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Sample records for 2-hour urokinase regime

  1. Molecular-specific urokinase antibodies

    NASA Technical Reports Server (NTRS)

    Atassi, M. Zouhair (Inventor); Morrison, Dennis R. (Inventor)

    2009-01-01

    Antibodies have been developed against the different molecular forms of urokinase using synthetic peptides as immunogens. The peptides were synthesized specifically to represent those regions of the urokinase molecules which are exposed in the three-dimensional configuration of the molecule and are uniquely homologous to urokinase. Antibodies are directed against the lysine 158-isoleucine 159 peptide bond which is cleaved during activation from the single-chain (ScuPA) form to the bioactive double chain (54 KDa and 33 KDa) forms of urokinase and against the lysine 135 lysine 136 bond that is cleaved in the process of removing the alpha-chain from the 54 KDa form to produce the 33 KDa form of urokinase. These antibodies enable the direct measurement of the different molecular forms of urokinase from small samples of conditioned medium harvested from cell cultures.

  2. Development of immunoassays for human urokinase

    NASA Technical Reports Server (NTRS)

    Atassi, M. Zouhair

    1988-01-01

    Radioimmune assays (RIA) and enzyme linked immune assays for measurement of pro-urokinase and the two active forms of the enzyme were developed. Polyclonal and monoclonal antibodies, with desired specificities against preselected synthetic regions of urokinase (UK), were obtained by immunization with the respective synthetic peptides and used to develop RIA for zymogen and the two activated forms of UK.

  3. 29 CFR 2530.200b-2 - Hour of service.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... MINIMUM STANDARDS FOR EMPLOYEE PENSION BENEFIT PLANS UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF 1974 RULES AND REGULATIONS FOR MINIMUM STANDARDS FOR EMPLOYEE PENSION BENEFIT PLANS Scope and General Provisions § 2530.200b-2 Hour of service. (a) General rule. An hour of service which must, as a minimum,...

  4. Human Trials of a 2-Hour Prebreathe Protocol

    NASA Technical Reports Server (NTRS)

    Butler, Bruce D.; Vann, R. D.; Nishi, Ronald Y.; Gerth, W. A.; Beltran, E.; Conkin, J.; Schneider, Suzanne; Loftin, K. C.; Sullivan, Pat A.; Homick, Jerry L. (Technical Monitor)

    2000-01-01

    We evaluate 2-hour prebreathe protocols combining simulated microgravity and exercise during prebreathe with the objective of validating a protocol for use on International Space Station (ISS). The protocol was tested with four different exercise doses during prebreathe in a multi-center trial involving three laboratories. Subject selection, Doppler monitoring techniques for venous gas emboli (VGE), test termination criteria, and definitions of decompression sickness (DCS) were standardized in all laboratories. The Phase II protocol met the accept criteria for a prebreathe procedure for use by astronauts during assembly and maintenance of the ISS Dual-cycle ergometry or light exercise individually was not sufficient to protect against DCS at acceptable levels. The combination of both was successful.

  5. Quantitative method of measuring cancer cell urokinase and metastatic potential

    NASA Technical Reports Server (NTRS)

    Morrison, Dennis R. (Inventor)

    1993-01-01

    The metastatic potential of tumors can be evaluated by the quantitative detection of urokinase and DNA. The cell sample selected for examination is analyzed for the presence of high levels of urokinase and abnormal DNA using analytical flow cytometry and digital image analysis. Other factors such as membrane associated urokinase, increased DNA synthesis rates and certain receptors can be used in the method for detection of potentially invasive tumors.

  6. Antibodies Against Three Forms of Urokinase

    NASA Technical Reports Server (NTRS)

    Morrison, Dennis R.; Atassi, M. Zouhair

    2007-01-01

    Antibodies that bind to preselected regions of the urokinase molecule have been developed. These antibodies can be used to measure small quantities of each of three molecular forms of urokinase that could be contained in microsamples or conditioned media harvested from cultures of mammalian cells. Previously available antibodies and assay techniques do not yield both clear distinctions among, and measurements of, all three forms. Urokinase is a zymogen that is synthesized in a single-chain form, called ScuPA, which is composed of 411 amino acid residues (see figure). ScuPA has very little enzyme activity, but it can be activated in two ways: (1) by cleavage of the peptide bond lysine 158/isoleucine 159 and the loss of lysine 158 to obtain the high molecular-weight (HMW) form of the enzyme or (2) by cleavage of the bond lysine 135/lysine 136 to obtain the low-molecular-weight (LMW) form of the enzyme. The antibodies in question were produced in mice and rabbits by use of peptides as immunogens. The peptides were selected to obtain antibodies that bind to regions of ScuPA that include the lysine 158/isoleucine 159 and the lysine 135/lysine 136 bonds. The antibodies include monoclonal and polyclonal ones that yield indications as to whether either of these bonds is intact. The polyclonal antibodies include ones that preferentially bind to the HMW or LMW forms of the urokinase molecule. The monoclonal antibodies include ones that discriminate between the ScuPA and the HMW form. A combination of these molecular-specific antibodies will enable simultaneous assays of the ScuPA, HMW, and LMW forms in the same specimen of culture medium.

  7. Increased Plasminogen Activator (Urokinase) in Tissue Culture After Fibrin Deposition

    PubMed Central

    Bernik, Maria B.

    1973-01-01

    Lysis of fibrin in tissue culture has been shown to be due to plasminogen activator identified immunologically as urokinase. The present study examines fibrinolytic events in culture, particularly mechanisms leading to increased urokinase levels and accelerated fibrinolysis. Deposition of fibrin on cells in culture was followed by a two- to six-fold increase in urokinase in the supernates and rapid disappearance of the fibrin. Investigation of factors that might be responsible for these events (including fibrin, fibrinogen, vasoactive stimuli, and the enzymes thrombin and plasmin) indicated that the enhanced urokinase yields were mediated through plasmin and thrombin. Study of the possible modes of action of thrombin and plasmin indicated that these enzymes are capable of acting on the cells themselves as well as on cell-produced material. The effect on cells was manifested by mitotic activity or, occasionally, cell injury and death. Although these effects influenced urokinase levels, enhanced yields were explained best by the action of enzymes on cellproduced material. Studies with plasmin and thrombin, and also trypsin, indicated that proteolytic enzymes may act in various ways—affect the stability of urokinase, interfere with inhibition of urokinase by naturally occurring inhibitor(s), and induce urokinase activity from inactive material. Plasma and thrombin appeared to act primarily through the latter mechanism. Inactive material, which gave rise to urokinase upon exposure to proteolytic enzymes and which may represent urokinase precursor, was found in cultures of kidney, lung, spleen, and thyroid. Urokinase in such inactive state appears to be readily accessible to activation by enzymes, particularly plasmin and thrombin, thus facilitating removal of fibrin and possibly also providing pathways to excessive fibrinolysis. PMID:4266421

  8. Inflight Exercise Regimen for the 2-Hour Prebreathe Protocol

    NASA Technical Reports Server (NTRS)

    Foster, Philip P.; Gernhardt, Michael L.; Woodruff, Kristin K.; Schneider, Susan M.; Homick, Jerry L. (Technical Monitor)

    2000-01-01

    A 10 min aerobic prebreathe exercise up to 75% V-O2(sub max) on a dual-cycle ergometer, included in the 2-hour prebreathe protocol, has been shown to dramatically reduce the incidence of decompression sickness (DCS) at altitude. In-flight only leg ergometry will be available. A balanced exercise was developed using surgical tubing with the ergometer on-orbit. We hypothesize that a 75% V02max workload, individually prescribed, would be achieved using a target heart rate to regulate the intensity of the arm exercise. VO2, heart rate (HR) / ECG, V-CO2 /V-O2, V(sub E), and V(sub T), and rate of perceived exertion (Borg scale) were measured in eleven healthy subjects who passed a US Air Force Class III Physical examination. A V-O2 peak test was performed to assess the sub-maximal exercise prescription. Two series of sub-maximal tests were performed: (1) leg ergometer/hand ergometer and (2) leg ergometer/surgical tubes. We found no significant differences (P > 0.05) in comparing the means for V-O2 and HR between the predicted and measured values during the final 4 minute-stage at "75% V-O2 workload" or between the two types of sub-maximal tests. The prescribed prebreathe sub-maximal exercise performed with flight certified surgical tubes was achieved using the target HR.

  9. Interaction of urokinase A chain with the receptor of human keratinocytes stimulates release of urokinase-like plasminogen activator

    SciTech Connect

    Fibbi, G.; Magnelli, L.; Pucci, M.; Del Rosso, M. )

    1990-03-01

    On the basis of a fibrinolytic assay with {sup 125}I-fibrin, zymography, and immunoprobing with anti-human urokinase antibody, the authors have observed that the in vitro established NCTC human keratinocyte cell line releases into the culture medium a 54,000-Da plasminogen activator which is indistinguishable from human urokinase. Only the early release following the washing of keratinocyte monolayers is accounted for by secretion of preformed enzyme, while late secretory events require the de novo synthesis of urokinase. The released enzyme can interact by autocriny with its own receptor present on keratinocytes. The addition to the keratinocyte culture medium of the urokinase A chain can stimulate a concentration-dependent urokinase oversecretion, which is not paralleled by oversecretion of plasminogen activator inhibitor-1. Since stimulation of urokinase production can be obtained by an A chain concentration which was previously shown to be efficient in inducing keratinocyte mobilization in an in vitro migration model system, they hypothesize that this mechanism may be important in vivo during the process of wound repair.

  10. Fluorescent-Antibody Measurement Of Cancer-Cell Urokinase

    NASA Technical Reports Server (NTRS)

    Morrison, Dennis R.

    1993-01-01

    Combination of laboratory techniques provides measurements of amounts of urokinase in and between normal and cancer cells. Includes use of fluorescent antibodies specific against different forms of urokinase-type plasminogen activator, (uPA), fluorescence microscopy, quantitative analysis of images of sections of tumor tissue, and flow cytometry of different uPA's and deoxyribonucleic acid (DNA) found in suspended-tumor-cell preparations. Measurements provide statistical method for indicating or predicting metastatic potentials of some invasive tumors. Assessments of metastatic potentials based on such measurements used in determining appropriate follow-up procedures after surgical removal of tumors.

  11. Urokinase-controlled tumor penetrating peptide.

    PubMed

    Braun, Gary B; Sugahara, Kazuki N; Yu, Olivia M; Kotamraju, Venkata Ramana; Mölder, Tarmo; Lowy, Andrew M; Ruoslahti, Erkki; Teesalu, Tambet

    2016-06-28

    Tumor penetrating peptides contain a cryptic (R/K)XX(R/K) CendR element that must be C-terminally exposed to trigger neuropilin-1 (NRP-1) binding, cellular internalization and malignant tissue penetration. The specific proteases that are involved in processing of tumor penetrating peptides identified using phage display are not known. Here we design de novo a tumor-penetrating peptide based on consensus cleavage motif of urokinase-type plasminogen activator (uPA). We expressed the peptide, uCendR (RPARSGR↓SAGGSVA, ↓ shows cleavage site), on phage or coated it onto silver nanoparticles and showed that it is cleaved by uPA, and that the cleavage triggers binding to recombinant NRP-1 and to NPR-1-expressing cells. Upon systemic administration to mice bearing uPA-overexpressing breast tumors, FAM-labeled uCendR peptide and uCendR-coated nanoparticles preferentially accumulated in tumor tissue. We also show that uCendR phage internalization into cultured cancer cells and its penetration in explants of murine tumors and clinical tumor explants can be potentiated by combining the uCendR peptide with tumor-homing module, CRGDC. Our work demonstrates the feasibility of designing tumor-penetrating peptides that are activated by a specific tumor protease. As upregulation of protease expression is one of the hallmarks of cancer, and numerous tumor proteases have substrate specificities compatible with proteolytic unmasking of cryptic CendR motifs, the strategy described here may provide a generic approach for designing proteolytically-actuated peptides for tumor-penetrative payload delivery. PMID:27106816

  12. A comparison between 24-hour and 2-hour urine collection for the determination of proteinuria.

    PubMed

    Somanathan, N; Farrell, T; Galimberti, A

    2003-07-01

    Proteinuria is one of the fundamental criteria for the diagnosis of pre-eclampsia with quantitative assessment based on the 24-hour urine protein estimation as the gold standard. This study was undertaken to determine whether a 2-hour protein estimation correlated with that of a formal 24-hour collection. Thirty women with proteinuric hypertension were recruited. There was significant correlation between the 2-hour and 24-hour urine protein levels (Pearson's correlation coefficient 0.76 (P 0.000). A positive 2-hour test was associated more closely with significant levels of 24-hour proteinuria than dipstick analysis alone. We conclude from this study that a random 2-hour sample could be used for the initial assessment of proteinuria and so avoid the delay associated with 24-hour quantification of urinary protein. PMID:12881076

  13. Signaling through urokinase and urokinase receptor in lung cancer cells requires interactions with beta1 integrins.

    PubMed

    Tang, Chi-Hui; Hill, Marla L; Brumwell, Alexis N; Chapman, Harold A; Wei, Ying

    2008-11-15

    The urokinase receptor (uPAR) is upregulated upon tumor cell invasion and correlates with poor lung cancer survival. Although a cis-interaction with integrins has been ascribed to uPAR, whether this interaction alone is critical to urokinase (uPA)- and uPAR-dependent signaling and tumor promotion is unclear. Here we report the functional consequences of point mutations of uPAR (H249A-D262A) that eliminate beta1 integrin interactions but maintain uPA binding, vitronectin attachment and association with alphaV integrins, caveolin and epidermal growth factor receptor. Disruption of uPAR interactions with beta1 integrins recapitulated previously reported findings with beta1-integrin-derived peptides that attenuated matrix-dependent ERK activation, MMP expression and in vitro migration by human lung adenocarcinoma cell lines. The uPAR mutant cells acquired enhanced capacity to adhere to vitronectin via uPAR-alphaVbeta5-integrin, rather than through the uPAR-alpha3beta1-integrin complex and they were unable to initiate uPA signaling to activate ERK, Akt or Stat1. In an orthotopic lung cancer model, uPAR mutant cells exhibited reduced tumor size compared with cells expressing wild-type uPAR. Taken together, the results indicate that uPAR-beta1-integrin interactions are essential to signals induced by integrin matrix ligands or uPA that support lung cancer cell invasion in vitro and progression in vivo. PMID:18940913

  14. Urokinase production by electrophoretically separated cultured human embryonic kidney cells

    NASA Technical Reports Server (NTRS)

    Kunze, M. E.; Plank, L. D.; Giranda, V.; Sedor, K.; Todd, P. W.

    1985-01-01

    Urokinase is a plasminogen activator found in urine. Relatively pure preparations have been tested in Europe, Japan and the United States for the treatment of deep vein thrombosis and other dangerous blood clots. Human embryonic kidney cell cultures have been found to produce urokinase at much higher concentrations, but less than 5% of the cells in typical cultures are producers. Since human diploid cells become senescent in culture the selection of clones derived from single cells will not provide enough material to be useful, so a bulk purification method is needed for the isolation of urokinase producing cell populations. Preparative cell electrophoresis was chosen as the method, since evidence exists that human embryonic cell cultures are richly heterogeneous with respect to electrophoretic mobility, and preliminary electrophoretic separations on the Apollo-Soyuz space flight produced cell populations that were rich in urokinase production. Similarly, erythropoietin is useful in the treatment of certain anemias and is a kidney cell duct, and electrophoretically enriched cell populations producing this product have been reported. Thus, there is a clear need for diploid human cells that produce these products, and there is evidence that such cells should be separable by free-flow cell electrophoresis.

  15. Soluble Urokinase Receptor and Chronic Kidney Disease

    PubMed Central

    Hayek, Salim S.; Sever, Sanja; Ko, Yi-An; Trachtman, Howard; Awad, Mosaab; Wadhwani, Shikha; Altintas, Mehmet M.; Wei, Changli; Hotton, Anna L.; French, Audrey L.; Sperling, Laurence S.; Lerakis, Stamatios; Quyyumi, Arshed A.; Reiser, Jochen

    2015-01-01

    BACKGROUND Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease. METHODS We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m2 of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables. RESULTS A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was −0.9 ml per minute per 1.73 m2 among participants in the lowest quartile of suPAR levels as compared with −4.2 ml per minute per 1.73 m2 among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (≥90 ml per minute per 1.73 m2) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m2, the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile. CONCLUSIONS An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation

  16. Urokinase and the intestinal mucosa: evidence for a role in epithelial cell turnover

    PubMed Central

    Gibson, P; Birchall, I; Rosella, O; Albert, V; Finch, C; Barkla, D; Young, G

    1998-01-01

    Background—The functions of urokinase in intestinal epithelia are unknown. 
Aims—To determine the relation of urokinase expressed by intestinal epithelial cells to their position in the crypt-villus/surface axis and of mucosal urokinase activity to epithelial proliferative kinetics in the distal colon. 
Methods—Urokinase expression was examined immunohistochemically in human intestinal mucosa. Urokinase activity was measured colorimetrically in epithelial cells isolated sequentially from the crypt-villus axis of the rat small intestine. In separate experiments, urokinase activity and epithelial kinetics (measured stathmokinetically) were measured in homogenates of distal colonic mucosa of 14 groups of eight rats fed diets known to alter epithelial turnover. 
Results—From the crypt base, an ascending gradient of expression and activity of urokinase was associated with the epithelial cells. Median mucosal urokinase activities in each of the dietary groups of rats correlated positively with autologous median number of metaphase arrests per crypt (r=0.68; p<0.005) and per 100 crypt cells (r=0.75; p<0.001), but not with crypt column height. 
Conclusions—Localisation of an enzyme capable of leading to digestion of cell substratum in the region where cells are loosely attached to their basement membrane, and the association of its activity with indexes of cell turnover, suggest a role for urokinase in facilitating epithelial cell loss in the intestine. 

 Keywords: urokinase; intestinal epithelium; colon; epithelial proliferation PMID:9824347

  17. Immunohistochemical Detection of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor in Canine Vascular Endothelial Tumours.

    PubMed

    Anwar, Sh; Yanai, T; Sakai, H

    2015-11-01

    Immunohistochemistry was used to assess the expression of urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in 57 canine primary haemangiosarcomas (HSAs), 26 canine cutaneous haemangiomas (HAs) and in control sections of canine cutaneous granulation tissue. The correlation between uPA/uPAR expression and the Ki67 labelling index (LI) was estimated in the HSA and HA tissues. uPA was expressed by 73.2% and 75.0% of splenic HSAs and non-splenic HSAs, respectively. All HSA tissues tested expressed uPAR. Expression of both molecules was significantly higher in HSAs than in cutaneous HAs (3.8% for uPA and 30.7% for uPAR). The average Ki67 LI of the uPA(+)/uPAR(+) HSAs was significantly higher than that of uPA(-)/uPAR(+) HSAs and HA tissues (mean ± SDs 32.8 ± 15.3, 15.2 ± 7.2 and 2.1 ± 0.7, respectively; P <0.05). These results suggest that uPA and uPAR play a significant role in the malignant proliferation of canine HSA, regardless of the primary origin of the tumour. PMID:26286429

  18. Characterization of urokinase receptor expression by human placental trophoblasts.

    PubMed

    Zini, J M; Murray, S C; Graham, C H; Lala, P K; Karikó, K; Barnathan, E S; Mazar, A; Henkin, J; Cines, D B; McCrae, K R

    1992-06-01

    The processes of implantation and placentation are both dependent on the invasion and remodeling of the uterine endometrium and vasculature by trophoblasts. Because the secretion and autocrine binding of urokinase (uPA) appears to be a common mechanism used by cells to facilitate plasmin-dependent tissue invasion, we measured the production of uPA and expression of uPA receptors by trophoblasts. Prourokinase bound specifically, reversibly, and with high affinity to cultured trophoblasts, via the uPA epidermal growth factor-like domain. Trophoblasts derived from two first-trimester placentae bound more prourokinase than cells isolated from term placentae. Furthermore, in vitro differentiation of cultured cytotrophoblasts into syncytiotrophoblasts was associated with diminished expression of urokinase receptors and a parallel decrease in the cellular content of uPA receptor mRNA. Trophoblasts also secreted prourokinase and plasminogen activator inhibitors types 1 and 2 (PAI-1 and PAI-2). Although prourokinase was secreted in amounts sufficient to endogenously saturate trophoblast uPA receptors, trophoblasts secreted greater amounts of PAI-1 and PAI-2 than uPA, and no net plasminogen activator activity was detected in trophoblast conditioned medium. In contrast, plasminogen added directly to cultured trophoblasts was readily converted to plasmin. Although the invasion and remodeling of uterine tissues by trophoblasts is a complex process dependent on several proteases of varying specificity, our findings suggest that the expression and modulation of urokinase receptors on the trophoblast cell surface may play an important role in this process. PMID:1316787

  19. Purification of urokinase by combined cation exchanger and affinity chromatographic cartridges.

    PubMed

    Hou, K C; Zaniewski, R

    1990-02-23

    Crude urokinase from human urine processed through foam flotation and ammonium sulfate precipitation containing 720 National Health Institute Committee on Thrombolytic Agents U/mg activity was purified by an SP cation exchanger followed by a zinc-chelated affinity chromatographic cartridge. The cartridges were of a radial-flow type formed by using acrylic and cellulose composite matrices. The high rigidity of the matrix structure permits fast flow of protein solutions (liters per minute) and thus allows processing of a large volume of crude urokinase under low operating pressures. A greater than six-fold increase in specific enzyme activity of urokinase was achieved by adsorbing and eluting 1 l of a 3 mg/ml crude urokinase solution on an SP cartridge. The eluent was further purified by passing through a zinc-chelated affinity cartridge to achieve greater than a eighteen-fold increase in urokinase specific activity. This report demonstrates the combined use of a cation exchanger with zinc-chelated chromatographic cartridges in purifying urokinase on a relatively large scale. The relationship between the amount of zinc chelated in the matrix to its effect on urokinase purification is also discussed. PMID:2329161

  20. Single-chain urokinase in empyema induced by Pasturella multocida.

    PubMed

    Idell, Steven; Jun Na, Moon; Liao, Huai; Gazar, A E; Drake, Wonder; Lane, Kirk B; Koenig, Kathy; Komissarov, Andrey; Tucker, Torry; Light, Richard W

    2009-10-01

    Intrapleural fibrin deposition and subsequent fibrosis characterize evolving empyema and contribute to the morbidity associated with this condition. Single-chain urokinase (scuPA) is proenzyme form of the urokinase plasminogen activator, which has recently been shown to effectively clear intrapleural loculation in tetracycline-induced pleurodesis in rabbits. The authors therefore hypothesized that scuPA could likewise improve intrapleural injury associated with empyema. The authors used a rabbit model of empyema induced by intrapleural administration of Pasturella multocida to test this hypothesis and determined the effects of intrapleural scuPA on pleural fluids indices of inflammation and intrapleural fibrosis. The authors found that intrapleural administration of scuPA was well tolerated, generated readily detectable fibrinolytic activity in the empyema fluids and did not induce intrapleural or systemic bleeding. Pleural fluid volume, intrapleural protein, and D-dimer concentrations were increased at 24 and 48 hours (P < .01, respectively) after induction of empyema. Intrapleural loculation did not occur in the scuPA- or vehicle control-treated animals and there was no significant change in the pleural empyema or thickening scores. These findings confirm that intrapleural scuPA generates fibrinolysis in empyema fluids but does not alter fibrotic repair at the pleural surface or the intensity of intrapleural inflammation in this empyema model. PMID:19895321

  1. Clinical study of urokinase-bound fibrocollagenous tubes.

    PubMed

    Senatore, F; Bernath, F; Meisner, K

    1986-02-01

    Dacron-reinforced fibrocollagenous tubes (FCT) were synthesized from canine mongrels using the mandril-rod technique in order to develop a small diameter (i.e., 4 mm i.d.) vascular graft. They were rendered fibrinolytic by immobilizing urokinase on to the inner surface of the tubes. Urokinase-bound fibrocollagenous tubes (UK-FCT), control FCTs (i.e., no bound enzyme), Perloff grafts (Dr. Perloff, Department of Surgery, University Medical Center, Sidney Australia, has developed a mandril-derived collagenous tube from goats. Samples were implanted for comparative purposes.) and autogeneous saphenous veins, were interposed in the carotid or femoral artery in chronic studies involving 21 canine mongrels. On the basis of Doppler auscultation and palpation, the UK-FCTs were statistically more patent than other candidate prostheses. Fibrin degradation product (FDP) increased in the dogs' systemic circulation with a postoperative peak of 5 days. The host's increase in fibrinolytic activity was shown to be local to the anastamosis. A carotid arterial extracorporeal shunt was designed to evaluate acute patency. Results indicated a rapid thrombosis but no platlet or fibrin adherence to the graft surface was observed, as evidenced by scanning electron microscopy. PMID:2937788

  2. Nuclear translocation of urokinase-type plasminogen activator.

    PubMed

    Stepanova, Victoria; Lebedeva, Tatiana; Kuo, Alice; Yarovoi, Serge; Tkachuk, Sergei; Zaitsev, Sergei; Bdeir, Khalil; Dumler, Inna; Marks, Michael S; Parfyonova, Yelena; Tkachuk, Vsevolod A; Higazi, Abd Al-Roof; Cines, Douglas B

    2008-07-01

    Urokinase-type plasminogen activator (uPA) participates in diverse (patho)physiological processes through intracellular signaling events that affect cell adhesion, migration, and proliferation, although the mechanisms by which these occur are only partially understood. Here we report that upon cell binding and internalization, single-chain uPA (scuPA) translocates to the nucleus within minutes. Nuclear translocation does not involve proteolytic activation or degradation of scuPA. Neither the urokinase receptor (uPAR) nor the low-density lipoprotein-related receptor (LRP) is required for nuclear targeting. Rather, translocation involves the binding of scuPA to the nucleocytoplasmic shuttle protein nucleolin through a region containing the kringle domain. RNA interference and mutational analysis demonstrate that nucleolin is required for the nuclear transport of scuPA. Furthermore, nucleolin is required for the induction smooth muscle alpha-actin (alpha-SMA) by scuPA. These data reveal a novel pathway by which uPA is rapidly translocated to the nucleus where it might participate in regulating gene expression. PMID:18337556

  3. Operational Implementation of a 2-Hour Prebreathe Protocol for International Space Station

    NASA Technical Reports Server (NTRS)

    Waligora, James M.; Conkin, J.; Foster, P. P.; Schneider, S.; Loftin, Karin C.; Gernhardt, Michael L.; Vann, R.

    2000-01-01

    Procedures, equipment, and analytical techniques were developed to implement the ground tested 2-hour protocol in-flight operations. The methods are: 1) The flight protocol incorporates additional safety margin over the ground tested protocol. This includes up to 20 min of additional time on enriched O2 during suit purge and pressure check, increased duration of extravehicular activity (EVA) preparation exercise during O2 prebreathing (up to 90 min vs; the tested 24 min), and reduced rates of depressurization. The ground test observations were combined with model projections of the conservative measures (using statistical models from Duke University and NASA JSQ to bound the risk of Type I and Type II decompression sickness (DCS). 2) An inflight exercise device using the in-flight ergometer and elastic tubes for upper body exercise was developed to replicate the dual cycle exercise in the ground trials. 3) A new in-flight breathing system was developed and man-tested. 4) A process to monitor inflight experience with the protocol, including the use of an in-suit Doppler bubble monitor when available, was developed. The results are: 1) The model projections of the conservative factors of the operational protocol were shown to reduce the risk of DCS to levels consistent with the observations of no DCS to date in the shuttle program. 2) Cross over trials of the dual cycle ergometer used in ground tests and the in-flight exercise system verified that02consumption and the % division of work between upper and lower body was not significantly different at the p= 0.05 level. 3) The in-flight breathing system was demonstrated to support work rates generating 75% O2(max) in 95 percentile subjects. 4) An in-flight monitoring plan with acceptance criteria was put in place for the 2-hour prebreathe protocol. And the conclusions are: The 2-hour protocol has been approved for flight, and all implementation efforts are in place to allow use of the protocol as early as flight ISS 7A

  4. Structural investigations of recombinant urokinase growth factor-like domain.

    PubMed

    Beloglazova, I B; Beabealashvilli, R Sh; Gursky, Ya G; Bocharov, E V; Mineev, K S; Parfenova, E V; Tkachuk, V A

    2013-05-01

    Urokinase-type plasminogen activator (uPA) is a serine protease that converts the plasminogen zymogen into the enzymatically active plasmin. uPA is synthesized and secreted as the single-chain molecule (scuPA) composed of an N-terminal domain (GFD) and kringle (KD) and C-terminal proteolytic (PD) domains. Earlier, the structure of ATF (which consists of GFD and KD) was solved by NMR (A. P. Hansen et al. (1994) Biochemistry, 33, 4847-4864) and by X-ray crystallography alone and in a complex with the soluble form of the urokinase receptor (uPAR, CD87) lacking GPI (C. Barinka et al. (2006) J. Mol. Biol., 363, 482-495). According to these data, GFD contains two β-sheet regions oriented perpendicularly to each other. The area in the GFD responsible for binding to uPAR is localized in the flexible Ω-loop, which consists of seven amino acid residues connecting two strings of antiparallel β-sheet. It was shown by site-directed mutagenesis that shortening of the Ω-loop length by one amino acid residue leads to the inability of GFD to bind to uPAR (V. Magdolen et al. (1996) Eur. J. Biochem., 237, 743-751). Here we show that, in contrast to the above-mentioned studies, we found no sign of the β-sheet regions in GFD in our uPA preparations either free or in a complex with uPAR. The GFD seems to be a rather flexible and unstructured domain, demonstrating in spite of its apparent flexibility highly specific interaction with uPAR both in vitro and in cell culture experiments. Circular dichroism, tryptophan fluorescence during thermal denaturation of the protein, and heteronuclear NMR spectroscopy of ¹⁵N/¹³C-labeled ATF both free and in complex with urokinase receptor were used to judge the secondary structure of GFD of uPA. PMID:23848154

  5. Dialysis Access Graft Thrombolysis: Randomized Study of Pulse-Spray Versus Continuous Urokinase Infusion

    SciTech Connect

    Goodwin, Scott C.; Arora, Lokesh C.; Razavi, Mahmood K.; Sayre, James; McNamara, Thomas O.; Yoon, Chun

    1998-03-15

    Purpose: To compare pulse-spray to continuous-infusion thrombolysis with high-dose urokinase in thrombosed dialysis access grafts. Methods: A prospective randomized controlled trial was performed. From August 1992 to September 1993, 30 thrombosed polytetrafluoroethylene (PTFE) grafts in 24 patients were included, 15 grafts in each group. The success of thrombolysis, mean time to thrombolysis, mean urokinase dose, and 60-day patency rate were evaluated. Results: In the pulse-spray group, the mean time to thrombolysis was 72 min with a mean urokinase dose of 560,000 U. The 60-day patency rate was 71%. In the continuous-infusion group, the mean infusion time to thrombolysis was 55 min with a mean dose of 479,000 U. The 60-day patency rate was 73%. Conclusion: No statistically significant difference was found between the two techniques in the mean time to thrombolysis, the mean urokinase dose used, or the 60-day patency rate.

  6. Thrombolytic Therapy Using Urokinase for Management of Central Venous Catheter Thrombosis

    PubMed Central

    Son, Jung Tack; Min, Sun Young; Kim, Jae Il; Choi, Pyong Wha; Heo, Tae Gil; Lee, Myung Soo; Kim, Chul-Nam; Kim, Hong-Yong; Yi, Seong Yoon; Lee, Hye Ran; Roh, Young-Nam

    2014-01-01

    Purpose: The management of central venous catheters (CVCs) and catheter thrombosis vary among centers, and the efficacy of the methods of management of catheter thrombosis in CVCs is rarely reported. We investigated the efficacy of bedside thrombolysis with urokinase for the management of catheter thrombosis. Materials and Methods: We retrospectively reviewed data from patients who had undergone CVC insertion by a single surgeon in a single center between April 2012 and June 2014. We used a protocol for the management of CVCs and when catheter thrombosis was confirmed, 5,000 U urokinase was infused into the catheter. Results: A total of 137 CVCs were inserted in 126 patients. The most common catheter-related complication was thrombosis (12, 8.8%) followed by infection (8, 5.8%). Nine of the 12 patients (75%) with catheter thrombosis were recanalized successfully with urokinase. The rate of CVC recanalization was higher in the peripherally inserted central catheter (PICC) group (87.5%) than the chemoport group (50%). Reintervention for catheter-related thrombosis was needed in only 2.2% of patients when thrombolytic therapy using urokinase was applied. Age <60 years (P=0.035), PICC group (P=0.037) and location of the catheter tip above the superior vena cava (P=0.044) were confirmed as independent risk factors for catheter thrombosis. Conclusion: Thrombolysis therapy using urokinase could successfully manage CVC thrombosis. Reintervention was rarely needed when a protocol using urokinase was applied for the management of CVC thromboses. PMID:26217634

  7. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents.

    PubMed

    Busso, N; Nicodeme, E; Chesne, C; Guillouzo, A; Belin, D; Hyafil, F

    1994-07-01

    We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology. PMID:8020888

  8. Urokinase receptor is a multifunctional protein: influence of receptor occupancy on macrophage gene expression.

    PubMed Central

    Rao, N K; Shi, G P; Chapman, H A

    1995-01-01

    Binding of urokinase to the glycolipid-anchored urokinase receptor (uPAR) has been implicated in macrophage differentiation. However, no biochemical markers of differentiation have yet been directly linked to uPAR occupancy. As extensive changes in proteolytic profile characterize monocytic differentiation, we have examined the role of uPAR occupancy on protease expression by differentiating phagocytes. Antibodies to either urokinase or to uPAR that prevent receptor binding inhibited induction of cathepsin B in cultured monocytes and both cathepsin B and 92-kD gelatinase mRNA and protein in phorbol diester-stimulated myeloid cells. Mannosamine, an inhibitor of glycolipid anchor assembly, also blocked protease expression. Anti-catalytic urokinase antibodies, excess inactive urokinase, or aprotinin had no effect, indicating that receptor occupancy per se regulated protease expression. Antibodies to the integrins CD11a and CD29 or to the glycolipid-anchored proteins CD14 and CD55 also had no effect. Protease induction was independent of matrix attachment. Antibodies to urokinase or uPAR affected neither the decrease in cathepsin G nor the increase in tumor necrosis factor-alpha in phorbol ester-stimulated cells. These data establish that uPAR is a multifunctional receptor, not only promoting pericellular proteolysis and matrix attachment, but also effecting cysteine- and metallo-protease expression during macrophage differentiation. Images PMID:7615819

  9. Rationale for monitoring cyclosporine concentration at 2 hours after administration in infants posttransplantation.

    PubMed

    Furlan, V; Lykavieris, P; Maubert, M A; Habes, D; Debray, D

    2009-10-01

    Therapeutic drug monitoring is critical to avoid overimmunosuppression or underimmunosuppression in young pediatric transplant recipients. The objective of this study was to examine cyclosporine (CsA) trough (C0) and 2-hour post-dose (C2) concentrations in the early period after liver transplantation (OLT) to determine whether CsA C2 monitoring is justified. Seventeen infants younger than 2 years treated with CsA (Neoral) were monitored at C0. The biopsy-proved acute rejection rate was 65% at 3 months post-OLT. No correlation was observed between values at C0 and C2. Poor absorption of CsA was observed in most infants during the first 2 weeks post-OLT, as well as interindividual variability in CsA clearance. Exposure to CsA could not be estimated using either C0 or C2 determinations in the early post-OLT period. As a marker of poor absorption, C2 is useful but does not indicate delayed or rapid clearance of drug without simultaneous measurement of concentration at C0. We suggest the use of both C0 and C2 monitoring, or AUC monitoring on an individual basis during at least the first 2 weeks post-OLT. PMID:19857744

  10. Involvement of the Soluble Urokinase Receptor in Chondrosarcoma Cell Mobilization

    PubMed Central

    Bifulco, Katia; Longanesi-Cattani, Immacolata; Masucci, Maria Teresa; De Chiara, Annarosaria; Fazioli, Flavio; Di Carluccio, Gioconda; Pirozzi, Giuseppe; Gallo, Michele; La Rocca, Antonello; Apice, Gaetano; Rocco, Gaetano; Carriero, Maria Vincenza

    2011-01-01

    High levels of urokinase receptor (uPAR) in tissue and serum of patients with chondrosarcoma correlate with poor prognosis. First, we analyzed the uPAR levels in tissues and plasma of five patients affected by chondrosarcoma. Interestingly, very high levels of uPAR and its soluble forms (SuPAR) were found on tumor cell surfaces and plasma, respectively, of two patients with lung metastases. Therefore, to investigate the role of SuPAR in chondrosaromas, we generated a primary cell culture from a chondrosarcoma tissue overexpressing uPAR on cell surfaces. We found that chondrosarcoma-like primary culture cells release a large amount of SuPAR in the medium. In vitro, SuPAR elicits chondrosarcoma cell migration likely through its uPAR88-92 sequence, since the DII88-183 or DIIDIIR88-284 uPAR domains retain motogen effect whereas DI1-87 or DIII184-284 domains, both lacking the uPAR88-92 sequence, are ineffective. Chondrosarcoma cells cross matrigel in response to SuPAR, and their invasion capability is abrogated by RERF peptide which inhibits uPAR88-92 signalling. These findings assign a role to uPAR in mobilizing chondrosarcoma cells and suggest that RERF peptide may be regarded as a prototype to generate new therapeutics for the chondrosarcoma treatment. PMID:21253510

  11. Application of Molecular Modeling to Urokinase Inhibitors Development

    PubMed Central

    Sulimov, V. B.; Katkova, E. V.; Oferkin, I. V.; Sulimov, A. V.; Romanov, A. N.; Roschin, A. I.; Beloglazova, I. B.; Plekhanova, O. S.; Tkachuk, V. A.; Sadovnichiy, V. A.

    2014-01-01

    Urokinase-type plasminogen activator (uPA) plays an important role in the regulation of diverse physiologic and pathologic processes. Experimental research has shown that elevated uPA expression is associated with cancer progression, metastasis, and shortened survival in patients, whereas suppression of proteolytic activity of uPA leads to evident decrease of metastasis. Therefore, uPA has been considered as a promising molecular target for development of anticancer drugs. The present study sets out to develop the new selective uPA inhibitors using computer-aided structural based drug design methods. Investigation involves the following stages: computer modeling of the protein active site, development and validation of computer molecular modeling methods: docking (SOL program), postprocessing (DISCORE program), direct generalized docking (FLM program), and the application of the quantum chemical calculations (MOPAC package), search of uPA inhibitors among molecules from databases of ready-made compounds to find new uPA inhibitors, and design of new chemical structures and their optimization and experimental examination. On the basis of known uPA inhibitors and modeling results, 18 new compounds have been designed, calculated using programs mentioned above, synthesized, and tested in vitro. Eight of them display inhibitory activity and two of them display activity about 10 μM. PMID:24967388

  12. Secretion of macrophage urokinase plasminogen activator is dependent on proteoglycans.

    PubMed

    Pejler, Gunnar; Winberg, Jan-Olof; Vuong, Tram T; Henningsson, Frida; Uhlin-Hansen, Lars; Kimata, Koji; Kolset, Svein O

    2003-10-01

    The importance of proteoglycans for secretion of proteolytic enzymes was studied in the murine macrophage cell line J774. Untreated or 4beta-phorbol 12-myristate 13-acetate (PMA)-stimulated macrophages were treated with hexyl-beta-d-thioxyloside to interfere with the attachment of glycosaminoglycan chains to their respective protein cores. Activation of the J774 macrophages with PMA resulted in increased secretion of trypsin-like serine proteinase activity. This activity was completely inhibited by plasminogen activator inhibitor 1 and by amiloride, identifying the activity as urokinase plasminogen activator (uPA). Treatment of both the unstimulated or PMA-stimulated macrophages with xyloside resulted in decreased uPA activity and Western blotting analysis revealed an almost complete absence of secreted uPA protein after xyloside treatment of either control- or PMA-treated cells. Zymography analyses with gels containing both gelatin and plasminogen confirmed these findings. The xyloside treatment did not reduce the mRNA levels for uPA, indicating that the effect was at the post-translational level. Treatment of the macrophages with xylosides did also reduce the levels of secreted matrix metalloproteinase 9. Taken together, these findings indicate a role for proteoglycans in the secretion of uPA and MMP-9. PMID:14511379

  13. Effects of a 2-hour run on metabolic economy and lower extremity strength in men and women.

    PubMed

    Glace, B W; McHugh, M P; Gleim, G W

    1998-03-01

    Changes in running economy, or the oxygen cost of running at a given submaximal speed (ml/m/kg), during prolonged exercise have been well described in men but not in women. Lower extremity strength changes associated with prolonged exercise have never been addressed. We examined changes in running economy and strength following a 2-hour run in eight men and eight women. Knee and hip strength were measured pre- and post-running. Peak oxygen consumption (VO2peak) and oxygen consumption at ventilatory threshold were determined. Subjects then ran for 2 hours at an intensity which elicited ventilatory threshold (68.7% vs. 66.6% of VO2peak for men and women, p = 0.5). Water was ingested at a rate of 0.5% of body weight each half hour. Oxygen uptake (VO2) and respiratory exchange ratio were measured initially and at 1 and 2 hours. Body weight declined in the men (p = 0.001) but not in the women (p = 0.12). Running economy decreased in the men (p < 0.001) but not in the women (p = 0.084). At 2 hours of running, knee flexion and extension strength declined significantly in the men only (effect of gender x time, p < 0.014), but hip flexion, abduction, and adduction strength declined in both genders. Decreased knee extensor/flexor strength was evident in men only, while decreased hip strength was independent of gender. We conclude that 2 hours of running produced changes in knee strength and running economy in men only. PMID:9513864

  14. Efficacy of 2-hour post glucose insulin levels in predicting insulin resistance in polycystic ovarian syndrome with infertility

    PubMed Central

    Saxena, Pikee; Prakash, Anupam; Nigam, Aruna

    2011-01-01

    BACKGROUND: Insulin resistance (IR) is central to the pathogenesis of polycystic ovarian syndrome (PCOS), but tests for determining IR are elaborate, tedious and expensive. AIMS: To evaluate if “2-hour post-glucose insulin level” is an effective indicator of IR and can aid in diagnosing IR in infertile PCOS women. SETTINGS AND DESIGN: Observational study at infertility clinic of a tertiary care center. MATERIALS AND METHODS: 50 infertile women with PCOS and 20 females with tubal/male factor infertility were evaluated for the presence of IR, as defined by the fasting/2-hour post-glucose insulin levels cutoffs of >25/>41 μU/mL, respectively. The clinical, metabolic and endocrinologic profile was determined in both the groups. STATISTICAL ANALYSIS: Statistical analysis was performed using SPSS (Chicago, IL, USA). RESULTS: Body mass index, post load glucose, insulin, glucose/insulin ratio, area under curve (AUC) of glucose and insulin and insulinogenic index were significantly lower in the controls as compared to the PCOS group. “2-hour post-glucose insulin levels” were elevated in 88% of PCOS individuals but were normal in all females not suffering from PCOS. These levels significantly correlated with AUC of glucose and insulin, and insulinogenic index and inversely correlated with 2-hour glucose to insulin ratio (r=0.827, 0.749 and –0.732, respectively). CONCLUSIONS: “2-hour post-glucose insulin levels” appears to be a good indicator of IR. It can be a useful tool, especially in low resource setting where a single sample can confirm the diagnosis, thus reducing cost and repeat visits. PMID:21772735

  15. Imaging Active Urokinase Plasminogen Activator in Prostate Cancer

    PubMed Central

    LeBeau, Aaron M.; Sevillano, Natalia; Markham, Kate; Winter, Michael B.; Murphy, Stephanie T.; Hostetter, Daniel R.; West, James; Lowman, Henry; Craik, Charles S.; VanBrocklin, Henry F.

    2015-01-01

    The increased proteolytic activity of membrane-bound and secreted proteases on the surface of cancer cells and in the transformed stroma is a common characteristic of aggressive metastatic prostate cancer. We describe here the development of an active site-specific probe for detecting a secreted peritumoral protease expressed by cancer cells and the surrounding tumor microenvironment. Using a human fragment antigen binding phage display library, we identified a human antibody termed U33 that selectively inhibited the active form of the protease urokinase plasminogen activator (uPA, PLAU). In the full-length immunoglobulin form, U33 IgG labeled with near-infrared fluorophores or radionuclides allowed us to non-invasively detect active uPA in prostate cancer xenograft models using optical and single-photon emission computed tomography (SPECT) imaging modalities. U33 IgG labeled with 111In had a remarkable tumor uptake of 43.2% injected dose per gram (%ID/g) 72hr post tail vein injection of the radiolabeled probe in subcutaneous xenografts. Additionally, U33 was able to image active uPA in small soft-tissue and osseous metastatic lesions using a cardiac dissemination prostate cancer model that recapitulated metastatic human cancer. The favorable imaging properties were the direct result of U33 IgG internalization through an uPA receptor mediated mechanism where U33 mimicked the function of the endogenous inhibitor of uPA to gain entry into the cancer cell. Overall, our imaging probe targets a prostate cancer-associated protease, through a unique mechanism, allowing for the non-invasive preclinical imaging of prostate cancer lesions. PMID:25672980

  16. Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

    PubMed Central

    Chen, Zaixing; Zhao, Runzhen; Zhao, Meimi; Liang, Xinrong; Bhattarai, Deepa; Dhiman, Rohan; Shetty, Sreerama; Idell, Steven

    2014-01-01

    Epithelial sodium channels (ENaC) govern transepithelial salt and fluid homeostasis. ENaC contributes to polarization, apoptosis, epithelial-mesenchymal transformation, etc. Fibrinolytic proteases play a crucial role in virtually all of these processes and are elaborated by the airway epithelium. We hypothesized that urokinase-like plasminogen activator (uPA) regulates ENaC function in airway epithelial cells and tested that possibility in primary murine tracheal epithelial cells (MTE). Both basal and cAMP-activated Na+ flow through ENaC were significantly reduced in monolayers of uPA-deficient cells. The reduction in ENaC activity was further confirmed in basolateral membrane-permeabilized cells. A decrease in the Na+-K+-ATPase activity in the basolateral membrane could contribute to the attenuation of ENaC function in intact monolayer cells. Dysfunctional fluid resolution was seen in uPA-disrupted cells. Administration of uPA and plasmin partially restores ENaC activity and fluid reabsorption by MTEs. ERK1/2, but not Akt, phosphorylation was observed in the cells and lungs of uPA-deficient mice. On the other hand, cleavage of γ ENaC is significantly depressed in the lungs of uPA knockout mice vs. those of wild-type controls. Expression of caspase 8, however, did not differ between wild-type and uPA−/− mice. In addition, uPA deficiency did not alter transepithelial resistance. Taken together, the mechanisms for the regulation of ENaC by uPA in MTEs include augmentation of Na+-K+-ATPase, proteolysis, and restriction of ERK1/2 phosphorylation. We demonstrate for the first time that ENaC may serve as a downstream signaling target by which uPA controls the biophysical profiles of airway fluid and epithelial function. PMID:25172911

  17. Urokinase plasminogen activator gene deficiency inhibits fracture cartilage remodeling.

    PubMed

    Popa, Nicoleta L; Wergedal, Jon E; Lau, K-H William; Mohan, Subburaman; Rundle, Charles H

    2014-03-01

    Urokinase plasminogen activator (uPA) regulates a proteolytic cascade of extracellular matrix degradation that functions in tissue development and tissue repair. The development and remodeling of the skeletal extracellular matrix during wound healing suggests that uPA might regulate bone development and repair. To determine whether uPA functions regulate bone development and repair, we examined the basal skeletal phenotype and endochondral bone fracture repair in uPA-deficient mice. The skeletal phenotype of uPA knockout mice was compared with that of control mice under basal conditions by dual-energy X-ray absorptiometry and micro-CT analysis, and during femur fracture repair by micro-CT and histological examination of the fracture callus. No effects of uPA gene deficiency were observed in the basal skeletal phenotype of the whole body or the femur. However, uPA gene deficiency resulted in increased fracture callus cartilage abundance during femur fracture repair at 14 days healing. The increase in cartilage corresponded to reduced tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts in the uPA knockout fracture callus at this time, consistent with impaired osteoclast-mediated remodeling of the fracture cartilage. CD31 staining was reduced in the knockout fracture tissues at this time, suggesting that angiogenesis was also reduced. Osteoclasts also colocalized with CD31 expression in the endothelial cells of the fracture tissues during callus remodeling. These results indicate that uPA promotes remodeling of the fracture cartilage by osteoclasts that are associated with angiogenesis and suggest that uPA promotes angiogenesis and remodeling of the fracture cartilage at this time of bone fracture repair. PMID:23700285

  18. Regime change?

    SciTech Connect

    Pilat, Joseph F.; Budlong-Sylvester, K. W.

