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• W2096562496 abstract "Human immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. This increase in YKL-40 correlated with an increase in CSF viral load; it may therefore represent a biomarker for the development of encephalitis. Analysis of banked human CSF from human immunodeficiency virus-infected patients also demonstrated a correlation between YKL-40 concentration and CSF viral load. In vitro studies demonstrated increased YKL-40 expression and secretion by macrophages and microglia but not by neurons or astrocytes. We found that YKL40 displaced extracellular matrix-bound basic fibroblast growth factor (bFGF) as well as inhibited the mitogenic activity of both fibroblast growth factor receptor 1-expressing BaF3 cells and bFGF-induced axonal branching in hippocampal cultures. Taken together, these findings demonstrate that during lentiviral encephalitis, YKL-40 may interfere with the biological activity of bFGF and potentially of other heparin-binding growth factors and chemokines that can affect neuronal function or survival. Human immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. This increase in YKL-40 correlated with an increase in CSF viral load; it may therefore represent a biomarker for the development of encephalitis. Analysis of banked human CSF from human immunodeficiency virus-infected patients also demonstrated a correlation between YKL-40 concentration and CSF viral load. In vitro studies demonstrated increased YKL-40 expression and secretion by macrophages and microglia but not by neurons or astrocytes. We found that YKL40 displaced extracellular matrix-bound basic fibroblast growth factor (bFGF) as well as inhibited the mitogenic activity of both fibroblast growth factor receptor 1-expressing BaF3 cells and bFGF-induced axonal branching in hippocampal cultures. Taken together, these findings demonstrate that during lentiviral encephalitis, YKL-40 may interfere with the biological activity of bFGF and potentially of other heparin-binding growth factors and chemokines that can affect neuronal function or survival. Human immunodeficiency virus (HIV)-1-associated dementia [acquired immune deficiency syndrome (AIDS) dementia complex] is marked by deficits in motor control, cognition, and behavior.1Navia BA Jordan BD Price RW The AIDS dementia complex: I. Clinical features.Ann Neurol. 1986; 19: 517-524Crossref PubMed Scopus (1390) Google Scholar At autopsy, AIDS patients with dementia exhibit neuropathological changes including infiltration of mononuclear cells as shown by abundance of perivascular macrophages and microglial nodules, glial cell activation, loss of synaptic integrity, and loss of select neuronal populations consistent with HIV encephalitis (HIVE).2Wiley CA Achim C Human immunodeficiency virus encephalitis is the pathological correlate of dementia in acquired immunodeficiency syndrome.Ann Neurol. 1994; 36: 673-676Crossref PubMed Scopus (216) Google Scholar, 3Everall I Luthert P Lantos P A review of neuronal damage in human immunodeficiency virus infection: its assessment, possible mechanism and relationship to dementia.J Neuropathol Exp Neurol. 1993; 52: 561-566Crossref PubMed Scopus (165) Google Scholar The pathogenesis of HIVE is not fully understood. One possible mechanism of neurodegeneration is that the neuroinflammatory cascade initiated by infiltrating monocytes disrupts the neuronal extracellular matrix (ECM) that normally provides physical support as well as a repository of growth and survival factors.4Medina-Flores R Wang G Bissel SJ Murphey-Corb M Wiley CA Destruction of extracellular matrix proteoglycans is pervasive in simian retroviral neuroinfection.Neurobiol Dis. 2004; 16: 604-616Crossref PubMed Scopus (26) Google Scholar To elucidate mechanisms leading to neurodegeneration in lentiviral encephalitis, we used mass spectrometry-based proteomics to identify proteins that are differentially expressed in the cerebrospinal fluid (CSF) of simian immunodeficiency virus (SIV)-infected macaques that do or