Adhesion Failures Determine the Pattern of Choroidal Neovascularization in the Eye: A Computer Simulation Study
Publication Date
May 03, 2012
Journal
PLOS Computational Biology
Authors
Abbas Shirinifard, James Alexander Glazier, Maciej Swat, J. Scott Gens, et al
Volume
8
Issue
5
Pages
e1002440
DOI
http://doi.org/10.1371/journal.pcbi.1002440
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1002440
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/22570603
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342931
Europe PMC
http://europepmc.org/abstract/MED/22570603
Web of Science
000305964600002
Scopus
84863667691
Mendeley
http://www.mendeley.com/research/adhesion-failures-determine-pattern-choroidal-neovascularization-eye-computer-simulation-study
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{"title"=>"Adhesion failures determine the pattern of choroidal neovascularization in the eye: A computer simulation study", "type"=>"journal", "authors"=>[{"first_name"=>"Abbas", "last_name"=>"Shirinifard", "scopus_author_id"=>"24832435500"}, {"first_name"=>"James Alexander", "last_name"=>"Glazier", "scopus_author_id"=>"7006830681"}, {"first_name"=>"Maciej", "last_name"=>"Swat", "scopus_author_id"=>"6602992275"}, {"first_name"=>"J. Scott", "last_name"=>"Gens", "scopus_author_id"=>"57154522400"}, {"first_name"=>"Fereydoon", "last_name"=>"Family", "scopus_author_id"=>"7004272302"}, {"first_name"=>"Yi", "last_name"=>"Jiang", "scopus_author_id"=>"13608424700"}, {"first_name"=>"Hans E.", "last_name"=>"Grossniklaus", "scopus_author_id"=>"7103034799"}], "year"=>2012, "source"=>"PLoS Computational Biology", "identifiers"=>{"sgr"=>"84863667691", "issn"=>"1553734X", "isbn"=>"0022-3077", "pmid"=>"22570603", "doi"=>"10.1371/journal.pcbi.1002440", "pui"=>"365220653", "scopus"=>"2-s2.0-84863667691"}, "id"=>"ab8754df-8cfe-34f6-93b2-ed3888f6232b", "abstract"=>"Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in adults. In CNV, after choriocapillaries initially penetrate Bruch's membrane (BrM), invading vessels may regress or expand (CNV initiation). Next, during Early and Late CNV, the expanding vasculature usually spreads in one of three distinct patterns: in a layer between BrM and the retinal pigment epithelium (sub-RPE or Type 1 CNV), in a layer between the RPE and the photoreceptors (sub-retinal or Type 2 CNV) or in both loci simultaneously (combined pattern or Type 3 CNV). While most studies hypothesize that CNV primarily results from growth-factor effects or holes in BrM, our three-dimensional simulations of multi-cell model of the normal and pathological maculae recapitulate the three growth patterns, under the hypothesis that CNV results from combinations of impairment of: 1) RPE-RPE epithelial junctional adhesion, 2) Adhesion of the RPE basement membrane complex to BrM (RPE-BrM adhesion), and 3) Adhesion of the RPE to the photoreceptor outer segments (RPE-POS adhesion). Our key findings are that when an endothelial tip cell penetrates BrM: 1) RPE with normal epithelial junctions, basal attachment to BrM and apical attachment to POS resists CNV. 2) Small holes in BrM do not, by themselves, initiate CNV. 3) RPE with normal epithelial junctions and normal apical RPE-POS adhesion, but weak adhesion to BrM (e.g. due to lipid accumulation in BrM) results in Early sub-RPE CNV. 4) Normal adhesion of RBaM to BrM, but reduced apical RPE-POS or epithelial RPE-RPE adhesion (e.g. due to inflammation) results in Early sub-retinal CNV. 5) Simultaneous reduction in RPE-RPE epithelial binding and RPE-BrM adhesion results in either sub-RPE or sub-retinal CNV which often progresses to combined pattern CNV. These findings suggest that defects in adhesion dominate CNV initiation and progression.", "link"=>"http://www.mendeley.com/research/adhesion-failures-determine-pattern-choroidal-neovascularization-eye-computer-simulation-study", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Engineering"=>1, "Environmental Science"=>1, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>2, "Physics and Astronomy"=>5, "Social Sciences"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Computer Science"=>{"Computer Science"=>2}, "Unspecified"=>{"Unspecified"=>1}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"United Kingdom"=>1, "Russia"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/644738"], "description"=>"<p>A) Total number of <b>stalk cells</b> vs. <b>time</b>. B) Total number of <b>stalk cells</b> confined in the <b>sub-RPE</b> space vs. <b>time</b>. C) Total number of <b>stalk cells</b> in contact with the <b>POS</b> (<b>stalk cells</b> in the <b>sub-retinal</b> space) vs. <b>time</b>. D) Total number of <b>RPE cells</b> vs. <b>time</b>. E) Total contact area between <b>RPE cells</b> and <b>BrM</b> vs. <b>time</b>. F) Total contact area between <b>POS cells</b> and <b>BrM</b> vs. <b>time</b>. The different colors represent the results of 10 simulation replicas of the adhesion scenario (<i>RRl</i> = 1, <i>RRp</i> = 1, <i>RBl</i> = 1, <i>RBp</i> = 1, <i>ROl</i> = 1) (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s009\" target=\"_blank\">Table S9</a>, adhesion scenario ID: 108). <b>CNV</b> initiates in all replicas and all develop <b>ET2 CNV</b>. A few <b>stalk cells</b> in most replicas die due to lack of <b>RPE-derived VEGF-A</b>. (B) <b>Stalk cells</b> cross the <b>RPE</b> and invade the <b>sub-RPE</b> space once the number of <b>stalk cells</b> in the <b>sub-RPE</b> space reaches ∼50 <b>cells</b>, which usually occurs during the first <b>month</b> after initiation. <b>Stalk cells</b> gradually invade the <b>sub-RPE</b> space during one simulated <b>year</b>. (D) Up to 30 <b>RPE cells</b> (30% of the total) die. The number of <b>RPE cell</b> deaths increases with the number of <b>sub-RPE stalk cells</b>. (E) The contact area between the <b>RPE</b> and <b>BrM</b> decreases as <b>P23 CNV</b> develops. (F) In all replicas the <b>POS</b> contacts <b>BrM</b> persistently and extensively, as the <b>RPE</b> develops substantial holes (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-g017\" target=\"_blank\">Figure 17</a>).</p>", "links"=>[], "tags"=>["sub-retinal", "cnv", "sub-rpe", "progression"], "article_id"=>315223, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g016", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_sub_retinal_CNV_to_sub_RPE_CNV_progression_P23_CNV_Progression_/315223", "title"=>"Dynamics of sub-retinal CNV to sub-RPE CNV progression (P23 CNV Progression).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:27:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/643396"], "description"=>"<p>3D plot of the regression-inferred probability of occurrence of <b>Stable Type 1 CNV</b> (<b>S11 CNV</b> probability) using 10 simulation replicas for each adhesion scenario in the <i>asymmetrically</i> reduced parameter space obtained by setting <i>RRp</i> = <i>RRl</i> and <i>RBp</i> = 3 (indicated by the <b>RPE-BrM*</b> axis label). Red corresponds to a <b>S11 CNV</b> probability of 1 and purple corresponds to a <b>S11 CNV</b> probability of 0. The black region at the top-left corner indicates the locus of normal adhesion. The maximal regression-inferred probability of <b>S11 CNV</b> is 0.93 when <b>RPE-RPE junctional adhesion</b> is normal (<i>RRp</i> = <i>RRl</i>), <b>RPE-BrM labile adhesion</b> is severely impaired (<i>RBl</i> = 1), <b>RPE-BrM plastic coupling</b> is normal (<i>RBp</i> = 3), and <b>RPE-POS labile adhesion</b> is normal. The three isosurfaces correspond to <b>S11 CNV</b> probabilities of 0.25 (back), 0.5 (middle) and 0.8 (front). The five parameters and their (multi)linear combinations account for 76% of the observed variance in the probability of occurrence of <b>S11 CNV</b> (<i>R</i><sup>2</sup> = 0.67). Severe impairment of <b>RPE-POS labile adhesion</b> and <b>RPE-RPE junctional adhesion</b> greatly reduces <i>MW</i>, so <b>S11 CNV</b> can only occur when both adhesion strengths are near normal. To show the structure of the isosurfaces, we have rotated the axes relative to <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-g003\" target=\"_blank\">Figure 3</a>.</p>", "links"=>[], "tags"=>["cnv", "dependence"], "article_id"=>313886, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g006", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stable_Type_1_CNV_dependence_on_adhesion_/313886", "title"=>"Stable Type 1 CNV dependence on adhesion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:04:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/645428"], "description"=>"<p>Geometrical and transport parameters.</p>", "links"=>[], "tags"=>["immunology", "ophthalmology", "physiology", "Computational biology", "oncology", "biophysics", "computer science", "physics"], "article_id"=>315906, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t008", "stats"=>{"downloads"=>1, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Geometrical_and_transport_parameters_/315906", "title"=>"Geometrical and transport parameters.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:38:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/645469"], "description"=>"<p>We classify <b>CNV</b> progression dynamics in each simulation based on its <b>early</b> and <b>late</b><b>CNV types</b>, allowing for nine <b>CNV</b>-dynamics scenarios. We use the term <i>progression</i> when a simulation replica initially develops either <b>Early Type 1 CNV</b> or <b>Early Type 2 CNV</b> and then develops <b>Late Type 3 CNV</b> and <i>translocation</i> when a replica initially develops either <b>Early Type 1 CNV</b> or <b>Early Type 3 CNV</b>, then <b>Late Type 2 CNV</b> or initially develops either <b>Early Type 2 CNV</b> or <b>Early Type 3 CNV</b>, then <b>Late Type 1 CNV</b>. Three translocation scenarios, <b>T21</b>, <b>T31</b> and <b>T32</b>, did not occur in our simulations.</p>", "links"=>[], "tags"=>["cnv"], "article_id"=>315960, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t005", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nomenclature_for_CNV_dynamics_/315960", "title"=>"Nomenclature for CNV dynamics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:39:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/645504"], "description"=>"<p>To classify <b>CNV</b> progression dynamics during a simulated <b>year</b>, we determine the <b><i>early</i></b> and <b><i>late</i></b> loci of <b>stalk cells</b> using the mean <i>MW</i>s during the first and last three <b>months</b> of each simulation (we can make this calculation whether or not <b>CNV</b> initiates).</p>", "links"=>[], "tags"=>["nomenclature"], "article_id"=>315991, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Temporal_Nomenclature_for_CNV_/315991", "title"=>"(Temporal) Nomenclature for CNV.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:39:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/645792"], "description"=>"<p>Negative contact energies represent adhesive interactions; positive contact energies represent repulsive interactions. More negative contact energies indicate stronger adhesive interactions. (/) separates the reference, moderately impaired and severely impaired levels of <b>labile adhesion</b>.</p>", "links"=>[], "tags"=>["adhesion", "parameters"], "article_id"=>316286, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t010", "stats"=>{"downloads"=>4, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Labile_adhesion_parameters_contact_energies_/316286", "title"=>"Labile adhesion parameters (contact energies).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:44:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/643473"], "description"=>"<p>A) Total number of <b>stalk cells</b> vs. <b>time</b>. B) Total number of <b>stalk cells</b> confined in the <b>sub-RPE</b> space vs. <b>time</b>. C) Total number of <b>stalk cells</b> in contact with the <b>POS</b> (<b>stalk cells</b> in the <b>sub-retinal</b> space) vs. <b>time</b>. D) Total number of <b>RPE cells</b> vs. <b>time</b>. E) Total contact area between <b>RPE cells</b> and <b>BrM</b> vs. <b>time</b>. F) Total contact area between <b>POS cells</b> and <b>BrM</b> vs. <b>time</b>. The different colors represent the dynamics of 10 simulation replicas of the adhesion scenario (<i>RRl</i> = 3, <i>RRp</i> = 3, <i>RBl</i> = 2, <i>RBp</i> = 2, <i>ROl</i> = 3) (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s005\" target=\"_blank\">Table S5</a>, adhesion scenario ID: 38). (A, B) <b>CNV</b> initiates in 9 out of 10 simulation replicas. All develop <b>Early Type 1 CNV</b>. <b>CNV</b> remains confined in the <b>sub-RPE</b> space during one simulated <b>year</b> (<b>Stable Type 1 CNV</b>). A Fully developed <b>sub-RPE</b> capillary network contains about 45 <b>stalk cells</b> (∼3000 <b>cells</b>/mm<sup>2</sup>). In 5 simulation replicas a few <b>stalk cells</b> die during the simulated <b>year</b> due to lack of <b>RPE-derived VEGF-A</b>. (C) <b>Stalk cells</b> have minimal contact with the <b>POS</b>. (D, E) The <b>RPE</b> remains viable and its total contact area with <b>BrM</b> decreases as <b>stalk cells</b> proliferate. (F) The <b>POS</b> never contacts <b>BrM</b>, indicating that the <b>RPE</b> does not develop any holes.</p>", "links"=>[], "tags"=>["cnv"], "article_id"=>313959, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g007", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_stable_Type_1_CNV_S11_CNV_/313959", "title"=>"Dynamics of stable Type 1 CNV (S11 CNV).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:05:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/645186"], "description"=>"<p>3D and 2D visualization of a simulation replica developing <b>S33 CNV</b> in one simulated <b>year</b> (<i>RRl</i> = 1, <i>RRp</i> = 1, <i>RBl</i> = 2, <i>RBp</i> = 2, <i>ROl</i> = 3) (adhesion scenario ID: 53, simulation ID: 917). Snapshots of the simulation at <b>months</b> 1 (A), 2 (B), 6 (C) and 12 (D). (A2-D2) Cross-sections of (A1-D1). All cross-section planes in (A1-D1) panels defined by the two thick black lines in A1. (A) <b>Stalk cells</b> invade the <b>sub-RPE</b> space through a hole in <b>BrM</b> (A1-2, black outline arrows) that the <b>tip cell</b> form during the first 24 <b>hours</b> of the simulation. These <b>stalk cells</b> then form a fully developed <b>sub-RPE</b> capillary network. (A2) Only a few <b>stalk cells</b> (black arrow, A1-2) reach the <b>sub-retinal</b> space during the first <b>month</b>. (B1, C1) The <b>sub-retinal</b> and <b>sub-RPE</b> capillary networks do not grow significantly. (C2) A capillary (black arrows), enveloped by a bilayer of <b>RPE cells</b>, connects the <b>sub-retinal</b> space to the <b>CC</b> via the hole in <b>BrM</b> (D) <b>Stalk cells</b> disrupt the <b>RPE</b>, forming small holes in the <b>RPE</b> (D2, black arrow). The <b>stalk cells</b> at the location of the hole in the <b>RPE</b> (D2, black arrow) contact both the <b>POSs</b> and <b>BrM</b>. The black outline arrow shows <b>sub-retinal stalk cells</b>. <b>Cell </b><b>type</b> colors: 1) <b>POS</b> and <b>PIS</b>: light purple, 2) <b>RPE</b>: brown, 3) <b>Stalk cells</b>: green, 4) <b>Vascular cells</b> (<b>CC</b>): red, 5) <b>BrM</b>: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells in A1-D1 as semi-transparent membranes. <b>POS</b>, <b>PIS</b> and <b>RPE</b> cells are rendered more transparent to show the underlying structures. See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s022\" target=\"_blank\">Video S6</a>.</p>", "links"=>[], "tags"=>["simulation", "replica", "exhibiting", "cnv"], "article_id"=>315669, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g019", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Snapshots_of_a_simulation_replica_exhibiting_stable_Type_3_CNV_S33_CNV_/315669", "title"=>"Snapshots of a simulation replica exhibiting stable Type 3 CNV (S33 CNV).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:34:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/645587"], "description"=>"<p>Key: <i>RRl</i>: <b>RPE-RPE labile adhesion</b> strength, <i>RRp</i>: <b>RPE-RPE plastic coupling</b> strength, <i>RBl</i>: <b>RPE-BrM labile adhesion</b> strength, <i>RBp</i>: <b>RPE-BrM plastic coupling</b> strength, <i>ROl</i>: <b>RPE-POS labile adhesion</b> strength. Scaled adhesion strengths: 3: normal, 2: moderately impaired, 1: severely impaired (weak),</p>*<p>: all strength levels.</p>", "links"=>[], "tags"=>["classification", "cnv"], "article_id"=>316079, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t006", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Adhesion_scenario_classification_based_on_early_CNV_type_/316079", "title"=>"Adhesion scenario classification based on early CNV type.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:41:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/645378"], "description"=>"<p>Field object names.</p>", "links"=>[], "tags"=>["immunology", "ophthalmology", "physiology", "Computational biology", "oncology", "biophysics", "computer science", "physics"], "article_id"=>315859, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t009", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Field_object_names_/315859", "title"=>"Field object names.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:37:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/643244"], "description"=>"<p>3D plot of the regression-inferred average <i>MW</i> using 10 simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting <i>RRp</i> = <i>RRl</i> and <i>RBp</i> = <i>RBl</i>. The average <i>MW</i> shows the <b>stalk cell</b> locus even when <b>CNV</b> fails to initiate, so a region <i>prone</i> to <b>ET1 CNV</b> develops <b>ET1 CNV</b> only if <b>CNV</b> initiates. Red corresponds to <i>MW</i> = 1 and purple corresponds to <i>MW</i> = 0. The black region at the top-left corner indicates the locus of normal adhesion. <i>MW</i> = 1.0 for <b>RPE-RPE junctional adhesion</b> normal, <b>RPE-BrM junctional adhesion</b> severely impaired (weak) and <b>RPE-POS labile adhesion</b> normal. The three isosurfaces correspond to <i>MW</i> = 0.25 (back), 0.5 (middle) and 0.90 (front). The five adhesion parameters and their (multi)linear combinations account for 93% of the observed variance in average <i>MW</i> for all 108 adhesion scenarios (adjusted <i>R</i><sup>2</sup> = 0.89). Severe impairment of <b>RPE-POS labile adhesion</b> greatly reduces the <i>MW</i>, so <b>ET1 CNV</b> can only occur when <b>RPE-POS labile adhesion</b> is near normal. Scenarios with severe impairment of <b>RPE-BrM junctional adhesion</b> (<i>RBp</i> = <i>RBl</i> = 1), and normal <b>RPE-POS labile adhesion</b> are prone to <b>ET1 CNV</b> for a wide range of <b>RPE-RPE junctional adhesion</b> impairment (<i>MW</i>>0.95 for <i>RRp</i> = <i>RRl</i>>1.5). The red region with <i>MW</i>>0.9 has <i>P</i><sub>init</sub>>0.8. We have rotated the axes from their orientation in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-g003\" target=\"_blank\">Figure 3</a> to show the regions in the parameter space prone to <b>ET1 CNV</b>. To show the structure of the isosurfaces, we have rotated the axes relative to <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-g003\" target=\"_blank\">Figure 3</a>.</p>", "links"=>[], "tags"=>["cnv", "dependence"], "article_id"=>313732, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sub_RPE_CNV_dependence_on_adhesion_/313732", "title"=>"Sub-RPE CNV dependence on adhesion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:02:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/643596"], "description"=>"<p>3D visualization of a simulation replica exhibiting <b>Stable Type 1 CNV</b> over one simulated <b>year</b> (adhesion scenario ID: 38, simulation ID: 902) (<i>RRl</i> = 3, <i>RRp</i> = 3, <i>RBl</i> = 2, <i>RBp</i> = 2, <i>ROl</i> = 3). Snapshots of the simulation at <b>months</b> 3 (A), 6 (B), 9 (C) and 12 (D). (A) <b>Stalk cells</b> (black arrows) invade the <b>sub-RPE</b> space through a hole (black outline arrow) in <b>BrM</b> (light blue outline arrow) that the <b>tip cell</b> opens during the first 24 <b>hours</b>. Brown outline arrow shows the <b>RPE cells</b>. Red outline arrow shows the <b>CC</b> (B, C) <b>Stalk cells</b> proliferate until they fill the <b>sub-RPE</b> space in <b>month</b> 9, after which proliferation slows down (D) The 45 <b>stalk cells</b> form a connected capillary network in the <b>sub-RPE</b> space. <b>Cell type</b> colors: 1) <b>POS</b> and <b>PIS</b>: light purple, 2) <b>RPE</b>: brown, 3) <b>Stalk cells</b>: green, 4) <b>Vascular cells</b> (<b>CC</b>): red, 5) <b>BrM</b>: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. <b>POS</b>, <b>PIS</b> and <b>RPE</b> cells are more transparent to show the underlying structures. See also Video S1.</p>", "links"=>[], "tags"=>["simulation", "replica"], "article_id"=>314086, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g008", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Snapshots_of_a_simulation_replica_with_stable_Type_1_CNV_/314086", "title"=>"Snapshots of a simulation replica with stable Type 1 CNV.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:08:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/644547"], "description"=>"<p>3D visualization of a simulation replica showing <b>S22 CNV</b> in one simulated <b>year</b> (<i>RRl</i> = 1, <i>RRp</i> = 1, <i>RBl</i> = 3, <i>RBp</i> = 3, <i>ROl</i> = 3) (adhesion scenario ID: 16, simulation ID: 556). Snapshots of the simulation at <b>months</b> 1 (A), 2 (B), 6 (C) and 12 (D). (A) <b>Stalk cells</b> (solid black arrow) invade the <b>sub-retinal</b> space through a hole in <b>BrM</b> (black outline arrow) and form a partially developed capillary network (B). <b>CNV</b> finishes <b>sub-retinal</b> invasion around <b>month</b> 5 and remains in the <b>sub-retinal</b> space throughout <b>LT2 CNV</b> (C–D). A few <b>vascular cells</b> (A, black outline arrow) fill the hole in <b>BrM</b> to connect the <b>CNV</b> capillaries to the <b>CC</b> (red outline arrow). Brown outline arrow shows an <b>RPE cell</b>. <b>Cell type</b> colors: 1) <b>POS</b> and <b>PIS</b>: light purple, 2) <b>RPE</b>: brown (<b>stalk cells</b> in the <b>sub-retinal</b> space have lighter shading), 3) <b>Stalk cells</b>: green, 4) <b>Vascular cells</b> (<b>CC</b>): red, 5) <b>BrM</b>: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. <b>POS</b>, <b>PIS</b> and <b>RPE</b> cells are more transparent to show the underlying structures. See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s020\" target=\"_blank\">Video S4</a>.</p>", "links"=>[], "tags"=>["simulation", "replica", "cnv"], "article_id"=>315038, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g015", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Snapshots_of_a_simulation_replica_showing_stable_Type_CNV_S22_CNV_/315038", "title"=>"Snapshots of a simulation replica showing stable Type CNV (S22 CNV).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:23:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/645060"], "description"=>"<p>A) Total number of <b>stalk cells</b> vs. <b>time</b>. B) Total number of <b>stalk cells</b> confined in the <b>sub-RPE</b> space vs. <b>time</b>. C) Total number of <b>stalk cells</b> in contact with the <b>POS</b> (<b>stalk cells</b> in the <b>sub-retinal</b> space) vs. <b>time</b>. D) Total number of <b>RPE cells</b> vs. <b>time</b>. E) Total contact area between <b>RPE cells</b> and <b>BrM</b> vs. <b>time</b>. F) Total contact area between <b>POS cells</b> and <b>BrM</b> vs. <b>time</b>. The different colors represent the results of 10 simulation replicas of the adhesion scenario (<i>RRl</i> = 1, <i>RRp</i> = 1, <i>RBl</i> = 2, <i>RBp</i> = 2, <i>ROl</i> = 3) (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s010\" target=\"_blank\">Table S10</a>, adhesion scenario ID: 53). (A, B, C) <b>CNV</b> initiates in all replicas and all replicas develop <b>ET3 CNV</b>. During the first <b>month</b> after initiation, stalk cells gradually invade both the <b>sub-RPE</b> space and the <b>sub-retinal</b> space, with more invading the <b>sub-RPE</b> space. Between <b>months</b> 1 and 2 about 30% of the <b>sub-RPE stalk cells</b> transmigrate into the <b>sub-retinal</b> space. After <b>month</b> 3, the number of <b>sub-RPE stalk cells</b> increases slowly, while the number of <b>sub-retinal stalk cells</b> remains constant. (E) During the first <b>month</b> of the simulation, the contact area between the <b>RPE</b> and <b>BrM</b> rapidly decreases as <b>stalk cells</b> invade the <b>sub-RPE</b> space. Between <b>months</b> 1 and 2, the contact area between the <b>RPE</b> and <b>BrM</b> rapidly increases as <b>sub-RPE stalk cells</b> transmigrate into the <b>sub-retinal</b> space. The contact area between the <b>RPE</b> and <b>BrM</b> slowly decreases after <b>month</b> 3 throughout the simulated <b>year</b>. (D) A few <b>RPE cells</b> die in most replicas. (F) In a few replicas the <b>POS</b> persistently contacts <b>BrM</b>, as the <b>RPE</b> develops small holes.</p>", "links"=>[], "tags"=>["cnv"], "article_id"=>315547, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g018", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_stable_Type_3_CNV_S33_CNV_/315547", "title"=>"Dynamics of stable Type 3 CNV (S33 CNV).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:32:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/645750"], "description"=>"<p>Larger plastic coupling strengths represent stiffer linear springs. (-) denotes values of not used in our simulations.</p>", "links"=>[], "tags"=>["coupling", "strengths", "links", "cell-type"], "article_id"=>316233, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t012", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Plastic_coupling_strengths_links_between_cell_type_pairs_/316233", "title"=>"Plastic coupling strengths () links between cell-type pairs.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:43:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/645667"], "description"=>"<p>We define the type of <b>CNV</b> based on the mean morphometric weight during a three <b>month</b> window. A <i>MW</i>≥0.75 throughout the window indicates that most <b>stalk cells</b> lie between <b>BrM</b> and the <b>RPE</b> (in the <b>sub-RPE</b> space) and do not contact the <b>POS</b>. We therefore assign the time window to <b>Type 1</b>. A <i>MW</i>≤0.25 throughout the window indicates that most <b>stalk cells</b> lie between <b>RPE</b> and the <b>POS</b> (in <b>sub-retinal</b> space) and do not contact <b>BrM</b>. We therefore assign the time window to <b>Type 2 CNV</b>. 0.25<<i>MW</i><0.75 usually indicates that <b>stalk cells</b> occur in both the sub-<b>RPE</b> and <b>sub</b>-<b>retinal</b> spaces. In a few exceptional cases (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s010\" target=\"_blank\">Table S10</a>) with 0.25<<i>MW</i><0.75, most <b>stalk cells</b> lie between neighboring <b>RPE cells</b> rather than in either the <b>sub</b>-<b>RPE</b> or <b>sub</b>-<b>retinal</b> spaces (discussed in the <i>Stable Type 3 CNV</i> subsection in supplementary <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s015\" target=\"_blank\">Text S5</a>).</p>", "links"=>[], "tags"=>["cnv", "morphometric"], "article_id"=>316154, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t003", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Classification_of_CNV_type_based_on_Morphometric_Weight_/316154", "title"=>"Classification of CNV type based on Morphometric Weight.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:42:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/644888"], "description"=>"<p>3D and 2D visualization of a simulation replica forming <b>P23 CNV</b> in one simulated <b>year</b> (<i>RRl</i> = 1, <i>RRp</i> = 1, <i>RBl</i> = 1, <i>RBp</i> = 1, <i>ROl</i> = 1) (adhesion scenario ID: 108, simulation ID: 1080). Snapshots of the simulation at <b>months</b> 1 (A), 3 (B), 6 (C) and 12 (D). (A2-D2) Cross-sections of (A1-D1) parallel and adjacent to <b>BrM</b>, so <b>stalk cells</b> shown in (A2-D2) contact <b>BrM</b>. The black open circles (A1-2) at the top corner and outline back arrows (A1-2) at the location of the hole in <b>BrM</b> are guides to the eye to align A2 to A1. The alignment is consistent across all panels. (A) <b>Stalk cells</b> (solid black arrow) invade the <b>sub-retinal</b> space through the hole in <b>BrM</b> (A1-2, black outline arrows) that the <b>tip cell</b> form during the first 24 <b>hours</b> of the simulation and form a fully developed <b>sub-retinal</b> capillary network by <b>month</b> 1. (A2) Only a few <b>stalk cells</b>, mostly near the hole in <b>BrM</b>, invade the <b>sub-RPE</b> space during the first <b>month</b>. (B1, C1) The <b>sub-retinal</b> capillary network does not grow significantly. (B2, C2) Additional <b>stalk cells</b> invade the <b>sub-RPE</b> space. (D) More <b>stalk cells</b> invade the <b>sub-RPE</b> space, disrupting the <b>RPE</b> and causing a micro-tear (D1-2, black arrows). The <b>POS</b> contacts <b>BrM</b> at the location of the <b>RPE</b> tear. <b>Cell type</b> colors: 1) <b>POS</b> and <b>PIS</b>: light purple, 2) <b>RPE</b>: brown (<b>stalk cells</b> in the <b>sub-retinal</b> space have lighter shading), 3) <b>Stalk cells</b>: green (3D-visualized <b>stalk cells</b> in the <b>sub-retinal</b> space have lighter shading), 4) <b>Vascular cells</b> (<b>CC</b>): red, 5) <b>BrM</b>: light blue. Scale bars ∼50 µm. We have rendered the boundaries of individual cells in A1-D1 as semi-transparent membranes. <b>POS</b>, <b>PIS</b> and <b>RPE</b> cells are rendered more transparent to show the underlying structures. See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s021\" target=\"_blank\">Video S5</a>.</p>", "links"=>[], "tags"=>["simulation", "replica", "exhibiting", "sub-retinal", "cnv", "sub-rpe", "progression"], "article_id"=>315366, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g017", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Snapshots_of_a_simulation_replica_exhibiting_sub_retinal_CNV_to_sub_RPE_CNV_progression_P23_CNV_/315366", "title"=>"Snapshots of a simulation replica exhibiting sub-retinal CNV to sub-RPE CNV progression (P23 CNV).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:29:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/644091"], "description"=>"<p>A) Total number of <b>stalk cells</b> vs. <b>time</b>. B) Total number of <b>stalk cells</b> confined in the <b>sub-RPE</b> space vs. <b>time</b>. C) Total number of <b>stalk cells</b> in contact with the <b>POS</b> (<b>stalk cells</b> in the <b>sub-retinal</b> space) vs. <b>time</b>. D) Total number of <b>RPE cells</b> vs. <b>time</b>. E) Total contact area between <b>RPE cells</b> and <b>BrM</b> vs. <b>time</b>. F) Total contact area between <b>POS cells</b> and <b>BrM</b> vs. <b>time</b>. The different colors represent the results of 10 simulation replica of the adhesion scenario (<i>RRl</i> = 1, <i>RRp</i> = 3, <i>RBl</i> = 1, <i>RBp</i> = 2, <i>ROl</i> = 3) (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s007\" target=\"_blank\">Table S7</a>, adhesion scenario ID: 83). <b>CNV</b> initiates in all replicas and all develop <b>ET1 CNV</b>. A few <b>stalk cells</b> in most replicas die due to lack of <b>RPE-derived VEGF-A</b>. (C) <b>Stalk cells</b> cross the <b>RPE</b> and invade the <b>sub-retinal</b> space once the number of stalk cells in the <b>sub-RPE</b> space reaches ∼60 <b>cells</b>, which usually occurs within first two <b>months</b> after initiation. <b>CNV</b> progression to the <b>sub-retinal</b> space is complete around <b>month</b> 5. (D) The <b>RPE</b> remains viable in all replicas. (E) The contact area between the <b>RPE</b> and <b>BrM</b> decreases as <b>ET1 CNV</b> develops, and remains constant afterwards throughout <b>LT3 CNV</b>. (F) The <b>POS</b> contacts <b>BrM</b> a few times, but the contact area and duration are both small, so the <b>RPE</b> does not develop any persistent or substantial holes.</p>", "links"=>[], "tags"=>["sub-rpe", "cnv", "sub-retinal", "progression"], "article_id"=>314575, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g011", "stats"=>{"downloads"=>4, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_sub_RPE_CNV_to_sub_retinal_CNV_progression_P13_Progression_/314575", "title"=>"Dynamics of sub-RPE CNV to sub-retinal CNV progression (P13 Progression).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:16:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/643925"], "description"=>"<p>3D visualization of a simulation replica exhibiting <b>T12 CNV</b> translocation during one simulated <b>year</b> (<i>RRl</i> = 3, <i>RRp</i> = 3, <i>RBl</i> = 1, <i>RBp</i> = 1, <i>ROl</i> = 1) (adhesion scenario ID: 93, simulation ID: 849). Snapshots of the simulation at <b>months</b> 3 (A), 5 (B), 9 (C) and 12 (D). (A) <b>Stalk cells</b> (solid black arrow) invade the <b>sub-RPE</b> space through a hole in <b>BrM</b> (black outline arrow) and form a capillary network. All <b>stalk cells</b> remain in the <b>sub-RPE</b> space during the first 3 <b>months</b>. A few <b>vascular cells</b> fill the hole in <b>BrM</b> (black outline arrow) to connect <b>CNV</b> capillaries to the <b>CC</b> (red outline arrow). Brown outline arrow shows an <b>RPE cell</b>. (B) Half of the <b>stalk cells</b> (black outline arrow) have crossed the <b>RPE</b> and transmigrated into the <b>sub-retinal</b> space, forming a new capillary network in the <b>sub-retinal</b> space. The black arrow shows a <b>stalk cell</b> in the <b>sub-RPE</b> space. (C) Most <b>stalk cells</b> have transmigrated into the <b>sub-retinal</b> space and the <b>RPE</b> has completely reattached to <b>BrM</b> (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-g009\" target=\"_blank\">Figure 9E</a>, dark green line). A few <b>vascular cells</b> of the <b>CC</b> have transmigrated into the <b>sub-retinal</b> space (red outline arrow) (D) The <b>sub-retinal</b> capillary network has fewer <b>stalk cells</b> than (C) since <b>stalk cells</b> that migrate into the retina far from the <b>RPE</b> die. <b>Cell type</b> colors: 1) <b>POS</b> and <b>PIS</b>: light purple, 2) <b>RPE</b>: brown, 3) <b>Stalk cells</b>: green (<b>stalk cells</b> in the <b>sub-retinal</b> space have lighter shading), 4) <b>Vascular cells</b> (<b>CC</b>): red, 5) <b>BrM</b>: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. <b>POS</b>, <b>PIS</b> and <b>RPE</b> cells are more transparent to show the underlying structures. See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s018\" target=\"_blank\">Video S2</a>.</p>", "links"=>[], "tags"=>["simulation", "replica", "sub-rpe", "sub-retinal", "translocation"], "article_id"=>314411, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g010", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Snapshots_of_a_simulation_replica_showing_sub_RPE_to_sub_retinal_translocation_T12_Translocation_/314411", "title"=>"Snapshots of a simulation replica showing sub-RPE to sub-retinal translocation (T12 Translocation).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:13:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/644358"], "description"=>"<p>3D plot of the regression-inferred probability of occurrence of <b>Stable Type 2 CNV</b> (<b>S22 CNV</b> probability) using 10 simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting <i>RRp</i> = <i>RRl</i> and <i>RBp</i> = <i>RBl</i>. Red corresponds to a <b>S22 CNV</b> probability of 1 and purple corresponds to a <b>S22 CNV</b> probability of 0. The black region at the top-back corner indicates the locus of normal adhesion. The three isosurfaces correspond to <b>S22 CNV</b> probabilities of 0.25 (right), 0.5 (middle) and 0.9 (left). The five parameters and their (multi)linear combinations account for 89% of the observed variance in the probability of occurrence of <b>S22 CNV</b> in all 108 adhesion scenarios (adjusted <i>R</i><sup>2</sup> = 0.84 ). <b>S22 CNV</b> occurs primarily when <b>RPE-RPE junctional adhesion</b> is moderately to severely impaired, <b>RPE-BrM junctional adhesion</b> is normal or moderately impaired, independent of <b>RPE-POS labile</b> adhesion (red region with <b>S22 CNV</b> probability>0.9). The red region does not include all adhesion scenarios in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s008\" target=\"_blank\">Table S8</a> leading to <b>S22 CNV</b>. To show the structure of the isosurfaces, we have rotated the axes relative to <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-g003\" target=\"_blank\">Figure 3</a>.</p>", "links"=>[], "tags"=>["cnv", "dependence"], "article_id"=>314844, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g013", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stable_Type_2_CNV_dependence_on_adhesion_/314844", "title"=>"Stable Type 2 CNV dependence on adhesion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:20:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/643171"], "description"=>"<p>3D plot of the regression-inferred <b>CNV</b> initiation probability (<i>P</i><sub>init</sub>) vs. three key adhesion strengths using ten simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting <i>RRp</i> = <i>RRl</i> and <i>RBp</i> = <i>RBl</i>. Red corresponds to <i>P</i><sub>init</sub> = 1 and purple to <i>P</i><sub>init</sub> = 0. The black region at the top-front corner indicates the locus of normal adhesion. The three isosurfaces of <b>CNV</b> initiation probability correspond to <i>P</i><sub>init</sub> = 0.25 (front), 0.5 (middle) and 0.75 (back). The five adhesion parameters and their (multi)linear combinations account for 88% of the observed variance in <b>CNV</b> initiation probability (adjusted <i>R<sup>2</sup></i> = 0.83). Regression predicts a minimum <b>CNV</b> initiation probability of 0.08 for normal adhesion, much higher than observed in either our simulations or experiments. For normal <b>RPE-POS labile adhesion</b>, moderate impairment of either <b>RPE-RPE</b> (<i>RRp</i> = <i>RRl</i>) or <b>RPE-BrM</b> (<i>RBp</i> = <i>RBl</i>) <b>junctional adhesion</b> increases the <b>CNV</b> initiation probability to ∼50%. Severe impairment of <b>RPE-POS</b> increases the <b>CNV</b> initiation probability to ∼50% even when both <b>RPE-RPE</b> and <b>RPE-BrM</b> are normal.</p>", "links"=>[], "tags"=>["initiation", "probability", "dependence", "adhesion"], "article_id"=>313656, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CNV_Initiation_probability_dependence_on_key_adhesion_mechanisms_/313656", "title"=>"CNV Initiation probability dependence on key adhesion mechanisms.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:00:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/643098"], "description"=>"<p>Our model includes two types of <b>cell-cell</b> and <b>cell-BrM</b> adhesion: 1) <b><i>labile adhesion</i></b> and 2) <b><i>junctional adhesion</i></b>. Modeled <b>labile adhesion</b> represents cell-cell or cell-ECM labile adhesion in the absence of strong junctional structures (<i>e.g.</i>, RPE-POS adhesion). <b>Junctional adhesion</b> combines <b>labile adhesion</b> at <b>cell</b> boundaries with <b>plastic coupling</b> (<i>e.g.</i>, between neighboring <b>cells</b> or between <b>BrM</b> and <b>cells</b>). <b>Plastic coupling</b> simulates cytoskeletally-coupled junctional structures as breakable springs (see the <i><a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#s4\" target=\"_blank\">Methods</a></i> section in supplementary <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s013\" target=\"_blank\">Text S3</a>) that mechanically connect neighboring <b>cells</b> and also connect <b>cells</b> to <b>BrM</b>. <b>Junctional adhesion</b> represents biological epithelial or endothelial junctional adhesion or cell-ECM focal adhesion. In the model, a single <b>junctional adhesion</b> between RPE cells and BrM represents the complex biological adhesion between RPE cells and their basal laminae (RBaL), adhesion between the basal laminae and their basement membrane (RBaM) and adhesion between RBaM and BrM (inset). Modeled adhesion processes are: <b>EC-EC</b> and <b>EC-BrM junctional adhesion</b>; <b>EC-RPE</b>, <b>EC-POS</b> and <b>EC-PIS labile adhesion</b>; <b>RPE-RPE</b> and <b>RPE-BrM junctional adhesion</b>; <b>RPE-PIS</b> and <b>RPE-POS labile adhesion</b>; <b>PIS-PIS</b>, <b>PIS-POS</b> and <b>POS-POS junctional adhesion</b>. Key: <b>BrM</b>: Bruch's membrane, <b>RPE</b>: retinal pigment epithelium, <b>RBaM</b>: basement membrane of the RPE, <b>RBaL</b>: basal lamina of the RPE, <b>POS</b>: photoreceptor outer segment, <b>PIS</b>: photoreceptor inner segment.</p>", "links"=>[], "tags"=>["processes"], "article_id"=>313590, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Adhesive_interaction_processes_in_the_model_retina_/313590", "title"=>"Adhesive interaction processes in the model retina.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 00:59:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/643023"], "description"=>"<p><i>Left large-scale</i>: Structure of the outer retinal layers, the RPE and the CC. <i>Right</i>: Detail of the CC-BrM-RPE-POS complex. <i>CC</i>: choriocapillaris, <i>BrM</i>: Bruch's membrane, <i>RPE</i>: Retinal pigment epithelium, <i>CC BaM</i>: Basement membrane of the CC, <i>OCL</i>: Outer collagenous layer, <i>EL</i>: Elastin layer, <i>ICL</i>: Inner collagenous layer, RPE BaM: Basement membrane of the RPE (we abbreviate RPE BaM as <i>RBaM</i>), <i>POS</i>: Photoreceptor outer segment, <i>PIS</i>: Photoreceptor inner segment, <i>ONL</i>: Outer nuclear layer. Light purple shading indicates the location of the inner retina. Scale bars ∼10 µm.</p>", "links"=>[], "tags"=>["retinal", "pigment", "membrane"], "article_id"=>313508, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Retinal_structure_the_retinal_pigment_epithelium_Bruch_s_membrane_and_the_choriocapillaris_/313508", "title"=>"Retinal structure, the retinal pigment epithelium, Bruch's membrane and the choriocapillaris.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 00:58:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/644418"], "description"=>"<p>A) Total number of <b>stalk cells</b> vs. <b>time</b>. B) Total number of <b>stalk cells</b> confined in the <b>sub-RPE</b> space vs. <b>time</b>. C) Total number of <b>stalk cells</b> in contact with the <b>POS</b> (<b>stalk cells</b> in the <b>sub-retinal</b> space) vs. <b>time</b>. D) Total number of <b>RPE cells</b> vs. <b>time</b>. E) Total contact area between <b>RPE </b><b>cells</b> and <b>BrM</b> vs. <b>time</b>. F) Total contact area between <b>POS cells</b> and <b>BrM</b> vs. <b>time</b>. The different colors represent the results of 10 simulation replicas of the adhesion scenario (<i>RRl</i> = 1, <i>RRp</i> = 1, <i>RBl</i> = 3, <i>RBp</i> = 3, <i>ROl</i> = 3) (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s008\" target=\"_blank\">Table S8</a>, adhesion scenario ID: 16). (A, C) <b>CNV</b> initiates in all replicas and all develop <b>ET2 CNV</b> during the first three <b>months</b> of the simulation. All replicas exhibit <b>S22 CNV</b>. A few <b>stalk cells</b> in most replicas die due to lack of <b>RPE-derived VEGF-A</b>. (C) Few or no <b>stalk cells</b> reach the <b>sub-RPE</b> space. (D) The <b>RPE</b> remains viable in all replicas. (E) The contact area between the <b>RPE</b> and <b>BrM</b> does not change as <b>S22</b> develops. (F) The <b>POS</b> contacts <b>BrM</b> a few times, but the contact area and duration are both small, so the <b>RPE</b> does not develop any persistent or substantial holes.</p>", "links"=>[], "tags"=>["cnv"], "article_id"=>314913, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g014", "stats"=>{"downloads"=>2, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_stable_Type_2_CNV_S22_CNV_/314913", "title"=>"Dynamics of stable Type 2 CNV (S22 CNV).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:21:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/643321"], "description"=>"<p>3D plot of the regression-inferred average (1−<i>MW</i>) using 10 simulation replicas for each adhesion scenario in the 3D parameter space obtained by setting <i>RRp</i> = <i>RRl</i> and <i>RBp</i> = <i>RBl</i>. The average (1−<i>MW</i>) shows the <b>stalk cell</b> locus even when <b>CNV</b> fails to initiate, so a region <i>prone</i> to <b>ET2 CNV</b>, develops <b>ET2 CNV</b> only if <b>CNV</b> initiates. Red corresponds to (1−<i>MW</i>) = 1 and purple corresponds to (1−<i>MW</i>) = 0. The black region at the top-back corner indicates the locus of normal adhesion. The three isosurfaces correspond to (1−<i>MW</i>) = 0.25 (right), 0.5 (middle) and 0.90 (left). The five adhesion parameters and their (multi)linear combinations account for 93% of the observed variance in average <i>MW</i> for all 108 adhesion scenarios (<i>R</i><sup>2</sup> = 0.89). The red region with (1−<i>MW</i>)>0.9, can be divided into three sub-regions: 1) When <b>RPE-RPE junctional adhesion</b> is normal, <b>RPE-BrM junctional adhesion</b> is moderately impaired, and <b>RPE-POS labile adhesion</b> is severely impaired (weak). 2) When <b>RPE-RPE junctional adhesion</b> is severely impaired (weak) and <b>RPE-BrM junctional adhesion</b> is normal, independent of <b>RPE-POS labile adhesion</b>. 3) When <b>RPE-RPE</b> adhesion is weak, <b>RPE-BrM</b> adhesion is moderately to severely impaired, and <b>RPE-POS</b> adhesion is severely impaired. The red region does not include all adhesion scenarios in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s003\" target=\"_blank\">Table S3</a> leading to <b>Early Type 2 CNV</b>. To show the structure of the isosurfaces, we have rotated the axes relative to <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-g003\" target=\"_blank\">Figure 3</a>.</p>", "links"=>[], "tags"=>["cnv", "dependence"], "article_id"=>313810, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g005", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sub_Retinal_CNV_dependence_on_adhesion_/313810", "title"=>"Sub-Retinal CNV dependence on adhesion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:03:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/645709"], "description"=>"<p>Model objects and processes.</p>", "links"=>[], "tags"=>["objects"], "article_id"=>316199, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_objects_and_processes_/316199", "title"=>"Model objects and processes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:43:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/645631"], "description"=>"<p><b>Columns: Condition</b>: type of condition, injury or perturbation in clinical or experimental observations. <b>Subject</b>: human or animal. <b>Adhesion</b>: strength of adhesion (+ = normal, − = moderately impaired, − = severely impaired). <b>Effects</b>: RPE viability (+ = most RPE cells remain viable, − = some RPE cells die, − = most RPE cells die), CNV loci (− = no or low probability of initiation and progression, sub-RPE = Type 1, sub-retinal = Type 2, combined pattern = Type 3, * = no data presented/available). Simulation results (<b>boldface</b> words = model objects. <b>CNV</b> Type definitions: see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-t004\" target=\"_blank\">Table 4</a> and <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-t005\" target=\"_blank\">Table 5</a>. * = no data presented/available. See the <i><a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#s2\" target=\"_blank\">Results</a></i> and <i><a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#s3\" target=\"_blank\">Discussion</a></i> sections for details of simulation results).</p>", "links"=>[], "tags"=>["conditions", "adhesion", "correlations"], "article_id"=>316117, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pathological_conditions_and_injuries_their_effects_on_adhesion_and_their_correlations_with_CNV_/316117", "title"=>"Pathological conditions and injuries, their effects on adhesion and their correlations with CNV.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:41:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/645541"], "description"=>"<p>To simplify, we list only the adhesion scenarios most prone to each type of <b>CNV</b> progression dynamics. Key: <i>RRl</i>: <b>RPE-RPE labile adhesion</b> strength, <i>RRp</i>: <b>RPE-RPE plastic coupling</b> strength, <i>RBl</i>: <b>RPE-BrM labile adhesion</b> strength, <i>RBp</i>: <b>RPE-BrM plastic coupling</b> strength, <i>ROl</i>: <b>RPE-POS labile adhesion</b> strength. Scaled adhesion strengths: 3: normal, 2: moderately impaired, 1: severely impaired (weak), *: all strength levels. See <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi-1002440-t005\" target=\"_blank\">Table 5</a>, for nomenclature for CNV dynamics.</p>", "links"=>[], "tags"=>["classification", "cnv"], "article_id"=>316035, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t007", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Adhesion_scenario_classification_based_on_CNV_dynamics_/316035", "title"=>"Adhesion scenario classification based on CNV dynamics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:40:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/332625", "https://ndownloader.figshare.com/files/332682", "https://ndownloader.figshare.com/files/332741", "https://ndownloader.figshare.com/files/332830", "https://ndownloader.figshare.com/files/332887", "https://ndownloader.figshare.com/files/332952", "https://ndownloader.figshare.com/files/333007", "https://ndownloader.figshare.com/files/333065", "https://ndownloader.figshare.com/files/333131", "https://ndownloader.figshare.com/files/333202", "https://ndownloader.figshare.com/files/333282", "https://ndownloader.figshare.com/files/333474", "https://ndownloader.figshare.com/files/333562", "https://ndownloader.figshare.com/files/333745", "https://ndownloader.figshare.com/files/333807", "https://ndownloader.figshare.com/files/333914", "https://ndownloader.figshare.com/files/333932", "https://ndownloader.figshare.com/files/334016", "https://ndownloader.figshare.com/files/334088", "https://ndownloader.figshare.com/files/334168", "https://ndownloader.figshare.com/files/334252", "https://ndownloader.figshare.com/files/334321"], "description"=>"<div><p>Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in adults. In CNV, after choriocapillaries initially penetrate Bruch's membrane (BrM), invading vessels may regress or expand (CNV initiation). Next, during Early and Late CNV, the expanding vasculature usually spreads in one of three distinct patterns: in a layer between BrM and the retinal pigment epithelium (sub-RPE or Type 1 CNV), in a layer between the RPE and the photoreceptors (sub-retinal or Type 2 CNV) or in both loci simultaneously (combined pattern or Type 3 CNV). While most studies hypothesize that CNV primarily results from growth-factor effects or holes in BrM, our three-dimensional simulations of multi-cell model of the normal and pathological maculae recapitulate the three growth patterns, under the hypothesis that CNV results from combinations of impairment of: 1) RPE-RPE epithelial junctional adhesion, 2) Adhesion of the RPE basement membrane complex to BrM (RPE-BrM adhesion), and 3) Adhesion of the RPE to the photoreceptor outer segments (RPE-POS adhesion). Our key findings are that when an endothelial tip cell penetrates BrM: 1) RPE with normal epithelial junctions, basal attachment to BrM and apical attachment to POS resists CNV. 2) Small holes in BrM do not, by themselves, initiate CNV. 3) RPE with normal epithelial junctions and normal apical RPE-POS adhesion, but weak adhesion to BrM (e.g. due to lipid accumulation in BrM) results in Early sub-RPE CNV. 4) Normal adhesion of RBaM to BrM, but reduced apical RPE-POS or epithelial RPE-RPE adhesion (e.g. due to inflammation) results in Early sub-retinal CNV. 5) Simultaneous reduction in RPE-RPE epithelial binding and RPE-BrM adhesion results in either sub-RPE or sub-retinal CNV which often progresses to combined pattern CNV. These findings suggest that defects in adhesion dominate CNV initiation and progression.