    2004-01-01

    Following the 1998 nuclear tests in South Asia and later reinforced by revelations about North Korean and Iraqi nuclear activities, there has been growing concern about increasing proliferation dangers. At the same time, the prospects of radiological/nuclear terrorism are seen to be rising - since 9/11, concern over a proliferation/terrorism nexus has never been higher. In the face of this growing danger, there are urgent calls for stronger measures to strengthen the current international nuclear nonproliferation regime, including recommendations to place civilian processing of weapon-useable material under multinational control. As well, there are calls for entirely new tools, including military options. As proliferation and terrorism concerns grow, the regime is under pressure and there is a temptation to consider fundamental changes to the regime. In this context, this paper will address the following: Do we need to change the regime centered on the Treaty on the Nonproliferation of Nuclear Weapons (NPT) and the International Atomic Energy Agency (IAEA)? What improvements could ensure it will be the foundation for the proliferation resistance and physical protection needed if nuclear power grows? What will make it a viable centerpiece of future nonproliferation and counterterrorism approaches?

  19. Effects of acute and 2-hour postphysical activity on the estimation of body fat made by the bod pod.

    PubMed

    Harrop, Bradley J; Woodruff, Sarah J

    2015-06-01

    The Bod Pod has been found to be reliable/valid against several criterion methods, including hydrostatic weighing and dual-energy x-ray absorptiometry, and under different conditions, such as clothing, dehydrated states, and body temperature changes. However, questions remain regarding the effects of an acute bout of exercise. Therefore, the purpose was to determine the effects of an acute bout of exercise on the estimations made by the Bod Pod. Participants (15 men and 22 women) were of age 18-27 years and were currently exercising. Baseline Bod Pod measures were completed followed by a 30-minute cycling trial at 75% of maximum heart rate. Bod Pod measures were taken immediately after exercise and 2 hours after exercise. Differences between men and women were found at baseline between height (p < 0.001), weight (p < 0.001), body volume (BV; p < 0.001), and body density (Db; p < 0.001). Among men, body mass (p < 0.001), body fat percentage (%BF; p < 0.001), and BV (p < 0.001) decreased, whereas Db (p < 0.001) and body temperature (p < 0.001) increased directly after exercise; body mass (p < 0.001) and BV (p < 0.001) remained lower after 2 hours. Among women, body mass (p < 0.001) and BV (p < 0.001) decreased, whereas thoracic gas volume (p = 0.014) and temperature (p < 0.001) increased directly after exercise; body mass (p < 0.001) and BV (p < 0.001) remained lower, whereas %BF (p < 0.001) and Db (p = 0.006) remained higher 2 hours after exercise. These results suggest that a single bout of exercise immediately before Bod Pod testing seems to alter the estimate of %BF, and continues to affect the prediction 2 hours after exercise in women. PMID:25756324

  20. Dietary Fatty Acids Differentially Associate with Fasting Versus 2-Hour Glucose Homeostasis: Implications for The Management of Subtypes of Prediabetes

    PubMed Central

    Guess, Nicola; Perreault, Leigh; Kerege, Anna; Strauss, Allison; Bergman, Bryan C.

    2016-01-01

    Over-nutrition has fuelled the global epidemic of type 2 diabetes, but the role of individual macronutrients to the diabetogenic process is not well delineated. We aimed to examine the impact of dietary fatty acid intake on fasting and 2-hour plasma glucose concentrations, as well as tissue-specific insulin action governing each. Normoglycemic controls (n = 15), athletes (n = 14), and obese (n = 23), as well as people with prediabetes (n = 10) and type 2 diabetes (n = 11), were queried about their habitual diet using a Food Frequency Questionnaire. All subjects were screened by an oral glucose tolerance test (OGTT) and studied using the hyperinsulinemic/euglycemic clamp with infusion of 6,62H2-glucose. Multiple regression was performed to examine relationships between dietary fat intake and 1) fasting plasma glucose, 2) % suppression of endogenous glucose production, 3) 2-hour post-OGTT plasma glucose, and 4) skeletal muscle insulin sensitivity (glucose rate of disappearance (Rd) and non-oxidative glucose disposal (NOGD)). The %kcal from saturated fat (SFA) was positively associated with fasting (β = 0.303, P = 0.018) and 2-hour plasma glucose (β = 0.415, P<0.001), and negatively related to % suppression of hepatic glucose production (β = -0.245, P = 0.049), clamp Rd (β = -0.256, P = 0.001) and NOGD (β = -0.257, P = 0.001). The %kcal from trans fat was also negatively related to clamp Rd (β = -0.209, P = 0.008) and NOGD (β = -0.210, P = 0.008). In contrast, the %kcal from polyunsaturated fat (PUFA) was negatively associated with 2-hour glucose levels (β = -0.383, P = 0.001), and positively related to Rd (β = 0.253, P = 0.007) and NOGD (β = 0.246, P = 0.008). Dietary advice to prevent diabetes should consider the underlying pathophysiology of the prediabetic state. PMID:26999667

  1. Dietary Fatty Acids Differentially Associate with Fasting Versus 2-Hour Glucose Homeostasis: Implications for The Management of Subtypes of Prediabetes.

    PubMed

    Guess, Nicola; Perreault, Leigh; Kerege, Anna; Strauss, Allison; Bergman, Bryan C

    2016-01-01

    Over-nutrition has fuelled the global epidemic of type 2 diabetes, but the role of individual macronutrients to the diabetogenic process is not well delineated. We aimed to examine the impact of dietary fatty acid intake on fasting and 2-hour plasma glucose concentrations, as well as tissue-specific insulin action governing each. Normoglycemic controls (n = 15), athletes (n = 14), and obese (n = 23), as well as people with prediabetes (n = 10) and type 2 diabetes (n = 11), were queried about their habitual diet using a Food Frequency Questionnaire. All subjects were screened by an oral glucose tolerance test (OGTT) and studied using the hyperinsulinemic/euglycemic clamp with infusion of 6,62H2-glucose. Multiple regression was performed to examine relationships between dietary fat intake and 1) fasting plasma glucose, 2) % suppression of endogenous glucose production, 3) 2-hour post-OGTT plasma glucose, and 4) skeletal muscle insulin sensitivity (glucose rate of disappearance (Rd) and non-oxidative glucose disposal (NOGD)). The %kcal from saturated fat (SFA) was positively associated with fasting (β = 0.303, P = 0.018) and 2-hour plasma glucose (β = 0.415, P<0.001), and negatively related to % suppression of hepatic glucose production (β = -0.245, P = 0.049), clamp Rd (β = -0.256, P = 0.001) and NOGD (β = -0.257, P = 0.001). The %kcal from trans fat was also negatively related to clamp Rd (β = -0.209, P = 0.008) and NOGD (β = -0.210, P = 0.008). In contrast, the %kcal from polyunsaturated fat (PUFA) was negatively associated with 2-hour glucose levels (β = -0.383, P = 0.001), and positively related to Rd (β = 0.253, P = 0.007) and NOGD (β = 0.246, P = 0.008). Dietary advice to prevent diabetes should consider the underlying pathophysiology of the prediabetic state. PMID:26999667

  2. Urokinase-Treated Antithrombogenic Drains and Optimized Drain Placement in Endoscopic Lumbar Decompressive Surgery.

    PubMed

    Nakamura, Shu; Ikeda, Shoji; Taguchi, Mitsuto

    2016-07-01

    Background Spinal epidural hematoma (SEH) frequently occurs after microendoscopic decompressive laminotomy (MEDL), and a drain may not be functioning sufficiently. Objective To reduce the incidence of SEH after MEDL. Methods  A urokinase-treated antithrombogenic drain, which is available only with a large diameter, was reduced in diameter and used after MEDL. Magnetic resonance imaging (MRI) and computed tomography (CT) were performed 36 to 48 hours after surgery. The size of the SEH was measured by MRI, and the location of the drain tip was assessed by CT scan. After imaging, the drain was removed. Results Use of the urokinase-treated antithrombogenic drain reduced the incidence of SEH. However, the drain was not adequately placed in many cases, limiting the effect of the drainage. When the urokinase-treated antithrombogenic drain was placed contralaterally to the approach side using an unsheathed endoscope, the incidence of SEH was further reduced. Conclusions The urokinase-treated antithrombogenic drain prevented thrombus-related drain obstruction. In addition, unsheathed endoscopic contralateral placement of the drain was effective for SEH prevention. PMID:26935298

  3. Soluble urokinase plasminogen activation receptor - An emerging new biomarker of cardiovascular disease and critical illness

    PubMed Central

    Cyrille, Nicole B.; Villablanca, Pedro A.; Ramakrishna, Harish

    2016-01-01

    Soluble urokinase plasminogen activation receptor (suPAR) is an emerging new biomarker, which has been shown to not only correlate with traditional biomarkers but also outperform CRP at prognosticating CVD. More clinical trials on suPAR is in the future research agenda. PMID:27052059

  4. Delta CK-MB outperforms delta troponin I at 2 hours during the ED rule out of acute myocardial infarction.

    PubMed

    Fesmire, F M

    2000-01-01

    It has been shown that a rise in creatine kinase MB bank (CK-MB) of > or = + 1.6 ng/mL in 2 hours is more sensitive and equally specific for detection of acute myocardial infarction (AMI) as compared with a 2-hour CK-MB > or = 6 ng/mL during the emergency department (ED) evaluation of chest pain. Because cardiac specific troponin I (cTnI) is thought to have similar early release kinetics as compared with CK-MB mass, we undertook a retrospective cohort study in 578 chest pain patients whose baseline CK-MB and cTnI was less than two times the hospital's upper limits of normal and who underwent a 2-hour CK-MB and cTnI to compare sensitivities and specificities of the 2-hour delta CK-MB (deltaCK-MB) and delta cTnI (delta cTnI) for AMI and 30-day Adverse Outcome (AO). Thirty day AO was defined as AMI, life-threatening complication, death, or percutaneous transluminal coronary angioplasty (PTCA)/coronary artery bypass graft (CABG) within 30 days of ED presentation. Optimum delta values were determined by choosing the smallest cutoff value greater than the assay precision where the deltaCK-MB and delta cTnI had a positive likelihood ratio for 30-day AO of > or = 15. A deltaCK-MB > or = +1.5 ng/mL was more sensitive than a deltaTnI > or = +0.2 ng/mL for AMI (87.7% versus 61.4%; P < .0005) and 30-day AO (56.7% versus 42.3%; P < .005). There were no differences in specificities for AMI and 30-day AO. Combining the two tests (MBdelta > or = +1.5 ng/mL and/or a deltaTnI > or = +0.2 ng/mL) resulted in an incremental increase in sensitivity of 89.5% for AMI and 61.9% for AO (P < .005). Patients with either a rise in CK-MB of > or = +1.5 ng/mL or rise in cTnI of > or = +0.2 ng/mL in 2 hours should receive consideration for aggressive antiischemic therapy and further diagnostic testing before making an exclusionary diagnosis of nonischemic chest pain. PMID:10674522

  5. Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

    PubMed Central

    Wang, Fang; Li, Jing; Sinn, Anthony L.; Knabe, William Eric; Khanna, May; Jo, Inha; Silver, Jayne M.; Oh, Kyungsoo; Li, Liwei; Sandusky, George E.; Sledge, George W.; Nakshatri, Harikrishna; Jones, David R.; Pollok, Karen E.; Meroueh, Samy O.

    2011-01-01

    Virtual screening targeting the urokinase receptor (uPAR) led to (3R)-4-cyclohexyl-3-(hexahydrobenzo[d][1,3]dioxol-5-yl)-N-((hexahydrobenzo[d][1,3]dioxol-5-yl)methyl)butan-1-aminium 1 (IPR-1) and 4-(4-((3,5-dimethylcyclohexyl)carbamoyl)-2-(4-isopropylcyclohexyl)pyrazolidin-3-yl)piperidin-1-ium 3 (IPR-69). Synthesis of an analog of 1, namely 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC50 near 30 μM. Both compounds blocked angiogenesis with IC50 of 3 μM. Compounds 2 and 3 inhibited cell growth with IC50 of 6 and 18 μM and induced apoptosis. Biochemical assays revealed lead-like properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 hours. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds. PMID:21851064

  6. Induction of Brain Microvascular Endothelial Cell Urokinase Expression by Cryptococcus neoformans Facilitates Blood-Brain Barrier Invasion

    PubMed Central

    Stie, Jamal; Fox, Deborah

    2012-01-01

    The invasive ability of the blood-borne fungal pathogen Cryptococcus neoformans can be enhanced through interactions with host plasma components, such as plasminogen. Previously we showed by in vitro studies that plasminogen coats the surface of C. neoformans and is converted to the active serine protease, plasmin, by host plasminogen activators. Viable, but not formaldehyde- or sodium azide-killed, cryptococcal strains undergo brain microvascular endothelial cell-dependent plasminogen-to-plasmin activation, which results in enhanced, plasmin-dependent cryptococcal invasion of primary bovine brain microvascular endothelial cells and fungal ability to degrade plasmin substrates. In the present work, brain microvascular endothelial cells cultured with viable, but not killed, cryptococcal strains led to significant increases in both urokinase mRNA transcription and cell-associated urokinase protein expression. Soluble urokinase was also detected in conditioned medium from brain microvascular endothelial cells cultured with viable, but not killed, C. neoformans. Exposure of plasminogen pre-coated viable C. neoformans to conditioned medium from strain-matched brain microvascular endothelial cell-fungal co-cultures resulted in plasminogen-to-plasmin activation and plasmin-dependent cryptococcal invasion. siRNA-mediated silencing of urokinase gene expression or the use of specific inhibitors of urokinase activity abrogated both plasminogen-to-plasmin activation on C. neoformans and cryptococcal-brain microvascular endothelial cell invasion. Our results suggest that pathogen exploitation of the host urokinase-plasmin(ogen) system may contribute to C. neoformans virulence during invasive cryptococcosis. PMID:23145170

  7. Effect of urokinase on the proliferation of primary cultures of human prostatic cells

    SciTech Connect

    Kirchheimer, J.C.; Wojta, J.; Hienert, G.; Christ, G.; Heger, M.E.; Pflueger, H.B.; Binder, B.R.

    1987-11-01

    The effects of exogenously added urokinase type plasminogen activator, tissue type plasminogen activator, plasmin and thrombin on the proliferation of primary cultures of cells derived from prostatic hyperplasia or prostatic carcinomas were investigated by measuring the incorporation of /sup 3/H-thymidine into the cultures. Addition of urokinase type plasminogen activator (1.35 x 10(-9) M) or thrombin (10(-7) M) to the culture medium caused a two-fold increase of /sup 3/H-thymidine incorporation, regardless of the origin of the prostatic cells. Tissue type plasminogen activator did not alter the rate of /sup 3/H-thymidine incorporation, whereas plasmin caused a 25% decrease of /sup 3/H-thymidine incorporation in all cultures.

  8. Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia

    PubMed Central

    Drapkin, Paola T.; O’Riordan, Catherine R.; Yi, Su Min; Chiorini, John A.; Cardella, Jonathan; Zabner, Joseph; Welsh, Michael J.

    2000-01-01

    Developing gene therapy for cystic fibrosis has been hindered by limited binding and endocytosis of vectors by human airway epithelia. Here we show that the apical membrane of airway epithelia express the urokinase plasminogen activator receptor (uPAR). Urokinase plasminogen activator (uPA), or a 7-residue peptide derived from this protein (u7-peptide), bound the receptor and stimulated apical endocytosis. Both ligands enhanced gene transfer by nonspecifically bound adenovirus and adeno-associated virus vectors and by a modified adenovirus vector that had been coupled to the u7-peptide. These data provide the first evidence that targeting an apical receptor can circumvent the two most important barriers to gene transfer in airway epithelia. Thus, the uPA/uPAR system may offer significant advantages for delivering genes and other pharmaceuticals to airway epithelia. PMID:10712430

  9. Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia.

    PubMed

    Drapkin, P T; O'Riordan, C R; Yi, S M; Chiorini, J A; Cardella, J; Zabner, J; Welsh, M J

    2000-03-01

    Developing gene therapy for cystic fibrosis has been hindered by limited binding and endocytosis of vectors by human airway epithelia. Here we show that the apical membrane of airway epithelia express the urokinase plasminogen activator receptor (uPAR). Urokinase plasminogen activator (uPA), or a 7-residue peptide derived from this protein (u7-peptide), bound the receptor and stimulated apical endocytosis. Both ligands enhanced gene transfer by nonspecifically bound adenovirus and adeno-associated virus vectors and by a modified adenovirus vector that had been coupled to the u7-peptide. These data provide the first evidence that targeting an apical receptor can circumvent the two most important barriers to gene transfer in airway epithelia. Thus, the uPA/uPAR system may offer significant advantages for delivering genes and other pharmaceuticals to airway epithelia. PMID:10712430

  10. Design of a 2-Hour Prebreathe Protocol for Space Walks (EVAs) from the International Space Station (ISS)

    NASA Technical Reports Server (NTRS)

    Gernhardt, M. L.; Conkin, J.; Foster, P. P.; Pilmanis, A. A.; Butler, B. D.; Fife, C.; Vann, R. D.; Gerth, W. A.; Loftin, K. C.; Dervay, J.; Waligora, J. M.; Powell, M. R.; Homick, Jerry L. (Technical Monitor)

    2000-01-01

    The majority of extravehicular activities (EVAs) performed from the shuttle use a 10.2 psi staged decompression. The International Space Station (ISS) will operate at 14.7 psi, requiring crews to "campout" in the airlock at 10.2 psi. The constraints associated with campout (crew isolation, oxygen usage, and waste management), provided the rationale to develop a 2-hour prebreathe protocol from 14.7 psi. Previous studies on the affect of microgravity and exercise during prebreathe suggested the feasibility of this approach. Various combinations of adynamia (nonwalking subjects), prebreathe exercise doses, and space suit donning options (10.2 vs. 14.7 psi) were analyzed against timeline and consumable constraints. Prospective decompression sickness (DCS) and venous gas emboli (VGE) accept/reject criteria were defined from statistical analysis of historical DCS data, combined with risk management of DCS under ISS mission circumstances. Maximum operational DCS levels were defined based on protecting for EVA capability with two crew members at 95% confidence, throughout ISS lifetime (within the constraints of NASA DCS disposition policy JPG 1800.3). The accept / reject limits were adjusted for greater safety (including Grade IV VGE criteria) based on analysis of related medical factors. Monte-Carlo simulation was performed to design a closed sequential, multi-center laboratory trial, including the capability of rejecting the primary protocol and testing at least one alternate exercise dose, within the 2-hour prebreathe. The 2-hour protocol incorporates 0, breathing for 5 0 min at 14.7 psi, including 10 min dual cycle ergometry at 75%VO(2max). It requires an additional 30 minO2breathing during depress from 14.7 to 10.2 psi, followed by a 30-60 min suit donning break at 10.2 psi/26.5% O2. It concludes with a 40 min in-suit O2 prebreathe. The protocol would be accepted for operations, if the incidence of DCS was less than 15% and Grade IV VGE less than 20%, both at 95

  11. Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures.

    PubMed

    Pietersen, Lars C; den Dulk, A Claire; Braat, Andries E; Putter, Hein; Korkmaz, Kerem Sebib; Baranski, Andre G; Schaapherder, Alexander F M; Dubbeld, Jeroen; van Hoek, Bart; Ringers, Jan

    2016-04-01

    The aim of the present study was to assess whether flushing the donor liver with urokinase immediately before implantation reduces the incidence of nonanastomotic biliary strictures (NASs) after liver transplantation, without causing increased blood loss, analyzed as a historical cohort study. Between January 2005 and October 2012, all liver (re-)transplantations were included. Of the 185 liver transplant recipients included, 63 donor livers between January 2010 and October 2012 received urokinase (study group), whereas the donor liver of 122 consecutive recipients, who served as a historical control group, between January 2005 and January 2010 did not receive urokinase. Basic donor (Eurotransplant donor risk index) and recipient (age, body mass index, laboratory Model for End-Stage Liver Disease score) characteristics did not significantly differ in both groups. Thirty-three recipients developed NASs: 22 in the control group (18%) and 11 (17.5%) in the study group (P = 0.68). Analyzed separately for donation after circulatory death (P = 0.42) or donation after brain death (P = 0.89), there was no difference between the groups in incidence of NAS. Of all the recipients developing NAS, 7 (21%) needed retransplantation and all others were treated conservatively. Autologous blood transfusion requirements did not differ significantly between both groups (P = 0.91), whereas interestingly, more heterologous blood transfusions were needed in the control group (P < 0.001). This study has its limitations by its retrospective character. A multi-institutional prospective study could clarify this issue. In conclusion, arterial flushing of the liver with urokinase immediately before implantation did not lead to a lower incidence of NAS in this study, nor did it lead to increased blood loss. Liver Transplantation 22 420-426 2016 AASLD. PMID:26600096

  12. [Significance of urokinase and its inhibitors in the invasiveness and metastasing of malignant tumors].

    PubMed

    Halámková, J; Kiss, I; Tomášek, J; Pavlovský, Z; Tuček, S; Penka, M

    2012-02-01

    Fibrinolysis is process, which leads to the degradation of fibrin to fibrin monomers. Fibrinolysis helps to regulate hemostasis and prevents the creation of inappropriately large thrombus, which could reduce blood flow to the bloodstream. The main enzyme involved in fibrinolysis is plasmin. Tissue plasminogen activator (tPA) and urokinase (uPA) are agents converting plasminogen into active plasmin, together with urokinase receptor (uPAR) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) form plasminogen activator system (PAS) which is among others also part of the metastatic cascade and significantly contributes to invasive growth and angiogenesis of malignant tumours. In contrast to tPA that is fundamental in fibrinolysis, uPA plays an essential role in tissue degradation as part of physiological and pathological processes. uPAR is a GPI (glycosylphosphatidylinositol)-anchored protein. The binding of uPA to uPAR results in activation of protein tyrosine kinase, protein kinase C and MAP kinase. At the same time, direct signalling pathway via Jak/STAT cascade utilising signalling transduction of Scr-like protein tyrosine kinase have also been described. uPAR expression is regulated by many growth factors, e.g. EGF, FGF-2 and HGF. It seems that individual PAS factors are involved in the process of rendering malignant tumors invasive. To what degree this influence is essential to specific malignancies, should be answered by further research. In the article the authors present a summary of findings about the interaction of fibrinolysis and tumor process, especially on the effects of urokinase and other activators and their inhibitors in metastasis of malignant tumors. The text contains information on the factors theirs introduction into practice is still the subject of numerous discussions, but in the future, individual PAS factors could play an important role in planning treatment strategies and also could become targets of targeted therapy. PMID

  13. Proteolytic regulation of epithelial sodium channels by urokinase plasminogen activator: cutting edge and cleavage sites.

    PubMed

    Ji, Hong-Long; Zhao, Runzhen; Komissarov, Andrey A; Chang, Yongchang; Liu, Yongfeng; Matthay, Michael A

    2015-02-27

    Plasminogen activator inhibitor 1 (PAI-1) level is extremely elevated in the edematous fluid of acutely injured lungs and pleurae. Elevated PAI-1 specifically inactivates pulmonary urokinase-type (uPA) and tissue-type plasminogen activators (tPA). We hypothesized that plasminogen activation and fibrinolysis may alter epithelial sodium channel (ENaC) activity, a key player in clearing edematous fluid. Two-chain urokinase (tcuPA) has been found to strongly stimulate heterologous human αβγ ENaC activity in a dose- and time-dependent manner. This activity of tcuPA was completely ablated by PAI-1. Furthermore, a mutation (S195A) of the active site of the enzyme also prevented ENaC activation. By comparison, three truncation mutants of the amino-terminal fragment of tcuPA still activated ENaC. uPA enzymatic activity was positively correlated with ENaC current amplitude prior to reaching the maximal level. In sharp contrast to uPA, neither single-chain tPA nor derivatives, including two-chain tPA and tenecteplase, affected ENaC activity. Furthermore, γ but not α subunit of ENaC was proteolytically cleaved at ((177)GR↓KR(180)) by tcuPA. In summary, the underlying mechanisms of urokinase-mediated activation of ENaC include release of self-inhibition, proteolysis of γ ENaC, incremental increase in opening rate, and activation of closed (electrically "silent") channels. This study for the first time demonstrates multifaceted mechanisms for uPA-mediated up-regulation of ENaC, which form the cellular and molecular rationale for the beneficial effects of urokinase in mitigating mortal pulmonary edema and pleural effusions. PMID:25555911

  14. Structural Basis of Interaction Between Urokinase-type Plasminogen Activator and its Receptor

    SciTech Connect

    Barinka,C.; Parry, G.; Callahan, J.; Shaw, D.; Kuo, A.; Cines, B.; Mazar, A.; Lubkowski, J.

    2006-01-01

    Recent studies indicate that binding of the urokinase-type plasminogen activator (uPA) to its high-affinity receptor (uPAR) orchestrates uPAR interactions with other cellular components that play a pivotal role in diverse (patho-)physiological processes, including wound healing, angiogenesis, inflammation, and cancer metastasis. However, notwithstanding the wealth of biochemical data available describing the activities of uPAR, little is known about the exact mode of uPAR/uPA interactions or the presumed conformational changes that accompany uPA/uPAR engagement. Here, we report the crystal structure of soluble urokinase plasminogen activator receptor (suPAR), which contains the three domains of the wild-type receptor but lacks the cell-surface anchoring sequence, in complex with the amino-terminal fragment of urokinase-type plasminogen activator (ATF), at the resolution of 2.8 {angstrom}. We report the 1.9 {angstrom} crystal structure of free ATF. Our results provide a structural basis, represented by conformational changes induced in uPAR, for several published biochemical observations describing the nature of uPAR/uPA interactions and provide insight into mechanisms that may be responsible for the cellular responses induced by uPA binding.

  15. Urokinase perfusion prevents intrahepatic ischemic-type biliary lesion in donor livers

    PubMed Central

    Lang, Ren; He, Qiang; Jin, Zhong-Kui; Han, Dong-Dong; Chen, Da-Zhi

    2009-01-01

    AIM: To evaluate whether urokinase perfusion of non-heart-beating cadaveric donor livers reduces the incidence of intrahepatic ischemic-type biliary lesions (IITBLs). METHODS: A prospective study was conducted to investigate potential microthrombosis in biliary microcirculation when non-heart-beating cadaveric livers were under warm or cold ischemic conditions. The experimental group included 140 patients who underwent liver transplantation during the period of January 2006 to December 2007, and survived for more than 1 year. The control group included 220 patients who received liver transplantation between July 1999 and December 2005 and survived for more than 1 year. In the experimental group, the arterial system of the donor liver was perfused twice with urokinase during cold perfusion and after trimming of the donor liver. The incidence of IITBLs was compared between the two groups. RESULTS: In the control group, the incidence of IITBLs was 5.9% (13/220 cases) after 3-11 mo of transplantation. In the experimental group, two recipients (1.4%) developed IITBLs at 3 and 6 mo after transplantation, respectively. The difference in the incidence between the two groups was statistically significant (P < 0.05). CONCLUSION: Double perfusion of cadaveric livers from non-heart-beating donors with urokinase may reduce the incidence of IITBLs. PMID:19630111

  16. Design and Testing of a 2-Hour Oxygen Prebreathe Protocol for Space Walks from the International Space Station

    NASA Technical Reports Server (NTRS)

    Gernhardt, Michael L.; Conkin, J.; Foster, P. P.; Pilmanis, A. A.; Butler, B. D.; Beltran, E.; Fife, C. E.; Vann, R. D.; Gerth, W. A.; Loftin, K. C.; Paloski, William H. (Technical Monitor)

    2000-01-01

    To develop and test a 2-hour prebreathe protocol for performing extravehicular activities (EVAs) from the International Space Station (ISS). Combinations of adynamia (non-walking), prebreathe exercise, and space suit donning options (10.2 vs. 14.7 psi) were evaluated, against timeline and consumable contraints to develop an operational 2- hour prebreathe protocol. Prospective accept/reject criteria were defined for decompression sickness (DCS) and venous gas emboli (VGE) from analysis of historical DCS data, combined with risk management of DCS under ISS mission circumstances. Maximum operational DCS levels were defined based on protecting for EVA capability with two crew-members at 95% confidence, throughout ISS lifetime (within the constraints of NASA DCS disposition policy JPG 1800.3). The accept/reject limits were adjusted for greater safety based on analysis of related medical factors. Monte-Carlo simulation was performed to design a closed sequential, multi-center human trial. Protocols were tested with 4 different prebreathe exercises (Phases I-IV), prior to exposure to 4.3 psi for 4 hrs. Subject selection, Doppler monitoring for VGE, test termination criteria, and DCS definitions were standardized. Phase I: upper and lower body exercises using dual-cycle ergometry (75% VO2 max for 10 min). Phase II: ergometry plus 24 min of light exercise (simulating space-suit preparations). Phase III: same 24 min of light exercise but no ergometry, and Phase IV: 56 min of light exercise without ergometry. A prebreathe procedure was accepted if, at 95% confidence, the incidence of DCS was less than 15% (with no Type II DCS), and Grade IV VGE was less than 20%.

  17. Tirofiban combined with urokinase selective intra-arterial thrombolysis for the treatment of middle cerebral artery occlusion

    PubMed Central

    FENG, LEI; LIU, JUN; LIU, YUNZHEN; CHEN, JIAN; SU, CHUNHAI; LV, CHUANFENG; WEI, YUZHEN

    2016-01-01

    The aims of the present study were to establish a model of embolic stroke in rabbits and to evaluate the efficacy and safety of intra-arterially administered tirofiban combined with urokinase thrombolysis. The middle cerebral artery occlusion model (MCAO) of embolic stroke was established in New Zealand rabbits via an autologous clot. The model rabbits were allocated at random into four groups: Tirofiban group (T group), urokinase group (UK group), tirofiban and urokinase group (T + UK group) and the control group (C group). The recanalization rate, relative-apparent diffusion coefficient (rADC) and neurological function deficit score (NFDS) values were compared among the four groups. The recanalization rate, rADC and NFDS values were improved in the T + UK group compared with the other groups. In summary, the intra-arterial administration of tirofiban combined with urokinase thrombolysis was a more effective intervention in an MCAO model compared with intra-arterial urokinase alone, and may promote reperfusion and reduce infarct volume. PMID:26998029

  18. Reproducibility of the pulmonary function response of older men and women to a 2-hour ozone exposure

    SciTech Connect

    Bedi, J.F.; Horvath, S.M.; Drechsler-Parks, D.M.

    1988-08-01

    To test the reproducibility of the pulmonary function response to ozone exposure in older individuals, eight men and eight women, average age 62.8 years, participated in three 2-hour exposures to 0.45 ppm ozone at 23.3 C and 62.5 percent relative humidity. The first and second exposures were separated by an average time of 17.2 days, and 27.3 days separated the second and third exposures. Subjects alternated riding a bicycle ergometer for 20 minutes at an average minute ventilation of 26 liters BTPS (body temperature pressure, saturated), with 20-minute rest periods. Forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV-1), and forced expiratory flow between 25 and 75% of FVC (FEF 25-75%) were measured pre and post exposure. The reproducibility of individual pre-post changes were assessed by calculation of the best linear fit and correlation coefficients between exposures. For FVC and FEV-1, the slopes were significantly different from 1, and correlation coefficients not significantly different from zero, implying that older individuals may not respond consistently to similar ozone exposures.

  19. Effects of bacteria involved with the pathogenesis of infection-induced urolithiasis on the urokinase and sialidase (neuraminidase) activity.

    PubMed

    du Toit, P J; van Aswegen, C H; Steyn, P L; Pols, A; du Plessis, D J

    1992-01-01

    It has been hypothesized that urinary urokinase and sialidase may play a role in urolithiasis. If these theories have substance it is to be expected that microorganisms may also affect these enzymes, since the association between urinary tract infection and renal stone formation is well known. It is generally assumed that Proteus mirabilis and Staphylococcus albus, which produce the urea-splitting enzyme urease, are responsible for stone formation. However, the importance of non-urease-producing microorganisms (Escherichia coli and Enterococcus) in urolithiasis is unclear. Spectrophotometric studies were therefore devised to clarify this problem. Microorganisms associated with infection-induced stones (Proteus mirabilis and Escherichia coli) respectively inhibited the urokinase and stimulated the sialidase activity. In contrast, microorganisms which were not associated with infection stones (Bacillus subtilis) had significantly less effect on urokinase and sialidase activity. This study may explain infection-induced stone formation and could open a completely new line of research. PMID:1462476

  20. Role of urokinase and its receptor in basal and stimulated colonic epithelial cell migration in vitro

    PubMed Central

    Wilson, A; Gibson, P

    2000-01-01

    BACKGROUND—Migration of colonic epithelial cells is important for mucosal repair following injury. The urokinase (u-PA) system regulates migration in other cell types.
AIM—To examine the role of u-PA and its receptor (u-PAR) in colonic epithelial cell migration.
METHODS—Migration was assessed over 24 hours in circular wounds made in confluent monolayers of LIM1215 and Caco-2 human colon cancer cells. The function of u-PA and u-PAR was ablated with antisense oligonucleotides to block expression, with synthetic u-PA peptides to block interaction, and with aprotinin to block u-PA mediated proteolysis.
RESULTS—Migration was stimulated two to threefold by exogenous u-PA, an effect dependent on u-PAR binding but independent of u-PA mediated mitogenesis and proteolysis. Expression of u-PA and u-PAR was inhibited by 80% by the appropriate antisense oligonucleotide. Basal migration and the motogenic effects of butyrate, epidermal growth factor, and phorbol-12-myristate-13-acetate were suppressed by the u-PAR antisense oligonucleotide (40-60%) but were at best minimally affected following inhibition of u-PA expression and binding. 
CONCLUSIONS—In an in vitro model of wounded colonic epithelium, u-PAR promotes cell migration through mechanisms that are not exclusively dependent on u-PA binding. Therefore, u-PA and u-PAR may contribute to colonic mucosal repair in vivo.


Keywords: colon; migration; urokinase; urokinase receptor; epidermal growth factor; butyrate; protein kinase C PMID:10861271

  1. Performance of the 2-hour Accelerated Diagnostic Protocol Within the American College of Radiology Imaging Network PA 4005 Cohort

    PubMed Central

    Mahler, Simon A.; Miller, Chadwick D.; Litt, Harold I.; Gatsonis, Constantine A.; Snyder, Bradley S.; Hollander, Judd E.

    2015-01-01

    Objectives The 2-hour accelerated diagnostic protocol (ADAPT) is a decision rule designed to identify emergency department (ED) patients with chest pain for early discharge. Previous studies in the Asia-Pacific region demonstrated high sensitivity (97.9% to 99.7%) for major adverse cardiac events (MACE) at 30 days. The objective of this study was to determine the validity of ADAPT for risk stratification in a cohort of U.S. ED patients with suspected acute coronary syndrome (ACS). Methods A secondary analysis of participants enrolled in the American College of Radiology Imaging Network (ACRIN) PA 4005 trial was conducted. This trial enrolled 1,369 patients at least 30 years old with symptoms suggestive of ACS. All data elements were collected prospectively at the time of enrollment. Each patient was classified as low risk or at risk by ADAPT. Early discharge rate and sensitivity for MACE, defined as cardiac death, myocardial infarction (MI), or coronary revascularization at 30 days, were calculated. Results Of 1,140 patients with complete biomarker data, MACE occurred in 31 patients (2.7%). Among 551 of the 1,140 (48.3%, 95% confidence interval [CI] = 45.4% to 51.3%), ADAPT identified for early discharge; five of the 551 (0.9%, 95% CI = 0.3% to 2.1%) had MACE at 30 days. ADAPT was 83.9% (95% CI = 66.3% to 94.5%) sensitive, identifying 26 of 31 patients with MACE. Of the five patients identified for early discharge by ADAPT with MACE, there were no deaths, one patient with MI, and five with revascularizations. Conclusions In this first North American application of the ADAPT strategy, sensitivity for MACE within 30 days was 83.9%. One missed adverse event was a MI, with the remainder representing coronary revascularizations. The effect of missing revascularization events needs further investigation. PMID:25810343

  2. Urokinase infusion of chronically occluded femoropopliteal Gortex bypass grafts via the popliteal approach.

    PubMed

    Dorros, G; Hall, P; Iyer, S S

    1991-11-01

    Thrombolysis of two occluded above-knee femoropopliteal Gortex bypass grafts utilizing the popliteal approach for catheter placement was successfully performed without complication. In both cases, the proximal anastomoses of the graft could not be identified. A percutaneous popliteal approach was used for catheter placement and delivery of urokinase. Angioplasty was performed on the unveiled stenoses that, presumptively, led to graft closure. Selective thrombolysis via catheter placed from popliteal approach is a new technique for recanalization of occluded femoropopliteal bypass grafts and warrants further investigation. PMID:1764742

  3. Comparison of the Current Diagnostic Criterion of HbA1c with Fasting and 2-Hour Plasma Glucose Concentration

    PubMed Central

    Karnchanasorn, Rudruidee; Huang, Jean; Feng, Wei; Chuang, Lee-Ming

    2016-01-01

    To determine the effectiveness of hemoglobin A1c (HbA1c) ≥ 6.5% in diagnosing diabetes compared to fasting plasma glucose (FPG) ≥ 126 mg/dL and 2-hour plasma glucose (2hPG) ≥ 200 mg/dL in a previously undiagnosed diabetic cohort, we included 5,764 adult subjects without established diabetes for whom HbA1c, FPG, 2hPG, and BMI measurements were collected. Compared to the FPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 43.3% (106 subjects). Compared to the 2hPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 28.1% (110 subjects). Patients who were diabetic using 2hPG criterion but had HbA1c < 6.5% were more likely to be older (64 ± 15 versus 60 ± 15 years old, P = 0.01, mean ± STD), female (53.2% versus 38.2%, P = 0.008), leaner (29.7 ± 6.1 versus 33.0 ± 6.6 kg/m2, P = 0.000005), and less likely to be current smokers (18.1% versus 29.1%, P = 0.02) as compared to those with HbA1c ≥ 6.5%. The diagnostic agreement in the clinical setting revealed the current HbA1c ≥ 6.5% is less likely to detect diabetes than those defined by FPG and 2hPG. HbA1c ≥ 6.5% detects less than 50% of diabetic patients defined by FPG and less than 30% of diabetic patients defined by 2hPG. When the diagnosis of diabetes is in doubt by HbA1c, FPG and/or 2hPG should be obtained. PMID:27597979

  4. Comparison of the Current Diagnostic Criterion of HbA1c with Fasting and 2-Hour Plasma Glucose Concentration.

    PubMed

    Karnchanasorn, Rudruidee; Huang, Jean; Ou, Horng-Yih; Feng, Wei; Chuang, Lee-Ming; Chiu, Ken C; Samoa, Raynald

    2016-01-01

    To determine the effectiveness of hemoglobin A1c (HbA1c) ≥ 6.5% in diagnosing diabetes compared to fasting plasma glucose (FPG) ≥ 126 mg/dL and 2-hour plasma glucose (2hPG) ≥ 200 mg/dL in a previously undiagnosed diabetic cohort, we included 5,764 adult subjects without established diabetes for whom HbA1c, FPG, 2hPG, and BMI measurements were collected. Compared to the FPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 43.3% (106 subjects). Compared to the 2hPG criterion, the sensitivity of HbA1c ≥ 6.5% was only 28.1% (110 subjects). Patients who were diabetic using 2hPG criterion but had HbA1c < 6.5% were more likely to be older (64 ± 15 versus 60 ± 15 years old, P = 0.01, mean ± STD), female (53.2% versus 38.2%, P = 0.008), leaner (29.7 ± 6.1 versus 33.0 ± 6.6 kg/m(2), P = 0.000005), and less likely to be current smokers (18.1% versus 29.1%, P = 0.02) as compared to those with HbA1c ≥ 6.5%. The diagnostic agreement in the clinical setting revealed the current HbA1c ≥ 6.5% is less likely to detect diabetes than those defined by FPG and 2hPG. HbA1c ≥ 6.5% detects less than 50% of diabetic patients defined by FPG and less than 30% of diabetic patients defined by 2hPG. When the diagnosis of diabetes is in doubt by HbA1c, FPG and/or 2hPG should be obtained. PMID:27597979

  5. The Heparin-Induced Thrombocytopenia and Thrombosis Syndrome: Treatment with Intraarterial Urokinase and Systemic Platelet Aggregation Inhibitors

    SciTech Connect

    Murphy, Kenneth D.; McCrohan, Gerard; DeMarta, Deborah A.; Shirodkar, Nitin B.; Kwon, Oun J.; Chopra, Paramjit S.

    1996-03-15

    We report a case of the heparin-induced thrombocytopenia and thrombosis syndrome presenting with acute ischemia of a lower limb. The patient was successfully treated by withdrawal of heparin products, intraarterial urokinase, and platelet anti-aggregation therapy consisting of Dextran and aspirin.

  6. Bound plasminogen is rate-limiting for cell-surface-mediated activation of plasminogen by urokinase.

    PubMed Central

    Namiranian, S; Naito, Y; Kakkar, V V; Scully, M F

    1995-01-01

    The ability of U937 monocyte-like cells and KATO III cells (a human gastric carcinoma line) to potentiate activation of plasminogen by single-chain urokinase-type plasminogen activator (scu-PA), as mediated by the cell receptor for urokinase (u-PAR), was compared. It was observed that, although the concentration of u-PAR on these cell lines differed considerably (U937 cells: 5000 receptors/cell, Kd 0.35 nM; KATO III cells: 400 receptors/cell, Kd 0.85 nM), the rate of activation of plasminogen by scu-PA in the presence of the same density of each cell line was equivalent. From data generated in the presence of increasing concentrations of scu-PA, the kcat, for plasminogen activation in the presence of each cell line was calculated and found to differ by 26-fold (0.36 s-1 on U937 cells; 9.25 s-1 on KATO III cells). However, the Km for plasminogen with respect to the rate of formation of plasmin was lower than the Kd for binding (0.2 microM compared with 0.5 microM on U937 cells; 0.34 microM compared with 1.6 microM on KATO III cells). A rapid transformation from Glu-plasminogen (native plasminogen with N-terminal Glu) to Lys-plasminogen (plasmin-degraded plasminogen with primarily N-terminal Lys-77) occurred on the surface of U937 cells (unlike KATO III cells), but this transition did not coincide with faster rates of plasminogen activation. From this evidence it is concluded that the accessibility of bound plasminogen acts to limit the rate of activation by cell-bound urokinase. The significance of this proposal is that the proteolytic potential of the cell-mediated activation of plasminogen would be controlled by the accessibility of plasminogen for activation rather than by the concentration of u-PAR (the latter may act to localize proteolysis to appropriate domains on the surface of the cell). PMID:7639718

  7. Overexpression of urokinase-type plasminogen activator in transgenic mice is correlated with impaired learning.

    PubMed Central

    Meiri, N; Masos, T; Rosenblum, K; Miskin, R; Dudai, Y

    1994-01-01

    Transgenic mice designated alpha MUPA overproduce in the brain murine urokinase-type plasminogen activator (uPA), an extracellular protease implicated in tissue remodeling. We have now localized, by in situ hybridization, extensive signal of uPA mRNA in the alpha MUPA cortex, hippocampus, and amygdala, sites that were not labeled in counterpart wild-type mice. Furthermore, biochemical measurements reveal a remarkably high level of enzymatic activity of uPA in the cortex and hippocampus of alpha MUPA compared with wild-type mice. We have used the alpha MUPA mice to examine whether the abnormal level of uPA in the cortex and the limbic system affects learning ability. We report that alpha MUPA mice perform poorly in tasks of spatial, olfactory, and taste-aversion learning, while displaying normal sensory and motor capabilities. Our results suggest that uPA is involved in neural processes subserving a variety of learning types. Images PMID:8159723

  8. Ligand Binding Alters Dimerization and Sequestering of Urokinase Receptors in Raft-Mimicking Lipid Mixtures

    PubMed Central

    Ge, Yifan; Siegel, Amanda P.; Jordan, Rainer; Naumann, Christoph A.

