor, nor the the specificity or redundancy of each tyrosine residue's kinase are known.

Anmerkungen

The source is not mentioned here. Neither image nor caption can be found in Basu et al. (2000).


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Neutrophil granulocytes (a.k.a., polymorphonuclear leukocytes) are normally found circulating in the bloodstream (half-life of ≅7 h) and migrating through tissues (2–3 days), devoting their short lifetime to surveillance55. During an infection, the neutrophil lifespan is increased, and large numbers of neutrophils are rapidly recruited to the site(s) of infection where they function to destroy invading pathogens. In this manner, neutrophils serve as one of the body’s first lines of defence against infection. These cells use an extraordinary array of oxygen-dependent and oxygen-independent microbicidal weapons to destroy and remove infectious agents56. Oxygen-dependent mechanisms involve the production of ROS, which can be microbicidal57, and oxygen-independent mechanisms include most other neutrophil functions, such as chemotaxis, phagocytosis, degranulation, and release of lytic enzymes and bactericidal peptides56.

55. Steinfeld JL. Principles of Hematology. Cancer Res. 1967;27:208-a-.

56. Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L. Neutrophils: Molecules, Functions and Pathophysiological Aspects. Lab Invest. 2000;80:617-653.

57. Roos D, Bruggena Rv, Meischl C. Oxidative killing of microbes by neutrophils. Microbes and Infection. 2003;5:1307-1315.

Neutrophils (a.k.a., polymorphonuclear leukocytes) are normally found circulating in the bloodstream (circulating half-life of ~7 h) and migrating through tissues (2–3 days) and devote their short lifetime to surveillance [3]. However, during an infection, the neutrophil lifespan is increased, and large numbers of neutrophils are rapidly recruited to the site(s) of infection where they function to destroy invading pathogens. In this capacity, neutrophils serve as one of the body’s first lines of defense against infection. These cells use an extraordinary array of oxygen-dependent and oxygen-independent microbicidal weapons to destroy and remove infectious agents [4]. Oxygen-dependent mechanisms involve the production of reactive oxygen species (ROS), which can be microbicidal [5], and oxygen-independent mechanisms include most other neutrophil functions, such as chemotaxis, phagocytosis, degranulation, and release of lytic enzymes and bactericidal peptides (reviewed in ref. [4]).

3. Haen, P. J. (1995) Principles of Hematology, Dubuque, IA, Wm. C. Brown.

4. Witko-Sarsat, V., Rieu, P., Descamps-Latscha, B., Lesavre, P., Halbwachs-Mecarelli, L. (2000) Neutrophils: molecules, functions and pathophysiological aspects. Lab. Invest. 80, 617–653.

5. Roos, D., Van Bruggen, R., Meischl, C. (2003) Oxidative killing of microbes by neutrophils. Microbes Infect. 5, 1307–1315.

Anmerkungen

The source is not given here.


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ROS are oxygen-derived small molecules, including oxygen radicals [superoxide (O2•–), hydroxyl (OH), peroxyl (RO2), and alkoxyl (RO) radicals] and certain non-radicals that are either oxidizing agents and/or are easily converted into radicals, such as hypochlorous acid (HOCl), ozone (O3), singlet oxygen (1O2), and hydrogen peroxide (H2O2). ROS generation is generally a cascade of reactions that starts with the production of superoxide. Superoxide rapidly dismutates to hydrogen peroxide either spontaneously (at low pH) or catalyzed by superoxide dismutase (SOD). Other elements in the cascade of ROS generation include the reaction of superoxide with nitric oxide to form peroxynitrite (ONOO), the peroxidase-catalyzed formation of hypochlorous acid [(HOCl) from hydrogen peroxide, and the iron-catalyzed Fenton reaction leading to the generation of hydroxyl radical58.]

Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1005-1028.

Reactive oxygen species (ROS) are oxygen-derived small molecules, including oxygen radicals [superoxide (O2•–), hydroxyl (OH), peroxyl (RO2•), and alkoxyl (RO•)] and certain nonradicals that are either oxidizing agents and/or are easily converted into radicals, such as hypochlorous acid (HOCl), ozone (O3), singlet oxygen (1O2), and hydrogen peroxide (H2O2). Nitrogen-containing oxidants, such as nitric oxide, are called reactive nitrogen species (RNS). ROS generation is generally a cascade of reactions that starts with the production of superoxide. Superoxide rapidly dismutates to hydrogen peroxide either spontaneously, particularly at low pH or catalyzed by superoxide dismutase. Other elements in the cascade of ROS generation include the reaction of superoxide with nitric oxide to form peroxynitrite, the peroxidase-catalyzed formation of hypochlorous acid from hydrogen peroxide, and the iron-catalyzed Fenton reaction leading to the generation of hydroxyl radical (468, 874).

468. Klebanoff SJ. Oxygen metabolism and the toxic properties of phagocytes. Ann Intern Med 93: 480–489, 1980.

874. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279: L1005–L1028, 2000.

Anmerkungen

The source is mentioned further down on the next page, without any indication that everything including references to the literature are taken from it.

To be continued on the next page: Arc/Fragment_022_01


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[Other elements in the cascade of ROS generation include the reaction of superoxide with nitric oxide to form peroxynitrite (ONOO-), the peroxidase-catalyzed formation of hypochlorous acid] (HOCl) from hydrogen peroxide, and the iron-catalyzed Fenton reaction leading to the generation of hydroxyl radical58. ROS avidly interact with a large number of molecules including other small inorganic molecules as well as proteins, lipids, carbohydrates, and nucleic acids. Through such interactions, ROS may irreversibly destroy or alter the function of the target molecule and consequently, ROS have been increasingly identified as major contributors to damage in biological organisms. However, ROS are involved not only in cellular damage and killing of pathogens, but also in a large number of reversible regulatory signalling processes in virtually all cells and tissues59. The physiological generation of ROS can occur as a result of other biological reactions. For example, ROS generation occurs as a byproduct in the mitochondria, peroxisomes, cytochrome P-450, and other cellular elements58. The phagocyte NADPH oxidase was the first identified example of a system that generates ROS not as a byproduct, but rather as the primary function of this enzyme system59.

58. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1005-1028.

59. Bedard K, Krause K-H. The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiol. Rev. 2007;87:245-313.

Other elements in the cascade of ROS generation include the reaction of superoxide with nitric oxide to form peroxynitrite, the peroxidase-catalyzed formation of hypochlorous acid from hydrogen peroxide, and the iron-catalyzed Fenton reaction leading to the generation of hydroxyl radical (468, 874).

ROS avidly interact with a large number of molecules including other small inorganic molecules as well as proteins, lipids, carbohydrates, and nucleic acids. Through such interactions, ROS may irreversibly destroy or alter the function of the target molecule. Consequently, ROS have been increasingly identified as major contributors to damage in biological organisms. [...] In fact, ROS are involved not only in cellular damage and killing of pathogens, but also in a large number of reversible regulatory processes in virtually all cells and tissues. [...]

[...]

The physiological generation of ROS can occur as a byproduct of other biological reactions. ROS generation as a byproduct occurs with mitochondria, peroxisomes, cytochrome P-450, and other cellular elements (50, 307, 314, 356, 588, 636, 715, 791, 874). However, the phagocyte NADPH oxidase was the first identified example of a system that generates ROS not as a byproduct, but rather as the primary function of the enzyme system.


[...]

874. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279: L1005–L1028, 2000.

[...]

Anmerkungen

The copied text starts on the previous page: see: Arc/Fragment_021_22.

The source is given twice, but still it is not clear to the reader that everything is taken more or less verbatim from the source, including the reference to Thannickal & Fanburg (2000).


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In general, the best characterized plasma membrane oxidase is the phagocytic NADPH oxidase, a multicomponent enzyme composed of four oxidase-specific proteins (p22phox, p47phox, p67phox, and gp91phox) and a GTPase (Rac1/2). One other oxidase-specific protein (p40phox) and a second GTPase (Rap1A) have also been shown to play roles in regulating oxidase activity; however, their specific functions are still not well understood60. Originally, the nomenclature for the various components differed throughout the literature (Table 1); however, the generally accepted nomenclature for the phagocyte oxidase specific components now includes the suffix phox, which refers to phagocyte oxidase61. The only one exception is gp91phox, which has also been named NADPH oxidase 2 (Nox2)62.

60. Quinn MT, Gauss KA. Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol. 2004;76:760-781.

61. Babior BM. NADPH oxidase. Current Opinion in Immunology. 2004;16:42-47.

62. Lambeth JD, Cheng G, Arnold RS, Edens WA. Novel homologs of gp91phox. Trends Biochem Sci. 2000;25:459-461.

It is now generally accepted that the core NADPH oxidase enzyme is composed of four oxidase-specific proteins (p22phox, p47phox, p67phox, and gp91phox) and a GTPase (Rac1/2). One other oxidase-specific protein (p40phox) and a second GTPase (Rap1A) have also been shown to play roles in regulating oxidase activity; however, their specific functions are still not well understood. Originally, the nomenclature for the various components differed throughout the literature; however, the generally accepted nomenclature for the phagocyte oxidasespecific components now includes the suffix phox, which refers to phagocyte oxidase [10]. The one exception is gp91phox, which has also been named NADPH oxidase 2 (Nox2) [11].

10. Babior, B. M. (1991) The respiratory burst oxidase and the molecular basis of chronic granulomatous disease. Am. J. Hematol. 37, 263–266.