do not develop encephalitis. Among the proteins that showed differential up-regulation in the CSF of SIVE cases was YKL-40. It is not known which cell types synthesize and release YKL-40 protein within the central nervous system (CNS) or what role YKL-40 may play in the neuropathogenesis of SIVE. YKL-40 (HC-gp39, chitinase 3-like protein 1, CHI3L1, gp38k) is a member of the glycosyl hydrolase family 18 that lacks hydrolytic activity. From crystallographic analysis, YKL-40 has a carbohydrate-binding groove that can bind long or short oligosaccharides and it is speculated that it can also bind short chito-oligosacharides used as primers for the synthesis of hyaluronic acid. Although YKL-40 contains a consensus motif for heparin binding, there is no conclusive evidence that heparin binds to this site. The less sulfated heparan sulfates are more likely to bind to the oligosaccharide-binding groove of YKL-40.5Fusetti F Pijning T Kalk KH Bos E Dijkstra BW Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39.J Biol Chem. 2003; 278: 37753-37760Crossref PubMed Scopus (158) Google Scholar Recently, YKL-40 was found to bind to types I, II, and III collagen in an interaction that required recognition of the collagen triple helix.6Bigg HF Wait R Rowan AD Cawston TE The mammalian chitinase-like lectin, YKL-40, binds specifically to type I collagen and modulates the rate of type I collagen fibril formation.J Biol Chem. 2006; 281: 21082-21095Crossref PubMed Scopus (114) Google Scholar YKL-40 is expressed and released by chondrocytes, synovial cells, neutrophils, and macrophages in late stages of differentiation. YKL-40 is up-regulated in inflamed tissue in ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, scleroderma, and liver cirrhosis, as well as in cancers like melanoma, glioblastoma, and myeloid leukemia.7Kirkpatrick RB Emery JG Connor JR Dodds R Lysko PG Rosenberg M Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages.Exp Cell Res. 1997; 237: 46-54Crossref PubMed Scopus (107) Google Scholar, 8Rehli M Niller HH Ammon C Langmann S Schwarzfischer L Andreesen R Krause SW Transcriptional regulation of CHI3L1, a marker gene for late stages of macrophage differentiation.J Biol Chem. 2003; 278: 44058-44067Crossref PubMed Scopus (180) Google Scholar The physiological role of YKL-40 is not clear, and the receptor through which it exerts its biological activity is not known. It has been shown to stimulate growth of chondrocytes, synoviocytes, and fibroblasts through activation of ERK and Akt signaling, promote adhesion and migration of vascular endothelial cells, increase proteoglycan synthesis in chondrocytes, inhibit cellular responses to tumor necrosis factor-α and interleukin (IL)-1β in fibroblasts, and suppress the cytokine-induced secretion of matrix metalloproteinases 1, 3, and 13.9Recklies AD White C Ling H The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways.Biochem J. 2002; 365: 119-126Crossref PubMed Scopus (315) Google Scholar, 10Recklies AD Ling H White C Bernier SM Inflammatory cytokines induce production of CHI3L1 by articular chondrocytes.J Biol Chem. 2005; 280: 41213-41221Crossref PubMed Scopus (131) Google Scholar, 11Ling H Recklies AD The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha.Biochem J. 2004; 380: 651-659Crossref PubMed Scopus (192) Google Scholar, 12Nishikawa KC Millis AJ gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells.Exp Cell Res. 2003; 287: 79-87Crossref PubMed Scopus (167) Google Scholar Here, we report the identification of YKL-40 as a biomarker for SIVE. We show that YKL-40 is found in association with microglial nodules in SIVE and that it can bind to the ECM, modulating basic fibroblast growth factor (bFGF) biological activity. Purified YKL-40 was purchased from Quidel (San Diego, CA). Recombinant bFGF was purchased from R&D Systems (Minneapolis, MN) and iodinated bFGF was purchased from Perkin Elmer (Waltham, MA). Low-molecular weight heparin sodium salt from porcine intestinal mucosa and all other chemicals and media were purchased from Sigma (St. Louis, MO). All animals were housed and maintained according to strict standards of the Association for Assessment and Accreditation of Laboratory Animal Care, and experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee. Two groups of six and seven pigtailed macaques (Macaca nemestrina) varying in age from 74 to 93 months were intravenously infected with SIVDeltaB670 viral swarm (SIVdB670).13Zhang JY Martin LN Watson EA Montelaro RC West M Epstein L Murphey-Corb M Simian immunodeficiency virus/delta-induced immunodeficiency disease in rhesus monkeys: relation of antibody response and antigenemia.J Infect Dis. 1988; 158: 1277-1286Crossref PubMed Scopus (109) Google Scholar The length of infection varied from 42 to 287 days. Tissue samples from the first group of six macaques were available to measure YKL-40 before infection and at necropsy. Tissue samples from the second group of seven macaques were available to measure YKL-40 kinetics in CSF and plasma and compare them to viral load measurements. Plasma and CSF samples were drawn every 2 weeks. Macaques were sacrificed when moribund with AIDS or after 9 months of infection. Virions from 500 μl of CSF were pelleted by centrifuging at 17,000 rpm for 1 hour. For SIV quantitation, total RNA was extracted from the virus pellet using Trizol (Invitrogen, Carlsbad, CA). Real-time reverse transcriptase-polymerase chain reaction (PCR) was performed with 20 μl of each RNA sample as previously described.14Bissel SJ Wang G Ghosh M Reinhart TA Capuano III, S Stefano Cole K Murphey-Corb M Piatak Jr, M Lifson JD Wiley CA Macrophages relate presynaptic and postsynaptic damage in simian immunodeficiency virus encephalitis.Am J Pathol. 2002; 160: 927-941Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 15Fuller DH Rajakumar PA Wilson LA Trichel AM Fuller JT Shipley T Wu MS Weis K Rinaldo CR Haynes JR Murphey-Corb M Induction of mucosal protection against primary, heterologous simian immunodeficiency virus by a DNA vaccine.J Virol. 2002; 76: 3309-3317Crossref PubMed Scopus (104) Google Scholar Primers and probes were specific for the SIV U5/LTR region. For HIV quantitation, HIV CSF quantitation was performed as previously described.16Wiley CA Soontornniyomkij V Radhakrishnan L Masliah E Mellors J Hermann SA Dailey P Achim CL Distribution of brain HIV load in AIDS.Brain Pathol. 1998; 8: 277-284Crossref PubMed Scopus (217) Google Scholar Strong anion exchange surface Q10 ProteinChips (Ciphergen Biosystems, Inc., Palo Alto, CA) were equilibrated with 100 mmol/L HEPES, pH 7.3 (titrated with NH4OH). CSF samples from five SIVE macaques and three SIV without encephalitis macaques were first concentrated and desalted via C4 ZipTips (Millipore Corporation, Billerica, MA) and eluted onto the spots of the Q10 ProteinChip arrays using 70% acetonitrile and 0.1% trifluoroacetic acid. The arrays were incubated and washed in a ProteinChip bioprocessor (Ciphergen Biosystems, Inc.) and allowed to dry. A solution of sinapic acid (Fluka, Neu-Ulm, Germany) in 50% acetonitrile (ACN) and 0.3% trifluoroacetic acid was then added to each spot at 40°C. Spectra were acquired using the Ciphergen PBS IIC Chip Reader (Ciphergen Biosystems, Inc.). Low-mass (2 to 20 kDa) time-of-flight spectra were generated by averaging 195 ionizations per spot with a laser intensity of 175 and a detector sensitivity of 7, and high mass (20 to 160 kDa) spectra were acquired by using a laser intensity of 182 and a detector sensitivity of 8. The spectra were calibrated using All-in-1 protein standard (Ciphergen Biosystems, Inc.). Spectra were normalized using total ion current, baseline subtraction, and a normalization coefficient of 0.2. CSF samples were analyzed in duplicate within each experiment, and a standard CSF sample was used on each separate array to control for variability between chips. All experiments were performed three times. Univariate analysis was performed using the clustering feature of the ProteinChip software (Ciphergen Biosystems, Inc.). For anion exchange fractionation, pooled CSF (500 μl) was