    2014-01-01

    Lipid heterogeneities, such as lipid rafts, are widely considered to be important for the sequestering of membrane proteins in plasma membranes, thereby influencing membrane protein functionality. However, the underlying mechanisms of such sequestration processes remain elusive, in part, due to the small size and often transient nature of these functional membrane heterogeneities in cellular membranes. To overcome these challenges, here we report the sequestration behavior of urokinase receptor (uPAR), a glycosylphosphatidylinositol-anchored protein, in a planar model membrane platform with raft-mimicking lipid mixtures of well-defined compositions using a powerful optical imaging platform consisting of confocal spectroscopy XY-scans, photon counting histogram, and fluorescence correlation spectroscopy analyses. This methodology provides parallel information about receptor sequestration, oligomerization state, and lateral mobility with single molecule sensitivity. Most notably, our experiments demonstrate that moderate changes in uPAR sequestration are not only associated with modifications in uPAR dimerization levels, but may also be linked to ligand-mediated allosteric changes of these membrane receptors. Our data show that these modifications in uPAR sequestration can be induced by exposure to specific ligands (urokinase plasminogen activator, vitronectin), but not via adjustment of the cholesterol level in the planar model membrane system. Good agreement of our key findings with published results on cell membranes confirms the validity of our model membrane approach. We hypothesize that the observed mechanism of receptor translocation in the presence of raft-mimicking lipid mixtures is also applicable to other glycosylphosphatidylinositol-anchored proteins. PMID:25418095

  9. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect.

    PubMed Central

    Resnati, M; Guttinger, M; Valcamonica, S; Sidenius, N; Blasi, F; Fazioli, F

    1996-01-01

    Physiological concentrations of urokinase plasminogen activator (uPA) stimulated a chemotactic response in human monocytic THP-1 through binding to the urokinase receptor (uPAR). The effect did not require the protease moiety of uPA, as stimulation was achieved also with the N-terminal fragment (ATF), while the 33 kDa low molecular weight uPA was ineffective. Co-immunoprecipitation experiments showed association of uPAR with intracellular kinase(s), as demonstrated by in vitro kinase assays. Use of specific antibodies identified p56/p59hck as a kinase associated with uPAR in THP-1 cell extracts. Upon addition of ATF, p56/p59hck activity was stimulated within 2 min and returned to normal after 30 min. Since uPAR lacks an intracellular domain capable of interacting with intracellular kinase, activation of p56/p59hck must require a transmembrane adaptor. Evidence for this was strongly supported by the finding that a soluble form of uPAR (suPAR) was capable of inducing chemotaxis not only in THP-1 cells but also in cells lacking endogenous uPAR (IC50, 5 pM). However, activity of suPAR require chymotrypsin cleavage between the N-terminal domain D1 and D2 + D3. Chymotrypsin-cleaved suPAR also induced activation of p56/p59hck in THP-1 cells, with a time course comparable with ATF. Our data show that uPA-induced signal transduction takes place via uPAR, involves activation of intracellular tyrosine kinase(s) and requires an as yet undefined adaptor capable of connecting the extracellular ligand binding uPAR to intracellular transducer(s). Images PMID:8612581

  10. Purification of rabbit kidney cytokinase and a comparison of its properties with human urokinase

    PubMed Central

    Ali, S. Y.; Evans, Lois

    1968-01-01

    1. The cytokinase (tissue activator of plasminogen) content of several mammalian tissues was evaluated by a quantitative casein hydrolysis method. 2. An alkaline (pH10·5) extraction of cytokinase from rabbit kidney lysosome–microsome fraction, followed by chromatography on DEAE-cellulose at pH7·6 with stepwise or linear increase in concentration of phosphate buffer, gave an 86-fold purification of the enzyme. The purified material was non-proteolytic against casein and heated fibrin and was freeze-dried without significant loss of activity or solubility. 3. Cytokinase is a protein with E0·1%1cm.=0·87 at 280mμ, and does not possess sufficient hexose or sialic acid to be classified as a glycoprotein. It has S20,w 2·9–3·1s and molecular weight 50000 when measured on a calibrated Sephadex G-100 column. It has an isoelectric point between pH8 and pH9, and is maximally active and stable at pH8·5. It is inactivated by heat at 78°. 4. Cytokinase and human urokinase have the same Km value and are inhibited in a partially competitive manner by ∈-aminohexanoic acid and aminomethylcyclohexanecarboxylic acid. They are also inhibited by cysteine and arginine, but are unaffected by iodoacetamide and p-chloromercuribenzoate. 5. On the basis of this and other evidence it is suggested that rabbit kidney cytokinase and human urokinase are similar, if not identical, enzymes. PMID:5641883

  11. Urokinase Receptors Promote β1 Integrin Function through Interactions with Integrin α3β1

    PubMed Central

    Wei, Ying; Eble, Johannes A.; Wang, Zemin; Kreidberg, Jordan A.; Chapman, Harold A.

    2001-01-01

    The urokinase receptor (uPAR) is linked to cellular migration through its capacity to promote pericellular proteolysis, regulate integrin function, and mediate cell signaling in response to urokinase (uPA) binding. The mechanisms for these activities remain incompletely defined, although uPAR was recently identified as a cis-acting ligand for the β2 integrin CD11b/CD18 (Mac-1). Here we show that a major β1 integrin partner for uPAR/uPA signaling is α3. In uPAR-transfected 293 cells uPAR complexed (>90%) with α3β1 and antibodies to α3 blocked uPAR-dependent vitronectin (Vn) adhesion. Soluble uPAR bound to recombinant α3β1 in a uPA-dependent manner (Kd < 20 nM) and binding was blocked by a 17-mer α3β1 integrin peptide (α325) homologous to the CD11b uPAR-binding site. uPAR colocalized with α3β1 in MDA-MB-231 cells and uPA (1 nM) enhanced spreading and focal adhesion kinase phosphorylation on fibronectin (Fn) or collagen type I (Col) in a pertussis toxin- and α325-sensitive manner. A critical role of α3β1 in uPA signaling was verified by studies of epithelial cells from α3-deficient mice. Thus, uPAR preferentially complexes with α3β1, promoting direct (Vn) and indirect (Fn, Col) pathways of cell adhesion, the latter a heterotrimeric G protein-dependent mechanism of signaling between α3β1 and other β1 integrins. PMID:11598185

  12. Conformation of one- and two-chain high molecular weight urokinase analyzed by small-angle neutron scattering and vacuum ultraviolet circular dichroism

    SciTech Connect

    Mangel, W.F.; Lin, B.H.; Ramakrishnan, V. )

    1991-05-25

    The structures of one- and two-chain high molecular weight human urokinase were analyzed by small-angle neutron scattering and vacuum ultraviolet circular dichroism. Both one- and two-chain high molecular weight urokinases exhibited a radius of gyration of 31 A and a maximum dimension of 90 A. Neither parameter was affected by the presence of lysine sufficient to saturate all the lysine-binding sites in human plasminogen. These physical parameters are consistent with the sedimentation coefficient of high molecular weight urokinase and indicate that both proteins are highly asymmetric. Neither protein contained much alpha-helix or parallel beta-sheet. Most of the secondary structure was in the form of antiparallel beta-sheet and beta-turns, very similar to the secondary structure of plasminogen. The macroscopic kinetic constants, Km and kcat, for the hydrolysis of (pyroGlu-Gly-Arg-NH)2-rhodamine by two-chain high molecular weight urokinase and low molecular weight urokinase which lacks the epidermal growth factor and kringle domains were similar. These structural and kinetic data are consistent with the domains in both forms of urokinase being independent structural and functional units.

  13. Successful lung transplantation after donor lung reconditioning with urokinase in ex vivo lung perfusion system.

    PubMed

    Inci, Ilhan; Yamada, Yoshito; Hillinger, Sven; Jungraithmayr, Wolfgang; Trinkwitz, Michael; Weder, Walter

    2014-11-01

    Acute pulmonary embolism is considered a contraindication to lung donation for transplantation as it might result in graft dysfunction. Ex vivo lung perfusion (EVLP) is a novel method to assess and recondition a questionable donor graft before transplantation. In this report we present a case of successful bilateral lung transplant after donor lung assessment and treatment with a fibrinolytic agent, urokinase, during EVLP. PMID:25441801

  14. In vitro inhibition of human malignant brain tumour cell line proliferation by anti-urokinase-type plasminogen activator monoclonal antibodies.

    PubMed Central

    Abaza, M. S.; Shaban, F. A.; Narayan, R. K.; Atassi, M. Z.

    1998-01-01

    A brain tumour-associated marker, urokinase (UK), was investigated using rabbit anti-UK polyclonal and murine anti-UK monoclonal antibodies, which were prepared by immunization with low molecular weight UK (LMW-UK) and high molecular weight urokinase (HMW-UK) synthetic peptide respectively. The polyclonal antibody cross-reacted with both LMW-UK and HMW-UK, whereas the murine MAbs were specific for HMW-UK. These immunological probes were used to study urokinase in glioma extracts, tissues, sera and cell lines that had been prepared from primary cultures of freshly dissected gliomas. Radioimmunoassays showed that glioma extracts had much higher level (5- to 44-fold) of UK than normal human brain extracts. This result was confirmed by immunoblotting of electrophoresis gels of glioma and human brain extracts. Immunohistochemical study using anti-UK MAb demonstrated much higher levels of UK in glioma tissue than normal brain tissue. Immunohistochemical study using anti-UK MAbs localized UK on the cell surface of glioma cells. Anti-UK MAbs inhibited the proliferation of AA cell lines and GB cell lines (50% to > 90%) and exerted minor effects (< or = 20%) on normal human liver, intestine and lymphocyte cell lines. Taken together, these results suggest that anti-UK MAbs may have therapeutic potential for human gliomas and cancer metastasis. Images Figure 2 Figure 3 PMID:9862567

  15. Single Amino Acid Substitutions in the Chemotactic Sequence of Urokinase Receptor Modulate Cell Migration and Invasion

    PubMed Central

    Franco, Paola; Pavone, Vincenzo; Mugione, Pietro; Di Carluccio, Gioconda; Masucci, Maria Teresa; Arra, Claudio; Pirozzi, Giuseppe; Stoppelli, Maria Patrizia; Carriero, Maria Vincenza

    2012-01-01

    The receptor for urokinase-type plasminogen activator (uPAR) plays an important role in controlling cell migration. uPAR binds urokinase and vitronectin extracellular ligands, and signals in complex with transmembrane receptors such as Formyl-peptide Receptors (FPR)s and integrins. Previous work from this laboratory has shown that synthetic peptides, corresponding to the uPAR88–92 chemotactic sequence, when carrying the S90P or S90E substitutions, up- or down-regulate cell migration, respectively. To gain mechanistic insights into these opposite cell responses, the functional consequences of S90P and S90E mutations in full-length uPAR were evaluated. First, (HEK)-293 embryonic kidney cells expressing uPARS90P exhibit enhanced FPR activation, increased random and directional cell migration, long-lasting Akt phosphorylation, and increased adhesion to vitronectin, as well as uPAR/vitronectin receptor association. In contrast, the S90E substitution prevents agonist-triggered FPR activation and internalization, decreases binding and adhesion to vitronectin, and inhibits uPAR/vitronectin receptor association. Also, 293/uPARS90P cells appear quite elongated and their cytoskeleton well organized, whereas 293/uPARS90E cells assume a large flattened morphology, with random orientation of actin filaments. Interestingly, when HT1080 cells co-express wild type uPAR with uPAR S90E, the latter behaves as a dominant-negative, impairing uPAR-mediated signaling and reducing cell wound repair as well as lung metastasis in nude mice. In contrast, signaling, wound repair and in vivo lung metastasis of HT1080 cells bearing wild type uPAR are enhanced when they co-express uPARS90P. In conclusion, our findings indicate that Ser90 is a critical residue for uPAR signaling and that the S90P and S90E exert opposite effects on uPAR activities. These findings may be accommodated in a molecular model, in which uPARS90E and uPARS90P are forced into inactive and active forms, respectively

  16. Targeting of peptide conjugated magnetic nanoparticles to urokinase plasminogen activator receptor (uPAR) expressing cells

    NASA Astrophysics Data System (ADS)

    Hansen, Line; Unmack Larsen, Esben Kjær; Nielsen, Erik Holm; Iversen, Frank; Liu, Zhuo; Thomsen, Karen; Pedersen, Michael; Skrydstrup, Troels; Nielsen, Niels Chr.; Ploug, Michael; Kjems, Jørgen

    2013-08-01

    Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are currently being used as a magnetic resonance imaging (MRI) contrast agent in vivo, mainly by their passive accumulation in tissues of interest. However, a higher specificity can ideally be achieved when the nanoparticles are targeted towards cell specific receptors and this may also facilitate specific drug delivery by an enhanced target-mediated endocytosis. We report efficient peptide-mediated targeting of magnetic nanoparticles to cells expressing the urokinase plasminogen activator receptor (uPAR), a surface biomarker for poor patient prognosis shared by several cancers including breast, colorectal, and gastric cancers. Conjugation of a uPAR specific targeting peptide onto polyethylene glycol (PEG) coated USPIO nanoparticles by click chemistry resulted in a five times higher uptake in vitro in a uPAR positive cell line compared to nanoparticles carrying a non-binding control peptide. In accordance with specific receptor-mediated recognition, a low uptake was observed in the presence of an excess of ATF, a natural ligand for uPAR. The uPAR specific magnetic nanoparticles can potentially provide a useful supplement for tumor patient management when combined with MRI and drug delivery.Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are currently being used as a magnetic resonance imaging (MRI) contrast agent in vivo, mainly by their passive accumulation in tissues of interest. However, a higher specificity can ideally be achieved when the nanoparticles are targeted towards cell specific receptors and this may also facilitate specific drug delivery by an enhanced target-mediated endocytosis. We report efficient peptide-mediated targeting of magnetic nanoparticles to cells expressing the urokinase plasminogen activator receptor (uPAR), a surface biomarker for poor patient prognosis shared by several cancers including breast, colorectal, and gastric cancers. Conjugation of a uPAR specific

  17. Posttranscriptional regulation of urokinase receptor mRNA: identification of a novel urokinase receptor mRNA binding protein in human mesothelioma cells.

    PubMed Central

    Shetty, S; Kumar, A; Idell, S

    1997-01-01

    Treatment of human pleural mesothelioma (MS-1) cells with phorbol myristate acetate (PMA) and cycloheximide results in 17- and 10-fold, respectively, increases in steady-state expression of urokinase-type plasminogen activator receptor (uPAR) mRNA. Studies of transcriptional inhibition by actinomycin D showed four- and sixfold extensions of uPAR mRNA half-life in MS-1 cells treated with PMA and cycloheximide, respectively, suggesting that uPAR gene expression involves a posttranscriptional regulatory mechanism. Using gel mobility shift and UV cross-linking assays, we identified a 50-kDa uPAR mRNA binding protein (uPAR mRNABp) that selectively bound to a 51-nucleotide (nt) fragment of mRNA corresponding to the uPAR coding region. We investigated the possibility that this 51-nt protein binding fragment of uPAR mRNA contains regulatory information for message stability. Chimeric beta-globin/uPAR/beta-globin mRNA containing the 51-nt protein binding fragment was able to destabilize otherwise stable beta-globin mRNA. Conversely, a control chimeric beta-globin/uPAR/beta-globin mRNA containing a 51-nt fragment of the uPAR coding region that does not bind uPAR mRNABp was stable under identical conditions. Binding of uPAR mRNABp to uPAR mRNA was abolished after treatment with cycloheximide and rapidly down-regulated by PMA. These data suggest that the 51-nt protein binding fragment of uPAR mRNA may be involved in mRNA turnover as well as in cycloheximide-induced uPAR message stabilization. Our results indicate a novel mechanism of uPAR gene regulation in which cis elements within a 51-nt coding region interact with a uPAR mRNABp to regulate uPAR message stability. PMID:9032234

  18. Percutaneous treatment of intrabdominal abscess: urokinase versus saline serum in 100 cases using two surgical scoring systems in a randomized trial.

    PubMed

    Laborda, A; De Gregorio, M A; Miguelena, J M; Medrano, J; Gómez-Arrue, J; Serrano, C; de Blas, I; Gimenez, M; D'Agostino, H

    2009-07-01

    The purpose of this study was to assess whether regular instillation of urokinase during abscess drainage leads to an improved outcome compared to saline irrigation alone. One hundred patients referred for image-guided abdominal abscess drainage were randomized between thrice daily urokinase instillation or saline irrigation alone. At the end of the study, patient medical records were reviewed to determine drainage, study group, Altona (PIA II) and Mannheim (MPI) scoring, duration of drainage, procedure-related complications, hospital stay duration, and clinical outcome. The technical success rate of the percutaneous abscess drainage was 100%. The success or failure of abscess remission did not differ significantly between groups (success rate of 91.5% in the urokinase group vs. 88.8% in the saline group; failure rate was of 8.5 vs. 21.2%, respectively); however, days of drainage, main hospital stay, and overall costs were significantly reduced in patients treated with urokinase compared to the control group (P < 0.05). No adverse effects from urokinase were observed. Surgical scores were a useful homogeneity factor, and MPI showed a good correlation with prognosis, while PIA results did not have a significant correlation. For drainage of complex abscesses (loculations, hemorrhage, viscous material), fibrinolytics safely accelerate drainage and recovery, reducing the length of the hospital stay and, therefore, the total cost. PMID:19190912

  19. Soluble Urokinase Receptors in Focal Segmental Glomerulosclerosis: A Review on the Scientific Point of View

    PubMed Central

    Saleem, Moin A.; Meijers, Björn

    2016-01-01

    Focal segmental glomerulosclerosis (FSGS) is one of the primary glomerular disorders in both children and adults which can progress to end-stage renal failure. Although there are genetic and secondary causes, circulating factors have also been regarded as an important factor in the pathogenesis of FSGS, because about 40% of the patients with FSGS have recurrence after renal transplantation. Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble form of uPAR, which is a membrane-bound protein linked to GPI in various immunologically active cells, including podocytes. It has recently been suggested as a potential circulating factor in FSGS by in vitro podocyte experiments, in vivo mice models, and human studies. However, there have also been controversies on this issue, because subsequent studies showed conflicting results. suPAR levels were also increased in patients with other glomerular diseases and were inversely correlated with estimated glomerular filtration rate. Nevertheless, there has been no balanced review on this issue. In this review, we compare the conflicting data on the involvement of suPAR in the pathogenesis of FSGS and shed light on interpretation by taking into account many points and the potential variables and confounders influencing serum suPAR levels. PMID:27504461

  20. Density enhanced phosphatase-1 down-regulates urokinase receptor surface expression in confluent endothelial cells

    PubMed Central

    Brunner, Patrick M.; Heier, Patricia C.; Mihaly-Bison, Judit; Priglinger, Ute; Binder, Bernd R.

    2011-01-01

    VEGF165, the major angiogenic growth factor, is known to activate various steps in proangiogenic endothelial cell behavior, such as endothelial cell migration and invasion, or endothelial cell survival. Thereby, the urokinase-type plasminogen activator (uPA) system has been shown to play an essential role not only by its proteolytic capacities, but also by induction of intracellular signal transduction. Therefore, expression of its cell surface receptor uPAR is thought to be an essential regulatory mechanism in angiogenesis. We found that uPAR expression on the surface of confluent endothelial cells was down-regulated compared with subconfluent proliferating endothelial cells. Regulation of uPAR expression was most probably affected by extracellular signal-regulated kinase 1/2 (ERK1/2) activation, a downstream signaling event of the VEGF/VEGF-receptor system. Consistently, the receptor-like protein tyrosine phosphatase DEP-1 (density enhanced phosphatase-1/CD148), which is abundantly expressed in confluent endothelial cells, inhibited the VEGF-dependent activation of ERK1/2, leading to down-regulation of uPAR expression. Overexpression of active ERK1 rescued the DEP-1 effect on uPAR. That DEP-1 plays a biologic role in angiogenic endothelial cell behavior was demonstrated in endothelial cell migration, proliferation, and capillary-like tube formation assays in vitro. PMID:21304107

  1. [Preparation of novel magnetic dextran affinity adsorbents and their application to purify urokinase].

    PubMed

    Dong, Y S; Liang, F; Yu, X Y; Guo, L A; Chang, J H

    2001-01-01

    The reverse phase suspension and embedment technique were adopted to prepare magnetic dextran microsphere (MDMS). The dispersion medium was mixture of some organic solvents. Span-80 was used as stabilizer. The aqueous dextran with magnetic fluid was suspended in dispersion medium with epichlorohydrin as cross-linking reagent. The mixture was stirred for 30 minutes at room temperature and then heated at 70 degrees C for 4 hours, MDMS was thus obtained. MDMS was activated by epichlorohydrin on which 6-aminohexanoic acid, glycine or ethylene diamine was bonded as spacers. Then it was coupled with p-aminobenzamide, L-arginine methyl ester or guanidohexanoic acid and five magnetic affinity adsorbents were prepared. The MDMS was polydisperse particles with the size of 50-300 meshes and the content of Fe3O4 was about 6.2 per cent in the MDMS. Influence of some parameters such as viscosity and density of organic phase, the volume ratio of organic and aqueous phase, the quantity of surfactant and stirring speed on preparing MDMS was studied. Magnetic affinity adsorbents were used to purify crude urokinase in a bath mode and the effect of coupling reagents and ligands on results of purification was discussed. The bioactivity recovery was 40.0 to 60.7 per cent, the purification-fold was between 14.9 and 32.8, and the adsorptive capacity varies from 89 mg to 121 mg per milliliter of adsorbent. PMID:12541840

  2. Challenges for drug discovery - a case study of urokinase receptor inhibition

    PubMed Central

    Chen, Zhuo; Lin, Lin; Huai, Qing; Huang, Mingdong

    2009-01-01

    Urokinase receptor (uPAR) is a widely recognized target for potential treatment of cancer. The development of uPAR inhibitors has been going on for over a decade. Despite the identification and validation of many highly potent hits using screening or medicinal approaches, none of them has been moved further along the drug discovery pipeline. The development of uPAR inhibitors exemplifies several challenges now faced by drug discovery. These include 1) hydrophobicity and thus poor bioavailability of the inhibitors from screening approaches; 2) specificity of the inhibitor, where a peptidyl inhibitor causes conformational change of the receptor; 3) species specificity, where some inhibitors developed based on the human receptor do not inhibit the murine receptor and thus cannot be validated in mouse models. The recently determined crystal structures of uPAR in complex with its ligand or inhibitor not only provide the structural insight to understand these challenges but also offer a potential solution for further inhibitor development and thus illustrate the importance of structural information in facilitating drug discovery. PMID:20025562

  3. Tyk2 mediates effects of urokinase on human vascular smooth muscle cell growth

    SciTech Connect

    Patecki, Margret; Schaewen, Markus von; Tkachuk, Sergey; Jerke, Uwe; Dietz, Rainer; Dumler, Inna; Kusch, Angelika . E-mail: angelika.kusch@charite.de

    2007-08-03

    The urokinase (uPA)/uPA receptor (uPAR) system plays a role in the response of the vessel wall to injury, presumably by modulating vascular smooth muscle cell (VSMC) functional behaviour. The Jak/Stat signaling pathway has been implicated to mediate the uPA/uPAR-directed cell migration and proliferation in VSMC. We have therefore investigated the underlying molecular mechanisms, which remained not completely understood. In particular, we aimed at identification of the kinase involved in the signaling cascade leading to Stat1 phosphorylation by uPA and its impact on VSMC growth. We performed expression in VSMC of kinase-deficient mutant forms of the Janus kinases Jak1 and Tyk2 and used different cell culture models imitating the response to vascular injury. We provide evidence that Tyk2, but not Jak1, mediates uPA-induced Stat1 phosphorylation and VSMC growth inhibition and suggest a novel function for Tyk2 as an important modulator of the uPA-directed VSMC functional behaviour at the place of injury.

  4. Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin.

    PubMed

    De Lorenzi, Valentina; Sarra Ferraris, Gian Maria; Madsen, Jeppe B; Lupia, Michela; Andreasen, Peter A; Sidenius, Nicolai

    2016-07-01

    Components of the plasminogen activation system including urokinase (uPA), its inhibitor (PAI-1) and its cell surface receptor (uPAR) have been implicated in a wide variety of biological processes related to tissue homoeostasis. Firstly, the binding of uPA to uPAR favours extracellular proteolysis by enhancing cell surface plasminogen activation. Secondly, it promotes cell adhesion and signalling through binding of the provisional matrix protein vitronectin. We now report that uPA and plasmin induces a potent negative feedback on cell adhesion through specific cleavage of the RGD motif in vitronectin. Cleavage of vitronectin by uPA displays a remarkable receptor dependence and requires concomitant binding of both uPA and vitronectin to uPAR Moreover, we show that PAI-1 counteracts the negative feedback and behaves as a proteolysis-triggered stabilizer of uPAR-mediated cell adhesion to vitronectin. These findings identify a novel and highly specific function for the plasminogen activation system in the regulation of cell adhesion to vitronectin. The cleavage of vitronectin by uPA and plasmin results in the release of N-terminal vitronectin fragments that can be detected in vivo, underscoring the potential physiological relevance of the process. PMID:27189837

  5. Terminalia catappa attenuates urokinase-type plasminogen activator expression through Erk pathways in Hepatocellular carcinoma

    PubMed Central

    2014-01-01

    Background The survival rate of malignant tumors, and especially hepatocellular carcinoma (HCC), has not improved primarily because of uncontrolled metastasis. In our previous studies, we have reported that Terminalia catappa leaf extract (TCE) exerts antimetastasis effects on HCC cells. However, the molecular mechanisms of urokinase-type plasminogen activator (u-PA) in HCC metastasis have not been thoroughly investigated, and remain poorly understood. Methods The activities and protein levels of u-PA were determined by casein zymography and western blotting. Transcriptional levels of u-PA were detected by real-time PCR and promoter assays. Results We found that treatment of Huh7 cells with TCE significantly reduced the activities, protein levels and mRNA levels of u-PA. A chromatin immunoprecipitation (ChIP) assay showed that TCE inhibited the transcription protein of nuclear factors SP-1 and NF-κB. TCE also did inhibit the effects of u-PA by reducing the phosphorylation of ERK1/2 pathway. Conclusions These results show that u-PA expression may be a potent therapeutic target in the TCE-mediated suppression of HCC metastasis. PMID:24886639

  6. Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes.

    PubMed

    Alfano, Massimo; Cinque, Paola; Giusti, Guido; Proietti, Silvia; Nebuloni, Manuela; Danese, Silvio; D'Alessio, Silvia; Genua, Marco; Portale, Federica; Lo Porto, Manuela; Singhal, Pravin C; Rastaldi, Maria Pia; Saleem, Moin A; Mavilio, Domenico; Mikulak, Joanna

    2015-01-01

    Increased plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) was associated recently with focal segmental glomerulosclerosis (FSGS). In addition, different clinical studies observed increased concentration of suPAR in various glomerular diseases and in other human pathologies with nephrotic syndromes such as HIV and Hantavirus infection, diabetes and cardiovascular disorders. Here, we show that suPAR induces nephrin down-modulation in human podocytes. This phenomenon is mediated only by full-length suPAR, is time-and dose-dependent and is associated with the suppression of Wilms' tumor 1 (WT-1) transcription factor expression. Moreover, an antagonist of αvβ3 integrin RGDfv blocked suPAR-induced suppression of nephrin. These in vitro data were confirmed in an in vivo uPAR knock out Plaur(-/-) mice model by demonstrating that the infusion of suPAR inhibits expression of nephrin and WT-1 in podocytes and induces proteinuria. This study unveiled that interaction of full-length suPAR with αvβ3 integrin expressed on podocytes results in down-modulation of nephrin that may affect kidney functionality in different human pathologies characterized by increased concentration of suPAR. PMID:26380915

  7. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease

    PubMed Central

    Spinale, Joann M.; Mariani, Laura H.; Kapoor, Shiv; Zhang, Jidong; Weyant, Robert; Song, Peter X.; Wong, Hetty N.; Troost, Jonathan P.; Gadegbeku, Crystal A.; Gipson, Debbie S.; Kretzler, Matthias; Nihalani, Deepak; Holzman, Lawrence B.

    2014-01-01

    It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 hours. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multi-center observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared to other diagnoses. Thus, these results do not support a pathological role for suPAR in FSGS. PMID:25354239

  8. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease.

    PubMed

    Spinale, Joann M; Mariani, Laura H; Kapoor, Shiv; Zhang, Jidong; Weyant, Robert; Song, Peter X; Wong, Hetty N; Troost, Jonathan P; Gadegbeku, Crystal A; Gipson, Debbie S; Kretzler, Matthias; Nihalani, Deepak; Holzman, Lawrence B

    2015-03-01

    It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 h. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multicenter observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria, and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared with other diagnoses. Thus these results do not support a pathological role for suPAR in FSGS. PMID:25354239

  9. Regulation of plasminogen activator inhibitor-1 and urokinase by hyaluronan fragments in mouse macrophages.

    PubMed

    Horton, M R; Olman, M A; Bao, C; White, K E; Choi, A M; Chin, B Y; Noble, P W; Lowenstein, C J

    2000-10-01

    Pulmonary inflammation and fibrosis are characterized by increased turnover and production of the extracellular matrix as well as an impairment of lung fibrinolytic activity. Although fragments of the extracellular matrix component hyaluronan induce macrophage production of inflammatory mediators, the effect of hyaluronan on the fibrinolytic mediators plasminogen activator inhibitor (PAI)-1 and urokinase-type plasminogen activator (uPA) is unknown. This study demonstrates that hyaluronan fragments augment steady-state mRNA, protein, and inhibitory activity of PAI-1 as well as diminish the baseline levels of uPA mRNA and inhibit uPA activity in an alveolar macrophage cell line. Hyaluronan fragments alter macrophage expression of PAI-1 and uPA at the level of gene transcription. Similarly, hyaluronan fragments augment PAI-1 and diminish uPA mRNA levels in freshly isolated inflammatory alveolar macrophages from bleomycin-treated rats. These data suggest that hyaluronan fragments influence alveolar macrophage expression of PAI-1 and uPA and may be a mechanism for regulating fibrinolytic activity during lung inflammation. PMID:11000131

  10. Electroanalysis of pM-levels of urokinase plasminogen activator in serum by phosphorothioated RNA aptamer.

    PubMed

    Jarczewska, Marta; Kékedy-Nagy, László; Nielsen, Jesper S; Campos, Rui; Kjems, Jørgen; Malinowska, Elżbieta; Ferapontova, Elena E

    2015-06-01

    Protein biomarkers of cancer allow a dramatic improvement in cancer diagnostics as compared to the traditional histological characterisation of tumours by enabling a non-invasive analysis of cancer development and treatment. Here, an electrochemical label-free assay for urokinase plasminogen activator (uPA), a universal biomarker of several cancers, has been developed based on the recently selected uPA-specific fluorinated RNA aptamer, tethered to a gold electrode via a phosphorothioated dA tag, and soluble redox indicators. The binding properties of the uPA-aptamer couple and interference from the non-specific adsorption of bovine serum albumin (BSA) were modulated by the electrode surface charge. A nM uPA electroanalysis at positively charged surfaces, complicated by the competitive adsorption of BSA, was tuned to the pM uPA analysis at negative surface charges of the electrode, being improved in the presence of negatively charged BSA. The aptamer affinity for uPA displayed via the binding/dissociation constant relationship correspondingly increased, ca. three orders of magnitude, from 0.441 to 367. Under optimal conditions, the aptasensor allowed 10(-12)-10(-9) M uPA analysis, also in serum, being practically useful for clinical applications. The proposed strategy for optimization of the electrochemical protein sensing is of particular importance for the assessment and optimization of in vivo protein ligand binding by surface-tethered aptamers. PMID:25620243

  11. The steady states and dynamics of urokinase-mediated plasmin activation.

    PubMed

    Venkatraman, Lakshmi; Yu, Hanry; Bhowmick, Sourav S; Dewey, Forbes; Tucker-Kellogg, Lisa

    2010-01-01

    Plasmin and urokinase-type plasminogen activator (uPA) are ubiquitous proteases regulating the extracellular environment. They can activate each other via proteolytic cleavage, suggesting the potential for complex dynamic behaviors that could be elucidated by computational modeling. Ordinary differential equations are constructed to model the activation dynamics of plasminogen into plasmin, and single-chain uPA (scUPA) into two-chain uPA (tcUPA). Computational simulations and phase plane analysis reveal two stable steady states for the activation of each protein. Bifurcation analysis shows the in silico system to be bistable. Cell-free experiments verify the system to have ultrasensitive activation behavior, where scUPA is the stimulus and plasmin the output. Furthermore, two significantly different steady states could be seen in vitro for the same stimulus levels, depending on the initial activation level of the plasmin. The switch-like dynamics of the uPA-plasmin system could have potential relevance to many normal and disease processes including angiogenesis, migration and metastasis, wound healing and fibrosis. PMID:19908371

  12. Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.

    PubMed

    Bao, Ying-Na; Cao, Xue; Luo, Dong-Hua; Sun, Rui; Peng, Li-Xia; Wang, Lin; Yan, Yong-Pan; Zheng, Li-Sheng; Xie, Ping; Cao, Yun; Liang, Ying-Ying; Zheng, Fang-Jing; Huang, Bi-Jun; Xiang, Yan-Qun; Lv, Xing; Chen, Qiu-Yan; Chen, Ming-Yuan; Huang, Pei-Yu; Guo, Ling; Mai, Hai-Qiang; Guo, Xiang; Zeng, Yi-Xin; Qian, Chao-Nan

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China and Southeast Asia, with the highest metastasis rate among head and neck cancers. The mechanisms underlying NPC progression remain poorly understood. Genome-wide expression profiling on 18 NPC vs. 18 noncancerous nasopharyngeal tissues together with GeneGo pathway analysis and expression verification in NPC cells and tissues revealed a potential role of urokinase-type plasminogen activator receptor (uPAR) in NPC progression, which has not been investigated in NPC. We then observed that uPAR expression is increased in poorly differentiated, highly metastatic NPC cells compared with lowly metastatic cells or differentiated NPC cells. In vitro studies demonstrated that uPAR regulates NPC cell growth, colony formation, migration, and invasion and promotes the epithelial-mesenchymal transition (EMT). Additional tumor xenograft and spontaneous metastasis experiments revealed that uPAR promotes NPC cell growth and metastasis in vivo. The JAK-STAT pathway is involved in uPAR-regulated signaling in NPC cells as determined by immunoblotting. Moreover, uPAR-mediated growth and motility is partially abolished upon treatment with the Jak1/Jak2 inhibitor INCB018424. We suppressed uPA expression in uPAR-overexpressing NPC cells and found that uPAR-mediated cellular growth and motility is not exclusively dependent on uPA. In summary, uPAR is a significant regulator of NPC progression and could serve as a promising therapeutic target. PMID:24763226

  13. Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway.

    PubMed

    Graham, C H; Fitzpatrick, T E; McCrae, K R

    1998-05-01

    Hypoxia underlies a number of biologic processes in which cellular migration and invasion occur. Because earlier studies have shown that the receptor for urokinase-type plasminogen activator (uPAR) may facilitate such events, we studied the effect of hypoxia on the expression of uPAR by first trimester human trophoblasts (HTR-8/SVneo) and human umbilical vein endothelial cells (HUVEC). Compared with control cells cultured under standard conditions (20% O2), HTR-8/SVneo cells and HUVEC cultured in 1% O2 expressed more uPAR, as determined by flow cytometric and [125I]-prourokinase ligand binding analyses. Increased uPAR expression paralleled increases in uPAR mRNA. The involvement of a heme protein in the hypoxia-induced expression of uPAR was suggested by the observations that culture of cells with cobalt chloride, or sodium 4, 5-dihydroxybenzene-1,3-disulfonate (Tiron), an iron-chelating agent, also stimulated uPAR expression, and that the hypoxia-induced uPAR expression was inhibited by adding carbon monoxide to the hypoxic atmosphere. Culture of HTR-8/SVneo cells with vascular endothelial growth factor (VEGF) did not increase uPAR mRNA levels, suggesting that the hypoxia-mediated effect on uPAR expression by these cells did not occur through a VEGF-dependent mechanism. The functional importance of these findings is suggested by the fact that HTR-8/SVneo cells cultured under hypoxia displayed higher levels of cell surface plasminogen activator activity and greater invasion through a reconstituted basement membrane. These results suggest that hypoxia may promote cellular invasion by stimulating the expression of uPAR through a heme protein-dependent pathway. PMID:9558386

  14. Preclinical evaluation of a urokinase plasminogen activator receptor-targeted nanoprobe in rhesus monkeys

    PubMed Central

    Chen, Yushu; Gong, Li; Gao, Ning; Liao, Jichun; Sun, Jiayu; Wang, Yuqing; Wang, Lei; Zhu, Pengjin; Fan, Qing; Wang, Yongqiang Andrew; Zeng, Wen; Mao, Hui; Yang, Lily; Gao, Fabao

    2015-01-01

    Purpose To translate a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator receptor-targeted magnetic iron oxide (IO) nanoparticles (uPAR-targeted human ATF-IONPs) into clinical applications, we conducted a pilot study to evaluate the toxicity and pharmacokinetics of this nanoparticle in normal rhesus monkeys. Methods We assessed the changes in the following: magnetic resonance imaging (MRI) signals from pretreatment stage to 14 days posttreatment, serum iron concentrations from 5 minutes posttreatment to 12 weeks posttreatment, routine blood examination and serum chemistry analysis results from pretreatment stage to 12 weeks after administration, and results of staining of the liver with Perls’ Prussian Blue and hematoxylin–eosin at 24 hours and 3 months posttreatment in two rhesus monkeys following an intravenous administration of the targeted nanoparticles either with a polyethylene glycol (ATF-PEG-IONP) or without a PEG (ATF-IONP) coating. Results The levels of alkaline phosphatase, alanine transaminase, and direct bilirubin in the two monkeys increased immediately after the administration of the IONPs but returned to normal within 20 days and stayed within the normal reference range 3 months after the injection. The creatinine levels of the two monkeys stayed within the normal range during the study. In addition, red blood cells, white blood cells, hemoglobin level, and platelets remained normal during the 3 months of the study. Conclusion All of the results suggest that a transient injury in terms of normal organ functions, but no microscopic necrotic lesions, was observed at a systemic delivery dose of 5 mg/kg of iron equivalent concentration in the acute phase, and that no chronic toxicity was found 3 months after the injection. Therefore, we conclude that uPAR-targeted IONPs have the potential to be used as receptor-targeted MRI contrasts as well as theranostic agents for the detection and treatment of

  15. A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation

    PubMed Central

    Fuentes, Rudy E.; Zaitsev, Sergei; Ahn, Hyun Sook; Hayes, Vincent; Kowalska, M. Anna; Lambert, Michele P.; Wang, Yuhuan; Siegel, Donald L.; Bougie, Daniel W.; Aster, Richard H.; Myers, Daniel D.; Stepanova, Victoria; Cines, Douglas B.; Muzykantov, Vladimir R.; Poncz, Mortimer

    2015-01-01

    The use of fibrinolytic agents to prevent new thrombus formation is limited by an increased risk of bleeding due to lysis of hemostatic clots that prevent hemorrhage in damaged blood vessels. We sought to develop an agent that provides thromboprophylaxis without carrying a significant risk of causing systemic fibrinolysis or disrupting hemostatic clots. We previously showed that platelet (PLT) α granule–delivered urokinase plasminogen activator (uPA) is highly effective in preventing thrombosis, while being associated with little systemic fibrinolysis or bleeding. Here, we generated a chimeric prodrug composed of a single-chain version of the variable region of an anti-αIIbβ3 mAb fused to a thrombin-activatable, low-molecular-weight pro-uPA (PLT/uPA-T). PLT/uPA-T recognizes human αIIbβ3 on both quiescent and activated platelets and is enzymatically activated specifically by thrombin. We found that this prodrug binds tightly to human platelets even after gel filtration, has a prolonged half-life in mice transgenic for human αIIb compared with that of uPA-T, and prevents clot formation in a microfluidic system. Importantly, in two murine injury models, PLT/uPA-T did not lyse preexisting clots, even when administration was delayed by as little as 10 minutes, while it concurrently prevented the development of nascent thrombi. Thus, PLT/uPA-T represents the prototype of a platelet-targeted thromboprophylactic agent that selectively targets nascent over preexisting thrombi. PMID:26690701

  16. Urokinase, a constitutive component of the inflamed synovial fluid, induces arthritis

    PubMed Central

    Jin, Tao; Tarkowski, Andrej; Carmeliet, Peter; Bokarewa, Maria

    2003-01-01

    Urokinase plasminogen activator (uPA) is an important regulator of fibrinolysis in synovial fluid. An increase of uPA activity and expression of its receptor have been reported in joints of patients with rheumatoid arthritis (RA). The aim of the present study was to assess the arthritogenic capacity of uPA and the mechanisms by which this effect is mediated. uPA was injected into the knee joints of healthy mice, and morphological signs of arthritis were assessed 4 days after the injection. The prerequisite of different leukocyte populations for the development of uPA-triggered arthritis was assessed by selective cell depletion. The inflammatory capacity of uPA was assessed in vitro. Finally, levels of uPA were measured in 67 paired blood and synovial fluid samples from RA patients. The synovial fluid from RA patients displayed higher levels of uPA compared with blood samples. Morphological signs of arthritis were found in 72% of uPA-injected joints compared with in only 18% of joints injected with PBS (P < 0.05). Synovitis was characterised by infiltration of CD4-Mac-1+ mononuclear cells, by the formation of pannus and by occasional cartilage destruction. The absence of monocytes and lymphocytes diminished the frequency of synovitis (P < 0.01), indicating an arthritogenic role of both these leukocyte populations. Synthetic uPA inhibitor downregulated the incidence of uPA-triggered arthritis by 50%. uPA induced arthritis, stimulating the release of proinflammatory cytokines IL-6, IL-1β and tumour necrosis factor alpha. Accumulation of uPA locally in the joint cavity is a typical finding in erosive RA. uPA exerts potent arthritogenic properties and thus may be viewed as one of the essential mediators of joint inflammation. PMID:12716448

  17. Probing Binding and Cellular Activity of Pyrrolidinone and Piperidinone Small Molecules Targeting the Urokinase Receptor

    PubMed Central

    Mani, Timmy; Liu, Degang; Zhou, Donghui; Li, Liwei; Knabe, William Eric; Wang, Fang; Oh, Kyungsoo; Meroueh, Samy O.

    2014-01-01

    The urokinase receptor (uPAR) is a cell-surface protein that is part of an intricate web of transient and tight protein interactions that promote cancer cell invasion and metastasis. Here we evaluate the binding and biological activity of a new class of pyrrolidinone (3) and piperidinone (4) compounds, along with derivatives of previously-identified pyrazole (1) and propylamine (2) compounds. Competition assays revealed that the compounds displaced a fluorescently-labeled peptide (AE147-FAM) with inhibition constant Ki ranging from 6 to 63 μM. Structure-based computational pharmacophore analysis followed by extensive explicit-solvent molecular dynamics simulations and free energy calculations suggested pyrazole-based 1a and piperidinone-based 4 adopt different binding modes, despite their similar two-dimensional structures. In cells, compounds 1b and 1f showed significant inhibition of breast MDA-MB-231 and pancreatic ductal adenocarcinoma (PDAC) cell proliferation, but 4b exhibited no cytotoxicity even at concentrations of 100 μM. 1f impaired MDA-MB-231 invasion, adhesion, and migration in a concentration-dependent manner, while 4b inhibited only invasion. 1f inhibited gelatinase (MMP-9) activity in a concentration-dependent manner, while 4b showed no effect suggesting different mechanisms for inhibition of cell invasion. Signaling studies further highlighted these differences, showing that pyrazole compounds completely inhibited ERK phosphorylation and impaired HIF1α and NF-κB signaling, while pyrrolidinone and piperidinone (3 and 4b) had no effect. Annexin V staining suggested that the effect of pyrazole-based 1f on proliferation was due to cell killing through an apoptotic mechanism. PMID:24115356

  18. Imaging the urokinase plasminongen activator receptor in preclinical breast cancer models of acquired drug resistance.