11. Lambeth, J. D., Cheng, G., Arnold, R. S., Edens, W. A. (2000) Novel homologs of gp91phox. Trends Biochem. Sci. 25, 459–461.

Anmerkungen

The source is mentioned somewhere in the middle, but it is not clear to the reader that the entire passage is taken from it, including a reference to the literature.


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23a diss.png

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Table 1 – A: Nox enzymes and subunits: alternative names, chromosomal localization, gene length, number of amino acids, and total number of single-nucleotide polymorphisms (total SNP).

B: Tissue distribution of Nox enzymes: Nox enzymes are expressed in a small number of tissues at high levels (readily detected by Northern blotting) but show intermediate- to low-level expression in many other tissues57.


57. Roos D, Bruggena Rv, Meischl C. Oxidative killing of microbes by neutrophils. Microbes and Infection. 2003;5:1307-1315.

[page 248]

23a source.png

Alternative names, chromosomal localization, gene length, number of amino acids, total number of single-nucleotide polymorphisms (total SNP), number of coding nonsynonymous single-nucleotide polymorphisms (cnSNP), amino acid changes in cnSNPs, and nucleotide substitutions in cnSNPs are shown. The number of SNPs is based on presently available NCBI databank entries. The position of the nucleotide substitution is given relative to the start codon (207). * C214T in p22phox was originally called C242T (411), a name still widely used in the literature.

[page 252]

23b source.png

NOX enzymes are expressed in a small number of tissues at high levels (readily detected by Northern blotting) but show intermediate- to low-level expression in many other tissues.


207. Den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations. Hum Genet 109: 121–1

411. Inoue N, Kawashima S, Kanazawa K, Yamada S, Akita H, Yokoyama M. Polymorphism of the NADH/NADPH oxidase p22phox gene in patients with coronary artery disease. Circulation 97: 135–137, 1998.

Anmerkungen

The two tables are copied verbatim from the source, which is not referenced.

The source given, Roos et al. (2003). does not contain any of the copied material.


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The activation of Nox2 occurs through a complex series of protein/protein interactions, where Nox2 constitutively associates with p22phox, forming a heterodimeric complex known as cytochrome b558 (Cyt b558)58. NADPH oxidase activation requires translocation of cytosolic factors to the Nox2/p22phox complex and the present working model functions in the following way (Fig. 4): First, phosphorylation of p47phox leads to a conformational change allowing its interaction with p22phox. It is thought that p47phox organizes the translocation of other cytosolic factors, hence its designation as “organizer subunit.” The relocalization of p47phox to the membrane brings the “activator subunit” p67phox into contact with Nox2 and also brings the small subunit p40phox to the complex. Finally, the GTPase Rac interacts with Nox2 via a two-step mechanism involving an initial direct interaction with Nox2, followed by a subsequent interaction with p67phox. Once assembled, the complex is active and generates superoxide by transferring an electron from NADPH in the cytosol to oxygen on the luminal or extracellular space59.

24a diss.png

Fig. 4 - Assembly of the phagocyte NADPH oxidase Nox2. Nox2 and p22phox are found primarily in the membrane of intracellular vesicles. Upon activation, there is an exchange of GDP for GTP on Rac leading to its activation. Phosphorylation of the cytosolic p47phox subunit leads to conformational changes allowing interaction with p22phox. The movement of p47phox brings with it the other cytoplasmic subunits, p67phox and p40phox, to form the active Nox2 enzyme complex. Once activated, there is a fusion of Nox2-containing vesicles with the plasma membrane or the phagosomal membrane. The active enzyme complex transports electrons from cytoplasmic NADPH to extracellular or phagosomal oxygen to generate superoxide57


57. Roos D, Bruggena Rv, Meischl C. Oxidative killing of microbes by neutrophils. Microbes and Infection. 2003;5:1307-1315.

58. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1005-1028.

59. Bedard K, Krause K-H. The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiol. Rev. 2007;87:245-313.

The activation of NOX2 occurs through a complex series of protein/protein interactions (Fig. 2; for more detailed recent reviews, see Refs. 328, 652, 844). NOX2 constitutively associates with p22phox. [...] Activation of NOX2 requires translocation of cytosolic factors to the NOX2/p22phox complex (Fig. 3). The present working model is as follows. Phosphorylation of p47phox leads to a conformational change allowing its interaction with p22phox(327, 843). It is thought that p47phox organizes the translocation

[page 250]


24a source.png

FIG. 3. Assembly of the phagocyte NADPH oxidase NOX2. [...] In resting neutrophil granulocytes, NOX2 and p22phox are found primarily in the membrane of intracellular vesicles. They exist in close association, costabilizing one another. Upon activation, there is an exchange of GDP for GTP on Rac leading to its activation. Phosphorylation of the cytosolic p47phox subunit leads to conformational changes allowing interaction with p22phox. The movement of p47phox brings with it the other cytoplasmic subunits, p67phox and p40phox, to form the active NOX2 enzyme complex. Once activated, there is a fusion of NOX2-containing vesicles with the plasma membrane or the phagosomal membrane. The active enzyme complex transports electrons from cytoplasmic NADPH to extracellular or phagosomal oxygen to generate superoxide (O2-).

of other cytosolic factors, hence its designation as “organizer subunit.” The localization of p47phox to the membrane brings the “activator subunit” p67phox into contact with NOX2 (342) and also brings the small subunit p40phox to the complex. Finally, the GTPase Rac interacts with NOX2 via a two-step mechanism involving an initial direct interaction with NOX2 (214), followed by a subsequent interaction with p67phox (476, 508). Once assembled, the complex is active and generates superoxide by transferring an electron from NADPH in the cytosol to oxygen on the luminal or extracellular space.


[...]

Anmerkungen

The source is given once, but it is not clear that so much text and in particular the illustration are taken from it.

The image is taken via copy-paste without reference. The source given, Roos et al. (2003), does not contain any of the copied material.


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Chapter II: Mechanisms of vascular growth

When Leonardo da Vinci first speculated about the heart and the circulatory system, he could only analyse the mechanism of organ formation by analogy. So he suggested that the vasculature developed like a tree from a seed (the heart) by sprouting roots (the liver capillary network) and a trunk with major branches (the aorta and arteries, Fig. 5).

28a diss.png

Fig. 5 – Analogy between the botanic and vascular tree as drawn by Leonardo da Vinci (taken from “The anatomy of man: the cardiovascular system (1508)). The drawing is annotated in his cryptic mirror-writing, for example the big seed of the left plant labelled “core” (heart) is indicated by the arrowhead71.

Although sprouting of vessels is indeed a principal mechanism of the blood vessel formation termed angiogenesis, other mechanisms are now known. Rather than sprouting from the heart, the vascular system is laid down before the heart starts beating. Conversely, adult blood vessels generally form from pre-existing vessels in direct response to tissue demands74.

II.1 Vasculogenesis and Angiogenesis

The early vascular plexus forms from the mesoderm by differentiation of angioblasts (vascular endothelial cells that have not yet formed a lumen), which subsequently generate primitive blood vessels. The molecular mechanisms responsible for this process, termed vasculogenesis74, are starting to emerge (Fig. 6).


71. Haghighat A WD, Whalin MK, Cowan DP, Taylor WR. . Granulocyte colonystimulating factor and granulocyte macrophage colony-stimulating factor exacerbate atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2007;115:2049-2054.

74. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671-674.

Mechanisms of angiogenesis

[...]

When Leonardo da Vinci first speculated about the heart and circulatory system (see Nature 380, 9; 1996), he could only analyse the mechanisms of organ formation by analogy, so he suggested that the vasculature developed like a tree from a seed (the heart) by sprouting roots (the liver capillary meshwork) and a trunk with major branches (the aorta and arteries) (Fig. 1). Although sprouting of blood vessels is indeed a principal mechanism of blood vessel formation, termed angiogenesis, other mechanisms are now known. Rather than sprouting from the heart, the vascular system is laid down before the heart starts beating. Conversely, adult blood vessels generally form from pre-existing vessels in direct response to tissue demands.

[...]

Vasculogenesis

The early vascular plexus forms from mesoderm by differentiation of angioblasts (vascular endothelial cells that have not yet formed a lumen), which subsequently generate primitive blood vessels. The molecular mechanisms responsible for this process, termed vasculogenesis1, are emerging (Fig. 2).

28a source.png

Figure 1 Analogy between the botanic and the vascular tree as drawn by Leonardo da Vinci (taken from ‘the anatomy of man: the cardiovascular system’ (ca. 1508)). The drawing is annotated by notes in his trademark cryptic mirror-writing, for example the big seed of the left plant labelled ‘core’ (heart) is indicated by the arrowhead.


1. Risau, W. & Flamme, I. Vasculogenesis. Annu. Rev. Cell Dev. Biol. 11, 73-91 (1995).

Anmerkungen

Although the source is given (in passing) nothing has been marked as a citation. The copied text is mostly taken verbatim. Figure 5 and its legend are also taken from Risau (1997), this time without the source being named.

The named source Haghighat et al. (2007) does not contain any of the copied material.


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Fig. 6 – The processes (red labels), molecules (green labels) and appearances (black labels) involved in vascular development. Red tips in the primary capillary plexus represent sprouts, yellow circles represent splitting pillars. The hemangioblast as a bipotential precursor is still under debate and intermediate steps between some processes have been omitted. Remodelling and maturation is dependent on the tissue and organ context. It is schematized here from observations in the avian yolk-sac vascular system. A, arteriole; V, venule; SMC, smoothe muscle cells; PCT, pericytes71.