diluted with 1 mol/L Tris-HCl at pH 9.0 and then added by gravity flow to a Micro Bio-Spin chromatography column (Bio-Rad, Hercules, CA) that had been equilibrated with 50 mmol/L Tris-HCl at pH 9.0 and loaded with a slurry of Q HyperD F matrix (Ciphergen Biosystems). Fractions were collected with buffers containing 0.1% OGP detergent at varying pH: pH 9.0 (20 mmol/L Tris-HCl), pH 7.0 (50 mmol/L HEPES), pH 5.0 (100 mmol/L sodium acetate), pH 4.0 (100 mmol/L sodium acetate), and pH 3.0 (50 mmol/L sodium citrate). The column was then washed with 33% isopropanol, 17% ACN, and 0.1% trifluoroacetic acid to collect any proteins not eluted by pH. To determine which fraction contains the protein peak of interest, 2 μl of each fraction was applied to both Q10 and NP20 ProteinChip arrays (Ciphergen Biosystems) and analyzed by SELDI-TOF-MS for the presence of the 38.2-kDa peak present in SIVE animals. To determine the protein identity of the 38.2-kDa mass peak, proteins from the appropriate column fractions were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gel slices at ∼38 kDa were washed with NH4HCO3 and 50% ACN and dried in a speed vacuum. The gel pieces were incubated with 10 mmol/L dithiothreitol in 25 mmol/L NH4HCO3 at 56°C for 1 hour followed by 55 mmol/L iodoacetamide in 25 mmol/L NH4HCO3 at room temperature for 45 minutes in the dark. To dehydrate the protein, pellets were washed with 50 mmol/L NH4HCO3 followed by 25 mmol/L NH4HCO3 in 50% ACN and dried in a speed vacuum. The protein was rehydrated with 12.5 ng/μl sequence grade trypsin (Promega, Madison, WI) in 25 mmol/L NH4HCO3 for 10 minutes on ice and incubated at 37°C overnight. The aqueous phase was transferred into a clean siliconized tube, and the pellet was agitated with 50% ACN and 5% formic acid for 20 to 30 minutes. The supernatant was dried in a speed vacuum and resuspended in 50% high performance liquid chromatography-grade H2O/50% ACN/ 0.3% trifluoroacetic acid containing 4-hydroxy-α-cinnamic acid. Tryptic digests were applied for peptide sequencing using an Applied Biosystems 4700 proteomics analyzer (Applied Biosystems Inc., Foster City, CA). Peptide amino acid sequences were compared with Mascot protein databases with a peptide mass tolerance of ±50 ppm to confirm protein identity. YKL-40 levels were determined, in duplicate, for all of the CSF samples using the Metra YKL-40 ELISA kit from Quidel according to the manufacturer's protocol. Absorbance was measured using a microplate reader (Beckman Coulter, Fullerton, CA). Protein was extracted from 100 mg of middle frontal cortex as described previously.17Zhu JH Kulich SM Oury TD Chu CT Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases.Am J Pathol. 2002; 161: 2087-2098Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar In brief, samples were homogenized in extraction buffer (25 mmol/L Hepes, 50 mmol/L NaCl, 5 mmol/L ethylenediaminetetraacetic acid, pH 7.5) containing 10 μl/ml of Halt protease inhibitor cocktail (Pierce Biotechnology, Inc., Rockford, IL) using a Tissue-Tearor homogenizer (Biospec Products, Inc., Bartlesville, OK). Tissue extracts were centrifuged (two times), supernatants collected, and protein quantified using Coomassie Plus protein assay reagent (Pierce). For immunoblot analysis, 50 μg of protein from each sample was separated on 16% Novex Tris-glycine gels (Invitrogen), transferred to polyvinylidene difluoride membranes (Bio-Rad Laboratories), blocked with 5% milk or bovine serum albumin (Fisher Scientific, Pittsburgh, PA) in phosphate-buffered saline (PBS) containing Tween 20 (Bio-Rad), and then incubated with either anti-human chitinase 3-like 1 (goat polyclonal, 1:50; R&D Systems) or anti-β-actin (mouse monoclonal, 1:5000; Abcam, Cambridge, MA). Membranes were washed and incubated with species-specific secondary antibodies tagged with horseradish peroxidase (Pierce). A signal was visualized with a SuperSignal West Pico chemiluminescent substrate system (Pierce). Macrophage cultures were obtained from human peripheral blood mononuclear cells isolated from HIV and hepatitis B sero-negative buffy coats obtained from the Central Blood Bank (Pittsburgh, PA) using Cellgro lymphocyte separation medium (Mediatech Inc., Herndon, VA).18Repnik U Knezevic M Jeras M Simple and cost-effective isolation of monocytes from buffy coats.J Immunol Methods. 