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Sample records for matrix metalloproteinase-7 promotes

  1. Active matrix metalloproteinase-7 is associated with invasion in buccal squamous cell carcinoma.

    PubMed

    Chuang, Hui-Ching; Su, Chih-Ying; Huang, Hsuang-Ying; Huang, Chao-Cheng; Chien, Chih-Yen; Du, Yung-Ying; Chuang, Jiin-Haur

    2008-12-01

    Protein microarrays have shown that matrix metalloproteinase-7 is upregulated in head and neck squamous cell carcinomas, but its role in local tissue invasion is still uncertain. We investigated the expression of active matrix metalloproteinase-7, using tissue microarray, immunohistochemistry, and western blotting, in oral tissues from 24 patients with buccal squamous cell carcinoma, and correlated the findings with clinicopathological features. Normal buccal tissue samples from the same patients, obtained at sites at least 1 cm from tumor tissue, served as normal controls. Total matrix metalloproteinase-7 was detected on western blots in 9 of 15 (60%) tumor tissue samples and in 2 of 15 (13%) normal mucosal samples; this difference was significant (P=0.008). Moreover, the active matrix metalloproteinase-7 was expressed only in eight of the nine (89%) tumor samples that expressed matrix metalloproteinase-7, and in none of the normal tissue samples, regardless of the expression status of the pro-matrix metalloproteinase-7. Immunostaining of matrix metalloproteinase-7 was observed histologically in both tumor and nonneoplastic epithelium, but immunostaining of active matrix metalloproteinase-7 was present only in tumor nests. Expression of active matrix metalloproteinase-7 was associated with larger tumor size (P=0.022) and was significantly higher in buccal squamous cell carcinoma with adjacent skin or bone invasion (P=0.036). In conclusion, active matrix metalloproteinase-7 expression was associated with more aggressive buccal squamous cell carcinomas. PMID:18931651

  2. Transforming growth factor-B1 and matrix metalloproteinase-7 promoter variants induce risk for Helicobacter pylori-associated gastric precancerous lesions.

    PubMed

    Achyut, B R; Ghoshal, Uday C; Moorchung, Nikhil; Mittal, Balraj

    2009-06-01

    The expression of growth factors, proteolytic enzymes, fibrogenic factors, and cytokines is altered in the Helicobacter pylori-infected gastric mucosa. Therefore, we aimed to evaluate the association of functional promoter variants of transforming growth factor (TGF)-B1 and matrix metalloproteinase (MMP)-7 genes with gastritis and gastric precancerous lesions. After upper gastrointestinal endoscopy, a total of 130 rapid urease test-positive patients with nonulcer dyspepsia were examined for H. pylori infection using modified Giemsa stain and IgG anti-CagA ELISA. All patients and 200 asymptomatic controls were genotyped for TGF-B1 (-509 C>T) and MMP-7 (-181 A>G) substitutions using PCR-RFLP. The genotype and allele frequencies of TGF-B1 and MMP-7 polymorphisms did not differ between patients and controls (p > 0.05). However, the CagA-positive patients with TGF-B1 -509 T allele had higher risk for gastric atrophy (p = 0.026, odds ratio [OR] = 2.38) and lymphoid follicle development (p = 0.028, OR = 2.29). In addition, CagA-positive patients carrying MMP-7 -181 G allele had risk for lymphoid follicle formation (p = 0.027, OR = 2.30). Thus, the present study revealed significant association of functional MMP-7 and TGF-B1 gene variants toward susceptibility to H. pylori-induced precancerous gastric lesions. PMID:19317620

  3. Charge-Triggered Membrane Insertion of Matrix Metalloproteinase-7, Supporter of Innate Immunity and Tumors.

    PubMed

    Prior, Stephen H; Fulcher, Yan G; Koppisetti, Rama K; Jurkevich, Alexander; Van Doren, Steven R

    2015-11-01

    Matrix metalloproteinase-7 (MMP-7) sheds signaling proteins from cell surfaces to activate bacterial killing, wound healing, and tumorigenesis. The mechanism targeting soluble MMP-7 to membranes has been investigated. Nuclear magnetic resonance structures of the zymogen, free and bound to membrane mimics without and with anionic lipid, reveal peripheral binding to bilayers through paramagnetic relaxation enhancements. Addition of cholesterol sulfate partially embeds the protease in the bilayer, restricts its diffusion, and tips the active site away from the bilayer. Its insertion of hydrophobic residues organizes the lipids, pushing the head groups and sterol sulfate outward toward the enzyme's positive charge on the periphery of the enlarged interface. Fluorescence probing demonstrates a similar mode of binding to plasma membranes and internalized vesicles of colon cancer cells. Binding of bilayered micelles induces allosteric activation and conformational change in the auto-inhibitory peptide and the adjacent scissile site, illustrating a potential intermediate in the activation of the zymogen. PMID:26439767

  4. Matrilysin (Matrix Metalloproteinase-7) Mediates E-Cadherin Ectodomain Shedding in Injured Lung Epithelium

    PubMed Central

    McGuire, John K.; Li, Qinglang; Parks, William C.

    2003-01-01

    Matrilysin (matrix metalloproteinase-7) is highly expressed in lungs of patients with pulmonary fibrosis and other conditions associated with airway and alveolar injury. Although matrilysin is required for closure of epithelial wounds ex vivo, the mechanism of its action in repair is unknown. We demonstrate that matrilysin mediates shedding of E-cadherin ectodomain from injured lung epithelium both in vitro and in vivo. In alveolar-like epithelial cells, transfection of activated matrilysin resulted in shedding of E-cadherin and accelerated cell migration. In vivo, matrilysin co-localized with E-cadherin at the basolateral surfaces of migrating tracheal epithelium, and the reorganization of cell-cell junctions seen in wild-type injured tissue was absent in matrilysin-null samples. E-cadherin ectodomain was shed into the bronchoalveolar lavage fluid of bleomycin-injured wild-type mice, but was not shed in matrilysin-null mice. These findings identify E-cadherin as a novel substrate for matrilysin and indicate that shedding of E-cadherin ectodomain is required for epithelial repair. PMID:12759241

  5. Proliferative effects of apical, but not basal, matrix metalloproteinase-7 activity in polarized MDCK cells

    SciTech Connect

    Harrell, Permila C.; McCawley, Lisa J.; Fingleton, Barbara; McIntyre, J. Oliver; Matrisian, Lynn M. . E-mail: lynn.matrisian@vanderbilt.edu

    2005-02-15

    Matrix metalloproteinase-7 (MMP-7) is primarily expressed in glandular epithelium. Therefore, its mechanism of action may be influenced by its regulated vectorial release to either the apical and/or basolateral compartments, where it would act on its various substrates. To gain a better understanding of where MMP-7 is released in polarized epithelium, we have analyzed its pattern of secretion in polarized MDCK cells expressing stably transfected human MMP-7 (MDCK-MMP-7), and HCA-7 and Caco2 human colon cancer cell lines. In all cell lines, latent MMP-7 was secreted to both cellular compartments, but was 1.5- to 3-fold more abundant in the basolateral compartment as compared to the apical. However, studies in the MDCK system demonstrated that MMP-7 activity was 2-fold greater in the apical compartment of MDCK-MMP-7{sup HIGH}-polarized monolayers, which suggests the apical co-release of an MMP-7 activator. In functional assays, MMP-7 over-expression increased cell saturation density as a result of increased cell proliferation with no effect on apoptosis. Apical MMP-7 activity was shown to be responsible for the proliferative effect, which occurred, as demonstrated by media transfer experiments, through cleavage of an apical substrate and not through the generation of a soluble factor. Taken together, our findings demonstrate the importance of MMP-7 secretion in relation to its mechanism of action when expressed in a polarized epithelium.

  6. The matrix metalloproteinase-7 regulates the extracellular shedding of syndecan-2 from colon cancer cells.

    PubMed

    Choi, Sojoong; Kim, Jin-Yung; Park, Jun Hyoung; Lee, Seung-Teak; Han, Inn-Oc; Oh, Eok-Soo

    2012-01-27

    The cell surface heparan sulfate proteoglycan syndecan-2 regulates the activation of matrix metalloproteinase-7 (MMP-7) as a docking receptor. Here, we demonstrate the role of MMP-7 on syndecan-2 shedding in colon cancer cells. Western blot analysis showed that shed syndecan-2 was found in the culture media from various colon cancer cells. Overexpression of MMP-7 enhanced syndecan-2 shedding, whereas the opposite was true when MMP-7 levels were knocked-down using small inhibitory RNAs. Consistently, HT29 cells treated with MMP-7, but neither MMP-2 nor MMP-9, showed increased shed syndecan-2 in a time- and concentration-dependent manner. Furthermore, MALDI-TOF MS analysis and N-terminal amino acid sequencing revealed that MMP-7 cleaved both recombinant syndecan-2 and an endogenously glycosylated syndecan-2 ectodomain in the N-terminus at Leu(149) residue in vitro. Taken together, the data suggest that MMP-7 directly mediates shedding of syndecan-2 from colon cancer cells. PMID:22227189

  7. Prognostic significance of matrix metalloproteinase 7 immunohistochemical expression in colorectal cancer: a meta-analysis

    PubMed Central

    Chen, Haiyan; Hu, Yeting; Xiang, Weibo; Cai, Yibo; Wang, Zhanhuai; Xiao, Qian; Liu, Yue; Li, Qiong; Ding, Kefeng

    2015-01-01

    Matrix metalloproteinase 7 (MMP-7) was speculated to have a key role in the development and progression of human cancer. Considerable studies investigated the relationship between its expression and survival in colorectal cancer (CRC), but inconsistent results were obtained. The clinical significance of MMP-7 overexpression in CRC remains controversial. Therefore, in this article, we conducted a meta-analysis to analyze the prognostic value of MMP-7 in CRC. We searched studies in PubMed, Medline, and Web of Science databases until August 2014 to find relevant studies. A total of six high-quality studies met the inclusion criteria and 1631 patients were included in our study. Combined hazard ratios (HRs) suggested that MMP-7 overexpression had an unfavorable impact on overall survival (HR = 1.83, 95% CI: 1.24-2.71). Subgroup and sensitivity analyses further validated the role of MMP-7 as a predictor for prognosis. In conclusion, MMP-7 overexpression detected by immunohistochemistry indicated worse prognosis in CRC and may help to guide clinical therapy. PMID:26064217

  8. Estrogen Decrease in Tight Junctional Resistance Involves Matrix-Metalloproteinase-7-Mediated Remodeling of Occludin

    PubMed Central

    Gorodeski, George I.

    2008-01-01

    Estrogen modulates tight junctional resistance through estrogen receptor-α-mediated remodeling of occludin. The objective of the study was to understand the mechanisms involved. Experiments using human normal vaginal-cervical epithelial cells showed that human normal vaginal-cervical epithelial cells secrete constitutively matrix-metalloproteinase-7 (MMP-7) into the luminal solution and that MMP-7 is necessary and sufficient to produce estrogen decrease of tight junctional resistance and remodeling of occludin. Treatment with estrogen stimulated activation of the pro-MMP-7 intracellularly and augmented secretion of the activated MMP-7 form. Steady-state levels of MMP-7 mRNA and protein were not affected by estrogen. Estrogen modulated phosphorylation of the MMP-7, but the changes were most likely secondary to changes in cellular MMP-7 mass. Estrogen increased coimmunoreactivity of MMP-7 with the Golgi protein GPP130. Tunicamycin and brefeldin-A had no effect on cellular MMP-7 but monensin (inhibitor of Golgi traffic) blocked estrogen effects, suggesting estrogen site of action is at the Golgi system. Estrogen increased generalized secretory activity, including of luminal exocytosis of polycarbohydrates. However, estrogen increased coimmunoreactivity of MMP-7 with synaptosomal-associated protein of 25 kDa in apical membranes, suggesting soluble N-ethylmaleimide sensitive fusion factor attachment protein receptor-facilitated exocytosis of MMP-7. Treatment with the vesicular-ATPase inhibitor bafilomycin A1 inhibited activation of MMP-7. These data suggest that estrogen up-regulates activation of the MMP-7 intracellularly, at the level of Golgi, and augments secretion of activated MMP-7 through soluble N-ethylmaleimide sensitive fusion factor attachment protein receptor-dependent exocytosis. On the other hand, estrogen acidification of the luminal solution would tend to alkalinize exocytotic vesicles and may lead to decreased activation of the MMP-7. These mechanisms

  9. Differential Processing of α- and β-Defensin Precursors by Matrix Metalloproteinase-7 (MMP-7)*

    PubMed Central

    Wilson, Carole L.; Schmidt, Amy P.; Pirilä, Emma; Valore, Erika V.; Ferri, Nicola; Sorsa, Timo; Ganz, Tomas; Parks, William C.

    2009-01-01

    Proteolytic processing of defensins is a critical mode of posttranslational regulation of peptide activity. Because mouse α-defensin precursors are cleaved and activated by matrix metalloproteinase-7 (MMP-7), we determined if additional defensin molecules, namely human neutrophil defensin pro-HNP-1 and β-defensins, are targets for MMP-7. We found that MMP-7 cleaves within the pro-domain of the HNP-1 precursor, a reaction that does not generate the mature peptide but produces a 59-amino acid intermediate. This intermediate, which retains the carboxyl-terminal end of the pro-domain, had antimicrobial activity, indicating that the residues important for masking defensin activity reside in the amino terminus of this domain. Mature HNP-1 was resistant to processing by MMP-7 unless the peptide was reduced and alkylated, demonstrating that only the pro-domain of α-defensins is normally accessible for cleavage by this enzyme. From the 47-residue HBD-1 precursor, MMP-7 catalyzed removal of 6 amino acids from the amino terminus. Neither a 39-residue intermediate form of HBD-1 nor the mature 36-residue form of HBD-1 was cleaved by MMP-7. In addition, both pro-HBD-2, with its shorter amino-terminal extension, and pro-HBD-3 were resistant to MMP-7. However, human and mouse β-defensin precursors that lack disulfide bonding contain a cryptic MMP-7-sensitive site within the mature peptide moiety. These findings support and extend accumulating evidence that the native three-dimensional structure of both α- and β-defensins protects the mature peptides against proteolytic processing by MMP-7. We also conclude that sites for MMP-7 cleavage are more common at the amino termini of α-defensin rather than β-defensin precursors, and that catalysis at these sites in α-defensin pro-domains results in acquisition of defensin activity. PMID:19181662

  10. The Matrix Metalloproteinase-7 Polymorphism Rs10895304 Is Associated With Increased Recurrence Risk in Patients With Clinically Localized Prostate Cancer

    SciTech Connect

    Jaboin, Jerry J.; Hwang, Misun; Lopater, Zachary; Chen Heidi; Ray, Geoffrey L.; Perez, Carmen; Cai Qiuyin; Wills, Marcia L.; Lu Bo

    2011-04-01

    Purpose: To evaluate whether selected high-risk matrix metalloproteinase-7 single nucleotide polymorphisms influence clinicopathologic outcomes in patients with early-stage prostate cancer. Methods and Materials: Two hundred twelve prostate cancer patients treated with radical prostatectomy were evaluated with a median follow-up of 9.8 years. Genotyping was performed using hybridization with custom-designed allele-specific probes. Three single nucleotide polymorphisms within the matrix metalloproteinase-7 gene were assessed with respect to age at diagnosis, margin status, extracapsular extension, lymph node involvement, recurrence-free survival, and overall survival in paraffin-embedded prostate tissue specimens from patients with early-stage prostate cancer who underwent radical prostatectomy. Results: Rs10895304 was the sole significant polymorphism. The A/G genotype of rs10895304 had a statistically significant association with recurrence-free survival in postprostatectomy patients (p = 0.0061, log-rank test). The frequency of the risk-reducing genotype (A/A) was 74%, whereas that of the risk-enhancing genotypes (A/G and G/G) were 20% and 6%, respectively. Multivariable Cox regression analyses detected a significant association between rs10895304 and recurrences after adjustment for known prognostic factors. The G allele of this polymorphism was associated with increased risk of prostate cancer recurrence (adjusted hazards ratio, 3.375; 95% confidence interval 1.567-7.269; p < 0.001). The other assayed polymorphisms were not significant, and no correlations were made to other clinical variables. Conclusions: The A/G genotype of rs10895304 is predictive of decreased recurrence-free survival in patients with clinically localized prostate cancer. Our data suggest that for this subset of patients, prostatectomy alone may not be adequate for local control. This is a novel and relevant marker that should be evaluated for improved risk stratification of patients who

  11. Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

    PubMed Central

    Abbas, Azhar; Aukrust, Pål; Russell, David; Krohg-Sørensen, Kirsten; Almås, Trine; Bundgaard, Dorte; Bjerkeli, Vigdis; Sagen, Ellen Lund; Michelsen, Annika E.; Dahl, Tuva B.; Holm, Sverre; Ueland, Thor

    2014-01-01

    Background Atherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process. Methods Plasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50–69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined. Results Our major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality. Conclusion Our findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms. PMID:24400123

  12. Roles of osteopontin and matrix metalloproteinase-7 in occurrence, progression, and prognosis of nonsmall cell lung cancer

    PubMed Central

    Sun, Ying; Li, Dan; Lv, Xiao-Hong; Hua, Shu-Cheng; Han, Ji-Chang; Xu, Feng; Li, Xian-Dong

    2015-01-01

    Background: This study detected osteopontin (OPN) and matrix metalloproteinase-7 (MMP-7) expressions to explore the roles of OPN and MMP-7 in the occurrence, progression, and prognosis of nonsmall cell lung cancer (NSCLC). Materials and Methods: A retrospective study was conducted on NSCLC tissues (n = 152; case group) and adjacent nonneoplastic lung parenchyma (adjacent to tumor >5 cm; n = 152; control group) collected from 152 NSCLC patients. The protein expressions of OPN and MMP-7 were detected by immunohistochemistry. OPN and MMP-7 messenger RNA (mRNA) expressions were detected by reverse transcription polymerase chain reaction (RT-PCR). Results: The protein and mRNA expressions of OPN and MMP-7 in NSCLC tissues were evidently higher than those in adjacent nonneoplastic lung parenchyma (all P < 0.05). OPN protein and mRNA expression were associated with the degree of differentiation, tumor node metastasis (TNM) staging, and lymph node metastasis in NSCLC (all P < 0.05). MMP-7 protein expression was associated with TNM staging and lymph node metastasis (both P < 0.05) while MMP-7 mRNA expression was associated with the degree of differentiation, TNM staging, and lymph node metastasis (all P < 0.05). A significantly positive relativity was revealed between OPN expression and MMP-7 expression (protein: r = 0.789, P < 0.001; mRNA: r = 0.377, P < 0.001). Lymph node metastasis, TNM staging, OPN, and MMP-7 protein expressions were independent risk factors for the prognosis of NSCLC (all P < 0.05). Conclusion: High MMP-7 and OPN protein expressions are closely related to the occurrence, progression, and prognosis of NSCLC, and can be served as unfavorable prognostic factors for NSCLC. PMID:26958047

  13. Tauroursodeoxycholic acid reduces the invasion of MDA-MB-231 cells by modulating matrix metalloproteinases 7 and 13

    PubMed Central

    Park, Ga-Young; Han, Yu Kyeong; Han, Jeong Yoon; Lee, Chang Geun

    2016-01-01

    Tauroursodeoxycholic acid (TUDCA) is a conjugated form of UDCA that modulates several signaling pathways and acts as a chemical chaperone to relieve endoplasmic reticulum (ER) stress. The present study showed that TUDCA reduced the invasion of the MDA-MB-231 metastatic breast cancer cell line under normoxic and hypoxic conditions using an in vitro invasion assay. Quantitative polymerase chain reaction assay revealed that the reduced invasion following TUDCA treatment was associated with a decreased expression of matrix metalloproteinase (MMP)-7 and −13, which play important roles in invasion and metastasis. Inhibitors and short hairpin RNAs were used to show that the effect of TUDCA in the reduction of invasion appeared to be dependent on the protein kinase RNA-like ER kinase pathway, a downstream ER stress signaling pathway. Thus, TUDCA is a candidate anti-metastatic agent to target the ER stress pathway. PMID:27602168

  14. Matrilysin/Matrix Metalloproteinase-7(MMP7) Cleavage of Perlecan/HSPG2 Creates A Molecular Switch to Alter Prostate Cancer Cell Behavior

    PubMed Central

    Grindel, B.J.; Martinez, J.R.; Pennington, C.L.; Muldoon, M.; Stave, J.; Chung, L.W.; Farach-Carson, M.C.

    2015-01-01

    Perlecan/HSPG2, a large heparan sulfate (HS) proteoglycan, normally is expressed in the basement membrane (BM) underlying epithelial and endothelial cells. During prostate cancer (PCa) cell invasion, a variety of proteolytic enzymes are expressed that digest BM components including perlecan. An enzyme upregulated in invasive PCa cells, matrilysin/matrix metalloproteinase-7 (MMP-7), was examined as a candidate for perlecan proteolysis both in silico and in vitro. Purified perlecan showed high sensitivity to MMP-7 digestion even when fully decorated with HS or when presented in native context connected with other BM proteins. In both conditions, MMP-7 produced discrete perlecan fragments corresponding to an origin in immunoglobulin (Ig) repeat region domain IV. While not predicted by in silico analysis, MMP-7 cleaved every subpart of recombinantly generated perlecan domain IV. Other enzymes relevant to PCa that were tested had limited ability to cleave perlecan including prostate specific antigen, hepsin, or fibroblast activation protein α. A long C-terminal portion of perlecan domain IV, Dm IV-3, induced a strong clustering phenotype in the metastatic PCa cell lines, PC-3 and C4-2. MMP-7 digestion of Dm IV-3 reverses the clustering effect into one favoring cell dispersion. In a C4-2 Transwell® invasion assay, perlecan-rich human BM extract that was pre-digested with MMP-7 showed loss of barrier function and permitted a greater level of cell penetration than untreated BM extract. We conclude that enzymatic processing of perlecan in the BM or territorial matrix by MMP-7 as occurs in the invasive tumor microenvironment acts as a molecular switch to alter PCa cell behavior and favor cell dispersion and invasiveness. PMID:24833109

  15. Association of Matrix Metalloproteinases -7, -8 and -9 and TIMP -1 with Disease Severity in Acute Pancreatitis. A Cohort Study

    PubMed Central

    Nukarinen, Eija; Lindström, Outi; Kuuliala, Krista; Kylänpää, Leena; Pettilä, Ville; Puolakkainen, Pauli; Kuuliala, Antti; Hämäläinen, Mari; Moilanen, Eeva; Repo, Heikki; Hästbacka, Johanna

    2016-01-01

    Objectives Several biomarkers for early detection of severe acute pancreatitis (SAP) have been presented. Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are released early in inflammation. We aimed to assess levels of MMP-7, -8, -9 and TIMP-1 in acute pancreatitis (AP) and explore their ability to detect disease severity. Our second aim was to find an association between MMPs, TIMP and creatinine. Methods We collected plasma samples for MMP-7, -8, -9 and TIMP-1 analyses from 176 patients presenting within 96 h from onset of acute pancreatitis (AP) symptoms. We used samples from 32 control subjects as comparison. The revised Atlanta Classification was utilised to assess severity of disease. Receiver operating characteristic curve analysis and Spearman´s Rho-test were utilised for statistical calculations. Results Compared with controls, patients showed higher levels of all studied markers. MMP-8 was higher in moderately severe AP than in mild AP (p = 0.005) and MMP-8, -9 and TIMP-1 were higher in severe than in mild AP (p<0.001, p = 0.005 and p = 0.019). MMP-8 detected SAP with an AUC of 0.939 [95% CI 0.894–0.984], LR+ 9.03 [5.30–15.39]. MMP-8, -9 and TIMP-1 failed to discern moderately severe AP from SAP. MMP-7 was not different between patient groups. MMP-7 and TIMP-1 correlated weakly with creatinine (Rho = 0.221 and 0.243). MMP-8 might be a useful biomarker in early detection of SAP. PMID:27561093

  16. Measurement of serum carcinoembryonic antigen, carbohydrate antigen 19-9, cytokeratin-19 fragment and matrix metalloproteinase-7 for detecting cholangiocarcinoma: a preliminary case-control study.

    PubMed

    Lumachi, Franco; Lo Re, Giovanni; Tozzoli, Renato; D'Aurizio, Federica; Facomer, Flavio; Chiara, Giordano B; Basso, Stefano M M

    2014-11-01

    Cholangiocarcinoma is a malignant tumor of the liver arising from the bile duct epithelium, accounting for 10-25% of all primary hepatic cancers. The clinical presentation of this tumor is not specific and the diagnosis of early cholangiocarcinoma is difficult, especially in patients with other biliary diseases. Measurement of serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) are commonly used to monitor response to therapy, but are also useful for confirming the presence of a cholangiocarcinoma. In this setting, other biomarkers have been previously tested, including cytokeratin-19 fragment (CYFRA 21-1) and the matrix metalloproteinase-7 (MMP7). The purpose of this retrospective study was to determine the clinical usefulness of the assay of serum CEA, CA 19-9, CYFRA 21-1 and MMP7, individually and together, as tumor markers for the diagnosis of cholangiocarcinoma. Twenty-four patients (14 men, 10 women, 62.6±8.2 years of age) with histologically-confirmed cholangiocarcinoma (cases) and 25 age- and sex-matched patients with benign liver disease (controls) underwent measurement of these biomarkers. The mean values of all serum markers of patients with cholangiocarcinoma were significantly higher (p<0.01) than that of the controls. No correlation was found between serum tumor markers and total bilirubin, aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The sensitivity, specificity and accuracy were: CEA: 52%, 55%, and 58%; CA 19-9: 74%, 82% and 78%; CYFRA 21-1: 76%, 79% and 78%; MMP7: 78%, 77% and 80%, respectively. The combination of all serum markers afforded 92.0% sensitivity and 96% specificity in detecting cholangiocarcinoma, showing the highest diagnostic accuracy (94%). In conclusion, our preliminary results suggest that the measurement of all four biomarkers together can help in the early detection of cholangiocarcinoma. PMID:25368272

  17. Development of a novel fluorogenic proteolytic beacon for in vivo detection and imaging of tumour-associated matrix metalloproteinase-7 activity.

    PubMed Central

    McIntyre, J Oliver; Fingleton, Barbara; Wells, K Sam; Piston, David W; Lynch, Conor C; Gautam, Shiva; Matrisian, Lynn M

    2004-01-01

    The present study describes the in vivo detection and imaging of tumour-associated MMP-7 (matrix metalloproteinase-7 or matrilysin) activity using a novel polymer-based fluorogenic substrate PB-M7VIS, which serves as a selective 'proteolytic beacon' (PB) for this metalloproteinase. PB-M7VIS is built on a PAMAM (polyamido amino) dendrimer core of 14.2 kDa, covalently coupled with an Fl (fluorescein)-labelled peptide Fl(AHX)RPLALWRS(AHX)C (where AHX stands for aminohexanoic acid) and with TMR (tetramethylrhodamine). PB-M7VIS is efficiently and selectively cleaved by MMP-7 with a k (cat)/ K (m) value of 1.9x10(5) M(-1).s(-1) as measured by the rate of increase in Fl fluorescence (up to 17-fold for the cleavage of an optimized PB-M7VIS) with minimal change in the TMR fluorescence. The K (m) value for PB-M7VIS is approx. 0.5 microM, which is approx. two orders of magnitude lower when compared with that for an analogous soluble peptide, indicating efficient interaction of MMP-7 with the synthetic polymeric substrate. With MMP-2 or -3, the k (cat)/ K (m) value for PB-M7VIS is approx. 56- or 13-fold lower respectively, when compared with MMP-7. In PB-M7VIS, Fl(AHX)RPLALWRS(AHX)C is a selective optical sensor of MMP-7 activity and TMR serves to detect both the uncleaved and cleaved reagents. Each of these can be visualized as subcutaneous fluorescent phantoms in a mouse and optically discriminated based on the ratio of green/red (Fl/TMR) fluorescence. The in vivo specificity of PB-M7VIS was tested in a mouse xenograft model. Intravenous administration of PB-M7VIS gave significantly enhanced Fl fluorescence from MMP-7-positive tumours, but not from control tumours ( P <0.0001), both originally derived from SW480 human colon cancer cells. Prior systemic treatment of the tumour-bearing mice with an MMP inhibitor BB-94 ([4-( N -hydroxyamino)-2 R -isobutyl-3 S -(thienylthiomethyl)-succinyl]-L-phenylalanine- N -methylamide), markedly decreased the Fl fluorescence over the MMP-7

  18. Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis

    PubMed Central

    Kim, Jin-Hong; Lee, Gyuseok; Won, Yoonkyung; Lee, Minju; Kwak, Ji-Sun; Chun, Churl-Hong; Chun, Jang-Soo

    2015-01-01

    Osteoarthritis (OA) is characterized by impairment of the load-bearing function of articular cartilage. OA cartilage matrix undergoes extensive biophysical remodeling characterized by decreased compliance. In this study, we elucidate the mechanistic origin of matrix remodeling and the downstream mechanotransduction pathway and further demonstrate an active role of this mechanism in OA pathogenesis. Aging and mechanical stress, the two major risk factors of OA, promote cartilage matrix stiffening through the accumulation of advanced glycation end-products and up-regulation of the collagen cross-linking enzyme lysyl oxidase, respectively. Increasing matrix stiffness substantially disrupts the homeostatic balance between chondrocyte catabolism and anabolism via the Rho–Rho kinase–myosin light chain axis, consequently eliciting OA pathogenesis in mice. Experimental enhancement of nonenzymatic or enzymatic matrix cross-linking augments surgically induced OA pathogenesis in mice, and suppressing these events effectively inhibits OA with concomitant modulation of matrix degrading enzymes. Based on these findings, we propose a central role of matrix-mediated mechanotransduction in OA pathogenesis. PMID:26170306

  19. Serum Matrix Metalloproteinase-7 is an independent prognostic biomarker in advanced bladder cancer

    PubMed Central

    2014-01-01

    Background Urine markers have been studied extensively but there is a lack of blood prognostic markers in bladder cancer. MMP-7 is produced by stromal cells and by tumor cells and is overexpressed in a variety of epithelial and mesenchymal tumors. In this study, we assessed with an immunoassay we developed, the prognostic value of serum MMP-7 in a series of patients with advanced bladder cancer. Methods Serum samples were collected from 56 patients with advanced bladder cancer who were treated at the Montpellier Cancer Institute between March 2003 and December 2004. MMP-7 was quantified in serum samples by using a homogeneous sandwich fluoroimmunoassay we developed based on the time resolved amplified cryptate emission (TRACE) technology. Results The median overall survival of the study population was 2.2 years (95% CI, 1.4 to 3.0) with 1- and 5-year survival rates of 73% (95% CI, 59% to 82%) and 25% (95% CI, 14% to 37%), respectively. High MMP-7 serum levels were associated with poor survival. Using a cut-off value of 11.5 ng/mL, the median overall survival was 3.0 years (95% CI, 1.5 to 5.1) for patients with MMP-7 serum level <11.5 ng/mL and 1.3 years (95% CI, 0.8 to 2.5) for patients with serum level ?11.5 ng/mL. Multivariate analysis identified high MMP-7 serum concentration as an independent prognostic factor for survival in patients with advanced bladder cancer (R?=?2.1, 95% CI, 1.1 to 4.4). Conclusions Our results show that the MMP-7 serum concentration is an independent prognostic factor in patients with locally advanced and or metastatic bladder cancer. PMID:25984271

  20. Inhibitory effects of green tea catechins on the activity of human matrix metalloproteinase 7 (matrilysin).

    PubMed

    Oneda, Hiroshi; Shiihara, Misa; Inouye, Kuniyo

    2003-05-01

    Inhibitory effects of green tea catechins and their derivatives on the matrilysin-catalyzed hydrolysis of a synthetic substrate, (7-methoxycoumarin-4-yl)acetyl-L-Pro-L-Leu-Gly-L-Leu-[N(3)-(2,4-dinitrophenyl)-L-2,3-diamino-propionyl]-L-Ala-L-Arg-NH(2) [MOCAc-PLGL(Dpa)AR], were examined. The 10 catechins examined were classified into three groups according to their inhibition potency. Catechins with a galloyl group at the 3 position, including a major component of green tea catechin, (-)-epigallo-3-catechin gallate [(-)-EGCG], were the most potent inhibitors and inhibited matrilysin in a non-competitive manner with K(i) values of 0.47-1.65 micro M. The inhibitory potency of (-)-EGCG was not influenced by the presence of an inhibitor, ZnCl(2), suggesting that the inhibitions of matrilysin by (-)-EGCG and by ZnCl(2) might be independent of each other. The inhibitory effects of green tea catechins suggest that a high intake of green tea might be effective for the prevention of tumor metastasis and invasion in which matrilysin is concerned. PMID:12801907

  1. Neoplastic extracellular matrix environment promotes cancer invasion in vitro.

    PubMed

    Sundquist, Elias; Renko, Outi; Salo, Sirpa; Magga, Johanna; Cervigne, Nilva K; Nyberg, Pia; Risteli, Juha; Sormunen, Raija; Vuolteenaho, Olli; Zandonadi, Flávia; Paes Leme, Adriana F; Coletta, Ricardo D; Ruskoaho, Heikki; Salo, Tuula

    2016-06-10

    The invasion of carcinoma cells is a crucial feature in carcinogenesis. The penetration efficiency not only depends on the cancer cells, but also on the composition of the tumor microenvironment. Our group has developed a 3D invasion assay based on human uterine leiomyoma tissue. Here we tested whether human, porcine, mouse or rat hearts as well as porcine tongue tissues could be similarly used to study carcinoma cell invasion in vitro. Three invasive human oral tongue squamous cell carcinoma (HSC-3, SCC-25 and SCC-15), melanoma (G-361) and ductal breast adenocarcinoma (MDA-MB-231) cell lines, and co-cultures of HSC-3 and carcinoma-associated or normal oral fibroblasts were assayed. Myoma tissue, both native and lyophilized, promoted invasion and growth of the cancer cells. However, the healthy heart or tongue matrices were unable to induce the invasion of any type of cancer cells tested. Moreover, when studied in more detail, small molecular weight fragments derived from heart tissue rinsing media inhibited HSC-3 horizontal migration. Proteome analysis of myoma rinsing media, on the other hand, revealed migration enhancing factors. These results highlight the important role of matrix composition for cancer invasion studies in vitro and further demonstrate the unique properties of human myoma organotypic model. PMID:27090016

  2. Adaptable Lipid Matrix Promotes Protein-Protein Association in Membranes.

    PubMed

    Kuznetsov, Andrey S; Polyansky, Anton A; Fleck, Markus; Volynsky, Pavel E; Efremov, Roman G

    2015-09-01

    The cell membrane is "stuffed" with proteins, whose transmembrane (TM) helical domains spontaneously associate to form functionally active complexes. For a number of membrane receptors, a modulation of TM domains' oligomerization has been shown to contribute to the development of severe pathological states, thus calling for detailed studies of the atomistic aspects of the process. Despite considerable progress achieved so far, several crucial questions still remain: How do the helices recognize each other in the membrane? What is the driving force of their association? Here, we assess the dimerization free energy of TM helices along with a careful consideration of the interplay between the structure and dynamics of protein and lipids using atomistic molecular dynamics simulations in the hydrated lipid bilayer for three different model systems - TM fragments of glycophorin A, polyalanine and polyleucine peptides. We observe that the membrane driven association of TM helices exhibits a prominent entropic character, which depends on the peptide sequence. Thus, a single TM peptide of a given composition induces strong and characteristic perturbations in the hydrophobic core of the bilayer, which may facilitate the initial "communication" between TM helices even at the distances of 20-30 Å. Upon tight helix-helix association, the immobilized lipids accommodate near the peripheral surfaces of the dimer, thus disturbing the packing of the surrounding. The dimerization free energy of the modeled peptides corresponds to the strength of their interactions with lipids inside the membrane being the lowest for glycophorin A and similarly higher for both homopolymers. We propose that the ability to accommodate lipid tails determines the dimerization strength of TM peptides and that the lipid matrix directly governs their association. PMID:26575933

  3. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion.

    PubMed

    Yahalom-Ronen, Yfat; Rajchman, Dana; Sarig, Rachel; Geiger, Benjamin; Tzahor, Eldad

    2015-01-01

    Cardiomyocyte (CM) maturation in mammals is accompanied by a sharp decline in their proliferative and regenerative potential shortly after birth. In this study, we explored the role of the mechanical properties of the underlying matrix in the regulation of CM maturation. We show that rat and mouse neonatal CMs cultured on rigid surfaces exhibited increased myofibrillar organization, spread morphology, and reduced cell cycle activity. In contrast, compliant elastic matrices induced features of CM dedifferentiation, including a disorganized sarcomere network, rounding, and conspicuous cell-cycle re-entry. The rigid matrix facilitated nuclear division (karyokinesis) leading to binucleation, while compliant matrices promoted CM mitotic rounding and cell division (cytokinesis), associated with loss of differentiation markers. Moreover, the compliant matrix potentiated clonal expansion of CMs that involves multiple cell divisions. Thus, the compliant microenvironment facilitates CM dedifferentiation and proliferation via its effect on the organization of the myoskeleton. Our findings may be exploited to design new cardiac regenerative approaches. PMID:26267307

  4. Impact of Different Promoters on Episomal Vectors Harbouring Characteristic Motifs of Matrix Attachment Regions.

    PubMed

    Wang, Xiao-Yin; Zhang, Jun-He; Zhang, Xi; Sun, Qiu-Li; Zhao, Chun-Peng; Wang, Tian-Yun

    2016-01-01

    We previously demonstrated that the characteristic sequence of matrix attachment regions (MARs) allows transgenes to be maintained episomally in CHO cells. In the present study, six commonly used promoters from human cytomegalovirus major immediate-early (CMV), simian vacuolating virus 40 (SV40), Rous sarcoma virus, Homo sapiens ubiquitin C, phosphoglycerate kinase, and β-globin, respectively, were evaluated to determine their effects on transgene expression and stability in CHO cells stably transfected via the episomal vector harbouring characteristic MAR motifs. The CHO cells were transfected with vectors and then screened using G418, after which the stably transfected cells were split into two and further cultured either in the presence or absence of G418. Of the six promoters, the CMV promoter yielded the highest transgene expression levels and the highest transfection efficiency, whereas the SV40 promoter maintained transgene expression more stably during long-term culture than the other promoters did. The CMV and SV40 promoter-containing vectors were furthermore episomally maintained and conferred sustained eGFP expression in the cells even under nonselective conditions. On the basis of these findings, we conclude that the CMV promoter performs best in terms of yielding both high expression levels and high levels of stability using this episomal vector system. PMID:27226236

  5. Impact of Different Promoters on Episomal Vectors Harbouring Characteristic Motifs of Matrix Attachment Regions

    PubMed Central

    Wang, Xiao-Yin; Zhang, Jun-He; Zhang, Xi; Sun, Qiu-Li; Zhao, Chun-Peng; Wang, Tian-Yun

    2016-01-01

    We previously demonstrated that the characteristic sequence of matrix attachment regions (MARs) allows transgenes to be maintained episomally in CHO cells. In the present study, six commonly used promoters from human cytomegalovirus major immediate-early (CMV), simian vacuolating virus 40 (SV40), Rous sarcoma virus, Homo sapiens ubiquitin C, phosphoglycerate kinase, and β-globin, respectively, were evaluated to determine their effects on transgene expression and stability in CHO cells stably transfected via the episomal vector harbouring characteristic MAR motifs. The CHO cells were transfected with vectors and then screened using G418, after which the stably transfected cells were split into two and further cultured either in the presence or absence of G418. Of the six promoters, the CMV promoter yielded the highest transgene expression levels and the highest transfection efficiency, whereas the SV40 promoter maintained transgene expression more stably during long-term culture than the other promoters did. The CMV and SV40 promoter-containing vectors were furthermore episomally maintained and conferred sustained eGFP expression in the cells even under nonselective conditions. On the basis of these findings, we conclude that the CMV promoter performs best in terms of yielding both high expression levels and high levels of stability using this episomal vector system. PMID:27226236

  6. Incorporation of Pentraxin 3 into Hyaluronan Matrices Is Tightly Regulated and Promotes Matrix Cross-linking

    PubMed Central

    Baranova, Natalia S.; Inforzato, Antonio; Briggs, David C.; Tilakaratna, Viranga; Enghild, Jan J.; Thakar, Dhruv; Milner, Caroline M.; Day, Anthony J.; Richter, Ralf P.