Mesoderm inducing factors of the fibroblast growth factor family are crucial in inducing paraxial and lateral plate mesoderm to form angioblasts and hematopoietic cells. The existence of a bipotential precursor of these cell types (the so-called hemangioblast) is suggested by defects in both the hematopoietic and angioblastic lineages of embryos lacking VEGF-receptor 2 (VEGF-R2, also called Flk-1 and KDR in mice and humans, respectively). After differentiation, VEGF-R2 is downregulated in hematopoietic but not in endothelial cells. The other receptor for VEGF, VEGF-R1 (Flt-1), plays a later role, as mice lacking VEGF-R1 produce angioblasts, but their assembly into functional blood vessels is impaired75. VEGF acts in a paracrine manner as it is produced by the endoderm, whereas its receptors are expressed by mesoderm-derived angioblasts. Some angioblasts can migrate over long distances and form a vascular plexus at a site distant from the original location74.

After the primary plexus is formed, more ECs are generated, which can form new capillaries by sprouting or by splitting from their vessel of origin in a process termed angiogenesis. There are at least two different types of angiogenesis: 1) nonsprouting or intussusception angiogenesis and 2) true sprouting of capillaries from preexisting vessels (Fig. 7)74.


71. Haghighat A WD, Whalin MK, Cowan DP, Taylor WR. . Granulocyte colonystimulating factor and granulocyte macrophage colony-stimulating factor exacerbate atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2007;115:2049-2054.

74. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671-674.

75. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995;376:66-70.

[Page 671]

Mesoderm-inducing factors of the fibroblast growth factor family are crucial in inducing paraxial and lateral plate mesoderm to form angioblasts and haematopoietic cells. The existence of a bipotential precursor for these cell types (the so-called haemangioblast) is suggested by defects in both the haematopoietic and angioblastic lineages of embryos lacking vascular endothelial growth factor receptor-2 (VEGF-R2, also called Flk-1 and KDR in mice and humans, respectively; Fig. 2)4. But only haematopoietic stem cells are affected5,6 in embryos lacking the transcription factor Scl/tal-1. After differentiation, VEGF-R2 is downregulated in haematopoietic but not in endothelial cells.

The other receptor for VEGF, VEGF-R1 (Flt-1), plays a role later, as mice lacking VEGF-R1 produce angioblasts, but their assembly into functional blood vessels is impaired7. VEGF itself acts in a paracrine manner as it is produced by the endoderm, whereas its receptors are expressed by mesoderm-derived angioblasts. [...] Rather than forming blood vessels where they originate, some angioblasts migrate over long distances12, forming a vascular plexus at a distant site (such as the perineural vascular plexus).

[Page 672]

29a source.png

Figure 2 The processes (red labels), molecules (green labels) and appearances (black labels) involved in vascular development. Red tips in the primary capillary plexus represent sprouts, yellow circles represent splitting pillars (Fig. 3). The haemangioblast as a bipotential precursor is still hypothetical and intermediate steps between some processes have been omitted. Remodelling and maturation is dependent on the tissue and organ context. It is schematized here from observations in the avian yolk-sac vascular system. A, arteriole; V, venule; SMC, smooth muscle cells; PCT, pericytes. None of the figures is drawn to scale.

[...]

After the primary vascular plexus is formed, more endothelial cells are generated, which can form new capillaries by sprouting or by splitting from their vessel of origin in a process termed angiogenesis. There are at least two different types: true sprouting of capillaries from pre-existing vessels, and non-sprouting angiogenesis or intussusception (Figs 2 and 3).


4. Shalaby, F. et al. Failure o f blood-island formation and vasculogenesis in flk-1-deficient mice. Nature 376, 62-66 (1995).

5. Porcher, C. et al. The T cell leukemia oncoprotein Scl/Tal-1 is essential for development of all hematopoietic lineages. Cell 86, 47-57 (1996).

6. Robb, L. et al. The Scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. EMBO J. 15, 4123-4129 (1996).

7. Fong, G. H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the fit-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66-70 (1995).

8. Carmeliet, P. et a l Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435-439 (1996).

9. Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 435-439 (1996).

12. Noden, D. M. in The development of the vascular system (eds Feinberg, R. N., Sherer, G. K. & Auerbach, R.) 1-24 (Karger, Basel, 1991).

Anmerkungen

Although the source is given (in passing) nothing has been marked as a citation. The material is mostly copied verbatim. Figure 6 and its legend are also taken from Risau (1997), without the source being named. The source given Haghighat et al. (2007) does not contain any of the copied material.


[21.] Arc/Fragment 030 01

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In sprouting angiogenesis, endothelial cells proliferate behind the tip cell of a growing branch in response to cytokines, such as VEGF, and lumens can form by vacuole fusion. Both forms of angiogenesis require the recruitment of smooth muscle cells (SMCs) to stabilize the nascent vessels.

30a diss.png

Fig. 7 – Representation of vasculogenesis and two types of angiogenesis: intussusceptive and sprouting angiogenesis. Vasculogenesis involves the differentiation of endothelial cells (ECs) from precursor angioblast cells to form a primitive plexus of capillaries, which remodel and grow by angiogenesis. Intussusceptive angiogenesis involves the splitting and growing of vessels in situ. Vessel splitting occurs by the formation of translumen pillars (arrowheads) but the molecular mechanisms are not well understood74.


74. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671-674.

30a source.png

Figure 3 TGFβ signalling in vasculogenesis and angiogenesis. Vasculogenesis and two types of angiogenesis are shown: intussusceptive and sprouting angiogenesis (BOX 1). Vasculogenesis involves the differentiation of endothelial cells (ECs) from precursor angioblast cells to form a primitive plexus of capillaries, which remodel and grow by angiogenesis. Intussusceptive angiogenesis involves the splitting and growing of vessels in situ in a metabolically efficient manner, and is found, for example, in the developing yolk sac and lung. Vessel splitting occurs by the formation of translumen pillars (arrowheads) but the molecular mechanisms are not well understood. In sprouting angiogenesis, endothelial cells proliferate behind the tip cell of a growing branch in response to cytokines such as vascular endothelial growth factor (VEGF) and lumens can form by vacuole fusion. Both forms of angiogenesis require the recruitment of smooth muscle cells (SMCs) to stabilize the nascent vessels.

Anmerkungen

The source is not mentioned here. Risau (1997) does not contain the copied material.


[22.] Arc/Fragment 031 22

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Coronary collaterals, or “natural bypasses,” are anastomotic connections without an interposed capillary bed either between portions of the same coronary artery or between different coronary arteries83, potentially offering an important alternative source of blood supply when the original vessel fails to provide sufficient blood84. Collateral growth (commonly termed arteriogenesis) refers to the transformation of pre-existing (collateral) arterioles into functional (muscular) collateral arteries, as a thick muscular coat is added, concomitant with the acquisition of viscoelastic and vasomotor properties76.

76. Carmeliet P, Conway EM. Growing better blood vessels. Nat Biotechnol. 2001;19:1019-1020.

83. Koerselman J vdGY [sic], de Jaegere PP, Grobbee DE. Coronary collaterals: an important and underexposed aspect of coronary artery disease. Circulation. . 2003 107:2507-2511.

84. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation. 1992;85:1197-1204.

Coronary collaterals, or “natural bypasses,” are anastomotic connections without an intervening capillary bed between portions of the same coronary artery and between different coronary arteries (Figure 1).1 Collateral circulation potentially offers an important alternative source of blood supply when the original vessel fails to provide sufficient blood.2 [...]

Finally, arteriogenesis refers to the transformation of preexisting (collateral) arterioles into functional (muscular) collateral arteries, as a thick muscular coat is added, concomitant with acquisition of viscoelastic and vasomotor properties.10


1. Popma JJ, Bittl J. Coronary angiography and intravascular ultrasonography. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: W.B. Saunders Company; 2001:387–418.

2. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation. 1992;85:1197–1204.

10. Conway EM, Collen D, Carmeliet P. Molecular mechanisms of blood vessel growth. Cardiovasc Res. 2001;49:507–521.

Anmerkungen

The source is given, but it is not clear to the reader that text has been copied 1-to-1 and that the copied text continues after the reference to Koerselman et al. (2003).

The reference to Sasayama & Fujita (1992) is also taken from the source. None of the copied text can be found either in Sasayama & Fujita (1992) or in Carmeliet & Conway (2001).


[23.] Arc/Fragment 032 10

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32b diss.png

Fig. 8 – A: Collateral vessels can develop around the site of coronary occlusion, via remodelling of pre-existing vessels (arteriogenesis) that gradually enlarge to the point at which they can carry the bulk of blood flow84.

[...]

While the development of vasculature in the course of embryonic growth is beginning to be well understood, comparatively little information is available about the processes responsible for coronary collateral growth.


84. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation. 1992;85:1197-1204.

Whereas the development of vasculature in the course of embryonic growth is beginning to be well understood, comparatively little information is available about the processes responsible for vessel growth and maintenance

[page 3]

in mature adult tissues.

[page 4]

32b source.png

Figure 2 Arteriogenesis. Collateral vessels (arteriogenesis) can develop around the site of coronary occlusion. Although the exact mechanism is not clear, there are two distinct possibilities. One option (a) for arteriogenesis is to proceed via remodelling of pre-existing vessels that gradually enlarge to the point at which they can carry the bulk of blood flow.