2003; 278: 283-292Crossref PubMed Scopus (130) Google Scholar CD14-positive cells were isolated by positive selection with magnetic beads conjugated to anti-CD14 (Miltenyi Biotech, Auburn, CA). Isolated monocytes were cultured in plates coated with poly-d-lysine (20 μg/ml) with the presence of M-CSF (100 ng/ml) for 7 days. More than 95% of the cells were macrophages and stained for CD68. Primary human embryonic mixed glial-neuronal cultures were obtained from human fetal tissue collected as per standards of the University of Pittsburgh ethics and biosafety guidelines and established protocols.19Barami K Grever WE Diaz FG Lyman WD An efficient method for the culturing and generation of neurons and astrocytes from second trimester human central nervous system tissue.Neurol Res. 2001; 23: 321-326Crossref PubMed Scopus (14) Google Scholar In brief, brain tissues from week 18 embryos were incubated with trypsin-ethylenediaminetetraacetic acid for 45 minutes. The tissue was triturated with a 10-ml pipette followed by a 5-ml pipette and then passed through 100 μm, 70 μm, and 40 μm meshes. The cells were cultured on Permanox chamber slides coated with 20 μg/ml of poly-d-lysine or in flasks with Dulbecco's modified Eagle's medium/F12 supplemented with 10% FBS (HyClone, Logan, UT). Microglia were separated from the mixed glial-neuronal cultures by shaking the cultures on an orbital shaker and collecting the detached cells. Purified astrocyte cultures were obtained by trypsinization of the mixed glial-neuronal cultures followed by two passages. Neurons were cultured at low density from embryonic day 18 (E18) Sprague Dawley rat hippocampi, as previously described.20Aridor M Guzik AK Bielli A Fish KN Endoplasmic reticulum export site formation and function in dendrites.J Neurosci. 2004; 24: 3770-3776Crossref PubMed Scopus (77) Google Scholar After 2 days in culture the cultures were transferred from the feeder layer and grown in serum-free N2.1 medium in the absence or presence of bFGF, heparin, and YKL-40. Formalin-fixed, paraffin-embedded sections were deparaffinized in Histoclear (National Diagnostics, Atlanta, GA) and rehydrated for 3 minutes in 100%, 95%, and 70% alcohol followed by PBS. Endogenous peroxidase activity was inactivated by immersing the section in 3% H2O2 for 20 minutes. Antigen unmasking was performed using antigen retrieval citra solution (BioGenex, San Ramon, CA). Tissue sections were blocked with protein blocking agent (Thermo, Pittsburgh, PA) for 20 minutes. Tissue cultures were fixed with 4% paraformaldehyde and sucrose for 20 minutes. YKL-40 staining was performed using goat anti-human chitinase 3-like antibody (1:1000, R&D Systems) as primary antibody followed by mouse anti-goat biotin-conjugated antibody (1:200; Jackson ImmunoResearch Laboratories, West Grove, PA) and detected by the tyramide amplification system (Perkin Elmer Life Sciences, Boston, MA). For double-label immunofluorescent antibodies: polyclonal rabbit anti-human GFAP (1:500; DAKO, Carpinteria, CA), monoclonal mouse anti-human MAP2 (1:1000; Sternberger Monoclonals, Inc., Lutherville, MD), and monoclonal mouse anti-human CD68 (1:100, DAKO) were used at stated dilutions without amplification. Dissociated primary hippocampal cultures were stained with monoclonal anti-β-tubulin isotype III (Sigma). All of the secondary antibodies were used from Jackson Laboratories (Bar Harbor, ME). Slides were mounted in gelvatol and analyzed by laser confocal microscopy (Carl Zeiss MicroImaging, Inc., Thornwood, NY). Antisense YKL-40 DNA templates containing the T7 promoter were generated by RT-PCR from cDNA prepared from primary pigtailed macaque primary macrophage culture. Two probes were made from different regions of the cDNA one corresponding to bases 19 to 241, forward primer, 5′-TTATACGACTCACTATAGGGAGAAAACAGGCTTTGTGGTCCTG-3′; reverse primer, 3′-CTGTGAGATGCCGTACGAGT-5′. The second probe was corresponding to bases 429 to 673, forward primer, 5′-TTATACGACTCACTATAGGGAGAACGGAGAGACAAGCAGCATT-3′; reverse primer, 3′-AGTATCAGGGGACAAGGCTC-5′. Sense probes were made by adding the T7 promoter sequence to the reverse primers. 