    2014-01-01

    Mammalian oocytes are surrounded by a highly hydrated hyaluronan (HA)-rich extracellular matrix with embedded cumulus cells, forming the cumulus cell·oocyte complex (COC) matrix. The correct assembly, stability, and mechanical properties of this matrix, which are crucial for successful ovulation, transport of the COC to the oviduct, and its fertilization, depend on the interaction between HA and specific HA-organizing proteins. Although the proteins inter-α-inhibitor (IαI), pentraxin 3 (PTX3), and TNF-stimulated gene-6 (TSG-6) have been identified as being critical for COC matrix formation, its supramolecular organization and the molecular mechanism of COC matrix stabilization remain unknown. Here we used films of end-grafted HA as a model system to investigate the molecular interactions involved in the formation and stabilization of HA matrices containing TSG-6, IαI, and PTX3. We found that PTX3 binds neither to HA alone nor to HA films containing TSG-6. This long pentraxin also failed to bind to products of the interaction between IαI, TSG-6, and HA, among which are the covalent heavy chain (HC)·HA and HC·TSG-6 complexes, despite the fact that both IαI and TSG-6 are ligands of PTX3. Interestingly, prior encounter with IαI was required for effective incorporation of PTX3 into TSG-6-loaded HA films. Moreover, we demonstrated that this ternary protein mixture made of IαI, PTX3, and TSG-6 is sufficient to promote formation of a stable (i.e. cross-linked) yet highly hydrated HA matrix. We propose that this mechanism is essential for correct assembly of the COC matrix and may also have general implications in other inflammatory processes that are associated with HA cross-linking. PMID:25190808

  7. Polymorphism, Genetic Effect and Association with Egg Production Traits of Chicken Matrix Metalloproteinases 9 Promoter

    PubMed Central

    Zhu, Guiyu; Jiang, Yunliang

    2014-01-01

    Matrix metalloproteinases (MMP) are key enzymes involved in cell and tissue remodeling during ovarian follicle development and ovulation. The control of MMP9 transcription in ovarian follicles occurs through a core promoter region (−2,400 to −1,700 bp). The aim of this study was to screen genetic variations in the core promoter region and examine MMP9 transcription regulation and reproduction performance. A single cytosine deletion/insertion polymorphism was found at −1954 C+/C−. Genetic association analysis indicated significant correlation between the deletion genotype (C−) with total egg numbers at 28 weeks (p = 0.031). Furthermore, luciferase-reporter assay showed the deletion genotype (C−) had significantly lower promoter activity than the insertion genotype (C+) in primary granulosa cells (p<0.01). Therefore, the identified polymorphism could be used for marker-assisted selection to improve chicken laying performance. PMID:25358310

  8. Differential effects of mechanical and biological stimuli on matrix metalloproteinase promoter activation in the thoracic aorta

    PubMed Central

    Ruddy, Jean Marie; Jones, Jeffrey A.; Stroud, Robert E.; Mukherjee, Rupak; Spinale, Francis G.; Ikonomidis, John S.

    2009-01-01

    Background The effect of multiple integrated stimuli on vascular wall expression of matrix metalloproteinases (MMPs) remains unknown. Accordingly, this study has examined the influence of the vasoactive peptide angiotensin II (AngII) on wall tension-induced promoter activation of MMP-2, MMP-9, and membrane type-1 MMP (MT1-MMP). Methods and Results Thoracic aortic rings harvested from transgenic reporter mice containing the MMP-2, MMP-9, or MT1-MMP promoter sequence fused to a reporter gene were subjected to three hours of wall tension at 70, 85, or 100 mmHg with or without 100nM AngII. Total RNA was harvested from the aortic rings, and reporter gene transcripts were quantified by QPCR to measure MMP promoter activity. MT1-MMP promoter activity was increased at both 85 and 100 mmHg compared to baseline tension of 70 mmHg, while treatment with AngII stimulated MT1-MMP promoter activity to the same degree at all tension levels (p<0.05). Elevated tension and AngII displayed a potential synergistic enhancement of MMP-2 promoter activation at 85 and 100mmHg, while the same stimuli caused a decrease in MMP-9 promoter activity (p<0.05) at 100 mmHg. Conclusions This study has demonstrated that exposure to a relevant biological stimulus (AngII) in the presence of elevated tension modulated MMP promoter activation. Furthermore, these data suggest that a mechanical-molecular set point exists for the induction of MMP promoter activation, and that this set point can be adjusted up or down by a secondary biological stimulus. Together, these results may have significant clinical implications toward the regulation of hypertensive vascular remodeling. PMID:19752377

  9. Decellularized Matrix from Tumorigenic Human Mesenchymal Stem Cells Promotes Neovascularization with Galectin-1 Dependent Endothelial Interaction

    PubMed Central

    Burns, Jorge S.; Kristiansen, Malthe; Kristensen, Lars P.; Larsen, Kenneth H.; Nielsen, Maria O.; Christiansen, Helle; Nehlin, Jan; Andersen, Jens S.; Kassem, Moustapha

    2011-01-01

    Background Acquisition of a blood supply is fundamental for extensive tumor growth. We recently described vascular heterogeneity in tumours derived from cell clones of a human mesenchymal stem cell (hMSC) strain (hMSC-TERT20) immortalized by retroviral vector mediated human telomerase (hTERT) gene expression. Histological analysis showed that cells of the most vascularized tumorigenic clone, -BD11 had a pericyte-like alpha smooth muscle actin (ASMA+) and CD146+ positive phenotype. Upon serum withdrawal in culture, -BD11 cells formed cord-like structures mimicking capillary morphogenesis. In contrast, cells of the poorly tumorigenic clone, -BC8 did not stain for ASMA, tumours were less vascularized and serum withdrawal in culture led to cell death. By exploring the heterogeneity in hMSC-TERT20 clones we aimed to understand molecular mechanisms by which mesenchymal stem cells may promote neovascularization. Methodology/Principal Findings Quantitative qRT-PCR analysis revealed similar mRNA levels for genes encoding the angiogenic cytokines VEGF and Angiopoietin-1 in both clones. However, clone-BD11 produced a denser extracellular matrix that supported stable ex vivo capillary morphogenesis of human endothelial cells and promoted in vivo neovascularization. Proteomic characterization of the -BD11 decellularized matrix identified 50 extracellular angiogenic proteins, including galectin-1. siRNA knock down of galectin-1 expression abrogated the ex vivo interaction between decellularized -BD11 matrix and endothelial cells. More stable shRNA knock down of galectin-1 expression did not prevent -BD11 tumorigenesis, but greatly reduced endothelial migration into -BD11 cell xenografts. Conclusions Decellularized hMSC matrix had significant angiogenic potential with at least 50 angiogenic cell surface and extracellular proteins, implicated in attracting endothelial cells, their adhesion and activation to form tubular structures. hMSC -BD11 surface galectin-1 expression was

  10. Securin promotes migration and invasion via matrix metalloproteinases in glioma cells

    PubMed Central

    YAN, HAICHENG; WANG, WEI; DOU, CHANGWU; TIAN, FUMING; QI, SONGTAO

    2015-01-01

    Human securin, encoded by pituitary tumor transforming gene 1, is implicated in several oncogenic processes in the pathogenesis of brain tumors, including glioma. The aim of the present study was to examine the effect of securin on the migration and invasion of glioma cells. The results revealed that the overexpression of securin in glioma LN-229 cells significantly increased the invasion and transmigration abilities. By contrast, these abilities were significantly reduced by the downregulation of securin in glioma U373 cells. Furthermore, the results demonstrated that securin overexpression and downregulation significantly increased and decreased the levels of matrix metalloproteinase 2 and 9, respectively. These findings indicate a promotive role for securin in glioma migration and invasion, which may involve the action of matrix metalloproteinases. PMID:26137166

  11. In situ proteolysis of the Vibrio cholerae matrix protein RbmA promotes biofilm recruitment

    PubMed Central

    Smith, Daniel R.; Maestre-Reyna, Manuel; Lee, Gloria; Gerard, Harry; Wang, Andrew H.-J.; Watnick, Paula I.

    2015-01-01

    The estuarine gram-negative rod and human diarrheal pathogen Vibrio cholerae synthesizes a VPS exopolysaccharide-dependent biofilm matrix that allows it to form a 3D structure on surfaces. Proteins associated with the matrix include, RbmA, RbmC, and Bap1. RbmA, a protein whose crystallographic structure suggests two binding surfaces, associates with cells by means of a VPS-dependent mechanism and promotes biofilm cohesiveness and recruitment of cells to the biofilm. Here, we show that RbmA undergoes limited proteolysis within the biofilm. This proteolysis, which is carried out by the hemagglutinin/protease and accessory proteases, yields the 22-kDa C-terminal polypeptide RbmA*. RbmA* remains biofilm-associated. Unlike full-length RbmA, the association of RbmA* with cells is no longer VPS-dependent, likely due to an electropositive surface revealed by proteolysis. We provide evidence that this proteolysis event plays a role in recruitment of VPS− cells to the biofilm surface. Based on our findings, we propose that association of RbmA with the matrix reinforces the biofilm structure and leads to limited proteolysis of RbmA to RbmA*. RbmA*, in turn, promotes recruitment of cells that have not yet initiated VPS synthesis to the biofilm surface. The assignment of two functions to RbmA, separated by a proteolytic event that depends on matrix association, dictates an iterative cycle in which reinforcement of recently added biofilm layers precedes the recruitment of new VPS− cells to the biofilm. PMID:26240338

  12. Virus activated filopodia promote human papillomavirus type 31 uptake from the extracellular matrix

    PubMed Central

    Smith, Jessica L.; Lidke, Diane S.; Ozbun, Michelle A.

    2011-01-01

    Human papillomaviruses (HPVs), etiological agents of epithelial tumors and cancers, initiate infection of basal human keratinocytes (HKs) facilitated by wounding. Virions bind to HKs and their secreted extracellular matrix (ECM), but molecular roles for wounding or ECM binding during infection are unclear. Herein we demonstrate HPV31 activates signals promoting cytoskeletal rearrangements and virion transport required for internalization and infection. Activation of tyrosine and PI3 kinases precedes induction of filopodia whereon virions are transported toward the cell body. Coupled with loss of ECM bound virions this supports a model whereby virus activated filopodial transport contributes to increased and protracted virion uptake into susceptible cells. PMID:18834609

  13. Activation of matrix metalloproteinase-26 by HOXA10 promotes embryo adhesion in vitro.

    PubMed

    Jiang, Yue; Yan, Guijun; Zhang, Hui; Shan, Huizhi; Kong, Chengcai; Yan, Qiang; Xue, Bai; Diao, Zhenyu; Hu, Yali; Sun, Haixiang

    2014-03-14

    Successful embryonic implantation requires an effective maternal-embryonic molecular dialogue. However, the detailed mechanisms of epithelial-embryo adhesion remain poorly understood. Here, we report that matrix metalloproteinase-26 (MMP-26) is a novel downstream target gene of homeobox a 10 (HOXA10) in human endometrial cells. HOXA10 binds directly to a conserved TTAT unit (-442 to -439) located within the 5' regulatory region of the MMP-26 gene and regulates the expression and secretion of MMP-26 in a concentration-dependent manner. Moreover, the adenovirus-mediated overexpression of MMP-26 in Ishikawa cells markedly increased BeWo spheroid adhesion. An antibody blocking assay further demonstrated that the promotion of BeWo spheroid adhesion by HOXA10 and MMP-26 was significantly inhibited by pre-treatment with a specific antibody against MMP-26. These results demonstrate that the HOXA10-mediated expression of MMP-26 promotes embryo adhesion during the process of embryonic implantation. PMID:24565841

  14. A nutrient mixture reduces the expression of matrix metalloproteinases in an animal model of spinal cord injury by modulating matrix metalloproteinase-2 and matrix metalloproteinase-9 promoter activities

    PubMed Central

    ZHANG, HONGQI; CHU, GE; PAN, CHAO; HU, JIANZHONG; GUO, CHAOFENG; LIU, JINYANG; WANG, YUXIANG; WU, JIANHUANG

    2014-01-01

    This study aimed to determine whether a novel nutrient mixture (NM), composed of lysine, ascorbic acid, proline, green tea extracts and other micronutrients, attenuates impairments induced by spinal cord injury (SCI) and to investigate the related molecular mechanisms. A mouse model of SCI was established. Thirty-two mice were divided into four groups. The sham group received vehicle only. The SCI groups were treated orally with saline (saline group), a low dose (500 μg 3 times/day) of NM (NM-LD group) or a high dose (2,000 μg 3 times/day) of NM (NM-HD group). The levels of mouse hindlimb movement were determined every day in the first week post-surgery. The protein expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by western blotting. Wild-type and mutant MMP-2- and MMP-9-directed luciferase constructs were generated and their luciferase activities were determined. NM significantly facilitated the recovery of hindlimb movement of the mice in comparison to that in the saline group. The expression levels of MMP-2 in the NM-LD and NM-HD groups were decreased by ~50% compared with the saline group as indicated by western blotting results. The expression levels of MMP-9 in the NM-LD and NM-HD groups were decreased to ~25 and ~10%, respectively. These results suggest that NM significantly inhibits the expression of MMP-2 and MMP-9 proteins. Reverse transcription quantitative polymerase chain reaction results indicated that NM reduced the levels of MMP-2 and MMP-9 mRNA. Furthermore, the luciferase results indicated that site-directed mutagenesis comprising a −1306 C to T (C/T) base change in the MMP-2 promoter and a −1562 C/T base change in the MMP-9 promoter abolished the inhibitory effects of NM on MMP-2 and MMP-9 promoters. These results suggest that NM attenuates SCI-induced impairments in mice movement by negatively affecting the promoter activity of MMP-2 and MMP-9 genes and thus decreasing the expression of MMP-2 and MMP-9

  15. TGFβ Signaling Promotes Matrix Assembly During Mechanosensitive Embryonic Salivary Gland Restoration

    PubMed Central

    Peters, Sarah B.; Nelson, Deirdre A.; Kwon, Hae Ryong; Koslow, Mathew; DeSantis, Kara A.; Larsen, Melinda

    2016-01-01

    Mechanical properties of the microenvironment regulate cell morphology and differentiation within complex organs. However, methods to restore morphogenesis and differentiation in organs in which compliance is suboptimal are poorly understood. We used mechanosensitive mouse salivary gland organ explants grown at different compliance levels together with deoxycholate extraction and immunocytochemistry of the intact, assembled matrices to examine the compliance-dependent assembly and distribution of the extracellular matrix and basement membrane in explants grown at permissive or non-permissive compliance. Extracellular matrix and basement membrane assembly were disrupted in the glands grown at low compliance compared to those grown at high compliance, correlating with defective morphogenesis and decreased myoepithelial cell differentiation. Extracellular matrix and basement membrane assembly as well as myoepithelial differentiation were restored by addition of TGFβ1 and by mechanical rescue, and mechanical rescue was prevented by inhibition of TGFβ signaling during the rescue. We detected a basal accumulation of active integrin β1 in the differentiating myoepithelial cells that formed a continuous peripheral localization around the proacini and in clefts within active sites of morphogenesis in explants that were grown at high compliance. The pattern and levels of integrin β1 activation together with myoepithelial differentiation were interrupted in explants grown at low compliance but were restored upon mechanical rescue or with application of exogenous TGFβ1. These data suggest that therapeutic application of TGFβ1 to tissues disrupted by mechanical signaling should be examined as a method to promote organ remodeling and regeneration. PMID:25652203

  16. Identification of molecules in leech extracellular matrix that promote neurite outgrowth.

    PubMed

    Masuda-Nakagawa, L; Beck, K; Chiquet, M

    1988-12-22

    The molecular composition of the substrate is of critical importance for neurite extension by isolated identified leech nerve cells in culture. One substrate upon which rapid growth occurs in defined medium is a cell-free extract of extracellular matrix (ECM) that surrounds the leech central nervous system (CNS). Here we report the co-purification of neurite-promoting activity with a laminin-like molecule. High molecular mass proteins from leech ECM purified by gel filtration exhibited increased specific activity for promoting neurite outgrowth. The most active fractions contained three major polypeptide bands of ca. 340, 250 and 220 kDa. Electron microscopy of rotary-shadowed samples showed three macromolecules, one of which had a cross-shaped structure similar to vertebrate laminin. A second six-armed molecule resembled vertebrate tenascin and a third rod-like molecule resembled vertebrate collagen type IV. The most active fractions contained a protein of ca. 1 MDa on non-reducing gels with disulphide-linked subunits of ca. 220 and 340 kDa, with cross-shaped laminin-like molecules. We conclude that a laminin-like molecule represents a major neurite promoting component present in leech ECM. The experiments represent a first step in determining the location of leech laminin within the CNS and assessing its role in neurite outgrowth during development and regeneration. PMID:2907383

  17. Collagen-Glycosaminoglycan Matrix Implantation Promotes Angiogenesis following Surgical Brain Trauma

    PubMed Central

    Hsu, Wei-Cherng; Hsiao, Jong-Kai; Chen, Gunng-Shinng; Wang, Jia-Yi

    2014-01-01

    Surgical brain injury (SBI) is unavoidable during many neurosurgical procedures intrinsically linked to postoperative neurological deficits. We have previously demonstrated that implantation of collagen glycosaminoglycan (CG) following surgical brain injury could significantly promote functional recovery and neurogenesis. In this study we further hypothesized that this scaffold may provide a microenvironment by promoting angiogenesis to favor neurogenesis and subsequent functional recovery. Using the rodent model of surgical brain injury as we previously established, we divided Sprague-Dawley male rats (weighting 300–350 g) into three groups: (1) sham (2) surgical injury with a lesion (L), and (3) L with CG matrix implantation (L + CG). Our results demonstrated that L + CG group showed a statistically significant increase in the density of vascular endothelial cells and blood vessels over time. In addition, tissue concentrations of angiogenic growth factors (such as VEGF, FGF2, and PDGF) significantly increased in L + CG group. These results suggest that implantation of a CG scaffold can promote vascularization accompanied by neurogenesis. This opens prospects for use of CG scaffolds in conditions such as brain injury including trauma and ischemia. PMID:25309917

  18. Matrix metalloproteinase-3 gene promoter polymorphisms: A potential risk factor for pelvic organ prolapse

    PubMed Central

    Karachalios, Charalampos; Bakas, Panagiotis; Kaparos, Georgios; Demeridou, Styliani; Liapis, Ilias; Grigoriadis, Charalampos; Liapis, Aggelos

    2016-01-01

    Pelvic organ prolapse (POP) is a common multifactorial condition. Matrix metalloproteinases (MMPs) are enzymes capable of breaking down various connective tissue elements. Single-nucleotide polymorphisms (SNPs) in regulatory areas of MMP-encoding genes can alter their transcription rate, and therefore the possible effect on pelvic floor supporting structures. The insertion of an adenine (A) base in the promoter of the MMP-3 gene at position −1612/−1617 produces a sequence of six adenines (6A), whereas the other allele has five (5A). The aim of the present study was to investigate the possible association of MMP-3 gene promoter SNPs with the risk of POP. The patient group comprised 80 women with clinically significant POP [Stage II, III or IV; POP quantification (POP-Q) system]. The control group consisted of 80 females without any or important pelvic floor support defects (Stages 0 or I; POP-Q system). All the participants underwent the same preoperative evaluation. SNP detection was determined with whole blood sample DNA analysis by quantitative polymerase chain reaction (PCR) in LightCycler® PCR platforms, using the technique of sequence-specific hybridization probe-binding assays and melting temperature curve analysis. The results showed there was no statistically significant difference between 5A/5A, 5A/6A and 6A/6A MMP-3 gene promoter variants in the two study groups (P=0.4758). Therefore, MMP-3 gene promoter SNPs alone is insufficient to increase the genetic susceptibility to POP development. PMID:27588175

  19. Leucine-enkephalin promotes wound repair through the regulation of hemidesmosome dynamics and matrix metalloprotease.

    PubMed

    Yang, Dong Joo; Lee, Kyung Suk; Ko, Chang Mann; Moh, Sang Hyun; Song, Jihyeok; Hur, Lucia C; Cheon, Young Woo; Yang, Seung Ho; Choi, Yun-Hee; Kim, Ki Woo

    2016-02-01

    The skin responds to environmental stressors by coordinated actions of neuropeptides and their receptors. An endogenous peptide for δ-opioid receptor (DOPr), Leu-enkephalin (L-ENK), is expressed in the skin and its expression is altered in pathological conditions. Although the importance of DOPr is rapidly gaining recognition, the molecular mechanisms underlying its effects on wound healing are largely undefined. We show here that L-ENK induced activation of Erk, P90(RSK), and Elk-1 and promoted the disruption of hemidesmosomes and the expression of matrix metalloprotease (MMP)-2 and MMP-9, important processes for wound healing. Treatment with Erk inhibitor blocked activation of P90(RSK) and Elk-1 and significantly blunted wound repair. Therefore, our results suggest that activation of Erk and its downstream effectors, P90(RSK) and Elk-1, are critical for DOPr-mediated skin homeostasis. PMID:26763532

  20. Endpoint matrix: a conceptual tool to promote consideration of the multiple dimensions of humane endpoints.

    PubMed

    Ashall, Vanessa; Millar, Kate

    2014-01-01

    This paper proposes a framework to support appropriate application of endpoints in animal experiments. It is recommended that unpredicted endpoints should be explicitly considered alongside scientific endpoints and justifiable endpoints as the three types of endpoint which comprise the "humane." We suggest there is a need for clear identification of each type of endpoint and an understanding of the interactions between these types. The use of an "endpoint matrix" during study planning is proposed to promote methodically sound and consistent definition, determination, and detection of unpredicted, scientific, and justifiable endpoints in animal experiments. It is claimed that the further development and use of this tool will support a more effective and harmonized practical application of humane endpoints for all animal use in line with best practice recommendations. PMID:24794004

  1. Membrane-Type 1 Matrix Metalloproteinase Cleaves Cd44 and Promotes Cell Migration

    PubMed Central

    Kajita, Masahiro; Itoh, Yoshifumi; Chiba, Tadashige; Mori, Hidetoshi; Okada, Akiko; Kinoh, Hiroaki; Seiki, Motoharu

    2001-01-01

    Migratory cells including invasive tumor cells frequently express CD44, a major receptor for hyaluronan and membrane-type 1 matrix metalloproteinase (MT1-MMP) that degrades extracellular matrix at the pericellular region. In this study, we demonstrate that MT1-MMP acts as a processing enzyme for CD44H, releasing it into the medium as a soluble 70-kD fragment. Furthermore, this processing event stimulates cell motility; however, expression of either CD44H or MT1-MMP alone did not stimulate cell motility. Coexpression of MT1-MMP and mutant CD44H lacking the MT1-MMP–processing site did not result in shedding and did not promote cell migration, suggesting that the processing of CD44H by MT1-MMP is critical in the migratory stimulation. Moreover, expression of the mutant CD44H inhibited the cell migration promoted by CD44H and MT1-MMP in a dominant-negative manner. The pancreatic tumor cell line, MIA PaCa-2, was found to shed the 70-kD CD44H fragment in a MT1-MMP–dependent manner. Expression of the mutant CD44H in the cells as well as MMP inhibitor treatment effectively inhibited the migration, suggesting that MIA PaCa-2 cells indeed use the CD44H and MT1-MMP as migratory devices. These findings revealed a novel interaction of the two molecules that have each been implicated in tumor cell migration and invasion. PMID:11381077

  2. INTRANUCLEAR MATRIX METALLOPROTEINASES PROMOTE DNA DAMAGE AND APOPTOSIS INDUCED BY OXYGEN–GLUCOSE DEPRIVATION IN NEURONS

    PubMed Central

    HILL, J. W.; PODDAR, R.; THOMPSON, J. F.; ROSENBERG, G. A.; YANG, Y.

    2016-01-01

    Degradation of the extracellular matrix by elevated matrix metalloproteinase (MMP) activity following ischemia/reperfusion is implicated in blood–brain barrier disruption and neuronal death. In contrast to their characterized extracellular roles, we previously reported that elevated intranuclear MMP-2 and -9 (gelatinase) activity degrades nuclear DNA repair proteins and promotes accumulation of oxidative DNA damage in neurons in rat brain at 3-h reperfusion after ischemic stroke. Here, we report that treatment with a broad-spectrum MMP inhibitor significantly reduced neuronal apoptosis in rat ischemic hemispheres at 48-h reperfusion after a 90-min middle cerebral artery occlusion (MCAO). Since extracellular gelatinases in brain tissue are known to be neurotoxic during acute stroke, the contribution of intranuclear MMP-2 and -9 activities in neurons to neuronal apoptosis has been unclear. To confirm and extend our in vivo observations, oxygen–glucose deprivation (OGD), an in vitro model of ischemia/reperfusion, was employed. Primary cortical neurons were subjected to 2-h OGD with reoxygenation. Increased intranuclear gelatinase activity was detected immediately after reoxygenation onset and was maximal at 24 h, while extracellular gelatinase levels remained unchanged. We detected elevated levels of both MMP-2 and -9 in neuronal nuclear extracts and gelatinase activity in neurons co-localized primarily with MMP-2. We found a marked decrease in PARP1, XRCC1, and OGG1, and decreased PARP1 activity. Pretreatment of neurons with selective MMP-2/9 inhibitor II significantly decreased gelatinase activity and downregulation of DNA repair enzymes, decreased accumulation of oxidative DNA damage, and promoted neuronal survival after OGD. Our results confirm the nuclear localization of gelatinases and their nuclear substrates observed in an animal stroke model, further supporting a novel role for intranuclear gelatinase activity in an intrinsic apoptotic pathway in neurons

  3. Promoting external inosculation of prevascularised tissue constructs by pre-cultivation in an angiogenic extracellular matrix.

    PubMed

    Laschke, M W; Mussawy, H; Schuler, S; Eglin, D; Alini, M; Menger, M D

    2010-01-01

    The engineering of preformed microvessels offers the promising opportunity to rapidly vascularise implanted tissue constructs by the process of inosculation. Herein, we analyzed whether this process may further be accelerated by cultivation of prevascularised tissue constructs in Matrigel before implantation. Nano-size hydroxyapatite particles/poly(ester-urethane) scaffolds were implanted into the flank of FVB/N-TgN (Tie2/GFP) 287 Sato mice to allow the ingrowth of a granulation tissue with green fluorescent protein (GFP)-positive blood vessels. After harvesting, these prevascularised constructs were then transferred into dorsal skinfold chambers of FVB/N recipient mice to study the process of inosculation. The constructs were implanted directly after embedding in Matrigel or after 3 days of cultivation in the extracellular matrix. Matrigel-free constructs served as control. Cultivation in Matrigel resulted in the outgrowth of CD31/GFP-positive vascular sprouts. Vascularisation of these constructs was markedly improved when compared to the other two groups, as indicated by a significantly elevated functional microvessel density between days 6 to 14 after implantation into the dorsal skinfold chamber. This was associated with an increased number of GFP-positive blood vessels growing into the surrounding host tissue. Thus, the blood supply to prevascularised tissue constructs can be accelerated by their pre-cultivation in an angiogenic extracellular matrix, promoting external inosculation of the preformed microvascular networks with the host microvasculature. PMID:21154242

  4. Amyloid β-Protein as a Substrate Interacts with Extracellular Matrix to Promote Neurite Outgrowth

    NASA Astrophysics Data System (ADS)

    Koo, Edward H.; Park, Lisa; Selkoe, Dennis J.

    1993-05-01

    Progressive deposition of amyloid β-protein (Aβ) in brain parenchyma and blood vessels is a characteristic feature of Alzheimer disease. Recent evidence suggests that addition of solubilized synthetic Aβ to medium may produce toxic or trophic effects on cultured hippocampal neurons. Because soluble Aβ may not accumulate in significant quantities in brain, we asked whether immobilized Aβ peptide as a substrate alters neurite outgrowth from cultured rat peripheral sensory neurons. This paradigm may closely mimic the conditions in Alzheimer disease brain tissue, in which neurites contact insoluble, extracellular aggregates of β-amyloid. We detected no detrimental effects of Aβ substrate on neurite outgrowth. Rather, Aβ in combination with low doses of laminin or fibronectin enhanced neurite out-growth from these neuronal explants. Our results suggest that insoluble Aβ in the cerebral neuropil may serve as a neurite-promoting matrix, perhaps explaining the apparent regenerative response of neurites observed around amyloid plaques in Alzheimer disease. Moreover, in concert with the recent discovery of Aβ production by cultured neurons, our data suggest that Aβ plays a normal physiological role in brain by complexing with the extracellular matrix.

  5. Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression

    PubMed Central

    Bourguignon, Lilly Y. W.

    2016-01-01

    Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely linked to tumor cell properties. One of the candidates is matrix hyaluronan (HA), which is known as one of the major extracellular matrix (ECM) components. HA serves as a physiological ligand for surface CD44 molecule and also functions as a bio-regulator. The binding of HA to CD44 has been shown to stimulate concomitant activation of a number of oncogenic pathways and abnormal cellular processes in cancer cells and cancer stem cells (CSCs). MicroRNAs (miRNAs) belong to a class of small RNAs containing ~20–25 nucleotides and are known to promote aberrant cellular functions in cancer cells. In this article, I have focused on the role of HA interaction with CD44 and several important signaling molecules in the regulation of unique miRNAs (e.g., miR-21, miR-302 and miR-10b) and their downstream targets leading to multiple tumor cell-specific functions (e.g., tumor cell growth, drug resistance and metastasis) and cancer progression. This new knowledge could provide the groundwork necessary for establishing new tumor markers and developing important, novel drugs targeted against HA/CD44-associated tumor progression, which can be utilized in the therapeutic treatment of metastatic cancer patients. PMID:27070574

  6. Angiopoietin-1 peptide QHREDGS promotes osteoblast differentiation, bone matrix deposition and mineralization on biomedical materials†

    PubMed Central

    Feric, Nicole; Cheng, Calvin C.H.; Goh, M. Cynthia; Dudnyk, Vyacheslav; Di Tizio, Val; Radisic, Milica

    2014-01-01

    Bone loss occurs as a consequence of a variety of diseases as well as from traumatic injuries, and often requires therapeutic intervention. Strategies for repairing and replacing damaged and/or lost bone tissue include the use of biomaterials and medical implant devices with and without osteoinductive coatings. The soluble growth factor angiopoietin-1 (Ang-1) has been found to promote cell adhesion and survival in a range of cell types including cardiac myocytes, endothelial cells and fibroblasts through an integrin-dependent mechanism. Furthermore, the short sequence QHREDGS has been identified as the integrin-binding sequence of Ang-1 and as a synthetic peptide has been found to possess similar integrin-dependent effects as Ang-1 in the aforementioned cell types. Integrins have been implicated in osteoblast differentiation and bone mineralization, processes critical to bone regeneration. By binding integrins on the osteoblast surface, QHREDGS could promote cell survival and adhesion, as well as conceivably osteoblast differentiation and bone mineralization. Here we immobilized QHREDGS onto polyacrylate (PA)-coated titanium (Ti) plates and polyethylene glycol (PEG) hydrogels. The osteoblast differentiation marker, alkaline phosphatase, peaked in activity 4-12 days earlier on the QHREDGS-immobilized PA-coated Ti plates than on the unimmobilized, DGQESHR (scrambled)- and RGDS-immobilized surfaces. Significantly more bone matrix was deposited on the QHREDGS-immobilized Ti surface than on the other surfaces as determined by atomic force microscopy. The QHREDGS-immobilized hydrogels also had a significantly higher mineral-to-matrix (M/M) ratio determined by Fourier transform infrared spectroscopy. Alizarin Red S and von Kossa staining and quantification, and environmental scanning electron microscopy showed that while both the QHREDGS- and RGDS-immobilized surfaces had extensive mineralization relative to the unimmobilized and DGQESHR-immobilized surfaces, the

  7. Targeting Inflammatory Cytokines and Extracellular Matrix Composition to Promote Wound Regeneration

    PubMed Central

    Zgheib, Carlos; Xu, Junwang; Liechty, Kenneth W.

    2014-01-01

    Significance: Delayed wound healing is one of the most challenging complications of several diseases, including diabetes. There is a vast interest in finding efficient treatments that promote scarless wound healing. The ability of the fetus to regenerate skin wounds after injury has generated much interest in the fetus as a model of regeneration. In this review, we evaluate the role and differential regulation of inflammation, extracellular matrix (ECM) composition, and mechanical stress in determining wound phenotype after injury. Recent Advances: Comparisons between postnatal and fetal wounds have revealed many differences in the healing process. Fetal skin wound healing is characterized by a reduced inflammatory response, an ECM rich in type III collagen and high-molecular-weight hyaluronic acid (HMW-HA), and minimal mechanical stress. In contrast, adult wounds have a sustained inflammatory response, an ECM with increased type I collagen, and low-molecular-weight (LMW-HA) and are subject to significant mechanical load. Critical Issues: The differential regulation of these processes in the fetus compared with the adult plays a critical role in promoting regeneration in the fetus while resulting in scar formation in the adult. Future Directions: Understanding the significance of inflammation and biomechanical forces in wound healing may help in designing therapeutic strategies for the management of chronic nonhealing wounds. PMID:24757589

  8. Targeting Inflammatory Cytokines and Extracellular Matrix Composition to Promote Wound Regeneration.

    PubMed

    Zgheib, Carlos; Xu, Junwang; Liechty, Kenneth W

    2014-04-01

    Significance: Delayed wound healing is one of the most challenging complications of several diseases, including diabetes. There is a vast interest in finding efficient treatments that promote scarless wound healing. The ability of the fetus to regenerate skin wounds after injury has generated much interest in the fetus as a model of regeneration. In this review, we evaluate the role and differential regulation of inflammation, extracellular matrix (ECM) composition, and mechanical stress in determining wound phenotype after injury. Recent Advances: Comparisons between postnatal and fetal wounds have revealed many differences in the healing process. Fetal skin wound healing is characterized by a reduced inflammatory response, an ECM rich in type III collagen and high-molecular-weight hyaluronic acid (HMW-HA), and minimal mechanical stress. In contrast, adult wounds have a sustained inflammatory response, an ECM with increased type I collagen, and low-molecular-weight (LMW-HA) and are subject to significant mechanical load. Critical Issues: The differential regulation of these processes in the fetus compared with the adult plays a critical role in promoting regeneration in the fetus while resulting in scar formation in the adult. Future Directions: Understanding the significance of inflammation and biomechanical forces in wound healing may help in designing therapeutic strategies for the management of chronic nonhealing wounds. PMID:24757589

  9. Transcriptional Factor DLX3 Promotes the Gene Expression of Enamel Matrix Proteins during Amelogenesis

    PubMed Central

    Zhang, Zhichun; Tian, Hua; Lv, Ping; Wang, Weiping; Jia, Zhuqing; Wang, Sainan; Zhou, Chunyan; Gao, Xuejun

    2015-01-01

    Mutation of distal-less homeobox 3 (DLX3) is responsible for human tricho-dento-osseous syndrome (TDO) with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP) genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre-secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO) inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease. PMID:25815730

  10. Transcriptional factor DLX3 promotes the gene expression of enamel matrix proteins during amelogenesis.

    PubMed

    Zhang, Zhichun; Tian, Hua; Lv, Ping; Wang, Weiping; Jia, Zhuqing; Wang, Sainan; Zhou, Chunyan; Gao, Xuejun

    2015-01-01

    Mutation of distal-less homeobox 3 (DLX3) is responsible for human tricho-dento-osseous syndrome (TDO) with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP) genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre-secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO) inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease. PMID:25815730

  11. Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR-20a targeting ANKH expression

    PubMed Central

    Liu, Ming-Han; Sun, Chao; Yao, Yuan; Fan, Xin; Liu, Huan; Cui, You-Hong; Bian, Xiu-Wu; Huang, Bo; Zhou, Yue

    2016-01-01

    The mechanical environment is crucial for intervertebral disc degeneration (IDD). However, the mechanisms underlying the regulation of cartilage endplate (CEP) calcification by altered matrix stiffness remain unclear. In this study, we found that matrix stiffness of CEP was positively correlated with the degree of IDD, and stiff matrix, which mimicked the severe degeneration of CEP, promoted inorganic phosphate-induced calcification in CEP chondrocytes. Co-expression analysis of the miRNA and mRNA profiles showed that increasing stiffness resulted in up-regulation of miR-20a and down-regulation of decreased ankylosis protein homolog (ANKH) during inorganic phosphate-induced calcification in CEP chondrocytes. Through a dual luciferase reporter assay, we confirmed that miR-20a directly targets 3′-untranslated regions of ANKH. The inhibition of miR-20a attenuated the calcium deposition and calcification-related gene expression, whereas the overexpression of miR-20a enhanced calcification in CEP chondrocytes on stiff matrix. The rescue of ANKH expression restored the decreased pyrophosphate efflux and inhibited calcification. In clinical samples, the levels of ANKH expression were inversely associated with the degeneration degree of CEP. Thus, our findings demonstrate that the miR-20a/ANKH axis mediates the stiff matrix- promoted CEP calcification, suggesting that miR-20a and ANKH are potential targets in restraining the progression of IDD. PMID:27142968

  12. Dentin Matrix Protein-1 Isoforms Promote Differential Cell Attachment and Migration*S⃞

    PubMed Central

    von Marschall, Zofia; Fisher, Larry W.