Anmerkungen

The source is not given. The copied material cannot be found in the given reference Sasayama & Fujita (1992).

Note that the part B of figure 8 has been taken from another publication: Arc/Fragment_032_11


[24.] Arc/Fragment 032 11

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32a diss.png

Fig. 8 – A: [...]

B: Left anterior oblique view of the right coronary arteriogram. The left circumflex coronary artery (LCX) is proximally occluded and fills completely by means of collateral circulation from the right coronary artery (RCA)81.


81. Bloor CM, Liebow AA. Coronary Collateral Circulation. Am J Cardiol. 1965;16:238-252.

32a source.png

Figure 1. Left anterior oblique view of the right coronary arteriogram. The left circumflex coronary artery (LCX) is proximally occluded and fills completely by means of collateral circulation from the right coronary artery (RCA). Image courtesy of the Department of Cardiology at the Heronimus Bosch Hospital, Den Bosch, the Netherlands.

Anmerkungen

The given source has not been checked. However, the copied image contains the date "7-Apr-93" (or "7-Apr-98"), such that it cannot have been taken from a publication of 1965.

The source is mentioned on the previous page, but without any indication that this image might have been taken from it.

Note that the part A of figure 8 has been taken from a different publication: Arc/Fragment_032_10


[25.] Arc/Fragment 033 25

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[The role of shear stress in collateral growth has been discussed extensively by Wolfgang Schaper’s research group and others91, 92. Their model is based on the following concept (Fig. 9):] After occlusion of an artery, the pressure in its distal stump falls to very low levels. When a vascular connection like a pre-existent collateral anastomoses [sic] exists between the high-pressure (proximal to the occlusion) and the low pressure (distal from the occlusion) region, a steep pressure gradient develops which increases blood flow through these connections.

91. Helisch A, Wagner S, Khan N, Drinane M, Wolfram S, Heil M, Ziegelhoeffer T, Brandt U, Pearlman JD, Swartz HM, Schaper W. Impact of mouse strain differences in innate hindlimb collateral vasculature. Arterioscler Thromb Vasc Biol. 2006;26:520-526.

92. Cai Z, Zhong H, Bosch-Marce M, Fox-Talbot K, Wang L, Wei C, Trush MA, Semenza GL. Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1{alpha}. Cardiovasc Res. 2008;77:463-470.

On occlusion of an artery, the pressure in its distal stump falls to very low levels. When a vascular connection like a preexistent collateral anastomosis exists between the high-pressure proximal to the occlusion with the low-pressure region distal from the occlusion, a steep pressure gradient develops which increases blood flow through these connections (Figure 1).
Anmerkungen

To be continued on the next page: Arc/Fragment 034 01

The authors of the source are mentioned, the source itself is not. The given sources Cai et al. (2009) and Helisch et al. (2006) do not contain the copied text.

Nothing is marked as a quotation.


[26.] Arc/Fragment 034 01

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34a diss.png

Fig. 9 – Diagram of blood flow changes after occlusion of the femoral artery in the rabbit hind limb. After occlusion of the femoral artery (X), blood flow (arrows) follows the gradient between pressures proximal to the occlusion site and very low distal pressures, recruting pre-existing collateral arterioles89.

According to Heil and Schaper91, the vessel wall is now exposed to pronounced mechanical forces: increased blood flow directly augments fluid shear stress (FSS), i.e., the viscous drag that flowing blood exerts on the endothelial lining. By assuming Newtonian fluid dynamics, FSS can be estimated using the following equation:

34b diss.png

The authors demonstrate that blood flow (Q) will directly result in increased FSS (&tao;). The wall of the collateral arteriole is influenced by pressure-related forces like longitudinal-, circumferential- and radial-wall stresses. The distension of the vessel wall, structurally weakened by intravascular pressure, increases the circumferential wall stress (CWS). FSS is a relatively weak force compared with CWS, which is 106 times higher, posing the hypothesis that FSS can only act in concert with pressure-dependent forces91.


89. Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996;94:2193-2200.

91. Helisch A, Wagner S, Khan N, Drinane M, Wolfram S, Heil M, Ziegelhoeffer T, Brandt U, Pearlman JD, Swartz HM, Schaper W. Impact of mouse strain differences in innate hindlimb collateral vasculature. Arterioscler Thromb Vasc Biol. 2006;26:520-526.

34a source.png

Figure 1. Diagram of blood flow changes after occlusion of the femoral artery in the rabbit hind limb. After occlusion of the femoral artery (X), blood flow (arrows) follows the gradient between high pressures proximal to the occlusion site and very low distal pressures. Preexisting collateral arterioles are recruited.

[...]

[...] Hence, the collateral vessel wall is now exposed to various pronounced mechanical forces: increased blood flow directly augments fluid shear stress (FSS), ie, the viscous drag that flowing blood exerts on the endothelial lining. Assuming Newtonian fluid dynamics, FSS can be estimated using the following equation:

34b source.png

The equation that already includes blood viscosity (η) and the internal radius of a vessel (R), demonstrates that increased blood flow (Q) will directly result in increased FSS (&tao;).8

Furthermore, the wall of the collateral arteriole is influenced by pressure-related forces like longitudinal-, circumferential-, and radial wall stresses. The distention of the vessel wall, structurally weakened by matrix digestion, by the intravascular pressure, increases the circumferential wall stress, a known activator of smooth muscle cells (SMCs) proliferation.9

In contrast, FSS is a relatively weak force, more than two orders of magnitude lower than the pressure-derived forces

[page 451]

acting on the arterial wall. The difference is so impressive that other authors questioned the morphogenic force of FSS or posed the hypothesis that FSS can act only in concert with the pressure-dependent forces.9


8. Cox R. Physiology and hemodynamics of the macrocirculation. In: Stehbens W, eds. Hemodynamics and the Blood Vessel Wall. Springfield, Ill: Charles C. Thomas; 1979:75–156.

9. Scheel KW, Fitzgerald EM, Martin RO, Larsen RA. The possible role of mechanical stresses on coronary collateral development during gradual coronary occlusion. In: Schaper W, eds. The Pathophysiology of Myocardial Perfusion. Amsterdam: Elsevier/North-Holland; 1979:489–518.

Anmerkungen

The source is mentioned in the text (also on the previous page: Arc/Fragment 033 25), but it is not clear that the text as well as the diagram is taken 1-to-1 from the source, which is not listed in the bibliography. Note also that in the given sources Gho et al. (1996) and Helisch et al. (2006) the copied material cannot be found.


[27.] Arc/Fragment 036 12

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Through such interactions, ROS may irreversibly destroy or alter the function of the target molecule and consequently, ROS have been identified as major contributors to damage in biological organisms. Through such interactions, ROS may irreversibly destroy or alter the function of the target molecule. Consequently, ROS have been increasingly identified as major contributors to damage in biological organisms.
Anmerkungen

A reference to the source is missing.

Note that this phrase has been used before here: Arc/Fragment 022 01


[28.] Arc/Fragment 037 01

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[In Fig. 10, Ushio-Fukai describes important ROS-dependent genes and proteins associated with anigiogenesis, like urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and metalloproteinases (MMPs).]

37a diss.png

Fig. 10 - Role of ROS derived from NADPH oxidase in the induction of transcription factors and genes involved in angiogenesis. Ischemia/hypoxia stimulates VEGF induction and NADPH oxidase, thereby promoting activation of redox signalling events and induction of redox sensitive transcription factors and genes involved in angiogenesis. ROS derived from NADPH oxidase also upregulate mitochondrial SOD (MnSOD), increasing mitochondrial H2O2 production, which could represent a feed-forward mechanism by which ROS-triggered H2O2 formation plays an important role in angiogenesis101.


101. Tuttle JL, Sanders BM, Burkhart HM, Fath SW, Kerr KA, Watson WC, Herring BP, Dalsing MC, Unthank JL. Impaired collateral artery development in spontaneously hypertensive rats. Microcirculation. 2002;9:343-351.

37a source.png

Fig. 4. Role of ROS derived from NADPH oxidase in induction of transcription factors and genes involved in angiogenesis. Ischemia/hypoxia stimulates VEGF induction and NADPH oxidase, thereby promoting activation of redox signaling events and induction of redox sensitive transcription factors and genes involved in angiogenesis. ROS derived from NADPH oxidase also upregulate MnSOD which increases mitochondrial H2O2 production, which could represent a feed-forward mechanism by which ROS-triggered H2O2 formation plays an important role in angiogenesis.

Anmerkungen

On the previous page it is mentioned that "In Fig. 10, Ushio-Fukai describes important ...". However, there is no reference to a publication by Usio-Fukai to be found in the list of references, and it is also not clear that the caption of figure 10 is also taken from that source.

In the given source Tuttle et al. (2002) none of the copied material can be found.


[29.] Arc/Fragment 037 11

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Quelle: Maulik et al 1998
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Tissue such as the myocardium can be adapted to ischemic stress by repeatedly subjecting it to short terms of reversible ischemia, each followed by another short duration of reperfusion108, 109. This phenomenon causes the production of oxidative stress, leading to the induction of gene expression, which is subsequently translated into the development of beneficial proteins responsible for the heart’s defence97.