35S-labeled RNA probes were generated using MAXIscript kit (Ambion, Austin, TX). Sections from SIVE cases in paraffin blocks were cut into serial sections of 6 μm, deparaffinated, and processed for immunohistochemistry and then to in situ hybridization as described previously.21Reinhart TA Fallert BA Pfeifer ME Sanghavi S Capuano III, S Rajakumar P Murphey-Corb M Day R Fuller CL Schaefer TM Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome.Blood. 2002; 99: 3119-3128Crossref PubMed Scopus (69) Google Scholar Bovine corneal endothelial cells (American Type Culture Collection, Manassas, VA) were maintained in high-glucose Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. For ECM preparation, the cells were plated at a density of 5000 cells per well in a 96-well plate in growth medium supplemented with 5% dextran. When the culture reached confluency, the cells were lysed with a solution containing 0.5% Triton X-100, 20 mmol/L NH4OH in PBS for 3 minutes at room temperature followed by four washes with PBS.22Benezra M Ishai-Michaeli R Ben-Sasson SA Vlodavsky I Structure-activity relationships of heparin-mimicking compounds in induction of bFGF release from extracellular matrix and inhibition of smooth muscle cell proliferation and heparanase activity.J Cell Physiol. 2002; 192: 276-285Crossref PubMed Scopus (26) Google Scholar ECM was incubated with iodinated bFGF (80,000 cpm/well, 3 hours, room temperature) in RPMI medium containing 0.2% gelatin, and unbound bFGF was removed by four washes with PBS containing 0.02% gelatin. The ECM was then incubated (3 hours, 37°C, PBS containing 0.02% gelatin) with increasing concentrations of heparin, bovine serum albumin, or YKL-40. Aliquots (0.25 ml) of the incubation medium were counted in a γ-counter to determine the amount of released iodinated material. The remaining ECM was washed twice. The percentage of released 125I-bFGF was calculated from the total ECM-associated radioactivity, solubilized with 1 mol/L NaOH, and counted in a γ-counter.22Benezra M Ishai-Michaeli R Ben-Sasson SA Vlodavsky I Structure-activity relationships of heparin-mimicking compounds in induction of bFGF release from extracellular matrix and inhibition of smooth muscle cell proliferation and heparanase activity.J Cell Physiol. 2002; 192: 276-285Crossref PubMed Scopus (26) Google Scholar Suspension cultures of FGFR1a (IIIc)-expressing BaF3 cells (a generous gift from professor D.M. Ornitz, Washington University, St. Louis, MO) were maintained in RPMI 1640 medium (Sigma) supplemented with 10% newborn calf serum (Sigma), 0.5 ng/ml murine recombinant IL-3 (Peprotech, Rocky Hill, NJ), 2 mmol/L l-glutamine, penicillin-streptomycin, 50 nmol/L β-mercaptoethanol, and G418 (600 μg/ml).23Ornitz DM Yayon A Flanagan JG Svahn CM Levi E Leder P Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells.Mol Cell Biol. 1992; 12: 240-247Crossref PubMed Scopus (558) Google Scholar For the mitogenic assay, the cells were washed three times with PBS and plated at a density of 30,000 cells per well in a 96-well plate in growth medium without IL-3 with the absence or presence of 5 ng/ml bFGF, 1 μg/ml heparan sulfate, and varying concentrations of YKL-40 for 48 hours. Heparan sulfate and YKL-40 were mixed and incubated on ice for 1 hour before their addition. Proliferation of the cells was evaluated using Promega's CellTiter kit.24Zhang X Ibrahimi OA Olsen SK Umemori H Mohammadi M Ornitz DM Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.J Biol Chem. 2006; 281: 15694-15700Crossref PubMed Scopus (887) Google Scholar Cells (14 to 48) bearing neurites were selected randomly in each group. Images were collected on an Olympus IX-81 microscope (Olympus