    2008-01-01

    Dentin matrix protein-1 (DMP1), bone sialoprotein (BSP), and osteopontin (OPN) are three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) co-expressed/secreted by skeletal and active ductal epithelial cells. Although etiological mechanisms remain unclear, DMP1 is the only one of these three genes currently known to have mutations resulting in human disease, and yet it remains the least studied. All three contain the highly conserved integrin-binding tripeptide, RGD, and experiments comparing the cell attachment and haptotactic migration-enhancing properties of DMP1 to BSP and OPN were performed using human skeletal (MG63 and primary dental pulp cells) and salivary gland (HSG) cells. Mutation of any SIBLING's RGD destroyed all attachment and migration activity. Using itsαVβ5 integrin, HSG cells attached to BSP but not to DMP1 or OPN. However, HSG cells could not migrate onto BSP in a modified Boyden chamber assay. Expression of αVβ3 integrin enhanced HSG attachment to DMP1 and OPN and promoted haptotactic migration onto all three proteins. Interchanging the first four coding exons or the conserved amino acids adjacent to the RGD of DMP1 with corresponding sequences of BSP did not enhance the ability of DMP1 to bindαVβ5. For αVβ3-expressing cells, intact DMP1, its BMP1-cleaved C-terminal fragment, and exon six lacking all post-translational modifications worked equally well but the proteoglycan isoform of DMP1 had greatly reduced ability for cell attachment and migration. The sequence specificity of the proposed BMP1-cleavage site of DMP1 was verified by mutation analysis. Direct comparison of the three proteins showed that cells discriminate among these SIBLINGs and among DMP1 isoforms. PMID:18819913

  13. CD14{sup +} monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells

    SciTech Connect

    Wang, Ding; TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin ; Chen, Ke; TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin ; Du, Wei Ting; Han, Zhi-Bo; TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin ; Ren, He; Chi, Ying; TEDA Life and Technology Research Center, Institute of Hematology, Chinese Academy of Medical Sciences, TEDA, Tianjin ; and others

    2010-09-10

    Here, the effect of CD14{sup +} monocytes on human umbilical cord matrix stem cell (hUC-MSC)-mediated immunosuppression was studied in vitro. hUC-MSCs exerted a potent inhibitory effect on the proliferation and interferon-{gamma} (IFN-{gamma}) secretion capacities of CD4{sup +} and CD8{sup +} T cells in response to anti-CD3/CD28 stimulation. Transwell co-culture system revealed that the suppressive effect was primarily mediated by soluble factors. Addition of prostaglandin synthesis inhibitors (indomethacin or NS-398) almost completely abrogated the immunosuppression activity of hUC-MSCs, identifying prostaglandin E{sub 2} (PGE{sub 2}) as an important soluble mediator. CD14{sup +} monocytes were found to be able to enhance significantly the immunosuppressive effect of hUC-MSCs in a dose-dependent fashion. Moreover, the inflammatory cytokine IL-1{beta}, either exogenously added or produced by CD14{sup +} monocytes in culture, could trigger expression of high levels of PGE{sub 2} by hUC-MSCs, whereas inclusion of the IL-1 receptor antagonist (IL-1RA) in the culture down-regulated not only PGE{sub 2} expression, but also reversed the promotional effect of CD14{sup +} monocytes and partially restored CD4{sup +} and CD8{sup +} T cell proliferation and IFN-{gamma} secretion. Our data demonstrate an important role of monocytes in the hUC-MSC-induced immunomodulation, which may have important implications in future efforts to explore the clinical potentials of hUC-MSCs.

  14. Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation. Correlation with ischaemic events.

    PubMed

    Lenti, Massimo; Falcinelli, Emanuela; Pompili, Marcella; de Rango, Paola; Conti, Valentina; Guglielmini, Giuseppe; Momi, Stefania; Corazzi, Teresa; Giordano, Giuseppe; Gresele, Paolo

    2014-06-01

    Purified active matrix metalloproteinase-2 (MMP-2) is able to promote platelet aggregation. We aimed to assess the role of MMP-2 expressed in atherosclerotic plaques in the platelet-activating potential of human carotid plaques and its correlation with ischaemic events. Carotid plaques from 81 patients undergoing endarterectomy were tested for pro-MMP-2 and TIMP-2 content by zymography and ELISA. Plaque extracts were incubated with gel-filtered platelets from healthy volunteers for 2 minutes before the addition of a subthreshold concentration of thrombin receptor activating peptide-6 (TRAP-6) and aggregation was assessed. Moreover, platelet deposition on plaque extracts immobilised on plastic coverslips under high shear-rate flow conditions was measured. Forty-three plaque extracts (53%) potentiated platelet aggregation (+233 ± 26.8%), an effect prevented by three different specific MMP-2 inhibitors (inhibitor II, TIMP-2, moAb anti-MMP-2). The pro-MMP-2/TIMP-2 ratio of plaques potentiating platelet aggregation was significantly higher than that of plaques not potentiating it (3.67 ± 1.21 vs 1.01 ± 0.43, p<0.05). Moreover, the platelet aggregation-potentiating effect, the active-MMP-2 content and the active MMP-2/pro-MMP-2 ratio of plaque extracts were significantly higher in plaques from patients who developed a subsequent major cardiovascular event. In conclusion, atherosclerotic plaques exert a prothrombotic effect by potentiating platelet activation due to their content of MMP-2; an elevated MMP-2 activity in plaques is associated with a higher rate of subsequent ischaemic cerebrovascular events. PMID:24499865

  15. Engineering a growth factor embedded nanofiber matrix niche to promote vascularization for functional cardiac regeneration.

    PubMed

    Lakshmanan, Rajesh; Kumaraswamy, Priyadharshini; Krishnan, Uma Maheswari; Sethuraman, Swaminathan

    2016-08-01

    The major loss of tissue extracellular matrix (ECM) after myocardial ischemia is a serious burden that gradually leads to heart failure. Due to lack of available treatment methods to restore the cardiac function, various research strategies have come up to treat the ischemic myocardium. However these have met with limited success due to the complexity of the cardiac tissue, which exhibits a nanofibrous collagenous matrix with spatio-temporal localization of a combination of growth factors. To mimic the topographical and chemical cues of the natural cardiac tissue, we have fabricated a growth factor embedded nanofibrous scaffold through electrospinning. In our previous work, we have reported a nanofibrous matrix made of PLCL and PEOz with an average diameter of 500 nm. The scaffold properties were specifically characterized in vitro for cardio-compatibility. In the present study, we have loaded dual growth factors VEGF and bFGF in the nanofiber matrix and investigated its suitability for cardiac tissue engineering. The encapsulation and release of dual growth factors from the matrix were studied using XPS and ELISA. Bioactivity of the loaded growth factors towards proliferation and migration of endothelial cells (HUVECs) was evaluated through MTS and Boyden chamber assays respectively. The efficiency of growth factors on the nanofibrous matrix to activate signaling molecules was studied in HUVECs through gene expression analysis. Preclinical evaluation of the growth factor embedded nanofibrous patch in a rabbit acute myocardial infarction (AMI) model was studied and cardiac function assessment was made through ECG and echocardiography. The evidence for angiogenesis in the patch secured regions was analyzed through histopathology and immunohistochemistry. Our results confirm the effectiveness of growth factor embedded nanofiber matrix in restoration of cardiac function after ischemia when compared to conventional patch material thereby exhibiting promise as a

  16. Biophysical and Biochemical Outcomes of Chlamydia pneumoniae Infection Promotes Pro-atherogenic Matrix Microenvironment.

    PubMed

    Evani, Shankar J; Dallo, Shatha F; Ramasubramanian, Anand K

    2016-01-01

    Multiple studies support the hypothesis that infectious agents may be involved in the pathogenesis of atherosclerosis. Chlamydia pneumoniae is strongly implicated in atherosclerosis, but the precise role has been underestimated and poorly understood due to the complexity of the disease process. In this work, we test the hypothesis that C. pneumoniae-infected macrophages lodged in the subendothelial matrix contribute to atherogenesis through pro-inflammatory factors and by cell-matrix interactions. To test this hypothesis, we used a 3D infection model with freshly isolated PBMC infected with live C. pneumoniae and chlamydial antigens encapsulated in a collagen matrix, and analyzed the inflammatory responses over 7 days. We observed that infection significantly upregulates the secretion of cytokines TNF-α, IL-1β, IL-8, MCP-1, MMP, oxidative stress, transendothelial permeability, and LDL uptake. We also observed that infected macrophages form clusters, and substantially modify the microstructure and mechanical properties of the extracellular matrix to an atherogenic phenotype. Together, our data demonstrates that C. pneumoniae-infection drives a low-grade, sustained inflammation that may predispose in the transformation to atherosclerotic foci. PMID:27582738

  17. Biophysical and Biochemical Outcomes of Chlamydia pneumoniae Infection Promotes Pro-atherogenic Matrix Microenvironment

    PubMed Central

    Evani, Shankar J.; Dallo, Shatha F.; Ramasubramanian, Anand K.

    2016-01-01

    Multiple studies support the hypothesis that infectious agents may be involved in the pathogenesis of atherosclerosis. Chlamydia pneumoniae is strongly implicated in atherosclerosis, but the precise role has been underestimated and poorly understood due to the complexity of the disease process. In this work, we test the hypothesis that C. pneumoniae-infected macrophages lodged in the subendothelial matrix contribute to atherogenesis through pro-inflammatory factors and by cell-matrix interactions. To test this hypothesis, we used a 3D infection model with freshly isolated PBMC infected with live C. pneumoniae and chlamydial antigens encapsulated in a collagen matrix, and analyzed the inflammatory responses over 7 days. We observed that infection significantly upregulates the secretion of cytokines TNF-α, IL-1β, IL-8, MCP-1, MMP, oxidative stress, transendothelial permeability, and LDL uptake. We also observed that infected macrophages form clusters, and substantially modify the microstructure and mechanical properties of the extracellular matrix to an atherogenic phenotype. Together, our data demonstrates that C. pneumoniae-infection drives a low-grade, sustained inflammation that may predispose in the transformation to atherosclerotic foci. PMID:27582738

  18. A functional polyester carrying free hydroxyl groups promotes the mineralization of osteoblast and human mesenchymal stem cell extracellular matrix.

    PubMed

    Bi, Xiaoping; You, Zhengwei; Gao, Jin; Fan, Xianqun; Wang, Yadong

    2014-06-01

    Functional groups can control biointerfaces and provide a simple way to make therapeutic materials. We recently reported the design and synthesis of poly(sebacoyl diglyceride) (PSeD) carrying a free hydroxyl group in its repeating unit. This paper examines the use of this polymer to promote biomineralization for application in bone tissue engineering. PSeD promoted more mineralization of extracellular matrix secreted by human mesenchymal stem cells and rat osteoblasts than poly(lactic-co-glycolic acid) (PLGA), which is currently widely used in bone tissue engineering. PSeD showed in vitro osteocompatibility and in vivo biocompatibility that matched or surpassed that of PLGA, as well as supported the attachment, proliferation and differentiation of rat osteoblasts and human mesenchymal stem cells. This demonstrates the potential of PSeD for use in bone regeneration. PMID:24560799

  19. ADAMTSL-6 Is a Novel Extracellular Matrix Protein That Binds to Fibrillin-1 and Promotes Fibrillin-1 Fibril Formation*

    PubMed Central

    Tsutsui, Ko; Manabe, Ri-ichiroh; Yamada, Tomiko; Nakano, Itsuko; Oguri, Yasuko; Keene, Douglas R.; Sengle, Gerhard; Sakai, Lynn Y.; Sekiguchi, Kiyotoshi

    2010-01-01

    ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs)-like (ADAMTSL) proteins, a subgroup of the ADAMTS superfamily, share several domains with ADAMTS proteinases, including thrombospondin type I repeats, a cysteine-rich domain, and an ADAMTS spacer, but lack a catalytic domain. We identified two new members of ADAMTSL proteins, ADAMTSL-6α and -6β, that differ in their N-terminal amino acid sequences but have common C-terminal regions. When transfected into MG63 osteosarcoma cells, both isoforms were secreted and deposited into pericellular matrices, although ADAMTSL-6α, in contrast to -6β, was barely detectable in the conditioned medium. Immunolabeling at the light and electron microscopic levels showed their close association with fibrillin-1-rich microfibrils in elastic connective tissues. Surface plasmon resonance analyses demonstrated that ADAMTSL-6β binds to the N-terminal half of fibrillin-1 with a dissociation constant of ∼80 nm. When MG63 cells were transfected or exogenously supplemented with ADAMTSL-6, fibrillin-1 matrix assembly was promoted in the early but not the late stage of the assembly process. Furthermore, ADAMTSL-6 transgenic mice exhibited excessive fibrillin-1 fibril formation in tissues where ADAMTSL-6 was overexpressed. All together, these results indicated that ADAMTSL-6 is a novel microfibril-associated protein that binds directly to fibrillin-1 and promotes fibrillin-1 matrix assembly. PMID:19940141

  20. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters

    PubMed Central

    Naba, Alexandra; Clauser, Karl R; Lamar, John M; Carr, Steven A; Hynes, Richard O

    2014-01-01

    The extracellular matrix (ECM) is a major component of tumors and a significant contributor to cancer progression. In this study, we use proteomics to investigate the ECM of human mammary carcinoma xenografts and show that primary tumors of differing metastatic potential differ in ECM composition. Both tumor cells and stromal cells contribute to the tumor matrix and tumors of differing metastatic ability differ in both tumor- and stroma-derived ECM components. We define ECM signatures of poorly and highly metastatic mammary carcinomas and these signatures reveal up-regulation of signaling pathways including TGFβ and VEGF. We further demonstrate that several proteins characteristic of highly metastatic tumors (LTBP3, SNED1, EGLN1, and S100A2) play causal roles in metastasis, albeit at different steps. Finally we show that high expression of LTBP3 and SNED1 correlates with poor outcome for ER−/PR−breast cancer patients. This study thus identifies novel biomarkers that may serve as prognostic and diagnostic tools. DOI: http://dx.doi.org/10.7554/eLife.01308.001 PMID:24618895

  1. Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis.

    PubMed

    Zandueta, Carolina; Ormazábal, Cristina; Perurena, Naiara; Martínez-Canarias, Susana; Zalacaín, Marta; Julián, Mikel San; Grigoriadis, Agamemnon E; Valencia, Karmele; Campos-Laborie, Francisco J; Rivas, Javier De Las; Vicent, Silvestre; Patiño-García, Ana; Lecanda, Fernando

    2016-08-01

    Osteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo-naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix-Gla protein (MGP), a non-collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans-endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFβ-induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep.usal.es/osteosarcoma/ Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27172275

  2. The NuRD Chromatin-Remodeling Enzyme CHD4 Promotes Embryonic Vascular Integrity by Transcriptionally Regulating Extracellular Matrix Proteolysis

    PubMed Central

    Ingram, Kyle G.; Curtis, Carol D.; Silasi-Mansat, Robert; Lupu, Florea; Griffin, Courtney T.

    2013-01-01

    The extracellular matrix (ECM) supports vascular integrity during embryonic development. Proteolytic degradation of ECM components is required for angiogenesis, but excessive ECM proteolysis causes blood vessel fragility and hemorrhage. Little is understood about how ECM proteolysis is transcriptionally regulated during embryonic vascular development. We now show that the NuRD ATP-dependent chromatin-remodeling complex promotes vascular integrity by preventing excessive ECM proteolysis in vivo. Mice lacking endothelial CHD4—a catalytic subunit of NuRD complexes—died at midgestation from vascular rupture. ECM components surrounding rupture-prone vessels in Chd4 mutants were significantly downregulated prior to embryonic lethality. Using qPCR arrays, we found two critical mediators of ECM stability misregulated in mutant endothelial cells: the urokinase-type plasminogen activator receptor (uPAR or Plaur) was upregulated, and thrombospondin-1 (Thbs1) was downregulated. Chromatin immunoprecipitation assays showed that CHD4-containing NuRD complexes directly bound the promoters of these genes in endothelial cells. uPAR and THBS1 respectively promote and inhibit activation of the potent ECM protease plasmin, and we detected increased plasmin activity around rupture-prone vessels in Chd4 mutants. We rescued ECM components and vascular rupture in Chd4 mutants by genetically reducing urokinase (uPA or Plau), which cooperates with uPAR to activate plasmin. Our findings provide a novel mechanism by which a chromatin-remodeling enzyme regulates ECM stability to maintain vascular integrity during embryonic development. PMID:24348274

  3. Urinary bladder matrix promotes site appropriate tissue formation following right ventricle outflow tract repair

    PubMed Central

    Remlinger, Nathaniel T; Gilbert, Thomas W; Yoshida, Masahiro; Guest, Brogan N; Hashizume, Ryotaro; Weaver, Michelle L; Wagner, William R; Brown, Bryan N; Tobita, Kimimasa; Wearden, Peter D

    2013-01-01

    The current prevalence and severity of heart defects requiring functional replacement of cardiac tissue pose a serious clinical challenge. Biologic scaffolds are an attractive tissue engineering approach to cardiac repair because they avoid sensitization associated with homograft materials and theoretically possess the potential for growth in similar patterns as surrounding native tissue. Both urinary bladder matrix (UBM) and cardiac ECM (C-ECM) have been previously investigated as scaffolds for cardiac repair with modest success, but have not been compared directly. In other tissue locations, bone marrow derived cells have been shown to play a role in the remodeling process, but this has not been investigated for UBM in the cardiac location, and has never been studied for C-ECM. The objectives of the present study were to compare the effectiveness of an organ-specific C-ECM patch with a commonly used ECM scaffold for myocardial tissue repair of the right ventricle outflow tract (RVOT), and to examine the role of bone marrow derived cells in the remodeling response. A chimeric rat model in which all bone marrow cells express green fluorescent protein (GFP) was generated and used to show the ability of ECM scaffolds derived from the heart and bladder to support cardiac function and cellular growth in the RVOT. The results from this study suggest that urinary bladder matrix may provide a more appropriate substrate for myocardial repair than cardiac derived matrices, as shown by differences in the remodeling responses following implantation, as well as the presence of site appropriate cells and the formation of immature, myocardial tissue. PMID:23974174

  4. Tenascin-R promotes assembly of the extracellular matrix of perineuronal nets via clustering of aggrecan

    PubMed Central

    Morawski, Markus; Dityatev, Alexander; Hartlage-Rübsamen, Maike; Blosa, Maren; Holzer, Max; Flach, Katharina; Pavlica, Sanja; Dityateva, Galina; Grosche, Jens; Brückner, Gert; Schachner, Melitta

    2014-01-01

    Perineuronal nets (PNs) in the brains of tenascin-R-deficient (tn-r−/−) mice develop in temporal concordance with those of wild-type (tn-r+/+) mice. However, the histological appearance of PNs is abnormal in adult tn-r−/− mice. Here, we investigated whether similar defects are also seen in dissociated and organotypic cultures from hippocampus and forebrain of tn-r−/− mice and whether the structure of PNs could be normalized. In tn-r−/− cultures, accumulations of several extracellular matrix molecules were mostly associated with somata, whereas dendrites were sparsely covered, compared with tn-r+/+ mice. Experiments to normalize the structure of PNs in tn-r−/− organotypic slice cultures by depolarization of neurons, or by co-culturing tn-r+/+ and tn-r−/− brain slices failed to restore a normal PN phenotype. However, formation of dendritic PNs in cultures was improved by the application of tenascin-R protein and rescued by polyclonal antibodies to aggrecan and a bivalent, but not monovalent form of the lectin Wisteria floribunda agglutinin. These results show that tenascin-R and aggrecan are decisive contributors to formation and stabilization of PNs and that tenascin-R may implement these functions by clustering of aggrecan. Proposed approaches for restoration of normal PN structure are noteworthy in the context of PN abnormalities in neurological disorders, such as epilepsy, schizophrenia and addiction. PMID:25225104

  5. Haemophilus influenzae P4 Interacts With Extracellular Matrix Proteins Promoting Adhesion and Serum Resistance.

    PubMed

    Su, Yu-Ching; Mukherjee, Oindrilla; Singh, Birendra; Hallgren, Oskar; Westergren-Thorsson, Gunilla; Hood, Derek; Riesbeck, Kristian

    2016-01-15

    Interaction with the extracellular matrix (ECM) is one of the successful colonization strategies employed by nontypeable Haemophilus influenzae (NTHi). Here we identified Haemophilus lipoprotein e (P4) as a receptor for ECM proteins. Purified recombinant P4 displayed a high binding affinity for laminin (Kd = 9.26 nM) and fibronectin (Kd = 10.19 nM), but slightly less to vitronectin (Kd = 16.51 nM). A P4-deficient NTHi mutant showed a significantly decreased binding to these ECM components. Vitronectin acquisition conferred serum resistance to both P4-expressing NTHi and Escherichia coli transformants. P4-mediated bacterial adherence to pharynx, type II alveolar, and bronchial epithelial cells was mainly attributed to fibronectin. Importantly, a significantly reduced bacterial infection was observed in the middle ear of the Junbo mouse model when NTHi was devoid of P4. In conclusion, our data provide new insight into the role of P4 as an important factor for Haemophilus colonization and subsequent respiratory tract infection. PMID:26153407

  6. The widely expressed extracellular matrix protein SMOC-2 promotes keratinocyte attachment and migration

    SciTech Connect

    Maier, Silke; Paulsson, Mats; Hartmann, Ursula

    2008-08-01

    SMOC-2 is a recently discovered member of the BM-40/SPARC/osteonectin family of extracellular multidomain proteins of so far unknown function. While we have shown earlier that the homologous protein SMOC-1 is associated with basement membranes, in this study we demonstrate that, in the mouse, SMOC-2 could be detected in a large number of non-basement membrane localizations, often showing a diffuse tissue distribution. A more distinct expression pattern was seen in skin where SMOC-2 is mainly present in the basal layers of the epidermis. Functionally, recombinant SMOC-2 stimulated attachment of primary epidermal cells as well as several epidermal-derived cell lines but had no effect on the attachment of non-epidermal cells. Inhibition experiments using blocking antibodies against individual integrin subunits allowed the identification of {alpha}v{beta}6 and {alpha}v{beta}1 integrins as important cellular receptors for SMOC-2. Cell attachment as well as the formation of focal adhesions could be attributed to the extracellular calcium-binding domain. The calcium-binding domain also stimulated migration, but not proliferation of keratinocyte-like HaCaT cells. We conclude that SMOC-2, like other members of the BM40/SPARC family, acts as a regulator of cell-matrix interactions.

  7. CAPN 7 promotes the migration and invasion of human endometrial stromal cell by regulating matrix metalloproteinase 2 activity

    PubMed Central

    2013-01-01

    Background Matrix metalloproteinase 2 (MMP-2) has been reported to be an important regulator of cell migration and invasion through degradation of the extracellular matrix (ECM) in many diseases, such as cancer and endometriosis. Here, we found calcium-activated neutral protease 7 (CAPN 7) expression was markedly upregulated in the eutopic endometrium and endometrial stromal cells of women diagnosed with endometriosis. Our studies were carried out to detect the effects of CAPN 7 on human endometrial stromal cell (hESC) migration and invasion. Methods Western blotting and quantitative real-time PCR were used to detect the expression of CAPN 7 in endometriosis patients and normal fertile women. Scratch-wound-healing and invasion chamber assay were used to investigate the role of CAPN 7 in hESC migration and invasion. Western blotting, quantitative real-time PCR and zymography were carried out to detect the effect of CAPN 7 on the expressions and activity of MMP-2. Results CAPN 7 was markedly up-regulated in endometriosis, thereby promoting the migration and invasion of hESC. CAPN 7 overexpression led to increased expression of MMP-2 and tissue inhibitor of metalloproteinases 2 (TIMP-2); CAPN 7 knockdown reversed these changes. CAPN 7 increased MMP-2 activity by increasing the ratio of MMP-2 to TIMP-2. We also found that OA-Hy (an MMP-2 inhibitor) decreased the effects of CAPN 7 overexpression on hESC migration and invasion by approximately 50% and 55%, respectively. Additionally, a coimmunoprecipitation assay demonstrated that CAPN 7 interacted with activator protein 2α (AP-2α): an important transcription factor of MMP-2. Conclusions CAPN 7 promotes hESC migration and invasion by increasing the activity of MMP-2 via an increased ratio of MMP-2 to TIMP-2. PMID:23855590

  8. A Fibrin Matrix Promotes the Differentiation of EMSCs Isolated from Nasal Respiratory Mucosa to Myelinating Phenotypical Schwann-Like Cells

    PubMed Central

    Chen, Qian; Zhang, Zhijian; Liu, Jinbo; He, Qinghua; Zhou, Yuepeng; Shao, Genbao; Sun, Xianglan; Cao, Xudong; Gong, Aihua; Jiang, Ping

    2015-01-01

    Because Schwann cells perform the triple tasks of myelination, axon guidance and neurotrophin synthesis, they are candidates for cell transplantation that might cure some types of nervous-system degenerative diseases or injuries. However, Schwann cells are difficult to obtain. As another option, ectomesenchymal stem cells (EMSCs) can be easily harvested from the nasal respiratory mucosa. Whether fibrin, an important transplantation vehicle, can improve the differentiation of EMSCs into Schwann-like cells (SLCs) deserves further research. EMSCs were isolated from rat nasal respiratory mucosa and were purified using anti-CD133 magnetic cell sorting. The purified cells strongly expressed HNK-1, nestin, p75NTR, S-100, and vimentin. Using nuclear staining, the MTT assay and Western blotting analysis of the expression of cell-cycle markers, the proliferation rate of EMSCs on a fibrin matrix was found to be significantly higher than that of cells grown on a plastic surface but insignificantly lower than that of cells grown on fibronectin. Additionally, the EMSCs grown on the fibrin matrix expressed myelination-related molecules, including myelin basic protein (MBP), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) and galactocerebrosides (GalCer), more strongly than did those grown on fibronectin or a plastic surface. Furthermore, the EMSCs grown on the fibrin matrix synthesized more neurotrophins compared with those grown on fibronectin or a plastic surface. The expression level of integrin in EMSCs grown on fibrin was similar to that of cells grown on fibronectin but was higher than that of cells grown on a plastic surface. These results demonstrated that fibrin not only promoted EMSC proliferation but also the differentiation of EMSCs into the SLCs. Our findings suggested that fibrin has great promise as a cell transplantation vehicle for the treatment of some types of nervous system diseases or injuries. PMID:25666351

  9. The matrix protein CCN1 (CYR61) promotes proliferation, migration and tube formation of endothelial progenitor cells

    SciTech Connect

    Yu Yang; Gao Yu; Wang, Hong; Huang Lan Qin Jun; Guo Ruiwei; Song Mingbao; Yu Shiyong; Chen Jianfei; Cui Bin; Gao Pan

    2008-10-15

    Neovascularization and re-endothelialization relies on circulating endothelial progenitor cells (EPCs), but their recruitment and angiogenic roles are subjected to regulation by the vascular microenvironment, which remains largely unknown. The present study was designed to investigate the effects of mature ECs and matrix protein CCN1 on the properties of EPCs. In a coculture system, effects of ECs on proliferation, migration and participation in tube-like formation of EPCs were evaluated, and functional assays were employed to identify the exact role of CCN1 in EPCs vitality and function. We demonstrated that ECs, as an indispensable part of the cellular milieu, significantly promoted the proliferation, migration and tube formation activities of EPCs, and more importantly, CCN1 was potentially involved in such effects of ECs. Expression of CCN1 in EPCs was significantly increased by serum, VEGF, ECs-cocultivation and ECs conditioned medium. Moreover, Ad-CCN1-mediated overexpression of CCN1 directly enhanced migration and tube formation of EPCs, whereas silencing of endogenous CCN1 in EPCs inhibits cell functions. Furthermore, CCN1 induced the expressions of chemokines and growth factors, such as MCP-1 and VEGF, suggesting a complex interaction between those proangiogenic factors. Our data suggest that matrix protein CCN1 may play an important role in microenvironment-mediated biological properties of EPCs.

  10. Therapeutic angiogenesis promotes efficacy of human umbilical cord matrix stem cell transplantation in cardiac repair

    PubMed Central

    Moradi, Kaveh; Abbasi, Mehdi; Aboulhasani, Farid; Abbasi, Niloufar; Babatunde, Kehinde Adebayo; Sargolzaeiaval, Fereydoon; Dehpour, Ahmad-Reza

    2015-01-01

    Objective(s): Although previous studies have confirmed the beneficial effects of human umbilical cord matrix stem cell (hUCM) transplantation post myocardial infarction (MI), but this stem cell resource has no potential to induce angiogenesis. In order to achieve the process of angiogenesis and cardiomyocyte regeneration, two required factors for cardiac repair agents were examined namely; hUCM and VEGF on an infarcted heart. The main objective of this research is to investigate the combinatory effect of dhUCM and VEGF transplantation on an infarcted heart. Materials and Methods: 45 min of ligating the left anterior descending coronary artery, the MI-induced animals received 50 μl PBS, 5 μg VEGF, 5×106 hUCM cells alone, combined with 5 μg VEGF and 5×106 differentiated hUCM cells alone or combined with 5 μg VEGF through intramyocardial injection. MI group, without hUCM and VEGF served as the control group. Left ventricular function and angiogenesis were also evaluated. Results: After eight weeks post MI, there were significant rise in left ventricular ejection farction in dhUCM+VEGF group compared to the other treated and non-treated groups (P<0.05). Fibrosis tissue was markedly lower in the dhUCM+VEGF and hUCM+VEGF groups compared to the other treated and non-treated groups (P<0.05). Despite these benefits, vascular density in dhUCM+VEGF group was not markedly different compared to VEGF and hUCM+VEGF groups. The transplanted hUCM and dhUCM cells survived and migrated to the infarcted area. Conclusion: Our findings demonstrated that the dhUCM cells transplantation combined with VEGF were more efficient on an infarcted heart. PMID:26221480

  11. Surface-Associated Plasminogen Binding of Cryptococcus neoformans Promotes Extracellular Matrix Invasion

    PubMed Central

    Fox, Deborah

    2009-01-01

    Background The fungal pathogen Cryptococcus neoformans is a leading cause of illness and death in persons with predisposing factors, including: malignancies, solid organ transplants, and corticosteroid use. C. neoformans is ubiquitous in the environment and enters into the lungs via inhalation, where it can disseminate through the bloodstream and penetrate the central nervous system (CNS), resulting in a difficult to treat and often-fatal infection of the brain, called meningoencephalitis. Plasminogen is a highly abundant protein found in the plasma component of blood and is necessary for the degradation of fibrin, collagen, and other structural components of tissues. This fibrinolytic system is utilized by cancer cells during metastasis and several pathogenic species of bacteria have been found to manipulate the host plasminogen system to facilitate invasion of tissues during infection by modifying the activation of this process through the binding of plasminogen at their surface. Methodology The invasion of the brain and the central nervous system by penetration of the protective blood-brain barrier is a prerequisite to the establishment of meningoencephalitis by the opportunistic fungal pathogen C. neoformans. In this study, we examined the ability of C. neoformans to subvert the host plasminogen system to facilitate tissue barrier invasion. Through a combination of biochemical, cell biology, and proteomic approaches, we have shown that C. neoformans utilizes the host plasminogen system to cross tissue barriers, providing support for the hypothesis that plasminogen-binding may contribute to the invasion of the blood-brain barrier by penetration of the brain endothelial cells and underlying matrix. In addition, we have identified the cell wall-associated proteins that serve as plasminogen receptors and characterized both the plasminogen-binding and plasmin-activation potential for this significant human pathogen. Conclusions The results of this study provide

  12. Correlations of polymorphisms in matrix metalloproteinase-1, -2, and -7 promoters to susceptibility to malignant gliomas

    PubMed Central

    Kawal, Priyanka; Chandra, Anil; Rajkumar; Dhole, Tapan N.; Ojha, Balkrishna

    2016-01-01

    Background: Oligodendrogliomas are infiltrative astrocytic tumors. They constitute about 1-5% of intracranial tumors. These have been graded into benign and malignant grades. The single nucleotide polymorphisms (SNPs) in the promoter regions of MMP genes may influence tumor development and progression. This study was done to explore the correlations of the promoter SNPs in MMP-1, MMP-2 and MMP-7 genes susceptibility in development and progression of oligodendrogliomas. Objectives: We aimed to investigate the association of MMP1 (−1607A > G), MMP-2 (−1306 C/T) and MMP-7(−181A > G) gene polymorphism in oligodendrogliomas (grade I, II, III). Materials and Methods: In the present case control study, we enrolled a total of 30 cases of oligodendrogliomas (grade I to III) confirmed by histopathology and 30 healthy cases as control. Polymorphism for MMP-1 gene (−1607A > G), MMP-2 (−1306 C/T), MMP-7(−181A > G) were genotyped by restriction fragment length polymorphism. Results: Frequencies of MMP-1 (−1607A > G) genotypes and 2G alleles were significantly associated with the cases of oligodendrogliomas (30%) in relation to healthy controls (13%). [OR = 6.89; P = 0.02; 95%CI= (1.33-35.62)] and [OR = 2.66; P =0.01; 95% CI= (1.26-5.64)]. A significant association of MMP-2 (−1306C/T) polymorphism with oligodendroglioma (P = 0.54) was not found, suggesting that MMP-2 (−1306C/T) polymorphism is not associated with increased oligodendroglioma susceptibility. Frequencies of MMP-7(−181A > G) genotypes and 2G alleles were significantly associated with the cases of oligodendrogliomas (33.33%) in relation to healthy controls (13.33%). [OR = 5.65; P = 0.02; 95%CI= (1.26-25.36)] and [OR = 2.49; P =0.01; 95% CI= (1.17-5.27)]. Conclusions: MMP-1 (−1607 A > G), MMP-7(−181A > G) genotypes and 2G alleles were significantly associated with oligodendroglioma (grade I, II, III), but MMP-2 (−1306C/T) polymorphism is not associated with increased oligodendroglioma

  13. Deficiency of the protein-tyrosine phosphatase DEP-1/PTPRJ promotes matrix metalloproteinase-9 expression in meningioma cells.

    PubMed

    Petermann, Astrid; Stampnik, Yvonn; Cui, Yan; Morrison, Helen; Pachow, Doreen; Kliese, Nadine; Mawrin, Christian; Böhmer, Frank-D

    2015-05-01

    Brain-invasive growth of a subset of meningiomas is associated with less favorable prognosis. The molecular mechanisms causing invasiveness are only partially understood, however, the expression of matrix metalloproteinases (MMPs) has been identified as a contributing factor. We have previously found that loss of density enhanced phosphatase-1 (DEP-1, also designated PTPRJ), a transmembrane protein-tyrosine phosphatase, promotes meningioma cell motility and invasive growth in an orthotopic xenotransplantation model. We have now analyzed potential alterations of the expression of genes involved in motility control, caused by DEP-1 loss in meningioma cell lines. DEP-1 depleted cells exhibited increased expression of mRNA encoding MMP-9, and the growth factors EGF and FGF-2. The increase of MMP-9 expression in DEP-1 depleted cells was also readily detectable at the protein level by zymography. MMP-9 upregulation was sensitive to chemical inhibitors of growth factor signal transduction. Conversely, MMP-9 mRNA levels could be stimulated with growth factors (e.g. EGF) and inflammatory cytokines (e.g. TNFα). Increase of MMP-9 expression by DEP-1 depletion, or growth factor/cytokine stimulation qualitatively correlated with increased invasiveness in vitro scored as transmigration through matrigel-coated membranes. The studies suggest induction of MMP-9 expression promoted by DEP-1 deficiency, or potentially by growth factors and inflammatory cytokines, as a mechanism contributing to meningioma brain invasiveness. PMID:25672645

  14. Inverted formin 2 in focal adhesions promotes dorsal stress fiber and fibrillar adhesion formation to drive extracellular matrix assembly

    PubMed Central

    Skau, Colleen T.; Plotnikov, Sergey V.; Doyle, Andrew D.; Waterman, Clare M.

    2015-01-01

    Actin filaments and integrin-based focal adhesions (FAs) form integrated systems that mediate dynamic cell interactions with their environment or other cells during migration, the immune response, and tissue morphogenesis. How adhesion-associated actin structures obtain their functional specificity is unclear. Here we show that the formin-family actin nucleator, inverted formin 2 (INF2), localizes specifically to FAs and dorsal stress fibers (SFs) in fibroblasts. High-resolution fluorescence microscopy and manipulation of INF2 levels in cells indicate that INF2 plays a critical role at the SF–FA junction by promoting actin polymerization via free barbed end generation and centripetal elongation of an FA-associated actin bundle to form dorsal SF. INF2 assembles into FAs during maturation rather than during their initial generation, and once there, acts to promote rapid FA elongation and maturation into tensin-containing fibrillar FAs in the cell center. We show that INF2 is required for fibroblasts to organize fibronectin into matrix fibers and ultimately 3D matrices. Collectively our results indicate an important role for the formin INF2 in specifying the function of fibrillar FAs through its ability to generate dorsal SFs. Thus, dorsal SFs and fibrillar FAs form a specific class of integrated adhesion-associated actin structure in fibroblasts that mediates generation and remodeling of ECM. PMID:25918420

  15. Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter.

    PubMed Central

    Bian, J; Sun, Y

    1997-01-01

    p53, a tumor suppressor and a transcription factor, has been shown to transcriptionally activate the expression of a number of important genes involved in the regulation of cell growth, DNA damage, angiogenesis, and apoptosis. In a computer search for other potential p53 target genes, we identified a perfect p53 binding site in the promoter of the human type IV collagenase (also called 72-kDa gelatinase or matrix metalloproteinase 2 [MMP-2]) gene. This p53 binding site was found to specifically bind to p53 protein in a gel shift assay. Transcription assays with luciferase reporters driven by the promoter or enhancer of the type IV collagenase gene revealed that (i) activation of the promoter activity is p53 binding site dependent in p53-positive cells but not in p53-negative cells and (ii) wild-type p53, but not p53 mutants commonly found in human cancers, transactivates luciferase expression driven by the type IV collagenase promoter as well as by a p53 site-containing enhancer element in the promoter. Significantly, expression of the endogenous type IV collagenase is also under the control of p53. Treatment of U2-OS cells, a wild-type p53-containing osteogenic sarcoma line, with a common p53 inducer, etoposide, induced p53 DNA binding and transactivation activities in a time-dependent manner. Induction of type IV collagenase expression followed the p53 activation pattern. No induction of type IV collagenase expression can be detected under the same experimental conditions in p53-negative Saos-2 cells. All these in vitro and in vivo assays strongly suggest that the type IV collagenase gene is a p53 target gene and that its expression is subject to p53 regulation. Our finding links p53 to a member of the MMP genes, a family of genes implicated in trophoblast implantation, wound healing, angiogenesis, arthritis, and tumor cell invasion. p53 may regulate these processes by upregulating expression of type IV collagenase. PMID:9343394

  16. Promotion

    PubMed Central

    Alam, Hasan B.

    2013-01-01

    This article gives an overview of the promotion process in an academic medical center. A description of different promotional tracks, tenure and endowed chairs, and the process of submitting an application is provided. Finally, some practical advice about developing skills and attributes that can help with academic growth and promotion is dispensed. PMID:24436683

  17. High-mobility group box 1 promotes extracellular matrix synthesis and wound repair in human bronchial epithelial cells.

    PubMed

    Ojo, Oluwaseun O; Ryu, Min Hyung; Jha, Aruni; Unruh, Helmut; Halayko, Andrew J

    2015-12-01

    High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that binds Toll-like receptors (e.g., TLR4) and the receptor for advanced glycated end products (RAGE). The direct effects of HMGB1 on airway structural cells are not fully known. As epithelial cell responses are fundamental drivers of asthma, including abnormal repair-restitution linked to changes in extracellular matrix (ECM) synthesis, we tested the hypothesis that HMGB1 promotes bronchial epithelial cell wound repair via TLR4 and/or RAGE signaling that regulates ECM (fibronectin and the γ2-chain of laminin-5) and integrin protein abundance. To assess impact of HMGB1 we used molecular and pharmacological inhibitors of RAGE or TLR4 signaling in scratch wound, immunofluorescence, and immunoblotting assays to assess wound repair, ECM synthesis, and phosphorylation of intracellular signaling. HMGB1 increased wound closure, and this effect was attenuated by blocking RAGE and TLR4 signaling. HMGB1-induced fibronectin and laminin-5 (γ2 chain) was diminished by blocking RAGE and/or blunting TLR4 signaling. Similarly, induction of α3-integrin receptor for fibronectin and laminin-5 was also diminished by blocking TLR4 signaling and RAGE. Lastly, rapid and/or sustained phosphorylation of SMAD2, ERK1/2, and JNK signaling modulated HMGB1-induced wound closure. Our findings suggest a role for HMGB1 in human airway epithelial cell repair and restitution via multiple pathways mediated by TLR4 and RAGE that underpin increased ECM synthesis and modulation of cell-matrix adhesion. PMID:26432865

  18. Heparin-induced conformational changes of fibronectin within the extracellular matrix promote hMSC osteogenic differentiation.