97. Murphy E, Steenbergen C. Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury. Physiol. Rev. 2008;88:581-609.

108. Maulik N, Yoshida T, Zu YL, Sato M, Banerjee A, Das DK. Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2. Am J Physiol. 1998;275:H1857-1864.

109. Maulik N, Yoshida T, Engelman RM, Deaton D, Flack JE, 3rd, Rousou JA, Das DK. Ischemic preconditioning attenuates apoptotic cell death associated with ischemia/reperfusion. Mol Cell Biochem. 1998;186:139-145.

Mammalian heart can be adapted to ischemia by repeatedly subjecting it to short-term reversible ischemia each followed by another short duration of reperfusion [1,2]. This phenomenon, known as ischemic adaptation, causes the production of oxidative stress leading to the induction of gene expression which is subsequently translated into the development of several stress-related proteins responsible for the heart's defense [3].

[1] Reimer, A., vander Heide, R.S. and Jennings, R.B. (1994) Ann. NY Acad. Sci. 723, 99-115.

[2] Banerjee, A., Locke-Winter, C., Rogers, K.B., Mitchell, M.B., Bensard, D.D., Brew, E.C., Cairns, C.B. and Harken, A.H. (1993) Circ. Res. 73, 656-670.

[3] Das, D.K., Maulik, N. and Moraru, I.I. (1995) J. Mol. Cell. Cardiol. 27, 181-193.

Anmerkungen

The source is not given (the two papers by Maulik et al. given are different to the source here documented). The papers referenced under 97, 108 and 109 do not contain the copied text.


[30.] Arc/Fragment 038 01

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[It was later found that the generation of ROS was a result of the opening of mitochondrial ATP-sensitive potassium channels (mKATP), acting as second messengers in a pathway that] ended in the activation of protein kinase C (PKC), which would then trigger the preconditioned state111. In those studies, ROS were recognized as part of the trigger pathway that preconditions the heart prior to the onset of ischemia. It was discovered that IPC actually exerts its protective effect in the first minutes of reperfusion112, presumably by inhibiting the formation of mitochondrial permeability transition pores (mPTP)113. It was also found that redox signalling is part of the pathway that mediates IPC protection at the time of reperfusion, meaning that ROS generation was required for IPC to be protective114. It is unknown how redox signalling acts to mediate protection at reperfusion115, but a number of signal transduction components have been identified in IPC’s mediator pathway, including phosphatidylinositol (PI) 3-kinase and extracellular signal-regulated kinase (ERK)112.

111. Pain T, Yang XM, Critz SD, Yue Y, Nakano A, Liu GS, Heusch G, Cohen MV, Downey JM. Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res. 2000;87:460-466.

112. Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol. 2005;288:H971-976.

113. Hausenloy DJ, Yellon DM, Mani-Babu S, Duchen MR. Preconditioning protects by inhibiting the mitochondrial permeability transition. Am J Physiol Heart Circ Physiol. 2004;287:H841-849.

114. Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G, Pagliaro P. Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol. 2006;101:180-189.

115. Liu F, Patient R. Genome-Wide Analysis of the Zebrafish ETS Family Identifies Three Genes Required for Hemangioblast Differentiation or Angiogenesis. Circ Res. 2008:CIRCRESAHA.108.179713.

[page 1]

Later it was found that ROS were generated as a result of opening of mitochondrial ATP-sensitive potassium channels (mKATP) and acted as second messengers in a pathway ending in activation of PKC which triggered the preconditioned state (20). In those studies ROS were recognized as part of the trigger pathway that preconditions the heart prior to the onset of the index ischemia. Several years ago it was discovered that IPC actually exerts its protective effect in the first minutes of reperfusion (9) presumably by inhibiting the formation of mitochondrial permeability

[page 2]

transition pores (mPTP) (11). Then it was found that redox signaling is part of the pathway that mediates IPC's protection at the time of reperfusion as well. Penna et al. (21) reported that ROS generation was required for ischemic postconditioning to be protective. [...]

It is unknown how redox signaling acts to mediate protection at reperfusion. A number of signal transduction components have been identified in IPC's mediator pathway including phosphatidylinositol (PI) 3-kinase and extracellular signal-regulated kinase (ERK) (9).


9. Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol 2005;288:H971–H976.

11. Hausenloy DJ, Yellon DM, Mani-Babu S, Duchen MR. Preconditioning protects by inhibiting the mitochondrial permeability transition. Am J Physiol 2004;287:H841–H849.

20. Pain T, Yang X-M, Critz SD, Yue Y, Nakano A, Liu GS, Heusch G, Cohen MV, Downey JM. Opening of mitochondrial KATP channels triggers the preconditioned state by generating free radicals. Circ Res 2000;87:460–466. [PubMed: 10988237]

21. Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G, Pagliaro P. Postconditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol 2006;101:180–189. [PubMed: 16450075]

Anmerkungen

The source is not mentioned. The copied text cannot be found in Liu & Patient (2008).


[31.] Arc/Fragment 040 03

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Male Sprague-Dawley rats (3–4 mo old, 300–350 g) were used for chronic (5 days) implantation of a pneumatic occluder over the left anterior descending coronary artery (LAD; as described by Toyota et al.96) to produce repetitive ischemia (RI). Briefly, for surgery, rats were premedicated (ketamine 50 mg/mL plus acepromazine 2.5 mg/mL plus torbuterol 2.0 mg/mL, 0.2 mL/100 g body weight, i.p.) and intubated. Oral intubation (I6-G polyethylene tubing) was done under direct observation of the vocal cords with an otoscope. General anesthesia was introduced and maintained by sevoflurane inhalation (1.0% to 2.0%, with 100% oxygen). Body temperature was controlled at 37°C by an electric heating table. Surgery was performed using aseptic technique. The animal was initially placed on its dorsal side, and after a neck incision, the right carotid artery was isolated, and a PE-50 catheter filled with heparin (10 U/mL)-saline was inserted. This tubing was used for monitoring of systemic hemodynamics, sampling arterial blood, and maintaining the blood volume. Blood pH, PaO2, PaCO2, and systemic hemodynamics were maintained within physiological ranges throughout the surgery. The animal was repositioned on its right side, and the heart was exposed by left thoracotomy. A mini-pneumatic snare occluder (see the Mini- Pneumatic Snare Occluder section for details) was implanted around the mid to proximal LAD. Confirmation that the occluder was functional, i.e., producing myocardial ischemia, was determined initially by observation of blanching and hypokinesis of the left ventricle (LV) during inflation. Rats were randomly divided into 3 groups based on the type of measurement: coronary blood flow (CBF) (neutron activated microspheres), oxidative stress analysis (Dihydroethidium, DHE) or vascular imaging (micro-CT). CBF was measured during coronary occlusion to determine flows to the normal and collateral-dependent zones (see the Microsphere measurements of myocardial and collateral-dependent blood flow and the Coronary Microvascular imaging with Cryomicrotome sections). After instrumentation and measurements, the chest was closed under positive end-expiratory pressure, and the thoracic cavity was evacuated of air. The occluder was tunnelled subcutaneously and exteriorized between the scapulae. This catheter was protected by a stainless steel spring coil connected to a ring that was secured subcutaneously between the scapulae.

96. Toyota E, Warltier DC, Brock T, Ritman E, Kolz C, O'Malley P, Rocic P, Focardi M, Chilian WM. Vascular endothelial growth factor is required for coronary collateral growth in the rat. Circulation. 2005;112:2108-2113.

Male Wistar rats (290- to 360-g body weight; n=50) were used for experiments (preparations were successful in 39 animals). For surgery, rats were premedicated (ketamine 50 mg/mL plus acepromazine 2.5 mg/mL plus torbuterol 2.0 mg/mL, 0.2 mL/100 g body weight IP) and intubated. Oral intubation (I6-G polyethylene tubing) was done under direct observation of the vocal cords with an otoscope. General anesthesia was introduced and maintained by sevoflurane inhalation (1.0% to 2.0%, with 100% oxygen). Body temperature was controlled at 37°C by an electric heating table. Surgery was performed using aseptic technique. The animal was initially placed on its dorsal side, and after a neck incision, the right carotid artery was isolated, and a PE-50 catheter filled with heparin (10 U/mL)-saline was inserted. This tubing was used for monitoring of systemic hemodynamics, sampling arterial blood, and maintaining the blood volume. Blood pH, PaO2, PaCO2, and systemic hemodynamics were maintained within physiological ranges throughout the surgery. The animal was repositioned on its right side, and the heart was exposed by left thoracotomy. A mini-pneumatic snare occluder (see the Mini-Pneumatic Snare Occluder section for details) was implanted around the mid to proximal left anterior descending coronary artery (LAD). Confirmation that the occluder was functional, ie, producing myocardial ischemia, was determined initially by observation of blanching and hypokinesis of the left ventricle (LV) during inflation. Rats were randomly divided into 2 groups based on the type of measurement: coronary blood flow (CBF) (radioactive microspheres, n=20) or vascular imaging (micro-CT, n=13). CBF was measured during coronary occlusion to determine flows to the normal and collateral-dependent zones (see the Measurement of Coronary Blood Flow and the Coronary Vascular Imaging With Micro-CT sections). After instrumentation and measurements, the chest was closed under positive end-expiratory pressure, and the thoracic cavity was evacuated of air. An intraperitoneal catheter (PE-50) for drug administration was inserted, and this catheter and the occluder were tunneled subcutaneously and exteriorized between the scapulae. These catheters were protected by a stainless steel spring coil connected to a ring that was secured subcutaneously between the scapulae.
Anmerkungen

The source is given at the beginning of the section in a way that indicates that the here described method is similar to the one employed by the authors of the source. However, it is not clear to the reader that the description of the method is a largely literal copy of the source.


[32.] Arc/Fragment 041 01

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[After the surgery, analgesic] (buprenorphine 0.05 mg/kg s.c.) and antibiotic (enrofloxacin 10 mg/kg s.c.) compounds were administered. Rats were observed in a recovery cage for 2 hours and then transferred to the animal care facility. For 3 days after the surgery, buprenorphine (0.5 mg/kg BID mixed in strawberry Jello) was taken orally for pain relief. On the fourth day after the surgery, the ischemic protocol was started (see the Experimental Protocol section). After 5 days of the experimental protocol, the rats were anesthetized and the chest was opened by mid thoracotomy. In CBF measurement or DHE analysis groups, the hearts were excised at the end of procedures, and the tissue was prepared for analyses.

3.2 Mini-Pneumatic Snare Occluder for Rat Heart

A mini-pneumatic snare occluder consisting of a mini-balloon, sheath tubing, suture, and catheter (Fig. 11) was placed on the LAD of the rat heart. The balloon (7 mm long) is made of soft latex membrane and is sufficiently pliable to give negligible physical force on the coronary vessels during balloon deflation. The balloon is mounted within an umbrella sheath (3.2 or 4.8 mm in diameter, 12 mm in length; protects the balloon from fibrous infiltration). Prolene (5– 0) is passed around the LAD and attached to the sheath, securing the occluder to the heart, so that myocardial ischemia is produced by balloon inflation. Inflation volume is small (0.2 to 0.25 mL air), but occlusion occurs by 2 physical actions: “crimping” the LAD toward upward/outside and compressing the LAD by the inflated balloon/sheath. The balloon is connected to a catheter (PE-50) that is exteriorized. Balloon inflation and deflation are controlled from outside the rat cage.

41a diss.png

Fig. 11 - Schematic diagram of the mini-pneumatic snare and its actions. Top: Cross-sectional and longitudinal views when the balloon is deflated. Bottom: Views during inflation. The artery is patent when the balloon is deflated, but during inflation, a snare situated underneath the artery is pulled “upward” during inflation, producing the coronary occlusion94.


94. Kappel A, Ronicke V, Damert A, Flamme I, Risau W, Breier G. Identification of Vascular Endothelial Growth Factor (VEGF) Receptor-2 (Flk-1) Promoter/Enhancer Sequences Sufficient for Angioblast and Endothelial Cell- Specific Transcription in Transgenic Mice. Blood. 1999;93:4284-4292.

After the surgery, analgesic (buprenorphine 0.05 mg/kg SC) and antibiotic (enrofloxacin 10 mg/kg SC) were administered. Rats were observed in a recovery cage for 2 hours and then transferred to the animal care facility. For 3 days after the surgery, buprenorphine (0.5 mg/kg BID mixed in strawberry Jello) was taken orally for pain. On the fourth day after the surgery, ischemic protocol was started (see the Experimental Protocol section).

After 10 days of the experimental protocol, the rats were anesthetized, and the chest was opened by mid thoracotomy. In the micro-CT group, the hearts were immediately excised. In CBF measurement group, blood flow to the normal and collateraldependent zones during coronary occlusion was measured. The heart was excised at the end of measurements, and the tissue was prepared for analyses of radioactivity.

Mini-Pneumatic Snare Occluder for Rat Heart

We developed a mini-pneumatic snare occluder (patent application serial number: 11/071,617, E.T. and W.M.C.) consisting of a mini-balloon, sheath tubing, suture, and catheter (Figure 1). The balloon (7 mm long) is made of soft latex membrane and is sufficiently pliable to give negligible physical force on the coronary vessels during balloon deflation. The balloon is mounted within an umbrella sheath (3.2 or 4.8 mm in diameter, 12 mm in length; protects the balloon from fibrous infiltration). Prolene (5– 0) is passed around the LAD and attached to the sheath, securing the occluder to the heart, so that myocardial ischemia is produced by balloon inflation. Inflation volume is small (0.2 to 0.25 mL air), but occlusion occurs by 2 physical actions: “crimping” the LAD toward upward/outside and compressing the LAD by the inflated balloon/sheath. The balloon is connected to a catheter (PE-50) that is exteriorized. Balloon inflation and deflation are controlled from outside the rat cage.

41a source.png

Figure 1. Schematic of the mini-pneumatic snare and its actions. Top, Cross-sectional and longitudinal views when the balloon is deflated. Bottom, Views during inflation. The artery is patent when the balloon is deflated, but during inflation, a snare situated underneath the artery is pulled “upward” during inflation, producing the coronary occlusion.

Anmerkungen

At the beginning of the previous page the source is mentioned, but without indication that the following two pages are taken from it.

The given source Kappel et al. (1999) doesn't contain any of the copied material.


[33.] Arc/Fragment 042 16

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Quelle: Toyota et al 2005
Seite(n): 2109, Zeilen: r.col: 13ff
CBF was measured with neutron activated microspheres (Biopal, 15 μm) before initiation of (after all the instruments had been implanted at the time of the initial surgery) and at the end of the repetitive occlusions (when the rats were anesthetized and the chest was open to mimic the conditions of the first measurement) to measure normal zone flows and flow in the developed collaterals. For the first measurement, neutron activated microspheres labelled with Samarium were mixed with fluorescent (FITC) microspheres (Invitrogen, 10 μm) to identify the collateral-dependent region as described below. For the second measurement, Gold labelled microspheres were used. The microspheres (5×105) were injected directly into the LV cavity via the LV apex during LAD occlusion with a 29-gauge insulin syringe over a 10-second period. During the course of the procedures, systemic pressure and heart rate were recorded (386- BIOS, American Megatrends Inc). The heart was excised and fresh LV was sliced along the short axis and observed with a dissecting microscope and fluorescent light source. The collateral-dependent area (ischemic zone, LAD region) was distinguished as the [area without fluorescent microspheres.] CBF was measured with radioactive microspheres (Perkins Elmer; φ; 15 μm; 95Nb and 103Ru, ≈4.5x105) before initiation of (after all the instruments had been implanted at the time of the initial surgery) and at the end of the repetitive occlusions (when the rats were anesthetized and the chest was open to mimic the conditions of the first measurement) to measure normal zone flows, native collateral flow, and flow in the developed collaterals. For the first measurement, radioactive microspheres were mixed with fluorescent (FITC) microspheres (φ, 10 μm; ≈9x105, Fluoresbrite Yellow Green, Polysciences, Inc) to identify the collateral-dependent region as described below. For the second measurement, the other nuclidelabeled microspheres were used. The microspheres were agitated for 15 minutes, suspended in saline (total volume, 150 μL), and then injected directly into the LV cavity via the LV apex during LAD occlusion with a 29-gauge insulin syringe over a 10-second period. [...] During the course of the procedures, systemic pressure and heart rate were recorded (386- BIOS, American Megatrends Inc).

The heart was excised and fixed in 4% paraformaldehyde solution overnight. The fixed LV was sliced along the short axis and observed with a dissecting microscope and fluorescent light source (LT-9800, Lightools Research). The collateral-dependent area (LAD region) was distinguished as the area without fluorescent microspheres.

Anmerkungen

The source is not given.


[34.] Arc/Fragment 043 01

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Seite: 43, Zeilen: 1-5
Quelle: Toyota et al 2005
Seite(n): 2109, Zeilen: r.col: 40ff
The control area (non-LAD LV region) was determined by the area of distribution of the fluorescent microspheres. The normal and collateral-dependent zones were divided with a blade, and for each the total weight was measured. Collateral flow was calculated as a ratio between activity (dpm/g) of the tissue samples from the LAD-dependent and normal zones. The control area (non-LAD LV region) was determined by the area distribution of the fluorescent microspheres. The normal and collateral-dependent zones were divided with a blade, and each total weight was measured. CBF (mL · min-1 · g-1) in each area was calculated from the following formula: CBF=[(radioactive counts in myocardial specimen)x(blood withdrawal rate)/(radioactive count in blood)]/(weight of myocardial specimen).
Anmerkungen

The copied text begins on the previous page: Arc/Fragment_042_16


[35.] Arc/Fragment 044 01

KomplettPlagiat
Untersuchte Arbeit:
Seite: 44, Zeilen: 1-6
Quelle: Becker et al 1999
Seite(n): H2241, Zeilen: l.col: 21-31
[Intracellular oxidant stress can be monitored by measuring] changes in fluorescence resulting from intracellular probe oxidation. DHE enters the cell and is oxidized by ROS, particularly superoxide, to yield fluorescent ethidium. Ethidium binds to DNA (Eth-DNA), further amplifying its fluorescence. Eth-DNA fluorescence is generally stable but can be decreased by hydroxyl radical attack. Thus increases in DHE oxidation to Eth-DNA (i.e., increases in Eth-DNA fluorescence) are suggestive of superoxide generation. Intracellular oxidant stress was monitored by measuring changes in fluorescence resulting from intracellular probe oxidation. Dihydroethidine (DHE, 1–10 μmol/l; Molecular Probes) enters the cell and is oxidized by ROS, particularly superoxide, to yield fluorescent ethidium. Ethidium binds to DNA (Eth-DNA), further amplifying its fluorescence (5). Eth-DNA fluorescence is generally stable but can be decreased by hydroxyl radical attack (27). Thus increases in DHE oxidation to Eth-DNA (i.e., increases in Eth-DNA fluorescence) are suggestive of superoxide generation.

