How Mobile Elements in “Junk” DNA Promote Cancer – Part 1: Transposon-mediated Tumorigenesis
Author, Writer and Curator: Stephen J. Williams, Ph.D.
Word Cloud by Daniel Menzin
SOURCE
Landscape of Somatic Retrotransposition in Human Cancers. Science (2012); Vol. 337:967-971. (1)
Sequencing of the human genome via massive programs such as the Cancer Genome Atlas Program (CGAP) and the Encyclopedia of DNA Elements (ENCODE) consortium in conjunction with considerable bioinformatics efforts led by the National Center for Biotechnology Information (NCBI) have unlocked a myriad of yet unclassified genes (for good review see (2). The project encompasses 32 institutions worldwide which, so far, have generated 1640 data sets, initially depending on microarray platforms but now moving to the more cost effective new sequencing technology. Initially the ENCODE project focused on three types of cells: an immature white blood cell line GM12878, leukemic line K562, and an approved human embryonic cell line H1-hESC. The analysis was rapidly expanded to another 140 cell types. DNA sequencing had revealed 20,687 known coding regions with hints of 50 more coding regions. Another 11,224 DNA stretches were classified as pseudogenes. The ENCODE project reveals that many genes encode for an RNA, not protein product, so called regulatory RNAs.
However some of the most recent and interesting results focus on the noncoding regions of the human genome, previously discarded as uninteresting or “junk” DNA . Only 2% of the human genome contains coding regions while 98% of this noncoding part of the genome is actually found to be highly active “with about 4 million constantly communicating switches” (3). Some of these “switches” in the noncoding portion contain small, repetitive elements which are mobile throughout the genome, and can control gene expression and/or predispose to disease such as cancer. These mobile elements, found in almost all organisms, are classified as transposable elements (TE), inserting themselves into far-reaching regions of the genome. Retro-transposons are capable of generating new insertions through RNA intermediates. These transposable elements are normally kept immobile by epigenetic mechanisms(4-6) however some TEs can escape epigenetic repression and insert in areas of the genome, a process described as insertional mutagenesis as the process can lead to gene alterations seen in disease(7). In addition, this insertional mutagenesis can lead to the transformation of cells and, as described in Post 2, act as a model system to determine drivers of oncogenesis. This insertional mutagenesis is a different mechanism of genetic alteration and rearrangement seen in cancer like recombination and fusion of gene fragments as seen with the Philadelphia chromosome and BCR/ABL fusion protein (8). The mechanism of transposition and putative effects leading to mutagenesis are described in the following figure:
Figure. Insertional mutagenesis based on transposon-mediated mechanism. A) Basic structure of transposon contains gene/sequence flanked by two inverted repeats (IR) and/or direct repeats (DR). An enzyme, the transposase (red hexagon) binds and cuts at the IR/DR and transposon is pasted at another site in DNA, containing an insertion site. B) Multiple transpositions may results in oncogenic events by inserting in promoters leading to altered expression of genes driving oncogenesis or inserting within coding regions and inactivating tumor suppressors or activating oncogenes. Deep sequencing of the resultant tumor genomes ( based on nested PCR from IR/DRs) may reveal common insertion sites (CIS) and oncogenic mutations could be identified.
In a bioinformatics study Eunjung Lee et al.(1), in collaboration with the Cancer Genome Atlas Research Network, the authors had analyzed 43 high-coverage whole-genome sequencing datasets from five cancer types to determine transposable element insertion sites. Using a novel computational method, the authors had identified 194 high-confidence somatic TE insertion sites present in cancers of epithelial origin such as colorectal, prostate and ovarian, but not in brain or blood cancers. Sixty four of the 194 detected somatic TE insertions were located within 62 annotated genes. Genes with TE insertion in colon cancers have commonly high mutation rates and enriched genes were associated with cell adhesion functions (CDH12, ROBO2,NRXN3, FPR2, COL1A1, NEGR1, NTM and CTNNA2) or tumor suppressor functions (NELL1m ROBO2, DBC1, and PARK2). None of the somatic events were located within coding regions, with the TE sequences being detected in untranslated regions (UTR) or intronic regions. Previous studies had shown insertion in these regions (UTR or intronic) can disrupts gene expression (9). Interestingly, most of the genes with insertion sites were down-regulated, suggested by a recent paper showing that local changes in methylation status of transposable elements can drive retro-transposition (10,11). Indeed, the authors found that somatic insertions are biased toward the hypomethylated regions in cancer cell DNA. The authors also confirmed that the insertion sites were unique to cancer and were somatic insertions, not germline (germline: arising during embryonic development) in origin by analyzing 44 normal genomes (41 normal blood samples from cancer patients and three healthy individuals).
