Talk:2016 Group 7 Project

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Revision as of 18:53, 11 May 2016 by Z5015719 (talk | contribs) (peer review)
2016 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7
Group Projects - Blood Cell Biology - Updated 21 April  
This year's main topic is Blood Cell Biology. Each group should discuss with group members the specific sub-topic that will be covered by their project.

Here is a list of some of the cell types (Structure and Function)

PuMed citations PuMed Central citations PuMed Central note
Note - that while full publications are available online at PuMed Central, not all these publications allow reuse. You should still always identify the copyright statement within the actual article that allows reuse. Many research labs that receive government grants are required to make their published research available on PMC, this does not mean that the publicly available copy content can be used in your projects.

Remember - No easily identifiable statement usually means that you cannot reuse.


Examples from Megakaryocyte references on PubMed Central

Embryology - content cannot be reused but a useful resource about cell development.

Histology - images these can be reused in your projects.

Group Assessment Criteria  

Group Assessment Criteria

  1. The key points relating to the topic that your group allocated are clearly described.
  2. The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
  3. Content is correctly cited and referenced.
  4. The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
  5. Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
  6. Relates the topic and content of the Wiki entry to learning aims of cell biology.
  7. Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
  8. Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
  9. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
  10. Develops and edits the wiki entries in accordance with the above guidelines.

Group 7: User:Z5021060 | User:Z5016365 | User:Z5016784 | User:Z3414546 | User:Z3417773

Links from main page

Cytoskeleton:

Integrins are Mechanosensors That Modulate Human Eosinophil Activation http://www.ncbi.nlm.nih.gov/pubmed/26539194

http://www.ncbi.nlm.nih.gov/pubmed/26939881

Tumour-associated eosinophilia: a review http://www.ncbi.nlm.nih.gov/pmc/articles/PMC494593/

peer review

z3461911

General pointers:

  • A little more detail is needed, try not to write out information in dot points.
  • Proof read before final submission, there are a few spelling and grammar errors.

A few more specific pointers:

  • include an introduction to provide a brief run down of eosinophil location, function, development etc. Just a brief touch on the topic.
  • in structure, go into a bit more detail by explaining the morphology diagram. The granules section is fine though as that is the main point of eosinophils.
  • Separate Role in Allergy and Disease into eosinophil function, and diseases.
  • More detail into Atopic Dermatitis (Eczema) if possible and more eosinophil related diseases should be addressed.
  • include a glossary

Good use of images. If more content is added to the page, more pictures should be inserted to maintain the current spaced out, easy to read display.

Group 7: peer review

Initially I wonder why there is no introduction giving me a basic overview of Who? (eosinophils) What they do? When the do it? Where? And why? I also notice there is no function section, whilst their function may be incorporated into other sections I think it is important to at least have a function heading for navigational purposes and then have subheadings beneath it.

History: some points are quite long I think sticking to key points and if there is more information that is essential incorporate into introduction

Birth, life and death: Hematopoietic progenitor cells need explaining, not everyone knows what they are. The second paragraph is really good, tells a chronological story that is easy to follow. The third paragraph almost seems like an introduction to section on function.

Structure: I really like the picture however it could be positioned on the left side with corresponding text next to it rather than below. I am confused in the paragraph is the enzyme catalyzing 3 different things? If so use of commas or dot points rather than +, or is it an equation? This isn’t clear. I really like the breakdown of granules it makes it super clear and easy to read and understand! The surface markers section definitely needs to be elaborated on and use of diagrams helps to show interaction between cells. What markers are present on the cell should be at the start of the paragraph not at the end, as this is the whole point of the paragraph.

Role in disease: In the helminth section I have no idea what is going on, what is a helminth? This needs introducing and then relating to eosinophils. Section on fungal infection is great, follow this format for other sections and elaborate when needed. I feel bacterial could also be expanded on, what happens next? “Eosinophilic Esophagitis, Eosinophilic Gastritis, and Eosinophilic Gastroenteritis” could be worded “Eosinophilic esophagitis, gastritis and gastroenteritis”. I also find the table on eosinophilia quite large for such a small section; it makes me assume it is really important when it is more of a minor addition. Overall this section needs to follow a common structure within each disease and have more equal amounts of content for each subheading if possible.

Overall good project! Just needs some work in having everything structured in a consistent manner and the addition of an introduction and function sections.


3463953

colourful with short punchy paragraphs that are informative! here are some notes: - History is great, but only goes until 1879! Did nothing happen between then and now! - In terms of the paragraph structure of the Birth, Life and Death in the Body section, there is the number 3 (perhaps a footnote) in the 3rd paragraph that needs to be removed or converted to a footnote. There’s also some other spelling mistakes like in MBP section you’ve spelt asthema instead of asthma. Perhaps it’s worth just rereading over the whole thing to correct the little errors. - Add some text for the images, and I would recommend having the image title in bold. - Video did not play in Wikipedia, but it was spectacular to watch in youtube! - I would be interested in knowing if anytreatments are being developed specifically targetging eosinophils in eczema - The schematic representation of eosinophil trafficking image should be enlarged. Also to add a text box below the image refer to our first lab class. This should be done with all your images

Group 7 peer review

It appears that most of the information about eosinophils are there, however it could be presented a little better. There are too many little subheadings which would be better presented in a table, such as "What role do the components play". A short introduction before the history table would also be nice to summarise the most basic information before going into the more complex details, and the history table itself needs to include more recent findings from the 20th and 21st centuries. The banner image should be resized to make it a bit smaller, and all other images should be thumbnails with a descriptive line underneath. I don't believe you've added a self-created image yet either. In regards to the lineages and skin lesions figures, I don't think Mark approves of using images from Wikipedia even if they are free of copyright. I think you should also add a section at the end for any current or recent research being performed on eosinophils, and the sections on viral and bacterial infections seem very hollow and could do with some more information. The codes for reference numbers 15 and 30 need to be fixed as well.

GROUP 7

Introduction

  • Needs an introduction! This is useful to introduce the reader to what eosinophils actually are and give a brief overview of their location, structure, function etc (Just one or two lines on each to give an overview of what the project is going to be talking about

History

  • This section is good, i like that each historical discovery is expanded on a little bit, however you should try to include some more recent discoveries

Birth, Life, Death

  • The images used in this section nicely back up the text
  • I think there is more detail that can be provided on each of the factors discussed under this subheading - production, function and destruction are all big areas and require more than a small paragraph on each. I would recommend using sub- subheadings to divide this section up, and expand on each within these. The information you have here is good, its just summarised to provide too little information
  • Showing the progression/ flow from production —> function —> death would make it clearer
  • I didn’t really gain an understanding of the what eosinophils actually do it the body and why they exist

Structure

  • This section is succinct and provides a clear description of the structure of eosinophils - the images used are well placed and support the text nicely

Role in Disease

  • The layout of this section made it confusing to read
  • The Asthma section doesn't really focus on the role of eosinophils in asthma development
  • Overall provides a good understanding of eosinophils in disease, however each subsection could be worked on the make eosinophils the focus, rather than the disease as a whole and other contributing factors

Overall

  • A few spelling errors, which should be picked up in the final editing process
  • The page is quite short overall - expanding on each of the subsections, and creating a few new subheadings (for introduction, function etc) should improve this
  • A glossary would be useful for the reader, as there were some terms used that i had never heard of and no explanation was provided
  • Good job so far, but improvements are needed

group 7

1. Key points are there however I feel like the very large section on structure could be split into structure and function.

2. Images and tables are good however I fell like more original content could greatly add to the project

3. All images and text is correctly cited with copyright information included

4. Good explanation of terms throughout, handy as a teaching tool.

5. A lot of useful references, the topic appears clearly researched

6. Meets the aims of the cell biology course.

Group 7

Really colourful page and well structured! I particularly like the pink table!!!

  • An inclusion of an introduction would be really helpful; especially providing a brief overview of the topic as a learning resource for students
  • I'm unsure of whether the history section is finished. The information provided so far is interesting and relevant, so a good start either way.
  • I really liked the section "Birth, life and death.." but something that could make it polished would be a small subheading of for each section to point out where you are explaining birth, life and death.
  • The layout of the structure section is good, the use of dotpoints is helpful to keep it short and straight to the point; however, a short sentence explaining each dot point would add so much more depth that most students would probably be looking for.
  • Role in allergy and disease is a really interesting section and I learnt a lot of things that I didn't know. However, I think its important to briefly explain the diseases such a helminth. You could even do this in a glossary which would be a nice touch.

Overall you guys have produced a good page and its just the last finishing touches to add now. Great job!!

Group 7

On the whole, this page provides a good amount of information regarding eosinophils in a clear and engaging manner. However, I feel that the page would benefit from including an introduction/ overview of the cell at the beginning, instead of starting immediately from the history of eosinophils. Additionally, while the history section is well detailed, It could benefit from having information from more recent dates as well (as it stops at 1879), as well as information from more sources than just one article. The use of images is well done and it complements the information in the structure and birth, life and death in the body sections well. Furthermore, the text itself in these sections is well presented and easy to follow. The section on role in allergy and disease provides a lot of good detail, however, some sections seem a little on the short side, such as the sections on viral, fungal and bacterial infection, and might benefit from adding more information there. The addition of the drop down videos was a good aspect on the page, and allows for a more interesting read. One other minor point would be the fact that the last two references in the reference list don’t appear to be linked properly as there is no pubmed reference for them.

On the whole this page is well done with a lot of good information provided. However, I do believe that it can be improved by the addition of more text to make the different sections more comprehensive. There is a nice balance of images and texts, and this could benefit even more by the addition of more information.

Assessment Discussion

Should we meet up and discuss how we are going to set out the entire project, or just write up a set up on here so we can add information I Did embryology last year, i dont know if yous want to use this as a guideline https://embryology.med.unsw.edu.au/embryology/index.php/2015_Group_Project_2


Maybe before lab 7 we should find more papers that have information on the subheadings that are empty and add the information that we found into the relevant subheadings and maybe the week after we can allocate subheadings to people to be responsible for making that section sound cohesive.


Before lab 5 please resummarise your 4 paper summaries in a form that can be put on the assessment page. Leave out all irrelevant information and add relevant info under the sub-headings. Thanks


Before lab 4 - Everyone find 1 Paper each on structure, function, History or Histamine interactions and 1 on a more specific topic that we can take the research project in the direction of, so that we have options to choose from after the midsem break. Cheers, Sam

Lab 4 Homework

Z5021060

Eosinophil Formation & Development

Eosinophils are created from the eosinophil lineage committed progenitors (EoP), CD34+ cells [1], [2]. They get produced in response to infections and diseases that cause an inflammatory responses which leads to an increase in amount of eosinophils present in the blood due to cytokine interleukin 5 (IL-5) [3], [4]. EoPs develop into its mature form via the influence of the regulatory molecules that control IL-5 [5], [6], [7]. The alteration of IL-5 levels affects the rate at which EoPs can mature but does not effect the ability of the bone marrow to produce CD34+ [8].

Surface Markers

Eosinophils migrating to different tissues in the body are part of its function[9]. Eosinophils that are part of the circulatory system remain inactive until they reach the tissue[10]. When eosinophils migrate to endothelial cells, interleukin (IL)-4 or IL-Beta encouragse further migration[10]. The rate of this process further increases if a chemoattractant is used[10]. In an experiment where a culture is used, the endothelial cells that were treated to prevent this chemotactic event lead to a decrease in the expression of CD68[10]. CD69 is an early marker and CD35 is a receptor[11]. Both of these are controlled by endothelial cells and thus their expression increased when the eosinophils migrated to the endothelial cells[11].

Activation & Apoptosis

Eosinophils are a type of leukocyte that has many functions in terms of inflammatory response: has a role in parasitic, bacterial and viral infection, allergies, tumours and injuries to tissues[12]. Therefore, maintaining a certain level of eosinophils via activation and programmed cell death is important for the immune system[13]. This is because eosinophils can regulate antigens, tissues and they can also encourage the inflammatory process via release of cytokines and lipid mediators[13]. In humans, eosinophil activation can be influenced by the increase in the CD69 protein activity and the decrease in CD62L activity[14]. On the other hand, eosinophil apoptosis can also be influenced by NK which could be seen as the rate of apoptosis was higher in the culture that was incubated with Natural Killer cells[14].