    PubMed

    LeBeau, Aaron M; Sevillano, Natalia; King, Mandy L; Duriseti, Sai; Murphy, Stephanie T; Craik, Charles S; Murphy, Laura L; VanBrocklin, Henry F

    2014-01-01

    Subtype-targeted therapies can have a dramatic impact on improving the quality and quantity of life for women suffering from breast cancer. Despite an initial therapeutic response, cancer recurrence and acquired drug-resistance are commonplace. Non-invasive imaging probes that identify drug-resistant lesions are urgently needed to aid in the development of novel drugs and the effective utilization of established therapies for breast cancer. The protease receptor urokinase plasminogen activator receptor (uPAR) is a target that can be exploited for non-invasive imaging. The expression of uPAR has been associated with phenotypically aggressive breast cancer and acquired drug-resistance. Acquired drug-resistance was modeled in cell lines from two different breast cancer subtypes, the uPAR negative luminal A subtype and the uPAR positive triple negative subtype cell line MDA-MB-231. MCF-7 cells, cultured to be resistant to tamoxifen (MCF-7 TamR), were found to significantly over-express uPAR compared to the parental cell line. uPAR expression was maintained when resistance was modeled in triple-negative breast cancer by generating doxorubicin and paclitaxel resistant MDA-MB-231 cells (MDA-MB-231 DoxR and MDA-MB-231 TaxR). Using the antagonistic uPAR antibody 2G10, uPAR was imaged in vivo by near-infrared (NIR) optical imaging and (111)In-single photon emission computed tomography (SPECT). Tumor uptake of the (111)In-SPECT probe was high in the three drug-resistant xenografts (> 46 %ID/g) and minimal in uPAR negative xenografts at 72 hours post-injection. This preclinical study demonstrates that uPAR can be targeted for imaging breast cancer models of acquired resistance leading to potential clinical applications. PMID:24505235

  19. Microglia and the urokinase plasminogen activator receptor/uPA system in innate brain inflammation.

    PubMed

    Cunningham, Orla; Campion, Suzanne; Perry, V Hugh; Murray, Carol; Sidenius, Nicolai; Docagne, Fabian; Cunningham, Colm

    2009-12-01

    The urokinase plasminogen activator (uPA) receptor (uPAR) is a GPI-linked cell surface protein that facilitates focused plasmin proteolytic activity at the cell surface. uPAR has been detected in macrophages infiltrating the central nervous system (CNS) and soluble uPAR has been detected in the cerebrospinal fluid during a number of CNS pathologies. However, its expression by resident microglial cells in vivo remains uncertain. In this work, we aimed to elucidate the murine CNS expression of uPAR and uPA as well as that of tissue plasminogen activator and plasminogen activator inhibitor 1 (PAI-1) during insults generating distinct and well-characterized inflammatory responses; acute intracerebral lipopolysaccharide (LPS), acute kainate-induced neurodegeneration, and chronic neurodegeneration induced by prion disease inoculation. All three insults induced marked expression of uPAR at both mRNA and protein level compared to controls (naïve, saline, or control inoculum-injected). uPAR expression was microglial in all cases. Conversely, uPA transcription and activity was only markedly increased during chronic neurodegeneration. Dissociation of uPA and uPAR levels in acute challenges is suggestive of additional proteolysis-independent roles for uPAR. PAI-1 was most highly expressed upon LPS challenge, whereas tissue plasminogen activator mRNA was constitutively present and less responsive to all insults studied. These data are novel and suggest much wider involvement of the uPAR/uPA system in CNS function and pathology than previously supposed. PMID:19459212

  20. Urokinase-type plasminogen activator receptor modulates epileptogenesis in mouse model of temporal lobe epilepsy.

    PubMed

    Ndode-Ekane, Xavier Ekolle; Pitkänen, Asla

    2013-06-01

    Mutation in Plaur gene encoding urokinase-type plasminogen activator receptor (uPAR) results in epilepsy and autistic phenotype in mice. In humans, a single nucleotide polymorphism in PLAUR gene represents a risk for autism spectrum disorders. Importantly, the expression of uPAR is elevated in the brain after various epileptogenic insults like traumatic brain injury and status epilepticus. So far, the consequences of altered uPAR expression on brain networks are poorly known. We tested a hypothesis that uPAR regulates post-injury neuronal reorganization and consequent functional outcome, particularly epileptogenesis. Epileptogenesis was induced by intrahippocampal injection of kainate in adult male wild type (Wt) or uPAR knockout (uPAR-/-) mice, and animals were monitored with continuous (24/7) video-electroencephalogram for 30 days. The severity of status epilepticus did not differ between the genotypes. The spontaneous electrographic seizures which developed were, however, longer and their behavioral manifestations were more severe in uPAR-/- than Wt mice. The more severe epilepsy phenotype in uPAR-/- mice was associated with delayed but augmented inflammatory response and more severe neurodegeneration in the hippocampus. Also, the distribution of newly born cells in the dentate gyrus was more scattered, and the recovery of hippocampal blood vessel length from status epilepticus-induced damage was compromised in uPAR-/- mice as compared to Wt mice. Our data demonstrate that a deficiency in uPAR represents a mechanisms which results in the development of a more severe epilepsy phenotype and progressive brain pathology after status epilepticus. We suggest that uPAR represents a rational target for disease-modifying treatments after epileptogenic brain insults. PMID:23263886

  1. Urokinase-coated chitosan nanoparticles for thrombolytic therapy: preparation and pharmacodynamics in vivo.

    PubMed

    Jin, Hai-jiang; Zhang, Hao; Sun, Min-li; Zhang, Bai-gen; Zhang, Ji-wei

    2013-11-01

    Blood reperfusion of affected limbs is the most effective therapy for peripheral vascular thrombotic disease, restoring nutrition and blood flow to threatened tissues. Because it is more cost-effective than other thrombolytics, urokinase (UK) is widely used to treat venous thrombosis in China. However, its use is limited because of the risk of UK-related hemorrhagic complications. UK-coated nanoparticles (NPs) may decrease adverse effects while simultaneously increasing thrombolytic benefits. The aim of this study was to combine the sustained-release properties of NPs with the clinical benefits of catheter-directed thrombolysis (CDT) to create a promising new therapy. NPs were prepared via self-assembled chitosan and tripolyphosphate, introduced into a thrombosis model in New Zealand white rabbits, and the ratio of the residual thrombus cross-sectional area to the vascular cross-sectional area was calculated. The NPs had a drug-bearing efficiency of 14.5 ± 1.3%, an encapsulation efficiency of 94.8 ± 2.1% while the particle size of UK-coated NPs was 236 nm. Transmission electron microscopy results showed that the shape of the NPs were spherical and regular. Whether delivered by intravenation or catheter, UK-coated NPs produced a significant increase in the thrombolytic effect compared with free UK and confirmed the superiority of CDT for improving clot lysis over drug-induced systemic thrombolysis. The intravenous NPs caused an abnormal increase in fibrinogen. In conclusion, a water-soluble UK-WCS-NP suspension with good encapsulation efficiency was easily prepared UK-WCS-NPs were capable of maintaining UK activity, provided sustained-release of UK and exhibited better thrombolytic function than free UK. PMID:23728739

  2. Reduction of mouse atherosclerosis by urokinase inhibition or with a limited-spectrum matrix metalloproteinase inhibitor

    PubMed Central

    Hu, Jie Hong; Touch, Phanith; Zhang, Jingwan; Wei, Hao; Liu, Shihui; Lund, Ida K.; Høyer-Hansen, Gunilla; Dichek, David A.

    2015-01-01

    Aims Elevated activity of urokinase plasminogen activator (uPA) and MMPs in human arteries is associated with accelerated atherosclerosis, aneurysms, and plaque rupture. We used Apoe-null mice with macrophage-specific uPA overexpression (SR-uPA mice; a well-characterized model of protease-accelerated atherosclerosis) to investigate whether systemic inhibition of proteolytic activity of uPA or a subset of MMPs can reduce protease-induced atherosclerosis and aortic dilation. Methods and results SR-uPA mice were fed a high-fat diet for 10 weeks and treated either with an antibody inhibiting mouse uPA (mU1) or a control antibody. mU1-treated mice were also compared with PBS-treated non-uPA-overexpressing Apoe-null mice. Other SR-uPA mice were treated with one of three doses of a limited-spectrum synthetic MMP inhibitor (XL784) or vehicle. mU1 reduced aortic root intimal lesion area (20%; P = 0.05) and aortic root circumference (12%; P = 0.01). All XL784 doses reduced aortic root intimal lesion area (22–29%) and oil-red-O-positive lesion area (36–42%; P < 0.05 for all doses and both end points), with trends towards reduced aortic root circumference (6–10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage. Several lines of evidence identified MMP-13 as a mediator of uPA-induced aortic MMP activity. Conclusions Pharmacological inhibition of either uPA or selected MMPs decreased atherosclerosis in SR-uPA mice. uPA inhibition decreased aortic dilation. Differential effects of both agents on aortic root vs. distal aortic atherosclerosis suggest prevention of atherosclerosis progression vs. initiation. Systemic inhibition of uPA or a subset of MMPs shows promise for treating atherosclerosis. PMID:25616415

  3. Cytokines in cerebrospinal fluid of neurosyphilis patients: Identification of Urokinase plasminogen activator using antibody microarrays.

    PubMed

    Lu, Ping; Zheng, Dao-Cheng; Fang, Chang; Huang, Jin-Mei; Ke, Wu-Jian; Wang, Liu-Yuan; Zeng, Wei-Ying; Zheng, He-Ping; Yang, Bin

    2016-04-15

    Little is known regarding protein responses to syphilis infection in cerebrospinal fluid (CSF) of patients presenting with neurosyphilis. Protein and antibody arrays offer a new opportunity to gain insights into global protein expression profiles in these patients. Here we obtained CSF samples from 46 syphilis patients, 25 of which diagnosed as having central nervous system involvement based on clinical and laboratory findings. The CSF samples were then analyzed using a RayBioH L-Series 507 Antibody Array system designed to simultaneously analyze 507 specific cytokines. The results indicated that 41 molecules showed higher levels in patients with neurosyphilis in comparison with patients without neural involvement. For validation by single target ELISA, we selected five of them (MIP-1a, I-TAC/CXCL11, Urokinase plasminogen activator [uPA], and Oncostatin M) because they have previously been found to be involved in central nervous system (CNS) disorders. The ELISA tests confirmed that uPA levels were significantly higher in the CSF of neurosyphilis patients (109.1±7.88pg/ml) versus patients without CNS involvement (63.86±4.53pg/ml, p<0.0001). There was also a clear correlation between CSF uPA levels and CSF protein levels (p=0.0128) as well as CSF-VDRL titers (p=0.0074) used to diagnose neurosyphilis. No significant difference between the two groups of patients, however, was found in uPA levels in the serum, suggesting specific activation of the inflammatory system in the CNS but not the periphery in neurosyphilis patients. We conclude that measurements of uPA levels in CSF may be an additional parameter for diagnosing neurosyphilis. PMID:27049560

  4. Effect of urokinase-type plasminogen activator system in gastric cancer with peritoneal metastasis

    PubMed Central

    DING, YOUCHENG; ZHANG, HUI; LU, AIGUO; ZHOU, ZHUQING; ZHONG, MINGAN; SHEN, DONGWEI; WANG, XUJING; ZHU, ZHENGGANG

    2016-01-01

    Peritoneal metastasis is a primary cause of mortality in patients with gastric cancer. Urokinase-type plasminogen activator (uPA) has been demonstrated to be associated with tumor cell metastasis through the degradation of the extracellular matrix. The present study aimed to investigate the mechanisms of the uPA system in gastric cancer with peritoneal metastasis. Expression of uPA, uPA receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) in four gastric cell lines (AGS, SGC7901, MKN45 and MKN28) was measured by semiquantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay and western blotting. uPA activity was detected using a uPA activity kit. Peritoneal implantation models of rats were established by injecting four gastric cancer cell lines for the selection of the cancer cells with a high planting potential. Biological behaviors, including adhesion, migration and invasion, were determined using a methyl thiazolyl tetrazolium assay. Expression of the uPA system was observed to be highest in the SGC7901 cells among the four gastric cell lines. uPA activity was observed to be highest in the MKN45 cells and lowest in the AGS cells. Furthermore, peritoneal implantation analysis demonstrated that no peritoneal tumors were identified in the AGS cells, whilst the tumor masses observed in the SGC7901 and MKN45 cells were of different sizes. The survival times of the rats injected with the MKN28 and SGC7901 cells were longer than those of the rats injected with the MKN45 cells. Antibodies for uPA, uPAR and PAI-1 in the uPA system had the ability to inhibit the adhesion, migration and invasion of peritoneal metastasis in the gastric cancer cells. The results of the present study demonstrated that the uPA system was positively associated with peritoneal metastasis in gastric cancer. PMID:27313768

  5. Inhibitors of Urokinase Type Plasminogen Activator and Cytostatic Activity from Crude Plants Extracts

    PubMed Central

    Zha, Xueqiang; Diaz, Ricardo; Franco, Jose Javier Rosado; Sanchez, Veronica Forbes; Fasoli, Ezio; Barletta, Gabriel; Carvajal, Augusto; Bansal, Vibha

    2014-01-01

    In view of the clear evidence that urokinase type plasminogen activator (uPA) plays an important role in the processes of tumor cell metastasis, aortic aneurysm, and multiple sclerosis, it has become a target of choice for pharmacological intervention. The goal of this study was thus to determine the presence of inhibitors of uPA in plants known traditionally for their anti-tumor properties. Crude methanol extracts were prepared from the leaves of plants (14) collected from the subtropical dry forest (Guanica, Puerto Rico), and tested for the presence of inhibitors of uPA using the fibrin plate assay. The extracts that tested positive (6) were then partitioned with petroleum ether, chloroform, ethyl acetate and n-butanol, in a sequential manner. The resulting fractions were then tested again using the fibrin plate assay. Extracts from leaves of Croton lucidus (C. lucidus) showed the presence of a strong uPA inhibitory activity. Serial dilutions of these C. lucidus partitions were performed to determine the uPA inhibition IC50 values. The chloroform extract showed the lowest IC50 value (3.52 μg/mL) and hence contained the most potent uPA inhibitor. Further investigations revealed that the crude methanol extract and its chloroform and n-butanol partitions did not significantly inhibit closely related proteases such as the tissue type plasminogen activator (tPA) and plasmin, indicating their selectivity for uPA, and hence superior potential for medicinal use with fewer side effects. In a further evaluation of their therapeutic potential for prevention of cancer metastasis, the C. lucidus extracts displayed cytostatic activity against human pancreatic carcinoma (PaCa-2) cells, as determined through an MTS assay. The cytostatic activities recorded for each of the partitions correlated with their relative uPA inhibitory activities. There are no existing reports of uPA inhibitors being present in any of the plants reported in this study. PMID:23896619

  6. Benefits of maltodextrin intake 2 hours before cholecystectomy by laparotomy in respiratory function and functional capacity: a prospective randomized clinical trial

    PubMed Central

    Zani, Fabiana Vieira Breijão; Aguilar-Nascimento, José Eduardo; Nascimento, Diana Borges Dock; da Silva, Ageo Mário Cândido; Caporossi, Fernanda Stephan; Caporossi, Cervantes

    2015-01-01

    ABSTRACT Objective: To evaluate the change in respiratory function and functional capacity according to the type of preoperative fasting. Methods: Randomized prospective clinical trial, with 92 female patients undergoing cholecystectomy by laparotomy with conventional or 2 hours shortened fasting. The variables measured were the peak expiratory flow, forced expiratory volume in the first second, forced vital capacity, dominant handgrip strength, and non-dominant handgrip strength. Evaluations were performed 2 hours before induction of anesthesia and 24 hours after the operation. Results: The two groups were similar in preoperative evaluations regarding demographic and clinical characteristics, as well as for all variables. However, postoperatively the group with shortened fasting had higher values than the group with conventional fasting for lung function tests peak expiratory flow (128.7±62.5 versus 115.7±59.9; p=0.040), forced expiratory volume in the first second (1.5±0.6 versus 1.2±0.5; p=0.040), forced vital capacity (2.3±1.1 versus 1.8±0.9; p=0.021), and for muscle function tests dominant handgrip strength (24.9±6.8 versus 18.4±7.7; p=0.001) and non-dominant handgrip strength (22.9±6.3 versus 17.0±7.8; p=0.0002). In the intragroup evaluation, there was a decrease in preoperative compared with postoperative values, except for dominant handgrip strength (25.2±6.7 versus 24.9±6.8; p=0.692), in the shortened fasting group. Conclusion: Abbreviation of preoperative fasting time with ingestion of maltodextrin solution is beneficial to pulmonary function and preserves dominant handgrip strength. PMID:26154547

  7. Arctic circulation regimes.

    PubMed

    Proshutinsky, Andrey; Dukhovskoy, Dmitry; Timmermans, Mary-Louise; Krishfield, Richard; Bamber, Jonathan L

    2015-10-13

    Between 1948 and 1996, mean annual environmental parameters in the Arctic experienced a well-pronounced decadal variability with two basic circulation patterns: cyclonic and anticyclonic alternating at 5 to 7 year intervals. During cyclonic regimes, low sea-level atmospheric pressure (SLP) dominated over the Arctic Ocean driving sea ice and the upper ocean counterclockwise; the Arctic atmosphere was relatively warm and humid, and freshwater flux from the Arctic Ocean towards the subarctic seas was intensified. By contrast, during anticylonic circulation regimes, high SLP dominated driving sea ice and the upper ocean clockwise. Meanwhile, the atmosphere was cold and dry and the freshwater flux from the Arctic to the subarctic seas was reduced. Since 1997, however, the Arctic system has been under the influence of an anticyclonic circulation regime (17 years) with a set of environmental parameters that are atypical for this regime. We discuss a hypothesis explaining the causes and mechanisms regulating the intensity and duration of Arctic circulation regimes, and speculate how changes in freshwater fluxes from the Arctic Ocean and Greenland impact environmental conditions and interrupt their decadal variability. PMID:26347536

  8. Arctic circulation regimes

    PubMed Central

    Proshutinsky, Andrey; Dukhovskoy, Dmitry; Timmermans, Mary-Louise; Krishfield, Richard; Bamber, Jonathan L.

    2015-01-01

    Between 1948 and 1996, mean annual environmental parameters in the Arctic experienced a well-pronounced decadal variability with two basic circulation patterns: cyclonic and anticyclonic alternating at 5 to 7 year intervals. During cyclonic regimes, low sea-level atmospheric pressure (SLP) dominated over the Arctic Ocean driving sea ice and the upper ocean counterclockwise; the Arctic atmosphere was relatively warm and humid, and freshwater flux from the Arctic Ocean towards the subarctic seas was intensified. By contrast, during anticylonic circulation regimes, high SLP dominated driving sea ice and the upper ocean clockwise. Meanwhile, the atmosphere was cold and dry and the freshwater flux from the Arctic to the subarctic seas was reduced. Since 1997, however, the Arctic system has been under the influence of an anticyclonic circulation regime (17 years) with a set of environmental parameters that are atypical for this regime. We discuss a hypothesis explaining the causes and mechanisms regulating the intensity and duration of Arctic circulation regimes, and speculate how changes in freshwater fluxes from the Arctic Ocean and Greenland impact environmental conditions and interrupt their decadal variability. PMID:26347536

  9. No consensus on gestational diabetes mellitus screening regimes in Sweden: pregnancy outcomes in relation to different screening regimes 2011 to 2012, a cross-sectional study

    PubMed Central

    2014-01-01

    Background Although associated adverse pregnancy outcomes, no international or Swedish consensus exists that identifies a cut-off value or what screening method to use for definition of gestational diabetes mellitus. This study investigates the following: i) guidelines for screening of GDM; ii) background and risk factors for GDM and selection to OGTT; and iii) pregnancy outcomes in relation to GDM, screening regimes and levels of OGTT 2 hour glucose values. Methods This cross-sectional and population-based study uses data from the Swedish Maternal Health Care Register (MHCR) (2011 and 2012) combined with guidelines for GDM screening (2011–2012) from each Maternal Health Care Area (MHCA) in Sweden. The sample consisted of 184,183 women: 88,140 in 2011 and 96,043 in 2012. Chi-square and two independent samples t-tests were used. Univariate and multivariate logistic regression analyses were performed. Results Four screening regimes of oral glucose tolerance test (OGTT) (75 g of glucose) were used: A) universal screening with a 2-hour cut-off value of 10.0 mmol/L; B) selective screening with a 2-hour cut-off value of 8.9 mmol/L; C) selective screening with a 2-hour cut-off value of 10.0 mmol/L; and D) selective screening with a 2-hour cut-off value of 12.2 mmol/L. The highest prevalence of GDM (2.9%) was found with a 2-hour cut-off value of 8.9 mmol/L when selective screening was applied. Unemployment and low educational level were associated with an increased risk of GDM. The OR was 4.14 (CI 95%: 3.81-4.50) for GDM in obese women compared to women with BMI <30 kg/m2. Women with non-Nordic origin presented a more than doubled risk for GDM compared to women with Nordic origin (OR = 2.24; CI 95%: 2.06-2.43). Increasing OGTT values were associated with increasing risks of adverse pregnancy outcomes. Conclusions There was no consensus regarding screening regimes for GDM from 2011 through 2012 when four different regimes were applied in Sweden. Increasing

  10. Design, Synthesis, Biochemical Studies, Cellular Characterization, and Structure-Based Computational Studies of Small Molecules Targeting the Urokinase Receptor

    PubMed Central

    Wang, Fang; Knabe, W. Eric; Li, Liwei; Jo, Inha; Mani, Timmy; Roehm, Hartmut; Oh, Kyungsoo; Li, Jing; Khanna, May; Meroueh, Samy O.

    2012-01-01

    The urokinase receptor (uPAR) serves as a docking site to the serine protease urokinase-type plasminogen activator (uPA) to promote extracellular matrix (ECM) degradation and tumor invasion and metastasis. Previously, we had reported a small molecule inhibitor of the uPAR•uPA interaction that emerged from structure-based virtual screening. Here, we measure the affinity of a large number of derivatives from commercial sources. Synthesis of additional compounds was carried out to probe the role of various groups on the parent compound. Extensive structure-based computational studies suggested a binding mode for these compounds that led to a structure-activity relationship study. Cellular studies in non-small cell lung cancer (NSCLC) cell lines that include A549, H460 and H1299 showed that compounds blocked invasion, migration and adhesion. The effects on invasion of active compounds were consistent with their inhibition of uPA and MMP proteolytic activity. These compounds showed weak cytotoxicity consistent with the confined role of uPAR to metastasis. PMID:22771232

  11. Relationship between urokinase plasminogen activator receptor (uPAR) and the invasion of human prenatal hair follicle.

    PubMed

    Gao, Qiangguo; Fu, Gang; Huang, Gang; Lian, Xiaohua; Yu, Jin; Yang, Tian

    2010-08-01

    During the morphogenesis of hair follicles, the invasive migration of basal keratinocytes resembles cell's dissemination of tissue remodeling. The urokinase-type plasminogen activator receptor (uPAR) appears to be a key molecule in the metastasis. In order to elucidate the relationship between uPAR and the invasion of the human hair follicle, immunohistochemistry, RT-PCR, plasmids transfection, and western blot were used. The results showed that uPAR was expressed in the outermost epithelial cells of the hair follicle and the basal keratinocytes of epidermis, and that the expression decreased with the development of the hair follicle. The cells of the outer root sheath (ORS) and interfollicle epidermis, which overexpressed uPAR, acquired increased invasiveness; however, they showed decreased invasion with overexpression of the urokinase-type plasminogen activator amino terminal fragment (uPA ATF), which inhibited the combination of uPAR and uPA competitively, and the cell invasive migration with overexpressed uPAR was required activated extracellular signal-regulated kinases (ERK). These results implied that overexpression of uPAR promote the invasive migration of hair follicle into the dermis in uPA-dependent and independent manner during human prenatal development. PMID:20012874

  12. The tyrosine phosphatase SHP-2 controls urokinase-dependent signaling and functions in human vascular smooth muscle cells

    SciTech Connect

    Kiyan, Julia Haller, Hermann; Dumler, Inna

    2009-04-01

    The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of functional behaviour of human vascular smooth muscle cells (VSMC). uPAR associates with platelet-derived growth factor receptor {beta} (PDGFR-{beta}), which serves as a transmembrane adaptor for uPAR in VSMC, to transduce intracellular signaling and initiate functional changes. The precise and rapid propagation of these signaling cascades demands both strict and flexible regulatory mechanisms that remain unexplored. We provide evidence that the tyrosine phosphatase SHP-2 mediates these processes. uPA regulated SHP-2 phosphorylation, catalytic activity, and its co-localization and association with the PDGFR-{beta}. Active PDGFR-{beta} was required for the uPA-induced SHP-2 phosphorylation. uPAR-directed STAT1 pathway was disturbed in cells expressing SHP-2 inactive mutant. Both, cell proliferation and migration were impaired in VSMC with downregulated SHP-2. Elucidating the underlying mechanisms, we found that uPA induced SHP-2 recruitment to lipid rafts. Disruption of rafts abolished uPA-related control of SHP-2 phosphorylation, its association with PDGFR-{beta} and finally the VSMC functional responses. Our results demonstrate that SHP-2 plays an important role in uPA-directed signaling and functional control of human VSMC and suggest that this phosphatase might contribute to the pathogenesis of the uPA-related vascular remodeling.

  13. Altered expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in high-risk soft tissue sarcomas.

    PubMed

    Benassi, M S; Ponticelli, F; Azzoni, E; Gamberi, G; Pazzaglia, L; Chiechi, A; Conti, A; Spessotto, P; Scapolan, M; Pignotti, E; Bacchini, P; Picci, P

    2007-09-01

    In recent years, classification of soft-tissue sarcomas (STS) has improved with cytogenetic analyses, but their clinical behavior is still not easily predictable. The aim of this study was to detect alterations in the urokinase-type plasminogen system, involved in tumor growth and invasion, by comparing mRNA levels of its components with those of paired normal tissues, and relating them with patient clinical course. Real-time PCR was performed on human STS cell lines and tissues from highly malignant STS, including leiomyosarcomas and malignant fibrous histiocytomas, to evaluate the expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of gene products was also performed. Median mRNA values of all genes studied were higher in tumors than in paired normal tissues. In agreement with data on STS cell lines, significant up-regulation for uPA and PAI-1 genes compared to reference values was seen. Moreover, different levels of expression were related to histotype and metastatic phenotype. There was accordance between uPA mRNA and protein expression, while immunodetection of PAI-1 product was weak and scattered. Clearly, the controversial role of PAI-1 protein requires further biological analyses, but evident involvement of uPA/PAI-1 gene overexpression in STS malignancy may highlight a molecular defect useful in discriminating STS high-risk patients. PMID:17523079

  14. Urokinase receptor-dependent and -independent p56/59(hck) activation state is a molecular switch between myelomonocytic cell motility and adherence.

    PubMed Central

    Chiaradonna, F; Fontana, L; Iavarone, C; Carriero, M V; Scholz, G; Barone, M V; Stoppelli, M P

    1999-01-01

    Anchorage-independent myelomonocytic cells acquire adherence within minutes of differentiation stimuli, such as the proteolytically inactive N-terminal fragment of urokinase binding to its cognate glycosylphosphatidylinositol (GPI)-anchored receptor. Here, we report that urokinase-treated differentiating U937 monocyte-like cells exhibit a rapid and transient inhibition of p56/59(hck) and p55(fgr) whereas no changes in the activity of other Src family kinases, such as p53/56(lyn) and p59(fyn) were observed. U937 transfectants expressing a kinase-defective (Lys267 to Met) p56/59(hck) variant exhibit enhanced adhesiveness and a marked F-actin redistribution in thin protruding structures. Conversely, urokinase as well as expression of wild-type or constitutively active (Tyr499 to Phe) p56/59(hck) stimulates the directional migration of uninduced U937 cells. Accordingly, expression of constitutively active or kinase inactive p56/59(hck) selectively prevents urokinase receptor-dependent induction of either adhesion or motility, indicating that a specific activation state of p56/59(hck) is required for each cell response. In conclusion, modulation of the intracellular p56/59(hck) tyrosine kinase activity switches cell motility towards adherence, providing a mutually exclusive mechanism to regulate these properties during monocyte/macrophage differentiation in vivo. PMID:10357814

  15. Regimes of Helium Burning

    SciTech Connect

    Timmes, F. X.; Niemeyer, J. C.

    2000-07-10

    The burning regimes encountered by laminar deflagrations and Zeldovich von Neumann Doering [ZND] detonations propagating through helium-rich compositions in the presence of buoyancy-driven turbulence are analyzed. Particular attention is given to models of X-ray bursts that start with a thermonuclear runaway on the surface of a neutron star and to the thin-shell helium instability of intermediate-mass stars. In the X-ray burst case, turbulent deflagrations propagating in the lateral or radial direction encounter a transition from the distributed regime to the flamelet regime at a density of {approx}108 g cm-3. In the radial direction, the purely laminar deflagration width is larger than the pressure scale height for densities smaller than {approx}106 g cm-3. Self-sustained laminar deflagrations traveling in the radial direction cannot exist below this density. Similarly, the planar ZND detonation width becomes larger than the pressure scale height at {approx}107 g cm-3, suggesting that steady state, self-sustained detonations cannot come into existence in the radial direction. In the thin helium shell case, turbulent deflagrations traveling in the lateral or radial direction encounter the distributed regime at densities below {approx}107 g cm-3 and the flamelet regime at larger densities. In the radial direction, the purely laminar deflagration width is larger than the pressure scale height for densities smaller than {approx}104 g cm-3, indicating that steady state laminar deflagrations cannot form below this density. The planar ZND detonation width becomes larger than the pressure scale height at {approx}5x10{sup 4} g cm-3, suggesting that steady state, self-sustained detonations cannot come into existence in the radial direction. (c) 2000 The American Astronomical Society.

  16. Characterization of the murine plasminogen/urokinase-type plasminogen-activator system.

    PubMed

    Lijnen, H R; Van Hoef, B; Collen, D

    1996-11-01

    The murine plasminogen/urokinase-type plasminogen-activator (u-PA) system was studied using purified proteins, plasma and endothelioma cells. Recombinant murine u-PA was obtained as a single-chain molecule of 45 kDa which was converted to two-chain u-PA with plasmin by cleavage of the Lys159-Ile160 peptide bond. Murine plasminogen, purified from plasma as a single-chain protein of 95 kDa, was resistant to quantitative activation with murine recombinant two-chain u-PA: only 15% activation within 1 h at 37 degrees C was obtained in mixtures of 1 microM plasminogen and 5 nM recombinant two-chain u-PA, whereas quantitative activation was observed in the autologous human system. Addition of 6-aminohexanoic acid to native murine plasminogen resulted in quantitative activation within 1 h. In murine plasma in vitro, plasminogen was also resistant to quantitative activation with u-PA (50% activation within 1 h at 37 degrees C with 50 nM recombinant two-chain u-PA, whereas in the human system nearly quantitative activation was obtained). Murine plasma clots submerged in murine plasma were resistant to lysis with u-PA; < or = 2% clot lysis in 2 h was obtained with 80 nM recombinant two-chain u-PA in the autologous murine system whereas 50% clot lysis in 2 h required only 15 nM recombinant two-chain u-PA in the autologous human system. Saturable binding of murine recombinant two-chain u-PA was observed to murine endothelioma cells that are genetically deficient in u-PA (u-PA-/- End cells). Binding was characterized by a Kd of 5.5 nM and 800000 binding sites/cell. However, u-PA-/- End cells did not significantly stimulate the activation rate of murine plasminogen by murine recombinant two-chain u-PA and did not enhance the plasmin-mediated conversion rate of murine recombinant single-chain u-PA to its two-chain derivative. Murine recombinant two-chain u-PA bound to murine endothelioma cells was quantitatively inhibited by murine plasminogen-activator inhibitor-1 (PAI-1). Thus

  17. High level of urokinase plasminogen activator contributes to cholangiocarcinoma invasion and metastasis

    PubMed Central

    Thummarati, Parichut; Wijitburaphat, Sitsom; Prasopthum, Aruna; Menakongka, Apaporn; Sripa, Banchob; Tohtong, Rutaiwan; Suthiphongchai, Tuangporn

    2012-01-01

    AIM: To investigate the role of urokinase plasminogen activator (uPA) in cholangiocarcinoma (CCA) invasion and its correlation with clinicopathological parameters. METHODS: uPA expression in CCA tissue was determined by immunohistochemistry. The level of uPA from two CCA cell lines (HuCCA-1 and KKU-M213) and a non-cancer immortalized cholangiocyte cell line (H69) was monitored by plasminogen-gelatin zymography and western blotting, whereas that of plasminogen activator inhibitor type 1 (PAI-1) protein and uPA receptor (uPAR) mRNA was monitored by western blotting and quantitative real-time reverse transcriptase polymerase chain reaction, respectively. Two independent methods were employed to suppress uPA function: a synthetic uPA inhibitor (B428) and silencing of uPA gene expression using siRNA. In vitro invasion of the uPA-disrupted cells was assessed by Matrigel-coated Transwell assay. RESULTS: The immunohistochemical study showed that 75.3% (131/174) of CCA tissues expressed uPA. High uPA expression was correlated with lymphatic invasion and metastasis of CCA patients. Plasminogen-gelatin zymography of the conditioned media and cell-surface eluates showed that both CCA cell lines, but not H69, expressed both secreted and membrane-bound forms of uPA. Although the two CCA cell lines, HuCCA-1 and KKU-M213, expressed a relatively high level of uPA and uPAR, the latter exhibited a much lower degree of in vitro invasiveness, correlating with a high expression of PAI-1 in the latter, but not in the former. Suppressing uPA function with a specific uPA inhibitor, B428, or with siRNA against uPA reduced in vitro invasiveness of KKU-M213 cells, demonstrating the requirement for uPA in the invasiveness of CCA cells. Therefore, our in vivo and in vitro studies suggest that uPA is an important requirement for the invasion process of CCA. CONCLUSION: uPA expression correlates with lymphatic invasion and metastasis in vivo and is required for CCA cell invasion in vitro

  18. Radiation-induced hypomethylation triggers urokinase plasminogen activator transcription in meningioma cells.

    PubMed

    Velpula, Kiran Kumar; Gogineni, Venkateswara Rao; Nalla, Arun Kumar; Dinh, Dzung H; Rao, Jasti S

    2013-02-01

    Our previous studies have shown the role of radiation-induced urokinase plasminogen activator (uPA) expression in the progression of meningioma. In the present study, we investigated whether modulation of DNA methylation profiles could regulate uPA expression. Initially, radiation treatment was found to induce hypomethylation in meningioma cells with a decrease in DNA (cytosine-5)-methyltransferase 1 (DNMT1) and methyl-CpG binding domain protein (MBD) expression. However, oxidative damage by H(2)O(2) or pretreatment of irradiated cells with N-acetyl cysteine (NAC) did not show any influence on these proteins, thereby indicating a radiation-specific change in the methylation patterns among meningioma cells. Further, we identified that hypomethylation is coupled to an increase in uPA expression in these cells. Azacytidine treatment induced a dose-dependent surge of uPA expression, whereas pre-treatment with sodium butyrate inhibited radiation-induced uPA expression, which complemented our prior results. Methylation-specific polymerase chain reaction on bisulfite-treated genomic DNA revealed a diminished methylation of uPA promoter in irradiated cells. Transfection with small hairpin RNA (shRNA)-expressing plasmids targeting CpG islands of the uPA promoter showed a marked decline in uPA expression with subsequent decrease in invasion and proliferation of meningioma cells. Further, radiation treatment was found to recruit SP1 transcription factor, which was abrogated by shRNA treatment. Analysis on signaling events demonstrated the activation of MAP kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) in radiation-treated cells, while U0126 (MEK/ERK inhibitor) blocked hypomethylation, recruitment of SP1, and uPA expression. In agreement with our in vitro data, low DNMT1 levels and high uPA were found in intracranial tumors treated with radiation compared to untreated tumors. In conclusion, our data suggest that radiation-mediated hypomethylation triggers u

  19. Radiation-Induced Hypomethylation Triggers Urokinase Plasminogen Activator Transcription in Meningioma Cells1

    PubMed Central

    Velpula, Kiran Kumar; Gogineni, Venkateswara Rao; Nalla, Arun Kumar; Dinh, Dzung H; Rao, Jasti S

    2013-01-01

    Our previous studies have shown the role of radiation-induced urokinase plasminogen activator (uPA) expression in the progression of meningioma. In the present study, we investigated whether modulation of DNA methylation profiles could regulate uPA expression. Initially, radiation treatment was found to induce hypomethylation in meningioma cells with a decrease in DNA (cytosine-5)-methyltransferase 1 (DNMT1) and methyl-CpG binding domain protein (MBD) expression. However, oxidative damage by H2O2 or pretreatment of irradiated cells with N-acetyl cysteine (NAC) did not show any influence on these proteins, thereby indicating a radiation-specific change in the methylation patterns among meningioma cells. Further, we identified that hypomethylation is coupled to an increase in uPA expression in these cells. Azacytidine treatment induced a dose-dependent surge of uPA expression, whereas pre-treatment with sodium butyrate inhibited radiation-induced uPA expression, which complemented our prior results. Methylation-specific polymerase chain reaction on bisulfite-treated genomic DNA revealed a diminished methylation of uPA promoter in irradiated cells. Transfection with small hairpin RNA (shRNA)-expressing plasmids targeting CpG islands of the uPA promoter showed a marked decline in uPA expression with subsequent decrease in invasion and proliferation of meningioma cells. Further, radiation treatment was found to recruit SP1 transcription factor, which was abrogated by shRNA treatment. Analysis on signaling events demonstrated the activation of MAP kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) in radiation-treated cells, while U0126 (MEK/ERK inhibitor) blocked hypomethylation, recruitment of SP1, and uPA expression. In agreement with our in vitro data, low DNMT1 levels and high uPA were found in intracranial tumors treated with radiation compared to untreated tumors. In conclusion, our data suggest that radiation-mediated hypomethylation triggers u

  20. Urine soluble urokinase-type plasminogen activator receptor levels correlate with proteinuria in Puumala hantavirus infection

    PubMed Central

    Outinen, Tuula K.; Mäkelä, Satu; Huttunen, Reetta; Mäenpää, Niina; Libraty, Daniel; Vaheri, Antti; Mustonen, Jukka; Aittoniemi, Janne

    2014-01-01

    Objectives Urokinase-type plasminogen activator receptor (uPAR) is upregulated during inflammation and known to bind to β3-integrins, receptors used by pathogenic hantaviruses to enter endothelial cells. It has been proposed that soluble uPAR (suPAR) is a circulating factor that causes focal segmental glomerulosclerosis and proteinuria by activating β3-integrin in kidney podocytes. Proteinuria is also a characteristic feature of hantavirus infections. The aim of this study was to evaluate the relation between urine suPAR levels and disease severity in acute Puumala hantavirus (PUUV) infection. Design A single-centre, prospective cohort study. Subjects and methods Urinary suPAR levels were measured twice during the acute phase and once during convalescence in 36 patients with serologically confirmed PUUV infection. Fractional excretion of suPAR (FE suPAR) and of albumin (FE alb) were calculated. Results The FE suPAR was significantly elevated during the acute phase of PUUV infection compared to the convalescent phase (median 3.2%, range 0.8–52.0%, vs. median 1.9%, range 1.0–5.8%, P = 0.005). Maximum FE suPAR was correlated markedly with maximum FE alb (r = 0.812, P < 0.001), and with several other variables that reflect disease severity. There was a positive correlation with the length of hospitalization (r = 0.455, P = 0.009) and maximum plasma creatinine level (r = 0.780, P < 0.001), and an inverse correlation with minimum urinary output (r = −0.411, P = 0.030). There was no correlation between FE suPAR and plasma suPAR (r = 0.180, P = 0.324). Conclusion Urinary suPAR is markedly increased during acute PUUV infection and is correlated with proteinuria. High urine suPAR level may reflect local production of suPAR in the kidney during the acute infection. PMID:24717117

  1. The "lipid accumulation product" is associated with 2-hour postload glucose outcomes in overweight/obese subjects with nondiabetic fasting glucose.

    PubMed

    Malavazos, Alexis Elias; Cereda, Emanuele; Ermetici, Federica; Caccialanza, Riccardo; Briganti, Silvia; Rondanelli, Mariangela; Morricone, Lelio

    2015-01-01

    "Lipid accumulation product" (LAP) is a continuous variable based on waist circumference and triglyceride concentration previously associated with insulin resistance. We investigated the accuracy of LAP in identifying oral glucose tolerance test (OGTT) abnormalities and compared it to the homeostasis model assessment of insulin resistance (HOMA-IR) in a population of overweight/obese outpatients presenting with nondiabetic fasting glucose. We studied 381 (male: 23%) adult (age: 18-70 years) overweight/obese Caucasians (body mass index: 36.9 ± 5.4 Kg/m(2)) having fasting plasma glucose < 7.0 mmol/L. OGTT was used to diagnose unknown glucose tolerance abnormalities: impaired glucose tolerance (IGT) and type-2 diabetes mellitus (T2-DM). According to OGTT 92, subjects had an IGT and 33 were diagnosed T2-DM. Logistic regression analysis detected a significant association for both LAP and HOMA-IR with single (IGT and T2-DM) and composite (IGT + T2-DM) abnormal glucose tolerance conditions. However, while the association with diabetes was similar between LAP and HOMA-IR, the relationship with IGT and composite outcomes by models including LAP was significantly superior to those including HOMA-IR (P = 0.006 and P = 0.007, resp.). LAP seems to be an accurate index, performing better than HOMA-IR, for identifying 2-hour postload OGTT outcomes in overweight/obese patients with nondiabetic fasting glucose. PMID:25792981

  2. The “Lipid Accumulation Product” Is Associated with 2-Hour Postload Glucose Outcomes in Overweight/Obese Subjects with Nondiabetic Fasting Glucose

    PubMed Central

    Malavazos, Alexis Elias; Cereda, Emanuele; Ermetici, Federica; Caccialanza, Riccardo; Briganti, Silvia; Rondanelli, Mariangela; Morricone, Lelio

    2015-01-01

    “Lipid accumulation product” (LAP) is a continuous variable based on waist circumference and triglyceride concentration previously associated with insulin resistance. We investigated the accuracy of LAP in identifying oral glucose tolerance test (OGTT) abnormalities and compared it to the homeostasis model assessment of insulin resistance (HOMA-IR) in a population of overweight/obese outpatients presenting with nondiabetic fasting glucose. We studied 381 (male: 23%) adult (age: 18–70 years) overweight/obese Caucasians (body mass index: 36.9 ± 5.4 Kg/m2) having fasting plasma glucose < 7.0 mmol/L. OGTT was used to diagnose unknown glucose tolerance abnormalities: impaired glucose tolerance (IGT) and type-2 diabetes mellitus (T2-DM). According to OGTT 92, subjects had an IGT and 33 were diagnosed T2-DM. Logistic regression analysis detected a significant association for both LAP and HOMA-IR with single (IGT and T2-DM) and composite (IGT + T2-DM) abnormal glucose tolerance conditions. However, while the association with diabetes was similar between LAP and HOMA-IR, the relationship with IGT and composite outcomes by models including LAP was significantly superior to those including HOMA-IR (P = 0.006 and P = 0.007, resp.). LAP seems to be an accurate index, performing better than HOMA-IR, for identifying 2-hour postload OGTT outcomes in overweight/obese patients with nondiabetic fasting glucose. PMID:25792981

  3. Dynamic Treatment Regimes

    PubMed Central

    Chakraborty, Bibhas; Murphy, Susan A.

    2014-01-01

    A dynamic treatment regime consists of a sequence of decision rules, one per stage of intervention, that dictate how to individualize treatments to patients based on evolving treatment and covariate history. These regimes are particularly useful for managing chronic disorders, and fit well into the larger paradigm of personalized medicine. They provide one way to operationalize a clinical decision support system. Statistics plays a key role in the construction of evidence-based dynamic treatment regimes – informing best study design as well as efficient estimation and valid inference. Due to the many novel methodological challenges it offers, this area has been growing in popularity among statisticians in recent years. In this article, we review the key developments in this exciting field of research. In particular, we discuss the sequential multiple assignment randomized trial designs, estimation techniques like Q-learning and marginal structural models, and several inference techniques designed to address the associated non-standard asymptotics. We reference software, whenever available. We also outline some important future directions. PMID:25401119

  4. QSAR study of substituted 2-pyridinyl guanidines as selective urokinase-type plasminogen activator (uPA) inhibitors.

    PubMed

    Karthikeyan, C; Moorthy, N S Hari Narayana; Trivedi, Piyush

    2009-02-01

    A quantitative structure-activity relationship analysis was conducted on two different series of pyridinylguanidines acting as inhibitors of urokinase-type plasminogen activator using QuaSAR descriptors of molecular modeling software MOE. Multiple linear regression analysis following a stepwise scheme was employed to generate QSARs that relate molecular descriptors to uPA inhibitory activity data of the title compounds. Among the several QSARs generated by MLR analysis, the best models were selected on the basis of their statistical significance and predictive potential. The interpretation of the selected QSAR models suggest that uPA inhibitory activity of compounds in series 1 is influenced by their molecular shape, molecular flexibility and halogen atoms in the molecule whereas the uPA inhibitory potency of compounds in series 2 is dependent on molecular lipophilicity, number of double bonds and spatial orientation of bulky substituents in the molecule. PMID:19012070

  5. Defect of vacuolar protein sorting stimulates proteolytic processing of human urokinase-type plasminogen activator in the yeast Hansenula polymorpha.

    PubMed

    Agaphonov, Michael; Romanova, Nina; Sokolov, Sviatoslav; Iline, Anna; Kalebina, Tatyana; Gellissen, Gerd; Ter-Avanesyan, Michael

    2005-11-01

    Human urokinase-type plasminogen activator (uPA) is poorly secreted by yeast cells. Here, we have selected Hansenula polymorpha mutants with increased productivity of active extracellular uPA. Several of the obtained mutants also demonstrated a defect of sorting of carboxypeptidase Y to the vacuole and the mutant loci have been identified in six of them. All these mutations damaged genes involved in protein traffic between the Golgi apparatus and the vacuole, namely PEP3, VPS8, VPS10, VPS17, and VPS35. We have shown that inactivation of the VPS10 gene encoding the vacuolar protein sorting receptor does not increase uPA secretion but stimulates its proteolytic processing. PMID:16181812

  6. Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor.

    PubMed

    Rullo, Anthony F; Fitzgerald, Kelly J; Muthusamy, Viswanathan; Liu, Min; Yuan, Cai; Huang, Mingdong; Kim, Minsup; Cho, Art E; Spiegel, David A

    2016-03-01

    Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody-recruiting small molecule (ARM) that is capable of recognizing the urokinase-type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell-surface marker, and facilitating the immune-mediated destruction of cancer cells. A co-crystal structure of the ARM-U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non-peptide ligand. Finally, we demonstrated that ARM-U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard-of-care agent doxorubicin. This work underscores the promise of antibody-recruiting molecules as immunotherapeutics for treating cancer. PMID:26879524

  7. Relationship of Exercise, Age, and Gender on Decompression Sickness and Venous Gas Emboli During 2-Hour Oxygen Prebreathe Prior to Hypobaric Exposure

    NASA Technical Reports Server (NTRS)

    Conkin, J.; Gernhardt, M. L.; Foster, P. P.; Pilmanis, A. A.; Butler, B. D.; Beltran, E.; Fife, C. E.; Vann, R. D.; Gerth, W. A.; Loftin, K. C.; Paloski, William H. (Technical Monitor)

    2000-01-01

    We evaluated four 2-hour oxygen prebreathe protocols combining adynamia (non-walking) and 4 different amounts of exercise for potential use with extravehicular activity (EVA) on the International Space Station. Phase I: upper and lower body exercises using dual-cycle ergometry (75% VO2 max for 10 min). Phase 11: same ergometry plus 24 min of light exercise that simulated space suit preparations. Phase III: same 24 min of light exercise but no ergometry, and Phase IV: 56 min of light exercise without ergometry. After 80 min on 100% O2, the subjects breathed 26.5% O2 - 73.5% N2 for 30 min at 10.2 psi. All subjects performed a series of upper body exercises from a recumbent position for 4 hrs at 4.3 psi to simulate EVA work. Venous gas emboli (VGE) were monitored every 12 min using precordial Doppler ultrasound. The 39 female and 126 male exposures were analyzed for correlations between decompression sickness (DCS) or VGE, and risk variables. The duration and quantity of exercise during prebreathe inversely relates to DCS and VGE incidence. The type and distribution of the 19 cases of DCS were similar to historical cases. There was no correlation of age, gender, body mass index, or fitness level with greater incidence of DCS or all VGE. However there were more Grade IV VGE in males > 40 years (10 of 19) than in those =< 40 years (3 of 107), with p<0.01 from Fisher's Exact Chi square The latency time for VGE was longer (103 min +/- 56 SD, n = 15 versus 53 min +/- 31, n =13) when the ergometry occurred about 15 min into the prebreathe than when performed at the start of the prebreathe, but the order of the ergometry did not influence the overall DCS and VGE incidence. An increasing amount of exercise during prebreathes reduced the risk of DCS during subsequent exposures to 4.3 psi. Age, gender, or fitness level did not correlate with the incidence of DCS or VGE (combination of Grades I-IV). However males greater than 40 years had a higher incidence of Grade IV VGE.

  8. Transradial Approach for Transcatheter Selective Superior Mesenteric Artery Urokinase Infusion Therapy in Patients with Acute Extensive Portal and Superior Mesenteric Vein Thrombosis

    SciTech Connect

    Wang Maoqiang Guo Liping; Lin Hanying; Liu Fengyong; Duan Feng; Wang Zhijun

    2010-02-15

    The purpose of this investigation was to assess the feasibility and effectiveness of transradial approach for transcatheter superior mesenteric artery (SMA) urokinase infusion therapy in patients with acute extensive portal and superior mesenteric venous thrombosis. During a period of 7 years, 16 patients with acute extensive thrombosis of the portal (PV) and superior mesenteric veins (SMV) were treated by transcatheter selective SMA urokinase infusion therapy by way of the radial artery. The mean age of the patients was 39.5 years. Through the radial sheath, a 5F Cobra catheter was inserted into the SMA, and continuous infusion of urokinase was performed for 5-11 days (7.1 {+-} 2.5 days). Adequate anticoagulation was given during treatment, throughout hospitalization, and after discharge. Technical success was achieved in all 16 patients. Substantial clinical improvement was seen in these 16 patients after the procedure. Minor complications at the radial puncture site were observed in 5 patients, but trans-SMA infusion therapy was not interrupted. Follow-up computed tomography scan before discharge demonstrated nearly complete disappearance of PV-SMV thrombosis in 9 patients and partial recanalization of PV-SMV thrombosis in 7 patients. The 16 patients were discharged 9-19 days (12 {+-} 6.0 days) after admission. Mean duration of follow-up after hospital discharge was 44 {+-} 18.5 months, and no recurrent episodes of PV-SMV thrombosis developed during that time period. Transradial approach for transcatheter selective SMA urokinase infusion therapy in addition to anticoagulation is a safe and effective therapy for the management of patients with acute extensive PV-SMV thrombosis.

  9. The human urokinase-plasminogen activator gene (PLAU) is located on chromosome 10q24 centromeric to the HOX11 gene

    SciTech Connect

    Stein, P.M.; Stass, S.A.; Kagan, J. )

    1993-04-01

    Urokinase-plasminogen activator is one of two soluble serine proteases that are produced by humans and that convert plasminogen, an inactive proenzyme present in plasma and other extracellular fluids, to plasmin, a protease with broad substrate specificities. Its activity is involved in processes requiring localized extracellular proteolysis such as fibrinolysis, tissue remodeling, and cell migration. Increased production of urokinase has been associated with cancer metastases. The gene for urokinase-plasminogen activator, PLAU, was mapped to chromosome 10q24-qter. By employing somatic cell genetics, polymerase chain reaction (PCR), and Southern blot analysis, the authors assign PLAU to chromosome 10q24. Human chromosome segment 10q23-q25 contains the genes for terminal deoxynucleotidyltransferase, cytochrome P450IIC, glutamic-oxaloacetic transaminase, and plasma retinol binding protein, which form a syntenic group on murine chromosome 19. It is therfore of interest that PLAU and glutamate dehydrogenase, which are on murine chromosome 14, also map in or close to this region of human chromosome 10.

  10. ApaL1 urokinase and Taq1 vitamin D receptor gene polymorphisms in first-stone formers, recurrent stone formers, and controls in a Caucasian population.

    PubMed

    Aykan, Serdar; Tuken, Murat; Gunes, Sezgin; Akin, Yigit; Ozturk, Murat; Seyhan, Serkan; Yuruk, Emrah; Temiz, Mustafa Zafer; Yılmaz, Ali Faik; Nguyen, Daniel P

    2016-04-01

    The purpose of this study was to determine differences in genotype distribution and allele frequency of urokinase and vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) between first-stone formers, recurrent stone formers, and controls in a Caucasian population. A total of 86 first-stone formers, 78 recurrent stone formers, and 167 controls were included. Urokinase and VDR SNPs were tested by gene amplification followed by ApaL1 and Taq1 endonuclease digestion, respectively. Baseline variables, genotype, and allele frequencies were compared between the three groups, using descriptive statistics. Adjusted odds ratios were calculated to estimate the risk for recurrent urolithiasis associated with genotypes. We found that differences in the distribution of ApaL1 SNP and Taq1 SNP genotypes were statistically different between recurrent stone formers and first-stone formers, and between recurrent stone formers and controls. Allele frequency analysis showed that the T allele for ApaL1 SNP and the C allele for Taq1 SNP were significantly associated with recurrent urolithiasis. For Taq1 SNP, logistic regression analysis showed that the C/C genotype was associated with a more than threefold higher risk for recurrent urolithiasis. We conclude that ApaL1 and Taq1 SNPs of the urokinase and VDR genes are associated with recurrent urolithiasis in a Caucasian population. PMID:26275878

  11. Examination Regimes and Student Achievement

    ERIC Educational Resources Information Center

    Cosentino de Cohen, Clemencia

    2010-01-01

    Examination regimes at the end of secondary school vary greatly intra- and cross-nationally, and in recent years have undergone important reforms often geared towards increasing student achievement. This research presents a comparative analysis of the relationship between examination regimes and student achievement in the OECD. Using a micro…

  12. Proximity oscillations of complement type 4 (alphaX beta2) and urokinase receptors on migrating neutrophils.

    PubMed Central

    Kindzelskii, A L; Eszes, M M; Todd, R F; Petty, H R

    1997-01-01

    Migrating neutrophils utilize beta2 integrins for substrate attachment and urokinase receptors (uPAR) to focus pericellular proteolysis. Our studies show that CR3 associates with uPAR on resting cells, whereas uPAR associates with CR4 at lamellipodia of migrating cells. Using resonance energy transfer (RET) microscopy, we show that the molecular proximity between CR4 and uPAR oscillates on migrating cells, thus suggesting that CR4 molecules periodically bind/release uPAR. Cell contact with fibrinogen, endothelial cells, chemotactic factors and indomethacin, and treatment with sub-optimal doses of signal transduction inhibitors, affect the oscillations' period, amplitude, and/or waveform. The oscillations were indistinguishable in period and 180 degrees out-of-phase with cytosolic NAD(P)H autofluorescence oscillations. Thus, CR4 and CR3 identify a neutrophil's axis of migration and CR4 may restrain uPAR at lamellipodia. Oscillations in signal transduction and energy metabolism may coordinate cell adherence, local proteolysis, oxidant release, actin assembly, and cell extension. Images FIGURE 1 PMID:9336173

  13. A high-affinity receptor for urokinase plasminogen activator on human keratinocytes: characterization and potential modulation during migration.

    PubMed Central

    McNeill, H; Jensen, P J

    1990-01-01

    Low passage cultures of normal human keratinocytes produce several components of the plasminogen activator/plasmin proteolytic cascade, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and two specific inhibitors. Studies here presented demonstrate that these cells also contain a high-affinity (Kd = 3 x 10(-10) M) plasma membrane-binding site for uPA. High molecular weight uPA, either as the single-chain precursor or two-chain activated form, bound to the receptor; however, low molecular weight (33 kD) uPA, tPA, or epidermal growth factor did not compete for binding, demonstrating specificity. Acid treatment, which removed endogenous uPA from the receptor, was required to detect maximal binding (45,000 sites per cell). To investigate the possibility that the uPA receptor on keratinocytes may be involved in epithelial migration during wound repair, cultures were wounded and allowed to migrate into the wounded site. Binding sites for uPA were localized by autoradiographic analysis of 125I-uPA binding as well as by immunocytochemical studies using anti-uPA IgG. With both techniques uPA binding sites were detected selectively on the plasma membrane of cells at the leading edge of the migrating epithelial sheet. This localization pattern suggests that uPA receptor expression on keratinocytes may be coupled to cell migration during cutaneous wounding. Images PMID:1965151

  14. Structure-based Engineering of Species Selectivity in the Interaction Between Urokinase and its Receptor: Implication for Preclinical Cancer Therapy

    SciTech Connect

    Lin, L.; Gardsvoll, H; Huai, Q; Huang, M; Ploug, M

    2010-01-01

    The high affinity interaction between the urokinase-type plasminogen activator (uPA) and its glycolipid-anchored receptor (uPAR) is decisive for cell surface-associated plasminogen activation. Because plasmin activity controls fibrinolysis in a variety of pathological conditions, including cancer and wound healing, several intervention studies have focused on targeting the uPA {center_dot} uPAR interaction in vivo. Evaluations of such studies in xenotransplanted tumor models are, however, complicated by the pronounced species selectivity in this interaction. We now report the molecular basis underlying this difference by solving the crystal structure for the murine uPA {center_dot} uPAR complex and demonstrate by extensive surface plasmon resonance studies that the kinetic rate constants for this interaction can be swapped completely between these orthologs by exchanging only two residues. This study not only discloses the structural basis required for a successful rational design of the species selectivity in the uPA {center_dot} uPAR interaction, which is highly relevant for functional studies in mouse models, but it also suggests the possible development of general inhibitors that will target the uPA {center_dot} uPAR interaction across species barriers.

  15. Zinc phthalocyanine conjugated with the amino-terminal fragment of urokinase for tumor-targeting photodynamic therapy.

    PubMed

    Chen, Zhuo; Xu, Peng; Chen, Jincan; Chen, Hongwei; Hu, Ping; Chen, Xueyuan; Lin, Lin; Huang, Yunmei; Zheng, Ke; Zhou, Shanyong; Li, Rui; Chen, Song; Liu, Jianyong; Xue, Jinping; Huang, Mingdong

    2014-10-01

    Photodynamic therapy (PDT) has attracted much interest for the treatment of cancer due to the increased incidence of multidrug resistance and systemic toxicity in conventional chemotherapy. Phthalocyanine (Pc) is one of main classes of photosensitizers for PDT and possesses optimal photophysical and photochemical properties. A higher specificity can ideally be achieved when Pcs are targeted towards tumor-specific receptors, which may also facilitate specific drug delivery. Herein, we develop a simple and unique strategy to prepare a hydrophilic tumor-targeting photosensitizer ATF-ZnPc by covalently coupling zinc phthalocyanine (ZnPc) to the amino-terminal fragment (ATF) of urokinase-type plasminogen activator (uPA), a fragment responsible for uPA receptor (uPAR, a biomarker overexpressed in cancer cells), through the carboxyl groups of ATF. We demonstrate the high efficacy of this tumor-targeting PDT agent for the inhibition of tumor growth both in vitro and in vivo. Our in vivo optical imaging results using H22 tumor-bearing mice show clearly the selective accumulation of ATF-ZnPc in tumor region, thereby revealing the great potential of ATF-ZnPc for clinical applications such as cancer detection and guidance of tumor resection in addition to photodynamic treatment. PMID:24969665

  16. Mutation of the protein-O-mannosyltransferase enhances secretion of the human urokinase-type plasminogen activator in Hansenula polymorpha.

    PubMed

    Agaphonov, Michael O; Sokolov, Sviatoslav S; Romanova, Nina V; Sohn, Jung-Hoon; Kim, So-Young; Kalebina, Tatyana S; Choi, Eui-Sung; Ter-Avanesyan, Michael D

    2005-10-15

    Human urokinase-type plasminogen activator (uPA) is poorly secreted and aggregates in the endoplasmic reticulum of yeast cells due to inefficient folding. A screen for Hansenula polymorpha mutants with improved uPA secretion revealed a gene encoding a homologue of the Saccharomyces cerevisiae protein-O-mannosyltransferase Pmt1p. Expression of the H. polymorpha PMT1 gene (HpPMT1) abolished temperature sensitivity of the S. cerevisiae pmt1 pmt2 double mutant. As in S. cerevisiae, inactivation of the HpPMT1 gene affected electrophoretic mobility of the O-glycosylated protein, extracellular chitinase. In contrast to S. cerevisiae, disruption of HpPMT1 alone caused temperature sensitivity. Inactivation of the HpPMT1 gene decreased intracellular aggregation of uPA, suggesting that enhanced secretion of uPA was due to improvement of its folding in the endoplasmic reticulum. Unlike most of the endoplasmic reticulum membrane proteins, HpPmt1p possesses the C-terminal KDEL retention signal. PMID:16200504

  17. Risk factors associated with serum levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor in a general population.

    PubMed

    Haupt, Thomas H; Kallemose, Thomas; Ladelund, Steen; Rasmussen, Line Jh; Thorball, Christian W; Andersen, Ove; Pisinger, Charlotta; Eugen-Olsen, Jesper

    2014-01-01

    The soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of mortality risk in various patient populations. However, little is known about the implications of lifestyle for suPAR levels in the general population. Lifestyle, demographic, and cardiovascular disease (CVD) risk factor data were collected from 5,538 participants in the Danish population-based Inter99 study. Their suPAR levels were measured using a sandwich enzyme-linked immunosorbent assay. In the final adjusted model, smoking and morbid obesity were strongly associated with higher suPAR levels (P < 0.001). An unhealthy diet and alcohol abstinence in men were also associated with higher suPAR levels. Physical activity in leisure time had a modest impact on suPAR levels in univariate analysis, but not in the final adjusted model. In conclusion, smoking and morbid obesity were strongly associated with higher serum suPAR levels in this general population. Diet and alcohol consumption also seemed to impact suPAR levels. Lifestyle changes are likely to affect suPAR since ex-smokers had suPAR levels comparable to those of never-smokers. PMID:25574132

  18. Increased Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in Plasma of Suicide Attempters

    PubMed Central

    Ventorp, Filip; Gustafsson, Anna; Träskman-Bendz, Lil; Westrin, Åsa; Ljunggren, Lennart

    2015-01-01

    The soluble form of the urokinase receptor, suPAR, has been suggested as a novel biomarker of low-grade inflammation. Activation of the immune system has been proposed to contribute to the development of depression and suicidal behavior. In order to identify depressed and suicidal individuals who could benefit from an anti-inflammatory treatment, a reliable biomarker of low-grade inflammation is vital. This study evaluates plasma suPAR levels as a biomarker of low-grade inflammation in patients with major depressive disorder and in patients who recently attempted suicide. The plasma suPAR and an established biomarker, C reactive protein (CRP) of suicide attempters (n = 54), depressed patients (n = 19) and healthy controls (n = 19) was analyzed with enzyme-linked immunosorbent assays. The biomarker attributes of sensitivity and sensibility were evaluated using ROC curve analysis. Both the depressed patients and suicide attempters had increased plasma suPAR. The levels of suPAR discriminated better between controls and suicide attempters than did CRP. In the future, plasma suPAR might be a superior prognosticator regarding outcome of treatment applying conventional antidepressants in conjunction with anti-inflammatory drugs. PMID:26451727

  19. Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer

    PubMed Central

    Asuthkar, Swapna; Stepanova, Victoria; Lebedeva, Tatiana; Holterman, AiXuan L.; Estes, Norman; Cines, Douglas B.; Rao, Jasti S.; Gondi, Christopher S.

    2013-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is almost always lethal. One of the underlying reasons for this lethality is believed to be the presence of cancer stem cells (CSC), which impart chemoresistance and promote recurrence, but the mechanisms responsible are unclear. Recently the poor prognosis of PDAC has been correlated with increased expression of urokinase plasminogen activator (uPA). In the present study we examine the role of uPA in the generation of PDAC CSC. We observe a subset of cells identifiable as a side population (SP) when sorted by flow cytometry of MIA PaCa-2 and PANC-1 pancreatic cancer cells that possess the properties of CSC. A large fraction of these SP cells are CD44 and CD24 positive, are gemcitabine resistant, possess sphere-forming ability, and exhibit increased tumorigenicity, known characteristics of cancer stemness. Increased tumorigenicity and gemcitabine resistance decrease after suppression of uPA. We observe that uPA interacts directly with transcription factors LIM homeobox-2 (Lhx2), homeobox transcription factor A5 (HOXA5), and Hey to possibly promote cancer stemness. uPA regulates Lhx2 expression by suppressing expression of miR-124 and p53 expression by repressing its promoter by inactivating HOXA5. These results demonstrate that regulation of gene transcription by uPA contributes to cancer stemness and clinical lethality. PMID:23864708

  20. Risk Factors Associated with Serum Levels of the Inflammatory Biomarker Soluble Urokinase Plasminogen Activator Receptor in a General Population

    PubMed Central

    Haupt, Thomas H; Kallemose, Thomas; Ladelund, Steen; Rasmussen, Line JH; Thorball, Christian W; Andersen, Ove; Pisinger, Charlotta; Eugen-Olsen, Jesper

    2014-01-01

    The soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of mortality risk in various patient populations. However, little is known about the implications of lifestyle for suPAR levels in the general population. Lifestyle, demographic, and cardiovascular disease (CVD) risk factor data were collected from 5,538 participants in the Danish population-based Inter99 study. Their suPAR levels were measured using a sandwich enzyme-linked immunosorbent assay. In the final adjusted model, smoking and morbid obesity were strongly associated with higher suPAR levels (P < 0.001). An unhealthy diet and alcohol abstinence in men were also associated with higher suPAR levels. Physical activity in leisure time had a modest impact on suPAR levels in univariate analysis, but not in the final adjusted model. In conclusion, smoking and morbid obesity were strongly associated with higher serum suPAR levels in this general population. Diet and alcohol consumption also seemed to impact suPAR levels. Lifestyle changes are likely to affect suPAR since ex-smokers had suPAR levels comparable to those of never-smokers. PMID:25574132

  1. Transforming Growth Factor-Beta and Urokinase-Type Plasminogen Activator: Dangerous Partners in Tumorigenesis—Implications in Skin Cancer

    PubMed Central

    Santibanez, Juan F.

    2013-01-01

    Transforming growth factor-beta (TGF-β) is a pleiotropic factor, with several different roles in health and disease. TGF-β has been postulated as a dual factor in tumor progression, since it represses epithelial tumor development in early stages, whereas it stimulates tumor progression in advanced stages. During tumorigenesis, cancer cells acquire the capacity to migrate and invade surrounding tissues and to metastasize different organs. The urokinase-type plasminogen activator (uPA) system, comprising uPA, the uPA cell surface receptor, and plasminogen-plasmin, is involved in the proteolytic degradation of the extracellular matrix and regulates key cellular events by activating intracellular signal pathways, which together allow cancer cells to survive, thus, enhancing cell malignance during tumor progression. Due to their importance, uPA and its receptor are tightly transcriptionally regulated in normal development, but are deregulated in cancer, when their activity and expression are related to further development of cancer. TGF-β regulates uPA expression in cancer cells, while uPA, by plasminogen activation, may activate the secreted latent TGF-β, thus, producing a pernicious cycle which contributes to the enhancement of tumor progression. Here we review the specific roles and the interplay between TGF-β and uPA system in cancer cells and their implication in skin cancer. PMID:23984088

  2. A multicenter cross-sectional study of circulating soluble urokinase receptor in Japanese patients with glomerular disease.

    PubMed

    Wada, Takehiko; Nangaku, Masaomi; Maruyama, Shoichi; Imai, Enyu; Shoji, Kumi; Kato, Sawako; Endo, Tomomi; Muso, Eri; Kamata, Kouju; Yokoyama, Hitoshi; Fujimoto, Keiji; Obata, Yoko; Nishino, Tomoya; Kato, Hideki; Uchida, Shunya; Sasatomi, Yoshie; Saito, Takao; Matsuo, Seiichi

    2014-03-01

    Elevated serum-soluble urokinase receptor (suPAR) levels have been described in patients with focal segmental glomerulosclerosis (FSGS) in several different cohorts. However, it remains unclear whether this is the case for Japanese patients and whether circulating suPAR can be clinically useful as a diagnostic marker. To determine this, we measured serum suPAR levels in 69 Japanese patients with biopsy-proven glomerular diseases in a cross-sectional manner. The serum suPAR levels showed a significant inverse correlation with renal function by univariate (R(2) of 0.242) and multivariate (β=0.226) analyses. Even after excluding patients with renal dysfunction, no significant difference in the suPAR levels was detected among the groups. Receiver operating characteristic analysis and measures of the diagnostic test performance showed that suPAR was not a useful parameter for differentiating FSGS from the other glomerular diseases (AUC-ROC: 0.621), although a small subgroup analysis showed that patients with FSGS, treated with steroids and/or immunosuppressants, had significantly lower suPAR levels. Patients with ANCA-associated glomerulonephritis had significantly higher levels of suPAR compared with the other disease groups, which may be owing to their lower renal function and systemic inflammation. Thus, suPAR levels are significantly affected by renal function and have little diagnostic value even in patients with normal renal function. PMID:24429394

  3. In vivo effects of urease-producing bacteria involved with the pathogenesis of infection-induced urolithiasis on renal urokinase and sialidase activity.

    PubMed

    du Toit, P J; van Aswegen, C H; Nel, J A; Steyn, P L; Ligthelm, A J; du Plessis, D J

    1995-01-01

    Many hypotheses have been proposed for renal stone formation. It has been argued that with infection-induced renal stones the hydrolysis of urea by bacterial urease increases urinary pH, with consequent stone formation. Unfortunately, this theory is not applicable to the micro-organisms that do not produce urease (e.g. Escherichia coli). It has been recently reported that E. coli reduces the urinary urokinase activity of male rats, but does not influence the urinary sialidase activity. This study has now been expanded to the urease-producing bacteria Proteus mirabilis, Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa and Micrococcus luteus. Subcutaneous injections with these bacteria were found to significantly (P < 0.003) reduce the UK activity of extrarenally obstructed kidneys. The urease-producing mammalian skin bacterium, M. luteus, was, however, the exception (P = 0.1079). In contrast to S. epidermidis, P. aeruginosa and M. luteus (P < 0.0213), P. mirabilis and S. aureus had no effect on renal sialidase activity (P < 0.4047). These results may explain why Proteus species are predominant in infection-induced renal stones. According to the urokinase-sialidase hypothesis, a decrease in urinary urokinase activity should increase the uromucoid levels, whilst no effect on the urinary sialidase activity should favour conversion of urinary uromucoid to mineralizable matrix. These conditions may lead to renal stone formation. An increase in urinary pH resulting from urease-producing micro-organisms will increase salt precipitation on the uromucoid. It is thus concluded that urease-producing bacteria may play a double role in renal stone formation. PMID:8839391

  4. Serum Soluble Urokinase-Type Plasminogen Activator Receptor Levels and Idiopathic FSGS in Children: A Single-Center Report

    PubMed Central

    Price, Heather E.; Gallon, Lorenzo; Langman, Craig B.

    2013-01-01

    Summary Background and objectives FSGS is the primary cause of childhood nephrotic syndrome leading to ESRD. Permeability factors, including circulating serum soluble urokinase-type plasminogen activator receptor (suPAR), have been postulated as putative causes in adults with primary FSGS. Similar results have yet to be proven in children. Design, setting, participants, & measurements This cross-sectional single-center study assessed the association of serum suPAR in children with FSGS or other glomerular and nonglomerular kidney diseases. Results This study examined 110 samples retrieved from 99 individuals (between January 2011 and April 2012), aged 1–21 years; of these individuals, 20 had primary FSGS, 24 had non-FSGS glomerular disease, 26 had nonglomerular kidney disease, and 29 were healthy controls. suPAR levels were not significantly different in children with FSGS, non-FSGS glomerular disease, and healthy controls (P>0.05). However, suPAR levels (median [25%–75%]) were higher in children with nonglomerular kidney disease (3385 pg/ml [2695–4392]) versus FSGS (2487 pg/ml [2191–3351]; P<0.05). Female patients with nephrotic-range proteinuria (U-Pr/Cr >2) had lower suPAR levels than those without proteinuria (2380 pg/ml [2116–2571] versus 3125 pg/ml [2516–4198], respectively; P<0.001). This trend was not seen among male participants; suPAR levels in all female participants were lower than in male participants (P=0.03). Thirty-four patients studied were kidney transplant recipients; transplant status was not associated with suPAR levels in patients with FSGS or non-FSGS diagnoses, independent of proteinuria, race, or sex (P>0.05). Conclusions On the basis of these results, circulating suPAR is unlikely the leading cause for childhood idiopathic FSGS. PMID:23620441

  5. Cytokines induce urokinase-dependent adhesion of human myeloid cells. A regulatory role for plasminogen activator inhibitors.

    PubMed Central

    Waltz, D A; Sailor, L Z; Chapman, H A

    1993-01-01

    Differentiation of monocytic precursors often results in adhesive properties thought to be important in migration. In this study, the influence of cytokines, known to induce macrophage differentiation, on the adhesiveness of the monocytic cell line U937 was examined in vitro. Despite development of a macrophage morphology, < 5% of cytokine-stimulated U937 cells were adherent at 24 h. Addition of 1-10 nM urokinase-type plasminogen activator (uPA) induced adherence in the presence of transforming growth factor type beta-1, 1,25-(OH)2 vitamin D3, granulocyte macrophage colony-stimulating factor, or tumor necrosis factor alpha. uPA-dependent adhesiveness was reversible after 24 h of stimulation with cytokines and uPA as adherence was prevented by the subsequent addition of anti-uPA antibodies. Adherence induced by diisopropylfluorophosphate-inactivated uPA was severalfold greater than that seen with active uPA. This difference was largely due to cell-surface turnover of active uPA complexed with plasminogen activator inhibitor (PAI). These data indicate that cytokines prime monocyte progenitors for uPA receptor-mediated signals leading to adherence, continued uPA receptor occupancy is required for adherence, and PAI decreases adherence by promoting clearance of uPA/PAI complexes. Thus the interaction of uPA and PAI at the cell surface, known to affect extracellular matrix proteolysis and hence myeloid cell migration, also regulates adhesion. The coordinated regulation of these two uPA functions by PAI may enhance the migratory potential of monocytic cells. Images PMID:8386190

  6. Thrombosis recanalization by paeoniflorin through the upregulation of urokinase-type plasminogen activator via the MAPK signaling pathway

    PubMed Central

    YE, SONGSHAN; MAO, BINGYU; YANG, LEI; FU, WEIYUN; HOU, JUNRAN

    2016-01-01

    Paeoniflorin, the major component of Paeonia lactiflora pall, has previously been reported to prevent thrombosis. Plasminogen activator urokinase (uPA) is a serine protease that markedly facilitates normal thrombosis resolution. Paeoniflorin and uPA have been linked to the mitogen-activated protein kinase (MAPK) signaling pathway. In the current study, the influence of paeoniflorin on the expression of uPA was investigated and the underlying regulatory mechanism was preliminarily determined. The prothrombotic state of the model animals treated with paeoniflorin were assessed by enzyme-linked immunosorbent assay (ELISA). Additionally, the cytotoxicity of paeoniflorin on human umbilical vein endothelial cell (HUVEC) cultures was estimated using a methyl thiazolyl tetrazolium assay and the possible pathways involved in the interaction between paeoniflorin and uPA were evaluated using western blot analysis. The ELISA results demonstrated that the levels of 6-keto prostaglandin F1a, fibronectin and uPA were significantly upregulated by treatment with paeoniflorin compared with control (P<0.05). By contrast, the expression of fibrinogen, D-dimer and thromboxane B2 were inhibited. With an increase in the concentration of paeoniflorin the cell viability of HUVECs decreased gradually. The results of western blot analysis demonstrated that paeoniflorin increased the phosphorylation of MAPK 14 (p38) and MAPK 8 (JNK). The present study demonstrated that paeoniflorin has the potential to improve the prethrombotic state and recanalize thrombosis by increasing the expression of uPA, which may be mediated via regulation of the p38 and JNK MAPK signaling pathways. However, this treatment effect was dependent on the concentration of paeoniflorin used, an unsuitable concentration of the agent would result in a negative effect on the anti-thrombosis pathways. PMID:27082639

  7. Overexpression of urokinase receptor increases matrix invasion without altering cell migration in a human osteosarcoma cell line.

    PubMed

    Karikó, K; Kuo, A; Boyd, D; Okada, S S; Cines, D B; Barnathan, E S

    1993-07-01

    Proteolysis triggered by receptor-bound urokinase-type plasminogen activator (uPA) involves a cascade of species-specific molecular interactions. To study the role of the uPA receptor (uPAR) in such interactions, a human osteosarcoma cell line (HOS), which normally expresses low levels of uPAR, was transfected with human uPAR complementary DNA. One of several stably transformed clonal cells lines, designated 2A2, was characterized and compared to the parental HOS, revealing the following: (a) stable incorporation of uPAR complementary DNA into the genome demonstrated by Southern blot analysis; (b) a 10-fold increase in steady state mRNA levels of uPAR assessed by Northern blot analysis; (c) a 2-fold increase in the surface expression of glycosylphosphatidylinositol anchored uPAR protein determined by enzyme-linked immunosorbent assay and by the specific binding of radiolabeled single chain uPA; (d) a 2-fold increase in internalization and degradation of radiolabeled uPA/PAI-1 complexes; and (e) a 2-fold increase in receptor-bound uPA-mediated plasmin generation measured by the cleavage of a chromogenic substrate and degradation of 125I-labeled laminin. The involvement of uPAR in cellular processes was determined by comparing 2A2 and HOS cells in in vitro migration and invasion assays. The migration of 2A2 cells were slower on fibronectin-coated surfaces in a linear under-agarose assay, but both cell lines migrated at the same rate on uncoated polycarbonate filters in Boyden chamber assays. In the invasion experiments, 4 times more 2A2 than HOS cells penetrated through the barrier of reconstituted basement membrane Matrigel. These data suggest that uPAR does not potentiate random cell migration but facilitates matrix degradation and subsequent cell invasion. PMID:8391387

  8. Cigarette Smoke and the Induction of Urokinase Plasminogen Activator Receptor In Vivo: Selective Contribution of Isoforms to Bronchial Epithelial Phenotype.

    PubMed

    Portelli, Michael A; Stewart, Ceri E; Hall, Ian P; Brightling, Christopher E; Sayers, Ian

    2015-08-01

    The urokinase plasminogen activator receptor (uPAR) gene (PLAUR) has been identified as an asthma susceptibility gene, with polymorphisms within that gene being associated with baseline lung function, lung function decline, and lung function in a smoking population. Soluble cleaved uPAR (scuPAR), a molecule identified as a marker of increased morbidity and mortality in a number of diseases, has been shown to be elevated in the airways of patients with asthma and in patients with chronic obstructive pulmonary disease. However, the functionality of soluble receptor isoforms and their relationship with an important initiator for obstructive lung disease, cigarette smoke, remains undefined. In this study, we set out to determine the effect of cigarette smoke on soluble uPAR isoforms, its regulatory pathway and the resultant effect on bronchial epithelial cell function. We identified a positive association between cigarette pack-years and uPAR expression in the airway bronchial epithelium of biopsies from patients with asthma (n = 27; P = 0.0485). In vitro, cigarette smoke promoted cleavage of uPAR from the surface of bronchial epithelial cells (1.5× induction; P < 0.0001) and induced the soluble spliced isoform through changes in messenger RNA expression (∼2× change; P < 0.001), driven by loss of endogenous 3' untranslated region suppression. Elevated expression of the soluble isoforms resulted in a proremodeling cell phenotype, characterized by increased proliferation and matrix metalloproteinase-9 expression in primary bronchial epithelial cells. This suggests that cigarette smoke elevates soluble receptor isoforms in bronchial epithelial cells through direct (cleavage) and indirect (messenger RNA expression) means. These findings provide further insight into how cigarette smoke may influence changes in the airways of importance to airway remodeling and obstructive lung disease progression. PMID:25490122

  9. Prognostic relevance of urokinase plasminogen activator detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.

    PubMed Central

    Solomayer, E. F.; Diel, I. J.; Wallwiener, D.; Bode, S.; Meyberg, G.; Sillem, M.; Gollan, C.; Kramer, M. D.; Krainick, U.; Bastert, G.

    1997-01-01

    Patients with an elevated level of urokinase plasminogen activator (uPA) in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of uPA detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both iliac crests in 280 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: 2E11, which detects TAG 12--a tumour-associated glycoprotein typically expressed by almost all breast cancer cells--and the anti-uPA antibody HD-UK9. Thirty-five of the 2E11-positive women (n = 132, 47%) developed metastatic disease (median follow-up time 44 months). Of these, most were uPA positive (n = 23, 65%) and only 12 were uPA negative. Patients with uPA-positive cells in bone marrow (n = 98, 35%) had a significantly shorter metastasis-free interval (36 months) than women who were uPA negative (44.5 months). The worst prognosis was seen in patients positive for both markers (29.5 months), followed by those who were uPA negative and 2E11 positive (37 months). The detection of uPA on disseminated tumour cells characterizes a subgroup of patients with an even worse prognosis, who should undergo more aggressive adjuvant systemic therapy. For the first time, it was possible to evaluate an important qualitative parameter involved in the process of breast cancer metastases. Images Figure 1 PMID:9310251

  10. CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer.

    PubMed

    Xie, C; Jiang, X H; Zhang, J T; Sun, T T; Dong, J D; Sanders, A J; Diao, R Y; Wang, Y; Fok, K L; Tsang, L L; Yu, M K; Zhang, X H; Chung, Y W; Ye, L; Zhao, M Y; Guo, J H; Xiao, Z J; Lan, H Y; Ng, C F; Lau, K M; Cai, Z M; Jiang, W G; Chan, H C

    2013-05-01

    Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is expressed in the epithelial cells of a wide range of organs/tissues from which most cancers are derived. Although accumulating reports have indicated the association of cancer incidence with genetic variations in CFTR gene, the exact role of CFTR in cancer development and the possible underlying mechanism have not been elucidated. Here, we report that CFTR expression is significantly decreased in both prostate cancer cell lines and human prostate cancer tissue samples. Overexpression of CFTR in prostate cancer cell lines suppresses tumor progression (cell growth, adhesion and migration), whereas knockdown of CFTR leads to enhanced malignancies both in vitro and in vivo. In addition, we demonstrate that CFTR knockdown-enhanced cell proliferation, cell invasion and migration are significantly reversed by antibodies against either urokinase plasminogen activator (uPA) or uPA receptor (uPAR), which are known to be involved in various malignant traits of cancer development. More interestingly, overexpression of CFTR suppresses uPA by upregulating the recently described tumor suppressor microRNA-193b (miR-193b), and overexpression of pre-miR-193b significantly reverses CFTR knockdown-enhanced malignant phenotype and abrogates elevated uPA activity in prostate cancer cell line. Finally, we show that CFTR gene transfer results in significant tumor repression in prostate cancer xenografts in vivo. Taken together, the present study has demonstrated a previously undefined tumor-suppressing role of CFTR and its involvement in regulation of miR-193b in prostate cancer development. PMID:22797075

  11. Cloud regimes as phase transitions

    NASA Astrophysics Data System (ADS)

    Stechmann, Samuel N.; Hottovy, Scott

    2016-06-01

    Clouds are repeatedly identified as a leading source of uncertainty in future climate predictions. Of particular importance are stratocumulus clouds, which can appear as either (i) closed cells that reflect solar radiation back to space or (ii) open cells that allow solar radiation to reach the Earth's surface. Here we show that these clouds regimes -- open versus closed cells -- fit the paradigm of a phase transition. In addition, this paradigm characterizes pockets of open cells as the interface between the open- and closed-cell regimes, and it identifies shallow cumulus clouds as a regime of higher variability. This behavior can be understood using an idealized model for the dynamics of atmospheric water as a stochastic diffusion process. With this new conceptual viewpoint, ideas from statistical mechanics could potentially be used for understanding uncertainties related to clouds in the climate system and climate predictions.

  12. Inhibitory effect of berberine on the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2

    SciTech Connect

    Peng, P.-L.; Hsieh, Y.-S.; Wang, C.-J.; Hsu, J.-L.; Chou, F.-P. . E-mail: fpchou@csmu.edu.tw

    2006-07-01

    Berberine, a compound isolated from medicinal herbs, has been reported with many pharmacological effects related to anti-cancer and anti-inflammation capabilities. In this study, we observed that berberine exerted a dose- and time-dependent inhibitory effect on the motility and invasion ability of a highly metastatic A549 cells under non-cytotoxic concentrations. In cancer cell migration and invasion process, matrix-degrading proteinases are required. A549 cell treated with berberine at various concentrations showed reduced ECM proteinases including matrix metalloproteinase-2 (MMP2) and urokinase-plasminogen activator (u-PA) by gelatin and casein zymography analysis. The inhibitory effect is likely to be at the transcriptional level, since the reduction in the transcripts levels was corresponding to the proteins. Moreover, berberine also exerted its action via regulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and urokinase-plasminogen activator inhibitor (PAI). The upstream mediators of the effect involved c-jun, c-fos and NF-{kappa}B, as evidenced by reduced phosphorylation of the proteins. These findings suggest that berberine possesses an anti-metastatic effect in non-small lung cancer cell and may, therefore, be helpful in clinical treatment.

  13. Epitope-mapped monoclonal antibodies as tools for functional and morphological analyses of the human urokinase receptor in tumor tissue.

    PubMed Central

    Luther, T.; Magdolen, V.; Albrecht, S.; Kasper, M.; Riemer, C.; Kessler, H.; Graeff, H.; Müller, M.; Schmitt, M.

    1997-01-01

    uPAR (CD87), the receptor for the urokinase-type plasminogen activator (uPA) facilitates tumor cell invasion and metastasis by focusing uPA proteolytic activity to the cell surface. As uPAR exists in various molecular forms, it is desirable to use well defined antibodies for analyses of uPAR antigen expression in human malignant tumors by immunological methods. Therefore, twelve monoclonal antibodies (MAbs) directed against uPAR were generated by using nonglycosylated, recombinant human uPAR (spanning amino acids 1 to 284), expressed in Escherichia coli, as the immunogen. The reaction pattern of these MAbs with the immunogen and a series of carboxyl-terminally truncated versions of uPAR demonstrated that at least six different epitopes of uPAR are recognized. All MAbs reacted under reducing conditions in immunoblot analyses with E. coli-expressed uPA and also with highly glycosylated, functionally intact, recombinant human uPAR expressed in Chinese hamster ovary (CHO) cells. Seven of the MAbs recognized CHO uPAR under nonreducing conditions as well. By flow cytofluorometric analyses, three of these MAbs were shown to bind to native human uPAR present on the cell surface of monocytoid U937 cells with MAb IIIF10 being the best. Saturation of uPAR with uPA on U937 cells completely blocked interaction of MAb IIIF10 with uPAR (mapped epitope, amino acids 52 to 60 of domain I of uPAR). In turn, preincubation of U937 cells with MAb IIIF10 efficiently reduced binding of uPA to uPAR, indicating that the epitope detected by MAb IIIF10 is located within or closely to the uPA-binding site of uPAR, and thus, this site may be a target to influence uPA/uPAR-mediated proteolysis in tumors. Binding of MAbs IID7 or IIIB11 (mapped epitope, amino acids 125 to 132 of domain II of uPAR) to uPAR is not affected when uPAR is occupied by uPA. As these MAbs reacted strongly with cellular uPAR antigen in formalin-fixed paraffin-embedded tumor sections, the domain-II-specific antibodies IID7

  14. Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema.

    PubMed

    Hilty, Matthias Peter; Zügel, Stefanie; Schoeb, Michele; Auinger, Katja; Dehnert, Christoph; Maggiorini, Marco

    2016-01-01

    Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR (1.9 ± 0.4 at SL versus 2.3 ± 0.5 at HA, p < 0.01), CRP (0.7 ± 0.5 at SL versus 3.6 ± 4.6 at HA, p < 0.01), and IL-6 (0.8 ± 0.4 at SL versus 3.3 ± 4.9 at HA, p < 0.01) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (r = 0.46, p < 0.001), but not suPAR (r = 0.27, p = 0.08); the increase in IL-6 was not correlated with suPAR (r = 0.16, p = 0.24). Baseline suPAR plasma concentration was higher in the HAPE-s group (2.0 ± 0.4 versus 1.8 ± 0.4, p = 0.04); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict

  15. Soluble Urokinase-Type Plasminogen Activator Receptor Plasma Concentration May Predict Susceptibility to High Altitude Pulmonary Edema

    PubMed Central

    Zügel, Stefanie; Schoeb, Michele; Auinger, Katja; Dehnert, Christoph; Maggiorini, Marco

    2016-01-01

    Introduction. Acute exposure to high altitude induces inflammation. However, the relationship between inflammation and high altitude related illness such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) is poorly understood. We tested if soluble urokinase-type plasminogen activator receptor (suPAR) plasma concentration, a prognostic factor for cardiovascular disease and marker for low grade activation of leukocytes, will predict susceptibility to HAPE and AMS. Methods. 41 healthy mountaineers were examined at sea level (SL, 446 m) and 24 h after rapid ascent to 4559 m (HA). 24/41 subjects had a history of HAPE and were thus considered HAPE-susceptible (HAPE-s). Out of the latter, 10/24 HAPE-s subjects were randomly chosen to suppress the inflammatory cascade with dexamethasone 8 mg bid 24 h prior to ascent. Results. Acute hypoxic exposure led to an acute inflammatory reaction represented by an increase in suPAR (1.9 ± 0.4 at SL versus 2.3 ± 0.5 at HA, p < 0.01), CRP (0.7 ± 0.5 at SL versus 3.6 ± 4.6 at HA, p < 0.01), and IL-6 (0.8 ± 0.4 at SL versus 3.3 ± 4.9 at HA, p < 0.01) in all subjects except those receiving dexamethasone. The ascent associated decrease in PaO2 correlated with the increase in IL-6 (r = 0.46, p < 0.001), but not suPAR (r = 0.27, p = 0.08); the increase in IL-6 was not correlated with suPAR (r = 0.16, p = 0.24). Baseline suPAR plasma concentration was higher in the HAPE-s group (2.0 ± 0.4 versus 1.8 ± 0.4, p = 0.04); no difference was found for CRP and IL-6 and for subjects developing AMS. Conclusion. High altitude exposure leads to an increase in suPAR plasma concentration, with the missing correlation between suPAR and IL-6 suggesting a cytokine independent, leukocyte mediated mechanism of low grade inflammation. The correlation between IL-6 and PaO2 suggests a direct effect of hypoxia, which is not the case for suPAR. However, suPAR plasma concentration measured before hypoxic exposure may predict

  16. Tissue and urokinase plasminogen activators instigate the degeneration of retinal ganglion cells in a mouse model of glaucoma.

    PubMed

    Chintala, Shravan K

    2016-02-01

    Elevated intraocular pressure (IOP) promotes the degeneration of retinal ganglion cells (RGCs) during the progression of Primary Open-Angle Glaucoma (POAG). However, the molecular mechanisms underpinning IOP-mediated degeneration of RGCs remain unclear. Therefore, by employing a mouse model of POAG, this study examined whether elevated IOP promotes the degeneration of RGCs by up-regulating tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) in the retina. IOP was elevated in mouse eyes by injecting fluorescent-microbeads into the anterior chamber. Once a week, for eight weeks, IOP in mouse eyes was measured by using Tono-Pen XL. At various time periods after injecting microbeads, proteolytic activity of tPA and uPA in retinal protein extracts was determined by fibrinogen/plasminogen zymography assays. Localization of tPA and uPA, and their receptor LRP-1 (low-density receptor-related protein-1) in the retina was determined by immunohistochemistry. RGCs' degeneration was assessed by immunostaining with antibodies against Brn3a. Injection of microbeads into the anterior chamber led to a progressive elevation in IOP, increased the proteolytic activity of tPA and uPA in the retina, activated plasminogen into plasmin, and promoted a significant degeneration of RGCs. Elevated IOP up-regulated tPA and LRP-1 in RGCs, and uPA in astrocytes. At four weeks after injecting microbeads, RAP (receptor associated protein; 0.5 and 1.0 μM) or tPA-Stop (1.0 and 4.0 μM) was injected into the vitreous humor. Treatment of IOP-elevated eyes with RAP led to a significant decrease in proteolytic activity of both tPA and uPA, and a significant decrease in IOP-mediated degeneration of RGCs. Also, treatment of IOP-elevated eyes with tPA-Stop decreased the proteolytic activity of both tPA and uPA, and, in turn, significantly attenuated IOP-mediated degeneration of RGCs. Results presented in this study provide evidence that elevated IOP promotes the degeneration of

  17. Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection

    PubMed Central

    Outinen, Tuula K.; Tervo, Laura; Mäkelä, Satu; Huttunen, Reetta; Mäenpää, Niina; Huhtala, Heini; Vaheri, Antti; Mustonen, Jukka; Aittoniemi, Janne

    2013-01-01

    Objectives Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β3-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease. Design A single-centre prospective cohort study. Subjects and Methods Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA). Results The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0–18.2 ng/ml vs. median 4.7 ng/ml, range 2.4–12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = −0.325, p = 0.001) and minimum hematocrit (r = −0.369, p<0.001). Conclusion Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β3-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease. PMID:23990945

  18. Structural analysis and tissue localization of human C4.4A: a protein homologue of the urokinase receptor.

    PubMed Central

    Hansen, Line V; Gårdsvoll, Henrik; Nielsen, Boye S; Lund, Leif R; Danø, Keld; Jensen, Ole N; Ploug, Michael

    2004-01-01

    C4.4A, a structural homologue of the urokinase-type plasminogen activator receptor (uPAR), was originally identified as a metastasis-associated membrane protein, but little is known about its structural and functional properties. Therefore, we expressed, purified and characterized a soluble truncated form of human C4.4A, and used this protein to produce specific polyclonal anti-C4.4A antibodies. By immunohistochemistry we observed a pronounced surface staining for C4.4A in suprabasal keratinocytes of chronic human wounds and found C4.4A expression markedly upregulated in migrating keratinocytes during re-epithelisation of incisional skin wounds. Phorbol-ester-induced hyperplasia of mouse skin is also accompanied by a significant induction of C4.4A expression in the multilayered, suprabasal keratinocytes. C4.4A contains two Ly-6 (leucocyte antigen 6)/uPAR/alpha-neurotoxin modules. Our recombinant human C4.4A is extensively modified by post-translational glycosylation, which include 5-6 N-linked carbohydrates primarily located in or close to its second Ly-6/uPAR/alpha-neurotoxin module and approximately 15 O-linked carbohydrates clustered in a Ser/Thr/Pro-rich region at the C-terminus. A highly protease-sensitive region (Tyr200-Arg204) is located between these two clusters of N- and O-linked carbohydrates. The natural, glycolipid-anchored C4.4A from amnion membranes of human term placenta exhibits similar properties. Using recombinant, soluble C4.4A or MCF 7 cells, which express significant amounts of GPI-anchored C4.4A, we find no evidence for an interaction between C4.4A and uPA, a property suggested previously for rat C4.4A. Collectively these data indicate that C4.4A, although being a structural homologue of uPAR, is unlikely to have a functional overlap with uPAR. PMID:15012588

  19. Optics in the Relativistic Regime

    NASA Astrophysics Data System (ADS)

    Tajima, Toshiki

    2012-06-01

    Optics has extended the frontier of low energy physics. Here we present the progress in the opposite direction of relativistic intensity regime of optics. With intense and large energy laser, particles may be accelerated to high energies via laser wakefield acceleration (Tajima and Dawson, 1979) over a compact distance orders of magnitude shorter than the RF approach. We should be able to accelerate electrons (over 30m) and ions (over cm) toward TeV with an existing kJ laser. We can check Lorentz invariance in the ultrarelativistic regime. Further, laser allows us to explore the presence of weakly coupling fields such as Dark Matter and Dark Energy with an unprecedented sensitivity. We call this emerging capability as the Laser Particle Physics Paradigm (LP^3).

  20. Demystifying optimal dynamic treatment regimes.

    PubMed

    Moodie, Erica E M; Richardson, Thomas S; Stephens, David A

    2007-06-01

    A dynamic regime is a function that takes treatment and covariate history and baseline covariates as inputs and returns a decision to be made. Murphy (2003, Journal of the Royal Statistical Society, Series B 65, 331-366) and Robins (2004, Proceedings of the Second Seattle Symposium on Biostatistics, 189-326) have proposed models and developed semiparametric methods for making inference about the optimal regime in a multi-interval trial that provide clear advantages over traditional parametric approaches. We show that Murphy's model is a special case of Robins's and that the methods are closely related but not equivalent. Interesting features of the methods are highlighted using the Multicenter AIDS Cohort Study and through simulation. PMID:17688497

  1. The emerging climate change regime

    SciTech Connect

    Bodansky, D.M.

    1995-11-01

    The emerging climate change regime--with the UN Framework Convention on Climate Change (FCCC) at its core--reflects the substantial uncertainties, high stakes and complicated politics of the greenhouse warming issue. The regime represents a hedging strategy. On the one hand, it treats climate change as a potentially serious problem, and in response, creates a long-term, evolutionary process to encourage further research, promote national planning, increase public awareness, and help create a sense of community among states. But it requires very little by way of substantive--and potentially costly--mitigation or adaptation measures. Although the FCCC parties have agreed to negotiate additional commitments, substantial progress is unlikely without further developments in science, technology, and public opinion. The FCCC encourages such developments, and is capable of evolution and growth, should the political will to take stronger international action emerge. 120 refs., 3 tabs.

  2. The International Climate Change Regime

    NASA Astrophysics Data System (ADS)

    Yamin, Farhana; Depledge, Joanna

    2005-01-01

    Aimed at the increasing number of policy-makers, stakeholders, researchers, and other professionals working on climate change, this volume presents a detailed description and analysis of the international regime established in 1992 to combat the threat of global climate change. It provides a comprehensive accessible guide to a high-profile area of international law and politics, covering not only the obligations and rights of countries, but ongoing climate negotiations as well.

  3. Hall effect in hopping regime

    NASA Astrophysics Data System (ADS)

    Avdonin, A.; Skupiński, P.; Grasza, K.

    2016-02-01

    A simple description of the Hall effect in the hopping regime of conductivity in semiconductors is presented. Expressions for the Hall coefficient and Hall mobility are derived by considering averaged equilibrium electron transport in a single triangle of localization sites in a magnetic field. Dependence of the Hall coefficient is analyzed in a wide range of temperature and magnetic field values. Our theoretical result is applied to our experimental data on temperature dependence of Hall effect and Hall mobility in ZnO.

  4. Merging of Rhine flow regimes

    NASA Astrophysics Data System (ADS)

    Boessenkool, Berry; Bronstert, Axel; Bürger, Gerd

    2016-04-01

    The Rhine flow regime is changing: (a) in the alpine nival regime, snow melt floods occur earlier in the year and (b) in the pluvial middle-Rhine regime, rainfall induced flood magnitudes rise. The seasonality of each is currently separated in time, but it is conceivable that this may shift due to climate change. If extremes of both flood types coincide, this would create a new type of hydrologic extreme with disastrous consequences. Quantifying the probability for a future overlap of pluvial and nival floods is therefore of high relevance to society and particularly to reinsurance companies. In order to investigate possible changes in magnitude and timing of flood types, we are developing a chain of physical models for spatio-temporal combination of flood probabilities. As input, we aim to use stochastically downscaled temperature and rainfall extremes from climate model weather projections. Preliminary research shows a six-week forward-shift of peak discharge at the nival gauge Maxau in the past century. The aim of presenting our early-stage work as a poster is to induce an exchange of ideas with fellow scientists in close research disciplines.

  5. Anti-Urokinase Receptor Antisense Oligonucleotide (uPAR-aODN) to Prevent and Cure Long-Term Space Exploration-Related Retinal Pathological Angiogenesis

    NASA Astrophysics Data System (ADS)

    Lazzarano, Stefano; Lulli, Matteo; Fibbi, Gabriella; Margheri, Francesca; Papucci, Laura; Serrati, Simona; Witort, Ewa; Chilla, Anastasia; Lapucci, Andrea; Donnini, Martino; Quaglierini, Paolo; Romiti, Alice; Specogna, Rebecca; Del Rosso, Mario; Capaccioli, Sergio

    2008-06-01

    Angiogenesis underlies a variety of physiological processes and its possible deregulation during long term space exploration needs to be investigated. Angiogenesis is a multistep process of new blood capillary formation, where degradation of the extracellular matrix (ECM) by proteolytic enzymes, including uPA (urokinase plasminogen activator) and opening the way to migration of endothelial cells (EC), is critical. Plasminogen activation system regulates angiogenesis by both uPA-driven ECM degradation and uPA receptor (uPAR). Microgravity and low dose irradiations promote tissue neoangiogeenesis and neovascularization is often common occurence in ophthalmologic pathologies. We have designed and patented the uPAR antisense oligonucleotide (aODN) and evaluated its antiangiogenetic activity by EC cellular migration and capillary morphogenesis assays. The uPAR aODN treatment caused a 75% inhibition of human microvascular EC migration and a complete inhibition of capillary morphogenesis, suggesting its therapeutic application to prevent neoangiogenesis-related ophthalmologic pathologies during space exploration.

  6. Optimization of Crystals of an Inhibitory Antibody of Urokinase Plasminogen Activator Receptor (uPAR) with Hydrogen Peroxide and Low Protein Concentration

    SciTech Connect

    Li, Yongdong; Shi, Xiaoli; Parry, Graham; Chen, Liqing; Callahan, Jennifer A.; Mazar, Andrew P.; Huang, Mingdong

    2010-07-19

    Optimization of protein crystal formation is often a necessary step leading to diffraction-quality crystals to enable collection of a full X-ray data set. Typical protein crystal optimization involves screening different components, e.g., pH, precipitants, and additives of the precipitant solution. Here we present an example using an inhibitory antibody of urokinase plasminogen activator receptor (uPAR) where such procedures did not yield diffracting crystals. In contrast, it was the treatment of the protein with hydrogen peroxide incubation and the protein concentration reduction that were found to be key factors in obtaining diffracting crystals. Final crystals diffracted to 1.75 {angstrom}, and belong to orthorhombic P212121 space group with unit cell parameters a = 37.162 {angstrom}, b = 84.474 {angstrom}, c = 134.030 {angstrom}, and contain one molecule of Fab fragment of anti-uro kinase receptor antibody in the asymmetric unit.

  7. The Role of Urokinase Plasminogen Activator and Plasmin Activator Inhibitor-1 on Vein Wall Remodeling in Experimental Deep Vein Thrombosis

    PubMed Central

    Baldwin, Joe F.; Sood, Vikram; Elfline, Megan A.; Luke, Cathy E.; Dewyer, Nicholas A.; Diaz, Jose A.; Myers, Dan D.; Wakefield, Thomas; Henke, Peter K.

    2012-01-01

    OBJECTIVE Deep vein thrombosis (DVT) resolution instigates an inflammatory response, resulting in vessel wall damage and scarring. Urokinase-plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), are integral components of the fibrinolytic system, essential for VT resolution. This study determined the vein wall response when exposed to increased and decreased plasmin activity. Methods A mouse inferior vena cava (IVC) ligation model in uPA −/− or PAI-1 −/− and their genetic wild types (B6/SvEv and C57/BL6, respectively) was used to create stasis thrombi, with tissue harvest at either 8 or 21d. Tissue analysis included gene expression of vascular smooth muscle cells (alpha SMA [αSMA], SM22) and endothelial marker (CD31), by real time PCR, ELISA, matrix metalloproteinase (MMP) -2 and 9 activity by zymography and vein wall collagen by picrosirius red histological analysis. A P < .05 was considered significant. RESULTS Thrombi were significantly larger in both 8d and 21d uPA −/− as compared to WT, and were significantly smaller in both 8 and 21d PAI-1 −/− as compared to WT. Correspondingly, 8d plasmin levels were reduced in half in uPA −/− and increased 3 fold in PAI-1 −/− when compared to respective WT thrombi (P < .05, N = 5 – 6). The endothelial marker CD31 was elevated 2 fold in PAI-1 −/− mice at 8d, but reduced 2.5 fold at 21d in uPA −/− as compared with WT (P = .02, N = 5 – 6), suggesting less endothelial preservation. Vein wall VSMC gene expression showed that 8d and 21d PAI-1 −/− mice had 2.3 and 3.8 fold more SM22 and 1.8 and 2.3 fold more αSMA expression than respective WT (P < .05, N = 5 – 7), as well as 1.8 fold increased αSMA (+) cells (N = 3 – 5, P ≤ .05). No significant difference in MMP2 or 9 activity was found in the PAI-1 −/− mice compared with WT, while 5.4 fold more MMP9 was present in 21d WT than 21d uPA −/− (P = .03, N = 5). Lastly, collagen was ~2 fold

  8. Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules.

    PubMed

    Gum, R; Juarez, J; Allgayer, H; Mazar, A; Wang, Y; Boyd, D

    1998-07-16

    The urokinase-type plasminogen activator receptor (u-PAR) has been implicated in tumor progression, and previous studies have shown that the expression of this gene is strongly up-regulated by PMA. Although the signaling mechanism by which PMA modulates u-PAR expression is not known, the effect of this phorbol ester on the expression of other genes has been ascribed to activation of the c-Raf-1-ERK signaling pathway. However, in the current study we examined an alternate possibility that the inductive effect of PMA on u-PAR expression also required a JNK1-dependent signaling cascade usually associated with stress-inducing stimuli. PMA treatment of the u-PAR-deficient OVCAR-3 ovarian cancer cells, which contain low JNK activities, resulted in a rapid (5 min) increase in JNK activity. Maximal JNK activity (12-fold induction) occurred after 30 min; this preceding the earliest detected rise in u-PAR protein (2 h). Dose-response studies with PMA also indicated that the increased JNK activity was tightly correlated with elevated u-PAR protein levels. The stimulation of u-PAR promoter activity by PMA required an intact upstream AP-1 motif (-184) and in PMA-treated cells this motif was bound with c-Jun as indicated from mobility shift assays. PMA up-regulated the c-Jun trans acting activity as indicated by the higher activity of a GAL4-regulated luciferase reporter in phorbol-ester-treated cells co-transfected with an expression vector encoding the c-Jun transactivation domain fused to the GAL4 DNA-binding domain. The ability of PMA to stimulate u-PAR promoter activity was effectively titrated out by the co-expression of either a kinase-defective JNK1 or a dominant negative MEKK1 the latter being an upstream activator of JNK1. Conversely, u-PAR promoter activity was stimulated by the co-expression of a constitutively active MEKK1 and this induction was antagonized by the inclusion of the kinase-defective JNK1 plasmid. We also determined the biological significance of the

  9. Urokinase-type Plasminogen Activator-like Proteases in Teleosts Lack Genuine Receptor-binding Epidermal Growth Factor-like Domains*

    PubMed Central

    Bager, René; Kristensen, Thomas K.; Jensen, Jan K.; Szczur, Agnieszka; Christensen, Anni; Andersen, Lisbeth M.; Johansen, Jesper S.; Larsen, Niels; Baatrup, Erik; Huang, Mingdong; Ploug, Michael; Andreasen, Peter A.

    2012-01-01

    Plasminogen activation catalyzed by urokinase-type plasminogen activator (uPA) plays an important role in normal and pathological tissue remodeling processes. Since its discovery in the mid-1980s, the cell membrane-anchored urokinase-type plasminogen activator receptor (uPAR) has been believed to be central to the functions of uPA, as uPA-catalyzed plasminogen activation activity appeared to be confined to cell surfaces through the binding of uPA to uPAR. However, a functional uPAR has so far only been identified in mammals. We have now cloned, recombinantly produced, and characterized two zebrafish proteases, zfuPA-a and zfuPA-b, which by several criteria are the fish orthologs of mammalian uPA. Thus, both proteases catalyze the activation of fish plasminogen efficiently and both proteases are inhibited rapidly by plasminogen activator inhibitor-1 (PAI-1). But zfuPA-a differs from mammalian uPA by lacking the exon encoding the uPAR-binding epidermal growth factor-like domain; zfuPA-b differs from mammalian uPA by lacking two cysteines of the epidermal growth factor-like domain and a uPAR-binding sequence comparable with that found in mammalian uPA. Accordingly, no zfuPA-b binding activity could be found in fish white blood cells or fish cell lines. We therefore propose that the current consensus of uPA-catalyzed plasminogen activation taking place on cell surfaces, derived from observations with mammals, is too narrow. Fish uPAs appear incapable of receptor binding in the manner known from mammals and uPA-catalyzed plasminogen activation in fish may occur mainly in solution. Studies with nonmammalian vertebrate species are needed to obtain a comprehensive understanding of the mechanism of plasminogen activation. PMID:22733817

  10. Mapping the topographic epitope landscape on the urokinase plasminogen activator receptor (uPAR) by surface plasmon resonance and X-ray crystallography.

    PubMed

    Zhao, Baoyu; Gandhi, Sonu; Yuan, Cai; Luo, Zhipu; Li, Rui; Gårdsvoll, Henrik; de Lorenzi, Valentina; Sidenius, Nicolai; Huang, Mingdong; Ploug, Michael

    2015-12-01

    The urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycolipid-anchored membrane protein often expressed in the microenvironment of invasive solid cancers and high levels are generally associated with poor patient prognosis (Kriegbaum et al., 2011 [1]). uPAR is organized as a dynamic modular protein structure composed of three homologous Ly6/uPAR domains (LU).This internally flexible protein structure of uPAR enables an allosteric regulation of the interactions with its two principal ligands: the serine protease urokinase-type plasminogen activator (uPA) and the provisional matrix protein vitronectin (Vn) (Mertens et al., 2012; Gårdsvoll et al., 2011; Madsen et al., 2007 [2-4]). The data presented here relates to the non-covalent trapping of one of these biologically relevant uPAR-conformations by a novel class of monoclonal antibodies (Zhao et al., 2015 [5]) and to the general mapping of the topographic epitope landscape on uPAR. The methods required to achieve these data include: (1) recombinant expression and purification of a uPAR-hybrid protein trapped in the desired conformation [patent; WO 2013/020898 A12013]; (2) developing monoclonal antibodies with unique specificities using this protein as antigen; (3) mapping the functional epitope on uPAR for these mAbs by surface plasmon resonance with a complete library of purified single-site uPAR mutants (Zhao et al., 2015; Gårdsvoll et al., 2006 [5,6]); and finally (4) solving the three-dimensional structures for one of these mAbs by X-ray crystallography alone and in complex with uPAR [deposited in the PDB database as 4QTH and 4QTI, respectively]. PMID:26504891

  11. Breddin's graph for tectonic regimes

    NASA Astrophysics Data System (ADS)

    Célérier, Bernard; Séranne, Michel

    2001-05-01

    A simple graphical method is proposed to infer the tectonic regime from a fault and slip data set. An abacus is overlaid on a plot of the rake versus strike of the data. This yields the horizontal principal stress directions and a constraint on the stress tensor aspect ratio, in a manner similar to Breddin's graph for two-dimensional strain analysis. The main requirement is that one of the principal stress directions is close to the vertical. This method is illustrated on monophase synthetic and natural data, but is also expected to help sort out multiphase data sets.

  12. Ireland unveils new license regime

    SciTech Connect

    Not Available

    1992-11-23

    Ireland has unveiled new terns designed to integrate the licensing regime for oil and gas exploration and development. They apply to new exploration and development authorizations and replace the exclusive offshore licensing terns introduced in 1975. Holders of existing licenses are still subject to the 1975 terms but can choose the new terns under appropriate circumstances. Frontier exploration licenses are currently available to complement the standard and deepwater exploration licenses in use. Rental fees are now spread evenly over the duration of the license, thereby eliminating large upfront payments. Lease extensions also have been introduced to enable operators to judge commerciality of a discovery beyond the set license period.

  13. A surfactant film spreading regime

    SciTech Connect

    Nikishov, V.I.

    1984-06-01

    Interest has recently increased in the study of the mechanisms whereby oil spills spread over sea and ocean surfaces. In the later stages of this process, when the petroleum film thickness becomes sufficiently small, the main forces determining the growth of its horizontal dimensions are surface tension and viscosity. In this case the flow characteristics do not depend on total quantity of spreading substance nor its surface concentration distribution. However, in the final stages of the spreading process the film becomes so thin that it is necessary to consider the effect of surface concentration distribution of the material on the process. Similar problems occur in the study of the spreading of a surfactant in the case where the total quantity of material is small and the surface tension regime sets in quickly. Therefore, the author examines here the spreading of a film in a regime wherein it is necessary to consider the total quantity of surfactant present, initially located on the surface of a viscous incompressible liquid.

  14. Adaptation in Collaborative Governance Regimes

    NASA Astrophysics Data System (ADS)

    Emerson, Kirk; Gerlak, Andrea K.

    2014-10-01

    Adaptation and the adaptive capacity of human and environmental systems have been of central concern to natural and social science scholars, many of whom characterize and promote the need for collaborative cross-boundary systems that are seen as flexible and adaptive by definition. Researchers who study collaborative governance systems in the public administration, planning and policy literature have paid less attention to adaptive capacity specifically and institutional adaptation in general. This paper bridges the two literatures and finds four common dimensions of capacity, including structural arrangements, leadership, knowledge and learning, and resources. In this paper, we focus on institutional adaptation in the context of collaborative governance regimes and try to clarify and distinguish collaborative capacity from adaptive capacity and their contributions to adaptive action. We posit further that collaborative capacities generate associated adaptive capacities thereby enabling institutional adaptation within collaborative governance regimes. We develop these distinctions and linkages between collaborative and adaptive capacities with the help of an illustrative case study in watershed management within the National Estuary Program.

  15. Adaptation in collaborative governance regimes.

    PubMed

    Emerson, Kirk; Gerlak, Andrea K

    2014-10-01

    Adaptation and the adaptive capacity of human and environmental systems have been of central concern to natural and social science scholars, many of whom characterize and promote the need for collaborative cross-boundary systems that are seen as flexible and adaptive by definition. Researchers who study collaborative governance systems in the public administration, planning and policy literature have paid less attention to adaptive capacity specifically and institutional adaptation in general. This paper bridges the two literatures and finds four common dimensions of capacity, including structural arrangements, leadership, knowledge and learning, and resources. In this paper, we focus on institutional adaptation in the context of collaborative governance regimes and try to clarify and distinguish collaborative capacity from adaptive capacity and their contributions to adaptive action. We posit further that collaborative capacities generate associated adaptive capacities thereby enabling institutional adaptation within collaborative governance regimes. We develop these distinctions and linkages between collaborative and adaptive capacities with the help of an illustrative case study in watershed management within the National Estuary Program. PMID:25073764

  16. Different regimes of dynamic wetting

    NASA Astrophysics Data System (ADS)

    Gustav, Amberg; Wang, Jiayu; Do-Quang, Minh; Shiomi, Junichiro; Physiochemical fluid mechanics Team; Maruyama-Chiashi Laboratory Team

    2014-11-01

    Dynamic wetting, as observed when a droplet contacts a dry solid surface, is important in various engineering processes, such as printing, coating, and lubrication. Our overall aim is to investigate if and how the detailed properties of the solid surface influence the dynamics of wetting. Here we discuss how surface roughness influences the initial dynamic spreading of a partially wetting droplet by studying the spreading on a solid substrate patterned with microstructures just a few micrometers in size. This is complemented by matching numerical simulations. We present a parameter map, based on the properties of the liquid and the solid surface, which identifies qualitatively different spreading regimes, where the spreading speed is limited by either the liquid viscosity, the surface properties, or the liquid inertia. The peculiarities of the different spreading regimes are studied by detailed numerical simulations, in conjuction with experiments. This work was financially supported in part by, the Japan Society for the Promotion of Science (J.W. and J.S) and Swedish Governmental Agency for Innovation Systems (M.D.-Q. and G.A).

  17. Discriminatory Proofreading Regimes in Nonequilibrium Systems

    NASA Astrophysics Data System (ADS)

    Murugan, Arvind; Huse, David A.; Leibler, Stanislas

    2014-04-01

    We use ideas from kinetic proofreading, an error-correcting mechanism in biology, to identify new kinetic regimes in nonequilibrium systems. These regimes are defined by the sensitivity of the occupancy of a state of the system to a change in its energy. In biological contexts, higher sensitivity corresponds to stronger discrimination between molecular substrates with different energetics competing in the same reaction. We study this discriminatory ability in systems with discrete states that are connected by a general network of transitions. We find multiple regimes of different discriminatory ability when the energy of a given state of the network is varied. Interestingly, the occupancy of the state can even increase with its energy, corresponding to an "antiproofreading" regime. The number and properties of such discriminatory regimes are limited by the topology of the network. Finally, we find that discriminatory regimes can be changed without modifying any "hard-wired" structural aspects of the system but rather by simply changing external chemical potentials.

  18. On unstable periodic regime of small HAWT

    NASA Astrophysics Data System (ADS)

    Dosaev, Marat Z.; Klimina, Liubov A.; Selyutskiy, Yury D.; Tsai, Mi-Ching; Yang, Hong-Tzer

    2012-11-01

    Dynamics of a small HAWT is studied. The closed mathematical model involving phenomenological description of both aerodynamic load upon turbine blades and permanent magnet electric generator is developed, in order to take into account the inductive reactance of the electric circuit. A series of experiments is performed in the subsonic wind tunnel of the LMSU Institute of Mechanics that allowed verifying the model and identifying its parameters. Parameters of dynamic model are identified, such as the coefficient of electromechanical interaction, the active internal resistance of generator, the circuit reactance. Parametric analysis of steady regimes is performed. The model prediction that HAWT operating dynamic system has two stable steady regimes (high speed regime and low speed one) is confirmed by experiments. Transient regimes are registered depending on parameters of the system, which allows estimating the unstable steady regime. The characteristics of the unstable regime are experimentally determined. Obtained results are used for estimation of aerodynamic moment acting on HAWT blades.

  19. Propagation Regime of Iron Dust Flames

    NASA Technical Reports Server (NTRS)

    Tang, Francois-David; Goroshin, Samuel; Higgins, Andrew J.

    2012-01-01

    A flame propagating through an iron-dust mixture can propagate in two asymptotic regimes. When the characteristic time of heat transfer between particles is much smaller than the characteristic time of particle combustion, the flame propagates in the continuum regime where the heat released by reacting particles can be modelled as a space-averaged function. In contrast, when the characteristic time of heat transfer is much larger than the particle reaction time, the flame can no longer be treated as a continuum due to dominating effects associated with the discrete nature of the particle reaction. The discrete regime is characterized by weak dependence of the flame speed on the oxygen concentration compared to the continuum regime. The discrete regime is observed in flames propagating through an iron dust cloud within a gas mixture containing xenon, while the continuum regime is obtained when xenon is substituted with helium.

  20. Multistability of synchronous regimes in rotator ensembles.

    PubMed

    Kryukov, A K; Petrov, V S; Osipov, G V; Kurths, J

    2015-12-01

    We study collective dynamics in rotator ensembles and focus on the multistability of synchronous regimes in a chain of coupled rotators. We provide a detailed analysis of the number of coexisting regimes and estimate in particular, the synchronization boundary for different types of individual frequency distribution. The number of wave-based regimes coexisting for the same parameters and its dependence on the chain length are estimated. We give an analytical estimation for the synchronization frequency of the in-phase regime for a uniform individual frequency distribution. PMID:26723160

  1. NFkappaB-dependent regulation of urokinase plasminogen activator by proanthocyanidin-rich grape seed extract: effect on invasion by prostate cancer cells.

    PubMed

    Uchino, Ryoji; Madhyastha, Radha; Madhyastha, Harishkumar; Dhungana, Sandra; Nakajima, Yuichi; Omura, Sayuri; Maruyama, Masugi

    2010-09-01

    Tumor invasion and metastasis present major obstacles to successful control of androgen-independent prostate cancer. Cell migration is a fundamental aspect of cancer cell metastasis. Urokinase plasminogen activator (uPA) system is implicated in cell migration and cancer metastasis and has potential to be developed as therapeutic target. In recent years, efficacy of dietary nutrients in preventing and curing cancer has gained increasing attention. One such promising candidate is proanthocyanidin-rich grape seed extract (GSE). We investigated the efficacy of GSE in regulating uPA expression and cell migration using highly metastatic androgen-independent PC3 prostate cancer cells as a model. GSE down-regulated uPA as a function of concentration. Additional studies showed that GSE inhibited DNA-binding activity of the transcription factor nuclear factor kappa B (NFkappaB), which in turn decreased NFkappaB-dependent uPA transcription. Invasion assays revealed the inhibitory effect of GSE on PC3 cell migration. These in-vitro experiments demonstrate the therapeutic property of GSE as an antimetastatic agent by targeting uPA. PMID:20502321

  2. Human single-chain urokinase is activated by the omptins PgtE of Salmonella enterica and Pla of Yersinia pestis despite mutations of active site residues.

    PubMed

    Järvinen, Hanna M; Laakkonen, Liisa; Haiko, Johanna; Johansson, Tiira; Juuti, Katri; Suomalainen, Marjo; Buchrieser, Carmen; Kalkkinen, Nisse; Korhonen, Timo K

    2013-08-01

    Fibrinolysis is important in cell migration and tightly regulated by specific inhibitors and activators; of the latter, urokinase (uPA) associates with enhancement of cell migration. Active uPA is formed through cleavage of the single-chain uPA (scuPA). The Salmonella enterica strain 14028R cleaved human scuPA at the peptide bond Lys158-Ile159, the site cleaved also by the physiological activator human plasmin. The cleavage led to activation of scuPA, while no cleavage or activation were detected with the mutant strain 14028R lacking the omptin protease PgtE. Complementation and expression studies confirmed the role of PgtE in scuPA activation. Similar cleavage and activation of scuPA were detected with recombinant Escherichia coli expressing the omptin genes pla from Yersinia pestis, ompT and ompP from E. coli, sopA from Shigella flexneri, and leo from Legionella pneumophila. For these omptins the activation of scuPA is the only shared function so far detected. Only poor cleavage and activation of scuPA were seen with YcoA of Y. pestis and YcoB of Yersinia pseudotuberculosis that are considered to be proteolytically inactive omptin variants. Point mutations of active site residues in Pla and PgtE had different effects on the proteolysis of plasminogen and of scuPA, indicating versatility in omptin proteolysis. PMID:23763588

  3. Hemangiosarcoma and its cancer stem cell subpopulation are effectively killed by a toxin targeted through epidermal growth factor and urokinase receptors.

    PubMed

    Schappa, Jill T; Frantz, Aric M; Gorden, Brandi H; Dickerson, Erin B; Vallera, Daniel A; Modiano, Jaime F

    2013-10-15

    Targeted toxins have the potential to overcome intrinsic or acquired resistance of cancer cells to conventional cytotoxic agents. Here, we hypothesized that EGFuPA-toxin, a bispecific ligand-targeted toxin (BLT) consisting of a deimmunized Pseudomonas exotoxin (PE) conjugated to epidermal growth factor and urokinase, would efficiently target and kill cells derived from canine hemangiosarcoma (HSA), a highly chemotherapy resistant tumor, as well as cultured hemangiospheres, used as a surrogate for cancer stem cells (CSC). EGFuPA-toxin showed cytotoxicity in four HSA cell lines (Emma, Frog, DD-1 and SB) at a concentration of ≤100 nM, and the cytotoxicity was dependent on specific ligand-receptor interactions. Monospecific targeted toxins also killed these chemoresistant cells; in this case, a "threshold" level of EGFR expression appeared to be required to make cells sensitive to the monospecific EGF-toxin, but not to the monospecific uPA-toxin. The IC₅₀ of CSCs was higher by approximately two orders of magnitude as compared to non-CSCs, but these cells were still sensitive to EGFuPA-toxin at nanomolar (i.e., pharmacologically relevant) concentrations, and when targeted by EGFuPA-toxin, resulted in death of the entire cell population. Taken together, our results support the use of these toxins to treat chemoresistant tumors such as sarcomas, including those that conform to the CSC model. Our results also support the use of companion animals with cancer for further translational development of these cytotoxic molecules. PMID:23553371

  4. The diagnostic value of soluble urokinase plasminogen activator receptor compared with C-reactive protein and procalcitonin in children with febrile neutropenia.

    PubMed

    Sirinoglu, Melis; Soysal, Ahmet; Karaaslan, Ayşe; Kepenekli Kadayifci, Eda; Cinel, Ismail; Koç, Ahmet; Tokuç, Gülnur; Yaman, Ali; Haklar, Goncagül; Şirikçi, Önder; Turan, Serap; Altınkanat Gelmez, Gülşen; Söyletir, Güner; Bakır, Mustafa

    2016-04-01

    The aim of the present study was to determine the diagnostic value of soluble urokinase plasminogen activator receptor (suPAR) in pediatric patients with febrile neutropenia. A prospective case-control study was performed. Patients included 29 children with febrile neutropenia (FN) and 27 control subjects without any infection or immunosuppressive condition. Blood samples were obtained on the day of admission and on the 4th to 7th days of the hospital stay. The median (minimum-maximum) serum levels of suPAR obtained on the first day of the admission were 2.08 (0.93-9.42) and 2.22 (1.08-5.13) ng/mL for the FN group and the control group, respectively. The median serum levels of suPAR in the FN and control groups were not significantly different (P = .053). The mean serum suPAR level was significantly higher in nonsurvivors than in survivors in the FN group (P < .05). In the FN group, the area under the receiver operating characteristics curve (AUCROC) for suPAR was 0.546, but no optimum cutoff value, sensitivity, specificity, negative predictive value (NPV), or positive predictive value (PPV) was obtained. We conclude that suPAR is not useful as a diagnostic biomarker in children with febrile neutropenia; however, persistent high serum suPAR level may predict mortality in FN in children. PMID:27057782

  5. The mRNA expression of soluble urokinase plasminogen activator surface receptor in human adipose tissue is positively correlated with body mass index.

    PubMed

    Ng, Hien Fuh; Chin, Kin Fah; Chan, Kok-Gan; Ngeow, Yun Fong

    2015-06-01

    suPLAUR is the transcript variant that encodes the soluble form of the urokinase plasminogen activator surface receptor (suPLAUR). This soluble protein has been shown to enhance leukocyte migration and adhesion, and its circulatory level is increased in inflammatory states. In this pilot study, we used RNA-Seq to examine the splicing pattern of PLAUR in omental adipose tissues from obese and lean individuals. Of the three transcript variants of the PLAUR gene, only the proportion of suPLAUR (transcript variant 2) increases in obesity. After removing the effects of gender and age, the expression of suPLAUR is positively correlated with body mass index. This observation was validated using RT-qPCR with an independent cohort of samples. Additionally, in our RNA-Seq differential expression analysis, we also observed, in obese adipose tissues, an up-regulation of genes encoding other proteins involved in the process of chemotaxis and leukocyte adhesion; of particular interest is the integrin beta 2 (ITGB2) that is known to interact with suPLAUR in leukocyte adhesion. These findings suggest an important role for suPLAUR in the recruitment of immune cells to obese adipose tissue, in the pathogenesis of obesity. PMID:26284904

  6. Incidence of Apoptosis in the Lymphoid Organs of Normal or Malaria Infected Mice is Decreased in CD18 and Urokinase - Receptor (UPAR, CD87) Deficient Mice

    PubMed Central

    da Laperrousaz, Chen; Vesin, Christian; Donati, Yves

    2001-01-01

    Incidence of apoptosis was investigated in the spleen and lymph nodes of +/+, CD18 -/- and urokinase receptor (uPAR, CD87) -/- mice, untreated or Plasmodium Berghei Anka (PbA) infected. In non infected mice, incidence of apoptosis was lower in the lymph nodes of CD18 -/- and uPAR -/- than in +/+ mice, as seen by FACS analysis to count the number of hypodiploid and Annexin-V binding cells. Infection of mice with PbA resulted in a marked increase in the size of spleen and lymph nodes 7–8 days after infection, which was slightly higher in uPAR -/- and CD18 -/- than in +/+ mice. PbA infection increased about 7 fold the incidence of apoptosis in the lymphoid organs of +/+, especially in the white pulp and germinal centers of the spleen and lymph nodes, while in contrast it was unchanged in PbA infected CD18 -/- or uPAR -/- mice. Serum IgG levels, and number of circulating leukocytes were significantly higher in both uPAR and CD18 -/- than in +/+ mice. These results indicate that the CD18 and uPAR surface molecules, which are known to be associated in the cell membrane, have an important influence upon the incidence of cell survival in both normal or stimulated lymphoid organs. PMID:11785668

  7. High Expression of Urokinase-Type Plasminogen Activator Is Associated with Lymph Node Metastasis of Invasive Ductal Carcinoma of the Breast

    PubMed Central

    Kim, Eun Young; Do, Sung-Im; Hyun, Keehoon; Park, Yong Lai; Kim, Dong-Hoon; Chae, Seoung Wan; Sohn, Jin Hee

    2016-01-01

    Purpose In the present study, we evaluated the levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) by performing immunohistochemical staining to determine whether they were reliable prognostic markers in patients with breast cancer. Methods Demographic and clinicopathological parameters of 214 patients with invasive ductal carcinoma (IDC) and 80 patients with ductal carcinoma in situ (DCIS) who were diagnosed and treated from 2006 to 2010 were analyzed. Tissue microarray was constructed and immunohistochemical staining was performed for each specimen. Results Univariate analyses showed that age at diagnosis, history of hormone replacement therapy, radiation therapy, skin and chest wall invasion, Paget disease, lymphovascular invasion, estrogen receptor positivity, and triple-negative subtype were significantly associated with patient prognosis (p<0.005). Patients with DCIS showed higher PAI-1 expression than patients with IDC (82.5% and 36.2%, respectively; p=0.012). Lymph node metastasis was more frequent in patients with high uPA levels than in patients with low uPA levels (p=0.001). Conclusion Our results suggested that PAI-1 was involved in tumor progression in the early stages of breast cancer, such as DCIS. In addition, our results suggested that high uPA levels were associated with the lymph node metastasis of IDC. PMID:27382391

  8. Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor.

    PubMed

    Xu, Peng; Xu, Mingming; Jiang, Longguang; Yang, Qinglan; Luo, Zhipu; Dauter, Zbigniew; Huang, Mingdong; Andreasen, Peter A

    2015-11-25

    All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 μM) without measurable affinity to plasma kallikrein (Ki > 1000 μM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 μM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases. PMID:26536069

  9. Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.

    PubMed

    Gladysz, Rafaela; Adriaenssens, Yves; De Winter, Hans; Joossens, Jurgen; Lambeir, Anne-Marie; Augustyns, Koen; Van der Veken, Pieter

    2015-12-10

    Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types. Its inhibition is regarded as a promising, noncytotoxic approach in cancer therapy by blocking growth and/or metastasis of solid tumors. Earlier, we reported the modified substrate activity screening (MSAS) approach and applied it for the identification of fragments with affinity for uPA's S1 pocket. Here, these fragments are transformed into a novel class of uPA inhibitors with an imidazo[1,2-a]pyridine scaffold. The SAR for uPA inhibition around this scaffold is explored, and the best compounds in the series have nanomolar uPA affinity and selectivity with respect to the related trypsin-like serine proteases (thrombin, tPA, FXa, plasmin, plasma kallikrein, trypsin, FVIIa). Finally, the approach followed for translating fragments into small molecules with a decorated scaffold architecture is conceptually straightforward and can be expected to be broadly applicable in fragment-based drug design. PMID:26575094

  10. Macromolecular interaction on a cAMP responsive region in the urokinase-type plasminogen activator gene: a role of protein phosphorylation.

    PubMed Central

    von der Ahe, D; Pearson, D; Nagamine, Y

    1990-01-01

    We have studied the regulation of urokinase-type plasminogen activator gene expression by cAMP in LLC-PK1 cells. We found a cAMP responsive region 3.4 kb upstream of the transcription initiation site, which comprised three protein-binding domains designated A, B, and C. Domains A and B both contain a sequence, TGACG, homologous to a consensus cAMP response element (CRE; TGACGTCA). Effective cAMP-mediated induction was achieved when these two domains were linked with domain C, which by itself did not confer cAMP responsiveness to a heterologous promoter nor contained CRE-like sequence, suggesting a functional cooperation among these domains. Results of competition studies using gel retardation and DNase I footprinting assays suggest that there is a protein-protein interaction between a CRE binding protein and a domain C binding protein. In gel retardation assays, binding of a nuclear protein to domains A and B was strongly augmented by addition of the catalytic subunit of cAMP-dependent protein kinase, whereas the protein binding to domain C was slightly inhibited, suggesting that protein phosphorylation is involved in the regulation of protein-DNA interaction. Images PMID:2159633

  11. Urokinase-type Plasminogen Activator Resulting from Endometrial Carcinogenesis Enhances Tumor Invasion and Correlates with Poor Outcome of Endometrial Carcinoma Patients

    PubMed Central

    Huang, Chia-Yen; Chang, Ming-Cheng; Huang, Wei-Yun; Huang, Ching-Ting; Tang, Yu-Chien; Huang, Hsien-Da; Kuo, Kuan-Ting; Chen, Chi-An; Cheng, Wen-Fang

    2015-01-01

    The purpose of this study was to identify the dysregulated genes involved in the tumorigenesis and progression of endometrial endometrioid adenocarcinoma (EEC), and their possible mechanisms. Endometrial specimens including normal endometrial tissues, atypical endometrial hyperplasia, and EEC were analyzed. The expression profiles were compared using GeneChip Array. The gene expression levels were determined by real-time RT-PCR in the training and testing sets to correlate the clinico-pathological parameters of EEC. Immunoblotting, in vitro cell migration and invasion assays were performed in human endometrial cancer cell lines and their transfectants. In microarray analysis, seven dysregulated genes were identified. Only the levels of urokinase-type plasminogen activator (uPA) were higher in EEC with deep myometrial invasion, positive lympho-vascular space invasion, lymph node metastasis, and advanced stages. After multivariate analysis, uPA was the only independent poor prognostic factor for disease-free survival in the EEC patients (hazard ratio: 4.65, p = 0.03). uPA may enhance the migratory and invasive capabilities of endometrial tumor cells by the phosphorylation of ERK1/2, Akt and p38 molecules. uPA is a dysregulated gene involved in the tumorigenesis, bio-pathological features and outcomes of EEC. uPA may be a potential molecule and target for the detection and treatment of EEC. PMID:26033187

  12. Cytoskeletal reorganization and TPA differently modify AP-1 to induce the urokinase-type plasminogen activator gene in LLC-PK1 cells.

    PubMed Central

    Lee, J S; von der Ahe, D; Kiefer, B; Nagamine, Y

    1993-01-01

    Urokinase-type plasminogen activator (uPA) is an extracellular protease and expressed in various cells that exhibit dynamic changes in cell morphology, suggesting a link between cytoskeletal reorganization (CSR) and uPA expression. CSR can be induced by pharmacological agents, such as by colchicine for microtubule cytoskeleton and by cytochalasin for microfilament cytoskeleton. Using these agents, we previously showed that CSR induced the uPA gene in LLC-PK1 cells independently of the protein kinase C and cAMP-dependent protein kinase. Here we show that the induction of the uPA gene by CSR is mediated by the activation of c-Jun which interacts with an AP-1-like site located 2 kb upstream of the uPA gene. 12-O-tetradecanoylphorbol 13-acetate (TPA) induces the uPA gene through the same elements, but additionally utilizes an adjacent PEA3 element and induces c-fos. Furthermore, CSR induces a greater accumulation and a more pronounced phosphorylation of c-Jun than TPA induction. AP-1 is a positive regulator of growth and oncogenesis, and CSR is an integral part of these processes. Our results provide a view how CSR and AP-1 could be coupled in these processes. We also show that TPA and CSR act synergistically, suggesting a model where an initial activation signal could be amplified by CSR. Images PMID:8346015

  13. FISHER INFORMATION AND ECOSYSTEM REGIME CHANGES

    EPA Science Inventory

    Following Fisher’s work, we propose two different expressions for the Fisher Information along with Shannon Information as a means of detecting and assessing shifts between alternative ecosystem regimes. Regime shifts are a consequence of bifurcations in the dynamics of an ecosys...

  14. Capacitance densitometer for flow regime identification

    DOEpatents

    Shipp, Jr., Roy L.

    1978-01-01

    This invention relates to a capacitance densitometer for determining the flow regime of a two-phase flow system. A two-element capacitance densitometer is used in conjunction with a conventional single-beam gamma densitometer to unambiguously identify the prevailing flow regime and the average density of a flowing fluid.

  15. Regimes of DNA confined in a nanochannel

    NASA Astrophysics Data System (ADS)

    Dai, Liang; Doyle, Patrick

    2014-03-01

    Scaling regimes for polymers confined to tubular channels are well established when the channel cross-sectional dimension is either very small (Odjik regime) or large (classic de Gennes regime) relative to the polymer Kuhn length. In the literature, there is no clear consensus regarding the intermediate region and if subregimes even exist to connect these two classic bounding regimes. The confluence of emerging single DNA mapping technologies and a resurged interest in the fundamental properties of confined polymers has led to extensive research in this area using DNA as a model system. Due to the DNA molecule's properties and limitations of nanofabrication, most experiments are performed in this intermediate regime with channel dimensions of a few Kuhn lengths. Here we use simulations and theory to reconcile conflicting theories and show that there are indeed extended de Gennes, partial alignment and hairpin regimes located between the two classic regimes. Simulations results for both chain extension and free energy support the existence of these regimes. This research was supported by the National Research Foundation Singapore through the Singapore MIT Alliance for Research and Technology's research program in BioSystems and Micromechanics, the National Science Foundation (CBET-1335938).

  16. Blowout regimes of plasma wakefield acceleration.

    PubMed

    Lotov, K V

    2004-04-01

    A wide region of beam parameters is numerically scanned and the dependence of wakefield properties on the beam length and current is clarified for the blowout regime of beam-plasma interaction. The main regimes of the plasma response are found, which qualitatively differ in the plasma behavior. To characterize the efficiency of the energy exchange between the beam and the plasma, the energy flux through the comoving window is introduced. Scalings of the energy flux for the linear plasma response and the main blowout regimes are studied. The most efficient energy transfer occurs in the so-called "strong beam" regime of interaction. For this regime, analytical approximations for various aspects of the plasma response are obtained. PMID:15169104

  17. Discrete fluorescent saturation regimes in multilevel systems

    NASA Technical Reports Server (NTRS)

    Kastner, S. O.; Bhatia, A. K.

    1988-01-01

    Using models of multilevel atoms, the fluorescent process was examined for the ratio of the photooxidation rate, Pij, to the collisional oxidation rate, Cij, in the pumped resonance transition i-j. It is shown that, in the full range of the parameter Pij/Cij, there exist three distinct regimes (I, II, and III) which may be usefully exploited. These regimes are defined, respectively, by the following conditions: Pij/Cij smaller than about 1; Pij/Cij much greater than 1 and Pij much lower than Cki; and Pij/Cij much greater than 1 and Pij much higher than Cki, where Cki is the collisional rate populating the source level i. The only regime which is characterized by the sensitivity of fluorescent-fluorescent line intensity ratios to Pij is regime I. If regime III is reached, even fluorescent-nonfluorescent line ratios become independent of Pij. The analysis is applied to the resonant photoexcitation of a carbonlike ion.

  18. Snowpack regimes of the Western United States

    NASA Astrophysics Data System (ADS)

    Trujillo, Ernesto; Molotch, Noah P.

    2014-07-01

    Snow accumulation and melt patterns play a significant role in the water, energy, carbon, and nutrient cycles in the montane environments of the Western United States. Recent studies have illustrated that changes in the snow/rainfall apportionments and snow accumulation and melt patterns may occur as a consequence of changes in climate in the region. In order to understand how these changes may affect the snow regimes of the region, the current characteristics of the snow accumulation and melt patterns must be identified. Here we characterize the snow water equivalent (SWE) curve formed by the daily SWE values at 766 snow pillow stations in the Western United States, focusing on several metrics of the yearly SWE curves and the relationships between the different metrics. The metrics are the initial snow accumulation and snow disappearance dates, the peak snow accumulation and date of peak, the length of the snow accumulation season, the length of the snowmelt season, and the snow accumulation and snowmelt slopes. Three snow regimes emerge from these results: a maritime, an intermountain, and a continental regime. The maritime regime is characterized by higher maximum snow accumulations reaching 300 cm and shorter accumulation periods of less than 220 days. Conversely, the continental regime is characterized by lower maximum accumulations below 200 cm and longer accumulation periods reaching over 260 days. The intermountain regime lies in between. The regions that show the characteristics of the maritime regime include the Cascade Mountains, the Klamath Mountains, and the Sierra Nevada Mountains. The intermountain regime includes the Eastern Cascades slopes and foothills, the Blue Mountains, Northern and Central basins and ranges, the Columbia Mountains/Northern Rockies, the Idaho Batholith, and the Canadian Rockies. Lastly, the continental regime includes the Middle and Southern Rockies, and the Wasatch and Uinta Mountains. The implications of snow regime

  19. The Association between HbA1c, Fasting Glucose, 1-Hour Glucose and 2-Hour Glucose during an Oral Glucose Tolerance Test and Cardiovascular Disease in Individuals with Elevated Risk for Diabetes

    PubMed Central

    Lind, Marcus; Tuomilehto, Jaakko; Uusitupa, Matti; Nerman, Olle; Eriksson, Johan; Ilanne-Parikka, Pirjo; Keinänen-Kiukaanniemi, Sirkka; Peltonen, Markku; Pivodic, Aldina; Lindström, Jaana

    2014-01-01

    Objective To determine the association between HbA1c, fasting plasma glucose (FPG), 1-hour (1 hPG) and 2-hour (2 hPG) glucose after an oral glucose tolerance test (OGTT) and cardiovascular disease in individuals with elevated risk for diabetes. Design We studied the relationship between baseline, updated mean and updated (last) value of HbA1c, FPG, 1 hPG and 2 hPG after an oral 75 g glucose tolerance test (OGTT) and acute CVD events in 504 individuals with impaired glucose tolerance (IGT) at baseline enrolled in the Finnish Diabetes Prevention Study. Setting Follow-up of clinical trial. Participants 504 individuals with IGT were followed with yearly evaluations with OGTT, FPG and HbA1c. Main Outcome Measure Relative risk of CVD. Results Over a median follow-up of 9.0 years 34 (6.7%) participants had a CVD event, which increased to 52 (10.3%) over a median follow-up of 13.0 years when including events that occurred among participants following a diagnosis of diabetes. Updated mean HbA1c, 1 hPG and 2 hPG, HR per 1 unit SD of 1.57 (95% CI 1.16 to 2.11), p = 0.0032, 1.51 (1.03 to 2.23), p = 0.036 and 1.60 (1.10 to 2.34), p = 0.014, respectively, but not FPG (p = 0.11), were related to CVD. In analyses of the last value prior to the CVD event the same three glycaemic measurements were associated with the CVD events, with HRs per 1 unit SD of 1.45 (1.06 to 1.98), p = 0.020, 1.55 (1.04 to 2.29), p = 0.030 and 2.19 (1.51 to 3.18), p<0.0001, respectively but only 2 hPG remained significant in pairwise comparisons. Including the follow-up period after diabetes onset updated 2 hPG (p = 0.003) but not updated mean HbA1c (p = 0.08) was related to CVD. Conclusions and Relevance Current 2 hPG level in people with IGT is associated with increased risk of CVD. This supports its use in screening for prediabetes and monitoring glycaemic levels of people with prediabetes. PMID:25285769

  20. Abrupt climate-independent fire regime changes

    USGS Publications Warehouse

    Pausas, Juli G.; Keeley, Jon E.

    2014-01-01

    Wildfires have played a determining role in distribution, composition and structure of many ecosystems worldwide and climatic changes are widely considered to be a major driver of future fire regime changes. However, forecasting future climatic change induced impacts on fire regimes will require a clearer understanding of other drivers of abrupt fire regime changes. Here, we focus on evidence from different environmental and temporal settings of fire regimes changes that are not directly attributed to climatic changes. We review key cases of these abrupt fire regime changes at different spatial and temporal scales, including those directly driven (i) by fauna, (ii) by invasive plant species, and (iii) by socio-economic and policy changes. All these drivers might generate non-linear effects of landscape changes in fuel structure; that is, they generate fuel changes that can cross thresholds of landscape continuity, and thus drastically change fire activity. Although climatic changes might contribute to some of these changes, there are also many instances that are not primarily linked to climatic shifts. Understanding the mechanism driving fire regime changes should contribute to our ability to better assess future fire regimes.

  1. Phospho-MEK1/2 and uPAR Expression Determine Sensitivity of AML Blasts to a Urokinase-Activated Anthrax Lethal Toxin (PrAgU2/LF)1

    PubMed Central

    Bekdash, Amira; Darwish, Manal; Timsah, Zahra; Kassab, Elias; Ghanem, Hadi; Najjar, Vicky; Ghosn, Marwan; Nasser, Selim; El-Hajj, Hiba; Bazerbachi, Ali; Liu, Shihui; Leppla, Stephen H.; Frankel, Arthur E.; Abi-Habib, Ralph J.

    2015-01-01

    In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primary AML blasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic and was associated with MAPK activation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels of MEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34+ bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7-fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule. We have shown, in this study, that PrAgU2/LF is a novel, dual-specific molecule for the selective targeting of AML. PMID:26500025

  2. Earth Regime Network Evolution Study (ERNESt)

    NASA Technical Reports Server (NTRS)

    Menrad, Bob

    2016-01-01

    Speaker and Presenter at the Lincoln Laboratory Communications Workshop on April 5, 2016 at the Massachusetts Institute of Technology Lincoln Laboratory in Lexington, MA. A visual presentation titled Earth Regimes Network Evolution Study (ERNESt).

  3. Electron transport fluxes in potato plateau regime

    SciTech Connect

    Shaing, K.C.; Hazeltine, R.D.

    1997-12-01

    Electron transport fluxes in the potato plateau regime are calculated from the solutions of the drift kinetic equation and fluid equations. It is found that the bootstrap current density remains finite in the region close to the magnetic axis, although it decreases with increasing collision frequency. This finite amount of the bootstrap current in the relatively collisional regime is important in modeling tokamak startup with 100{percent} bootstrap current. {copyright} {ital 1997 American Institute of Physics.}

  4. Molecular motors in conservative and dissipative regimes

    NASA Astrophysics Data System (ADS)

    Perez-Carrasco, R.; Sancho, J. M.

    2011-10-01

    We present a theoretical study of a rotatory molecular motor under a conservative torque regime. We show that conservative and dissipative regimes present a different observable phenomenology. Our approach starts with a preliminary deterministic calculation of the motor cycle, which is complemented with stochastic simulations of a Langevin equation under a flashing ratchet potential. Finally, by using parameter values obtained from independent experimental information, our theoretical predictions are compared with experimental data of the F1-ATPase motor of the Bacillus PS3.

  5. Regime Diagrams for K-Theory Dispersion

    NASA Astrophysics Data System (ADS)

    Smith, Ronald B.

    2011-06-01

    In atmospheric dispersion, the "non-Gaussian" effects of gravitational settling, the vertical gradient in diffusivity and the surface deposition do not enter uniformly but rather break up parameter space into several discrete regimes. Here, we describe regime diagrams that are constructed for K-theory dispersion of effluent from a surface line source in unsheared inhomogeneous turbulence, using a previously derived Fourier-Hankel method. This K-theory formulation differs from the traditional one by keeping a non-zero diffusivity at the ground. This change allows for turbulent exchange between the canopy and the atmosphere and allows new natural length scales to emerge. The axes on the regime diagrams are non-dimensional distance defined as the ratio of downwind distance to the characteristic length scale for each effect. For each value of the ratio of settling speed to the K gradient, two to four regimes are found. Concentration formulae are given for each regime. The regime diagrams allow real dispersion problems to be categorized and the validity of end-state concentration formulae to be judged.

  6. Cyclization of the urokinase receptor-derived ser-arg-ser-arg-tyr Peptide generates a potent inhibitor of trans-endothelial migration of monocytes.

    PubMed

    Yousif, Ali Munaim; Minopoli, Michele; Bifulco, Katia; Ingangi, Vincenzo; Di Carluccio, Gioconda; Merlino, Francesco; Motti, Maria Letizia; Grieco, Paolo; Carriero, Maria Vincenza

    2015-01-01

    The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility. We and others have previously documented that the uPAR88-92 sequence, even in the form of synthetic linear peptide (SRSRY), interacts with the formyl peptide receptor type 1 (FPR1), henceforth inducing cell migration of several cell lines, including monocytes. FPR1 is mainly expressed by mammalian phagocytic leukocytes and plays a crucial role in chemotaxis. In this study, we present evidence that the cyclization of the SRSRY sequence generates a new potent and stable inhibitor of monocyte trafficking. In rat basophilic leukaemia RBL-2H3/ETFR cells expressing high levels of constitutively activated FPR1, the cyclic SRSRY peptide ([SRSRY]) blocks FPR1 mediated cell migration by interfering with both internalization and ligand-uptake of FPR1. Similarly to RBL-2H3/ETFR cells, [SRSRY] competes with fMLF for binding to FPR1 and prevents agonist-induced FPR1 internalization in human monocyte THP-1 cells. Unlike scramble [RSSYR], [SRSRY] inhibits fMLF-directed migration of monocytes in a dose-dependent manner, with IC50 value of 0.01 nM. PMA-differentiated THP-1 cell exposure to fMLF gradient causes a marked cytoskeletal re-organization with the formation of F-actin rich pseudopodia that are prevented by the addition of [SRSRY]. Furthermore, [SRSRY] prevents migration of human primary monocytes and trans-endothelial migration of monocytes. Our findings indicate that [SRSRY] is a new FPR1 inhibitor which may suggest the development of new drugs for treating pathological conditions sustained by increased motility of monocytes, such as chronic inflammatory diseases. PMID:25938482

  7. Cyclization of the Urokinase Receptor-Derived Ser-Arg-Ser-Arg-Tyr Peptide Generates a Potent Inhibitor of Trans-Endothelial Migration of Monocytes

    PubMed Central

    Bifulco, Katia; Ingangi, Vincenzo; Di Carluccio, Gioconda; Merlino, Francesco; Motti, Maria Letizia; Grieco, Paolo; Carriero, Maria Vincenza

    2015-01-01

    The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility. We and others have previously documented that the uPAR88-92 sequence, even in the form of synthetic linear peptide (SRSRY), interacts with the formyl peptide receptor type 1 (FPR1), henceforth inducing cell migration of several cell lines, including monocytes. FPR1 is mainly expressed by mammalian phagocytic leukocytes and plays a crucial role in chemotaxis. In this study, we present evidence that the cyclization of the SRSRY sequence generates a new potent and stable inhibitor of monocyte trafficking. In rat basophilic leukaemia RBL-2H3/ETFR cells expressing high levels of constitutively activated FPR1, the cyclic SRSRY peptide ([SRSRY]) blocks FPR1 mediated cell migration by interfering with both internalization and ligand-uptake of FPR1. Similarly to RBL-2H3/ETFR cells, [SRSRY] competes with fMLF for binding to FPR1 and prevents agonist-induced FPR1 internalization in human monocyte THP-1 cells. Unlike scramble [RSSYR], [SRSRY] inhibits fMLF-directed migration of monocytes in a dose-dependent manner, with IC50 value of 0.01 nM. PMA-differentiated THP-1 cell exposure to fMLF gradient causes a marked cytoskeletal re-organization with the formation of F-actin rich pseudopodia that are prevented by the addition of [SRSRY]. Furthermore, [SRSRY] prevents migration of human primary monocytes and trans-endothelial migration of monocytes. Our findings indicate that [SRSRY] is a new FPR1 inhibitor which may suggest the development of new drugs for treating pathological conditions sustained by increased motility of monocytes, such as chronic inflammatory diseases. PMID:25938482

  8. The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style.

    PubMed

    Margheri, Francesca; Luciani, Cristina; Taddei, Maria Letizia; Giannoni, Elisa; Laurenzana, Anna; Biagioni, Alessio; Chillà, Anastasia; Chiarugi, Paola; Fibbi, Gabriella; Del Rosso, Mario

    2014-03-30

    The receptor for the urokinase plasminogen activator (uPAR) is up-regulated in malignant tumors. Historically the function of uPAR in cancer cell invasion is strictly related to its property to promote uPA-dependent proteolysis of extracellular matrix and to open a path to malignant cells. These features are typical of mesenchymal motility. Here we show that the full-length form of uPAR is required when prostate and melanoma cancer cells convert their migration style from the "path generating" mesenchymal to the "path finding" amoeboid one, thus conferring a plasticity to tumor cell invasiveness across three-dimensional matrices. Indeed, in response to a protease inhibitors-rich milieu, prostate and melanoma cells activated an amoeboid invasion program connoted by retraction of cell protrusions, RhoA-mediated rounding of the cell body, formation of a cortical ring of actin and a reduction of Rac-1 activation. While the mesenchymal movement was reduced upon silencing of uPAR expression, the amoeboid one was almost completely abolished, in parallel with a deregulation of small Rho-GTPases activity. In melanoma and prostate cancer cells we have shown uPAR colocalization with β1/β3 integrins and actin cytoskeleton, as well integrins-actin co-localization under both mesenchymal and amoeboid conditions. Such co-localizations were lost upon treatment of cells with a peptide that inhibits uPAR-integrin interactions. Similarly to uPAR silencing, the peptide reduced mesenchymal invasion and almost abolished the amoeboid one. These results indicate that full-length uPAR bridges the mesenchymal and amoeboid style of movement by an inward-oriented activity based on its property to promote integrin-actin interactions and the following cytoskeleton assembly. PMID:24681666

  9. Modulation of Cellular Migration and Survival by c-Myc through the Downregulation of Urokinase (uPA) and uPA Receptor▿ †

    PubMed Central

    Alfano, Daniela; Votta, Giuseppina; Schulze, Almut; Downward, Julian; Caputi, Mario; Stoppelli, Maria Patrizia; Iaccarino, Ingram

    2010-01-01

    It has been proposed that c-Myc proapoptotic activity accounts for most of its restraint of tumor formation. We established a telomerase-immortalized human epithelial cell line expressing an activatable c-Myc protein. We found that c-Myc activation induces, in addition to increased sensitivity to apoptosis, reductions in cell motility and invasiveness. Transcriptome analysis revealed that urokinase (uPA) and uPA receptor (uPAR) were strongly downregulated by c-Myc. Evidence is provided that the repression of uPA and uPAR may account for most of the antimigratory and proapoptotic activities of c-Myc. c-Myc is known to cooperate with Ras in cellular transformation. We therefore investigated if this cooperation could converge in the control of uPA/uPAR expression. We found that Ras is able to block the effects of c-Myc activation on apoptosis and cellular motility but not on cell invasiveness. Accordingly, the activation of c-Myc in the context of Ras expression had only minor influence on uPAR expression but still had a profound repressive effect on uPA expression. Thus, the differential regulation of uPA and uPAR by c-Myc and Ras correlates with the effects of these two oncoproteins on cell motility, invasiveness, and survival. In conclusion, we have discovered a novel link between c-Myc and uPA/uPAR. We propose that reductions of cell motility and invasiveness could contribute to the inhibition of tumorigenesis by c-Myc and that the regulation of uPA and uPAR expression may be a component of the ability of c-Myc to reduce motility and invasiveness. PMID:20123981

  10. Epithelial and Stromal Cell Urokinase Plasminogen Activator Receptor Expression Differentially Correlates with Survival in Rectal Cancer Stages B and C Patients

    PubMed Central

    Ahn, Seong Beom; Chan, Charles; Dent, Owen F.; Mohamedali, Abidali; Kwun, Sun Young; Clarke, Candice; Fletcher, Julie; Chapuis, Pierre H.; Nice, Edouard C.; Baker, Mark S.

    2015-01-01

    Urokinase plasminogen activator receptor (uPAR) has been proposed as a potential prognostic factor for colorectal cancer (CRC) patient survival. However, CRC uPAR expression remains controversial, especially regarding cell types where uPAR is overexpressed (e.g., epithelium (uPARE) or stroma-associated cells (uPARS)) and associated prognostic relevance. In this study, two epitope-specific anti-uPAR monoclonal antibodies (MAbs) could discriminate expression of uPARE from uPARS and were used to examine this association with survival of stages B and C rectal cancer (RC) patients. Using immunohistochemistry, MAbs #3937 and R4 were used to discriminate uPARE from uPARS respectively in the central and invasive frontal regions of 170 stage B and 179 stage C RC specimens. Kaplan-Meier and Cox regression analyses were used to determine association with survival. uPAR expression occurred in both epithelial and stromal compartments with differential expression observed in many cases, indicating uPARE and uPARS have different cellular roles. In the central and invasive frontal regions, uPARE was adversely associated with overall stage B survival (HR = 1.9; p = 0.014 and HR = 1.5; p = 0.031, respectively) reproducing results from previous studies. uPARS at the invasive front was associated with longer stage C survival (HR = 0.6; p = 0.007), reflecting studies demonstrating that macrophage peritumoural accumulation is associated with longer survival. This study demonstrates that different uPAR epitopes should be considered as being expressed on different cell types during tumour progression and at different stages in RC. Understanding how uPARE and uPARS expression affects survival is anticipated to be a useful clinical prognostic marker of stages B and C RC. PMID:25692297

  11. Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion*♦

    PubMed Central

    Gilder, Andrew S.; Jones, Karra A.; Hu, Jingjing; Wang, Lei; Chen, Clark C.; Carter, Bob S.; Gonias, Steven L.

    2015-01-01

    Genomic heterogeneity is characteristic of glioblastoma (GBM). In many GBMs, the EGF receptor gene (EGFR) is amplified and may be truncated to generate a constitutively active form of the receptor called EGFRvIII. EGFR gene amplification and EGFRvIII are associated with GBM progression, even when only a small fraction of the tumor cells express EGFRvIII. In this study, we show that EGFRvIII-positive GBM cells express significantly increased levels of cellular urokinase receptor (uPAR) and release increased amounts of soluble uPAR (suPAR). When mice were xenografted with human EGFRvIII-expressing GBM cells, tumor-derived suPAR was detected in the plasma, and the level was significantly increased compared with that detected in plasma samples from control mice xenografted with EGFRvIII-negative GBM cells. suPAR also was increased in plasma from patients with EGFRvIII-positive GBMs. Purified suPAR was biologically active when added to cultures of EGFRvIII-negative GBM cells, activating cell signaling and promoting cell migration and invasion. suPAR did not significantly stimulate cell signaling or migration of EGFRvIII-positive cells, probably because cell signaling was already substantially activated in these cells. The activities of suPAR were replicated by conditioned medium (CM) from EGFRvIII-positive GBM cells. When the CM was preincubated with uPAR-neutralizing antibody or when uPAR gene expression was silenced in cells used to prepare CM, the activity of the CM was significantly attenuated. These results suggest that suPAR may function as an important paracrine signaling factor in EGFRvIII-positive GBMs, inducing an aggressive phenotype in tumor cells that are EGFRvIII-negative. PMID:25837250

  12. Protease Nexin-1 affects the migration and invasion of C6 glioma cells through the regulation of urokinase Plasminogen Activator and Matrix Metalloproteinase-9/2.

    PubMed

    Pagliara, Valentina; Adornetto, Annagrazia; Mammì, Maria; Masullo, Mariorosario; Sarnataro, Daniela; Pietropaolo, Concetta; Arcone, Rosaria

    2014-11-01

    Protease Nexin-1 (PN-1) or Serpine2 is a physiological regulator of extracellular proteases as thrombin and urokinase (uPA) in the brain. Besides, PN-1 is also implicated in some human cancers and further identified as a substrate for Matrix Metalloproteinase (MMP)-9, a key enzyme in tumor invasiveness. Our aim was to study the role of PN-1 in the migration and invasive potential of glioma cells, using the rat C6 glioma cell line as stable clones transfected with pAVU6+27 vector expressing PN-1 short-hairpin RNA. We find that PN-1 knockdown enhanced the in vitro migration and invasiveness of C6 cells which also showed a strong gelatinolytic activity by in situ zymography. PN-1 silencing did not alter prothrombin whereas increased uPA, MMP-9 and MMP-2 expression levels and gelatinolytic activity in a conditioned medium from stable C6 cells. Selective inhibitors for MMP-9 (Inhibitor I), MMP-2 (Inhibitor III) or exogenous recombinant PN-1 added to the culture medium of C6 silenced cells restored either the migration and invasive ability or gelatinolytic activity thus validating the specificity of PN-1 silencing strategy. Phosphorylation levels of extracellular signal-related kinases (Erk1/2 and p38 MAPK) involved in MMP-9 and MMP-2 signaling were increased in PN-1 silenced cells. This study shows that PN-1 affects glioma cell migration and invasiveness through the regulation of uPA and MMP-9/2 expression levels which contribute to the degradation of extracellular matrix during tumor invasion. PMID:25072751

  13. Aberrant glomerular filtration of urokinase-type plasminogen activator in nephrotic syndrome leads to amiloride-sensitive plasminogen activation in urine.

    PubMed

    Stæhr, Mette; Buhl, Kristian B; Andersen, René F; Svenningsen, Per; Nielsen, Flemming; Hinrichs, Gitte Rye; Bistrup, Claus; Jensen, Boye L

    2015-08-01

    In nephrotic syndrome, aberrant glomerular filtration of plasminogen and conversion to active plasmin in preurine are thought to activate proteolytically epithelial sodium channel (ENaC) and contribute to sodium retention and edema. The ENaC blocker amiloride is an off-target inhibitor of urokinase-type plasminogen activator (uPA) in vitro. It was hypothesized that uPA is abnormally filtered to preurine and is inhibited in urine by amiloride in nephrotic syndrome. This was tested by determination of Na(+) balance, uPA protein and activity, and amiloride concentration in urine from rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. Urine samples from 6 adult and 18 pediatric patients with nephrotic syndrome were analyzed for uPA activity and protein. PAN treatment induced significant proteinuria in rats which coincided with increased urine uPA protein and activity, increased urine protease activity, and total plasminogen/plasmin concentration and Na(+) retention. Amiloride (2 mg·kg(-1)·24 h(-1)) concentration in urine was in the range 10-20 μmol/l and reduced significantly urine uPA activity, plasminogen activation, protease activity, and sodium retention in PAN rats, while proteinuria was not altered. In paired urine samples, uPA protein was significantly elevated in urine from children with active nephrotic syndrome compared with remission phase. In six adult nephrotic patients, urine uPA protein and activity correlated positively with 24 h urine protein excretion. In conclusion, nephrotic syndrome is associated with aberrant filtration of uPA across the injured glomerular barrier. Amiloride inhibits urine uPA activity which attenuates plasminogen activation and urine protease activity in vivo. Urine uPA is a relevant target for amiloride in vivo. PMID:25972510

  14. Characterization of the interaction between heterodimeric αvβ6 integrin and urokinase plasminogen activator receptor (uPAR) using functional proteomics.

    PubMed

    Ahn, Seong Beom; Mohamedali, Abidali; Anand, Samyuktha; Cheruku, Harish R; Birch, Debra; Sowmya, Gopichandran; Cantor, David; Ranganathan, Shoba; Inglis, David W; Frank, Ronald; Agrez, Michael; Nice, Edouard C; Baker, Mark S

    2014-12-01

    Urokinase plasminogen activator receptor (uPAR) and the epithelial integrin αvβ6 are thought to individually play critical roles in cancer metastasis. These observations have been highlighted by the recent discovery (by proteomics) of an interaction between these two molecules, which are also both implicated in the epithelial-mesenchymal transition (EMT) that facilitates escape of cells from tissue barriers and is a common signature of cancer metastases. In this study, orthogonal in cellulo and in vitro functional proteomic approaches were used to better characterize the uPAR·αvβ6 interaction. Proximity ligation assays (PLA) confirmed the uPAR·αvβ6 interaction on OVCA429 (ovarian cancer line) and four different colon cancer cell lines including positive controls in cells with de novo β6 subunit expression. PLA studies were then validated using peptide arrays, which also identified potential physical sites of uPAR interaction with αvβ6, as well as verifying interactions with other known uPAR ligands (e.g., uPA, vitronectin) and individual integrin subunits (i.e., αv, β1, β3, and β6 alone). Our data suggest that interaction with uPAR requires expression of the complete αβ heterodimer (e.g., αvβ6), not individual subunits (i.e., αv, β1, β3, or β6). Finally, using in silico structural analyses in concert with these functional proteomics studies, we propose and demonstrate that the most likely unique sites of interaction between αvβ6 and uPAR are located in uPAR domains II and III. PMID:25318615

  15. The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style

    PubMed Central

    Taddei, Maria Letizia; Giannoni, Elisa; Laurenzana, Anna; Biagioni, Alessio; Chillà, Anastasia; Chiarugi, Paola; Fibbi, Gabriella; Rosso1, Mario Del

    2014-01-01

    The receptor for the urokinase plasminogen activator (uPAR) is up-regulated in malignant tumors. Historically the function of uPAR in cancer cell invasion is strictly related to its property to promote uPA-dependent proteolysis of extracellular matrix and to open a path to malignant cells. These features are typical of mesenchymal motility. Here we show that the full-length form of uPAR is required when prostate and melanoma cancer cells convert their migration style from the “path generating” mesenchymal to the “path finding” amoeboid one, thus conferring a plasticity to tumor cell invasiveness across three-dimensional matrices. Indeed, in response to a protease inhibitors-rich milieu, prostate and melanoma cells activated an amoeboid invasion program connoted by retraction of cell protrusions, RhoA-mediated rounding of the cell body, formation of a cortical ring of actin and a reduction of Rac-1 activation. While the mesenchymal movement was reduced upon silencing of uPAR expression, the amoeboid one was almost completely abolished, in parallel with a deregulation of small Rho-GTPases activity. In melanoma and prostate cancer cells we have shown uPAR colocalization with β1/β3 integrins and actin cytoskeleton, as well integrins-actin co-localization under both mesenchymal and amoeboid conditions. Such co-localizations were lost upon treatment of cells with a peptide that inhibits uPAR-integrin interactions. Similarly to uPAR silencing, the peptide reduced mesenchymal invasion and almost abolished the amoeboid one. These results indicate that full-length uPAR bridges the mesenchymal and amoeboid style of movement by an inward-oriented activity based on its property to promote integrin-actin interactions and the following cytoskeleton assembly. PMID:24681666

  16. Soluble Urokinase Receptor Levels Are Correlated with Focal Segmental Glomerulosclerosis Lesions in IgA Nephropathy: A Cohort Study from China

    PubMed Central

    Guo, Shui-Ming; Han, Min; Chen, Mei-Xue; Ning, Yong; Pei, Guang-Chang; Li, Yue-Qiang; Dai, Wei; Ge, Shu-Wang; Deng, Yuan-Jun; Guo, Yan-Yan; Li, Xiao-Qing; Haller, Hermann; Xu, Gang; Rong, Song

    2015-01-01

    Background Soluble urokinase receptor (suPAR) may be involved in the pathological mechanisms of focal segmental glomerulosclerosis (FSGS) changes. However, it remains unclear whether suPAR is correlated with the FSGS-like lesions in IgA nephropathy (IgAN). Methods We measured the plasma suPAR levels in 138 patients with IgAN, and then their clinical and pathological relationships were analyzed. Results We found that the plasma suPAR levels were significantly correlated with age and renal function by both univariate and multivariate analysis in our IgAN patient cohort. Female had higher plasma suPAR levels and no significant correlation was observed between plasma suPAR levels and 24-h urine protein and highly sensitive C-reaction protein with multivariate analysis. In our cohort, sixty of these IgAN patients could be diagnosed with a type of FSGS lesions. The plasma suPAR levels were higher in the IgAN patients with FSGS lesions than in the IgAN patients without FSGS lesions by univariate (P < 0.0001) and multivariate (P < 0.001) analysis adjusting for other predictor variables, which might be helpful to differentiate the pathological changes with and without FSGS lesions. And the optimal cutoff value was 1806 pg/ml in this study. The plasma suPAR concentrations were also associated with the degree of tubular atrophy/interstitial fibrosis in both univariate and multivariate analysis. In multivariate analysis, the plasma suPAR levels were correlated with the percentage of crescents, not global sclerosis and arterial lesions. Conclusions Our study suggested that the plasma suPAR levels were associated with age, gender, renal function, the degree of tubular atrophy/interstitial fibrosis and the percentage of crescent formation. The plasma suPAR might be a potential predictor for the presence of FSGS pathological lesions in Chinese patients with IgAN. PMID:26380984

  17. Elevated urinary levels of urokinase-type plasminogen activator receptor (uPAR) in pancreatic ductal adenocarcinoma identify a clinically high-risk group

    PubMed Central

    2011-01-01

    Background The urokinase plasminogen activator receptor is highly expressed and its gene is amplified in about 50% of pancreatic ductal adenocarcinomas; this last feature is associated with worse prognosis. It is unknown whether the level of its soluble form (suPAR) in urine may be a diagnostic-prognostic marker in these patients. Methods The urinary level of suPAR was measured in 146 patients, 94 pancreatic ductal adenocarcinoma and 52 chronic pancreatitis. Urine from 104 healthy subjects with similar age and gender distribution served as controls. suPAR levels were normalized with creatinine levels (suPAR/creatinine, ng/mg) to remove urine dilution effect. Results Urinary suPAR/creatinine values of pancreatic ductal adenocarcinoma patients were significantly higher (median 9.8; 25th-75th percentiles 5.3-20.7) than those of either healthy donors (median 0; 0-0.5) or chronic pancreatitis patients (median 2.7; 0.9-4.7). The distribution of values among cancer patients was widespread and asymmetric, 53% subjects having values beyond the 95th percentile of healthy donors. The values of suPAR/creatinine did not correlate with tumour stage, Ca19-9 or CEA levels. Higher values correlated with poor prognosis among non-resected patients at univariate analysis; multivariate Cox regression identified high urinary suPAR/creatinine as an independent predictor of poor survival among all cancer patients (odds ratio 2.10, p = 0.0023), together with tumour stage (stage III odds ratio 2.65, p = 0.0017; stage IV odds ratio 4.61, p < 0.0001) and female gender (odds ratio 1.85, p = 0.01). Conclusions A high urinary suPAR/creatinine ratio represents a useful marker for the identification of a subset of patients with poorer outcome. PMID:21999221

  18. A holistic view of marine regime shifts

    PubMed Central

    Conversi, Alessandra; Dakos, Vasilis; Gårdmark, Anna; Ling, Scott; Folke, Carl; Mumby, Peter J.; Greene, Charles; Edwards, Martin; Blenckner, Thorsten; Casini, Michele; Pershing, Andrew; Möllmann, Christian

    2015-01-01

    Understanding marine regime shifts is important not only for ecology but also for developing marine management that assures the provision of ecosystem services to humanity. While regime shift theory is well developed, there is still no common understanding on drivers, mechanisms and characteristic of abrupt changes in real marine ecosystems. Based on contributions to the present theme issue, we highlight some general issues that need to be overcome for developing a more comprehensive understanding of marine ecosystem regime shifts. We find a great divide between benthic reef and pelagic ocean systems in how regime shift theory is linked to observed abrupt changes. Furthermore, we suggest that the long-lasting discussion on the prevalence of top-down trophic or bottom-up physical drivers in inducing regime shifts may be overcome by taking into consideration the synergistic interactions of multiple stressors, and the special characteristics of different ecosystem types. We present a framework for the holistic investigation of marine regime shifts that considers multiple exogenous drivers that interact with endogenous mechanisms to cause abrupt, catastrophic change. This framework takes into account the time-delayed synergies of these stressors, which erode the resilience of the ecosystem and eventually enable the crossing of ecological thresholds. Finally, considering that increased pressures in the marine environment are predicted by the current climate change assessments, in order to avoid major losses of ecosystem services, we suggest that marine management approaches should incorporate knowledge on environmental thresholds and develop tools that consider regime shift dynamics and characteristics. This grand challenge can only be achieved through a holistic view of marine ecosystem dynamics as evidenced by this theme issue.

  19. Greenland Meltwater and Arctic Circulation Regimes

    NASA Astrophysics Data System (ADS)

    Dukhovskoy, D. S.; Proshutinsky, A. Y.; Timmermans, M. L.; Myers, P. G.; Platov, G.

    2015-12-01

    Between 1948 and 1996, wind-driven components of ice drift and surface ocean currents experienced a well-pronounced decadal variability alternating between anticyclonic and cyclonic circulation regimes. During cyclonic regimes, low sea level atmospheric pressure dominated over the Arctic Ocean driving sea ice and the upper ocean clockwise; the Arctic atmosphere was relatively warm and humid and freshwater flux from the Arctic Ocean toward the sub-Arctic seas was intensified. During anticylonic circulation regimes, high sea level pressure dominated over the Arctic driving sea ice and ocean counter-clockwise; the atmosphere was cold and dry and the freshwater flux from the Arctic to the sub-Arctic seas was reduced. Since 1997, however, the Arctic system has been dominated by an anticyclonic circulation regime with a set of environmental parameters that are atypical for these regimes. Of essential importance is to discern the causes and consequences of the apparent break-down in the natural decadal variability of the Arctic climate system, and specifically: Why has the well-pronounced decadal variability observed in the 20th century been replaced by relatively weak interannual changes under anticyclonic circulation regime conditions in the 21st century? We discuss a hypothesis explaining the causes and mechanisms regulating the intensity and duration of Arctic circulation regimes, and speculate how changes in freshwater fluxes from Greenland impact environmental conditions and interrupt their decadal variability. In order to test this hypothesis, numerical experiments with several FAMOS (Forum for Arctic Modeling & Observational Synthesis) ice-ocean coupled models have been conducted. In these experiments, Greenland melt freshwater is tracked by passive tracers being constantly released along the Greenland coast. Propagation pathways and time scales of Greenland meltwater within the sub-Arctic seas are discussed.

  20. Identifying natural flow regimes using fish communities

    NASA Astrophysics Data System (ADS)

    Chang, Fi-John; Tsai, Wen-Ping; Wu, Tzu-Ching; Chen, Hung-kwai; Herricks, Edwin E.

    2011-10-01

    SummaryModern water resources management has adopted natural flow regimes as reasonable targets for river restoration and conservation. The characterization of a natural flow regime begins with the development of hydrologic statistics from flow records. However, little guidance exists for defining the period of record needed for regime determination. In Taiwan, the Taiwan Eco-hydrological Indicator System (TEIS), a group of hydrologic statistics selected for fisheries relevance, is being used to evaluate ecological flows. The TEIS consists of a group of hydrologic statistics selected to characterize the relationships between flow and the life history of indigenous species. Using the TEIS and biosurvey data for Taiwan, this paper identifies the length of hydrologic record sufficient for natural flow regime characterization. To define the ecological hydrology of fish communities, this study connected hydrologic statistics to fish communities by using methods to define antecedent conditions that influence existing community composition. A moving average method was applied to TEIS statistics to reflect the effects of antecedent flow condition and a point-biserial correlation method was used to relate fisheries collections with TEIS statistics. The resulting fish species-TEIS (FISH-TEIS) hydrologic statistics matrix takes full advantage of historical flows and fisheries data. The analysis indicates that, in the watersheds analyzed, averaging TEIS statistics for the present year and 3 years prior to the sampling date, termed MA(4), is sufficient to develop a natural flow regime. This result suggests that flow regimes based on hydrologic statistics for the period of record can be replaced by regimes developed for sampled fish communities.

  1. Learning Flow Regimes from Snapshot Data

    NASA Astrophysics Data System (ADS)

    Hemati, Maziar

    2015-11-01

    Fluid flow regimes are often categorized based on the qualitative patterns observed by visual inspection of the flow field. For example, bluff body wakes are traditionally classified based on the number and groupings of vortices shed per cycle (e.g., 2S, 2P, P+S), as seen in snapshots of the vorticity field. Subsequently, the existence and nature of these identified flow regimes can be explained through dynamical analyses of the fluid mechanics. Unfortunately, due to the need for manual inspection, the approach described above can be impractical for studies that seek to learn flow regimes from large volumes of numerical and/or experimental snapshot data. Here, we appeal to established techniques from machine learning and data-driven dynamical systems analysis to automate the task of learning flow regimes from snapshot data. Moreover, by appealing to the dynamical structure of the fluid flow, this approach also offers the potential to reveal flow regimes that may be overlooked by visual inspection alone. Here, we will introduce the methodology and demonstrate its capabilities and limitations in the context of several model flows.

  2. Dynamic treatment regimes: technical challenges and applications

    PubMed Central

    Lizotte, Daniel J.; Qian, Min; Pelham, William E.; Murphy, Susan A.

    2014-01-01

    Dynamic treatment regimes are of growing interest across the clinical sciences because these regimes provide one way to operationalize and thus inform sequential personalized clinical decision making. Formally, a dynamic treatment regime is a sequence of decision rules, one per stage of clinical intervention. Each decision rule maps up-to-date patient information to a recommended treatment. We briefly review a variety of approaches for using data to construct the decision rules. We then review a critical inferential challenge that results from nonregularity, which often arises in this area. In particular, nonregularity arises in inference for parameters in the optimal dynamic treatment regime; the asymptotic, limiting, distribution of estimators are sensitive to local perturbations. We propose and evaluate a locally consistent Adaptive Confidence Interval (ACI) for the parameters of the optimal dynamic treatment regime. We use data from the Adaptive Pharmacological and Behavioral Treatments for Children with ADHD Trial as an illustrative example. We conclude by highlighting and discussing emerging theoretical problems in this area. PMID:25356091

  3. Gradual regime shifts in fairy circles

    PubMed Central

    Zelnik, Yuval R.; Meron, Ehud; Bel, Golan

    2015-01-01

    Large responses of ecosystems to small changes in the conditions—regime shifts—are of great interest and importance. In spatially extended ecosystems, these shifts may be local or global. Using empirical data and mathematical modeling, we investigated the dynamics of the Namibian fairy circle ecosystem as a case study of regime shifts in a pattern-forming ecosystem. Our results provide new support, based on the dynamics of the ecosystem, for the view of fairy circles as a self-organization phenomenon driven by water–vegetation interactions. The study further suggests that fairy circle birth and death processes correspond to spatially confined transitions between alternative stable states. Cascades of such transitions, possible in various pattern-forming systems, result in gradual rather than abrupt regime shifts. PMID:26362787

  4. Spin glasses in the nonextensive regime

    NASA Astrophysics Data System (ADS)

    Wittmann, Matthew; Young, A. P.

    2012-04-01

    Spin systems with long-range interactions are “nonextensive” if the strength of the interactions falls off sufficiently slowly with distance. It has been conjectured for ferromagnets and, more recently, for spin glasses that, everywhere in the nonextensive regime, the free energy is exactly equal to that for the infinite range model in which the characteristic strength of the interaction is independent of distance. In this paper we present the results of Monte Carlo simulations of the one-dimensional long-range spin glasses in the nonextensive regime. Using finite-size scaling, our results for the transition temperatures are consistent with this prediction. We also propose and provide numerical evidence for an analogous result for diluted long-range spin glasses in which the coordination number is finite, namely, that the transition temperature throughout the nonextensive regime is equal to that of the infinite-range model known as the Viana-Bray model.

  5. Gradual regime shifts in fairy circles.

    PubMed

    Zelnik, Yuval R; Meron, Ehud; Bel, Golan

    2015-10-01

    Large responses of ecosystems to small changes in the conditions--regime shifts--are of great interest and importance. In spatially extended ecosystems, these shifts may be local or global. Using empirical data and mathematical modeling, we investigated the dynamics of the Namibian fairy circle ecosystem as a case study of regime shifts in a pattern-forming ecosystem. Our results provide new support, based on the dynamics of the ecosystem, for the view of fairy circles as a self-organization phenomenon driven by water-vegetation interactions. The study further suggests that fairy circle birth and death processes correspond to spatially confined transitions between alternative stable states. Cascades of such transitions, possible in various pattern-forming systems, result in gradual rather than abrupt regime shifts. PMID:26362787

  6. Massive superstring scatterings in the Regge regime

    SciTech Connect

    He Song; Lee, Jen-Chi; Takahashi, Keijiro; Yang Yi

    2011-03-15

    We calculate four classes of high-energy massive string scattering amplitudes of fermionic string theory at arbitrary mass levels in the Regge regime (RR). We show that all four leading order amplitudes in the RR can be expressed in terms of the Kummer function of the second kind. Based on the summation algorithm of a set of extended signed Stirling number identities, we show that all four ratios calculated previously by the method of decoupling of zero-norm states among scattering amplitudes in the Gross regime can be extracted from this Kummer function in the RR. Finally, we conjecture and give evidence that the existence of these four Gross regime ratios in the RR persists to subleading orders in the Regge expansion of all high-energy fermionic string scattering amplitudes.

  7. Determination of the Hall Thruster Operating Regimes

    SciTech Connect

    L. Dorf; V. Semenov; Y. Raitses; N.J. Fisch

    2002-04-09

    A quasi one-dimensional (1-D) steady-state model of the Hall thruster is presented. For the same discharge voltage two operating regimes are possible -- with and without the anode sheath. For given mass flow rate, magnetic field profile and discharge voltage a unique solution can be constructed, assuming that the thruster operates in one of the regimes. However, we show that for a given temperature profile the applied discharge voltage uniquely determines the operating regime: for discharge voltages greater than a certain value, the sheath disappears. That result is obtained over a wide range of incoming neutral velocities, channel lengths and widths, and cathode plane locations. It is also shown that a good correlation between the quasi 1-D model and experimental results can be achieved by selecting an appropriate electron mobility and temperature profile.

  8. Massive superstring scatterings in the Regge regime

    NASA Astrophysics Data System (ADS)

    He, Song; Lee, Jen-Chi; Takahashi, Keijiro; Yang, Yi

    2011-03-01

    We calculate four classes of high-energy massive string scattering amplitudes of fermionic string theory at arbitrary mass levels in the Regge regime (RR). We show that all four leading order amplitudes in the RR can be expressed in terms of the Kummer function of the second kind. Based on the summation algorithm of a set of extended signed Stirling number identities, we show that all four ratios calculated previously by the method of decoupling of zero-norm states among scattering amplitudes in the Gross regime can be extracted from this Kummer function in the RR. Finally, we conjecture and give evidence that the existence of these four Gross regime ratios in the RR persists to subleading orders in the Regge expansion of all high-energy fermionic string scattering amplitudes.

  9. Fermi's golden rule beyond the Zeno regime

    NASA Astrophysics Data System (ADS)

    Debierre, Vincent; Goessens, Isabelle; Brainis, Edouard; Durt, Thomas

    2015-08-01

    We reconsider the problem of the spontaneous emission of light by an excited atomic state. We scrutinize the survival probability of this excited state for very short times, in the so-called Zeno regime, for which we show that the dynamics is dictated by a coherent, in-phase, response of the on-shell and off-shell vacuum modes. We also develop a perturbative approach in order to interpolate between different temporal regimes: the Zeno, golden rule (linear), and Wigner-Weisskopf (exponential) regimes. We compare results obtained with the E ̂.x ̂ and A ̂.p ̂ interaction Hamiltonians, using successively the dipole approximation and the exact coupling.

  10. Transient regimes and crossover for epitaxial surfaces.

    PubMed

    Haselwandter, Christoph A; Vvedensky, Dimitri D

    2010-02-01

    We apply a formalism for deriving stochastic continuum equations associated with lattice models to obtain equations governing the transient regimes of epitaxial growth for various experimental scenarios and growth conditions. The first step of our methodology is the systematic transformation of the lattice model into a regularized stochastic equation of motion that provides initial conditions for differential renormalization-group (RG) equations for the coefficients in the regularized equation. The solutions of the RG equations then yield trajectories that describe the original model from the transient regimes, which are of primary experimental interest, to the eventual crossover to the asymptotically stable fixed point. We first consider regimes defined by the relative magnitude of deposition noise and diffusion noise. If the diffusion noise dominates, then the early stages of growth are described by the Mullins-Herring (MH) equation with conservative noise. This is the classic regime of molecular-beam epitaxy. If the diffusion and deposition noise are of comparable magnitude, the transient equation is the MH equation with nonconservative noise. This behavior has been observed in a recent report on the growth of aluminum on silicone oil surfaces [Z.-N. Fang, Thin Solid Films 517, 3408 (2009)]. Finally, the regime where deposition noise dominates over diffusion noise has been observed in computer simulations, but does not appear to have any direct experimental relevance. For initial conditions that consist of a flat surface, the Villain-Lai-Das Sarma (VLDS) equation with nonconservative noise is not appropriate for any transient regime. If, however, the initial surface is corrugated, the relative magnitudes of terms can be altered to the point where the VLDS equation with conservative noise does indeed describe transient growth. This is consistent with the experimental analysis of growth on patterned surfaces [H.-C. Kan, Phys. Rev. Lett. 92, 146101 (2004); T

  11. On the regimes of charge reversal.

    PubMed

    Jiménez-Angeles, Felipe; Lozada-Cassou, Marcelo

    2008-05-01

    Charge reversal of the planar electrical double layer is studied by means of a well known integral equation theory. By a numerical analysis, a diagram is constructed with the onset points of charge reversal in the space of the fundamental variables of the system. Within this diagram, two regimes of charge reversal are identified, which are referred to as oscillatory and nonoscillatory. We found that these two regimes can be distinguished through a simple formula. Furthermore, a symmetry between electrostatic and size correlations in charge reversal is exhibited. Agreement of our results with other theories and molecular simulations data is discussed. PMID:18465930

  12. Regimes of flow past a vortex generator

    NASA Astrophysics Data System (ADS)

    Velte, C. M.; Okulov, V. L.; Naumov, I. V.

    2012-04-01

    A complete parametric investigation of the development of multi-vortex regimes in a wake past simple vortex generator has been carried out. It is established that the vortex structure in the wake is much more complicated than a simple monopole tip vortex. The vortices were studied by stereoscopic particle image velocimetry (SPIV). Based on the obtained SPIV data, a map of the regimes of flow past the vortex generator has been constructed. One region with a developed stable multivortex system on this map reaches the vicinity of the optimum angle of attack of the vortex generator.

  13. Anomalous Hall effect in localization regime

    NASA Astrophysics Data System (ADS)

    Wu, Lin; Zhu, Kai; Yue, Di; Tian, Yuan; Jin, Xiaofeng

    2016-06-01

    The anomalous Hall effect in the ultrathin film regime is investigated in Fe(001)(1-3 nm) films epitaxial on MgO(001). The logarithmic localization correction to longitudinal resistivity and anomalous Hall resistivity are observed at low temperature. We identify that the coefficient of skew scattering has a reduction from metallic to localized regime, while the contribution of side jump has inconspicuous change except for a small drop below 10 K. Furthermore, we discover that the intrinsic anomalous Hall conductivity decreases with the reduction of thickness below 2 nm. Our results provide unambiguous experimental evidence to clarify the problem of localization correction to the anomalous Hall effect.

  14. Statistical regimes of random laser fluctuations

    SciTech Connect

    Lepri, Stefano; Cavalieri, Stefano; Oppo, Gian-Luca; Wiersma, Diederik S.

    2007-06-15

    Statistical fluctuations of the light emitted from amplifying random media are studied theoretically and numerically. The characteristic scales of the diffusive motion of light lead to Gaussian or power-law (Levy) distributed fluctuations depending on external control parameters. In the Levy regime, the output pulse is highly irregular leading to huge deviations from a mean-field description. Monte Carlo simulations of a simplified model which includes the population of the medium demonstrate the two statistical regimes and provide a comparison with dynamical rate equations. Different statistics of the fluctuations helps to explain recent experimental observations reported in the literature.

  15. Petrology, geochemistry, and fluid regime of tectonites

    NASA Astrophysics Data System (ADS)

    Letnikov, Feliks Artem'evich; Savel'Eva, Valentina Borisovna; Balyshev, Sergei Olegovich

    The book discusses the petrology, geochemisry, and fluid regime of the tectonite formation in rocks that differ with respect to the composition of their granulitic, amphylitic, and green-shale metamorphic facies. Tectonites in magma and metamorphic rocks of different composition are described in terms of their petrological, geochemical, and fluid-regime characteristics, and the pressure/temperature conditions of their formation. Using chemical and physical parameters, tectonites are classified according to their type models. The ore-generating capacity of tectonites in various rocks is estimated using a large geochemical database.

  16. Convective Regimes in Crystallizing Basaltic Magma Chambers

    NASA Astrophysics Data System (ADS)

    Gilbert, A. J.; Neufeld, J. A.; Holness, M. B.

    2015-12-01

    Cooling through the chamber walls drives crystallisation in crustal magma chambers, resulting in a cumulate pile on the floor and mushy regions at the walls and roof. The liquid in many magma chambers, either the bulk magma or the interstitial liquid in the mushy regions, may convect, driven either thermally, due to cooling, or compositionally, due to fractional crystallization. We have constructed a regime diagram of the possible convective modes in a system containing a basal mushy layer. These modes depend on the large-scale buoyancy forcing characterised by a global Rayleigh number and the proportion of the chamber height constituting the basal mushy region. We have tested this regime diagram using an analogue experimental system composed of a fluid layer overlying a pile of almost neutrally buoyant inert particles. Convection in this system is driven thermally, simulating magma convection above and within a porous cumulate pile. We observe a range of possible convective regimes, enabling us to produce a regime diagram. In addition to modes characterised by convection of the bulk and interstitial fluid, we also observe a series of regimes where the crystal pile is mobilised by fluid motions. These regimes feature saltation and scouring of the crystal pile by convection in the bulk fluid at moderate Rayleigh numbers, and large crystal-rich fountains at high Rayleigh numbers. For even larger Rayleigh numbers the entire crystal pile is mobilised in what we call the snowglobe regime. The observed mobilisation regimes may be applicable to basaltic magma chambers. Plagioclase in basal cumulates crystallised from a dense magma may be a result of crystal mobilisation from a plagioclase-rich roof mush. Compositional convection within such a mush could result in disaggregation, enabling the buoyant plagioclase to be entrained in relatively dense descending liquid plumes and brought to the floor. The phenocryst load in porphyritic lavas is often interpreted as a

  17. Comparative climatology of four marine stratocumulus regimes

    NASA Technical Reports Server (NTRS)

    Hanson, Howard P.