The authors conclude:
“that some TE insertions provide a selective advantage during tumorigenesis,
rather than being merely passenger events that precede clonal expansion(1).”
The authors also suggest that more bioinformatics studies, which utilize the expansive genomic and epigenetic databases, could determine functional consequences of such transposable elements in cancer. The following Post will describe how use of transposon-mediated insertional mutagenesis is leading to discoveries of the drivers (main genetic events) leading to oncogenesis.
1. Lee, E., Iskow, R., Yang, L., Gokcumen, O., Haseley, P., Luquette, L. J., 3rd, Lohr, J. G., Harris, C. C., Ding, L., Wilson, R. K., Wheeler, D. A., Gibbs, R. A., Kucherlapati, R., Lee, C., Kharchenko, P. V., and Park, P. J. (2012) Science 337, 967-971
2. Pennisi, E. (2012) Science 337, 1159, 1161
3. Park, A. (2012) Don’t Trash These Genes. “Junk DNA may lead to valuable cures. in Time, Time, Inc., New York, N.Y.
4. Maksakova, I. A., Mager, D. L., and Reiss, D. (2008) Cellular and molecular life sciences : CMLS 65, 3329-3347
5. Slotkin, R. K., and Martienssen, R. (2007) Nature reviews. Genetics 8, 272-285
6. Yang, N., and Kazazian, H. H., Jr. (2006) Nature structural & molecular biology 13, 763-771
7. Hancks, D. C., and Kazazian, H. H., Jr. (2012) Current opinion in genetics & development 22, 191-203
8. Sattler, M., and Griffin, J. D. (2001) International journal of hematology 73, 278-291
9. Han, J. S., Szak, S. T., and Boeke, J. D. (2004) Nature 429, 268-274
10. Reichmann, J., Crichton, J. H., Madej, M. J., Taggart, M., Gautier, P., Garcia-Perez, J. L., Meehan, R. R., and Adams, I. R. (2012) PLoS computational biology 8, e1002486
11. Byun, H. M., Heo, K., Mitchell, K. J., and Yang, A. S. (2012) Journal of biomedical science 19, 13
Other research paper on ENCODE and Cancer were published on this Scientific Web site as follows:
Expanding the Genetic Alphabet and linking the genome to the metabolome
Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes
Reveals from ENCODE project will invite high synergistic collaborations to discover specific targets
ENCODE: the key to unlocking the secrets of complex genetic diseases
Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets
Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz
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very good fit. It is also related to the ubiquinone-proteosome story, and I didn’t bring in this perspective.
Dr. Berstein, should I Tag ubiquinone on this post as well. I would like to know if there is a good way to make a map across posts/sites, cross-referenced. A relational database like that would, I feel, bring the knowledge base closer to the true goal of open source. Be very interested in your opinions on the matter.
Thanks
Do you mean for this post or for all posts?
The Uniquitin and this post will be part of our book on the Genome, read my e-mail: November 2012: Team Goal, I spelled out th FIVE Bookss, one is on THE ENCODE, do not have an Editor.
DO YOU say that this post belong to the Cancer book which you are one of three Editors?
I believe it may best fit in with the ENCODE book, however this is post1 of two (or maybe three) posts on the subject. However this may have interest in a Cancer book as well (under mechanisms of oncogenesis {subchapter}. The cancer book will probably be very complex. Thanks for your help. Sincerely
Stephen Williams, Ph.D.