Eosinophils in Parasitic Infections

Eosinophils can often be seen during allergic reactions and in parasitic diseases [15]. This can be investigated by looking at granules granule proteins of eosinophils. During parasitic infection, the granules such as eosinophil peroxides (EPO) and major basic protein-1 (MBP-1) eosinophil-derived neurotoxin and eosinophil catatonic protein can deposit its contents onto the helminth to kill it [16]. Thus eosinophils are needed for eliminating the the parasite as without it, the parasite would be able to survive in the body for a longer period of time [15].

Lab 3 Assessment

z5021060

Paper 1

Eosinophils migrating to different tissues in the body are part of its function[9]. Eosinophils that are part of the circulatory system remain inactive until they reach the tissue[10]. The article looks at what occurs in terms of the surface markers and release of leukotriene C4 when eosinophils reach these endothelial cells[10]. It was found that when eosinophils migrated to the endothelial cell, interleukin (IL)-4 or IL-Beta would encourage further migration. The rate of this process further increased if a chemoattractant was used. In the culture, the endothelial cells that were treated to prevent this chemotactic event would lead to a decrease in the expression of CD68. CD69 is an early marker and CD35 is a receptor[11]. Both of these are controlled by endothelial cells and thus their expression increased when the eosinophils migrated to the endothelial cells[11].

<pubmed>12797482</pubmed>

Paper 2

Eosinophils can often be seen during allergic reactions and in parasitic diseases [15]. This can be investigated by looking at granules granule proteins of eosinophils. During parasitic infection, the granules such as eosinophil peroxides (EPO) and major basic protein-1 (MBP-1) eosinophil-derived neurotoxin and eosinophil catatonic protein can deposit its contents onto the helminth to kill it [16]. Thus the article looks at the presence or absence of these proteins to see its effects on parasitic disease.The article looks at the parasite Brugia malayi microfilariae for the investigation. It was found that eosinophils were needed for eliminating the microfilariae during primary infection as its absence would allow for the microfilariae to survive in the body for a longer period of time [15]. The absence of EPO lead to the increase in levels of Immunoglobin E (IgE) which meant that eosinophils have a role in the controlling the levels of IgE [15]. The article also states that eosinophils can have both a positive and negative effect as the removal of MBP-1 lead to increased mucus production by goblet cell[15]s but the physiology of the respiratory system did not change with its absence [17].

<pubmed>24626328</pubmed>

Paper 3

Eosinophils are a type of leukocyte that has many functions in terms of inflammatory response: has a role in parasitic, bacterial and viral infection, allergies, tumours and injuries to tissues[12]. Therefore, maintaining a certain level of eosinophils via activation and programmed cell death is important for the immune system, as eosinophils can regulate antigens, tissues, as they can also encourage the inflammatory process via release of cytokines and lipid mediators[13]. This article further studies the regulation activation and apoptosis of eosinophils via the influence of Natural Killer (NK) cells. In humans, eosinophil activation can be influenced by the increase in the CD69 protein activity and the decrease in CD62L activity. On the other hand, eosinophil apoptosis can also be influenced by NK which could be seen as the rate of apoptosis was higher in the culture that was incubated with NK cells.

<pubmed>24727794</pubmed>

Paper 4

EoP count in eosinophila patients[6]

Eosinophils are created from the eosinophil lineage committed progenitors (EoP), CD34+ cells [1], [2]. They get produced in response to infections and diseases that cause an inflammatory responses which leads to an increase in amount of eosinophils present in the blood due to cytokine interleukin 5 (IL-5) [3], [4]. EoPs develop into its mature form via the influence of the regulatory molecules that control IL-5 [5], [6], [7]. The alteration of IL-5 levels affects the rate at which EoPs can mature but does not effect the ability of the bone marrow to produce CD34+ [8].

z3414546

Eosinophilic Inflammation in Allergic Asthma

<pubmed> PMC3627984</pubmed>

This paper broadly explores the molecular events that lead to eosinophil recruitment in allergic asthma and their participation in airway hyper responsiveness and remodelling. It also provides a good overview of the immune response (and pathogenesis) upon allergen challenge, hence would be a suitable source of information for the sub-section concerning the role of eosinophils in disease [18].

Evidence suggests that Phosphatidylinositol 3-kinase (PI3K) regulates the adhesion, distribution and morphologic changes in eosinophils. Whilst certain Leukotrienes (e.g. leukotriene B4 (LTB4)) promote the trafficking and recruitment of eosinophils to inflamed tissues and ensure their survival once there. According to the research, inhaled allergens activate mast cells and Th2 CD4+ lymphocytes to produce cytokines IL-13, IL-4, IL-5 and TNF-α[18][19]. These stimulate epithelial cells, smooth muscle cells and fibroblasts to produce eotaxin. IL-5 regulates migration of eosinophils out of bone marrow, eotaxin directs their movement to lung tissue through blood vessels (via CC chemokine receptors CCR3) [18][20]. Eosinophils then release granule proteins (e.g. eosinophil cationic protein and major basic protein) as well as other molecules such as leukotrienes and metalloproteinases. These are cytotoxic and induce further immune responses that lead to airway hyper-responsiveness and remodelling [18][21].

Research has also demonstrated that some leukotrienes are bronchoconstrictors and have been known to prolong the migration of eosinophils to the airways in allergic asthma [22]. It has further been revealed that eosinophil recruitment occurs in the lung parenchyma as well. Lastly, whilst eosinophils play a major role in the pathogenesis of asthma, research shows they also play a crucial role in lung defence, through the direct regulation of T-cell activities [18][23].


The early history of the eosinophil

<pubmed>25544991</pubmed> This paper is particularly useful for the subsection on the history of the eosinophil as it presents a comprehensive timeline and findings regarding morphology, formation, function and fate of the eosinophil as well as important events that contributed to these discoveries. According Kay 2015 eosinophils where first identified and named by Paul Ehrlich during the 1870s due to the development of specific staining techniques for blood films. The most significant stain utilised was Eosin, a synthetic red dye discovered by Heinrich Caro, 1874. Eosin stains basic proteins due to its acidic properties and eosinophil granules possess a particularly high affinity for it. Kay 2015 stated that Ehrlich was able to describe the features of eosinophils in great detail as a result of this essential stain, for example alpha granules appeared spherical or as short rods with round ends. He also observed beta-granules in eosinophils derived from the bone marrow, most likely immature alpha granules. He further identified inconsistencies in the number of nuclear lobes and granules from one cell to another[24].

Ehrlich documented the distribution of eosinophils in tissues and their formation in bone marrow. According Kay 2015, Ehrlich accurately recognised that granules possessed secretory components and that eosinophils were somewhat responsible for the reactions seen in asthma, helminth infections and certain skin diseases. Kay 2015 highlights that there were many others that observed this cell before Ehrlich, Thomas Wharton Jones first noted granulated cells in human and animal blood specimens in 1846. Julius Vogel observed eosinophils in inflammatory exudates, whilst Max Johann Sigismund Schultze first observed the movements and phagocytic nature of these cells[24].


Eosinophil granules function extracellularly as receptor-mediated secretory organelles

<pubmed>19017810</pubmed> This paper is appropriate for the subsection on eosinophil function, it highlights a rather specific function of their intracellular components as opposed to the generalized function of the cell as a whole. The article particularly focuses on eosinophil granules and granule protein release extracellularly and further provides a perspective on the mechanisms that drive this protein release and how this process may contribute to the severity of an inflammatory response (during eosinophil associated disease)[25].

Neves et al. observed that granules of eosinophils express receptors for cytokines and G protein coupled receptors (CCR3) for chemokines. They found that these receptors are located on the surface membranes of granules, and respond to external cytokines and chemokines by activating a signal-transduction pathway within granules. They also highlight that IFN-γ (cytokine) and eotaxin (chemokine) are responsible for stimulating the secretion of cationic proteins, enzymes and cytokines originating from granules[25].

Neves et al. suggest that this extracellular secretion process is regulated by the ability of granules to function as individual secretory vessels outside of eosinophils (in diseased tissue sites). This is how they may contribute to inflammation mediated by eosinophils and immunoregulation/immunomodulation[25].


IgE, Mast Cells, Basophils, and Eosinophils

<pubmed>20176269</pubmed> This article is relevant for the subsection on structure, the information in this article was derived from a broad range of investigations. It provides an overview of the major morphological features specific to eosinophils, with particular focus on granules, cytoplasmic components and surface markers. Stone et al. state that eosinophils possess a large bi-lobed nucleus, containing highly condensed chromatin within. Another specific feature that Stone et al. highlights are granules, there are two major types. Specific granules contain cationic proteins such as major basic protein, eosinophil peroxidase, eosinophil cationic protein and eosinophil-derived neurotoxin. These proteins give eosinophils their distinct staining property. Primary granules on the other hand, possess Charcot-Leyden crystal proteins [26][27]. Stone et al. also draw attention to lipid bodies that reside in the cytoplasm (not membrane bound) which contain eicosanoid synthetic enzymes and from rapidly after eosinophil activation[26][27].

Stone et al. specifies many of the cell surface markers present on eosinophils, some of these include cytokine receptors (IL-3R, IL-5R, GM-CSF) which promote their development, Immunoglobulin receptors (IgA, IgG); complement receptors (CR3, CD88) as well as receptors for chemokines (CCR1 and CCR3) and many other receptor molecules [27][28].

z5016784

Role of Eosinophils In Disease

Viral infection - Eosinophil granule proteins are known for their ribonuclease activity and have been shown to degrade single stranded RNA containing viruses. It has recently been shown that viruses such as parainfluenza virus, respiratory syncytial virus, or rhinovirus induce the release of EPO by eosinophils when co-incubated in the presence of antigen-presenting cells and T cells . Eosinophils may also have a protective role in other infections, especially against RNA viruses such as respiratory syncytial virus and pneumonia virus of mice (PVM)

Fungal infection - Recent investigation has focused on the role of eosinophils in fungal infections. Eosinophils release their cytotoxic granule proteins into the extracellular milieu and onto the surface of fungal organisms in order to kill fungi in a contact-dependent manner. However eosinophils do not react with chitin, a fungal cell wall component.

Bacterial infection - Eosinophils rapidly release mitochondrial DNA in response to exposure to bacteria, C5a or CCR3 ligands. The traps contain the granule protein ECP and MBP, and display antimicrobial activity. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures that bind and kill bacteria both in vitro and under inflammatory conditions in vivo. After cecal ligation and puncture, IL5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. This data suggests a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria .

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109275/

http://www.ncbi.nlm.nih.gov/pmc/?term=22475285[PMID]&report=imagesdocsum

http://www.ncbi.nlm.nih.gov/pmc/?term=19231593[PMID]&report=imagesdocsum

Targeting Eosinophils in Allergy, Inflammation and Beyond

Eosinophils can regulate local immune and inflammatory responses, and their accumulation in the blood and tissue is associated with several inflammatory and infectious diseases. As such, therapies aimed at eosinophils may help control diverse diseases, including disorders such as asthma and allergy, and also diseases that are not primarily associated with eosinophils such as autoimmunity and malignancy. Recently, eosinophil-targeted therapeutic agents aimed at blocking specific steps involved in eosinophil development, migration and activation have entered clinical testing and have produced encouraging results and insights into the role of eosinophils.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822762/

Eosinophila

Different stages and ways to treat it

References

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  16. 16.0 16.1 <pubmed>2324497</pubmed>
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  18. 18.0 18.1 18.2 18.3 18.4 <pubmed> PMC3627984</pubmed>
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  25. 25.0 25.1 25.2 <pubmed>19017810</pubmed>
  26. 26.0 26.1 <pubmed>1657792</pubmed>
  27. 27.0 27.1 27.2 <pubmed>20176269</pubmed>
  28. <pubmed>17337299</pubmed>