    PubMed

    Li, Bojun; Lin, Zhe; Mitsi, Maria; Zhang, Yang; Vogel, Viola

    2015-01-01

    An increasing body of evidence suggests important roles of extracellular matrix (ECM) in regulating stem cell fate. This knowledge can be exploited in tissue engineering applications for the design of ECM scaffolds appropriate to direct stem cell differentiation. By probing the conformation of fibronectin (Fn) using fluorescence resonance energy transfer (FRET), we show here that heparin treatment of the fibroblast-derived ECM scaffolds resulted in more extended conformations of fibrillar Fn in ECM. Since heparin is a highly negatively charged molecule while fibronectin contains segments of positively charged modules, including FnIII13, electrostatic interactions between Fn and heparin might interfere with residual quaternary structure in relaxed fibronectin fibers thereby opening up buried sites. The conformation of modules FnIII12-14 in particular, which contain one of the heparin binding sites as well as binding sites for many growth factors, may be activated by heparin, resulting in alterations in growth factor binding to Fn. Indeed, upregulated osteogenic differentiation was observed when hMSCs were seeded on ECM scaffolds that had been treated with heparin and were subsequently chemically fixed. In contrast, either rigidifying relaxed fibers by fixation alone, or heparin treatment without fixation had no effect. We hypothesize that fibronectin's conformations within the ECM are activated by heparin such as to coordinate with other factors to upregulate hMSC osteogenic differentiation. Thus, the conformational changes of fibronectin within the ECM could serve as a 'converter' to tune hMSC differentiation in extracellular matrices. This knowledge could also be exploited to promote osteogenic stem cell differentiation on biomedical surfaces. PMID:26214191

  19. Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

    PubMed

    Fong, Ashley H; Romero-López, Mónica; Heylman, Christopher M; Keating, Mark; Tran, David; Sobrino, Agua; Tran, Anh Q; Pham, Hiep H; Fimbres, Cristhian; Gershon, Paul D; Botvinick, Elliot L; George, Steven C; Hughes, Christopher C W

    2016-08-01

    Pluripotent stem cell-derived cardiomyocytes (CMs) have great potential in the development of new therapies for cardiovascular disease. In particular, human induced pluripotent stem cells (iPSCs) may prove especially advantageous due to their pluripotency, their self-renewal potential, and their ability to create patient-specific cell lines. Unfortunately, pluripotent stem cell-derived CMs are immature, with characteristics more closely resembling fetal CMs than adult CMs, and this immaturity has limited their use in drug screening and cell-based therapies. Extracellular matrix (ECM) influences cellular behavior and maturation, as does the geometry of the environment-two-dimensional (2D) versus three-dimensional (3D). We therefore tested the hypothesis that native cardiac ECM and 3D cultures might enhance the maturation of iPSC-derived CMs in vitro. We demonstrate that maturation of iPSC-derived CMs was enhanced when cells were seeded into a 3D cardiac ECM scaffold, compared with 2D culture. 3D cardiac ECM promoted increased expression of calcium-handling genes, Junctin, CaV1.2, NCX1, HCN4, SERCA2a, Triadin, and CASQ2. Consistent with this, we find that iPSC-derived CMs in 3D adult cardiac ECM show increased calcium signaling (amplitude) and kinetics (maximum upstroke and downstroke) compared with cells in 2D. Cells in 3D culture were also more responsive to caffeine, likely reflecting an increased availability of calcium in the sarcoplasmic reticulum. Taken together, these studies provide novel strategies for maturing iPSC-derived CMs that may have applications in drug screening and transplantation therapies to treat heart disease. PMID:27392582

  20. Exogenous stimulation with Eclipta alba promotes hair matrix keratinocyte proliferation and downregulates TGF-β1 expression in nude mice.

    PubMed

    Begum, Shahnaz; Lee, Mi Ra; Gu, Li Juan; Hossain, Jamil; Sung, Chang Keun

    2015-02-01

    Eclipta alba (L.) Hassk (E. alba) is a traditionally acclaimed medicinal herb used for the promotion of hair growth. However, to the best of our knowledge, no report has been issued to date on its effects on genetically distorted hair follicles (HFs). In this study, we aimed to identify an agent (stimuli) that may be beneficial for the restoration of human hair loss and which may be used as an alternative to synthetic drugs. We investigated the effects of petroleum ether extract (PEE) and different solvent fractions of E. alba on HFs of nude mice. Treatment was performed by topical application on the backs of nude mice and the changes in hair growth patterns were evaluated. Histological analysis was carried out to evaluate the HF morphology and the structural differences. Immunohistochemical (IHC) staining was performed to visualize follicular keratinocyte proliferation. The histological assessments revealed that the PEE-treated skin specimens exhibited prominent follicular hypertrophy. Subsequently, IHC staining revealed a significant increase (p<0.001) in the number of follicular keratinocytes in basal epidermal and matrix cells. Our results also demonstrated that PEE significantly (p<0.001) reduced the levels of transforming growth factor-β1 (TGF-β1) expression during early anagen and anagen-catagen transition. Our results suggest that PEE of E. alba acts as an important exogenous mediator that stimulates follicular keratinocyte proliferation and delays terminal differentiation by downregulating TGF-β1 expression. Thus, this study highlights the potential use of PEE of E. alba in the treatment of certain types of alopecia. PMID:25484129

  1. Products of dentin matrix protein-1 degradation by interleukin-1β-induced matrix metalloproteinase-3 promote proliferation of odontoblastic cells.

    PubMed

    Hase, Naoko; Ozeki, Nobuaki; Hiyama, Taiki; Yamaguchi, Hideyuki; Kawai, Rie; Kondo, Ayami; Nakata, Kazuhiko; Mogi, Makio

    2015-08-01

    We have previously reported that interleukin (IL)-1β induces matrix metalloproteinase (MMP)-3-regulated cell proliferation in mouse embryonic stem cell (ESC)-derived odontoblast-like cells, suggesting that MMP-3 plays a potentially unique physiological role in regeneration by odontoblast-like cells. MMPs are able to process virtually any component of the extracellular matrix, including collagen, laminin and bioactive molecules. Because odontoblasts produce dentin matrix protein-1 (DMP-1), we examined whether the degraded products of DMP-1 by MMP-3 contribute to enhanced proliferation in odontoblast-like cells. IL-1β increased mRNA and protein levels of odontoblastic marker proteins, including DMP-1, but not osteoblastic marker proteins, such as osteocalcin and osteopontin. The recombinant active form of MMP-3 could degrade DMP-1 protein but not osteocalcin and osteopontin in vitro. The exogenous degraded products of DMP-1 by MMP-3 resulted in increased proliferation of odontoblast-like cells in a dose-dependent manner. Treatment with a polyclonal antibody against DMP-1 suppressed IL-1β-induced cell proliferation to a basal level, but identical treatment had no effect on the IL-1β-induced increase in MMP-3 expression and activity. Treatment with siRNA against MMP-3 potently suppressed the IL-1β-induced increase in DMP-1 expression and suppressed cell proliferation (p < 0.05). Similarly, treatment with siRNAs against Wnt5a and Wnt5b suppressed the IL-1β-induced increase in DMP-1 expression and suppressed cell proliferation (p < 0.05). Rat KN-3 cells, representative of authentic odontoblasts, showed similar responses to the odontoblast-like cells. Taken together, our current study demonstrates the sequential involvement of Wnt5, MMP-3, DMP-1 expression, and DMP-1 degradation products by MMP-3, in effecting IL-1β-induced proliferation of ESC-derived odontoblast-like cells. PMID:26355224

  2. Gene delivery and expression in human retinal pigment epithelial cells: effects of synthetic carriers, serum, extracellular matrix and viral promoters.

    PubMed

    Urtti, A; Polansky, J; Lui, G M; Szoka, F C

    2000-01-01

    Non-viral gene therapy is a potential treatment to many incurable retinal diseases. To fulfill this promise, plasmid DNA must be delivered to the retinal target cells. We evaluated the efficacy of synthetic DNA complexing compounds in transfecting primary human retinal pigment epithelial (RPE) cells in vitro. Fetal human RPE cells were cultured with or without extracellular matrix (ECM), produced using calf corneal endothelial cells. Plasmids encoding nuclear localizing beta galactosidase or luciferase (pRSVLuc, pCLuc4, pSV2Luc) were complexed in water at various +/- charge ratios using cationic lipids (Lipofectin, DOTAP, DOGS), polyethylene imines (25 and 750 kDa), and with degraded 6th generation starburst polyamidoamine dendrimers. Luciferase was quantified using a luminometric assay and beta galactosidase with X-gal staining. Toxicities of transfections were evaluated with the MTT-assay. Using beta galactosidase as the reporter gene naked DNA did not transfect RPE cells at measurable levels whereas 1-5% of the cells expressed histochemically detectable amounts of the gene after transfection with cationic lipid DNA complexes. In RPE cells, Rous sarcoma virus and cytomegalovirus (CMV) were more efficient promoters than SV40 in driving luciferase expression, and CMV was chosen for further experiments. At optimal complex charge ratios, expression levels of luciferase were > 10(9) light units/mg protein after transfection using dendrimers and PEI25, while transfection mediated with the other carriers resulted in luciferase expression levels of 10(7)-10(9) light units/mg protein or less. In general, dendrimers and large molecular weight PEI were less toxic than cationic lipids or PEI25 to RPE cells. Serum and ECM decreased gene expression to the RPE cells with all carriers. Despite low percentage of transfected cells the transgene expression per RPE cell is high, important feature in the retinal tissue with small dimensions, in particular in the case of secreted gene

  3. T-box transcription factor brachyury promotes tumor cell invasion and metastasis in non-small cell lung cancer via upregulation of matrix metalloproteinase 12.

    PubMed

    Wan, Zongmiao; Jiang, Dongjie; Chen, Su; Jiao, Jian; Ji, Lei; Shah, Abdus Saboor; Wei, Haifeng; Yang, Xinghai; Li, Xiaotao; Wang, Ying; Xiao, Jianru

    2016-07-01

    T-box transcription factor brachyury and matrix metalloproteinases (MMPs) play important roles in non-small cell lung cancer (NSCLC) cell invasion and metastasis. However, the association between Brachyury and the MMP family has not yet been fully investigated. The present study aimed to assess the influence of Brachyury on the expression of 23 MMP members and to further explore the mechanisms involved in the promotion of NSCLC cell invasion by Brachyury and MMPs in the H460 and H1299 stable cell lines. The protein expression levels and correlations between the brachyury transcription factor and the targeted MMPs were also validated in 52 NSCLC patient tissue samples. We observed that brachyury significantly upregulated MMP12 expression to promote NSCLC cell invasion. We also found a potential binding site for the brachyury transcription factor in the MMP12 promoter. PMID:27176766

  4. Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton

    PubMed Central

    von Nandelstadh, Pernilla; Gucciardo, Erika; Lohi, Jouko; Li, Rui; Sugiyama, Nami; Carpen, Olli; Lehti, Kaisa

    2014-01-01

    Basal-like breast carcinomas, characterized by unfavorable prognosis and frequent metastases, are associated with epithelial-to-mesenchymal transition. During this process, cancer cells undergo cytoskeletal reorganization and up-regulate membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP14), which functions in actin-based pseudopods to drive invasion by extracellular matrix degradation. However, the mechanisms that couple matrix proteolysis to the actin cytoskeleton in cell invasion have remained unclear. On the basis of a yeast two-hybrid screen for the MT1-MMP cytoplasmic tail-binding proteins, we identify here a novel Src-regulated protein interaction between the dynamic cytoskeletal scaffold protein palladin and MT1-MMP. These proteins were coexpressed in invasive human basal-like breast carcinomas and corresponding cell lines, where they were associated in the same matrix contacting and degrading membrane complexes. The silencing and overexpression of the 90-kDa palladin isoform revealed the functional importance of the interaction with MT1-MMP in pericellular matrix degradation and mesenchymal tumor cell invasion, whereas in MT1-MMP–negative cells, palladin overexpression was insufficient for invasion. Moreover, this invasion was inhibited in a dominant-negative manner by an immunoglobulin domain–containing palladin fragment lacking the dynamic scaffold and Src-binding domains. These results identify a novel protein interaction that links matrix degradation to cytoskeletal dynamics and migration signaling in mesenchymal cell invasion. PMID:24989798

  5. Filamin A Mediates Wound Closure by Promoting Elastic Deformation and Maintenance of Tension in the Collagen Matrix

    PubMed Central

    Mohammadi, Hamid; Pinto, Vanessa I.; Wang, Yongqiang; Hinz, Boris; Janmey, Paul A.; McCulloch, Christopher A.

    2016-01-01

    Cell-mediated remodeling and wound closure are critical for efficient wound healing, but the contribution of actin-binding proteins to contraction of the extracellular matrix is not defined. We examined the role of filamin A (FLNa), an actin filament cross-linking protein, in wound contraction and maintenance of matrix tension. Conditional deletion of FLNa in fibroblasts in mice was associated with ~ 4 day delay of full-thickness skin wound contraction compared with wild-type (WT) mice. We modeled the healing wound matrix using cultured fibroblasts plated on grid-supported collagen gels that create lateral boundaries, which are analogues to wound margins. In contrast to WT cells, FLNa knockdown (KD) cells could not completely maintain tension when matrix compaction was resisted by boundaries, which manifested as relaxed matrix tension. Similarly, WT cells on cross-linked collagen, which requires higher levels of sustained tension, exhibited approximately fivefold larger deformation fields and approximately twofold greater fiber alignment compared with FLNa KD cells. Maintenance of boundary-resisted tension markedly influenced the elongation of cell extensions: in WT cells, the number (~50%) and length (~300%) of cell extensions were greater than FLNa KD cells. We conclude that FLNa is required for wound contraction, in part by enabling elastic deformation and maintenance of tension in the matrix. PMID:26134946

  6. NF-κB and Matrix-Dependent Regulation of Osteopontin Promoter Activity in Allylamine-Activated Vascular Smooth Muscle Cells

    PubMed Central

    Williams, E. Spencer; Wilson, Emily; Ramos, Kenneth S.

    2012-01-01

    Repeated cycles of oxidative injury by allylamine in vivo induce a proliferative rat vascular (aortic) smooth muscle cell (vSMC) phenotype characterized by matrix-dependent enhancement of mitogenic sensitivity, changes in cell surface integrin expression, and osteopontin (opn) overexpression. Here, we show that constitutive and mitogen-stimulated NF-κB DNA binding activity is enhanced in allylamine vSMCs. Matrix-specific changes in cellular Rel protein expression were observed in allylamine vSMCs. The NF-κB DNA binding element located at −1943 in the 5′-UTR strongly inhibited opn promoter activity in allylamine vSMCs, and this response was regulated by the extracellular matrix. Constitutive increases in opn promoter activity were only seen when allylamine cells were seeded on a fibronectin substrate, and this response was independent of the NF-κB DNA binding sequence within the regulatory region. Thus, NF-κB functions as a critical regulator of the allylamine-induced proliferative phenotype in vSMCs. PMID:22315656

  7. Nanocatalysts promote Streptococcus mutans biofilm matrix degradation and enhance bacterial killing to suppress dental caries in vivo.

    PubMed

    Gao, Lizeng; Liu, Yuan; Kim, Dongyeop; Li, Yong; Hwang, Geelsu; Naha, Pratap C; Cormode, David P; Koo, Hyun

    2016-09-01

    Dental biofilms (known as plaque) are notoriously difficult to remove or treat because the bacteria can be enmeshed in a protective extracellular matrix. It can also create highly acidic microenvironments that cause acid-dissolution of enamel-apatite on teeth, leading to the onset of dental caries. Current antimicrobial agents are incapable of disrupting the matrix and thereby fail to efficiently kill the microbes within plaque-biofilms. Here, we report a novel strategy to control plaque-biofilms using catalytic nanoparticles (CAT-NP) with peroxidase-like activity that trigger extracellular matrix degradation and cause bacterial death within acidic niches of caries-causing biofilm. CAT-NP containing biocompatible Fe3O4 were developed to catalyze H2O2 to generate free-radicals in situ that simultaneously degrade the biofilm matrix and rapidly kill the embedded bacteria with exceptional efficacy (>5-log reduction of cell-viability). Moreover, it displays an additional property of reducing apatite demineralization in acidic conditions. Using 1-min topical daily treatments akin to a clinical situation, we demonstrate that CAT-NP in combination with H2O2 effectively suppress the onset and severity of dental caries while sparing normal tissues in vivo. Our results reveal the potential to exploit nanocatalysts with enzyme-like activity as a potent alternative approach for treatment of a prevalent biofilm-associated oral disease. PMID:27294544

  8. Abnormal activation of calpain and protein kinase Cα promotes a constitutive release of matrix metalloproteinase 9 in peripheral blood mononuclear cells from cystic fibrosis patients.

    PubMed

    Averna, Monica; Bavestrello, Margherita; Cresta, Federico; Pedrazzi, Marco; De Tullio, Roberta; Minicucci, Laura; Sparatore, Bianca; Salamino, Franca; Pontremoli, Sandro; Melloni, Edon

    2016-08-15

    Matrix metalloproteinase 9 (MMP9) is physiologically involved in remodeling the extracellular matrix components but its abnormal release has been observed in several human pathologies. We here report that peripheral blood mononuclear cells (PBMCs), isolated from cystic fibrosis (CF) patients homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR), express constitutively and release at high rate MMP9 due to the alteration in their intracellular Ca(2+) homeostasis. This spontaneous and sustained MMP9 secretion may contribute to the accumulation of this protease in fluids of CF patients. Conversely, in PBMCs isolated from healthy donors, expression and secretion of MMP9 are undetectable but can be evoked, after 12 h of culture, by paracrine stimulation which also promotes an increase in [Ca(2+)]i. We also demonstrate that in both CF and control PBMCs the Ca(2+)-dependent MMP9 secretion is mediated by the concomitant activation of calpain and protein kinase Cα (PKCα), and that MMP9 expression involves extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation. Our results are supported by the fact that either the inhibition of Ca(2+) entry or chelation of [Ca(2+)]i as well as the inhibition of single components of the signaling pathway or the restoration of CFTR activity all promote the reduction of MMP9 secretion. PMID:27349634

  9. CagA promotes proliferation and secretion of extracellular matrix by inhibiting signaling pathway of apoptosis in rat glomerular mesangial cells.

    PubMed

    Wang, Li; Tan, Rui-Zhi; Chen, Yue; Wang, Hong-Lian; Liu, Yu-Hang; Wen, Dan; Fan, Jun-Ming

    2016-04-01

    Cytotoxin-associated antigen A (CagA), a major virulence factor of Helicobacter pylori (Hp), is associated with the pathogenesis of peptic ulcer and gastric cancer. Recent researches demonstrated that Hp exists in palatine tonsil in all studied IgA nephropathy (IgAN) patients, most of which were CagA-positive, suggesting that CagA may be a causative pathogenic factor of IgAN. However, the underlying molecular mechanisms and signaling pathway are still largely unclear. In the present study, CCK8 assay, enzyme-linked immunosorbent assay, and immunohistochemistry were performed to investigate the effect of CagA on cell proliferation and extracellular matrix secretion in rat glomerular mesangial cells. RT-PCR and western blotting were used to reveal the potential signaling pathway. Rat glomerular mesangial cells were treated with recombinant CagA protein for 72 h, in a dose- and time-dependent manner. We found that CagA promoted cell proliferation and extracellular matrix secretion by inhibiting signaling pathway of apoptosis. Taken together, these findings suggested that CagA induced cellular injury in glomerular mesangium by proliferation and secretion of extracellular matrix, and may play an important role in pathogenesis of IgAN. PMID:26837331

  10. Cell-surface serglycin promotes adhesion of myeloma cells to collagen type I and affects the expression of matrix metalloproteinases.

    PubMed

    Skliris, Antonis; Labropoulou, Vassiliki T; Papachristou, Dionysios J; Aletras, Alexios; Karamanos, Nikos K; Theocharis, Achilleas D

    2013-05-01

    Serglycin (SG) is mainly expressed by hematopoetic cells as an intracellular proteoglycan. Multiple myeloma cells constitutively secrete SG, which is also localized on the cell surface in some cell lines. In this study, SG isolated from myeloma cells was found to interact with collagen type I (Col I), which is a major bone matrix component. Notably, myeloma cells positive for cell-surface SG (csSG) adhered significantly to Col I, compared to cells lacking csSG. Removal of csSG by treatment of the cells with chondroitinase ABC or blocking of csSG by an SG-specific polyclonal antibody significantly reduced the adhesion of myeloma cells to Col I. Significant up-regulation of expression of the matrix metalloproteinases MMP-2 and MMP-9 at both the mRNA and protein levels was observed when culturing csSG-positive myeloma cells on Col I-coated dishes or in the presence of soluble Col I. MMP-9 and MMP-2 were also expressed in increased amounts by myeloma cells in the bone marrow of patients with multiple myeloma. Our data indicate that csSG of myeloma cells affects key functional properties, such as adhesion to Col I and the expression of MMPs, and imply that csSG may serve as a potential prognostic factor and/or target for pharmacological interventions in multiple myeloma. PMID:23387827

  11. Lactate promotes glioma migration by TGF-β2–dependent regulation of matrix metalloproteinase-2

    PubMed Central

    Baumann, Fusun; Leukel, Petra; Doerfelt, Anett; Beier, Christoph P.; Dettmer, Katja; Oefner, Peter J.; Kastenberger, Michael; Kreutz, Marina; Nickl-Jockschat, Thomas; Bogdahn, Ulrich; Bosserhoff, Anja-Katrin; Hau, Peter

    2009-01-01

    Lactate dehydrogenase type A (LDH-A) is a key metabolic enzyme catalyzing pyruvate into lactate and is excessively expressed by tumor cells. Transforming growth factor-β2 (TGF-β2) is a key regulator of invasion in high-grade gliomas, partially by inducing a mesenchymal phenotype and by remodeling the extracellular matrix. In this study, we tested the hypothesis that lactate metabolism regulates TGF-β2–mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDH-A) suppresses, and lactate induces, TGF-β2 expression, suggesting that lactate metabolism is strongly associated with TGF-β2 in glioma cells. Here we demonstrate that TGF-β2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin αvβ3 receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin αvβ3 abrogated glioma cell migration stimulated by TGF-β2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A–induced and TGF-β2–coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin αvβ3. This novel interaction between lactate metabolism and TGF-β2 might constitute a crucial mechanism for glioma migration. PMID:19033423

  12. TNF-{alpha} promotes human retinal pigment epithelial (RPE) cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression through activation of Akt/mTORC1 signaling

    SciTech Connect

    Wang, Cheng-hu; Cao, Guo-Fan; Jiang, Qin; Yao, Jin

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer TNF-{alpha} induces MMP-9 expression and secretion to promote RPE cell migration. Black-Right-Pointing-Pointer MAPK activation is not critical for TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer Akt and mTORC1 signaling mediate TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer SIN1 knockdown showed no significant effect on MMP-9 expression by TNF-{alpha}. -- Abstract: Tumor necrosis factor-alpha (TNF-{alpha}) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-{alpha} promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-{alpha}-induced in vitro RPE cell migration. Reversely, exogenously-added active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-{alpha}-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-{alpha} promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling.

  13. Hybrid chitosan/β-1,3-glucan matrix of bone scaffold enhances osteoblast adhesion, spreading and proliferation via promotion of serum protein adsorption.

    PubMed

    Przekora, Agata; Benko, Aleksandra; Blazewicz, Marta; Ginalska, Grazyna

    2016-01-01

    Initial protein adsorption to the material surface is crucial for osteoblast adhesion, survival, and rapid proliferation resulting in intensive new bone formation. The aim of this study was to demonstrate that modification of a chitosan matrix of chitosan/hydroxyapatite (chit/HA) biomaterial for bone tissue engineering applications with linear β-1,3-glucan (curdlan) leads to promotion of serum protein adsorption to the resultant scaffold (chit/glu/HA) and thus in enhancement of osteoblast adhesion, spreading and proliferation. Fabricated biomaterials were pre-adsorbed with different protein solutions and then protein adsorption and osteoblast behavior on the scaffolds were compared. Moreover, surface chemical composition, wettability and surface energy of biomaterials were compared. Modification of the chitosan matrix with β-1,3-glucan introduces a greater polarpart in the resultant chitosan/β-1,3-glucan matrix presumably resulting from more OH groups within the curdlan structure. Moreover, FTIR-ATR results suggest that there might be some sort of chemical interaction between the NH group of chitosan and the OH group of β-1,3-glucan. As a consequence, the chit/glu/HA scaffold adsorbs significantly more adhesion proteins that are crucial for osteoblasts compared to the chit/HA material, providing a higher density culture of well-spread osteoblasts on its surface. Obtained results revealed that not only is chit/glu/HA biomaterial a promising scaffold for bone tissue engineering applications, but the specific polysaccharide chit/glu matrix itself is promising for use in the biomedical material field to modify various biomaterials in order to enhance osteoblast adhesion and proliferation on their surfaces. PMID:27388048

  14. Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

    PubMed Central

    Akkari, Leila; Gocheva, Vasilena; Kester, Jemila C.; Hunter, Karen E.; Quick, Marsha L.; Sevenich, Lisa; Wang, Hao-Wei; Peters, Christoph; Tang, Laura H.; Klimstra, David S.; Reinheckel, Thomas

    2014-01-01

    During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg–Gly–Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function. PMID:25274726

  15. Extracellular matrix protein ITGBL1 promotes ovarian cancer cell migration and adhesion through Wnt/PCP signaling and FAK/SRC pathway.

    PubMed

    Sun, Li; Wang, Defeng; Li, Xiaotian; Zhang, Lingling; Zhang, Hui; Zhang, Yingjie

    2016-07-01

    Despite the advances in cancer treatment and the progresses in tumor biological, ovarian cancer remains a bad situation. In current study, we found a novel extracellular matrix protein, ITGBL1, which is highly expressed in ovarian cancer tissues by immunohistochemistry examination. The expression pattern of ITGBL1 in malignant tissues inspired us to investigate its role in ovarian cancer progression. Both loss- and gain-function assays revealed that ITGBL1 could promote ovarian cancer cell migration and adhesion. As it's a secreted protein, we further used recombinant ITGBL1 protein treated cancer cells and found that ITGBL1 promotes cell migration and adhesion in a concentration dependent manner. Furthermore, we found that ITGBL1 not only influences the activity of Wnt/PCP signaling but also affects FAK/src pathway in vitro. Taken together, our results suggest that highly expressed ITGBL1 could promotes cancer cell migration and adhesion in ovarian cancer and as a secreted protein, ITGBL1 might be a novel biomarker for ovarian cancer diagnosis. PMID:27261588

  16. Tenascin-C in the extracellular matrix promotes the selection of highly proliferative and tubulogenesis-defective endothelial cells.

    PubMed

    Alves, Tercia Rodrigues; da Fonseca, Anna Carolina Carvalho; Nunes, Sara Santana; da Silva, Aline Oliveira; Dubois, Luiz Gustavo Feijó; Faria, Jane; Kahn, Suzana Assad; Viana, Nathan Bessa; Marcondes, Jorge; Legrand, Chantal; Moura-Neto, Vivaldo; Morandi, Verônica

    2011-09-10

    The extracellular matrix (ECM) contains important cues for tissue homeostasis and morphogenesis. The matricellular protein tenascin-C (TN-C) is overexpressed in remodeling tissues and cancer. In the present work, we studied the effect of different ECM-which exhibited a significant diversity in their TN-C content-in endothelial survival, proliferation and tubulogenic differentiation: autologous (endothelial) ECM devoid of TN-C, but bearing large amounts of FN; fibroblast ECM, bearing both high TN-C and FN contents; and finally, glioma-derived matrices, usually poor in FN, but very rich in TN-C. HUVECs initially adhered to the immobilized matrix produced by U373 MG glioma cells, but significantly detached and died by anoikis (50 to 80%) after 24h, as compared with cells incubated with endothelial and fibroblast matrices. Surviving endothelial cells (20 to 50%) became up to 6-fold more proliferative and formed 74-97% less tube-like structures in vitro than cells grown on non-tumoral matrices. An antibody against the EGF-like repeats of tenascin-C (TN-C) partially rescued cells from the tubulogenic defect, indicating that this molecule is responsible for the selection of highly proliferative and tubulogenic defective endothelial cells. Interestingly, by using defined substrata, in conditions that mimic glioma and normal cell ECM composition, we observed that fibronectin (FN) modulates the TN-C-induced selection of endothelial cells. Our data show that TN-C is able to modulate endothelial branching morphogenesis in vitro and, since it is prevalent in matrices of injured and tumor tissues, also suggest a role for this protein in vascular morphogenesis, in these physiological contexts. PMID:21740900

  17. Tenascin-C in the extracellular matrix promotes the selection of highly proliferative and tubulogenesis-defective endothelial cells

    SciTech Connect

    Alves, Tercia Rodrigues; Dubois, Luiz Gustavo Feijo; Faria, Jane; Kahn, Suzana Assad; Marcondes, Jorge; Legrand, Chantal; Moura-Neto, Vivaldo [Universidade Federal do Rio de Janeiro , Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciencias Biomedicas, INNT and others

    2011-09-10

    The extracellular matrix (ECM) contains important cues for tissue homeostasis and morphogenesis. The matricellular protein tenascin-C (TN-C) is overexpressed in remodeling tissues and cancer. In the present work, we studied the effect of different ECM-which exhibited a significant diversity in their TN-C content-in endothelial survival, proliferation and tubulogenic differentiation: autologous (endothelial) ECM devoid of TN-C, but bearing large amounts of FN; fibroblast ECM, bearing both high TN-C and FN contents; and finally, glioma-derived matrices, usually poor in FN, but very rich in TN-C. HUVECs initially adhered to the immobilized matrix produced by U373 MG glioma cells, but significantly detached and died by anoikis (50 to 80%) after 24 h, as compared with cells incubated with endothelial and fibroblast matrices. Surviving endothelial cells (20 to 50%) became up to 6-fold more proliferative and formed 74-97% less tube-like structures in vitro than cells grown on non-tumoral matrices. An antibody against the EGF-like repeats of tenascin-C (TN-C) partially rescued cells from the tubulogenic defect, indicating that this molecule is responsible for the selection of highly proliferative and tubulogenic defective endothelial cells. Interestingly, by using defined substrata, in conditions that mimic glioma and normal cell ECM composition, we observed that fibronectin (FN) modulates the TN-C-induced selection of endothelial cells. Our data show that TN-C is able to modulate endothelial branching morphogenesis in vitro and, since it is prevalent in matrices of injured and tumor tissues, also suggest a role for this protein in vascular morphogenesis, in these physiological contexts.

  18. Matrix Metalloproteinase-10 Promotes Kras-Mediated Bronchio-Alveolar Stem Cell Expansion and Lung Cancer Formation

    PubMed Central

    Regala, Roderick P.; Justilien, Verline; Walsh, Michael P.; Weems, Capella; Khoor, Andras; Murray, Nicole R.; Fields, Alan P.

    2011-01-01

    Matrix metalloproteinase 10 (MMP-10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many of which have been implicated in tumor progression, invasion and metastasis. We recently identified Mmp10 as a gene that is highly induced in tumor-initiating lung bronchioalveolar stem cells (BASCs) upon activation of oncogenic Kras in a mouse model of lung adenocarcinoma. However, the potential role of Mmp10 in lung tumorigenesis has not been addressed. Here, we demonstrate that Mmp10 is overexpressed in lung tumors induced by either the smoke carcinogen urethane or oncogenic Kras. In addition, we report a significant reduction in lung tumor number and size after urethane exposure or genetic activation of oncogenic Kras in Mmp10 null (Mmp10−/−) mice. This inhibitory effect is reflected in a defect in the ability of Mmp10-deficient BASCs to expand and undergo transformation in response to urethane or oncogenic Kras in vivo and in vitro, demonstrating a role for Mmp10 in the tumor-initiating activity of Kras-transformed lung stem cells. To determine the potential relevance of MMP10 in human cancer we analyzed Mmp10 expression in publicly-available gene expression profiles of human cancers. Our analysis reveals that MMP10 is highly overexpressed in human lung tumors. Gene set enhancement analysis (GSEA) demonstrates that elevated MMP10 expression correlates with both cancer stem cell and tumor metastasis genomic signatures in human lung cancer. Finally, Mmp10 is elevated in many human tumor types suggesting a widespread role for Mmp10 in human malignancy. We conclude that Mmp10 plays an important role in lung tumor initiation via maintenance of a highly tumorigenic, cancer-initiating, stem-like cell population, and that Mmp10 expression is associated with stem-like, highly metastatic genotypes in human lung cancers. These results indicate that Mmp10 may represent a novel therapeutic approach to target lung cancer stem cells

  19. Interleukin 17A Promotes Hepatocellular Carcinoma Metastasis via NF-kB Induced Matrix Metalloproteinases 2 and 9 Expression

    PubMed Central

    Li, Jian; Lau, George Ka-Kit; Chen, Leilei; Dong, Sui-sui; Lan, Hui-Yao; Huang, Xiao-Ru; Li, Yan; Luk, John M.; Yuan, Yun-Fei; Guan, Xin-yuan

    2011-01-01

    Background  IL-17A is a pro-inflammatory cytokine that plays important role in inflammatory disease pathology and tumor microenvironment. The aim of this study is to investigate the effect of IL-17A on the progression of hepatocellular carcinoma (HCC). Methodology and Principal Finding Expression pattern of IL-17A in clinical HCC samples (n = 43) was determined by immunohistochemistry staining. Transcript levels of MMP2, MMP9 and IL-17A were measured in another 50 pairs (including tumor and related non-tumor tissues) HCC samples. Cell growth, focus formation, cell migration, invasion and western blot assays were used to characterize the functional and signaling mechanisms in IL-17A-treated HCC. Association study was used to identify clinical significance of IL-17A in HCC. Compared with paired non-tumor tissue, higher frequency of IL-17A-positive cells was detected in tumor tissues in HCCs with metastasis, and the frequency of IL-17A-positive cells was also significantly associated with poor prognosis of HCC (P = 0.01). Functional study found that IL-17A could promote HCC cell migration and invasion. Further molecular analysis also showed that IL-17A could upregulate MMP2 and MMP9 expression via NF-κB signaling activation. Conclusions  IL-17A could promote HCC metastasis by the upregulation of MMP2 and MMP9 expression via activating NF-κB signaling pathway. PMID:21760911

  20. Disrupted Endothelial Cell Layer and Exposed Extracellular Matrix Proteins Promote Capture of Late Outgrowth Endothelial Progenitor Cells.

    PubMed

    Zhao, Jing; Mitrofan, Claudia-Gabriela; Appleby, Sarah L; Morrell, Nicholas W; Lever, Andrew M L

    2016-01-01

    Late outgrowth endothelial progenitor cells (LO-EPC) possess a high proliferative potential, differentiate into vascular endothelial cells (EC), and form networks, suggesting they play a role in vascular repair. However, due to their scarcity in the circulation there is a requirement for ex vivo expansion before they could provide a practical cell therapy and it is currently unclear if they would home and engraft to an injury site. Using an in vitro flow system we studied LO-EPC under simulated injury conditions including EC activation, ischaemia, disrupted EC integrity, and exposed basement membrane. Perfused LO-EPC adhered to discontinuous EC paracellularly at junctional regions between adjacent cells under shear stress 0.7 dyn/cm(2). The interaction was not adhesion molecule-dependent and not enhanced by EC activation. LO-EPC expressed high levels of the VE-Cadherin which may explain these findings. Ischaemia reperfusion injury decreased the interaction with LO-EPC due to cell retraction. LO-EPC interacted with exposed extracellular matrix (ECM) proteins, fibronectin and vitronectin. The interaction was mediated by integrins α5β3, αvβ1, and αvβ3. This study has demonstrated that an injured local environment presents sufficient adhesive signals to capture flow perfused LO-EPC in vitro and that LO-EPC have properties consistent with their potential role in vascular repair. PMID:27413378

  1. Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy.

    PubMed

    Zhou, Q; Gil-Krzewska, A; Peruzzi, G; Borrego, F

    2013-07-01

    Activation of human natural killer (NK) cells is associated with the cleavage of CD16 from the cell surface, a process mediated by matrix metalloproteinases (MMPs). In this report, we examined whether inhibition of MMPs would lead to improved NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) function. Using an in-vitro ADCC assay, we tested the anti-tumour function of NK cells with three different therapeutic monoclonal antibodies (mAbs) in the presence of MMPs inhibitor GM6001 or its control. Loss of CD16 was observed when NK cells were co-cultured with tumour targets in the presence of specific anti-tumour antibodies, and was found particularly on the majority of degranulating NK responding cells. Treatment with MMPs inhibitors not only prevented CD16 down-regulation, but improved the quality of the responding cells significantly, as shown by an increase in the percentage of polyfunctional NK cells that are capable of both producing cytokines and degranulation. Furthermore, MMPs inhibition resulted in augmented and sustained CD16-mediated signalling, as shown by increased tyrosine phosphorylation of CD3ζ and other downstream signalling intermediates, which may account for the improved NK cell function. Collectively, our results provide a foundation for combining MMPs inhibitors and therapeutic mAbs in new clinical trials for cancer treatment. PMID:23607800

  2. Disrupted Endothelial Cell Layer and Exposed Extracellular Matrix Proteins Promote Capture of Late Outgrowth Endothelial Progenitor Cells

    PubMed Central

    Mitrofan, Claudia-Gabriela; Appleby, Sarah L.; Morrell, Nicholas W.; Lever, Andrew M. L.

    2016-01-01

    Late outgrowth endothelial progenitor cells (LO-EPC) possess a high proliferative potential, differentiate into vascular endothelial cells (EC), and form networks, suggesting they play a role in vascular repair. However, due to their scarcity in the circulation there is a requirement for ex vivo expansion before they could provide a practical cell therapy and it is currently unclear if they would home and engraft to an injury site. Using an in vitro flow system we studied LO-EPC under simulated injury conditions including EC activation, ischaemia, disrupted EC integrity, and exposed basement membrane. Perfused LO-EPC adhered to discontinuous EC paracellularly at junctional regions between adjacent cells under shear stress 0.7 dyn/cm2. The interaction was not adhesion molecule-dependent and not enhanced by EC activation. LO-EPC expressed high levels of the VE-Cadherin which may explain these findings. Ischaemia reperfusion injury decreased the interaction with LO-EPC due to cell retraction. LO-EPC interacted with exposed extracellular matrix (ECM) proteins, fibronectin and vitronectin. The interaction was mediated by integrins α5β3, αvβ1, and αvβ3. This study has demonstrated that an injured local environment presents sufficient adhesive signals to capture flow perfused LO-EPC in vitro and that LO-EPC have properties consistent with their potential role in vascular repair. PMID:27413378

  3. Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways.

    PubMed

    Wang, P; Chen, S-H; Hung, W-C; Paul, C; Zhu, F; Guan, P-P; Huso, D L; Kontrogianni-Konstantopoulos, A; Konstantopoulos, K

    2015-08-27

    Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm(2)) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified. PMID:25435370

  4. Cell-cell contact and matrix adhesion promote αSMA expression during TGFβ1-induced epithelial-myofibroblast transition via Notch and MRTF-A.