Any post can be in several books, per the relevance, eNOS belongs to the book on NO and to the book on metabolism, thus this post will be in ENCODE and in Cancer. Your consultation is very value able to me, as was your comment on Enzymology.
Yes. I think so. The mitochondrial genome is small, as I pointed out, but the outer membrane provides for up to 9o% of energy needs. Mutagenesis is frequent, and it involves a repair, loss and recovery process. The mitochondria are also involved in quality control of proteolysis, which gets into the ubiquitin-proteosome pathway. The discoveries involving what was termed “junk DNA” gives some evidence of the possibility that this ties in with that process. When you look at cancer, the cell has a survival mechanism that steals protein gluconeagenic precursors for self replication and biosynthesis with a block of entry into the Krebs cycle, and imcreased reliance on glycolysis for energy at the expense of the whole(cancer cachexia, driven by TNF-a). This happens with a different twist in severe and prolonged starvation, or with “veganism”. Why in veganism? The S:N ratio is inadequate to supply sulfur metabolites needed to produce S-adenosyl methionine, which increases oxidative stress. I haven’t put it all together in my own mind. That part of the equation has to wait for now.
This is a gem.
Oncogenesis needs further understanding, I am glad you are going to have more posts to elaborate on the scientific frontier on the subject.
In my domain, cardiovascular, we have a Research Category “Origins of Cardiovascular DIseases” I wonder where our Cancer Biology and Innovations in Cancer Treatment needs to have a couple of sub categories, among them “Origins of Oncogenesis” May our Cancer Researcher all comment on the need to augment the speciation and the specificity of the present Cancer Biology Research Category.
That step is necessary to be able in 2013 to address Dr. Williams statement cautioning us all that “The cancer book will probably be very complex.”
Please all note the following:
Point 1:
the Cancer Drug DB, as you know, this is a thirty year old Cancer Drugs and Clinical Trial DB, the only one in existence
http://www.nmok.net/Login.aspx?ReturnUrl=%2fnewindex.aspx
… a dynamic, daily updated,
fully relational, user-friendly,
comprehensive resource in global
drug development in oncology
Drugs profiled in nm|OK
nm|OK profiles over 4,310 drugs/in vivo imaging agents in development:
3,653 anticancer agents addressing over 100 cancer types and thousands of clinical indications. Of these, 1,695 are in active development; 821 have been or are currently being evaluated in clinical trials and 539 of these are targeted agents.
757 drugs for the management of complications of cancer and its treatment (pain, infection, mucositis, emesis, etc.)
nm|OK also profiles over 552 marketed drugs (anticancer agents=335, adjuncts=197) globally, providing trial results from monotherapy and combination therapy trials.
That description though portraits Cancer drugs, it also covers over 100 cancer types and thousands of clinical indications.
Point 2:
In my post today:
arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data, A Reference Resource for Genomic Copy Number Imbalances in Human Malignancies
The delineation of genomic copy number abnormalities (CNAs) from cancer samples has been instrumental for identification of tumor suppressor genes and oncogenes and proven useful for clinical marker detection. An increasing number of projects have mapped CNAs using high-resolution microarray based techniques. So far, no single resource does provide a global collection of readily accessible oncogenomic array data.
I believe that in order to further understand Oncogenesis for our forthcoming book, we need to Link three sources of data:
(a) over 100 cancer types and thousands of clinical indications (from the Cancer Drug DB).
(b) oncogenomic CNA data which readily could be used for genomic feature mining, across a representative range of cancer entities per http//www.arraymap.org.
(c) the mechanism of Transposon-mediated tumorigenesis
Thus, I request a Team effort to put together a series of posts to illuminate the links between a,b,c above, so as we will have innovative content for our forthcoming book on the “Cancer Existential Offense” as a potential title.
[…] How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis. […]
[…] How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis. […]
[…] How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis. […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette
I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette