Difference between revisions of "2011 Group 3 Project"

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==Structure==
 
==Structure==
  
[[File:EM tight junction.gif|300px|right|thumb|Electron microscope image of a tight junction]]
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[[File:Untitled.jpg‎|400px|left|thumb|Schematic model of the basic structural transmembrane components of tight junctions]]  
 
[[File:Untitled.jpg‎|400px|left|thumb|Schematic model of the basic structural transmembrane components of tight junctions]]  

Revision as of 16:46, 11 May 2011

Tight Junctions

--Mark Hill 15:32, 2 May 2011 (EST)--Mark Hill 14:01, 28 April 2011 (EST) R.D and E.C where are your contributions? The "bullet point" listing is also not the easiest form to get all your information across. No images on the page?

Introduction

Schematic of the various cell-cell junctions

Cell junctions are essential for cells in tissues to function in an integrated manner. The four major classes of junctions are: tight junctions, gap junctions, desmosomes, and hemidesmosomes organised into a manner otherwise known as the junctional complex.[1] Each is specialized to preform a specific function. Desmosomes and hemidesmosomes have a structural role and serve to anchor cells to each other or to the extracellular matrix, respectively. They do this by mediating the connection of a cell's internal cytoskeleton with that of another cell or to the extracellular matrix. [2] Gap junctions are channels between adjacent cells that help facilitate the passage of molecules between cells, and are therefore involved in cell-cell communication. [3] Tight junctions, the subject of this page, are also an extremely important type of cell junction.

Tight junctions, or zona occludens, are a branching network of anastomosing transmembrane protein strands that encircles the apical ends of epithelial cells.[4] These proteins associate with similar proteins on adjacent cells which seals the gaps between them.[5] Through the presence of small openings, tight junctions serve to create a barrier to diffusion across the epithelia as well as separating the membrane into apical and basolateral regions.[6] Tight junctions are only found in vertebrates.However, analogous forms of tight junctions are found in invertebrates which are called septate junctions. [7] The structure and function of tight junctions as well as their role in disease are further explored below.

History

Below is a timeline of important discoveries that have led to our current understanding of tight junctions.

Dr. Hans Ussing

Early 1940’s: Hans Ussing and associates propose the “two membrane model” to address the question of how sodium ions are moved in a directional fashion across the epithelium. This model stated that the apical and basal membrane surfaces have different conductance properties, namely that sodium enters the cell across the apical membrane down its concentration gradient. [8]

1963: Farquhar and Palade first visualizes the tight junctions at the ultrastructural level. [9]

Freeze fracture of mouse intestinal epithelial cells

1964: Hans Ussing and associates discover inconsistencies within their findings leading to the understanding that Chloride ions follow sodium ions in a passive fashion through the tight junction which they called the “shunt pathway”. [10]


Gradually, it was accepted that intact normal epithelia display a wide range of electrical resistances and that it was the tight junctions that determined whether the transepithelial resistance is high or low[11]


1986: Stevenson and associates isolate and localize a component of the cytoplasmic face of the tight junction naming the protein Zona occludens-1 (ZO-1). [12]

1988-1991: Citi and associates discover and localise major tight junction plaque protein cingulin. [13][14][15]

1991: Gumbiner and associates identify the tight junction protein ZO-2.[16]

1993: Furuse and associates immunolocalised a tetraspan transmembrane protein of the Zona Occludens naming it "occludin".[17]

1994-1997: Furuse and associates transfect "occludin" encoding cDNA. Transfection of cDNA and expression caused the construction of tight junction possessing cells with occludin integrated into pre-existing tight junction structures. When injected into tight junction lacking cells, it was able to form de novo tight junction typical intramembranous “ridges” as well as cytoplasmic stacks of lamellae resembling tight junction membrane structures. [18][19]

1995: Fasano and associates discover the Zonula occludens toxin which is thought to activate a complex cascade of events ultimately regulating tight junction permeability. [20]

1998: Furuse and associates identify 2 smaller polypeptides. Immunolocalisation and incorporation into tight junctions of living cells formed de novo intramembranous TJ typical ridge structures, even in TJ lacking cells naming these proteins as “claudins” nos. 1 and 2. [21][22]

1998: Haskins and associates identify the tight junction protein ZO-3. [23]

Schematic of "tricellulin"

2001-2002: Tsukita and associates discovery a total of 24 different claudin proteins encoded in the human genome.[24][25]

2002: Bradner & Furuse and associates observe typical tight junction structures, positive for claudins and occluding in the uppermost layers of the epidermis and other squamous stratified epithelia. [26][27]

2005: Ikenouchi & associates and Tsukita & associates– Discover small intercellular “gaps” formed by three cells meeting together posing a “three corner state problem” (Ikenouchi). The answer to this problem came in the form of a protein, which Tsukita named “tricellulin”. This protein was found to assemble exactly at those “three corner” sites. [28]

Structure

Electron microscope image of a tight junction
Schematic model of the basic structural transmembrane components of tight junctions

Tight junctions consist of a branching network of sealing strands of protein. Each strand is assembled from a series of transmembrane proteins(JAMs/Junctional Adhesion Molecules,Claudins and Occludin) embedded in plasma membranes. The extracellular domains join each other in tight junctions,whereas the intracellular domains are linked to peripheral membrane proteins,linking the transmembrane protein strands to actin cytoskeleton to create a functional network that plays a role in cellular processes. Each strand functions as an individual or linear barrie, therefore, the number of transmembrane protein strands is in relation with the degree of paracellular electrical resistance and impedance to solute flux in tight junctions[29]. Although other types of proteins are present at tight junctions, however, occludin and claudin are the major ones contributing to the structure of tight junctions.

Molecular components

Associated molecular components of tight junctions play an important role in creating and maintaining the structure of tight junctions as well as giving functions to them.Molecular components of tight junctions can be categorised into two groups,namely,Transmembraneproteins and Peripheral membrane proteins

Transmembrane proteins serve as important components of the tight junction that span across the junction, connecting two adjacent cells and making a seal tight at the junction.The group has three members, Occluddins,Claudins and Junctional Adhesion Molecules (JAMs)


In this cross-section of intestinal villi, occludin (green) concentrates at tight junctions.

Occludins

Occludins are family of transmembrane proteins which were the first tight junction associated transmembrane proteins identified in chicken liver.[30].Structurally ,they have four transmembrane domains,two extracellular loops and two intracellular domains[31].

Roles:

  • interacting directly with proteins zonula occludens,ZO-1 and ZO-2 and ZO-3 at the tight junction to localize occludins
  • interacting indirectly with the actin cytoskeleton and junctional adhesion molecules(JAMs) via interacting with ZO proteins[32]
  • involving in cell-cell adhesion with extracellular domains of occludin[33]
  • vital in tight junction assembly in Xenopus embryo development[34]
  • regulating various signaling events initiating from the tight junction[35]
  • may involve in RhoA activation via a tight junction–associated guanine nucleotide exchange factor,GEF-H1/Lfc[36][37]
  • targeting TGF-ß receptors to tight junctions[38].


Claudins

Claudins belong to transmembrane protein type and are also the main constituent of the tight junction intercellular strands.The claudin family is made up of a number of members.Among them,claudin-1 and claudin-2 were the first claudin family members identified in a chicken liver fraction[39] .The family has been claimed important for creating and maintaining the barrier function of tight junctions[40].

Roles

  • forming tight junction strands via interacting with each other between different tight junction strands or within individual strands in a homotypic and heterotypic manner [41]
  • structural components are similar to occuldin.Four transmembrane domains, two extracellular loops, and two intracellular domains,however,it does not have sequence similarity to occludin [42]
  • mediate calcium-independent cell-cell adhesion[43]
  • interacting directly with peripheral PDZ-domain-containing proteins(ZO-1, ZO-2, ZO-3,and protein associated with Lin seven 1 (PALS1)-associated tight junction protein (PATJ))[44]


Junctional adhesion molecules (JAMs)

JAMs belong to the immunoglobulin superfamily of proteins and are expressed in several cell types ,epithelial cells,leukocytes, endothelia, and platelets.The family is made up of four members JAM-A, JAM-B, JAM-C, and JAM4/JAML[45] ,with each serves different function.In epithelia,JAM-A are directed to tight junctions, whereas,JAM-B are directed to the lateral membrane [46] .In terms of general structure,the JAMs have a single transmembrane domain, an extracellular domain containing two Ig-like motifs, and a cytoplasmic tail[47].

Roles

  • may participate in cell adhesion via homophilic interactions[48]
  • interacting with each other. JAM-B interacts with JAM-C and integrins through heterophilic interactions[49]
  • forming intercellular junctions and epithelial barrier function[50].


Peripheral membrane proteins serve as intracellular binding sites for transmembrane proteins to allow transmembrane proteins to be organized in membrane and attached to the cytoskeleton to initiate cell signaling.The group has four members,namely Zonula occludens(ZOs),Cingulin,ZO-1-associated nucleic acid–binding protein(ZONAB)and Rab13.

Schematic representation of occludin and proteins that coprecipitate with ZO-1. Occludin has two extracellular loops that may interact with other molecules in the paracellular space. The COOH terminus (C) of occludin interacts with ZO-1, and immunoprecipitates of ZO-1 coprecipitate ZO-2 and several unidentified phosphoproteins


Zonula occludens(ZOs)

ZOs are tight junction proteins in the membrane-associated guanylate kinase (MAGUK) family of proteins containing a core structure consisting of one or more PDZ domains, an Src homology 3 (SH3) domain, and a guanylate kinase (GUK) domain.ZOs appear as three isoforms of ZO proteins, ZO-1, ZO-2, and ZO-3[51].

Roles:

  • serving as peripheral membrane scaffolding proteins
  • interacting with many binding partners at the tight junction
  • involving in the formation of tight junction[52].


Cingulin

Cingulin is a group of protein weighing 140–160kD and appear on the cytoplasmic surface of epithelial tight junctions.It was first identified as a peripheral membrane protein at the tight junction in avian brush border cells[53].It has globular head and tail domains as well as a central a-helical rod domain[54].

Roles

  • potential role in embryogenesis and epithelial maturation[55]
  • linking tight junction proteins to the actin cytoskeleton[56]
  • involving in transcriptional regulation and cell proliferation[57]
  • playing a role in cell-cycle progression[58].


ZO-1-associated nucleic acid–binding protein(ZONAB)

ZONAB was first identified by its function , as a binding partner of ZO-1.It has a Y-box transcription factor protein [59].

Roles

  • interacting with cell division kinase 4 (CDK4) to regulate cell proliferation
  • serving as a sensor of cell density[60].


Rab13

Rab 13 is member of the small GTPase Rab family of proteins.It was first identified as a mammalian homolog of the yeast secretory protein, Sec4[61]

Roles

  • involving in the regulation of exocytic and endocytic pathways, including vesicle movement and fusion[62]
  • involving in early junctional formation[63] .

Tight Junction Function

Tight junctions are specialized to perform several specific and roles in epithelia. They are extremely important not only to the structure and function of individual epithelial cells but also to the epithelium as a whole.

In the brain (left), the peroxidase reaction product (top, black) cannot get past endothelial junctions (arrow), but in the heart (right) peroxidase flows down a cleft (C) between endothelial cells.

Polarity of Epithelial Cells

Segregation of transmembrane proteins in the apical and basolateral surfaces of the plasma membrane is maintained by tight junctions

The polarized nature of epithelial sheets can be attributed to tight junctions. The tight seal between adjacent cells that prevents free diffusion of fluid from one side of the epithelia to the other also creates a barrier that prevents the diffusion of lipids and proteins between the apical and basolateral surfaces of individual epithelial cells. This allows for the localization of specific transmembrane proteins in the plasma membrane which, for many proteins in epithelial sheets, is very important for their function. [64] In the intestinal epthilia for example, transport across the epthilia involves the importation of substances from the lumen into the cell via the apical surface, followed by exportation from the basolateral surface. These processes are mediated by different sets of membrane transport proteins and, therefore, the different proteins must be restricted to either the apical or basolateral surfaces of the cells depending on their function. [65] Tight junctions create this barrier to the free migration of transmembrane proteins and thus maintain the polarity of the plasma membranes of epithelial cells.

In addition to their role in polarizing the plasma membrane, tight junctions also serve to maintain intracellular polarity. Claudins and occuldins, for example, can associate with certain proteins which serve as anchors for the actin cytoskeleton which is involved in directing organelle movement within the cell. In addition, many other intracellular proteins have been found to associate with tight junction proteins which are involved in directing the movement of proteins and substances within the cell and thus maintaining intracellular polarity. [66]

Barrier Funciton

The tight junction is also responsible for the selective permeability of epithelia. They create a barrier which separates the fluid on either side of the epithelium by joining together the plasma membranes of adjacent epithelial cells to form a tight seal, usually near the apical surface of the cells. This serves the crucial function of preventing the free diffusion of solutes across the epithelium via the inter-cellular spaces between the basolateral surfaces of the cells and helps to maintain the differences in chemical composition of one side of an epithelial sheet versus the other. [67] The creation of these two structural compartments is essential for the proper function of epithelia. This is very important in the intestine for example, which must be able to separate the contents of the intestinal lumen from the fluid on the other side of the epthilial sheet. [68] If the tight junction were not present then solutes from the lumen could freely diffuse across the epthilium and into the space surrounding the basolateral surfaces and vice versa. The presence of the tight junctional barrier means that most substances cannot passively cross the epthilia.

Differences in tight junction permeability based on tissue type, find articles

Transcellular and Paracellular Transport

Schematic drawing of a tight junction that shows the paracellular and transcellular transport pathways

Additionally, tight junctions are very important in the regulation of the transport of solutes across the epithelia.

Classification of Epithelia Using Tight Junctions

PAUL, CAN YOU PUT CITATIONS IN HERE? I'M NOT SURE WHERE YOU GOT THE INFO. ALSO CAN YOU EXPLAIN WHAT TER AND HOW IT'S RELATED TO TJ'S? -ROB


(SUBJECT TO CHANGE) Epithelia can be classified into separate categories - “tight” or “leaky” depending on their ability to pass solutes across their surface. It has been observed, through freeze-fracture studies, that the number of tight junctions correlated with the "tightness" or "leakiness" of the epithelia. The tight junctions, viewed as a number of anastomosing strands were seen to be more prevalent in “tight” epithelia typically consisting of approximately five or more strands whereas, “leaky” epithelia consisted of only a single strand (7 of leaky 1).

Another method by which we can classify epithelia is through the measure of transepithelial resistance, or TER. Tight “Tight” epithelia are able to maintain a high electrochemical gradient through active transcellular transport. These junctions function to produce either a highly concentrated or highly diluted secretions. A good example of “tight” epithelia is the epithelium of the mammalian proximal tubule. This “tight” conformation allows for the distal neprhon to produce urine which is several fold higher or lower than plasma. Leaky “leaky” epithelia are involved in the movement of large amounts of isosmotic fluids. An example of “leaky” epithelia are found in the human gastrointestinal tract. Generally the gastrointestinal tract consists of low TER except for the distal colon.

Tight Junction Assembly and Regulation

Comparison of the Ca2+ switch and ATP depletion-repletion models of TJ biogenesis.

Many different signalling pathways that regulate tight junction assembly within cells have been characterized. These include multiple kinases, Ca2+, G proteins, adenosine 3′,5′-cyclic monophosphate (cAMP), etc. [69]. Due to environmental factors or differences in tissue type, tight junction permeability must be very dynamic. Therefore, tight junction assembly and disassembly changes in response to many signaling agents such as hormones, growth factors, and cytokines. [70] There does not, however, appear to be a single universal pathway for tight junction assembly and it is likely that the process varies between different tissue types. [71].

One factor that has been found to be essential for the formation of intracellular junctions, including tight junctions, is Ca2+ due to its role in establishing homotropic interactions between E-cadherins [72]. In addition, Ca2+ has been found to interact with many different kinds of tight junctional proteins and appears to be a necessary factor for proper tight junction assembly. [73]. Thus, the regulation of Ca2+ ions inside and outside of the cell seems to be very important for the regulation of tight junction assembly. Based on extensive observation, if Ca2+ is removed from the growth medium containing epithelial cells then tight junctions begin to dissociate and become "leaky" meaning they are they begin to lose their barrier function. Conversely, addition of Ca2+ results in tight junctions reassembly and return of the epithelial barrier and TER. [74] Many experiments have been designed based on this calcium dependency when studying the role of tight junctions in epithelia. For example, in order to study the effects of the tight junction disruption in epithelia, cells can be grown in media containing low levels of calcium in order to destroy these intercellular contacts. [75].

Diseases

This endoscopic image is of Crohn's colitis showing diffuse loss of mucosal architecture, friability of mucosa in sigmoid colon and exudate on wall.‎
Pyoderma gangrenosum on the leg of a person with Crohn's disease


Dysfunction of tight junctions (TJ) leads to hyperpermeability of epithelia and is associated with numerous diseases. This inability to exclude certain macromolecules from traversing the paracellular space means that tissues are exposed to pathogens from the external environment. Increased TJ permeability can be induced by pathogens, toxins, proinflammatory cytokines, and environmental factors, and is present in many bacterial infections and autoimmune diseases[76][77]. Studies have suggested that some people are genetically predisposed to contracting illnesses related to barrier dysfunction [78]. Zonulin has been found to play a significant role in increased TJ permeability, and has been implicated in the pathogenesis of several autoimmune diseases, including celiac disease and type 1 diabetes, as well as various types of cancer. [79][80]. It seems likely that further research will reveal that zonulin modulates TJ permeability in numerous other diseases as well [81] [82].


A comprehensive review of zonulin signalling and it’s role in disease can be found here- Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer


Studies have implicated tight junctions in the following diseases, however this list is by no means exhaustive-


Disease TJ protein affected Reference
Asthma Occludin, Claudin-1 Wan et al. 1999
Autism de Magistris et al. 2010
Breast cancer- invasive ductal cancer Claudin-1, ZO-1, claudin-7 Hough et al. 2000, Itoh and Bissell 2003
Celiac disease ZO-1,

Occludin

Elli et al. 2011
Cholera ZO-1,

Occludin

Wu et al. 2000
Cholestasis 7H6, mrp2 Kawaguchi et al. 2000
Chronic cholestatic liver diseases 7H6, ZO-1 Sakisaka et al. 2001
Clostridium perfringens enterotoxin Claudin-3, Claudin-4 McClane 2001
Collagenous colitis Occludin, Claudin-2 Claudin-4 Burgel et al. 2002
Crohn's Disease Claudin-2, Claudin-3, Claudin-5, Claudin-8, ZO-1 Zeissig et al. 2007
Cystic fibrosis Occludin, Claudin-1, Claudin-4, JAM, ZO-1 Coyne et al. 2002
Diabetic retinopathy Occludin, ZO-1 Felinski and Antonetti 2005
Familial hypomagnesemia Claudin-16 Simon et al. 1999
Gastroesophageal reflux disease Claudin-18 Jovov et al. 2007
Hereditary deafness Claudin-14 Ben-Yosef et al. 2003
Leukaemia ZO-1 Yamamoto, T et al. 1997
Multiple sclerosis Occludin, Claudin-5 Förster et al. 2007
Ovarian cancer Claudin-3, Claudin-4 Hough et al. 2000
Prostate cancer- prostatic adenocarcinomas Claudin-1, Claudin-3, Claudin-4 claudin-7 Sheehan et al. 2007
Pulmonary edema Claudin-4, Claudin-18, Occludin Cohen et al. 2010
Reoviral infection JAM Forrest et al. 2003
Thyroid neoplasma, follicular adenoma Occludin, Claudin-1, Claudin-4, claudin-7 Tzelepi et al. 2007
Type 1 diabetes Claudin-1, Claudin-2 Visser et al. 2010, Uibo et al. 2011


The literature has suggested treatment methods that inhibit proinflammatory cytokines and increase TJ exposure to growth factors and probiotics may be useful in treating TJ dysfunction diseases[83]. It has also been observed that a gluten-casein-free diet may reduce the effects of autism, Crohn’s disease, and ulcerative colitis[84]. Due to the vast array of diseases associated with impaired TJ function and relatively new techniques for examining TJ, extensive research is still required to ascertain all causes of dysfunction, as well as potential treatments for these diseases.


Very few patents exist for compounds that claim to treat TJ malfunction, and most of the existing patents are based in the United States. The specifications for some of these patents can be found below-

WO 1998/005359

WO/2009/006246

WO/2008/113030

WO/2010/110210

Glossary

Further Information

Reference list

  1. Molecular Cell Biology. 4th edition. Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000.
  2. Molecular Cell Biology. 4th edition. Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000.
  3. Molecular Cell Biology. 4th edition. Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000.
  4. The Cell: A Molecular Approach. 2nd edition. Cooper GM. Sunderland (MA): Sinauer Associates; 2000.
  5. The Cell: A Molecular Approach. 2nd edition. Cooper GM. Sunderland (MA): Sinauer Associates; 2000.
  6. The Cell: A Molecular Approach. 2nd edition. Cooper GM. Sunderland (MA): Sinauer Associates; 2000.
  7. Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.
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  64. Molecular Cell Biology. 4th edition. Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000.
  65. Molecular Cell Biology. 4th edition. Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000.
  66. Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.
  67. Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002
  68. Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002
  69. <pubmed>9458817</pubmed>
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  76. Coyne,C., Vanhook,M., Gambling, T., Carson, J., Boucher, R., Johnson, L. (2002). Molecular Biology of the Cell 13(9): 3218-3234
  77. Catalioto, R., Maggi, C., Giuliani, S. (2011). Intestinal Epithelial Barrier Dysfunction in Disease and Possible Therapeutical Interventions. Current Medicinal Chemistry 18(3): 398-426
  78. Visser, J., Rozing, J., Sapone, A., Lammers, K., Fasano, A. (2009). Tight junctions, intestinal permeability, and autoimmunity. Annals of the New York Academy of Sciences 1165: 195-205.
  79. Visser, J., Rozing, J., Sapone, A., Lammers, K., Fasano, A. (2009). Tight junctions, intestinal permeability, and autoimmunity. Annals of the New York Academy of Sciences 1165: 195-205.
  80. Sapone, A., De Magistris, L., Pietzak, M., Clemente, MG., Tripathi, A., Cucca, F., Lampis, R., Kryszak, D et al. (2006). Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55 (5): 1443–1449
  81. Wang, W., Uzzau, S., Goldblum, S., Fasano, A. (2000) Human zonulin, a potential modulator of intestinal tight junctions. The Journal of Cell Science 113: 4435-4440
  82. Fassano, A. (2011). Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. Physiological Reviews 91(1): 151-175
  83. Catalioto, R., Maggi, C., Giuliani, S. (2011). Intestinal Epithelial Barrier Dysfunction in Disease and Possible Therapeutical Interventions. Current Medicinal Chemistry 18(3): 398-426
  84. de Magistris, L., Familiari, V., et al. (2010). Alterations of the Intestinal Barrier in Patients With Autism Spectrum Disorders and in Their First-degree Relatives. Journal of Pediatric Gastroenterology and Nutrition 51(4): 418-424


Coordinator Comment to all Groups

I will add a general comment that will be the same to all groups under this heading.

Referencing Extension Problem

--Mark Hill 13:16, 3 May 2011 (EST) As mentioned in the lecture, I am aware of the referencing extension problem on your project pages. I have the following temporary solution, of removing the extension, so that groups can continue to add content to their project pages. I am also giving everyone a 1 week extension before the peer assessment.

This should only be done if your project page is not allowing you to save changes!

A. The Easy Way....

The following 4 steps can be done on the webpage or select all content in edit mode, copy and paste into a text editor. All steps must be completed before you attempt to save.

  1. In page edit mode, find all <pubmed> reference tags.
  2. Replace this tag with [http://www.ncbi.nlm.nih.gov/pubmed/ Note, there should be no spaces between the internet address and the pmid number.
  3. Now find all </pubmed> reference tags.
  4. Replace this second tag with ]

This will generate a numbered reference list that we can later fix up.


B. The Better Looking Result....

Whatever is between the <ref> </ref></pubmed> tags is what will appear in your reference list, so you can format the reference and link to appear in your reference list.

2011 Projects: Synaptic Junctions | Gap Junctions | Tight Junctions | Desmosomes | Adherens Junctions | Neuromuscular Junction