</p> </div>", "links"=>[], "tags"=>["adhesion", "failures", "choroidal", "neovascularization", "simulation"], "article_id"=>125679, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1002440.s001", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s002", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s003", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s004", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s005", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s006", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s007", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s008", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s009", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s010", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s011", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s012", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s013", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s014", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s015", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s016", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s017", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s018", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s019", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s020", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s021", "https://dx.doi.org/10.1371/journal.pcbi.1002440.s022"], "stats"=>{"downloads"=>28, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Adhesion_Failures_Determine_the_Pattern_of_Choroidal_Neovascularization_in_the_Eye_A_Computer_Simulation_Study/125679", "title"=>"Adhesion Failures Determine the Pattern of Choroidal Neovascularization in the Eye: A Computer Simulation Study", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-03 01:34:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/645831"], "description"=>"<p>More negative contact energies indicate stronger adhesive interactions. (-) denotes <b>labile adhesion</b> strengths not used in our simulations.</p>", "links"=>[], "tags"=>["adhesion", "strengths"], "article_id"=>316317, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.t011", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Labile_adhesion_strengths_contact_energies_/316317", "title"=>"Labile adhesion strengths (contact energies).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-03 01:45:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/644238"], "description"=>"<p>3D and 2D visualizations of a simulation replica exhibiting <b>P13 CNV</b> progression during one simulated <b>year</b> (<i>RRl</i> = 1, <i>RRp</i> = 3, <i>RBl</i> = 1, <i>RBp</i> = 2, <i>ROl</i> = 3) (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s007\" target=\"_blank\">Table S7</a>, adhesion scenario ID: 83, simulation ID: 515). Snapshots of the simulation at <b>months</b> 1 (A), 2 (B), 6 (C) and 12 (D). (A) <b>Stalk cells</b> (solid black arrow) invade the <b>sub-RPE</b> space through a hole in <b>BrM</b> (blue outline arrow) and form a capillary network. The <b>vascular cells</b> (black outline arrow) of the <b>CC</b> (red outline arrow) occupy the hole that the <b>tip cell</b> forms during the first 24 <b>hours</b> of the simulation, connecting the <b>CNV</b> capillaries to the <b>CC</b>. All <b>stalk cells</b> remain in the <b>sub-RPE</b> space during the first <b>month</b> of the simulation. (B) A few <b>stalk cells</b> (black outline arrow) cross the <b>RPE</b> into the <b>sub-retinal</b> space. (C) Additional <b>stalk cells</b> migrate into the <b>sub-retinal</b> space and form vascular cords (black outline arrow). (D) A 2D cross-section of the <b>retina</b> showing the hole in <b>BrM</b>. The <b>stalk cells</b> form a <b>sub-RPE</b> capillary network (black arrow) connected to a <b>sub-retinal</b> capillary network (black outline arrows). Two <b>vascular cells</b> connect the <b>CC</b> to the <b>CNV</b> capillaries through the hole in <b>BrM</b>. <b>Cell type</b> colors: 1) <b>POS</b> and <b>PIS</b>: light purple, 2) <b>RPE</b>: brown, 3) <b>Stalk cells</b>: green (<b>stalk cells</b> in the <b>sub-retinal</b> space have lighter shading), 4) <b>Vascular cells</b> (<b>CC</b>): red, 5) <b>BrM</b>: light blue. Scale bar ∼50 µm. We have rendered the boundaries of individual cells as semi-transparent membranes. <b>POS</b>, <b>PIS</b> and <b>RPE</b> cells are more transparent to show the underlying structures. See also <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s019\" target=\"_blank\">Video S3</a>.</p>", "links"=>[], "tags"=>["simulation", "replica", "sub-rpe", "cnv", "sub-retinal", "progression"], "article_id"=>314725, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g012", "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Snapshots_of_a_simulation_replica_showing_sub_RPE_CNV_to_sub_retinal_CNV_progression_P13_Progression_/314725", "title"=>"Snapshots of a simulation replica showing sub-RPE CNV to sub-retinal CNV progression (P13 Progression).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:18:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/643775"], "description"=>"<p>A) Total number of <b>stalk cells</b> vs. <b>time</b>. B) Total number of <b>stalk cells</b> confined in the <b>sub-RPE</b> space vs. <b>time</b>. C) Total number of <b>stalk cells</b> in contact with the <b>POS</b> (<b>stalk cells</b> in the <b>sub-retinal</b> space) vs. <b>time</b>. D) Total number of <b>RPE cells</b> vs. <b>time</b>. E) Total contact area between <b>RPE cells</b> and <b>BrM</b> vs. <b>time</b>. F) Total contact area between <b>POS </b><b>cells</b> and <b>BrM</b> vs. <b>time</b>. The different colors represent the results of 10 simulation replicas of the adhesion scenario (<i>RRl</i> = 3, <i>RRp</i> = 3, <i>RBl</i> = 1, <i>RBp</i> = 1, <i>ROl</i> = 1) (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002440#pcbi.1002440.s006\" target=\"_blank\">Table S6</a> adhesion scenario ID: 93). (A, B) <b>CNV</b> initiates in all replicas. By 3 <b>months</b>, most replicas form a developed <b>sub-RPE</b> capillary network composed of ∼20 to 40 <b>stalk cells</b> (∼1500 to 3000 <b>cells</b>/mm<sup>2</sup>). 8 replicas develop <b>Early Type 1</b> (<b>ET1</b>) <b>CNV</b>. Only one replica shows <b>Stable Type 1</b> (<b>S11</b>) <b>CNV</b>. Some <b>stalk cells</b> in most replicas die due to lack of <b>RPE-derived VEGF-A</b>. (C) Two replicas show <b>Stable Type 2</b> (<b>S22</b>) <b>CNV</b> (<b>Early</b> (<b>ET2</b>) and <b>Late Type 2</b> (<b>LT2</b>) <b>CNV</b>, black and dark red lines). 7 replicas show <b>LT2 CNV</b>. (D) The <b>RPE</b> remains viable in all replicas. (E) The contact area between the <b>RPE</b> and <b>BrM</b> decreases as either <b>ET1 CNV</b> or <b>S11 CNV</b> develops, and remains constant during <b>ET2 CNV</b>. <b>RPE</b> reattaches to <b>BrM</b> during <b>T12 CNV</b>. (F) The <b>POS</b> contacts <b>BrM</b> once, but the contacts area and duration are both small, so the <b>RPE</b> does not develop any persistent or substantial holes.</p>", "links"=>[], "tags"=>["sub-rpe", "sub-retinal", "translocation"], "article_id"=>314262, "categories"=>["Physics", "Medicine", "Information And Computing Sciences", "Cancer", "Immunology", "Physiology", "Biological Sciences", "Biophysics"], "users"=>["Abbas Shirinifard", "James Alexander Glazier", "Maciej Swat", "J. Scott Gens", "Fereydoon Family", "Yi Jiang", "Hans E. Grossniklaus"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002440.g009", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamics_of_sub_RPE_to_sub_retinal_translocation_T12_Translocation_/314262", "title"=>"Dynamics of sub-RPE to sub-retinal translocation (T12 Translocation).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-03 01:11:02"}

PMC Usage Stats | Further Information

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Relative Metric

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