    PubMed

    O'Connor, Joseph W; Mistry, Krunal; Detweiler, Dayne; Wang, Clayton; Gomez, Esther W

    2016-01-01

    During epithelial-mesenchymal transition (EMT) epithelial cells lose cell-cell adhesion, exhibit morphological changes, and upregulate the expression of cytoskeletal proteins. Previous studies have demonstrated that complete disruption of cell-cell contact can promote transforming growth factor (TGF)-β1-induced EMT and the expression of the myofibroblast marker alpha smooth muscle actin (αSMA). Furthermore, increased cell spreading mediates TGFβ1-induced αSMA expression during EMT. Here, we sought to examine how the presence of partial cell-cell contacts impacts EMT. A microfabrication approach was employed to decouple the effects of cell-cell contact and cell-matrix adhesion in TGFβ1-induced EMT. When cell spreading is controlled, the presence of partial cell-cell contacts enhances expression of αSMA. Moreover, cell spreading and intercellular contacts together control the subcellular localization of activated Notch1 and myocardin related transcription factor (MRTF)-A. Knockdown of Notch1 or MRTF-A as well as pharmacological inhibition of these pathways abates the cell-cell contact mediated expression of αSMA. These data suggest that the interplay between cell-matrix adhesion and intercellular adhesion is an important determinant for some aspects of TGFβ1-induced EMT. PMID:27194451

  5. The multifunctional role of the pallilysin-associated Treponema pallidum protein, Tp0750, in promoting fibrinolysis and extracellular matrix component degradation.

    PubMed

    Houston, Simon; Russell, Shannon; Hof, Rebecca; Roberts, Alanna K; Cullen, Paul; Irvine, Kyle; Smith, Derek S; Borchers, Christoph H; Tonkin, Michelle L; Boulanger, Martin J; Cameron, Caroline E

    2014-02-01

    The mechanisms that facilitate dissemination of the highly invasive spirochaete, Treponema pallidum, are incompletely understood. Previous studies showed the treponemal metalloprotease pallilysin (Tp0751) possesses fibrin clot degradation capability, suggesting a role in treponemal dissemination. In the current study we report characterization of the functionally linked protein Tp0750. Structural modelling predicts Tp0750 contains a von Willebrand factor type A (vWFA) domain, a protein-protein interaction domain commonly observed in extracellular matrix (ECM)-binding proteins. We report Tp0750 is a serine protease that degrades the major clot components fibrinogen and fibronectin. We also demonstrate Tp0750 cleaves a matrix metalloprotease (MMP) peptide substrate that is targeted by several MMPs, enzymes central to ECM remodelling. Through proteomic analyses we show Tp0750 binds the endothelial fibrinolytic receptor, annexin A2, in a specific and dose-dependent manner. These results suggest Tp0750 constitutes a multifunctional protein that is able to (1) degrade infection-limiting clots by both inhibiting clot formation through degradation of host coagulation cascade proteins and promoting clot dissolution by complexing with host proteins involved in the fibrinolytic cascade and (2) facilitate ECM degradation via MMP-like proteolysis of host components. We propose that through these activities Tp0750 functions in concert with pallilysin to enable T. pallidum dissemination. PMID:24303899

  6. The Multifunctional Role of the Pallilysin-Associated Treponema pallidum Protein, Tp0750, in Promoting Fibrinolysis and Extracellular Matrix Component Degradation

    PubMed Central

    Houston, Simon; Russell, Shannon; Hof, Rebecca; Roberts, Alanna K.; Cullen, Paul; Irvine, Kyle; Smith, Derek S.; Borchers, Christoph H.; Tonkin, Michelle L.; Boulanger, Martin J.; Cameron, Caroline E.

    2014-01-01

    Summary The mechanisms that facilitate dissemination of the highly invasive spirochete, Treponema pallidum, are incompletely understood. Previous studies showed the treponemal metalloprotease pallilysin (Tp0751) possesses fibrin clot degradation capability, suggesting a role in treponemal dissemination. In the current study we report characterization of the functionally-linked protein Tp0750. Structural modelling predicts Tp0750 contains a von Willebrand factor type A (vWFA) domain, a protein-protein interaction domain commonly observed in extracellular matrix (ECM)-binding proteins. We report Tp0750 is a serine protease that degrades the major clot components fibrinogen and fibronectin. We also demonstrate Tp0750 cleaves a matrix metalloprotease (MMP) peptide substrate that is targeted by several MMPs, enzymes central to ECM remodelling. Through proteomic analyses we show Tp0750 binds the endothelial fibrinolytic receptor, annexin A2, in a specific and dose-dependent manner. These results suggest Tp0750 constitutes a multifunctional protein that is able to (1) degrade infection-limiting clots by both inhibiting clot formation through degradation of host coagulation cascade proteins and promoting clot dissolution by complexing with host proteins involved in the fibrinolytic cascade and (2) facilitate ECM degradation via MMP-like proteolysis of host components. We propose that through these activities Tp0750 functions in concert with pallilysin to enable T. pallidum dissemination. PMID:24303899

  7. Cell-cell contact and matrix adhesion promote αSMA expression during TGFβ1-induced epithelial-myofibroblast transition via Notch and MRTF-A

    PubMed Central

    O’Connor, Joseph W.; Mistry, Krunal; Detweiler, Dayne; Wang, Clayton; Gomez, Esther W.

    2016-01-01

    During epithelial-mesenchymal transition (EMT) epithelial cells lose cell-cell adhesion, exhibit morphological changes, and upregulate the expression of cytoskeletal proteins. Previous studies have demonstrated that complete disruption of cell-cell contact can promote transforming growth factor (TGF)-β1-induced EMT and the expression of the myofibroblast marker alpha smooth muscle actin (αSMA). Furthermore, increased cell spreading mediates TGFβ1-induced αSMA expression during EMT. Here, we sought to examine how the presence of partial cell-cell contacts impacts EMT. A microfabrication approach was employed to decouple the effects of cell-cell contact and cell-matrix adhesion in TGFβ1-induced EMT. When cell spreading is controlled, the presence of partial cell-cell contacts enhances expression of αSMA. Moreover, cell spreading and intercellular contacts together control the subcellular localization of activated Notch1 and myocardin related transcription factor (MRTF)-A. Knockdown of Notch1 or MRTF-A as well as pharmacological inhibition of these pathways abates the cell-cell contact mediated expression of αSMA. These data suggest that the interplay between cell-matrix adhesion and intercellular adhesion is an important determinant for some aspects of TGFβ1-induced EMT. PMID:27194451

  8. A SINGLE BLUNT IMPACT ON CARTILAGE PROMOTES FIBRONECTIN FRAGMENTATION AND UPREGULATES CARTILAGE DEGRADING STROMELYSIN-1/MATRIX METALLOPROTEINASE-3 IN A BOVINE EX-VIVO MODEL

    PubMed Central

    Ding, Lei; Guo, Danping; Homandberg, Gene A.; Buckwalter, Joseph A.; Martin, James A.

    2014-01-01

    Post-traumatic osteoarthritis (PTOA) is characterized by progressive cartilage degeneration in injured joints. Since fibronectin fragments (Fn-fs) degrade cartilage mainly through up-regulating matrix metalloproteinases (MMPs) and pro-inflammatory cytokines, we hypothesized that Fn-fs play a key role in PTOA by promoting chondrolysis in and around injured cartilage. To test this hypothesis, we profiled the catabolic events focusing on fibronectin fragmentation and proteinase expression in bovine osteochondral explants following a single blunt impact on cartilage with a drop tower device which created partial-thickness tissue damage. Injured and control explants were cultured for up to 14 days. The presence of Fn-fs, MMPs (-1, -3, -13), ADAMTS-5 in culture media and in cartilage was determined with immunoblotting. The daily proteoglycan (PG) depletion of cartilage matrix was assessed with DMMB assay. The effect of explant-conditioned media on chondrocytes was also examined with immunoblotting. Impacted cartilage released significantly higher amount of native Fn, three chondrolytic Fn-fs and PG than non-impacted controls did. Those increases coincided with up-regulation of MMP-3 both in conditioned media and in impacted cartilage. These findings support our hypothesis that PTOA may be propelled by Fn-fs which act as catabolic mediators through up-regulating cartilage-damaging proteinases. PMID:24610678

  9. High mobility group box-1 promotes hepatocellular carcinoma progression through miR-21-mediated matrix metalloproteinase activity

    PubMed Central

    Chen, Man; Liu, Yao; Varley, Patrick; Chang, Ying; He, Xing-xing; Huang, Hai; Tang, Daolin; Lotze, Michael T.; Lin, Jusheng; Tsung, Allan

    2015-01-01

    Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage associated molecular patterns (DAMPs), such as high mobility group box-1 (HMGB1), and dysregulated microRNAs (miRNAs) involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in over-expression of miR-21. These changes were found to be dependent on the IL-6/Stat3 signaling axis. Invasion and migration of HCC cells in vitro was inhibited by both Stat3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a post-transcriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL-6/Stat3-miR-21 axis. PMID:25720799

  10. Klf10 regulates odontoblast differentiation and mineralization via promoting expression of dentin matrix protein 1 and dentin sialophosphoprotein genes.

    PubMed

    Chen, Zhuo; Li, Wentong; Wang, Han; Wan, Chunyan; Luo, Daoshu; Deng, Shuli; Chen, Hui; Chen, Shuo

    2016-02-01

    Klf10, a member of the Krüppel-like family of transcription factors, is critical for osteoblast differentiation, bone formation and mineralization. However, whether Klf10 is involved in odontoblastic differentiation and tooth development has not been determined. In this study, we investigate the expression patterns of Klf10 during murine tooth development in vivo and its role in odontoblastic differentiation in vitro. Klf10 protein was expressed in the enamel organ and the underlying mesenchyme, ameloblasts and odontoblasts at early and later stages of murine molar formation. Furthermore, the expression of Klf10, Dmp1, Dspp and Runx2 was significantly elevated during the process of mouse dental papilla mesenchymal differentiation and mineralization. The overexpression of Klf10 induced dental papilla mesenchymal cell differentiation and mineralization as detected by alkaline phosphatase staining and alizarin red S assay. Klf10 additionally up-regulated the expression of odontoblastic differentiation marker genes Dmp1, Dspp and Runx2 in mouse dental papilla mesenchymal cells. The molecular mechanism of Klf10 in controlling Dmp1 and Dspp expression is thus to activate their regulatory regions in a dosage-dependent manner. Our results suggest that Klf10 is involved in tooth development and promotes odontoblastic differentiation via the up-regulation of Dmp1 and Dspp transcription. PMID:26310138

  11. Klf10 regulates odontoblast differentiation and mineralization via promoting expression of dentin matrix protein 1 and dentin sialophosphoprotein genes

    PubMed Central

    Chen, Zhuo; Li, Wentong; Wang, Han; Wan, Chunyan; Luo, Daoshu; Deng, Shuli

    2016-01-01

    Klf10, a member of the Krüppel-like family of transcription factors, is critical for osteoblast differentiation, bone formation and mineralization. However, whether Klf10 is involved in odontoblastic differentiation and tooth development has not been determined. In this study, we investigate the expression patterns of Klf10 during murine tooth development in vivo and its role in odontoblastic differentiation in vitro. Klf10 protein was expressed in the enamel organ and the underlying mesenchyme, ameloblasts and odontoblasts at early and later stages of murine molar formation. Furthermore, the expression of Klf10, Dmp1, Dspp and Runx2 was significantly elevated during the process of mouse dental papilla mesenchymal differentiation and mineralization. The overexpression of Klf10 induced dental papilla mesenchymal cell differentiation and mineralization as detected by alkaline phosphatase staining and alizarin red S assay. Klf10 additionally up-regulated the expression of odontoblastic differentiation marker genes Dmp1, Dspp and Runx2 in mouse dental papilla mesenchymal cells. The molecular mechanism of Klf10 in controlling Dmp1 and Dspp expression is thus to activate their regulatory regions in a dosage-dependent manner. Our results suggest that Klf10 is involved in tooth development and promotes odontoblastic differentiation via the up-regulation of Dmp1 and Dspp transcription. PMID:26310138

  12. Delivery of iPS-NPCs to the Stroke Cavity within a Hyaluronic Acid Matrix Promotes the Differentiation of Transplanted Cells

    PubMed Central

    Lam, Jonathan; Lowry, William E.; Carmichael, S. Thomas; Segura, Tatiana

    2015-01-01

    Stroke is the leading cause of adult disability with ~80% being ischemic. Stem cell transplantation has been shown to improve functional recovery. However, the overall survival and differentiation of these cells is still low. The infarct cavity is an ideal location for transplantation as it is directly adjacent to the highly plastic peri-infarct region. Direct transplantation of cells near the infarct cavity has resulted in low cell viability. Here we deliver neural progenitor cells derived from induce pluripotent stem cells (iPS-NPC) to the infarct cavity of stroked mice encapsulated in a hyaluronic acid hydrogel matrix to protect the cells. To improve the overall viability of transplanted cells, each step of the transplantation process was optimized. Hydrogel mechanics and cell injection parameters were investigated to determine their effects on the inflammatory response of the brain and cell viability, respectively. Using parameters that balanced the desire to keep surgery invasiveness minimal and cell viability high, iPS-NPCs were transplanted to the stroke cavity of mice encapsulated in buffer or the hydrogel. While the hydrogel did not promote stem cell survival one week post-transplantation, it did promote differentiation of the neural progenitor cells to neuroblasts. PMID:26213530

  13. Matrix Metalloproteinase Inhibition Enhances the Rate of Nerve Regeneration In Vivo by Promoting De-Differentiation and Mitosis of Supporting Schwann Cells

    PubMed Central

    Liu, Huaqing; Kim, Youngsoon; Chattopadhyay, Sharmila; Shubayev, Igor; Dolkas, Jennifer; Shubayev, Veronica I.

    2010-01-01

    Following peripheral nerve injury, Schwann cells (SCs) vigorously divide to survive and produce a sufficient number of cells to accompany regenerating axons. Matrix metalloproteinases (MMPs) have emerged as modulators of SC signaling and mitosis. Using a 5-bromo-2-deoxyuridine (BrdU) incorporation assay, we previously found that a broad-spectrum MMP inhibitor (MMPi), GM6001 (or Ilomastat), enhanced division of cultured primary SCs. Here, we tested the hypothesis that the ability of MMPi to stimulate SC mitosis may advance nerve regeneration in vivo. GM6001 administration immediately after rat sciatic nerve crush and daily thereafter produced increased nerve regeneration as determined by nerve pinch test and growth-associated protein-43 (GAP-43) expression. MMPi promoted endoneurial BrdU incorporation relative to vehicle control. The dividing cells were mainly SCs and were associated with GAP-43-positive regenerating axons. After MMP inhibition, myelin basic protein mRNA expression (determined by Taqman RT-qPCR) and active mitosis of myelin-forming SCs were reduced, indicating that MMPs suppressed their de-differentiation preceding mitosis. Intra-sciatic injection of the inhibitor of SC mitosis mitomycin suppressed nerve regrowth is reversed by MMPi, suggesting that its effect on axonal growth promotion depends on its pro-mitogenic action in SCs. These studies establish novel roles for MMPs in peripheral nerve repair via control of SC mitosis, differentiation and myelin protein mRNA expression. PMID:20448483

  14. Epidermal growth factor promotes a mesenchymal over an amoeboid motility of MDA-MB-231 cells embedded within a 3D collagen matrix

    NASA Astrophysics Data System (ADS)

    Geum, Dongil T.; Kim, Beum Jun; Chang, Audrey E.; Hall, Matthew S.; Wu, Mingming

    2016-01-01

    The receptor of epidermal growth factor (EGFR) critically regulates tumor cell invasion and is a potent therapeutic target for treatment of many types of cancers, including carcinomas and glioblastomas. It is known that EGF regulates cell motility when tumor cells are embedded within a 3D biomatrix. However, roles of EGF in modulating tumor cell motility phenotype are largely unknown. In this article, we report that EGF promotes a mesenchymal over an amoeboid motility phenotype using a malignant breast tumor cell line, MDA-MB-231, embedded within a 3D collagen matrix. Amoeboid cells are rounded in shape, while mesenchymal cells are elongated, and their migrations are governed by a distinctly different set of biomolecules. Using single cell tracking analysis, we also show that EGF promotes cell dissemination through a significant increase in cell persistence along with a moderate increase of speed. The increase of persistence is correlated with the increase of the percentage of the mesenchymal cells within the population. Our work reveals a novel role of microenvironmental cue, EGF, in modulating heterogeneity and plasticity of tumor cell motility phenotype. In addition, it suggests a potential visual cue for diagnosing invasive states of breast cancer cells. This work can be easily extended beyond breast cancer cells.

  15. Pomegranate as a cosmeceutical source: pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells.

    PubMed

    Aslam, Muhammad Nadeem; Lansky, Ephraim Philip; Varani, James

    2006-02-20

    Pomegranate (Punica granatum) is an ancient fruit with exceptionally rich ethnomedical applications. The peel (pericarp) is well regarded for its astringent properties; the seeds for conferring invulnerability in combat and stimulating beauty and fertility. Here, aqueous fractions prepared from the fruit's peel and fermented juice and lipophilic fractions prepared from pomegranate seeds were examined for effects on human epidermal keratinocyte and human dermal fibroblast function. Pomegranate seed oil, but not aqueous extracts of fermented juice, peel or seed cake, was shown to stimulate keratinocyte proliferation in monolayer culture. In parallel, a mild thickening of the epidermis (without the loss of ordered differentiation) was observed in skin organ culture. The same pomegranate seed oil that stimulated keratinocyte proliferation was without effect on fibroblast function. In contrast, pomegranate peel extract (and to a lesser extent, both the fermented juice and seed cake extracts) stimulated type I procollagen synthesis and inhibited matrix metalloproteinase-1 (MMP-1; interstitial collagenase) production by dermal fibroblasts, but had no growth-supporting effect on keratinocytes. These results suggest heuristic potential of pomegranate fractions for facilitating skin repair in a polar manner, namely aqueous extracts (especially of pomegranate peel) promoting regeneration of dermis, and pomegranate seed oil promoting regeneration of epidermis. PMID:16221534

  16. Slit2-Robo1 signaling promotes the adhesion, invasion and migration of tongue carcinoma cells via upregulating matrix metalloproteinases 2 and 9, and downregulating E-cadherin

    PubMed Central

    Zhao, Yuan; Zhou, Feng-Li; Li, Wei-Ping; Wang, Jing; Wang, Li-Jing

    2016-01-01

    Whether Slit homologue 2 (Slit2) inhibits or promotes tumor cell migration remains controversial, and the role of Slit2-Roundabout 1 (Robo1) signaling in oral cancer remains to be fully elucidated. The aim of the present study was to investigate the role of Slit2-Robo1 signaling in the adhesion, invasion and migration of tongue carcinoma cells, and the mechanism by which Slit2-Robo1 signaling inhibits or promotes tumor cell migration. Tca8113 tongue carcinoma cells were treated with the monoclonal anti-human Robo1 antibody, R5, to inhibit the Slit2-Robo1 signaling pathway, with immunoglobulin (Ig)G2b treatment as a negative control. The expression levels of Slit2 and Robo1 were determined using flow cytometry. The effects of R5 on the adhesion, invasion and migration of Tca8113 tongue carcinoma cells were investigated. Gelatin zymography was used to investigate the activity of matrix metalloproteinase 2 (MMP2) and MMP9. Western blot analysis was used to evaluate the expression levels of E-cadherin in Tca8113 cells treated with 10 µg/ml of either R5 or IgG2b. Slit2 and Robo1 proteins were found to be expressed in the Tca8113 cells. R5 significantly inhibited the adhesion, invasion and migration of Tca8113 cells in vitro. R5 also inhibited the activities of MMP2 and MMP9, and increased the expression of E-cadherin in the Tca8113 cells. These results suggested that Slit2-Robo1 signaling promoted the adhesion, invasion and migration of tongue carcinoma cells by upregulating the expression levels of MMP2 and MMP9 and, downregulating the expression of E-cadherin. PMID:27431199

  17. Matrix metalloproteinase (MMP) -2, -7 and -9 promoter polymorphisms in colorectal cancer in ethnic Kashmiri population - A case-control study and a mini review.

    PubMed

    Banday, Mujeeb Zafar; Sameer, Aga Syed; Mir, Ashaq Hussain; Mokhdomi, Taseem A; Chowdri, Nissar A; Haq, Ehtishamul

    2016-09-01

    Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a pivotal role in the transformation and progression of tumors at all stages, especially during the invasion and metastasis. The aim of this study was to determine the genetic association of MMP2, MMP7 and MMP9 promoter polymorphisms with colorectal cancer (CRC) susceptibility and development risk in ethnic Kashmiri population. The genotype frequencies of MMP2-1306C/T, MMP7-181A/G and MMP9-1562C/T SNPs were compared between 142 CRC patients and 184 healthy controls by using PCR-RFLP method. The association between all the three MMP promoter polymorphisms and the modulation of risk of CRC was found to be significant (p≤0.05). The heterozygous genotype (CT) of MMP2-1306C/T SNP and variant genotype (GG) of MMP7-181A/G SNP showed a significant association with decreased risk for the development of CRC [OR, 0.61 (95%CI, 0.37-1.01); p=0.05 and OR, 0.43 (95%CI, 0.20-0.90); p=0.02, respectively] whereas the heterozygous genotype (CT) of MMP9-1562C/T SNP showed a significant association with increased risk for the development of colorectal cancer [OR, 1.88 (95%CI, 1.11-3.18); p=0.02]. Further, the less common MMP9-1562T allele was found to be significantly associated with an increased risk of colorectal cancer [OR, 1.74 (95%CI, 1.15-2.62); p=0.007]. Our results suggest that these MMP2, MMP7 and MMP9 promoter polymorphisms play a role as one of the key modulators of the risk of developing colorectal cancer in Kashmiri population. PMID:27222481

  18. Electrochemical Proteolytic Beacon for Detection of Matrix Metalloproteinase Activities

    SciTech Connect

    Liu, Guodong; Wang, Jun; Wunschel, David S.; Lin, Yuehe

    2006-09-27

    This communication describes a novel method for detecting of matrix metalloproteinase-7 activity using a peptide substrate labeled with a ferrocene reporter. The substrate serves as a selective ‘electrochemical proteolytic beacon’ (EPB) for this metalloproteinase. The EPB is immobilized on a gold electrode surface to enable ‘on-off’ electrochemical signaling capability for uncleaved and cleaved events. The EPB is efficiently and selectively cleaved by MMP-7 as measured by the rate of decrease in redox current of ferrocene. Direct transduction of a signal corresponding to peptide cleavage events into an electronic signal thus provides a simple, sensitive route for detecting the MMP activity. The new method allows for identification of the activity of MMP-7 in concentrations as low as 3.4 pM. The concept can be extended to design multiple peptide substrate labeled with different electroactive reporters for assaying multiple MMPs activities.

  19. An extracellular matrix response element in the promoter of the LpS1 genes of the sea urchin Lytechinus pictus.

    PubMed

    Seid, C A; Ramachandran, R K; George, J M; Govindarajan, V; González-Rimbau, M F; Flytzanis, C N; Tomlinson, C R

    1997-08-01

    The extracellular matrix (ECM) has been shown to play an important role in development and tissue-specific gene expression, yet the mechanism by which genes receive signals from the ECM is poorly understood. The aboral ectoderm-specific LpS1-alpha and -beta genes of Lytechinus pictus , members of the Spec gene family, provide an excellent model system to study ECM- mediated gene regulation. Disruption of the ECM by preventing collagen deposition using the lathrytic agent beta-aminopropionitrile (BAPN) inhibits LpS1 gene transcription. LpS1 transcription resumes after removal of BAPN and subsequent collagen reformation. Using a chloramphenicol acetyltransferase (CAT) reporter gene assay, we show that a 125 bp region of the LpS1-beta promoter from -108 to +17 contains an ECM response element (ECM RE). Insertion of the 125 bp region into the promoter of the metallothionein gene of L. pictus, a gene unaffected by ECM disruption, caused the fused promoter to become ECM dependent. As with the endogenous LpS1 genes, CAT activity directed by the fused LpS1-beta promoter resumed in embryos recovered from ECM disruption. A mutation in a cis -acting element called the proximal G-string, which lies in the 125 bp region, caused CAT activity levels in ECM-disrupted embryos to equal that of the wild-type LpS1-bet apromoter in ECM-intact embryos. These results suggest that the intact ECM normally transmits signals to inhibit repressor activity at the proximal G-string in aboral ectoderm cells. Consistent with these results were our findings which showed that in addition to expression in the aboral ectoderm, the proximal G-string mutation caused expression of the CAT gene in oral ectoderm cells. These studies suggested that the proximal G-string serves as a binding site for negative regulation of the LpS1 genes in oral ectoderm during development. We also examined trans -acting factors binding the proximal G-string following ECM disruption. Band shift gels revealed a predominant

  20. An extracellular matrix response element in the promoter of the LpS1 genes of the sea urchin Lytechinus pictus.

    PubMed Central

    Seid, C A; Ramachandran, R K; George, J M; Govindarajan, V; González-Rimbau, M F; Flytzanis, C N; Tomlinson, C R

    1997-01-01

    The extracellular matrix (ECM) has been shown to play an important role in development and tissue-specific gene expression, yet the mechanism by which genes receive signals from the ECM is poorly understood. The aboral ectoderm-specific LpS1-alpha and -beta genes of Lytechinus pictus , members of the Spec gene family, provide an excellent model system to study ECM- mediated gene regulation. Disruption of the ECM by preventing collagen deposition using the lathrytic agent beta-aminopropionitrile (BAPN) inhibits LpS1 gene transcription. LpS1 transcription resumes after removal of BAPN and subsequent collagen reformation. Using a chloramphenicol acetyltransferase (CAT) reporter gene assay, we show that a 125 bp region of the LpS1-beta promoter from -108 to +17 contains an ECM response element (ECM RE). Insertion of the 125 bp region into the promoter of the metallothionein gene of L. pictus, a gene unaffected by ECM disruption, caused the fused promoter to become ECM dependent. As with the endogenous LpS1 genes, CAT activity directed by the fused LpS1-beta promoter resumed in embryos recovered from ECM disruption. A mutation in a cis -acting element called the proximal G-string, which lies in the 125 bp region, caused CAT activity levels in ECM-disrupted embryos to equal that of the wild-type LpS1-bet apromoter in ECM-intact embryos. These results suggest that the intact ECM normally transmits signals to inhibit repressor activity at the proximal G-string in aboral ectoderm cells. Consistent with these results were our findings which showed that in addition to expression in the aboral ectoderm, the proximal G-string mutation caused expression of the CAT gene in oral ectoderm cells. These studies suggested that the proximal G-string serves as a binding site for negative regulation of the LpS1 genes in oral ectoderm during development. We also examined trans -acting factors binding the proximal G-string following ECM disruption. Band shift gels revealed a predominant

  1. EGFR promoter exhibits dynamic histone modifications and binding of ASH2L and P300 in human germinal matrix and gliomas

    PubMed Central

    Erfani, Parsa; Tome-Garcia, Jessica; Canoll, Peter; Doetsch, Fiona; Tsankova, Nadejda M

    2015-01-01

    Several signaling pathways important for the proliferation and growth of brain cells are pathologically dysregulated in gliomas, including the epidermal growth factor receptor (EGFR). Expression of EGFR is high in neural progenitors during development and in gliomas but decreases significantly in most adult brain regions. Here we show that EGFR expression is maintained in the astrocyte ribbon of the adult human subventricular zone. The transcriptional regulation of EGFR expression is poorly understood. To investigate the role of epigenetics on EGFR regulation in the contexts of neural development and gliomagenesis, we measured levels of DNA methylation and histone H3 modifications at the EGFR promoter in human brain tissues, glioma specimens, and EGFR-expressing neural cells, acutely isolated from their native niche. While DNA was constitutively hypomethylated in non-neoplastic and glioma samples, regardless of their EGFR-expression status, the activating histone modifications H3K27ac and H3K4me3 were enriched only when EGFR is highly expressed (developing germinal matrix and gliomas). Conversely, repressive H3K27me3 marks predominated in adult white matter where EGFR is repressed. Furthermore, the histone methyltransferase core enzyme ASH2L was bound at EGFR in the germinal matrix and in gliomas where levels of H3K4me3 are high, and the histone acetyltransferase P300 was bound in samples with H3K27ac enrichment. Our studies use human cells and tissues undisturbed by cell-culture artifact, and point to an important, locus-specific role for chromatin remodeling in EGFR expression in human neural development that may be dysregulated during gliomagenesis, unraveling potential novel targets for future drug therapy. PMID:25996283

  2. Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms

    PubMed Central

    Hancox, Rachael A; Allen, Michael D; Holliday, Deborah L; Edwards, Dylan R; Pennington, Caroline J; Guttery, David S; Shaw, Jacqueline A; Walker, Rosemary A; Pringle, J Howard; Jones, J Louise

    2009-01-01

    Introduction The stromal microenvironment has a profound influence on tumour cell behaviour. In tumours, the extracellular matrix (ECM) composition differs from normal tissue and allows novel interactions to influence tumour cell function. The ECM protein tenascin-C (TNC) is frequently up-regulated in breast cancer and we have previously identified two novel isoforms – one containing exon 16 (TNC-16) and one containing exons 14 plus 16 (TNC-14/16). Methods The present study has analysed the functional significance of this altered TNC isoform profile in breast cancer. TNC-16 and TNC-14/16 splice variants were generated using PCR-ligation and over-expressed in breast cancer cells (MCF-7, T47D, MDA-MD-231, MDA-MB-468, GI101) and human fibroblasts. The effects of these variants on tumour cell invasion and proliferation were measured and compared with the effects of the large (TNC-L) and fully spliced small (TNC-S) isoforms. Results TNC-16 and TNC-14/16 significantly enhanced tumour cell proliferation (P < 0.05) and invasion, both directly (P < 0.01) and as a response to transfected fibroblast expression (P < 0.05) with this effect being dependent on tumour cell interaction with TNC, because TNC-blocking antibodies abrogated these responses. An analysis of 19 matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases 1 to 4 (TIMP 1 to 4) revealed that TNC up-regulated expression of MMP-13 and TIMP-3 two to four fold relative to vector, and invasion was reduced in the presence of MMP inhibitor GM6001. However, this effect was not isoform-specific but was elicited equally by all TNC isoforms. Conclusions These results demonstrate a dual requirement for TNC and MMP in enhancing breast cancer cell invasion, and identify a significant role for the tumour-associated TNC-16 and TNC-14/16 in promoting tumour invasion, although these isoform-specific effects appear to be mediated through MMP-independent mechanisms. PMID:19405959

  3. Upregulation of metastasis-associated gene 2 promotes cell proliferation and invasion in nasopharyngeal carcinoma

    PubMed Central

    Wu, Minhua; Ye, Xiaoxia; Deng, Xubin; Wu, Yanxia; Li, Xiaofang; Zhang, Lin

    2016-01-01

    Aims Metastasis-associated gene 2 (MTA2) is reported to play an important role in tumor progression, but little is known about the role of MTA2 in nasopharyngeal carcinoma (NPC). The aim of the study was to explore the expression and function of MTA2 in NPC. Methods Expression of MTA2 in NPC tissues and cell lines was detected by immunohistochemistry and Western blotting. Relationship between MTA2 expression and clinicopathological features was analyzed. Stable MTA2-overexpressing and MTA2-siliencing NPC cells were established by transfection with plasmids encoding MTA2 cDNA and lentivirus-mediated short hairpin RNA, respectively. Cell viability was determined by Cell Counting Kit-8 and colony formation assay. Cell migration ability was evaluated by wound healing and transwell invasion assay. The impact of MTA2 knockdown on growth and metastasis of CNE2 cells in vivo was determined by nude mouse xenograft models. Expression of several Akt pathway proteins was detected by Western blotting. Results MTA2 was upregulated in NPC tissues and three NPC cell lines detected (CNE1, CNE2, and HNE1). MTA2 expression was related to clinical stage and lymph node metastasis of patients with NPC. MTA2 upregulation promoted proliferation and invasion of CNE1 cells, while MTA2 depletion had opposite effects on CNE2 cells. Moreover, MTA2 depletion suppressed growth and metastasis of CNE2 cells in vivo. MTA2 overexpression activated Akt and upregulated the expression of matrix metalloproteinase 7 and cyclin D1. Conclusion We conclude that MTA2 acts as an oncogene in tumorigenesis of NPC. MTA2 may be a potential target for gene therapy in NPC. PMID:27051300

  4. A novel biomarker ARMc8 promotes the malignant progression of ovarian cancer.

    PubMed

    Jiang, Guiyang; Yang, Dalei; Wang, Liang; Zhang, Xiupeng; Xu, Hongtao; Miao, Yuan; Wang, Enhua; Zhang, Yong

    2015-10-01

    Ovarian cancer is the most lethal gynecologic malignancy worldwide, and the survival rates have remained low in spite of medical advancements. More research is dedicated to the identification of novel biomarkers for this deadly disease. The association between ARMc8 and ovarian cancer remained unraveled. In this study, immunohistochemical staining was used to examine ARMc8 expression in 247 cases of ovarian cancer, 19 cases of borderline ovarian tumors, 41 cases of benign ovarian tumors, and 9 cases of normal ovarian tissues. It was shown that ARMc8 was predominantly located in the cytoplasm of tumor cells, and its expression was up-regulated in the ovarian cancer (61.9%) and the borderline ovarian tumor tissues (57.9%), in comparison with the benign ovarian tumors (12.2%; P < .05) and the normal ovarian tissues (11.1%; P < .05). In ovarian cancer, ARMc8 expression was closely related to International Federation of Gynecology and Obstetrics stages (P = .002), histology grade (P < .001), lymph node metastasis (P = .008), and poor prognosis (P < .001). Univariate and multivariate Cox analyses revealed that ARMc8 expression was an independent prognostic factor for ovarian cancer (P = .039 and P = .005). In addition, ARMc8 could promote the invasion and migration of ovarian cancer cells. Overexpressing ARMc8 enhanced the invasion and metastasis capacity of ARMc8-low Cavo-3 cells (P < .001), whereas interfering ARMc8 significantly reduced cell invasion and metastasis in ARMc8-high SK-OV-3 cells (P < .001). Furthermore, ARMc8 could up-regulate matrix metalloproteinase-7 and snail and down-regulate α-catenin, p120ctn, and E-cadherin. Collectively, ARMc8 may enhance the invasion and metastasis of ovarian cancer cells and likely to become a potential therapeutic target for ovarian cancer. PMID:26232863

  5. Promotion of breast cancer cells MDA-MB-231 invasion by di(2-ethylhexyl)phthalate through matrix metalloproteinase-2/-9 overexpression.

    PubMed

    Zhang, Shuya; Ma, Jiehua; Fu, Ziyi; Zhang, Zhilei; Cao, Jian; Huang, Lei; Li, Wenqu; Xu, Pengfei; Cao, Xin

    2016-05-01

    Di(2-ethylhexyl)phthalate (DEHP) is an estrogenic chemical that is widely used in polyvinyl products. We aimed to determine the mechanisms behind the effects of DEHP on ERα-negative breast cancer cells MDA-MB-231 invasion and matrix metalloproteinases-2/-9 (MMP-2/-9) up-regulation in this study. Transwell assay indicated that DEHP exposure (>50 μg/ml) significantly enhanced the invasion ability of MDA-MB-231 cells. Quantitative real-time PCR (qPCR) and western blotting revealed that MMP-2/-9 is overexpressed in mRNA and protein levels after DEHP treatment. Gelatin zymography consistently demonstrated that DEHP exposure also enhances the activity of MMP-2/-9. Immunofluorescence assay showed that DEHP could accelerate NF-kappaB (NF-κB) subunits-p65 translocation into the nucleus, which is confirmed by western blotting assay, suggesting that the ratio of nuclear/cytosolic level of p65 was significantly increased. Furthermore, the invasion and MMP-2/-9 overexpression of MDA-MB-231 cells after DEHP-treated were reversed by the NF-κB chemical inhibitor JSH-23 via drug inhibition assay. This study suggested that DEHP could promote ERα-negative breast cancer cells MDA-MB-231 invasion through activating NF-κB and MMP-2/-9 overexpression. PMID:26850096

  6. Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside-out activation of integrin α5β1

    PubMed Central

    Sekine, Katsutoshi; Kawauchi, Takeshi; Kubo, Ken-ichiro; Honda, Takao; Herz, Joachim; Hattori, Mitsuharu; Kinashi, Tatsuo; Nakajima, Kazunori

    2012-01-01

    Summary Birth-date-dependent neuronal layering is fundamental to neocortical functions. The extracellular protein Reelin is essential for the establishment of the eventual neuronal alignments. Although this Reelin-dependent neuronal layering is mainly established by the final neuronal migration step called “terminal translocation” beneath the marginal zone (MZ), the molecular mechanism underlying the control by Reelin of terminal translocation and layer formation is largely unknown. Here, we show that after Reelin binds to its receptors, it activates integrin α5β1 through the intracellular Dab1-Crk/CrkL-C3G-Rap1 pathway. This intracellular pathway is required for terminal translocation and the activation of Reelin signaling promotes neuronal adhesion to fibronectin through integrin α5β1. Since fibronectin is localized in the MZ, the activated integrin α5β1 then controls terminal translocation, which mediates proper neuronal alignments in the mature cortex. These data indicate that Reelin-dependent activation of neuronal adhesion to the extracellular matrix is crucial for the eventual birth-date-dependent layeringof the neocortex. PMID:23083738

  7. Matrix Metalloproteinase-19 Promotes Metastatic Behavior In Vitro and Is Associated with Increased Mortality in Non–Small Cell Lung Cancer

    PubMed Central

    Yu, Guoying; Herazo-Maya, Jose D.; Nukui, Tomoko; Romkes, Marjorie; Parwani, Anil; Juan-Guardela, Brenda M.; Robertson, Jennifer; Gauldie, Jack; Siegfried, Jill M.; Kaminski, Naftali

    2014-01-01

    Rationale: Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Matrix metalloproteinases (MMPs) have been implicated in the development and progression of lung cancer, but their role in the molecular pathogenesis of lung cancer remains unclear. We have found that MMP19, a relatively novel member of the MMP family, is overexpressed in lung tumors when compared with control subjects. Objectives: To test the hypothesis that MMP19 plays a significant role in the development and progression of non–small cell lung cancer (NSCLC). Methods: We have analyzed lung cancer gene expression data, immunostained lung tumors for MMP19, and performed in vitro assays to test the effects of MMP19 in NSCLC cells. Measurements and Main Results: We found that MMP19 gene and protein expression is increased in lung cancer tumors compared with adjacent and histologically normal lung tissues. In three independent datasets, increased MMP19 gene expression conferred a poorer prognosis in NSCLC. In vitro, we found that overexpression of MMP19 promotes epithelial–mesenchymal transition, migration, and invasiveness in multiple NSCLC cell lines. Overexpression of MMP19 with a mutation at the catalytic site did not impair epithelial–mesenchymal transition or expression of prometastasis genes. We also found that miR-30 isoforms, a microRNA family predicted to target MMP19, is markedly down-regulated in human lung cancer and regulates MMP19 expression. Conclusions: Taken together, these findings suggest that MMP19 is associated with the development and progression of NSCLC and may be a potential biomarker of disease severity and outcome. PMID:25250855

  8. Paeoniflorin inhibits proliferation and promotes apoptosis of multiple myeloma cells via its effects on microRNA‑29b and matrix metalloproteinase‑2.

    PubMed

    Wang, Shaofeng; Liu, Wenhua

    2016-09-01

    Multiple myeloma (MM) is a type of cancer characterized by the excessive proliferation of malignant plasma cells. In China, the incidence of MM has been increasing annually. Paeoniflorin exerts numerous functions, including coronary vessel expansion, and anti‑inflammation and anticancer activities. The present study aimed to investigate the effects of paeoniflorin on the proliferation and apoptosis of SKO‑007 MM cells, via its effects on the regulation of matrix metalloproteinase‑2 (MMP‑2) and microRNA (miR)‑29b. In the present study, an MTT assay was used to analyze the proliferation of SKO‑007 cells treated with paeoniflorin. Annexin V‑fluorescein isothiocyanate/propidium iodide apoptosis and caspase‑3 activation assays were used to detect the levels of cellular apoptosis. The expression levels of MMP‑2 and miR‑29b were detected using gelatin zymography and quantitative‑polymerase chain reaction, respectively. In addition, miR‑29b and anti‑miR‑29b plasmids were transfected into SKO‑007 cells, and the effects of paeoniflorin on cell proliferation and apoptosis were subsequently detected. The results of the present in vitro studies demonstrated that paeoniflorin was able to inhibit the proliferation of SKO‑007 cells in a dose‑ and time‑dependent manner. Furthermore, paeoniflorin effectively increased cell apoptosis, and augmented the activation of caspase‑3 and caspase‑9 in the SKO‑007 cells. The expression levels of MMP‑2 were suppressed following treatment of the SKO‑007 cells with paeoniflorin. In addition, paeoniflorin was able to induce the expression of miR‑29b. Notably, the results of the present study indicated that miR‑29b expression may control the expression of MMP‑2 in SKO‑007 cells. In conclusion, the present study demonstrated that paeoniflorin was able to inhibit cell proliferation and promote apoptosis of MM cells by suppressing the expression of MMP‑2, via the upregulation of miR‑29b. PMID

  9. Demineralized Bone Matrix Combined Bone Marrow Mesenchymal Stem Cells, Bone Morphogenetic Protein-2 and Transforming Growth Factor-β3 Gene Promoted Pig Cartilage Defect Repair

    PubMed Central

    Wang, Xin; Li, Yanlin; Han, Rui; He, Chuan; Wang, Guoliang; Wang, Jianwei; Zheng, Jiali; Pei, Mei; Wei, Lei

    2014-01-01

    Objectives To investigate whether a combination of demineralized bone matrix (DBM) and bone marrow mesenchymal stem cells (BMSCs) infected with adenovirus-mediated- bone morphogenetic protein (Ad-BMP-2) and transforming growth factor-β3 (Ad-TGF-β3) promotes the repair of the full-thickness cartilage lesions in pig model. Methods BMSCs isolated from pig were cultured and infected with Ad-BMP-2(B group), Ad-TGF-β3 (T group), Ad-BMP-2 + Ad-TGF-β3(BT group), cells infected with empty Ad served as a negative group(N group), the expression of the BMP-2 and TGF-β3 were confirmed by immunofluorescence, PCR, and ELISA, the expression of SOX-9, type II collagen(COL-2A), aggrecan (ACAN) in each group were evaluated by real-time PCR at 1w, 2w, 3w, respectively. The chondrogenic differentiation of BMSCs was evaluated by type II collagen at 21d with immunohistochemical staining. The third-passage BMSCs infected with Ad-BMP-2 and Ad-TGF-β3 were suspended and cultured with DBM for 6 days to construct a new type of tissue engineering scaffold to repair full-thickness cartilage lesions in the femur condyles of pig knee, the regenerated tissue was evaluated at 1,2 and 3 months after surgery by gross appearance, H&E, safranin O staining and O'driscoll score. Results Ad-BMP-2 and Ad-TGF-β3 (BT group) infected cells acquired strong type II collagen staining compared with Ad-BMP-2 (B group) and Ad-TGF-β3 (T group) along. The Ad-BMP-2 and Ad-TGF-β3 infected BMSCs adhered and propagated well in DBM and the new type of tissue engineering scaffold produced hyaline cartilage morphology containing a stronger type II collagen and safranin O staining, the O'driscoll score was higher than other groups. Conclusions The DBM compound with Ad-BMP-2 and Ad-TGF-β3 infected BMSCs scaffold has a good biocompatibility and could well induce cartilage regeneration to repair the defects of joint cartilage. This technology may be efficiently employed for cartilage lesions repair in vivo. PMID

  10. Cyclic AMP-elevating Agents Promote Cumulus Cell Survival and Hyaluronan Matrix Stability, Thereby Prolonging the Time of Mouse Oocyte Fertilizability.

    PubMed

    Di Giacomo, Monica; Camaioni, Antonella; Klinger, Francesca G; Bonfiglio, Rita; Salustri, Antonietta

    2016-02-19

    Cumulus cells sustain the development and fertilization of the mammalian oocyte. These cells are retained around the oocyte by a hyaluronan-rich extracellular matrix synthesized before ovulation, a process called cumulus cell-oocyte complex (COC) expansion. Hyaluronan release and dispersion of the cumulus cells progressively occur after ovulation, paralleling the decline of oocyte fertilization. We show here that, in mice, postovulatory changes of matrix are temporally correlated to cumulus cell death. Cumulus cell apoptosis and matrix disassembly also occurred in ovulated COCs cultured in vitro. COCs expanded in vitro with FSH or EGF underwent the same changes, whereas those expanded with 8-bromo-adenosine-3',5'-cyclic monophosphate (8-Br-cAMP) maintained integrity for a longer time. It is noteworthy that 8-Br-cAMP treatment was also effective on ovulated COCs cultured in vitro, prolonging the vitality of the cumulus cells and the stability of the matrix from a few hours to >2 days. Stimulation of endogenous adenylate cyclase with forskolin or inhibition of phosphodiesterase with rolipram produced similar effects. The treatment with selective cAMP analogues suggests that the effects of cAMP elevation are exerted through an EPAC-independent, PKA type II-dependent signaling pathway, probably acting at the post-transcriptional level. Finally, overnight culture of ovulated COCs with 8-Br-cAMP significantly counteracted the decrease of fertilization rate, doubling the number of fertilized oocytes compared with control conditions. In conclusion, these studies suggest that cAMP-elevating agents prevent cumulus cell senescence and allow them to continue to exert beneficial effects on oocyte and sperm, thereby extending in vitro the time frame of oocyte fertilizability. PMID:26694612

  11. RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation

    PubMed Central

    Leung, Hoi-Wing; Zhao, Si-Meng; Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Fung, Kwok-Pui; Leung, Ping-Chung; Tan, Ning-Hua; Lau, Clara Bik-San

    2015-01-01

    Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer. PMID:26592552

  12. Methylobacterium Species Promoting Rice and Barley Growth and Interaction Specificity Revealed with Whole-Cell Matrix-Assisted Laser Desorption / Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF/MS) Analysis

    PubMed Central

    Tani, Akio; Sahin, Nurettin; Fujitani, Yoshiko; Kato, Akiko; Sato, Kazuhiro; Kimbara, Kazuhide

    2015-01-01

    Methylobacterium species frequently inhabit plant surfaces and are able to utilize the methanol emitted from plants as carbon and energy sources. As some of the Methylobacterium species are known to promote plant growth, significant attention has been paid to the mechanism of growth promotion and the specificity of plant–microbe interactions. By screening our Methylobacterium isolate collection for the high growth promotion effect in vitro, we selected some candidates for field and pot growth tests for rice and barley, respectively. We found that inoculation resulted in better ripening of rice seeds, and increased the size of barley grains but not the total yield. In addition, using whole-cell matrix-assister laser desorption/ionization- time-of-flight mass spectrometry (MALDI-TOF/MS) analysis, we identified and classified Methylobacterium isolates from Methylobacterium-inoculated rice plants. The inoculated species could not be recovered from the rice plants, and in some cases, the Methylobacterium community structure was affected by the inoculation, but not with predomination of the inoculated species. The isolates from non-inoculated barley of various cultivars grown in the same field fell into just two species. These results suggest that there is a strong selection pressure at the species level of Methylobacterium residing on a given plant species, and that selection of appropriate species that can persist on the plant is important to achieve growth promotion. PMID:26053875

  13. The HIV Matrix Protein p17 Promotes the Activation of Human Hepatic Stellate Cells through Interactions with CXCR2 and Syndecan-2

    PubMed Central

    Renga, Barbara; Francisci, Daniela; Schiaroli, Elisabetta; Carino, Adriana; Cipriani, Sabrina; D'Amore, Claudio; Sidoni, Angelo; Sordo, Rachele Del; Ferri, Ivana; Lucattelli, Monica; Lunghi, Benedetta; Baldelli, Franco; Fiorucci, Stefano

    2014-01-01

    Background The human immunodeficiency virus type 1 (HIV-1) p17 is a matrix protein involved in virus life's cycle. CXCR2 and Syndecan-2, the two major coreceptors for the p17 protein, are expressed in hepatic stellate cells (HSCs), a key cell type involved in matrix deposition in liver fibrotic disorders. Aim In this report we have investigated the in vitro impact of p17 on HSCs transdifferentiation and function and underlying signaling pathways involved in these processes. Methods LX-2 cells, a human HSC line, and primary HSC were challenged with p17 and expressions of fibrogenic markers and of p17 receptors were assessed by qRT-PCR and Western blot. Downstream intracellular signaling pathways were evaluated with qRT-PCR and Western blot as well as after pre-treatment with specific pathway inhibitors. Results Exposure of LX2 cells to p17 increases their contractile force, reshapes the cytoskeleton fibers and upregulates the expression of transdifferentiation markers including αSMA, COL1α1 and endothelin-1 through the activation of Jak/STAT and Rho signaling pathways. These effects are lost in HSCs pre-incubated with a serum from HIV positive person who underwent a vaccination with a p17 peptide. Confocal laser microscopy studies demonstrates that CXCR2 and syndecan-2 co-associate at the plasma membrane after exposure to p17. Immunostaining of HIV/HCV liver biopsies from co-infected patients reveals that the progression of liver fibrosis correlates with a reduced expression of CXCR2. Conclusions The HIV matrix protein p17 is pro-fibrogenic through its interactions both with CXCR2 and syndecan-2 on activated HSCs. PMID:24736615

  14. MT1-MMP promotes cell growth and ERK activation through c-Src and paxillin in three-dimensional collagen matrix

    SciTech Connect

    Takino, Takahisa; Tsuge, Hisashi; Ozawa, Terumasa; Sato, Hiroshi

    2010-06-11

    Membrane-type 1 matrix metalloproteinase (MT1-MMP) is essential for tumor invasion and growth. We show here that MT1-MMP induces extracellular signal-regulated kinase (ERK) activation in cancer cells cultured in collagen gel, which is indispensable for their proliferation. Inhibition of MT1-MMP by MMP inhibitor or small interfering RNA suppressed activation of focal adhesion kinase (FAK) and ERK in MT1-MMP-expressing cancer cells, which resulted in up-regulation of p21{sup WAF1} and suppression of cell growth in collagen gel. Cell proliferation was also abrogated by the inhibitor against ERK pathway without affecting FAK phosphorylation. MT1-MMP and integrin {alpha}{sub v}{beta}{sub 3} were shown to be involved in c-Src activation, which induced FAK and ERK activation in collagen gel. These MT1-MMP-mediated signal transductions were paxillin dependent, as knockdown of paxillin reduced cell growth and ERK activation, and co-expression of MT1-MMP with paxillin induced ERK activation. The results suggest that MT1-MMP contributes to proliferation of cancer cells in the extracellular matrix by activating ERK through c-Src and paxillin.

  15. Matrix Metalloproteinase 3 Promotes Cellular Anti-Dengue Virus Response via Interaction with Transcription Factor NFκB in Cell Nucleus

    PubMed Central

    Zuo, Xiangyang; Pan, Wen; Feng, Tingting; Shi, Xiaohong; Dai, Jianfeng

    2014-01-01

    Dengue virus (DENV), the causative agent of human Dengue hemorrhagic fever, is a mosquito-borne virus of immense global health importance. Characterization of cellular factors promoting or inhibiting DENV infection is important for understanding the mechanism of DENV infection. In this report, MMP3 (stromelysin-1), a secretory endopeptidase that degrades extracellular matrices, has been shown promoting cellular antiviral response against DENV infection. Quantitative RT-PCR and Western Blot showed that the expression of MMP3 was upregulated in DENV-infected RAW264.7 cells. The intracellular viral loads were significantly higher in MMP3 silenced cells compared with controls. The expression level of selective anti-viral cytokines were decreased in MMP3 siRNA treated cells, and the transcription factor activity of NFκB was significantly impaired upon MMP3 silencing during DENV infection. Further, we found that MMP3 moved to cell nucleus upon DENV infection and colocalized with NFκB P65 in nucleus. Co-immunoprecipitation analysis suggested that MMP3 directly interacted with NFκB in nucleus during DENV infection and the C-terminal hemopexin-like domain of MMP3 was required for the interaction. This study suggested a novel role of MMP3 in nucleus during viral infection and provided new evidence for MMPs in immunomodulation. PMID:24416274

  16. Hypoxia-inducible Factor 1 (HIF-1) Promotes Extracellular Matrix Remodeling under Hypoxic Conditions by Inducing P4HA1, P4HA2, and PLOD2 Expression in Fibroblasts*

    PubMed Central

    Gilkes, Daniele M.; Bajpai, Saumendra; Chaturvedi, Pallavi; Wirtz, Denis; Semenza, Gregg L.

    2013-01-01

    Extracellular matrix (ECM) composition, organization, and compliance provide both architectural and chemical cues that modulate tissue structure and function. ECM produced by stromal fibroblasts plays a key role in breast cancer invasion and metastasis, which are also stimulated by intratumoral hypoxia. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of ECM remodeling by fibroblasts under hypoxic conditions. HIF-1 activates expression of genes encoding collagen prolyl (P4HA1 and P4HA2) and lysyl (PLOD2) hydroxylases. P4HA1 and P4HA2 are required for collagen deposition, whereas PLOD2 is required for ECM stiffening and collagen fiber alignment. Together P4HA1, P4HA2, and PLOD2 mediate remodeling of ECM composition, alignment, and mechanical properties in response to hypoxia. HIF-1-dependent ECM remodeling by hypoxic fibroblasts induces changes in breast cancer cell morphology, adhesion, and motility that promote invasion and metastasis. PMID:23423382

  17. Testes-specific protease 50 promotes cell invasion and metastasis by increasing NF-kappaB-dependent matrix metalloproteinase-9 expression.

    PubMed

    Song, Z B; Ni, J-S; Wu, P; Bao, Y L; Liu, T; Li, M; Fan, C; Zhang, W J; Sun, L G; Huang, Y X; Li, Y X

    2015-01-01

    The high mortality in breast cancer is often associated with metastatic progression in patients. Previously we have demonstrated that testes-specific protease 50 (TSP50), an oncogene overexpressed in breast cancer samples, could promote cell proliferation and tumorigenesis. However, whether TSP50 also has a key role in cell invasion and cancer metastasis, and the mechanism underlying the process are still unclear. Here we found that TSP50 overexpression greatly promoted cell migration, invasion, adhesion and formation of the stellate structures in 3D culture system in vitro as well as lung metastasis in vivo. Conversely, TSP50 knockdown caused the opposite changes. Mechanistic studies revealed that NF-κB signaling pathway was required for TSP50-induced cell migration and metastasis, and further results indicated that TSP50 overexpression enhanced expression and secretion of MMP9, a target gene of NF-κB signaling. In addition, knockdown of MMP9 resulted in inhibition of cell migration and invasion in vitro and lung metastasis in vivo. Most importantly, immunohistochemical staining of human breast cancer samples strongly showed that the coexpression of TSP50 and p65 as well as TSP50 and MMP9 were correlated with increased metastasis and poor survival. Furthermore, we found that some breast cancer diagnosis-associated features such as tumor size, tumor grade, estrogen receptors (ER) and progesterone receptors (PR) levels, were correlated well with TSP50/p65 and TSP50/MMP9 expression status. Taken together, this work identified the TSP50 activation of MMP9 as a novel signaling mechanism underlying human breast cancer invasion and metastasis. PMID:25811800

  18. Oxidative stress promotes the increase of matrix metalloproteinases-2 and -9 activities in the feto-placental unit of diabetic rats.

    PubMed

    Pustovrh, María Carolina; Jawerbaum, Alicia; Capobianco, Evangelina; White, Verónica; Martínez, Nora; López-Costa, Juan José; González, Elida

    2005-12-01

    Maternal diabetes increases the risk of congenital malformations, placental dysfunction and diseases in both the neonate and the offspring's later life. Oxidative stress has been involved in the etiology of these abnormalities. Matrix metalloproteases (MMPs), involved in multiple developmental pathways, are increased in the fetus and placenta from diabetic experimental models. As oxidants could be involved in the activation of latent MMPs, we investigated a putative relationship between MMPs activities and oxidative stress in the feto-placental unit of diabetic rats at midgestation. We found that H2O2 enhanced and that superoxide dismutase (SOD) reduced MMPs activities in the maternal side of the placenta and in the fetuses from control and diabetic rats. MMPs were not modified by oxidative status in the fetal side of the placenta. Lipid peroxidation was enhanced in the maternal and fetal sides of the placenta and in the fetus from diabetic rats when compared to controls, and gradually decreased from the maternal placental side to the fetus in diabetic animals. The activities of the antioxidant enzymes SOD and catalase were decreased in the maternal placental side, catalase activity was enhanced in the fetal placental side and both enzymes were increased in the fetuses from diabetic rats when compared to controls. Our data demonstrate changes in the oxidative balance and capability of oxidants to upregulate MMPs activity in the feto-placental unit from diabetic rats, a basis to elucidate links between oxidative stress and alterations in the developmental pathways in which MMPs are involved. PMID:16298858

  19. SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca2+ buffering

    PubMed Central

    Traba, J; del Arco, A; Duchen, M R; Szabadkai, G; Satrústegui, J

    2012-01-01

    Ca2+-mediated mitochondrial permeability transition (mPT) is the final common pathway of stress-induced cell death in many major pathologies, but its regulation in intact cells is poorly understood. Here we report that the mitochondrial carrier SCaMC-1/SLC25A24 mediates ATP-Mg2−/Pi2− and/or HADP2−/Pi2− uptake into the mitochondria after an increase in cytosolic [Ca2+]. ATP and ADP contribute to Ca2+ buffering in the mitochondrial matrix, resulting in desensitization of the mPT. Comprehensive gene expression analysis showed that SCaMC-1 overexpression is a general feature of transformed and cancer cells. Knockdown of the transporter led to vast reduction of mitochondrial Ca2+ buffering capacity and sensitized cells to mPT-mediated necrotic death triggered by oxidative stress and Ca2+ overload. These findings revealed that SCaMC-1 exerts a negative feedback control between cellular Ca2+ overload and mPT-dependent cell death, suggesting that the carrier might represent a novel target for cancer therapy. PMID:22015608

  20. Mechanotransduction and extracellular matrix homeostasis

    PubMed Central

    Humphrey, Jay D.; Dufresne, Eric R.; Schwartz, Martin A.

    2015-01-01

    Preface Soft connective tissues at steady state are yet dynamic; resident cells continually read environmental cues and respond to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the matrix by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechano-regulation process that includes the deposition, rearrangement, or removal of matrix to maintain overall form and function. Progress toward understanding the molecular, cellular, and tissue scale effects that promote mechanical homeostasis has helped identify key questions for future research. PMID:25355505

  1. Sildenafil promotes smooth muscle preservation and ameliorates fibrosis through modulation of extracellular matrix and tissue growth factor gene expression after bilateral cavernosal nerve resection in the rat

    PubMed Central

    Sirad, Fara; Hlaing, Su; Kovanecz, Istvan; Artaza, Jorge N.; Garcia, Leah A.; Rajfer, Jacob; Ferrini, Monica G.

    2010-01-01

    Introduction It has been shown that PDE 5 inhibitors preserve smooth muscle (SM) content and ameliorate the fibrotic degeneration normally seen in the corpora cavernosa after bilateral cavernosal nerve resection (BCNR). However, the downstream mechanisms by which these drugs protect the corpora cavernosa remain poorly understood. Aim To provide insight into the mechanism, we aimed to determine the gene expression profile of angiogenesis related pathways within the penile tissue after BCNR with or without continuous sildenafil treatment. Methods 5-month old Fisher rats were subjected to BCNR or sham operation and treated with or without sildenafil (20 mg/Kg. B.W drinking water) for 3 days or 45 days (n=8 rats per group). Total RNAs isolated from the denuded penile shaft and prostate were subjected to reverse transcription and to angiogenesis real time-PCR arrays (84 genes). Changes in protein expression of selected genes such as epiregulin and CTGF were corroborated by western blot and immunohistochemistry. Main outcomes measures Genes modulated by BCNR and sildenafil treatment. Results A decreased expression of genes related to SM growth factors such as epiregulin (EREG), platelet derived growth factor (PDGF), extracellular matrix regulators such as metalloproteinases 3 and 9, endothelial growth factors, together with an up-regulation of pro-fibrotic genes such as connective tissue growth factor (CTGF) and TGFβ2 were found at both time points after BCNR. Sildenafil treatment reversed this process by up-regulating endothelial and SM growth factors and down-regulating pro-fibrotic factors. Sildenafil did not affect the expression of EREG, VEGF, PDGF in the ventral prostate of BCNR animals Conclusions Sildenafil treatment after BCNR activates genes related to SM preservation and down regulates genes related to fibrosis in the corpora cavernosa. These results provide a mechanistic justification for the use of sildenafil and other PDE5 inhibitors as protective therapy

  2. Silk Fibroin Scaffolds Promote Formation of the Ex Vivo Niche for Salivary Gland Epithelial Cell Growth, Matrix Formation, and Retention of Differentiated Function

    PubMed Central

    Zhang, Bin-Xian; Zhang, Zhi-Liang; Lin, Alan L.; Wang, Hanzhou; Pilia, Marcello; Ong, Joo L.; Dean, David D.

    2015-01-01

    Salivary gland hypofunction often results from a number of causes, including the use of various medications, radiation for head and neck tumors, autoimmune diseases, diabetes, and aging. Since treatments for this condition are lacking and adult salivary glands have little regenerative capacity, there is a need for cell-based therapies to restore salivary gland function. Development of these treatment strategies requires the establishment of a system that is capable of replicating the salivary gland cell “niche” to support the proliferation and differentiation of salivary gland progenitor cells. In this study, a culture system using three-dimensional silk fibroin scaffolds (SFS) and primary salivary gland epithelial cells (pSGECs) from rat submandibular (SM) gland and parotid gland (PG) was established and characterized. pSGECs grown on SFS, but not tissue culture plastic (TCP), formed aggregates of cells with morphological features resembling secretory acini. High levels of amylase were released into the media by both cell types after extended periods in culture on SFS. Remarkably, cultures of PG-derived cells on SFS, but not SM cells, responded to isoproterenol, a β-adrenergic receptor agonist, with increased enzyme release. This behavior mimics that of the salivary glands in vivo. Decellularized extracellular matrix (ECM) formed by pSGECs in culture on SFS contained type IV collagen, a major component of the basement membrane. These results demonstrate that pSGECs grown on SFS, but not TCP, retain important functional and structural features of differentiated salivary glands and produce an ECM that mimics the native salivary gland cell niche. These results demonstrate that SFS has potential as a scaffold for creating the salivary gland cell niche in vitro and may provide an approach for inducing multipotent stem cells to provide therapeutically meaningful numbers of salivary gland progenitor cells for regenerating these tissues in patients. PMID:25625623

  3. SM50 repeat-polypeptides self-assemble into discrete matrix subunits and promote appositional calcium carbonate crystal growth during sea urchin tooth biomineralization.

    PubMed

    Mao, Yelin; Satchell, Paul G; Luan, Xianghong; Diekwisch, Thomas G H

    2016-01-01

    The two major proteins involved in vertebrate enamel formation and echinoderm sea urchin tooth biomineralization, amelogenin and SM50, are both characterized by elongated polyproline repeat domains in the center of the macromolecule. To determine the role of polyproline repeat polypeptides in basal deuterostome biomineralization, we have mapped the localization of SM50 as it relates to crystal growth, conducted self-assembly studies of SM50 repeat polypeptides, and examined their effect on calcium carbonate and apatite crystal growth. Electron micrographs of the growth zone of Strongylocentrotus purpuratus sea urchin teeth documented a series of successive events from intravesicular mineral nucleation to mineral deposition at the interface between tooth surface and odontoblast syncytium. Using immunohistochemistry, SM50 was detected within the cytoplasm of cells associated with the developing tooth mineral, at the mineral secreting front, and adjacent to initial mineral deposits, but not in muscles and ligaments. Polypeptides derived from the SM50 polyproline alternating hexa- and hepta-peptide repeat region (SM50P6P7) formed highly discrete, donut-shaped self-assembly patterns. In calcium carbonate crystal growth studies, SM50P6P7 repeat peptides triggered the growth of expansive networks of fused calcium carbonate crystals while in apatite growth studies, SM50P6P7 peptides facilitated the growth of needle-shaped and parallel arranged crystals resembling those found in developing vertebrate enamel. In comparison, SM50P6P7 surpassed the PXX24 polypeptide repeat region derived from the vertebrate enamel protein amelogenin in its ability to promote crystal nucleation and appositional crystal growth. Together, these studies establish the SM50P6P7 polyproline repeat region as a potent regulator in the protein-guided appositional crystal growth that occurs during continuous tooth mineralization and eruption. In addition, our studies highlight the role of species

  4. Slit2‑Robo1 signaling promotes the adhesion, invasion and migration of tongue carcinoma cells via upregulating matrix metalloproteinases 2 and 9, and downregulating E‑cadherin.

    PubMed

    Zhao, Yuan; Zhou, Feng-Li; Li, Wei-Ping; Wang, Jing; Wang, Li-Jing

    2016-09-01

    Whether Slit homologue 2 (Slit2) inhibits or promotes tumor cell migration remains controversial, and the role of Slit2‑Roundabout 1 (Robo1) signaling in oral cancer remains to be fully elucidated. The aim of the present study was to investigate the role of Slit2‑Robo1 signaling in the adhesion, invasion and migration of tongue carcinoma cells, and the mechanism by which Slit2‑Robo1 signaling inhibits or promotes tumor cell migration. Tca8113 tongue carcinoma cells were treated with the monoclonal anti‑human Robo1 antibody, R5, to inhibit the Slit2‑Robo1 signaling pathway, with immunoglobulin (Ig)G2b treatment as a negative control. The expression levels of Slit2 and Robo1 were determined using flow cytometry. The effects of R5 on the adhesion, invasion and migration of Tca8113 tongue carcinoma cells were investigated. Gelatin zymography was used to investigate the activity of matrix metalloproteinase 2 (MMP2) and MMP9. Western blot analysis was used to evaluate the expression levels of E‑cadherin in Tca8113 cells treated with 10 µg/ml of either R5 or IgG2b. Slit2 and Robo1 proteins were found to be expressed in the Tca8113 cells. R5 significantly inhibited the adhesion, invasion and migration of Tca8113 cells in vitro. R5 also inhibited the activities of MMP2 and MMP9, and increased the expression of E‑cadherin in the Tca8113 cells. These results suggested that Slit2‑Robo1 signaling promoted the adhesion, invasion and migration of tongue carcinoma cells by upregulating the expression levels of MMP2 and MMP9 and, downregulating the expression of E‑cadherin. PMID:27431199

  5. Matrix superpotentials

    NASA Astrophysics Data System (ADS)

    Nikitin, Anatoly G.; Karadzhov, Yuri

    2011-07-01

    We present a collection of matrix-valued shape invariant potentials which give rise to new exactly solvable problems of SUSY quantum mechanics. It includes all irreducible matrix superpotentials of the generic form W=kQ+\\frac{1}{k} R+P, where k is a variable parameter, Q is the unit matrix multiplied by a real-valued function of independent variable x, and P and R are the Hermitian matrices depending on x. In particular, we recover the Pron'ko-Stroganov 'matrix Coulomb potential' and all known scalar shape invariant potentials of SUSY quantum mechanics. In addition, five new shape invariant potentials are presented. Three of them admit a dual shape invariance, i.e. the related Hamiltonians can be factorized using two non-equivalent superpotentials. We find discrete spectrum and eigenvectors for the corresponding Schrödinger equations and prove that these eigenvectors are normalizable.

  6. Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma.

    PubMed

    Wu, Xiao; Liu, Bao-Jun; Ji, Shumeng; Wu, Jing-Feng; Xu, Chang-Qing; Du, Yi-Jie; You, Xiao-Fang; Li, Bei; Le, Jing-Jing; Xu, Hai-Lin; Duan, Xiao-Hong; Dong, Jing-Cheng

    2015-07-01

    Numerous epidemiological and experimental animal studies have indicated that chronic psychological stress may promote tumor development. However, the underlying molecular mechanisms by which chronic stress promotes tumorigenesis remain to be fully elucidated and animal models have not yet been well established. In the present study, an established mouse model of repeated social defeat stress (RSDS), was generated and used to investigate the effect of stress on tumor growth and metastasis. C57BL/6 mice were exposed to RSDS for 10 days, followed by subcutaneousl inoculation with Lewis lung carcinoma cells for seven days. The tumor weight and volume as well as the number of the lung metastatic nodules were then determined. Vascular endothelial growth factor (VEGF) serum levels were measured using ELISAs. In addition, expression levels of VEGF receptor (VEGFR) and L1 cell adhesion molecule (L1CAM) messenger (m)RNA were confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, protein expression levels of phosphorlyated extracellular signal-regulated kinase (pERK), matrix metalloproteinase (MMP)-2 and MMP-9 were examined using western blot analysis. The results showed that RSDS significantly increased the weight and the volume of the primary tumor as well as the number of the lung metastatic nodules. Serum VEGF levels were significantly higher in the tumor-stress group compared with those of the unstressed tumor mice. In addition, tumors in stressed animals demonstrated markedly enhanced expression of VEGFR-2 and L1CAM mRNA as well as pERK, MMP-2 and MMP-9 protein expression. In conclusion, these results suggested that RSDS contributed to lung cancer progression, angiogenesis and metastasis, which was partially associated with increased VEGF secretion and therefore the activation of the ERK signaling pathway, resulting in the induction of MMP-2 and MMP-9 protein expression. PMID:25824133

  7. Sync Matrix

    Energy Science and Technology Software Center (ESTSC)

    2004-12-31

    Sync Matrix provides a graphic display of the relationships among all of the response activities of each jurisdiction. This is accomplished through software that organizes and displays the activities by jurisdiction, function, and time for easy review and analysis. The software can also integrate the displays of multiple jurisdictions to allow examination of the total response.

  8. Hybrid matrix fiber composites

    DOEpatents

    Deteresa, Steven J.; Lyon, Richard E.; Groves, Scott E.

    2003-07-15

    Hybrid matrix fiber composites having enhanced compressive performance as well as enhanced stiffness, toughness and durability suitable for compression-critical applications. The methods for producing the fiber composites using matrix hybridization. The hybrid matrix fiber composites include two chemically or physically bonded matrix materials, whereas the first matrix materials are used to impregnate multi-filament fibers formed into ribbons and the second matrix material is placed around and between the fiber ribbons that are impregnated with the first matrix material and both matrix materials are cured and solidified.

  9. A matrix lower bound

    SciTech Connect

    Grcar, Joseph F.

    2002-02-04

    A matrix lower bound is defined that generalizes ideas apparently due to S. Banach and J. von Neumann. The matrix lower bound has a natural interpretation in functional analysis, and it satisfies many of the properties that von Neumann stated for it in a restricted case. Applications for the matrix lower bound are demonstrated in several areas. In linear algebra, the matrix lower bound of a full rank matrix equals the distance to the set of rank-deficient matrices. In numerical analysis, the ratio of the matrix norm to the matrix lower bound is a condition number for all consistent systems of linear equations. In optimization theory, the matrix lower bound suggests an identity for a class of min-max problems. In real analysis, a recursive construction that depends on the matrix lower bound shows that the level sets of continuously differential functions lie asymptotically near those of their tangents.

  10. Johne's disease in cattle is associated with enhanced expression of genes encoding IL-5, GATA-3, tissue inhibitors of matrix metalloproteinases 1 and 2, and factors promoting apoptosis in peripheral blood mononuclear cells.

    PubMed

    Coussens, Paul M; Pudrith, Chas B; Skovgaard, Kerstin; Ren, Xiaoning; Suchyta, Steven P; Stabel, Judith R; Heegaard, Peter M H

    2005-05-15

    Infection of ruminants with Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) leads to a chronic and often fatal granulomatous enteritis known as Johne's disease. Most infections with M. paratuberculosis occur during the first 6 months of life, and there is some evidence for transmission in utero. Once established, infections typically exist in a subclinical state for several years. Recent gene-expression profiling studies suggested the hypothesis that inherent gene-expression profiles in peripheral blood mononuclear cells (PBMCs) from M. paratuberculosis-infected cattle may be different than expression profiles in PBMCs from uninfected controls. If true, this would suggest that it is possible to identify an M. paratuberculosis infection "signature" through transcriptional profiling of peripheral immune cells. In addition, identification of groups or classes of genes showing inherently different expression in PBMCs from M. paratuberculosis-infected cattle relative to PBMCs from uninfected controls might highlight important interactions between this pathogen and the host immune system. In this report, we describe studies aimed at testing this hypothesis. Our novel results indicate that, indeed expression profiles of at least 42 genes are inherently different in freshly isolated PBMCs from M. paratuberculosis-infected cattle when compared to similar cells from uninfected controls. Gene-expression differences observed following microarray analysis were verified and expanded upon by quantitative real-time PCR (Q-RT-PCR). Our results indicate that T cells within PBMCs from M. paratuberculosis-infected cows have adopted a predominant Th 2-like phenotype (enhanced expression of IL-5, GATA 3, and possibly IL-4 mRNA), that cells within infected cow PBMCs may exhibit tissue remodeling deficiencies through higher expression of tissue inhibitor of matrix metalloproteinase (TIMP) 1 and TIMP2 RNA and lower expression of matrix metalloproteinase (MMP) 14 RNA

  11. Carbonate fuel cell matrix

    DOEpatents

    Farooque, M.; Yuh, C.Y.

    1996-12-03

    A carbonate fuel cell matrix is described comprising support particles and crack attenuator particles which are made platelet in shape to increase the resistance of the matrix to through cracking. Also disclosed is a matrix having porous crack attenuator particles and a matrix whose crack attenuator particles have a thermal coefficient of expansion which is significantly different from that of the support particles, and a method of making platelet-shaped crack attenuator particles. 8 figs.

  12. Carbonate fuel cell matrix

    DOEpatents

    Farooque, Mohammad; Yuh, Chao-Yi

    1996-01-01

    A carbonate fuel cell matrix comprising support particles and crack attenuator particles which are made platelet in shape to increase the resistance of the matrix to through cracking. Also disclosed is a matrix having porous crack attenuator particles and a matrix whose crack attenuator particles have a thermal coefficient of expansion which is significantly different from that of the support particles, and a method of making platelet-shaped crack attenuator particles.

  13. Matrix differentiation formulas

    NASA Technical Reports Server (NTRS)

    Usikov, D. A.; Tkhabisimov, D. K.

    1983-01-01

    A compact differentiation technique (without using indexes) is developed for scalar functions that depend on complex matrix arguments which are combined by operations of complex conjugation, transposition, addition, multiplication, matrix inversion and taking the direct product. The differentiation apparatus is developed in order to simplify the solution of extremum problems of scalar functions of matrix arguments.

  14. Matrix with Prescribed Eigenvectors

    ERIC Educational Resources Information Center

    Ahmad, Faiz

    2011-01-01

    It is a routine matter for undergraduates to find eigenvalues and eigenvectors of a given matrix. But the converse problem of finding a matrix with prescribed eigenvalues and eigenvectors is rarely discussed in elementary texts on linear algebra. This problem is related to the "spectral" decomposition of a matrix and has important technical…

  15. Nanocrystal doped matrixes

    DOEpatents

    Parce, J. Wallace; Bernatis, Paul; Dubrow, Robert; Freeman, William P.; Gamoras, Joel; Kan, Shihai; Meisel, Andreas; Qian, Baixin; Whiteford, Jeffery A.; Ziebarth, Jonathan

    2010-01-12

    Matrixes doped with semiconductor nanocrystals are provided. In certain embodiments, the semiconductor nanocrystals have a size and composition such that they absorb or emit light at particular wavelengths. The nanocrystals can comprise ligands that allow for mixing with various matrix materials, including polymers, such that a minimal portion of light is scattered by the matrixes. The matrixes of the present invention can also be utilized in refractive index matching applications. In other embodiments, semiconductor nanocrystals are embedded within matrixes to form a nanocrystal density gradient, thereby creating an effective refractive index gradient. The matrixes of the present invention can also be used as filters and antireflective coatings on optical devices and as down-converting layers. Processes for producing matrixes comprising semiconductor nanocrystals are also provided. Nanostructures having high quantum efficiency, small size, and/or a narrow size distribution are also described, as are methods of producing indium phosphide nanostructures and core-shell nanostructures with Group II-VI shells.

  16. Fiber coatings for ceramic matrix composites

    SciTech Connect

    Carpenter, H.W.; Bohlen, J.W.

    1992-08-01

    Two fiber coating concepts for ceramic matrix composites were successfully demonstrated in a preliminary study. These coatings were designed to promote toughness in composites and resist oxidation. The concepts were: (1) thin, multiple unbonded layers, and (2) a single porous layer that provided low interfacial strengths between the fiber and matrix. Chemical vapor deposited (CVD) SiC and sol-gel derived oxides were used to produce the fiber coatings. Specimens consisted of a single coated monofilament fiber and a sheath of CVD SiC to represent the matrix. Results from flexure tests showed that matrix cracks were deflected and that fibers debonded the same as in specimens made using carbon-coated fibers. Crack deflection and fiber debonding were also evident after exposure in air at elevated temperatures. 5 refs.

  17. Toll-like receptor activation and mechanical force stimulation promote the secretion of matrix metalloproteinases 1, 3 and 10 of human periodontal fibroblasts via p38, JNK and NF-kB.

    PubMed

    Lisboa, Rodolfo Assis; Andrade, Marcus Vinícius; Cunha-Melo, José Renan

    2013-06-01

    Matrix metalloproteinases (MMPs) are known to play a key role during orthodontic treatment leading to periodontal remodelling and tooth movement. MMPs may be induced by mechanical forces. However, the role played by toll-like receptors (TLRs) in modulating the effects of the mechanical force on periodontal fibroblasts is not known. To investigate the interaction between mechanical force and TLR stimulation, primary cultures of human periodontal fibroblasts were submitted to centrifugation in the presence of LPS and Pam3Cys, which are known TLR-4 and TLR-2 ligands, respectively. The expression of MMP-1, -2, -3, -8, -9, -10 and -13; TIMP (Tissue Inhibitor of Metalloproteinases) -1, -2 and -4; TNF-α (Tumour Necrosis Factor alpha); IL-1β (Interleukin 1 beta); ERK 1/2 (Extracellular Signal-Regulated Kinase 1/2); p38; JNK (c-jun N-terminal Kinase); IRAK1 (Interleukin-1 Receptor-Associated Kinase); and NF-κB (Nuclear Factor kappa B) were measured by antibody array, ELISA and immunoblotting methods. The activation of TLRs associated with centrifugation induced an increase in the secretion of MMPs 1, 3 and 10, with no increase in TNF-α or IL-1β. An increase in the phosphorylation of the MAP kinases p38 and JNK and the transcription factor NF-κB, without an increase in TIMPs was also observed. These findings suggest that the secretion of MMPs by cultured periodontal fibroblasts that is induced by combined TLR activation and mechanical force stimulation is regulated via the p38, JNK and NF-κB pathways. The increased secretion of MMPs by TLR activation may be an important factor that should be considered during orthodontic treatment. PMID:23332208

  18. Critical Thinking: Some Problems with the Matrix Method.

    ERIC Educational Resources Information Center

    Ekelund, Robert B., Jr.; Hebert, Robert F.

    1998-01-01

    Criticizes the use of a conceptual matrix in an undergraduate history of economic thought course. A conceptual matrix is a visual display advocated by John Bean and Dean Peterson that cross references normative and economic issues with their historical contexts. Argues that this promotes rote learning and stifles critical thinking. (MJP)

  19. Evidence-Based Practice: A Matrix for Predicting Phonological Generalization

    ERIC Educational Resources Information Center

    Gierut, Judith A.; Hulse, Lauren E.

    2010-01-01

    This paper describes a matrix for clinical use in the selection of phonological treatment targets to induce generalization, and in the identification of probe sounds to monitor during the course of intervention. The matrix appeals to a set of factors that have been shown to promote phonological generalization in the research literature, including…

  20. Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma.

    PubMed

    Bourguignon, Lilly Y W; Wong, Gabriel; Shiina, Marisa

    2016-05-13

    Human head and neck squamous cell carcinoma is a solid tumor malignancy associated with major morbidity and mortality. In this study, we determined that human head and neck squamous cell carcinoma-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by a high level of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. Importantly, matrix hyaluronan (HA) induces the up-regulation of stem cell markers that display the hallmark CSC properties. Histone methyltransferase, DOT1L, is also up-regulated by HA in CSCs (isolated from HSC-3 cells). Further analyses indicate that the stimulation of microRNA-10b (miR-10b) expression is DOT1L-specific and HA/CD44-dependent in CSCs. This process subsequently results in the overexpression of RhoGTPases and survival proteins leading to tumor cell invasion and cisplatin resistance. Treatment of CSCs with DOT1L-specific small interfering RNAs (siRNAs) effectively blocks HA/CD44-mediated expression of DOT1L, miR-10b production, and RhoGTPase/survival protein up-regulation as well as reduces tumor cell invasion and enhances chemosensitivity. CSCs were also transfected with a specific anti-miR-10b inhibitor to silence miR-10b expression and block its target functions. Our results demonstrate that the anti-miR-10 inhibitor not only decreases RhoGTPase/survival protein expression and tumor cell invasion, but also increases chemosensitivity in HA-treated CSCs. Taken together, these findings strongly support the contention that histone methyltransferase, DOT1L-associated epigenetic changes induced by HA play pivotal roles in miR-10 production leading to up-regulation of RhoGTPase and survival proteins. All of these events are critically important for the acquisition of cancer stem cell properties, including self-renewal, tumor cell invasion, and chemotherapy resistance in HA/CD44-activated head and neck cancer. PMID:27002147

  1. Biofilm Matrix Proteins

    PubMed Central

    Fong, Jiunn N. C.; Yildiz, Fitnat H.

    2015-01-01

    Proteinaceous components of the biofilm matrix include secreted extracellular proteins, cell surface adhesins and protein subunits of cell appendages such as flagella and pili. Biofilm matrix proteins play diverse roles in biofilm formation and dissolution. They are involved in attaching cells to surfaces, stabilizing the biofilm matrix via interactions with exopolysaccharide and nucleic acid components, developing three-dimensional biofilm architectures, and dissolving biofilm matrix via enzymatic degradation of polysaccharides, proteins, and nucleic acids. In this chapter, we will review functions of matrix proteins in a selected set of microorganisms, studies of the matrix proteomes of Vibrio cholerae and Pseudomonas aeruginosa, and roles of outer membrane vesicles and of nucleoid-binding proteins in biofilm formation. PMID:26104709

  2. Automatic switching matrix

    DOEpatents

    Schlecht, Martin F.; Kassakian, John G.; Caloggero, Anthony J.; Rhodes, Bruce; Otten, David; Rasmussen, Neil

    1982-01-01

    An automatic switching matrix that includes an apertured matrix board containing a matrix of wires that can be interconnected at each aperture. Each aperture has associated therewith a conductive pin which, when fully inserted into the associated aperture, effects electrical connection between the wires within that particular aperture. Means is provided for automatically inserting the pins in a determined pattern and for removing all the pins to permit other interconnecting patterns.

  3. Inhibition of membrane-type 1 matrix metalloproteinase at cell-matrix adhesions.

    PubMed

    Takino, Takahisa; Saeki, Hiromi; Miyamori, Hisashi; Kudo, Tomoya; Sato, Hiroshi

    2007-12-15

    Membrane-type 1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion and metastasis. We previously reported that extracellular matrix degradation by MT1-MMP regulates cell migration via modulating sustained integrin-mediated signals. In this study, MT1-MMP-expressing cells were plated onto fibronectin-coated plates and monitored for cell-matrix adhesion formation and fibronectin degradation. The fibronectin was degraded and removed in line with the cell migration track. The migrating cells showed a polarized morphology and were in contact with the edge of fibronectin through the leading edge, in which cell-matrix adhesions are concentrated. Expression of MT1-MMP targeted to cell-matrix adhesions by fusing with the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK) promoted the initial fibronectin lysis at the cell periphery immediately after adhesion. These results suggest that fibronectin is degraded by MT1-MMP located at cell-matrix adhesions, which are concentrated at the leading edge of the migrating cells. To inhibit MT1-MMP at cell-matrix adhesion, the dominant negative form of MT1-MMP (MT1-Pex) was targeted to the cell-matrix adhesion by fusing with the FAT domain (MT1-Pex-FAT). MT1-Pex-FAT accumulated at cell-matrix adhesions and inhibited fibronectin degradation as well as FAK phosphorylation more effectively than parental MT1-Pex. MT1-Pex-FAT was also shown to suppress the invasion of tumor cells into three-dimensional collagen gel more strongly than MT1-Pex. These results suggest that MT1-MMP-mediated extracellular matrix lysis at cell-matrix adhesions induces the establishment of cell polarity, which facilitates cell-matrix adhesion turnover and subsequent cell migration. This model highlights the role of MT1-MMP at the leading edge of migrating cells. PMID:18089791

  4. Matrix cracking in ceramic-matrix composites

    SciTech Connect

    Danchaivijit, S.; Shetty, D.K. . Dept. of Materials Science and Engineering)

    1993-10-01

    Matrix cracking in ceramic-matrix composites with unbonded frictional interface has been studied using fracture mechanics theory. The critical stress for extension of a fiber-bridged crack has been analyzed using the stress-intensity approach. The analysis uses a new shear-lag formulation of the crack-closure traction applied by the bridging fibers based on the assumption of a constant sliding friction stress over the sliding length of the fiber-matrix interface. The new formulation satisfies two required limiting conditions: (a) when the stress in the bridging fiber approaches the far-field applied stress, the crack-opening displacement approaches a steady-state upper limit that is in agreement with the previous formulations; and (b) in the limit of zero crack opening, the stress in the bridging fiber approaches the far-field fiber stress. This lower limit of the bridging stress is distinctly different from the previous formulations. For all other conditions, the closure traction is a function of the far-field applied stress in addition to the local crack-opening displacement, the interfacial sliding friction stress, and the material properties. Numerical calculations using the stress-intensity approach indicate that the critical stress for crack extension decreases with increasing crack length and approaches a constant steady-state value for large cracks. The steady-state matrix-cracking stress agrees with a steady-state energy balance analysis applied to the continuum model, but it is slightly less than the matrix-cracking stress predicted by such theories of steady-state cracking as that of Aveston, Cooper, and Kelly. The origin of this difference and a method for reconciliation of the two theoretical approaches are discussed.

  5. Transfer function matrix

    NASA Technical Reports Server (NTRS)

    Seraji, H.

    1987-01-01

    Given a multivariable system, it is proved that the numerator matrix N(s) of the transfer function evaluated at any system pole either has unity rank or is a null matrix. It is also shown that N(s) evaluated at any transmission zero of the system has rank deficiency. Examples are given for illustration.

  6. MATRIX AND VECTOR SERVICES

    Energy Science and Technology Software Center (ESTSC)

    2001-10-18

    PETRA V2 provides matrix and vector services and the ability construct, query, and use matrix and vector objects that are used and computed by TRILINOS solvers. It provides all basic matr5ix and vector operations for solvers in TRILINOS.

  7. Matrix metalloproteinases and epileptogenesis.

    PubMed

    Ikonomidou, Chrysanthy

    2014-12-01

    Matrix metalloproteinases are vital drivers of synaptic remodeling in health and disease. It is suggested that at early stages of epileptogenesis, inhibition of matrix metalloproteinases may help ameliorate cell death, aberrant network rewiring, and neuroinflammation and prevent development of epilepsy. PMID:26567100

  8. Grassmann matrix quantum mechanics

    NASA Astrophysics Data System (ADS)

    Anninos, Dionysios; Denef, Frederik; Monten, Ruben

    2016-04-01

    We explore quantum mechanical theories whose fundamental degrees of freedom are rectangular matrices with Grassmann valued matrix elements. We study particular models where the low energy sector can be described in terms of a bosonic Hermitian matrix quantum mechanics. We describe the classical curved phase space that emerges in the low energy sector. The phase space lives on a compact Kähler manifold parameterized by a complex matrix, of the type discovered some time ago by Berezin. The emergence of a semiclassical bosonic matrix quantum mechanics at low energies requires that the original Grassmann matrices be in the long rectangular limit. We discuss possible holographic interpretations of such matrix models which, by construction, are endowed with a finite dimensional Hilbert space.

  9. Time rate collision matrix

    SciTech Connect

    Stoenescu, M.L.; Smith, T.M.

    1980-02-01

    The collision integral terms in Boltzmann equation are reformulated numerically leading to the substitution of the multiple integrals with a multiplicative matrix of the two colliding species velocity distribution functions which varies with the differential collision cross section. A matrix of lower rank may be constructed when one of the distribution functions is specified, in which case the matrix elements represent kinetic transition probabilities in the velocity space and the multiplication of the time rate collision matrix with the unknown velocity distribution function expresses the time rate of change of the distribution. The collision matrix may be used to describe the time evolution of systems in nonequilibrium conditions, to evaluate the rate of momentum and energy transfer between given species, or to generate validity criteria for linearized kinetic equations.

  10. Promoting Models

    NASA Astrophysics Data System (ADS)

    Li, Qin; Zhao, Yongxin; Wu, Xiaofeng; Liu, Si

    There can be multitudinous models specifying aspects of the same system. Each model has a bias towards one aspect. These models often override in specific aspects though they have different expressions. A specification written in one model can be refined by introducing additional information from other models. The paper proposes a concept of promoting models which is a methodology to obtain refinements with support from cooperating models. It refines a primary model by integrating the information from a secondary model. The promotion principle is not merely an academic point, but also a reliable and robust engineering technique which can be used to develop software and hardware systems. It can also check the consistency between two specifications from different models. A case of modeling a simple online shopping system with the cooperation of the guarded design model and CSP model illustrates the practicability of the promotion principle.

  11. Hybrid matrix amplifier

    DOEpatents

    Martens, J.S.; Hietala, V.M.; Plut, T.A.

    1995-01-03

    The present invention comprises a novel matrix amplifier. The matrix amplifier includes an active superconducting power divider (ASPD) having N output ports; N distributed amplifiers each operatively connected to one of the N output ports of the ASPD; and a power combiner having N input ports each operatively connected to one of the N distributed amplifiers. The distributed amplifier can included M stages of amplification by cascading superconducting active devices. The power combiner can include N active elements. The resulting (N[times]M) matrix amplifier can produce signals of high output power, large bandwidth, and low noise. 6 figures.

  12. Hybrid matrix amplifier

    DOEpatents

    Martens, Jon S.; Hietala, Vincent M.; Plut, Thomas A.

    1995-01-01

    The present invention comprises a novel matrix amplifier. The matrix amplifier includes an active superconducting power divider (ASPD) having N output ports; N distributed amplifiers each operatively connected to one of the N output ports of the ASPD; and a power combiner having N input ports each operatively connected to one of the N distributed amplifiers. The distributed amplifier can included M stages of amplification by cascading superconducting active devices. The power combiner can include N active elements. The resulting (N.times.M) matrix amplifier can produce signals of high output power, large bandwidth, and low noise.

  13. Measurement matrix optimization method based on matrix orthogonal similarity transformation

    NASA Astrophysics Data System (ADS)

    Pan, Jinfeng

    2016-05-01

    Optimization of the measurement matrix is one of the important research aspects of compressive sensing theory. A measurement matrix optimization method is presented based on the orthogonal similarity transformation of the information operator's Gram matrix. In terms of the fact that the information operator's Gram matrix is a singular symmetric matrix, a simplified orthogonal similarity transformation is deduced, and thus the simplified diagonal matrix that is orthogonally similar to it is obtained. Then an approximation of the Gram matrix is obtained by letting all the nonzero diagonal entries of the simplified diagonal matrix equal their average value. Thus an optimized measurement matrix can be acquired according to its relationship with the information operator. Results of experiments show that the optimized measurement matrix compared to the random measurement matrix is less coherent with dictionaries. The relative signal recovery error also declines when the proposed measurement matrix is utilized.

  14. Metal Matrix Composites

    SciTech Connect

    Hunt, Warren; Herling, Darrell R.

    2004-02-01

    Metal matrix composites have found selected application in areas that can cost-effectively capitalize on improvements in specific stiffness, specific strength, fatigue resistance, wear resistance, and coefficient of thermal expansion. Metal matrix composites comprise a relatively wide range of materials defined by the metal matrix, reinforcement type, and reinforcement geometry. In the area of the matrix, most metallic systems have been explored, including aluminum, beryllium, magnesium, titanium, iron, nickel, cobalt, and silver. However, aluminum is by far the most preferred. For reinforcements, the materials are typically ceramics, which provide a very beneficial combination of stiffness, strength, and relatively low density. Candidate reinforcement materials include SiC, Al2O3, B4C, TiC, TiB2, graphite, and a number of other ceramics. In addition, metallic materials such as tungsten and steel fibers have been considered.

  15. Pesticide-Exposure Matrix

    Cancer.gov

    The "Pesticide-exposure Matrix" was developed to help epidemiologists and other researchers identify the active ingredients to which people were likely exposed when their homes and gardens were treated for pests in past years.

  16. The Hill Interaction Matrix

    ERIC Educational Resources Information Center

    Hill, William Fawcett

    1971-01-01

    Leadership style, group composition, and group development are simultaneously quantified through the use of the matrix. It represents an attempt to objectify the art of group therapy. Comment by Richard C. Rank follows. (Author)

  17. Promoting Health.

    ERIC Educational Resources Information Center

    Mechanic, David

    1990-01-01

    Argues that culture change or modification of the social structure is necessary for effective health promotion because health behavior is closely tied to basic group structures and processes. Examines the health attitudes of Mormons, low income and minority groups, and developing Islamic nations, emphasizing attitudes towards education and women.…

  18. Matrix computations in MACSYMA

    NASA Technical Reports Server (NTRS)

    Wang, P. S.

    1977-01-01

    Facilities built into MACSYMA for manipulating matrices with numeric or symbolic entries are described. Computations will be done exactly, keeping symbols as symbols. Topics discussed include how to form a matrix and create other matrices by transforming existing matrices within MACSYMA; arithmetic and other computation with matrices; and user control of computational processes through the use of optional variables. Two algorithms designed for sparse matrices are given. The computing times of several different ways to compute the determinant of a matrix are compared.

  19. Optical coherency matrix tomography

    PubMed Central

    Kagalwala, Kumel H.; Kondakci, H. Esat; Abouraddy, Ayman F.; Saleh, Bahaa E. A.

    2015-01-01

    The coherence of an optical beam having multiple degrees of freedom (DoFs) is described by a coherency matrix G spanning these DoFs. This optical coherency matrix has not been measured in its entirety to date—even in the simplest case of two binary DoFs where G is a 4 × 4 matrix. We establish a methodical yet versatile approach—optical coherency matrix tomography—for reconstructing G that exploits the analogy between this problem in classical optics and that of tomographically reconstructing the density matrix associated with multipartite quantum states in quantum information science. Here G is reconstructed from a minimal set of linearly independent measurements, each a cascade of projective measurements for each DoF. We report the first experimental measurements of the 4 × 4 coherency matrix G associated with an electromagnetic beam in which polarization and a spatial DoF are relevant, ranging from the traditional two-point Young’s double slit to spatial parity and orbital angular momentum modes. PMID:26478452

  20. A Classification Matrix of Examination Items to Promote Transformative Assessment

    ERIC Educational Resources Information Center

    McMahon, Mark; Garrett, Michael

    2016-01-01

    The ability to assess learning hinges on the quality of the instruments that are used. This paper reports on the first stage of the design of software to assist educators in ensuring assessment questions meet educational outcomes. A review of the literature within the field of instructional psychology was undertaken with a view towards…

  1. Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch

    PubMed Central

    Dali-Youcef, Nassim; Hnia, Karim; Blaise, Sébastien; Messaddeq, Nadia; Blanc, Stéphane; Postic, Catherine; Valet, Philippe; Tomasetto, Catherine; Rio, Marie-Christine

    2016-01-01

    MMP11 overexpression is a bad prognostic factor in various human carcinomas. Interestingly, this proteinase is not expressed in malignant cells themselves but is secreted by adjacent non-malignant mesenchymal/stromal cells, such as cancer associated fibroblasts (CAFs) and adipocytes (CAAs), which favors cancer cell survival and progression. As MMP11 negatively regulates adipogenesis in vitro, we hypothesized that it may play a role in whole body metabolism and energy homeostasis. We used an in vivo gain- (Mmp11-Tg mice) and loss- (Mmp11−/− mice) of-function approach to address the systemic function of MMP11. Strikingly, MMP11 overexpression protects against type 2 diabetes while Mmp11−/− mice exhibit hallmarks of metabolic syndrome. Moreover, Mmp11-Tg mice were protected from diet-induced obesity and display mitochondrial dysfunction, due to oxidative stress, and metabolic switch from oxidative phosphorylation to aerobic glycolysis. This Warburg-like effect observed in adipose tissues might provide a rationale for the deleterious impact of CAA-secreted MMP11, favouring tumor progression. MMP11 overexpression also leads to increased circulating IGF1 levels and the activation of the IGF1/AKT/FOXO1 cascade, an important metabolic signalling pathway. Our data reveal a major role for MMP11 in controlling energy metabolism, and provide new clues for understanding the relationship between metabolism, cancer progression and patient outcome. PMID:27126782

  2. Matrix metalloproteinase 11 protects from diabesity and promotes metabolic switch.

    PubMed

    Dali-Youcef, Nassim; Hnia, Karim; Blaise, Sébastien; Messaddeq, Nadia; Blanc, Stéphane; Postic, Catherine; Valet, Philippe; Tomasetto, Catherine; Rio, Marie-Christine

    2016-01-01

    MMP11 overexpression is a bad prognostic factor in various human carcinomas. Interestingly, this proteinase is not expressed in malignant cells themselves but is secreted by adjacent non-malignant mesenchymal/stromal cells, such as cancer associated fibroblasts (CAFs) and adipocytes (CAAs), which favors cancer cell survival and progression. As MMP11 negatively regulates adipogenesis in vitro, we hypothesized that it may play a role in whole body metabolism and energy homeostasis. We used an in vivo gain- (Mmp11-Tg mice) and loss- (Mmp11-/- mice) of-function approach to address the systemic function of MMP11. Strikingly, MMP11 overexpression protects against type 2 diabetes while Mmp11-/- mice exhibit hallmarks of metabolic syndrome. Moreover, Mmp11-Tg mice were protected from diet-induced obesity and display mitochondrial dysfunction, due to oxidative stress, and metabolic switch from oxidative phosphorylation to aerobic glycolysis. This Warburg-like effect observed in adipose tissues might provide a rationale for the deleterious impact of CAA-secreted MMP11, favouring tumor progression. MMP11 overexpression also leads to increased circulating IGF1 levels and the activation of the IGF1/AKT/FOXO1 cascade, an important metabolic signalling pathway. Our data reveal a major role for MMP11 in controlling energy metabolism, and provide new clues for understanding the relationship between metabolism, cancer progression and patient outcome. PMID:27126782

  3. Matrix interdiction problem

    SciTech Connect

    Pan, Feng; Kasiviswanathan, Shiva

    2010-01-01

    In the matrix interdiction problem, a real-valued matrix and an integer k is given. The objective is to remove k columns such that the sum over all rows of the maximum entry in each row is minimized. This combinatorial problem is closely related to bipartite network interdiction problem which can be applied to prioritize the border checkpoints in order to minimize the probability that an adversary can successfully cross the border. After introducing the matrix interdiction problem, we will prove the problem is NP-hard, and even NP-hard to approximate with an additive n{gamma} factor for a fixed constant {gamma}. We also present an algorithm for this problem that achieves a factor of (n-k) mUltiplicative approximation ratio.

  4. Tendon Functional Extracellular Matrix

    PubMed Central

    Screen, H.R.C.; Birk, D.E.; Kadler, K.E.; Ramirez, F; Young, M.F.

    2015-01-01

    This article is one of a series, summarising views expressed at the Orthopaedic Research Society New Frontiers in Tendon Research Conference. This particular article reviews the three workshops held under the “Functional Extracellular Matrix” stream. The workshops focused on the roles of the tendon extracellular matrix, such as performing the mechanical functions of tendon, creating the local cell environment and providing cellular cues. Tendon is a complex network of matrix and cells, and its biological functions are influenced by widely-varying extrinsic and intrinsic factors such as age, nutrition, exercise levels and biomechanics. Consequently, tendon adapts dynamically during development, ageing and injury. The workshop discussions identified research directions associated with understanding cell-matrix interactions to be of prime importance for developing novel strategies to target tendon healing or repair. PMID:25640030

  5. Complex matrix model duality

    SciTech Connect

    Brown, T. W.

    2011-04-15

    The same complex matrix model calculates both tachyon scattering for the c=1 noncritical string at the self-dual radius and certain correlation functions of operators which preserve half the supersymmetry in N=4 super-Yang-Mills theory. It is dual to another complex matrix model where the couplings of the first model are encoded in the Kontsevich-like variables of the second. The duality between the theories is mirrored by the duality of their Feynman diagrams. Analogously to the Hermitian Kontsevich-Penner model, the correlation functions of the second model can be written as sums over discrete points in subspaces of the moduli space of punctured Riemann surfaces.

  6. Matrixed business support comparison study.

    SciTech Connect

    Parsons, Josh D.

    2004-11-01

    The Matrixed Business Support Comparison Study reviewed the current matrixed Chief Financial Officer (CFO) division staff models at Sandia National Laboratories. There were two primary drivers of this analysis: (1) the increasing number of financial staff matrixed to mission customers and (2) the desire to further understand the matrix process and the opportunities and challenges it creates.

  7. Small intestinal submucosa extracellular matrix (CorMatrix®) in cardiovascular surgery: a systematic review.

    PubMed

    Mosala Nezhad, Zahra; Poncelet, Alain; de Kerchove, Laurent; Gianello, Pierre; Fervaille, Caroline; El Khoury, Gebrine

    2016-06-01

    Extracellular matrix (ECM) derived from small intestinal submucosa (SIS) is widely used in clinical applications as a scaffold for tissue repair. Recently, CorMatrix® porcine SIS-ECM (CorMatrix Cardiovascular, Inc., Roswell, GA, USA) has gained popularity for 'next-generation' cardiovascular tissue engineering due to its ease of use, remodelling properties, lack of immunogenicity, absorbability and potential to promote native tissue growth. Here, we provide an overview of the biology of porcine SIS-ECM and systematically review the preclinical and clinical literature on its use in cardiovascular surgery. CorMatrix® has been used in a variety of cardiovascular surgical applications, and since it is the most widely used SIS-ECM, this material is the focus of this review. Since CorMatrix® is a relatively new product for cardiovascular surgery, some clinical and preclinical studies published lack systematic reporting of functional and pathological findings in sufficient numbers of subjects. There are also emerging reports to suggest that, contrary to expectations, an undesirable inflammatory response may occur in CorMatrix® implants in humans and longer-term outcomes at particular sites, such as the heart valves, may be suboptimal. Large-scale clinical studies are needed driven by robust protocols that aim to quantify the pathological process of tissue repair. PMID:26912574

  8. Matrix Synthesis and Characterization

    NASA Technical Reports Server (NTRS)

    1984-01-01

    The role of NASA in the area of composite material synthesis; evaluation techniques; prediction analysis techniques; solvent-resistant tough composite matrix; resistance to paint strippers; acceptable processing temperature and pressure for thermoplastics; and the role of computer modeling and fiber interface improvement were discussed.

  9. The Acrosomal Matrix.

    PubMed

    Foster, James A; Gerton, George L

    2016-01-01

    The acrosome, a single exocytotic vesicle on the head of sperm, has an essential role in fertilization, but the exact mechanisms by which it facilitates sperm-egg interactions remain unresolved. The acrosome contains dozens of secretory proteins that are packaged into the forming structure during spermatogenesis; many of these proteins are localized into specific topographical areas of the acrosome, while others are more diffusely distributed. Acrosomal proteins can also be biochemically classified as components of the acrosomal matrix, a large, relatively insoluble complex, or as soluble proteins. This review focuses on recent findings using genetically modified mice (gene knockouts and transgenic "green acrosome" mice) to study the effects of eliminating acrosomal matrix-associated proteins on sperm structure and function. Some gene knockouts produce infertile phenotypes with obviously missing, specific activities that affect acrosome biogenesis during spermatogenesis or interfere with acrosome function in mature sperm. Mutations that delete some components produce fertile phenotypes with subtler effects that provide useful insights into acrosomal matrix function in fertilization. In general, these studies enable the reassessment of paradigms to explain acrosome formation and function and provide novel, objective insights into the roles of acrosomal matrix proteins in fertilization. The use of genetically engineered mouse models has yielded new mechanistic information that complements recent, important in vivo imaging studies. PMID:27194348

  10. Matrix Embedded Organic Synthesis

    NASA Astrophysics Data System (ADS)

    Kamakolanu, U. G.; Freund, F. T.

    2016-05-01

    In the matrix of minerals such as olivine, a redox reaction of the low-z elements occurs. Oxygen is oxidized to the peroxy state while the low-Z-elements become chemically reduced. We assign them a formula [CxHyOzNiSj]n– and call them proto-organics.

  11. Constructing the matrix

    NASA Astrophysics Data System (ADS)

    Elliott, John

    2012-09-01

    As part of our 'toolkit' for analysing an extraterrestrial signal, the facility for calculating structural affinity to known phenomena must be part of our core capabilities. Without such a resource, we risk compromising our potential for detection and decipherment or at least causing significant delay in the process. To create such a repository for assessing structural affinity, all known systems (language parameters) need to be structurally analysed to 'place' their 'system' within a relational communication matrix. This will need to include all known variants of language structure, whether 'living' (in current use) or ancient; this must also include endeavours to incorporate yet undeciphered scripts and non-human communication, to provide as complete a picture as possible. In creating such a relational matrix, post-detection decipherment will be assisted by a structural 'map' that will have the potential for 'placing' an alien communication with its nearest known 'neighbour', to assist subsequent categorisation of basic parameters as a precursor to decipherment. 'Universal' attributes and behavioural characteristics of known communication structure will form a range of templates (Elliott, 2001 [1] and Elliott et al., 2002 [2]), to support and optimise our attempt at categorising and deciphering the content of an extraterrestrial signal. Detection of the hierarchical layers, which comprise intelligent, complex communication, will then form a matrix of calculations that will ultimately score affinity through a relational matrix of structural comparison. In this paper we develop the rationales and demonstrate functionality with initial test results.

  12. TAp73 promotes anabolism

    PubMed Central

    Amelio, Ivano; Antonov, Alexey A.; Catani, Maria Valeria; Massoud, Renato; Bernassola, Francesca; Knight, Richard A.; Melino, Gerry; Rufini, Alessandro

    2014-01-01

    Metabolic adaptation has emerged as a hallmark of cancer and a promising therapeutic target, as rapidly proliferating cancer cells adapt their metabolism increasing nutrient uptake and reorganizing metabolic fluxes to support biosynthesis. The transcription factor p73 belongs to the p53-family and regulates tumorigenesis via its two N-terminal isoforms, with (TAp73) or without (ΔNp73) a transactivation domain. TAp73 acts as tumor suppressor, at least partially through induction of cell cycle arrest and apoptosis and through regulation of genomic stability. Here, we sought to investigate whether TAp73 also affects metabolic profiling of cancer cells. Using high throughput metabolomics, we unveil a thorough and unexpected role for TAp73 in promoting Warburg effect and cellular metabolism. TAp73-expressing cells show increased rate of glycolysis, higher amino acid uptake and increased levels and biosynthesis of acetyl-CoA. Moreover, we report an extensive TAp73-mediated upregulation of several anabolic pathways including polyamine and synthesis of membrane phospholipids. TAp73 expression also increases cellular methyl-donor S-adenosylmethionine (SAM), possibly influencing methylation and epigenetics, and promotes arginine metabolism, suggestive of a role in extracellular matrix (ECM) modeling. In summary, our data indicate that TAp73 regulates multiple metabolic pathways that impinge on numerous cellular functions, but that, overall, converge to sustain cell growth and proliferation. PMID:25514460

  13. Paths correlation matrix.

    PubMed

    Qian, Weixian; Zhou, Xiaojun; Lu, Yingcheng; Xu, Jiang

    2015-09-15

    Both the Jones and Mueller matrices encounter difficulties when physically modeling mixed materials or rough surfaces due to the complexity of light-matter interactions. To address these issues, we derived a matrix called the paths correlation matrix (PCM), which is a probabilistic mixture of Jones matrices of every light propagation path. Because PCM is related to actual light propagation paths, it is well suited for physical modeling. Experiments were performed, and the reflection PCM of a mixture of polypropylene and graphite was measured. The PCM of the mixed sample was accurately decomposed into pure polypropylene's single reflection, pure graphite's single reflection, and depolarization caused by multiple reflections, which is consistent with the theoretical derivation. Reflection parameters of rough surface can be calculated from PCM decomposition, and the results fit well with the theoretical calculations provided by the Fresnel equations. These theoretical and experimental analyses verify that PCM is an efficient way to physically model light-matter interactions. PMID:26371930

  14. Hypercube matrix computation task

    NASA Technical Reports Server (NTRS)

    Calalo, Ruel H.; Imbriale, William A.; Jacobi, Nathan; Liewer, Paulett C.; Lockhart, Thomas G.; Lyzenga, Gregory A.; Lyons, James R.; Manshadi, Farzin; Patterson, Jean E.

    1988-01-01

    A major objective of the Hypercube Matrix Computation effort at the Jet Propulsion Laboratory (JPL) is to investigate the applicability of a parallel computing architecture to the solution of large-scale electromagnetic scattering problems. Three scattering analysis codes are being implemented and assessed on a JPL/California Institute of Technology (Caltech) Mark 3 Hypercube. The codes, which utilize different underlying algorithms, give a means of evaluating the general applicability of this parallel architecture. The three analysis codes being implemented are a frequency domain method of moments code, a time domain finite difference code, and a frequency domain finite elements code. These analysis capabilities are being integrated into an electromagnetics interactive analysis workstation which can serve as a design tool for the construction of antennas and other radiating or scattering structures. The first two years of work on the Hypercube Matrix Computation effort is summarized. It includes both new developments and results as well as work previously reported in the Hypercube Matrix Computation Task: Final Report for 1986 to 1987 (JPL Publication 87-18).

  15. Standard Errors for Matrix Correlations.

    ERIC Educational Resources Information Center

    Ogasawara, Haruhiko

    1999-01-01

    Derives the asymptotic standard errors and intercorrelations for several matrix correlations assuming multivariate normality for manifest variables and derives the asymptotic standard errors of the matrix correlations for two factor-loading matrices. (SLD)

  16. On the Matrix Exponential Function

    ERIC Educational Resources Information Center

    Hou, Shui-Hung; Hou, Edwin; Pang, Wan-Kai

    2006-01-01

    A novel and simple formula for computing the matrix exponential function is presented. Specifically, it can be used to derive explicit formulas for the matrix exponential of a general matrix A satisfying p(A) = 0 for a polynomial p(s). It is ready for use in a classroom and suitable for both hand as well as symbolic computation.

  17. The cellulose resource matrix.

    PubMed

    Keijsers, Edwin R P; Yılmaz, Gülden; van Dam, Jan E G

    2013-03-01

    The emerging biobased economy is causing shifts from mineral fossil oil based resources towards renewable resources. Because of market mechanisms, current and new industries utilising renewable commodities, will attempt to secure their supply of resources. Cellulose is among these commodities, where large scale competition can be expected and already is observed for the traditional industries such as the paper industry. Cellulose and lignocellulosic raw materials (like wood and non-wood fibre crops) are being utilised in many industrial sectors. Due to the initiated transition towards biobased economy, these raw materials are intensively investigated also for new applications such as 2nd generation biofuels and 'green' chemicals and materials production (Clark, 2007; Lange, 2007; Petrus & Noordermeer, 2006; Ragauskas et al., 2006; Regalbuto, 2009). As lignocellulosic raw materials are available in variable quantities and qualities, unnecessary competition can be avoided via the choice of suitable raw materials for a target application. For example, utilisation of cellulose as carbohydrate source for ethanol production (Kabir Kazi et al., 2010) avoids the discussed competition with easier digestible carbohydrates (sugars, starch) deprived from the food supply chain. Also for cellulose use as a biopolymer several different competing markets can be distinguished. It is clear that these applications and markets will be influenced by large volume shifts. The world will have to reckon with the increase of competition and feedstock shortage (land use/biodiversity) (van Dam, de Klerk-Engels, Struik, & Rabbinge, 2005). It is of interest - in the context of sustainable development of the bioeconomy - to categorize the already available and emerging lignocellulosic resources in a matrix structure. When composing such "cellulose resource matrix" attention should be given to the quality aspects as well as to the available quantities and practical possibilities of processing the

  18. Mechanisms of Melanoma Promotion by Ultraviolet Radiation.

    PubMed

    Rünger, Thomas M

    2016-09-01

    The mutagenic properties of ultraviolet radiation drive the initiation of melanoma. Induction of matrix metalloproteinases in melanoma cells by longwave UVA radiation, possibly via a Warburg-like effect, promotes melanoma invasiveness. This is one of several mechanisms by which ultraviolet radiation also promotes further growth of previously established melanomas. PMID:27542295

  19. Using a Conceptual Matrix to Organize a Course in the History of Economic Thought.

    ERIC Educational Resources Information Center

    Peterson, Dean; Bean, John C.

    1998-01-01

    Describes a method for organizing the subject matter associated with the history of economic thought. The conceptual matrix is an organizer and visual display that cross references normative and economic issues with their historical context. Maintains that the matrix promotes critical thinking and allows students to focus on the issues. (MJP)

  20. Ceramic matrix and resin matrix composites: A comparison

    NASA Technical Reports Server (NTRS)

    Hurwitz, Frances I.

    1987-01-01

    The underlying theory of continuous fiber reinforcement of ceramic matrix and resin matrix composites, their fabrication, microstructure, physical and mechanical properties are contrasted. The growing use of organometallic polymers as precursors to ceramic matrices is discussed as a means of providing low temperature processing capability without the fiber degradation encountered with more conventional ceramic processing techniques. Examples of ceramic matrix composites derived from particulate-filled, high char yield polymers and silsesquioxane precursors are provided.

  1. Ceramic matrix and resin matrix composites - A comparison

    NASA Technical Reports Server (NTRS)

    Hurwitz, Frances I.

    1987-01-01

    The underlying theory of continuous fiber reinforcement of ceramic matrix and resin matrix composites, their fabrication, microstructure, physical and mechanical properties are contrasted. The growing use of organometallic polymers as precursors to ceramic matrices is discussed as a means of providing low temperature processing capability without the fiber degradation encountered with more conventional ceramic processing techniques. Examples of ceramic matrix composites derived from particulate-filled, high char yield polymers and silsesquioxane precursors are provided.

  2. Light cone matrix product

    SciTech Connect

    Hastings, Matthew B

    2009-01-01

    We show how to combine the light-cone and matrix product algorithms to simulate quantum systems far from equilibrium for long times. For the case of the XXZ spin chain at {Delta} = 0.5, we simulate to a time of {approx} 22.5. While part of the long simulation time is due to the use of the light-cone method, we also describe a modification of the infinite time-evolving bond decimation algorithm with improved numerical stability, and we describe how to incorporate symmetry into this algorithm. While statistical sampling error means that we are not yet able to make a definite statement, the behavior of the simulation at long times indicates the appearance of either 'revivals' in the order parameter as predicted by Hastings and Levitov (e-print arXiv:0806.4283) or of a distinct shoulder in the decay of the order parameter.

  3. Google matrix of Twitter

    NASA Astrophysics Data System (ADS)

    Frahm, K. M.; Shepelyansky, D. L.

    2012-10-01

    We construct the Google matrix of the entire Twitter network, dated by July 2009, and analyze its spectrum and eigenstate properties including the PageRank and CheiRank vectors and 2DRanking of all nodes. Our studies show much stronger inter-connectivity between top PageRank nodes for the Twitter network compared to the networks of Wikipedia and British Universities studied previously. Our analysis allows to locate the top Twitter users which control the information flow on the network. We argue that this small fraction of the whole number of users, which can be viewed as the social network elite, plays the dominant role in the process of opinion formation on the network.

  4. Matrix membranes and integrability

    SciTech Connect

    Zachos, C.; Fairlie, D.; Curtright, T.

    1997-06-01

    This is a pedagogical digest of results reported in Curtright, Fairlie, {ampersand} Zachos 1997, and an explicit implementation of Euler`s construction for the solution of the Poisson Bracket dual Nahm equation. But it does not cover 9 and 10-dimensional systems, and subsequent progress on them Fairlie 1997. Cubic interactions are considered in 3 and 7 space dimensions, respectively, for bosonic membranes in Poisson Bracket form. Their symmetries and vacuum configurations are explored. Their associated first order equations are transformed to Nahm`s equations, and are hence seen to be integrable, for the 3-dimensional case, by virtue of the explicit Lax pair provided. Most constructions introduced also apply to matrix commutator or Moyal Bracket analogs.

  5. Hyaluronan: A Matrix Component

    NASA Astrophysics Data System (ADS)

    Rügheimer, Louise

    2008-09-01

    The glucosaminoglycan hyaluronan is a key component of the extracellular matrix. It is a large, negatively charged molecule that can act as an ion exchange reservoir for positive ions. Hyaluronan is involved in renomedullary water handling through its water-binding capacity. In the renal medulla, the main source for hyaluronan production is the renomedullary interstitial cells. Hyaluronan synthases are found in the inner part of the plasma membrane and polymerize hyaluronan chains which are extruded into the extracellular space. Hyaluronidases are a family of enzymes involved in the degradation of hyaluronan. They have a wide range of properties, including differences in size, inhibitor sensitivities, catalytic mechanisms, substrate specificities and pH optima.

  6. Mixed Mode Matrix Multiplication

    SciTech Connect

    Meng-Shiou Wu; Srinivas Aluru; Ricky A. Kendall

    2004-09-30

    In modern clustering environments where the memory hierarchy has many layers (distributed memory, shared memory layer, cache,...), an important question is how to fully utilize all available resources and identify the most dominant layer in certain computations. When combining algorithms on all layers together, what would be the best method to get the best performance out of all the resources we have? Mixed mode programming model that uses thread programming on the shared memory layer and message passing programming on the distributed memory layer is a method that many researchers are using to utilize the memory resources. In this paper, they take an algorithmic approach that uses matrix multiplication as a tool to show how cache algorithms affect the performance of both shared memory and distributed memory algorithms. They show that with good underlying cache algorithm, overall performance is stable. When underlying cache algorithm is bad, superlinear speedup may occur, and an increasing number of threads may also improve performance.

  7. A matrix model for WZW

    NASA Astrophysics Data System (ADS)

    Dorey, Nick; Tong, David; Turner, Carl

    2016-08-01

    We study a U( N) gauged matrix quantum mechanics which, in the large N limit, is closely related to the chiral WZW conformal field theory. This manifests itself in two ways. First, we construct the left-moving Kac-Moody algebra from matrix degrees of freedom. Secondly, we compute the partition function of the matrix model in terms of Schur and Kostka polynomials and show that, in the large N limit, it coincides with the partition function of the WZW model. This same matrix model was recently shown to describe non-Abelian quantum Hall states and the relationship to the WZW model can be understood in this framework.

  8. Matrix market: a web resource for test matrix collection

    SciTech Connect

    Boisvert, R.F.; Pozo, R.; Remington, K.; Barrett, R.F.; Dongarra, J.J. /

    1996-05-30

    We describe a repository of data for the testing of numerical algorithms and mathematical software for matrix computations. The repository is designed to accommodate both dense and sparse matrices, as well as software to generate matrices. It has been seeded with the well known Harwell-Boeing sparse matrix collection. The raw data files have been augmented with an integrated World Wide Web interface which describes the matrices in the collection quantitatively and visually, For example, each matrix has a Web page which details its attributes, graphically depicts its sparsity pattern, and provides access to the matrix itself in several formats. In addition, a search mechanism is included which allows retrieval of matrices based on a variety of attributes, such as type and size, as well as through free-text search in abstracts. The URL is http://math.nist.gov/MatrixMarket.

  9. Hybridized polymer matrix composites

    NASA Technical Reports Server (NTRS)

    House, E. E.; Hoggatt, J. T.; Symonds, W. A.

    1980-01-01

    The extent to which graphite fibers are released from resin matrix composites that are exposed to fire and impact conditions was determined. Laboratory simulations of those conditions that could exist in the event of an aircraft crash and burn situation were evaluated. The effectiveness of various hybridizing concepts in preventing this release of graphite fibers were also evaluated. The baseline (i.e., unhybridized) laminates examined were prepared from commercially available graphite/epoxy, graphite/polyimide, and graphite/phenolic materials. Hybridizing concepts investigated included resin fillers, laminate coatings, resin blending, and mechanical interlocking of the graphite reinforcement. The baseline and hybridized laminates' mechanical properties, before and after isothermal and humidity aging, were also compared. It was found that a small amount of graphite fiber was released from the graphite/epoxy laminates during the burn and impact conditions used in this program. However, the extent to which the fibers were released is not considered a severe enough problem to preclude the use of graphite reinforced composites in civil aircraft structure. It also was found that several hybrid concepts eliminated this fiber release. Isothermal and humidity aging did not appear to alter the fiber release tendencies.

  10. Emergency Response Synchronization Matrix

    Energy Science and Technology Software Center (ESTSC)

    1999-06-01

    An emergency response to a disaster is complex, requiring the rapid integration, coordination, and synchronization of multiple levels of governmental and non-governmental organizations from numerous jurisdictions into a unified community response. For example, a community’s response actions to a fixed site hazardous materials incident could occur in an area extending from an on-site storage location to points 25 or more miles away. Response actions are directed and controlled by local governments and agencies situated withinmore » the response area, as well as by state and federal operaticns centers quite removed from the area of impact. Time is critical and the protective action decision-making process is greatly compressed. The response community must carefully plan and coordinate response operations in order to have confidence that they will be effectively implemented when faced with the potentially catastrophic nature of such releases. A graphical depiction of the entire response process via an emergency response synchronization matrix is an effective tool in optimizing the planning, exercising, and implementation of emergency plans. This system—based approach to emergency planning depicts how a community organizes its response tasks across space and time in relation to hazard actions. It provides the opportunity to make real—time adjustments as necessary for maximizing the often limited resources in protecting area residents. A response must involve the entire community and must not be limited by individual jurisdictions and organizations acting on their own without coordination, integration, and synchronization.« less

  11. Glass matrix armor

    DOEpatents

    Calkins, Noel C.

    1991-01-01

    An armor system which utilizes glass. A plurality of constraint cells are mounted on a surface of a substrate, which is metal armor plate or a similar tough material, such that the cells almost completely cover the surface of the substrate. Each constraint cell has a projectile-receiving wall parallel to the substrate surface and has sides which are perpendicular to and surround the perimeter of the receiving wall. The cells are mounted such that, in one embodiment, the substrate surface serves as a sixth side or closure for each cell. Each cell has inside of it a plate, termed the front plate, which is parallel to and in contact with substantially all of the inside surface of the receiving wall. The balance of each cell is completely filled with a projectile-abrading material consisting of glass and a ceramic material and, in certain embodiments, a polymeric material. The glass may be in monolithic form or particles of ceramic may be dispersed in a glass matrix. The ceramic material may be in monolithic form or may be in the form of particles dispersed in glass or dispersed in said polymer.

  12. Hypercube matrix computation task

    NASA Technical Reports Server (NTRS)

    Calalo, R.; Imbriale, W.; Liewer, P.; Lyons, J.; Manshadi, F.; Patterson, J.

    1987-01-01

    The Hypercube Matrix Computation (Year 1986-1987) task investigated the applicability of a parallel computing architecture to the solution of large scale electromagnetic scattering problems. Two existing electromagnetic scattering codes were selected for conversion to the Mark III Hypercube concurrent computing environment. They were selected so that the underlying numerical algorithms utilized would be different thereby providing a more thorough evaluation of the appropriateness of the parallel environment for these types of problems. The first code was a frequency domain method of moments solution, NEC-2, developed at Lawrence Livermore National Laboratory. The second code was a time domain finite difference solution of Maxwell's equations to solve for the scattered fields. Once the codes were implemented on the hypercube and verified to obtain correct solutions by comparing the results with those from sequential runs, several measures were used to evaluate the performance of the two codes. First, a comparison was provided of the problem size possible on the hypercube with 128 megabytes of memory for a 32-node configuration with that available in a typical sequential user environment of 4 to 8 megabytes. Then, the performance of the codes was anlyzed for the computational speedup attained by the parallel architecture.

  13. Explicit examples of DIM constraints for network matrix models

    NASA Astrophysics Data System (ADS)

    Awata, Hidetoshi; Kanno, Hiroaki; Matsumoto, Takuya; Mironov, Andrei; Morozov, Alexei; Morozov, Andrey; Ohkubo, Yusuke; Zenkevich, Yegor

    2016-07-01

    Dotsenko-Fateev and Chern-Simons matrix models, which describe Nekrasov functions for SYM theories in different dimensions, are all incorporated into network matrix models with the hidden Ding-Iohara-Miki (DIM) symmetry. This lifting is especially simple for what we call balanced networks. Then, the Ward identities (known under the names of Virasoro/ {W} -constraints or loop equations or regularity condition for qq-characters) are also promoted to the DIM level, where they all become corollaries of a single identity.

  14. Ceramic matrix composite article and process of fabricating a ceramic matrix composite article

    DOEpatents

    Cairo, Ronald Robert; DiMascio, Paul Stephen; Parolini, Jason Robert

    2016-01-12

    A ceramic matrix composite article and a process of fabricating a ceramic matrix composite are disclosed. The ceramic matrix composite article includes a matrix distribution pattern formed by a manifold and ceramic matrix composite plies laid up on the matrix distribution pattern, includes the manifold, or a combination thereof. The manifold includes one or more matrix distribution channels operably connected to a delivery interface, the delivery interface configured for providing matrix material to one or more of the ceramic matrix composite plies. The process includes providing the manifold, forming the matrix distribution pattern by transporting the matrix material through the manifold, and contacting the ceramic matrix composite plies with the matrix material.

  15. How to Study a Matrix

    ERIC Educational Resources Information Center

    Jairam, Dharmananda; Kiewra, Kenneth A.; Kauffman, Douglas F.; Zhao, Ruomeng

    2012-01-01

    This study investigated how best to study a matrix. Fifty-three participants studied a matrix topically (1 column at a time), categorically (1 row at a time), or in a unified way (all at once). Results revealed that categorical and unified study produced higher: (a) performance on relationship and fact tests, (b) study material satisfaction, and…

  16. Synthetic Division and Matrix Factorization

    ERIC Educational Resources Information Center

    Barabe, Samuel; Dubeau, Franc

    2007-01-01

    Synthetic division is viewed as a change of basis for polynomials written under the Newton form. Then, the transition matrices obtained from a sequence of changes of basis are used to factorize the inverse of a bidiagonal matrix or a block bidiagonal matrix.

  17. Twist1-induced invadopodia formation promotes tumor metastasis

    PubMed Central

    Eckert, Mark A.; Lwin, Thinzar M.; Chang, Andrew T.; Kim, Jihoon; Danis, Etienne; Ohno-Machado, Lucila; Yang, Jing

    2011-01-01

    Summary The Twist1 transcription factor is known to promote tumor metastasis and induce Epithelial-Mesenchymal Transition (EMT). Here, we report that Twist1 is capable of promoting the formation of invadopodia, specialized membrane protrusions for extracellular matrix degradation. Twist1 induces PDGFRα expression, which in turn activates Src, to promote invadopodia formation. We show that Twist1 and PDGFRα are central mediators of invadopodia formation in response to various EMT-inducing signals. Induction of PDGFRα and invadopodia is essential for Twist1 to promote tumor metastasis. Consistent with PDGFRα being a direct transcriptional target of Twist1, coexpression of Twist1 and PDGFRα predicts poor survival in breast tumor patients. Therefore, invadopodia-mediated matrix degradation is a key function of Twist1 in promoting tumor metastasis. PMID:21397860

  18. Tailoring Material Properties of Cardiac Matrix Hydrogels to Induce Endothelial Differentiation of Human Mesenchymal Stem Cells

    PubMed Central

    Jeffords, Megan E.; Wu, Jinglei; Shah, Mickey; Hong, Yi; Zhang, Ge

    2015-01-01

    Cardiac matrix hydrogel has shown great promise as an injectable biomaterial due to the possession of cardiac-specific extracellular matrix composition. A cardiac matrix hydrogel facilitating neovascularization will further improve its therapeutic outcomes in cardiac repair. In this study, we explored the feasibility of tailoring material properties of cardiac matrix hydrogels using a natural compound, genipin, to promote endothelial differentiation of stem cells. Our results demonstrated that the genipin crosslinking could increase the mechanical properties of the cardiac matrix hydrogel to a stiffness range promoting endothelial differentiation of human mesenchymal stem cells (hMSCs). It also decreased the swelling ratio and prolonged degradation without altering gelation time. Human mesenchymal stem cells cultured on the genipin crosslinked cardiac matrix hydrogels showed great viability. After 1-day culture, hMSCs demonstrated down-regulation of early endothelial marker expression and up-regulation of mature endothelial marker expression. Especially for 1 mM genipin crosslinked cardiac matrix hydrogels, hMSCs showed particularly significant expression of mature endothelial cell marker vWF. These attractive results indicate the potential of using genipin crosslinked cardiac matrix hydrogels to promote rapid vascularization for cardiac infarction treatment through minimally invasive therapy. PMID:25946697

  19. Streptococcus mutans-derived extracellular matrix in cariogenic oral biofilms.

    PubMed

    Klein, Marlise I; Hwang, Geelsu; Santos, Paulo H S; Campanella, Osvaldo H; Koo, Hyun

    2015-01-01

    Biofilms are highly structured microbial communities that are enmeshed in a self-produced extracellular matrix. Within the complex oral microbiome, Streptococcus mutans is a major producer of extracellular polymeric substances including exopolysaccharides (EPS), eDNA, and lipoteichoic acid (LTA). EPS produced by S. mutans-derived exoenzymes promote local accumulation of microbes on the teeth, while forming a spatially heterogeneous and diffusion-limiting matrix that protects embedded bacteria. The EPS-rich matrix provides mechanical stability/cohesiveness and facilitates the creation of highly acidic microenvironments, which are critical for the pathogenesis of dental caries. In parallel, S. mutans also releases eDNA and LTA, which can contribute with matrix development. eDNA enhances EPS (glucan) synthesis locally, increasing the adhesion of S. mutans to saliva-coated apatitic surfaces and the assembly of highly cohesive biofilms. eDNA and other extracellular substances, acting in concert with EPS, may impact the functional properties of the matrix and the virulence of cariogenic biofilms. Enhanced understanding about the assembly principles of the matrix may lead to efficacious approaches to control biofilm-related diseases. PMID:25763359

  20. Streptococcus mutans-derived extracellular matrix in cariogenic oral biofilms

    PubMed Central

    Klein, Marlise I.; Hwang, Geelsu; Santos, Paulo H. S.; Campanella, Osvaldo H.; Koo, Hyun

    2015-01-01

    Biofilms are highly structured microbial communities that are enmeshed in a self-produced extracellular matrix. Within the complex oral microbiome, Streptococcus mutans is a major producer of extracellular polymeric substances including exopolysaccharides (EPS), eDNA, and lipoteichoic acid (LTA). EPS produced by S. mutans-derived exoenzymes promote local accumulation of microbes on the teeth, while forming a spatially heterogeneous and diffusion-limiting matrix that protects embedded bacteria. The EPS-rich matrix provides mechanical stability/cohesiveness and facilitates the creation of highly acidic microenvironments, which are critical for the pathogenesis of dental caries. In parallel, S. mutans also releases eDNA and LTA, which can contribute with matrix development. eDNA enhances EPS (glucan) synthesis locally, increasing the adhesion of S. mutans to saliva-coated apatitic surfaces and the assembly of highly cohesive biofilms. eDNA and other extracellular substances, acting in concert with EPS, may impact the functional properties of the matrix and the virulence of cariogenic biofilms. Enhanced understanding about the assembly principles of the matrix may lead to efficacious approaches to control biofilm-related diseases. PMID:25763359

  1. The matrix of inspiration

    NASA Astrophysics Data System (ADS)

    Oehlmann, Dietmar; Ohlmann, Odile M.; Danzebrink, Hans U.

    2005-04-01

    perform this exchange, as a matrix, understood as source, of new ideas.

  2. Matrix Metalloproteinases as Drug Targets in Preeclampsia

    PubMed Central

    Palei, Ana C.T.; Granger, Joey P.; Tanus-Santos, Jose E.

    2013-01-01

    Preeclampsia is an important syndrome complicating pregnancy. While the pathogenesis of preeclampsia is not entirely known, poor placental perfusion leading to widespread maternal endothelial dysfunction is accepted as a major mechanism. It has been suggested that altered placental expression of matrix metalloproteinases (MMPs) may cause shallow cytotrophoblastic invasion and incomplete remodeling of the spiral arteries. MMPs are also thought to link placental ischemia to the cardiovascular alterations of preeclampsia. In fact, MMPs may promote vasoconstriction and surface receptors cleavage affecting the vasculature. Therefore, the overall goal of this review article is to provide an overview of the pathophisiology of preeclampsia, more specifically regarding the role of MMPs in the pathogenesis of preeclampsia and the potential of MMP inhibitors as therapeutic options. PMID:23316964

  3. Ceramic matrix composites by microwave assisted CVI

    SciTech Connect

    Currier, R.P.; Devlin, D.J.

    1993-05-01

    Chemical vapor infiltration (CVI) processes for producing continuously reinforced ceramic composites are reviewed. The potential advantages of microwave assisted CVI are noted. Recent numerical studies of microwave assisted CVI are then reviewed. These studies predict inverted thermal gradients in fibrous ceramic preforms subjected to microwave radiation and suggest processing strategies for achieving uniformly dense composites. Comparisons are made to experimental results obtained using silicon based composite systems. The importance of microwave-material interactions is stressed. In particular, emphasis is placed on the role played by the relative ability of fiber and matrix to dissipate microwave energy. Results suggest that microwave induced inverted gradients can in fact be exploited using the CVI technique to promote inside-out densification.

  4. Ceramic matrix composites by microwave assisted CVI

    SciTech Connect

    Currier, R.P.; Devlin, D.J.

    1993-01-01

    Chemical vapor infiltration (CVI) processes for producing continuously reinforced ceramic composites are reviewed. The potential advantages of microwave assisted CVI are noted. Recent numerical studies of microwave assisted CVI are then reviewed. These studies predict inverted thermal gradients in fibrous ceramic preforms subjected to microwave radiation and suggest processing strategies for achieving uniformly dense composites. Comparisons are made to experimental results obtained using silicon based composite systems. The importance of microwave-material interactions is stressed. In particular, emphasis is placed on the role played by the relative ability of fiber and matrix to dissipate microwave energy. Results suggest that microwave induced inverted gradients can in fact be exploited using the CVI technique to promote inside-out densification.

  5. Matrix cracking in brittle-matrix composites with tailored interfaces

    SciTech Connect

    Danchaivijit, S.; Chao, L.Y.; Shetty, D.K.

    1995-10-01

    Matrix cracking from controlled through cracks with bridging filaments was studied in a model unidirectional composite of SiC filaments in an epoxy-bonded alumina matrix. An unbonded, frictional interface was produced by moderating the curing shrinkage of the epoxy with the alumina filler and coating the filaments with a releasing agent. Uniaxial tension test specimens (2.5 x 25 x 125 mm) with filament-bridged through cracks were fabricated by a novel two-step casting technique involving casting, precracking and joining of cracked and uncracked sections. Distinct matrix-cracking stresses, corresponding to the extension of the filament-bridged cracks, were measured in uniaxial tension tests using a high-sensitivity extensometer. The crack-length dependence of the matrix-cracking stress was found to be in good agreement with the prediction of a fracture-mechanics analysis that employed a new crack-closure force-crack-opening displacement relation in the calculation of the stress intensity for fiber-bridged cracks. The prediction was based on independent experimental measurements of the matrix fracture toughness (K{sub cm}), the interfacial sliding friction stress ({tau}) and the residual stress in the matrix ({sigma}{sub m}{sup I}). The matrix-cracking stress for crack lengths (2a) greater than 3 mm was independent of the crack length and agreed with the prediction of the steady-state theory of Budiansky, Hutchinson and Evans. Tests on specimens without the deliberately introduced cracks indicated a matrix-cracking stress significantly higher than the steady-state stress.

  6. High Temperature Polymer Matrix Composites

    NASA Technical Reports Server (NTRS)

    1985-01-01

    These are the proceedings of the High Temperature Polymer Matrix Composites Conference held at the NASA Lewis Research Center on March 16 to 18, 1983. The purpose of the conference is to provide scientists and engineers working in the field of high temperature polymer matrix composites an opportunity to review, exchange, and assess the latest developments in this rapidly expanding area of materials technology. Technical papers are presented in the following areas: (1) matrix development; (2) adhesive development; (3) characterization; (4) environmental effects; and (5) applications.

  7. Genotype imputation via matrix completion.

    PubMed

    Chi, Eric C; Zhou, Hua; Chen, Gary K; Del Vecchyo, Diego Ortega; Lange, Kenneth

    2013-03-01

    Most current genotype imputation methods are model-based and computationally intensive, taking days to impute one chromosome pair on 1000 people. We describe an efficient genotype imputation method based on matrix completion. Our matrix completion method is implemented in MATLAB and tested on real data from HapMap 3, simulated pedigree data, and simulated low-coverage sequencing data derived from the 1000 Genomes Project. Compared with leading imputation programs, the matrix completion algorithm embodied in our program MENDEL-IMPUTE achieves comparable imputation accuracy while reducing run times significantly. Implementation in a lower-level language such as Fortran or C is apt to further improve computational efficiency. PMID:23233546

  8. Canonical density matrix perturbation theory.

    PubMed

    Niklasson, Anders M N; Cawkwell, M J; Rubensson, Emanuel H; Rudberg, Elias

    2015-12-01

    Density matrix perturbation theory [Niklasson and Challacombe, Phys. Rev. Lett. 92, 193001 (2004)] is generalized to canonical (NVT) free-energy ensembles in tight-binding, Hartree-Fock, or Kohn-Sham density-functional theory. The canonical density matrix perturbation theory can be used to calculate temperature-dependent response properties from the coupled perturbed self-consistent field equations as in density-functional perturbation theory. The method is well suited to take advantage of sparse matrix algebra to achieve linear scaling complexity in the computational cost as a function of system size for sufficiently large nonmetallic materials and metals at high temperatures. PMID:26764847

  9. Matrix Elements for Hylleraas CI

    NASA Astrophysics Data System (ADS)

    Harris, Frank E.

    The limitation to at most a single interelectron distance in individual configurations of a Hylleraas-type multiconfiguration wave function restricts significantly the types of integrals occurring in matrix elements for energy calculations, but even then if the formulation is not handled efficiently the angular parts of these integrals escalate to create expressions of great complexity. This presentation reviews ways in which the angular-momentum calculus can be employed to systematize and simplify the matrix element formulas, particularly those for the kinetic-energy matrix elements.

  10. Matrix Gla protein inhibition of tooth mineralization.

    PubMed

    Kaipatur, N R; Murshed, M; McKee, M D

    2008-09-01

    Extracellular matrix (ECM) mineralization is regulated by mineral ion availability, proteins, and other molecular determinants. To investigate protein regulation of mineralization in tooth dentin and cementum, and in alveolar bone, we expressed matrix Gla protein (MGP) ectopically in bones and teeth in mice, using an osteoblast/odontoblast-specific 2.3-kb Col1a1 promoter. Mandibles were analyzed by radiography, micro-computed tomography, light microscopy, histomorphometry, and transmission electron microscopy. While bone and tooth ECMs were established in the Col1a1-Mgp mice, extensive hypomineralization was observed, with values of unmineralized ECM from four- to eight-fold higher in dentin and alveolar bone when compared with that in wild-type tissues. Mineralization was virtually absent in tooth root dentin and cellular cementum, while crown dentin showed "breakthrough" areas of mineralization. Acellular cementum was lacking in Col1a1-Mgp teeth, and unmineralized osteodentin formed within the pulp. These results strengthen the view that bone and tooth mineralization is critically regulated by mineralization inhibitors. PMID:18719210

  11. Matrix product operators, matrix product states, and ab initio density matrix renormalization group algorithms

    NASA Astrophysics Data System (ADS)

    Chan, Garnet Kin-Lic; Keselman, Anna; Nakatani, Naoki; Li, Zhendong; White, Steven R.

    2016-07-01

    Current descriptions of the ab initio density matrix renormalization group (DMRG) algorithm use two superficially different languages: an older language of the renormalization group and renormalized operators, and a more recent language of matrix product states and matrix product operators. The same algorithm can appear dramatically different when written in the two different vocabularies. In this work, we carefully describe the translation between the two languages in several contexts. First, we describe how to efficiently implement the ab initio DMRG sweep using a matrix product operator based code, and the equivalence to the original renormalized operator implementation. Next we describe how to implement the general matrix product operator/matrix product state algebra within a pure renormalized operator-based DMRG code. Finally, we discuss two improvements of the ab initio DMRG sweep algorithm motivated by matrix product operator language: Hamiltonian compression, and a sum over operators representation that allows for perfect computational parallelism. The connections and correspondences described here serve to link the future developments with the past and are important in the efficient implementation of continuing advances in ab initio DMRG and related algorithms.

  12. Matrix product operators, matrix product states, and ab initio density matrix renormalization group algorithms.

    PubMed

    Chan, Garnet Kin-Lic; Keselman, Anna; Nakatani, Naoki; Li, Zhendong; White, Steven R

    2016-07-01

    Current descriptions of the ab initio density matrix renormalization group (DMRG) algorithm use two superficially different languages: an older language of the renormalization group and renormalized operators, and a more recent language of matrix product states and matrix product operators. The same algorithm can appear dramatically different when written in the two different vocabularies. In this work, we carefully describe the translation between the two languages in several contexts. First, we describe how to efficiently implement the ab initio DMRG sweep using a matrix product operator based code, and the equivalence to the original renormalized operator implementation. Next we describe how to implement the general matrix product operator/matrix product state algebra within a pure renormalized operator-based DMRG code. Finally, we discuss two improvements of the ab initio DMRG sweep algorithm motivated by matrix product operator language: Hamiltonian compression, and a sum over operators representation that allows for perfect computational parallelism. The connections and correspondences described here serve to link the future developments with the past and are important in the efficient implementation of continuing advances in ab initio DMRG and related algorithms. PMID:27394094

  13. Stochastic determination of matrix determinants

    NASA Astrophysics Data System (ADS)

    Dorn, Sebastian; Enßlin, Torsten A.

    2015-07-01

    Matrix determinants play an important role in data analysis, in particular when Gaussian processes are involved. Due to currently exploding data volumes, linear operations—matrices—acting on the data are often not accessible directly but are only represented indirectly in form of a computer routine. Such a routine implements the transformation a data vector undergoes under matrix multiplication. While efficient probing routines to estimate a matrix's diagonal or trace, based solely on such computationally affordable matrix-vector multiplications, are well known and frequently used in signal inference, there is no stochastic estimate for its determinant. We introduce a probing method for the logarithm of a determinant of a linear operator. Our method rests upon a reformulation of the log-determinant by an integral representation and the transformation of the involved terms into stochastic expressions. This stochastic determinant determination enables large-size applications in Bayesian inference, in particular evidence calculations, model comparison, and posterior determination.

  14. Performance Appraisal for Matrix Management.

    ERIC Educational Resources Information Center

    Edwards, M. R.; Sproull, J. Ruth

    1985-01-01

    A matrix management system designed for use by a highly technical nuclear weapons research and development facility to improve productivity and flexibility by the use of multiple authority, responsibility, and accountability relationships is described. (MSE)

  15. Extracellular matrix and wound healing.

    PubMed

    Maquart, F X; Monboisse, J C

    2014-04-01

    Extracellular matrix has been known for a long time as an architectural support for the tissues. Many recent data, however, have shown that extracellular matrix macromolecules (collagens, elastin, glycosaminoglycans, proteoglycans and connective tissue glycoproteins) are able to regulate many important cell functions, such as proliferation, migration, protein synthesis or degradation, apoptosis, etc., making them able to play an important role in the wound repair process. Not only the intact macromolecules but some of their specific domains, that we called "Matrikines", are also able to regulate many cell activities. In this article, we will summarize main findings showing the effects of extracellular matrix macromolecules and matrikines on connective tissue and epithelial cells, particularly in skin, and their potential implication in the wound healing process. These examples show that extracellular matrix macromolecules or some of their specific domains may play a major role in wound healing. Better knowledge of these interactions may suggest new therapeutic targets in wound healing defects. PMID:24650524

  16. Stochastic determination of matrix determinants.

    PubMed

    Dorn, Sebastian; Ensslin, Torsten A

    2015-07-01

    Matrix determinants play an important role in data analysis, in particular when Gaussian processes are involved. Due to currently exploding data volumes, linear operations-matrices-acting on the data are often not accessible directly but are only represented indirectly in form of a computer routine. Such a routine implements the transformation a data vector undergoes under matrix multiplication. While efficient probing routines to estimate a matrix's diagonal or trace, based solely on such computationally affordable matrix-vector multiplications, are well known and frequently used in signal inference, there is no stochastic estimate for its determinant. We introduce a probing method for the logarithm of a determinant of a linear operator. Our method rests upon a reformulation of the log-determinant by an integral representation and the transformation of the involved terms into stochastic expressions. This stochastic determinant determination enables large-size applications in Bayesian inference, in particular evidence calculations, model comparison, and posterior determination. PMID:26274302

  17. Matrix interactions modulate neurotrophin-mediated neurite outgrowth and pathfinding

    PubMed Central

    Madl, Christopher M.; Heilshorn, Sarah C.

    2015-01-01

    Both matrix biochemistry and neurotrophic factors are known to modulate neurite outgrowth and pathfinding; however, the interplay between these two factors is less studied. While previous work has shown that the biochemical identity of the matrix can alter the outgrowth of neurites in response to neurotrophins, the importance of the concentration of cell-adhesive ligands is unknown. Using engineered elastin-like protein matrices, we recently demonstrated a synergistic effect between matrix-bound cell-adhesive ligand density and soluble nerve growth factor treatment on neurite outgrowth from dorsal root ganglia. This synergism was mediated by Schwann cell-neurite contact through L1CAM. Cell-adhesive ligand density was also shown to alter the pathfinding behavior of dorsal root ganglion neurites in response to a gradient of nerve growth factor. While more cell-adhesive matrices promoted neurite outgrowth, less cell-adhesive matrices promoted more faithful neurite pathfinding. These studies emphasize the importance of considering both matrix biochemistry and neurotrophic factors when designing biomaterials for peripheral nerve regeneration. PMID:26170800

  18. Molybdenum disilicide alloy matrix composite

    DOEpatents

    Petrovic, John J.; Honnell, Richard E.; Gibbs, W. Scott

    1990-01-01

    Compositions of matter consisting of matrix matrials having silicon carbide dispersed throughout them and methods of making the compositions. A matrix material is an alloy of an intermetallic compound, molybdenum disilicide, and at least one secondary component which is a refractory silicide. The silicon carbide dispersant may be in the form of VLS whiskers, VS whiskers, or submicron powder or a mixture of these forms.

  19. Form development sample test matrix

    SciTech Connect

    Ebbinghaus, B B

    1999-10-15

    This document summarizes the status of sample fabrication and analysis in the Form Development Sample Test Matrix. Since its publication in the ''Baseline Formulation'' report (UCRL-ID- 133089, PIP-99-O 12) and in the ''Complete Single-Phase Sample Fabrications that Support the Licensing Application and Complete Process and Compositional Extreme Sample Fabrications that Support the Licensing Application'' report (PIP-99-078), the Sample Test Matrix has been updated and expanded. This version is current though September 30, 1999.

  20. Molybdenum disilicide alloy matrix composite

    DOEpatents

    Petrovic, John J.; Honnell, Richard E.; Gibbs, W. Scott

    1991-01-01

    Compositions of matter consisting of matrix materials having silicon carbide dispersed throughout them and methods of making the compositions. A matrix material is an alloy of an intermetallic compound, molybdenum disilicide, and at least one secondary component which is a refractory silicide. The silicon carbide dispersant may be in the form of VLS whiskers, VS whiskers, or submicron powder or a mixture of these forms.

  1. Molybdenum disilicide alloy matrix composite

    DOEpatents

    Petrovic, J.J.; Honnell, R.E.; Gibbs, W.S.

    1991-12-03

    Compositions of matter consisting of matrix materials having silicon carbide dispersed throughout them and methods of making the compositions are disclosed. A matrix material is an alloy of an intermetallic compound, molybdenum disilicide, and at least one secondary component which is a refractory silicide. The silicon carbide dispersant may be in the form of VLS whiskers, VS whiskers, or submicron powder or a mixture of these forms. 3 figures.

  2. Universal Keplerian state transition matrix

    NASA Technical Reports Server (NTRS)

    Shepperd, S. W.

    1985-01-01

    A completely general method for computing the Keplerian state transition matrix in terms of Goodyear's universal variables is presented. This includes a new scheme for solving Kepler's problem which is a necessary first step to computing the transition matrix. The Kepler problem is solved in terms of a new independent variable requiring the evaluation of only one transcendental function. Furthermore, this transcendental function may be conveniently evaluated by means of a Gaussian continued fraction.

  3. Insidious Changes in Stromal Matrix Fuel Cancer Progression

    PubMed Central

    Miles, Fayth L.

    2014-01-01

    Reciprocal interactions between tumor and stromal cells propel cancer progression and metastasis. An understanding of the complex contributions of the tumor stroma to cancer progression necessitates a careful examination of the extracellular matrix (ECM), which is largely synthesized and modulated by Cancer Associated Fibroblasts (CAFs). This structurally supportive meshwork serves as a signaling scaffold for a myriad of biological processes and responses favoring tumor progression. The ECM is a repository for growth factors and cytokines that promote tumor growth, proliferation, and metastasis through diverse interactions with soluble and insoluble ECM components. Growth factors activated by proteases are involved in the initiation of cell signaling pathways essential to invasion and survival. Various transmembrane proteins produced by the cancer stroma bind the collagen and fibronectin-rich matrix to induce proliferation, adhesion and migration of cancer cells, as well as protease activation. Integrins are critical liaisons between tumor cells and the surrounding stroma, and with their mechano-sensing ability induce cell signaling pathways associated with contractility and migration. Proteoglycans also bind and interact with various matrix proteins in the tumor microenvironment to promote cancer progression. Together, these components function to mediate crosstalk between tumor cells and fibroblasts ultimately to promote tumor survival and metastasis. These stromal factors, which may be expressed differentially according to cancer stage, have prognostic utility and potential. In this review, we examine changes in the ECM of cancer associated fibroblasts induced through carcinogenesis, and the implications of these changes on cancer progression. PMID:24452359

  4. Effective management of major lower extremity wounds using an acellular regenerative tissue matrix: a pilot study.

    PubMed

    Brigido, Stephen A; Boc, Steven F; Lopez, Ramon C

    2004-01-01

    Wound healing is a significant problem in orthopedics. Graftjacket tissue matrix (Wright Medical Technology, Inc, Arlington, Tenn), a novel acellular regenerative tissue matrix, has been designed to aid wound closure. A prospective, randomized study was initiated to determine the efficacy of this tissue product in wound repair compared with conventional treatment. Lower extremity wounds are refractile to healing in patients with diabetes mellitus. Therefore, researchers used diabetic foot ulcers to evaluate the efficacy of GraftJacket tissue matrix in wound repair. Only a single administration of the tissue matrix was required. After 1 month of treatment, preliminary results demonstrate that this novel tissue matrix promotes faster healing at a statistically significant rate over conventional treatment. Because wounds in this series of patients are deep and circulation around the wound is poor, the preliminary results suggest that this tissue matrix will be applicable to other types of orthopedic wounds. PMID:14763548

  5. Developing a Promotional Video

    ERIC Educational Resources Information Center

    Epley, Hannah K.

    2014-01-01

    There is a need for Extension professionals to show clientele the benefits of their program. This article shares how promotional videos are one way of reaching audiences online. An example is given on how a promotional video has been used and developed using iMovie software. Tips are offered for how professionals can create a promotional video and…

  6. The Astrobiology Matrix and the "Drake Matrix" in Education

    NASA Technical Reports Server (NTRS)

    Mizser, A.; Kereszturi, A.

    2003-01-01

    We organized astrobiology lectures in the Eotvos Lorand University of Sciences and the Polaris Observatory in 2002. We present here the "Drake matrix" for the comparison of the astrobiological potential of different bodies [1], and astrobiology matrix for the visualization of the interdisciplinary connections between different fields of astrobiology. Conclusion: In Hungary it is difficult to integrate astrobiology in the education system but the great advantage is that it can connect different scientific fields and improve the view of students. We would like to get in contact with persons and organizations who already have experience in the education of astrobiology.

  7. Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation.

    PubMed

    Münch, Christian; Harper, J Wade

    2016-06-30

    The mitochondrial matrix is unique in that it must integrate the folding and assembly of proteins derived from the nuclear and mitochondrial genomes. In Caenorhabditis elegans, the mitochondrial unfolded protein response (UPRmt) senses matrix protein misfolding and induces a program of nuclear gene expression, including mitochondrial chaperonins, to promote mitochondrial proteostasis. While misfolded mitochondrial-matrix-localized ornithine transcarbamylase induces chaperonin expression, our understanding of mammalian UPRmt is rudimentary, reflecting a lack of acute triggers for UPRmt activation. This limitation has prevented analysis of the cellular responses to matrix protein misfolding and the effects of UPRmt on mitochondrial translation to control protein folding loads. Here we combine pharmacological inhibitors of matrix-localized HSP90/TRAP1 (ref. 8) or LON protease, which promote chaperonin expression, with global transcriptional and proteomic analysis to reveal an extensive and acute response of human cells to UPRmt. This response encompasses widespread induction of nuclear genes, including matrix-localized proteins involved in folding, pre-RNA processing and translation. Functional studies revealed rapid but reversible translation inhibition in mitochondria occurring concurrently with defects in pre-RNA processing caused by transcriptional repression and LON-dependent turnover of the mitochondrial pre-RNA processing nuclease MRPP3 (ref. 10). This study reveals that acute mitochondrial protein folding stress activates both increased chaperone availability within the matrix and reduced matrix-localized protein synthesis through translational inhibition, and provides a framework for further dissection of mammalian UPRmt. PMID:27350246

  8. Relativistic Dipole Matrix Element Zeros

    NASA Astrophysics Data System (ADS)

    Lajohn, L. A.; Pratt, R. H.

    2002-05-01

    There is a special class of relativistic high energy dipole matrix element zeros (RZ), whose positions with respect to photon energy ω , only depend on the bound state l quantum number according to ω^0=mc^2/(l_b+1) (independent of primary quantum number n, nuclear charge Z, central potential V and dipole retardation). These RZ only occur in (n,l_b,j_b)arrow (ɛ , l_b+1,j_b) transitions such as ns_1/2arrow ɛ p_1/2; np_3/2arrow ɛ d_3/2: nd_5/2arrow ɛ f_5/2 etc. The nonrelativistic limit of these matrix elements can be established explicitly in the Coulomb case. Within the general matrix element formalism (such as that in [1]); when |κ | is substituted for γ in analytic expressions for matrix elements, the zeros remain, but ω^0 now becomes dependent on n and Z. When the reduction to nonrelativistic form is completed by application of the low energy approximation ω mc^2 mc^2, the zeros disappear. This nonzero behavior was noted in nonrelativistic dipole Coulomb matrix elements by Fano and Cooper [2] and later proven by Oh and Pratt[3]. (J. H. Scofield, Phys. Rev. A 40), 3054 (1989 (U. Fano and J. W. Cooper, Rev. Mod. Phys. 40), 441 (1968). (D. Oh and R. H. Pratt, Phys. Rev. A 34), 2486 (1986); 37, 1524 (1988); 45, 1583 (1992).

  9. Matrix factorizations and elliptic fibrations

    NASA Astrophysics Data System (ADS)

    Omer, Harun

    2016-09-01

    I use matrix factorizations to describe branes at simple singularities of elliptic fibrations. Each node of the corresponding Dynkin diagrams of the ADE-type singularities is associated with one indecomposable matrix factorization which can be deformed into one or more factorizations of lower rank. Branes with internal fluxes arise naturally as bound states of the indecomposable factorizations. Describing branes in such a way avoids the need to resolve singularities. This paper looks at gauge group breaking from E8 fibers down to SU (5) fibers due to the relevance of such fibrations for local F-theory GUT models. A purpose of this paper is to understand how the deformations of the singularity are understood in terms of its matrix factorizations. By systematically factorizing the elliptic fiber equation, this paper discusses geometries which are relevant for building semi-realistic local models. In the process it becomes evident that breaking patterns which are identical at the level of the Kodaira type of the fibers can be inequivalent at the level of matrix factorizations. Therefore the matrix factorization picture supplements information which the conventional less detailed descriptions lack.

  10. The noncommutative S-Matrix

    NASA Astrophysics Data System (ADS)

    Raju, Suvrat

    2009-06-01

    As a simple example of how recently developed on-shell techniques apply to nonlocal theories, we study the S-matrix of noncommutative gauge theories. In the complex plane, this S-matrix has essential singularities that signal the nonlocal behavior of the theory. In spite of this, we show that tree-level amplitudes may be obtained by BCFW type recursion relations. At one loop we find a complete basis of master integrals (this basis is larger than the corresponding basis in the ordinary theory). Any one-loop noncommutative amplitude may be written as a linear combination of these integrals with coefficients that we relate to products of tree amplitudes. We show that the noncommutative Script N = 4 SYM theory has a structurally simple S-matrix, just like the ordinary Script N = 4 SYM theory.