5. Carter,W. O., P. K. Narayanan, and J. P. Robinson. Intracellular hydrogen peroxide and superoxide anion detection in endothelial cells. J. Leukoc. Biol. 55: 253–258, 1994.

27. Prutz, W. A. Inhibition of DNA-ethidium bromide intercalation due to free radical attack upon DNA. Radiat. Environ. Biophys. 23: 1–18, 1984.

Anmerkungen

The source is not mentioned.


[36.] Arc/Fragment 044 15

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Untersuchte Arbeit:
Seite: 44, Zeilen: 15-25
Quelle: Rocic et al 2007
Seite(n): H2730, Zeilen: left col. 33-47
For the in vitro studies in freshly isolated cardiomyocytes (Cardiomyocyte Isolation for details), G-CSF was administered for 10 min (total treatment time 30 min), and DHE was added during the last 20 min of treatment with G-CSF. Cells were then immediately observed under a fluorescent microscope. For in vivo studies, DHE was injected into the LV (60 μg/kg, n=3/group) for 20 min before two consecutive periods of ischemia-reperfusion (40s occlusion followed by 20min reperfusion and another 40s occlusion and 20min reperfusion). Animals were then sacrificed. The heart was removed, frozen in optimum cutting temperature compound on dry ice, and stored at -80°C until sectioning. Sections (5 μm) were made in a cryomicrotome and were mounted on glass slides. DHE fluorescence was detected with excitation/emission at 518/605 nm. All images were analyzed at the same microscope settings, and fluorescence intensity was obtained by Metamorph Software on three hearts (10 sections per heart). For HCAEC cell culture, DHE was administered during the last 20 min of treatment. Cells were then observed immediately under a fluorescent microscope. For in vivo studies, DHE or DCF were injected into the LV (60 μg/kg) for 20 min before two consecutive periods of ischemia-reperfusion (40 s occlusion followed by 20 min reperfusion and another 40 s occlusion and 20 min reperfusion). Animals were then killed. The heart was removed, frozen in optimum cutting temperature compound on dry ice, and stored at -70°C until sectioning. Sections (5 μm) were made in a cryomicrotome and were mounted on glass slides. DHE or DCF fluorescence was detected with excitation/emission at 518/605 nm (for DHE) or 480/515 nm (for DCF). All images were analyzed at the same microscope settings, and relative fluorescence readings were obtained by Metamorph Software on three hearts (5 consecutive sections per heart).
Anmerkungen

Though taken verbatim nothing has been marked as a citation and the source is not given.


[37.] Arc/Fragment 046 25

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Seite: 46, Zeilen: 25-27
Quelle: Rocic et al 2007
Seite(n): H2730, Zeilen: right col. 3-8
The extent of tube formation was quantified after 24h by superimposing a grid (25mm2/cube) on microscopic images, and the number of squares containing tubes were counted and [averaged from five randomly selected fields for each well to obtain the percentage of total field that contained tubes.] The extent of tube formation was quantified after two days by using Scion Image software. An electronic grid was superimposed on microscopic images, and the number of squares containing tubes were counted and averaged from five randomly selected fields for each well to obtain the percentage of total field that contained tubes.
Anmerkungen

Nearly identical, but not marked as a citation.


[38.] Arc/Fragment 047 01

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Seite: 47, Zeilen: 1-5 (complete)
Quelle: Rocic et al 2007
Seite(n): H2730, Zeilen: right col. 3-8, 22-26
[The extent of tube formation was quantified after 24h by superimposing a grid (25mm2/cube) on microscopic images, and the number of squares containing tubes were counted and] averaged from five randomly selected fields for each well to obtain the percentage of total field that contained tubes. Treatments were conducted in n=4.

3.9 Data analysis

ANOVA followed by t-tests was used for statistical analysis. A probability value of P<0.05 was used to determine statistical significance.

The extent of tube formation was quantified after two days by using Scion Image software. An electronic grid was superimposed on microscopic images, and the number of squares containing tubes were counted and averaged from five randomly selected fields for each well to obtain the percentage of total field that contained tubes.

[...] All experiments were performed in triplicate (n=3 animals/group).

Data analysis. ANOVA followed by t-tests with Bonferroni inequalities was used for statistical analysis. A probability value of P<0.05 was used to determine statistical significance.

Anmerkungen

Nearly identical, but not marked as a citation.


[39.] Arc/Fragment 049 02

Verschleierung
Untersuchte Arbeit:
Seite: 49, Zeilen: 2-11
Quelle: Toyota et al 2005
Seite(n): 2109, 2110, Zeilen: 2109: r.col: last two lines; 2110: l.col: 1ff
Evaluation of collateral growth was performed after completion of the protocol by a simple functional test: total coronary occlusion. The rationale for this procedure was that if collaterals were developed, then occlusion would not induce functional disturbances. Alternatively, if collaterals were not mature, then occlusion would cause hemodynamic disturbances. After the second measurement of coronary blood flow, the coronary occlusion was maintained, systemic hemodynamics were measured and also the number of arrhythmias. In animals without collaterals, coronary occlusion caused deterioration of systemic hemodynamics and arrhythmias, including premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation; in animals with well developed collaterals, no such adverse effects were noted. We evaluated collateral growth after completion of the protocol by a simple functional test: total coronary occlusion. The rationale for this

[page 2110]

procedure was that if collaterals were developed, then occlusion would not induce functional disturbances. Alternatively, if collaterals were not mature, then occlusion would cause hemodynamic disturbances. After the second measurement of coronary blood flow, we maintained the coronary occlusion (n=9 in control group, n=6 in anti-VEGF group) and measured systemic hemodynamics and the number of arrhythmias. In animals without collaterals, coronary occlusion caused deterioration of systemic hemodynamics and arrhythmias, including premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation; in animals with well-developed collaterals, no such adverse effects were noted.

Anmerkungen

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[40.] Arc/Fragment 049 14

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Untersuchte Arbeit:
Seite: 49, Zeilen: 14-19
Quelle: Toyota et al 2005
Seite(n): 2109, Zeilen: r.col: 36-42
After the completion of treatments, the heart was removed, and the left ventricle (LV) was sliced along the short axis and observed with a dissecting microscope under fluorescent light. The collateral-dependent area (LAD region, ischemic zone) was distinguished as the area without fluorescent microspheres. The control area (non-LAD LV region, normal zone) was determined by the area of distribution of the fluorescent microspheres (Fig. 13). The heart was excised and fixed in 4% paraformaldehyde solution overnight. The fixed LV was sliced along the short axis and observed with a dissecting microscope and fluorescent light source (LT-9800, Lightools Research). The collateral-dependent area (LAD region) was distinguished as the area without fluorescent microspheres. The control area (non-LAD LV region) was determined by the area distribution of the fluorescent microspheres.
Anmerkungen

The source is not given. To be continued on the next page: Arc/Fragment_050_01

Note that a similar text can also be found further up in the thesis, c.f. Arc/Fragment_042_16, Arc/Fragment_043_01


[41.] Arc/Fragment 050 01

KomplettPlagiat
Untersuchte Arbeit:
Seite: 50, Zeilen: 1-2
Quelle: Toyota et al 2005
Seite(n): 2109, Zeilen: r.col: 42-44
The normal and collateral-dependent zones were divided with a blade, and each total weight was measured. The normal and collateral-dependent zones were divided with a blade, and each total weight was measured.
Anmerkungen

The copied text starts on the previous page: Arc/Fragment_049_14


Sources

[1.] Quelle:Arc/Avalos 1996

Autor     Belinda R. Avalos
Titel    Molecular Analysis of the Granulocyte Colony-Stimulating Factor Receptor
Zeitschrift    Blood
Herausgeber    The American Society of Hematology
Ausgabe    88
Datum    1. August 1996
Nummer    3
Seiten    761-777
ISSN    0006-4971
URL    http://bloodjournal.hematologylibrary.org/content/88/3/761.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[2.] Quelle:Arc/Basu et al 2002

Autor     Sunanda Basu, George Hodgson, Melissa Katz, Ashley R. Dunn
Titel    Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation
Zeitschrift    Blood
Herausgeber    American Society of Hematology
Ausgabe    100
Jahr    2002
Nummer    3
Seiten    854-861
ISSN    1528-0020
DOI    10.1182/blood.V100.3.854
URL    http://bloodjournal.hematologylibrary.org/content/100/3/854.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[3.] Quelle:Arc/Becker et al 1999

Autor     Lance B. Becker, Terry L. Vanden Hoek, Zuo-Hui Shao, Chang-Qing Li, Paul T. Schumacker
Titel    Generation of superoxide in cardiomyocytes during ischemia before reperfusion
Zeitschrift    The American journal of Physiology
Herausgeber    American Physiological Society
Ausgabe    277
Jahr    1999
Seiten    H2240-H2246
URL    http://ajpheart.physiology.org/content/ajpheart/277/6/H2240.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[4.] Quelle:Arc/Bedard Krause 2007

Autor     Karen Bedard, Karl-Heinz Krause
Titel    The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Zeitschrift    Physiological Reviews
Herausgeber    American Physiological Society
Ausgabe    87
Jahr    2007
Seiten    245–313
DOI    10.1152/physrev.00044.2005
URL    http://physrev.physiology.org/content/87/1/245.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[5.] Quelle:Arc/Demetri and Griffin 1991

Autor     George D. Demetri, James D. Griffin
Titel    Granulocyte colony-stimulating factor and its receptor
Zeitschrift    Blood
Herausgeber    American Society of Hematology
Ausgabe    78
Datum    1. December 1991
Nummer    10
Seiten    2791-2808
ISSN    1528-0020
URL    http://www.researchgate.net/publication/21435817_Granulocyte_colony-stimulating_factor_and_its_receptor

Literaturverz.   

yes
Fußnoten    yes

[6.] Quelle:Arc/Fukunaga et al 1991

Autor     Rikiro Fukunaga, Etsuko Ishizaka-lkeda, Cai-Xi Pan, Yoshiyuki Seto, Shigekazu Nagata
Titel    Functional domains of the granulocyte colony-stimulating factor receptor
Zeitschrift    The EMBO Journal
Ausgabe    10
Jahr    1991
Nummer    10
Seiten    2855-2865
URL    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC452996/

Literaturverz.   

no
Fußnoten    no

[7.] Quelle:Arc/Haghighat et al 2007

Autor     Amir Haghighat, Daiana Weiss, Matthew K. Whalin, D. Patrick Cowan, W. Robert Taylor
Titel    Granulocyte Colony-Stimulating Factor and Granulocyte Macrophage Colony-Stimulating Factor Exacerbate Atherosclerosis in Apolipoprotein E-Deficient Mice
Zeitschrift    Circulation
Herausgeber    American Heart Association
Ausgabe    15
Jahr    2007
Seiten    2049-2054
ISSN    1524-4539
DOI    10.1161/CIRCULATIONAHA.106.665570
URL    http://circ.ahajournals.org/content/115/15/2049.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[8.] Quelle:Arc/Heil Schaper 2004

Autor     Matthias Heil, Wolfgang Schaper
Titel    Influence of Mechanical, Cellular, and Molecular Factors on Collateral Artery Growth (Arteriogenesis)
Zeitschrift    Circulation Research
Herausgeber    American Heart Association
Ausgabe    95
Jahr    2004
Seiten    449-458
ISSN    1524-4571
DOI    10.1161/01.RES.0000141145.78900.44
URL    http://circres.ahajournals.org/content/95/5/449.full.pdf

Literaturverz.   

no
Fußnoten    yes

[9.] Quelle:Arc/Koerselman et al 2003

Autor     Jeroen Koerselman, Yolanda van der Graaf, Peter P.Th. de Jaegere, Diederick E. Grobbee
Titel    Coronary Collaterals: An Important and Underexposed Aspect of Coronary Artery Disease
Zeitschrift    Circulation
Herausgeber    American Heart Association
Ausgabe    107
Jahr    2003
Seiten    2507-2511
ISSN    1524-4539
DOI    10.1161/01.CIR.0000065118.99409.5F
URL    http://circ.ahajournals.org/content/107/19/2507.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[10.] Quelle:Arc/Liu et al 2008

Autor     Yanping Liu, Xi-Ming Yang, Efstathios K. Iliodromitis, Dimitrios Th. Kremastinos, Turhan Dost, Michael V. Cohen, James M. Downey
Titel    Redox Signaling At Reperfusion Is Required For Protection From Ischemic Preconditioning But Not From A Direct PKC Activator
Zeitschrift    Basic Research in Cardiology
Ausgabe    103
Datum    January 2008
Nummer    1
Seiten    54-59
DOI    10.1007/s00395-007-0683-y
URL    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2660167/

Literaturverz.   

no
Fußnoten    no

[11.] Quelle:Arc/Maulik et al 1998

Autor     Nilanjana Maulik, Motoaki Sato, Brendan D. Price, Dipak K. Das
Titel    An essential role of NFUB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia
Zeitschrift    FEBS Letters
Herausgeber    Federation of European Biochemical Societies
Ausgabe    429
Jahr    1998
Seiten    365-369
URL    http://ac.els-cdn.com/S0014579398006322/1-s2.0-S0014579398006322-main.pdf?_tid=008400e4-9db9-11e3-9cc3-00000aacb35d&acdnat=1393290545_14a06ef9a39816cb741381c18c2b903d

Literaturverz.   

no
Fußnoten    no

[12.] Quelle:Arc/Nagata Fukunaga 1991

Autor     Shigekazu Nagata, Rikiro Fukunaga
Titel    Granulocyte colony-stimulating factor and its receptor
Zeitschrift    Progress in Growth Factor Research
Ausgabe    3
Jahr    1991
Seiten    131-141
URL    http://www.sciencedirect.com/science/article/pii/S0955223505800043

Literaturverz.   

yes
Fußnoten    yes

[13.] Quelle:Arc/Quinn and Gauss 2004

Autor     Mark T. Quinn, Katherine A. Gauss
Titel    Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases
Zeitschrift    Journal of Leukocyte Biology
Ausgabe    76
Datum    October 2004
URL    http://www.jleukbio.org/content/76/4/760.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[14.] Quelle:Arc/Risau 1997

Autor     Werner Risau
Titel    Mechanisms of angiogenesis
Zeitschrift    Nature
Ausgabe    386
Datum    17. April 1997
Seiten    671-674
URL    http://xa.yimg.com/kq/groups/15186538/764216019/name/for

Literaturverz.   

yes
Fußnoten    yes

[15.] Quelle:Arc/Rocic et al 2007

Autor     Petra Rocic, Christopher Kolz, Ryan Reed, Barry Potter, William M. Chilian
Titel    Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth
Zeitschrift    American Journal of Physiology: Heart and Circulatory Physiology
Herausgeber    American Physiological Society
Ausgabe    292
Datum    16. February 2007
Seiten    H2729-H2736
DOI    10.1152/ajpheart.01330.2006
URL    http://ajpheart.physiology.org/content/ajpheart/292/6/H2729.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[16.] Quelle:Arc/Sampson et al 2007

Autor     Matthew Sampson, Quan-Sheng Zhu, Seth J. Corey
Titel    Src kinases in G-CSF Receptor Signaling
Zeitschrift    Frontiers in Bioscience
Ausgabe    12
Datum    1. January 2007
Seiten    1463-1474
URL    http://www.bioscience.org/2007/v12/af/2160/fulltext.htm (figures: [1])

Literaturverz.   

yes
Fußnoten    yes

[17.] Quelle:Arc/Simons Ware 2003

Autor     Michael Simons, J. Anthony Ware
Titel    Therapeutic Angiogenesis in cardiovascular disease
Zeitschrift    Nature Reviews Drug discovery
Herausgeber    Nature Publishing Group
Ausgabe    2
Datum    November 2003
Seiten    1-9
DOI    10.1038/nrd1226
URL    http://www.nature.com/nrd/journal/v2/n11/full/nrd1226.html

Literaturverz.   

no
Fußnoten    no

[18.] Quelle:Arc/Ten Dijke Arthur 2007

Autor     Peter ten Dijke, Helen M. Arthur
Titel    Extracellular control of TGFβ signalling in vascular development and disease
Zeitschrift    Nature Reviews Molecular Cell Biology
Herausgeber    Nature Publishing Group
Ausgabe    8
Datum    November 2007
Seiten    857-869
DOI    10.1038/nrm2262
URL    http://www.nature.com/nrm/journal/v8/n11/full/nrm2262.html

Literaturverz.   

yes
Fußnoten    yes

[19.] Quelle:Arc/Toyota et al 2005

Autor     Eiji Toyota, David C. Warltier, Tommy Brock, Erik Ritman, Christopher Kolz, Peter O'Malley, Petra Rocic, Marta Focardi, William M. Chilian
Titel    Vascular Endothelial Growth Factor Is Required for Coronary Collateral Growth in the Rat
Zeitschrift    Circulation
Herausgeber    American Heart Association
Ausgabe    112
Jahr    2005
Seiten    2108-2113
ISSN    1524-4539
DOI    10.1161/CIRCULATIONAHA.104.526954
URL    http://circ.ahajournals.org/content/112/14/2108.full.pdf

Literaturverz.   

yes
Fußnoten    yes

[20.] Quelle:Arc/Ushio-Fukai 2006

Autor     Masuko Ushio-Fukai
Titel    Redox signaling in angiogenesis: Role of NADPH oxidase
Zeitschrift    Cardiovascular Research
Herausgeber    European Society of Cardiology
Verlag    Elsevier
Ausgabe    71
Jahr    2006
Seiten    226 – 235
DOI    10.1016/j.cardiores.2006.04.015
URL    http://cardiovascres.oxfordjournals.org/content/71/2/226.full.pdf

Literaturverz.   

no
Fußnoten    yes

[21.] Quelle:Arc/Ward et al 1999

Autor     Alister C. Ward, Louise Smith, John P. de Koning, Yvette van Aesch, Ivo P. Touw
Titel    Multiple Signals Mediate Proliferation, Differentiation, and Survival from the Granulocyte Colony-stimulating Factor Receptor in Myeloid 32D Cells
Zeitschrift    The journal of Biological Chemistry
Herausgeber    The American Society for Biochemistry and Molecular Biology
Ausgabe    274
Datum    May 1999
Nummer    21
Seiten    14956-14962
URL    http://www.jbc.org/content/274/21/14956.full.pdf

Literaturverz.   

no
Fußnoten    no

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