America Inc., Melville, NY) equipped with a Hamamatsu C4742–98 charge-coupled device camera (Hamamatsu Corporation, Bridgewater, NJ) and a Ludl motorized XYZ stage (LEP Ltd., Hawthorne, NY). To quantify axonal characteristic five sequential slices taken 0.5 μm apart through the midplane of the axon were collected with a U plan S Apo 20 × 0.75 N.A. objective using SlideBook 4.1 Imaging software (Intelligent Imaging Innovations, Inc., Denver, CO). A projection image was made of the image stack and the reconstructed images were then delineated and the threshold set. The number of axonal branch points per neuron counted. Importantly, the person counting the branch points was blind to the treatment conditions. A one-way analysis of variance with posthoc comparison via Tukey's honestly significant difference was used to evaluate between group differences. In all cases, diagnostic statistics were used to confirm that the data were normally distributed. In the past few years, researchers have used proteomic analyses of CSF to discover specific biomarkers in neurological diseases such as amyotrophic lateral sclerosis,25Ranganathan S Williams E Ganchev P Gopalakrishnan V Lacomis D Urbinelli L Newhall K Cudkowicz ME Brown Jr, RH Bowser R Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis.J Neurochem. 2005; 95: 1461-1471Crossref PubMed Scopus (182) Google Scholar multiple sclerosis,26Dumont D Noben JP Raus J Stinissen P Robben J Proteomic analysis of cerebrospinal fluid from multiple sclerosis patients.Proteomics. 2004; 4: 2117-2124Crossref PubMed Scopus (140) Google Scholar Alzheimer's disease,27Choe LH Dutt MJ Relkin N Lee KH Studies of potential cerebrospinal fluid molecular markers for Alzheimer's disease.Electrophoresis. 2002; 23: 2247-2251Crossref PubMed Scopus (83) Google Scholar, 28Davidsson P Sjogren M Andreasen N Lindbjer M Nilsson CL Westman-Brinkmalm A Blennow K Studies of the pathophysiological mechanisms in frontotemporal dementia by proteome analysis of CSF proteins.Brain Res Mol Brain Res. 2002; 109: 128-133Crossref PubMed Scopus (91) Google Scholar, 29Tsuji T Shiozaki A Kohno R Yoshizato K Shimohama S Proteomic profiling and neurodegeneration in Alzheimer's disease.Neurochem Res. 2002; 27: 1245-1253Crossref PubMed Scopus (91) Google Scholar or primary brain tumors.30Zheng PP Luider TM Pieters R Avezaat CJ van den Bent MJ Sillevis Smitt PA Kros JM Identification of tumor-related proteins by proteomic analysis of cerebrospinal fluid from patients with primary brain tumors.J Neuropathol Exp Neurol. 2003; 62: 855-862PubMed Google Scholar Such biomarker discovery studies may reveal biochemical or cellular processes involved in the neurodegenerative disease, and proteins that may represent biomarkers for that disease. This information would be useful because diagnosing chronic encephalitis induced by lentiviruses in human and nonhuman macaques is particularly complicated by the subtlety of early neurological signs and symptoms and the potential for systemic immune compromise to manifest neurological findings. Recent studies examining CSF or monocyte-derived macrophages from HIV-infected patients have found spectral peak differences between demented and nondemented individuals.31Luo X Carlson KA Wojna V Mayo R Biskup TM Stoner J Anderson J Gendelman HE Melendez LM Macrophage proteomic fingerprinting predicts HIV-1-associated cognitive impairment.Neurology. 2003; 60: 1931-1937Crossref PubMed Scopus (66) Google Scholar, 32Wojna V Carlson KA Luo X Mayo R Melendez LM Kraiselburd E Gendelman HE Proteomic fingerprinting of human immunodeficiency virus type 1-associated dementia from patient monocyte-derived macrophages: a case study.J Neurovirol" @default.
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• W2096562496 date "2008-07-01" @default.
• W2096562496 modified "2023-10-16" @default.
• W2096562496 title "YKL-40, a Marker of Simian Immunodeficiency Virus Encephalitis, Modulates the Biological Activity of Basic Fibroblast Growth Factor" @default.
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