    1990-01-01

    The climatology of marine stratocumulus (MSc) cloud regimes off the west coasts of California, Peru, Morocco, and Angola are examined. Long-term, annual averages are presented for several quantities of interest in the four MSc regimes. The climatologies were constructed using the Comprehensive Ocean-Atmosphere Data Set (COADS). A 40 year time series of observations was extracted for 32 x 32 deg analysis domains. The data were taken from the monthly-averaged, 2 deg product. The resolution of the analysis is therefore limited to scales of greater than 200 km with submonthly variability not resolved. The averages of total cloud cover, sea surface temperature, and surface pressure are presented.

  18. Supercurrent in the quantum Hall regime

    NASA Astrophysics Data System (ADS)

    Amet, F.; Ke, C. T.; Borzenets, I. V.; Wang, J.; Watanabe, K.; Taniguchi, T.; Deacon, R. S.; Yamamoto, M.; Bomze, Y.; Tarucha, S.; Finkelstein, G.

    2016-05-01

    A promising route for creating topological states and excitations is to combine superconductivity and the quantum Hall (QH) effect. Despite this potential, signatures of superconductivity in the QH regime remain scarce, and a superconducting current through a QH weak link has been challenging to observe. We demonstrate the existence of a distinct supercurrent mechanism in encapsulated graphene samples contacted by superconducting electrodes, in magnetic fields as high as 2 tesla. The observation of a supercurrent in the QH regime marks an important step in the quest for exotic topological excitations, such as Majorana fermions and parafermions, which may find applications in fault-tolerant quantum computing.

  19. Supercurrent in the quantum Hall regime.

    PubMed

    Amet, F; Ke, C T; Borzenets, I V; Wang, J; Watanabe, K; Taniguchi, T; Deacon, R S; Yamamoto, M; Bomze, Y; Tarucha, S; Finkelstein, G

    2016-05-20

    A promising route for creating topological states and excitations is to combine superconductivity and the quantum Hall (QH) effect. Despite this potential, signatures of superconductivity in the QH regime remain scarce, and a superconducting current through a QH weak link has been challenging to observe. We demonstrate the existence of a distinct supercurrent mechanism in encapsulated graphene samples contacted by superconducting electrodes, in magnetic fields as high as 2 tesla. The observation of a supercurrent in the QH regime marks an important step in the quest for exotic topological excitations, such as Majorana fermions and parafermions, which may find applications in fault-tolerant quantum computing. PMID:27199424

  20. Delinating Thermohaline Double-Diffusive Rayleigh Regimes

    NASA Astrophysics Data System (ADS)

    Graf, T.; Walther, M.; Kolditz, O.; Liedl, R.

    2013-12-01

    In natural systems, convective flow induced from density differences may occur in near-coastal aquifers, atmospheric boundary layers, oceanic streams or within the earth crust. Whether an initially stable, diffusive regime evolves into a convective (stable or chaotic) regime, or vice versa, depends on the system's framing boundary conditions. A conventional parameter to express the relation between diffusive and convective forces of such a density-driven regime is Rayleigh number (Ra). While most systems are mainly dominated by only a single significant driving force (i.e. only temperature or salinity), some systems need to consider two boundary processes (e.g. deep, thus warm, haline flow in porous media). In that case, a two-dimensional, 'double-diffusive' Rayleigh system can be defined. Nield (1998) postulated a boundary between diffusive and convective regime at RaT + RaC = 4pi^2 in the first quadrant (Q1), with Rayleigh numbers for temperature and concentration respectively. The boundary in the forth quadrant (Q4) could not exactly be determined, yet the approximate position estimated. Simulations with HydroGeoSphere (Therrien, 2010) using a vertical, quadratic, homogeneous, isotropic setup confirmed the existence of the 4pi^2-boundary and revealed additional regimes (diffusive, single-roll, double-roll, chaotic) in Q1. Also, non-chaotic, oscillating patterns could be identified in Q4. More detailed investigations with OpenGeoSys (Kolditz, 2012) confirmed the preceding HGS results, and, using a 1:10-scaled domain (height:length), uncovered even more distinctive regimes (diffusive, minimum ten roles, supposely up to 25 roles, and chaotic?) in Q1, while again, oscillating patterns were found in the transition zone between diffusive and chaotic regimes in Q4. Output of numerical simulations from Q1 and Q4 show the mentioned regimes (diffusive, stable-convective, stable-oscillatory, chaotic) while results are displayed in context of a possible delination between

  1. A combination of desmopressin and docetaxel inhibit cell proliferation and invasion mediated by urokinase-type plasminogen activator (uPA) in human prostate cancer cells

    SciTech Connect

    Sasaki, Hiroshi; Klotz, Laurence H.; Sugar, Linda M.; Kiss, Alexander; Venkateswaran, Vasundara

    2015-08-28

    Background: This study was designed to assess the effectiveness of a combination treatment using both desmopressin and docetaxel in prostate cancer treatment. Desmopressin is a well-known synthetic analogue of the antidiuretic hormone vasopressin. It has recently been demonstrated to inhibit tumor progression and metastasis in in vivo models. Docetaxel is widely used for the treatment of castration resistant prostate cancer (CRPC) patients. However, durable responses have been uncommon to date. In this study, we investigated the anti-tumor effect of desmopressin in combination with docetaxel in vitro and in vivo. Methods: Two prostate cancer cells (PC3, LNCaP) were treated with different concentrations of desmopressin alone, docetaxel alone, and a combination of desmopressin and docetaxel. Cell proliferation was determined by MTS assay. The anti-invasive and anti-migration potential of desmopressin and in combination with docetaxel were examined by wound healing assay, migration chamber assay, and matrigel invasion assay. Results: The combination of desmopressin and docetaxel resulted in a significant inhibition of PC3 and LNCaP cell proliferation (p < 0.01). Additionally, cell migration and invasion were also inhibited by the combination when compared to that of either treatment alone in PC3 cells (p < 0.01). The anti-tumor effect of this combination treatment was associated with down-regulation of both urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP-2 and MMP-9) in PC3 cells. Conclusions: We are the first to elucidate the anti-tumor and anti-metastatic potential of desmopressin in combination with docetaxel in a prostate cancer model via the uPA-MMP pathway. Our finding could potentially contribute to the therapeutic profile of desmopressin and enhance the efficacy of docetaxel based treatment for CRPC. - Highlights: • Desmopressin inhibits cell proliferation in prostate cancer cells. • The expression of cyclin A and CDK2

  2. H-Ras Increases Urokinase Expression and Cell Invasion in Genetically Modified Human Astrocytes Through Ras/Raf/MEK Signaling Pathway

    PubMed Central

    ZHAO, YUNGE; XIAO, AIZHEN; DIPIERRO, CHARLES G.; ABDEL-FATTAH, RANA; AMOS, SAMSON; REDPATH, GERARD T.; CARPENTER, JOAN E.; PIEPER, RUSSELL O.; HUSSAINI, ISA M.

    2008-01-01

    Previous study reported that the activation of Ras pathway cooperated with E6/E7-mediated inactivation of p53/pRb to transform immortalized normal human astrocytes (NHA/hTERT) into intracranial tumors strongly resembling human astrocytomas. The mechanism of how H-Ras contributes to astrocytoma formation is unclear. Using genetically modified NHA cells (E6/E7/hTERT and E6/E7/hTERT/Ras cells) as models, we investigated the mechanism of Ras-induced tumorigenesis. The overexpression of constitutively active H-RasV12 in E6/E7/hTERT cells robustly increased the levels of urokinase plasminogen activator (uPA) mRNA, protein, activity and invasive capacity of the E6/E7/hTERT/Ras cells. However, the expressions of MMP-9 and MMP-2 did not significantly change in the E6/E7/hTERT and E6/E7/hTERT/Ras cells. Furthermore, E6/E7/hTERT/Ras cells also displayed higher level of uPA activity and were more invasive than E6/E7/hTERT cells in 3D culture, and formed an intracranial tumor mass in a NOD-SCID mouse model. uPA specific inhibitor (B428) and uPA neutralizing antibody decreased uPA activity and invasion in E6/E7/hTERT/Ras cells. uPA-deficient U-1242 glioblastoma cells were less invasive in vitro and exhibited reduced tumor growth and infiltration into normal brain in xenograft mouse model. Inhibitors of Ras (FTA), Raf (Bay 54−9085) and MEK (UO126), but not of phosphatidylinositol 3-kinase (PI3K) (LY294002) and of protein kinase C (BIM) pathways, inhibited uPA activity and cell invasion. Our results suggest that H-Ras increased uPA expression and activity via the Ras/Raf/MEK signaling pathway leading to enhanced cell invasion and this may contribute to increased invasive growth properties of astrocytomas. PMID:18383343

  3. Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Regulation of WNT/β-Catenin Signaling Is Enhanced in Irradiated Medulloblastoma Cells*

    PubMed Central

    Asuthkar, Swapna; Gondi, Christopher S.; Nalla, Arun Kumar; Velpula, Kiran Kumar; Gorantla, Bharathi; Rao, Jasti S.

    2012-01-01

    Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration, and metastasis in cancer cells. In this report, we showed that ionizing radiation (IR)-induced uPAR has a role in WNT-β-catenin signaling and mediates induction of cancer stem cell (CSC)-like properties in medulloblastoma cell lines UW228 and D283. We observed that IR induced the expression of uPAR and CSC markers, such as Musashi-1 and CD44, and activated WNT-7a-β-catenin signaling molecules. Overexpression of uPAR alone or with IR treatment led to increased WNT-7a-β-catenin-TCF/LEF-mediated transactivation, thereby promoting cancer stemness. In contrast, treatment with shRNA specific for uPAR (pU) suppressed WNT-7a-β-catenin-TCF/LEF-mediated transactivation both in vitro and in vivo. Quercetin, a potent WNT/β-catenin inhibitor, suppressed uPAR and uPAR-mediated WNT/β-catenin activation, and furthermore, addition of recombinant human WNT-7a protein induced uPAR, indicating the existence of a mutual regulatory relationship between uPAR and WNT/β-catenin signaling. We showed that uPAR was physically associated with the WNT effector molecule β-catenin on the membrane, cytoplasm, and nucleus of IR-treated cells and CSC. Most interestingly, we demonstrated for the first time that localization of uPAR in the nucleus was associated with transcription factors (TF) and their specific response elements. We observed from uPAR-ChIP, TF protein, and protein/DNA array analyses that uPAR associates with activating enhancer-binding protein 2α (AP2a) and mediates β-catenin gene transcription. Moreover, association of uPAR with the β-catenin·TCF/LEF complex and various other TF involved during embryonic development and cancer indicates that uPAR is a potent activator of stemness, and targeting of uPAR in combination with radiation has significant therapeutic implications. PMID:22511755

  4. Urokinase-type plasminogen activator receptor (uPAR)-mediated regulation of WNT/β-catenin signaling is enhanced in irradiated medulloblastoma cells.

    PubMed

    Asuthkar, Swapna; Gondi, Christopher S; Nalla, Arun Kumar; Velpula, Kiran Kumar; Gorantla, Bharathi; Rao, Jasti S

    2012-06-01

    Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration, and metastasis in cancer cells. In this report, we showed that ionizing radiation (IR)-induced uPAR has a role in WNT-β-catenin signaling and mediates induction of cancer stem cell (CSC)-like properties in medulloblastoma cell lines UW228 and D283. We observed that IR induced the expression of uPAR and CSC markers, such as Musashi-1 and CD44, and activated WNT-7a-β-catenin signaling molecules. Overexpression of uPAR alone or with IR treatment led to increased WNT-7a-β-catenin-TCF/LEF-mediated transactivation, thereby promoting cancer stemness. In contrast, treatment with shRNA specific for uPAR (pU) suppressed WNT-7a-β-catenin-TCF/LEF-mediated transactivation both in vitro and in vivo. Quercetin, a potent WNT/β-catenin inhibitor, suppressed uPAR and uPAR-mediated WNT/β-catenin activation, and furthermore, addition of recombinant human WNT-7a protein induced uPAR, indicating the existence of a mutual regulatory relationship between uPAR and WNT/β-catenin signaling. We showed that uPAR was physically associated with the WNT effector molecule β-catenin on the membrane, cytoplasm, and nucleus of IR-treated cells and CSC. Most interestingly, we demonstrated for the first time that localization of uPAR in the nucleus was associated with transcription factors (TF) and their specific response elements. We observed from uPAR-ChIP, TF protein, and protein/DNA array analyses that uPAR associates with activating enhancer-binding protein 2α (AP2a) and mediates β-catenin gene transcription. Moreover, association of uPAR with the β-catenin·TCF/LEF complex and various other TF involved during embryonic development and cancer indicates that uPAR is a potent activator of stemness, and targeting of uPAR in combination with radiation has significant therapeutic implications. PMID:22511755

  5. Involvement of nitric oxide synthase in matrix metalloproteinase-9- and/or urokinase plasminogen activator receptor-mediated glioma cell migration

    PubMed Central

    2013-01-01

    Background Src tyrosine kinase activates inducible nitric oxide synthase (iNOS) and, in turn, nitric oxide production as a means to transduce cell migration. Src tyrosine kinase plays a key proximal role to control α9β1 signaling. Our recent studies have clearly demonstrated the role of α9β1 integrin in matrix metalloproteinase-9 (MMP-9) and/or urokinase plasminogen activator receptor (uPAR)-mediated glioma cell migration. In the present study, we evaluated the involvement of α9β1 integrin-iNOS pathway in MMP-9- and/or uPAR-mediated glioma cell migration. Methods MMP-9 and uPAR shRNAs and overexpressing plasmids were used to downregulate and upregulate these molecules, respectively in U251 glioma cells and 5310 glioma xenograft cells. The effect of treatments on migration and invasion potential of these glioma cells were assessed by spheroid migration, wound healing, and Matrigel invasion assays. In order to attain the other objectives we also performed immunocytochemical, immunohistochemical, RT-PCR, Western blot and fluorescence-activated cell sorting (FACS) analysis. Results Immunohistochemical analysis revealed the prominent association of iNOS with glioblastoma multiforme (GBM). Immunofluorescence analysis showed prominent expression of iNOS in glioma cells. MMP-9 and/or uPAR knockdown by respective shRNAs reduced iNOS expression in these glioma cells. RT-PCR analysis revealed elevated iNOS mRNA expression in either MMP-9 or uPAR overexpressed glioma cells. The migration potential of MMP-9- and/or uPAR-overexpressed U251 glioma cells was significantly inhibited after treatment with L-NAME, an inhibitor of iNOS. Similarly, a significant inhibition of the invasion potential of the control or MMP-9/uPAR-overexpressed glioma cells was noticed after L-NAME treatment. A prominent reduction of iNOS expression was observed in the tumor regions of nude mice brains, which were injected with 5310 glioma cells, after MMP-9 and/or uPAR knockdown. Protein expressions

  6. Staurosporine induces ganglion cell differentiation in part by stimulating urokinase-type plasminogen activator expression and activation in the developing chick retina

    SciTech Connect

    Kim, Yeoun-Hee; Chang, Yongmin; Jung, Jae-Chang

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer Staurosporine mediates stimulation of RGC differentiation in vitro cultured retinal neuroblasts. Black-Right-Pointing-Pointer Staurosporine mediates uPA activation during RGC differentiation in vitro. Black-Right-Pointing-Pointer Inhibition of uPA blocks the staurosporine mediated RGC differentiation both in vitro and in ovo. Black-Right-Pointing-Pointer Thus, uPA may play a role in the staurosporine-mediated stimulation of RGC differentiation. -- Abstract: Here, we investigated whether staurosporine-mediated urokinase-type plasminogen activator (uPA) activation is involved in retinal ganglion cell (RGC) differentiation. Retinal cells were isolated from developing chick retinas at embryonic day 6 (E6). Relatively few control cells grown in serum-free medium started to form processes by 12 h. In contrast, staurosporine-treated cells had processes within 3 h, and processes were evident at 8 h. Immunofluorescence staining showed that Tuj-1-positive cells with shorter neurites could be detected in control cultures at 18 h, whereas numerous Tuj-1 positive ganglion cells with longer neuritic extensions were seen in staurosporine-treated cultures. BrdU-positive proliferating cells were more numerous in control cultures than in staurosporine-treated cultures, and the BrdU staining was not detected in post-mitotic Tuj-1 positive ganglion cells. Western blotting of cell lysates showed that staurosporine induced high levels of the active form of uPA. The staurosporine-induced uPA signal was localized predominantly in the soma, neurites and axons of Tuj-1-positive ganglion cells. Amiloride, an inhibitor of uPA, markedly reduced staurosporine-induced Tuj-1 staining, neurite length, neurite number, and uPA staining versus controls. In developing retinas in ovo, amiloride administration remarkably reduced the staurosporine-induced uPA staining and RGC differentiation. Taken together, our in vitro and in vivo data collectively indicate that

  7. Nicotine stimulates urokinase-type plasminogen activator receptor expression and cell invasiveness through mitogen-activated protein kinase and reactive oxygen species signaling in ECV304 endothelial cells

    SciTech Connect

    Khoi, Pham Ngoc; Park, Jung Sun; Kim, Nam Ho; Jung, Young Do

    2012-03-01

    Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation, tissue remodeling and in many human cancers. This study investigated the effect of nicotine, a major alkaloid in tobacco, on uPAR expression and cell invasiveness in ECV304 endothelial cells. Nicotine stimulated uPAR expression in a dose-dependent manner and activated extracellular signal-regulated kinases-1/2 (Erk-1/2), c-Jun amino-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK). Specific inhibitors of MEK-1 (PD98059) and JNK (SP600125) inhibited the nicotine-induced uPAR expression, while the p38 MAPK inhibitor SB203580 did not. Expression vectors encoding dominant negative MEK-1 (pMCL-K97M) and JNK (TAM67) also prevented nicotine-induced uPAR promoter activity. The intracellular hydrogen peroxide (H{sub 2}O{sub 2}) content was increased by nicotine treatment. The antioxidant N-acetylcysteine prevented nicotine-activated production of reactive oxygen species (ROS) and uPAR expression. Furthermore, exogenous H{sub 2}O{sub 2} increased uPAR mRNA expression. Deleted and site-directed mutagenesis demonstrated the involvement of the binding sites of transcription factor nuclear factor-kappaB (NF-κB) and activator protein (AP)-1 in the nicotine-induced uPAR expression. Studies with expression vectors encoding mutated NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the nicotine-stimulated uPAR expression. MAPK (Erk-1/2 and JNK) and ROS functioned as upstream signaling molecules in the activation of AP-1 and NF-κB, respectively. In addition, ECV304 endothelial cells treated with nicotine displayed markedly enhanced invasiveness, which was partially abrogated by uPAR neutralizing antibodies. The data indicate that nicotine induces uPAR expression via the MAPK/AP-1 and ROS/NF-κB signaling pathways and, in turn, stimulates invasiveness in human ECV304 endothelial cells. -- Highlights: ► Endothelial cells

  8. Cross-talk of anosmin-1, the protein implicated in X-linked Kallmann's syndrome, with heparan sulphate and urokinase-type plasminogen activator.

    PubMed

    Hu, Youli; González-Martínez, David; Kim, Soo-Hyun; Bouloux, Pierre Marc Gilles

    2004-12-15

    Defective function of anosmin-1, the protein encoded by KAL-1, underlies X-linked Kallmann's syndrome (X-KS), a human hereditary developmental disorder. Anosmin-1 appears to play a role in neurite outgrowth and axon branching, although molecular mechanisms of its action are still unknown. Anosmin-1 contains a WAP (whey acidic protein-like) domain and four contiguous FnIII (fibronectin-like type III) repeats; its WAP domain shows similarity to known serine protease inhibitors, whereas the FnIII domains contain HS (heparan sulphate)-binding sequences. To investigate the functional role of these domains, we have generated both wild-type and mutant recombinant anosmin-1 proteins using a Drosophila S2 cell expression system. Here we present the first biochemical evidence demonstrating the high-binding affinity between HS and anosmin-1, as measured by SPR (surface plasmon resonance) (K(d)=2 nM). The FnIII domains, particularly the first, are essential for dose-dependent HS binding and HS-mediated cell surface association. Furthermore, we have identified uPA (urokinase-type plasminogen activator) as an anosmin-1 interactant. Anosmin-1 significantly enhances the amidolytic activity of uPA in vitro; and anosmin-1-HS-uPA co-operation induces cell proliferation in the PC-3 prostate carcinoma cell line. Both the HS interaction and an intact WAP domain are required for the mitogenic activity of anosmin-1. These effects appear to be mediated by a direct protein interaction between anosmin-1 and uPA, since anosmin-1-uPA could be co-immunoprecipitated from PC-3 cell lysates, and their direct binding with high affinity (K(d)=6.91 nM) was demonstrated by SPR. We thus propose that anosmin-1 may modulate the catalytic activity of uPA and its signalling pathway, whereas HS determines cell surface localization of the anosmin-1-uPA complex. PMID:15324302

  9. Production of a urokinase plasminogen activator-IgG fusion protein (uPA-IgG) in the baculovirus expression system.

    PubMed

    Kost, T A; Ignar, D M; Clay, W C; Andrews, J; Leray, J D; Overton, L; Hoffman, C R; Kilpatrick, K E; Ellis, B; Emerson, D L

    1997-04-29

    Numerous studies have demonstrated the importance of urokinase plasminogen activator (uPA) and its receptor, uPAR, in the processes of tumor progression and metastasis. Thus, the uPA/uPAR interaction may represent an important target for inhibiting metastatic disease. The baculovirus expression system was used to produce high levels of a secreted uPA-Immunoglobulin G fusion protein (uPA-IgG) which could then be used for displacing uPA from the surface of tumor cells. The recombinant uPA-IgG fusion protein was placed under the control of either the viral polyhedrin promoter or a copy of the viral basic protein promoter. Recombinant viruses were then used to infect Sf9 and BTI-Tn-5B1-4 cells. Infection of both cell types resulted in the production of secreted uPA-IgG. The molecular mass of the secreted protein as determined by SDS-PAGE was approximately 40 kDa. The highest level of secreted uPA-IgG, 444 microg/ml, was found in the culture medium of BTI-Tn-5B1-4 cells 72 h post-infection with the basic protein promoter-uPA-IgG virus. In the case of Sf9 cells, the highest level of secreted protein was 195 microg/ml. The amount of cell-associated uPA-IgG in infected BTI-Tn-5B1-4 cells was significantly less than that of infected Sf9 cells, reflecting the superior secretory capability of the BTI-Tn-5B1-4 cells. The uPA-IgG was readily purified using a combination of zinc chelate and sephacryl S-100 column chromatography. Routinely, greater than 100 mg of greater than 95% pure protein could be obtained per liter of culture medium collected at 72 h post-infection of BTI-Tn-5B1-4 cells with the basic protein promoter virus. BIAcore analysis and competition binding assays using LOX human malignant melanoma cells expressing uPAR indicated that the purified recombinant protein possessed similar ligand binding characteristics to that of human uPA. PMID:9185859

  10. Taxonomy of potential international safeguards regimes

    SciTech Connect

    Lemley, J.R.; Allentuck, J.

    1994-08-01

    Since the International Atomic Energy Agency`s (IAEA) search for the components of Iraq`s nuclear weapons program under the auspices of the United Nations Security Council, a consensus for enhancing, strengthening or expanding the scope of international safeguards has developed. Some of the enhanced safeguards concepts which have been suggested include the following: short-notice, challenge, and random inspections; effluent monitoring in onsite, near site, and fly-by modes; local and wide-area environmental monitoring; and utilization of data from space-platform sensors. Potential safeguards regimes can be classified according to the functional and technical criteria which would be necessary for implementation of various enhanced safeguards concepts. While the nature of the regime which will emerge cannot be predicted, the classification of possible regimes according to major characteristics can be useful for identifying functional criteria and implementation challenges, focusing development efforts on the functional criteria, and planning for efficient use of safeguards resources. Precedents established in previously negotiated treaties -- the Chemical Weapons Convention, the Treaty on Conventional Forces in Europe, START, and Open Skies -- are examined with regard to enhancement of the international safeguards regime for nuclear and other weapons of mass destruction. Bilateral, multilateral and regional integration of enhanced safeguards elements is considered.

  11. Prolonged Instability Prior to a Regime Shift

    PubMed Central

    Spanbauer, Trisha L.; Allen, Craig R.; Angeler, David G.; Eason, Tarsha; Fritz, Sherilyn C.; Garmestani, Ahjond S.; Nash, Kirsty L.; Stone, Jeffery R.

    2014-01-01

    Regime shifts are generally defined as the point of ‘abrupt’ change in the state of a system. However, a seemingly abrupt transition can be the product of a system reorganization that has been ongoing much longer than is evident in statistical analysis of a single component of the system. Using both univariate and multivariate statistical methods, we tested a long-term high-resolution paleoecological dataset with a known change in species assemblage for a regime shift. Analysis of this dataset with Fisher Information and multivariate time series modeling showed that there was a∼2000 year period of instability prior to the regime shift. This period of instability and the subsequent regime shift coincide with regional climate change, indicating that the system is undergoing extrinsic forcing. Paleoecological records offer a unique opportunity to test tools for the detection of thresholds and stable-states, and thus to examine the long-term stability of ecosystems over periods of multiple millennia. PMID:25280010

  12. Knowledge Regimes and Contradictions in Education Reforms

    ERIC Educational Resources Information Center

    Aasen, Petter; Prøitz, Tine Sophie; Sandberg, Nina

    2014-01-01

    The article outlines a theoretical framework for understanding education policy and education reforms based on the concept of knowledge regimes. The concept refers to understandings and definitions of governance and procedural aspects, manners of governing and curriculum issues, thus it comprises contents, structures, and processes of education…

  13. Drag-force regimes in granular impact

    NASA Astrophysics Data System (ADS)

    Tiwari, Mukesh; Mohan, T. R. Krishna; Sen, Surajit

    2014-12-01

    We study the penetration dynamics of a projectile incident normally on a substrate comprising of smaller granular particles in three-dimensions using the discrete element method. Scaling of the penetration depth is consistent with experimental observations for small velocity impacts. Our studies are consistent with the observation that the normal or drag force experienced by the penetrating grain obeys the generalized Poncelet law, which has been extensively invoked in understanding the drag force in the recent experimental data. We find that the normal force experienced by the projectile consists of position and kinetic-energy-dependent pieces. Three different penetration regimes are identified in our studies for low-impact velocities. The first two regimes are observed immediately after the impact and in the early penetration stage, respectively, during which the drag force is seen to depend on the kinetic energy. The depth dependence of the drag force becomes significant in the third regime when the projectile is moving slowly and is partially immersed in the substrate. These regimes relate to the different configurations of the bed: the initial loose surface packed state, fluidized bed below the region of impact, and the state after the crater formation commences.

  14. Radiative effects of global MODIS cloud regimes

    NASA Astrophysics Data System (ADS)

    Oreopoulos, Lazaros; Cho, Nayeong; Lee, Dongmin; Kato, Seiji

    2016-03-01

    We update previously published Moderate Resolution Imaging Spectroradiometer (MODIS) global cloud regimes (CRs) using the latest MODIS cloud retrievals in the Collection 6 data set. We implement a slightly different derivation method, investigate the composition of the regimes, and then proceed to examine several aspects of CR radiative appearance with the aid of various radiative flux data sets. Our results clearly show that the CRs are radiatively distinct in terms of shortwave, longwave, and their combined (total) cloud radiative effect. We show that we can clearly distinguish regimes based on whether they radiatively cool or warm the atmosphere, and thanks to radiative heating profiles, to discern the vertical distribution of cooling and warming. Terra and Aqua comparisons provide information about the degree to which morning and afternoon occurrences of regimes affect the symmetry of CR radiative contribution. We examine how the radiative discrepancies among multiple irradiance data sets suffering from imperfect spatiotemporal matching depend on CR and whether they are therefore related to the complexity of cloud structure, its interpretation by different observational systems, and its subsequent representation in radiative transfer calculations.

  15. Drag-force regimes in granular impact.

    PubMed

    Tiwari, Mukesh; Mohan, T R Krishna; Sen, Surajit

    2014-12-01

    We study the penetration dynamics of a projectile incident normally on a substrate comprising of smaller granular particles in three-dimensions using the discrete element method. Scaling of the penetration depth is consistent with experimental observations for small velocity impacts. Our studies are consistent with the observation that the normal or drag force experienced by the penetrating grain obeys the generalized Poncelet law, which has been extensively invoked in understanding the drag force in the recent experimental data. We find that the normal force experienced by the projectile consists of position and kinetic-energy-dependent pieces. Three different penetration regimes are identified in our studies for low-impact velocities. The first two regimes are observed immediately after the impact and in the early penetration stage, respectively, during which the drag force is seen to depend on the kinetic energy. The depth dependence of the drag force becomes significant in the third regime when the projectile is moving slowly and is partially immersed in the substrate. These regimes relate to the different configurations of the bed: the initial loose surface packed state, fluidized bed below the region of impact, and the state after the crater formation commences. PMID:25615080

  16. The future of the nuclear nonproliferation regime.

    SciTech Connect

    Pilat, Joseph F.

    2004-01-01

    Following the 1998 nuclear tests in South Asia and later reinforced by revelations about North Korean and Iraqi nuclear activities, there has been growing concern about increasing proliferation dangers. At the same time, the prospects of radiological/nuclear terrorism are seen to be rising - since 9/11, concern over a proliferation/terrorism nexus has never been higher. In the face of this growing danger, there are urgent calls for stronger measures to strengthen the current international nuclear nonproliferation regime, including recommendations to place civilian processing of weapon-useable material under multinational control. As well, there are calls for entirely new tools, including military options. As proliferation and terrorism concerns grow, the regime is under pressure and there is a temptation to consider fundamental changes to the regime. In this context, this paper will address the following: Do we need to change the regime centered on the Treaty on the Nonproliferation of Nuclear Weapons (NPT) and the International Atomic Energy Agency (IAEA)? What improvements could ensure it will be the foundation for the proliferation resistance and physical protection needed if nuclear power grows? What will make it a viable centerpiece of future nonproliferation and counterterrorism approaches?

  17. Forest damage and snow avalanche flow regime

    NASA Astrophysics Data System (ADS)

    Feistl, T.; Bebi, P.; Christen, M.; Margreth, S.; Diefenbach, L.; Bartelt, P.

    2015-06-01

    Snow avalanches break, uproot and overturn trees causing damage to forests. The extent of forest damage provides useful information on avalanche frequency and intensity. However, impact forces depend on avalanche flow regime. In this paper, we define avalanche loading cases representing four different avalanche flow regimes: powder, intermittent, dry and wet. Using a numerical model that simulates both powder and wet snow avalanches, we study documented events with forest damage. First we show that in the powder regime, although the applied impact pressures can be small, large bending moments in the tree stem can be produced due to the torque action of the blast. The impact area of the blast extends over the entire tree crown. We find that, powder clouds with velocities over 20 m s-1 can break tree stems. Second we demonstrate that intermittent granular loadings are equivalent to low-density uniform dry snow loadings under the assumption of homogeneous particle distributions. The intermittent regime seldom controls tree breakage. Third we calculate quasi-static pressures of wet snow avalanches and show that they can be much higher than pressures calculated using dynamic pressure formulas. Wet snow pressure depends both on avalanche volume and terrain features upstream of the tree.

  18. Forest damage and snow avalanche flow regime

    NASA Astrophysics Data System (ADS)

    Feistl, T.; Bebi, P.; Christen, M.; Margreth, S.; Diefenbach, L.; Bartelt, P.

    2015-01-01

    Snow avalanches break, uproot and overturn trees causing damage to forests. The extent of forest damage provides useful information on avalanche frequency and intensity. However, impact forces depend on avalanche flow regime. In this paper, we define avalanche loading cases representing four different avalanche flow regimes: powder, intermittent, dry and wet. In the powder regime, the blast of the cloud can produce large bending moments in the tree stem because of the impact area extending over the entire tree crown. We demonstrate that intermittent granular loadings are equivalent to low-density uniform dry snow loadings under the assumption of homogeneous particle distributions. In the wet snow case, avalanche pressure is calculated using a quasi-static model accounting for the motion of plug-like wet snow flows. Wet snow pressure depends both on avalanche volume and terrain features upstream of the tree. Using a numerical model that simulates both powder and wet snow avalanches, we study documented events with forest damage. We find (1) powder clouds with velocities over 20 m s-1 can break tree stems, (2) the intermittent regime seldom controls tree breakage and (3) quasi-static pressures of wet snow avalanches can be much higher than pressures calculated using dynamic pressure formulas.

  19. Impacts of different hydrodynamic regimes on flocculation

    NASA Astrophysics Data System (ADS)

    Ramirez-Mendoza, Rafael; Souza, Alejandro; Amoudry, Laurent

    2014-05-01

    A number of activities carried out in coastal zones and estuaries are affected by sediment transport. Therefore, good knowledge of the processes involved is necessary to adequately manage these areas. Flocculation is a key process on fine sediment dynamics, which affects the effective particle size and settling velocity. The process is further complicated under the combined effect of currents and waves. This research seeks to improve our understanding of the flocculation process under the combined effect of currents and waves. The study site is the Dee Estuary located in Liverpool Bay, United Kingdom. Measurements of volume concentration, grain size and current velocities near the sea bed were obtained from a mooring deployed between 12 February 2008 and 9 March 2008. Turbulent properties could also be calculated because of the fast sampling rate used for current velocities. Water samples were taken from a research vessel during the first two days of the study in order to calibrate moored instruments and convert volume to mass concentration. The observations almost covered two fortnightly periods and three different dynamic regimes can be distinguished: currents-only, combined waves and currents, and wave dominated. During the currents-only regime, floc aggregation and breakup coincide with periods of low and high turbulent stress respectively. The combination of waves and spring tide currents makes the second regime and the floc breakup is most dominant when waves are higher than one meter and small flocs are found even with low turbulent stress from both waves and currents. The third regime is identified as wave-dominant during neap tides with current speed less than 0.25 m/s and waves of 1-2 meters height. In this regime the wave effect takes large sediment into suspension at the same time as small particle sizes from floc breakup. In this case the median particle size is strongly related to the wave height which means that a slight particle aggregation is still

  20. Regime shifts in the anthropocene: drivers, risks, and resilience.

    PubMed

    Rocha, Juan Carlos; Peterson, Garry D; Biggs, Reinette

    2015-01-01

    Many ecosystems can experience regime shifts: surprising, large and persistent changes in the function and structure of ecosystems. Assessing whether continued global change will lead to further regime shifts, or has the potential to trigger cascading regime shifts has been a central question in global change policy. Addressing this issue has, however, been hampered by the focus of regime shift research on specific cases and types of regime shifts. To systematically assess the global risk of regime shifts we conducted a comparative analysis of 25 generic types of regime shifts across marine, terrestrial and polar systems; identifying their drivers, and impacts on ecosystem services. Our results show that the drivers of regime shifts are diverse and co-occur strongly, which suggests that continued global change can be expected to synchronously increase the risk of multiple regime shifts. Furthermore, many regime shift drivers are related to climate change and food production, whose links to the continued expansion of human activities makes them difficult to limit. Because many regime shifts can amplify the drivers of other regime shifts, continued global change can also be expected to increase the risk of cascading regime shifts. Nevertheless, the variety of scales at which regime shift drivers operate provides opportunities for reducing the risk of many types of regime shifts by addressing local or regional drivers, even in the absence of rapid reduction of global drivers. PMID:26267896

  1. Regime Shifts in the Anthropocene: Drivers, Risks, and Resilience

    PubMed Central

    Rocha, Juan Carlos; Peterson, Garry D.; Biggs, Reinette

    2015-01-01

    Many ecosystems can experience regime shifts: surprising, large and persistent changes in the function and structure of ecosystems. Assessing whether continued global change will lead to further regime shifts, or has the potential to trigger cascading regime shifts has been a central question in global change policy. Addressing this issue has, however, been hampered by the focus of regime shift research on specific cases and types of regime shifts. To systematically assess the global risk of regime shifts we conducted a comparative analysis of 25 generic types of regime shifts across marine, terrestrial and polar systems; identifying their drivers, and impacts on ecosystem services. Our results show that the drivers of regime shifts are diverse and co-occur strongly, which suggests that continued global change can be expected to synchronously increase the risk of multiple regime shifts. Furthermore, many regime shift drivers are related to climate change and food production, whose links to the continued expansion of human activities makes them difficult to limit. Because many regime shifts can amplify the drivers of other regime shifts, continued global change can also be expected to increase the risk of cascading regime shifts. Nevertheless, the variety of scales at which regime shift drivers operate provides opportunities for reducing the risk of many types of regime shifts by addressing local or regional drivers, even in the absence of rapid reduction of global drivers. PMID:26267896

  2. Photon blockade in the ultrastrong coupling regime.

    PubMed

    Ridolfo, A; Leib, M; Savasta, S; Hartmann, M J

    2012-11-01

    We explore photon coincidence counting statistics in the ultrastrong coupling regime, where the atom-cavity coupling rate becomes comparable to the cavity resonance frequency. In this regime, usual normal order correlation functions fail to describe the output photon statistics. By expressing the electric-field operator in the cavity-emitter dressed basis, we are able to propose correlation functions that are valid for arbitrary degrees of light-matter interaction. Our results show that the standard photon blockade scenario is significantly modified for ultrastrong coupling. We observe parametric processes even for two-level emitters and temporal oscillations of intensity correlation functions at a frequency given by the ultrastrong photon emitter coupling. These effects can be traced back to the presence of two-photon cascade decays induced by counterrotating interaction terms. PMID:23215383

  3. Cluster analysis of multiple planetary flow regimes

    NASA Technical Reports Server (NTRS)

    Mo, Kingtse; Ghil, Michael

    1988-01-01

    A modified cluster analysis method developed for the classification of quasi-stationary events into a few planetary flow regimes and for the examination of transitions between these regimes is described. The method was applied first to a simple deterministic model and then to a 500-mbar data set for Northern Hemisphere (NH), for which cluster analysis was carried out in the subspace of the first seven empirical orthogonal functions (EOFs). Stationary clusters were found in the low-frequency band of more than 10 days, while transient clusters were found in the band-pass frequency window between 2.5 and 6 days. In the low-frequency band, three pairs of clusters determined EOFs 1, 2, and 3, respectively; they exhibited well-known regional features, such as blocking, the Pacific/North American pattern, and wave trains. Both model and low-pass data exhibited strong bimodality.

  4. Steady and transient regimes in hydropower plants

    NASA Astrophysics Data System (ADS)

    Gajic, A.

    2013-12-01

    Hydropower plant that has been in operation for about 30 years has to be reconstructed. They have already installed 12 Kaplan turbines, the largest in the world at that time. The existing CAM relationship was determined based on hydraulic model tests and checked by efficiency on-site tests. It was also tested based on turbine bearing vibrations. In order to discover vibrations and long cracks on stay vanes detailed on-site measurements were performed. Influence of the modification of the trailing edges on the dynamic stresses of the stay vanes is also shown. In order to improve power output transient regimes were analyzed, both experimentally and numerically. Reversible hydropower plant, a pioneer in Europe since it was the first Pump storage power plant constructed with the highest head pump-turbines in the world. Analyses of transient regimes discover some problems with S-shaped characteristics coupled with non-symmetrical penstock.

  5. The optomechanical instability in the quantum regime

    NASA Astrophysics Data System (ADS)

    Ludwig, Max; Kubala, Björn; Marquardt, Florian

    2008-09-01

    We consider a generic optomechanical system, consisting of a driven optical cavity and a movable mirror attached to a cantilever. Systems of this kind (and analogues) have been realized in many recent experiments. It is well known that these systems can exhibit an instability towards a regime where the cantilever settles into self-sustained oscillations. In this paper, we briefly review the classical theory of the optomechanical instability, and then discuss the features arising in the quantum regime. We solve numerically a full quantum master equation for the coupled system, and use it to analyze the photon number, the cantilever's mechanical energy, the phonon probability distribution and the mechanical Wigner density, as a function of experimentally accessible control parameters. When a suitable dimensionless 'quantum parameter' is sent to zero, the results of the quantum mechanical model converge towards the classical predictions. We discuss this quantum-to-classical transition in some detail.

  6. Dominant takeover regimes for genetic algorithms

    NASA Technical Reports Server (NTRS)

    Noever, David; Baskaran, Subbiah

    1995-01-01

    The genetic algorithm (GA) is a machine-based optimization routine which connects evolutionary learning to natural genetic laws. The present work addresses the problem of obtaining the dominant takeover regimes in the GA dynamics. Estimated GA run times are computed for slow and fast convergence in the limits of high and low fitness ratios. Using Euler's device for obtaining partial sums in closed forms, the result relaxes the previously held requirements for long time limits. Analytical solution reveal that appropriately accelerated regimes can mark the ascendancy of the most fit solution. In virtually all cases, the weak (logarithmic) dependence of convergence time on problem size demonstrates the potential for the GA to solve large N-P complete problems.

  7. Bose polarons in the strongly interacting regime

    NASA Astrophysics Data System (ADS)

    Kedar, Dhruv; Hu, Ming-Guang; van de Graaff, Michael; Corson, John; Cornell, Eric; Jin, Deborah

    2016-05-01

    Impurities immersed in and interacting with a Bose-Einstein condensate (BEC) are predicted to form quasiparticle excitations called Bose polarons. I will present experimental evidence of Bose polarons in cold atoms obtained using radio-frequency spectroscopy to measure the excitation spectrum of fermionic K-40 impurities interacting with a BEC of Rb-87 atoms. We use an interspecies Feshbach resonance to tune the interactions between the impurities and the bosons, and we take data in the strongly interacting regime.

  8. Predictive Bayesian inference and dynamic treatment regimes.

    PubMed

    Saarela, Olli; Arjas, Elja; Stephens, David A; Moodie, Erica E M

    2015-11-01

    While optimal dynamic treatment regimes (DTRs) can be estimated without specification of a predictive model, a model-based approach, combined with dynamic programming and Monte Carlo integration, enables direct probabilistic comparisons between the outcomes under the optimal DTR and alternative (dynamic or static) treatment regimes. The Bayesian predictive approach also circumvents problems related to frequentist estimators under the nonregular estimation problem. However, the model-based approach is susceptible to misspecification, in particular of the "null-paradox" type, which is due to the model parameters not having a direct causal interpretation in the presence of latent individual-level characteristics. Because it is reasonable to insist on correct inferences under the null of no difference between the alternative treatment regimes, we discuss how to achieve this through a "null-robust" reparametrization of the problem in a longitudinal setting. Since we argue that causal inference can be entirely understood as posterior predictive inference in a hypothetical population without covariate imbalances, we also discuss how controlling for confounding through inverse probability of treatment weighting can be justified and incorporated in the Bayesian setting. PMID:26259996

  9. The kinetic regime of the Vicsek model

    NASA Astrophysics Data System (ADS)

    Chepizhko, A. A.; Kulinskii, V. L.

    2009-12-01

    We consider the dynamics of the system of self-propelling particles modeled via the Vicsek algorithm in continuum time limit. It is shown that the alignment process for the velocities can be subdivided into two regimes: "fast" kinetic and "slow" hydrodynamic ones. In fast kinetic regime the alignment of the particle velocity to the local neighborhood takes place with characteristic relaxation time. So, that the bigger regions arise with the velocity alignment. These regions align their velocities thus giving rise to hydrodynamic regime of the dynamics. We propose the mean-field-like approach in which we take into account the correlations between density and velocity. The comparison of the theoretical predictions with the numerical simulations is given. The relation between Vicsek model in the zero velocity limit and the Kuramoto model is stated. The mean-field approach accounting for the dynamic change of the neighborhood is proposed. The nature of the discontinuity of the dependence of the order parameter in case of vectorial noise revealed in Gregorie and Chaite, Phys. Rev. Lett., 92, 025702 (2004) is discussed and the explanation of it is proposed.

  10. Particle optics in the Rayleigh regime.

    PubMed

    Moosmüller, Hans; Arnott, W Patrick

    2009-09-01

    Light scattering and absorption by particles suspended in the atmosphere modifies the transfer of solar energy in the atmosphere, thereby influencing global and regional climate change and atmospheric visibility. Of particular interest are the optical properties of particles in the Rayleigh regime, where particles are small compared with the wavelength of the scattered or absorbed light, because these particles experience little gravitational settlement and may have long atmospheric lifetimes. Optical properties of particles in the Rayleigh regime are commonly derived from electromagnetic theory using Maxwell's equations and appropriate boundary conditions. The size dependence of particle scattering and absorption are derived here from the most basic principles for coherent processes such as Rayleigh scattering (i.e., add amplitudes if in phase) and incoherent processes such as absorption (i.e., add cross sections), at the same time yielding understanding of the upper particle size limit for the Rayleigh regime. The wavelength dependence of Rayleigh scattering and absorption are also obtained by adding a basic scale invariance for particle optics. Simple consequences for particle single-scattering albedo ("whiteness") and the optical measurement of particle mass densities are explained. These alternative derivations complement the conventional understanding obtained from electromagnetic theory. PMID:19785268

  11. Constructing an interdisciplinary flow regime recommendation

    USGS Publications Warehouse

    Bartholow, J.M.

    2010-01-01

    It is generally agreed that river rehabilitation most often relies on restoring a more natural flow regime, but credibly defining the desired regime can be problematic. I combined four distinct methods to develop and refine month-by-month and event-based flow recommendations to protect and partially restore the ecological integrity of the Cache la Poudre River through Fort Collins, Colorado. A statistical hydrologic approach was used to summarize the river's natural flow regime and set provisional monthly flow targets at levels that were historically exceeded 75% of the time. These preliminary monthly targets were supplemented using results from three Poudre-specific disciplinary studies. A substrate maintenance flow model was used to better define the high flows needed to flush accumulated sediment from the river's channel and help sustain the riparian zone in this snowmelt-dominated river. A hydraulic/habitat model and a water temperature model were both used to better define the minimum flows necessary to maintain a thriving cool water fishery. The result is a range of recommended monthly flows and daily flow guidance illustrating the advantage of combining a wide range of available disciplinary information, supplemented by judgment based on ecological principles and a general understanding of river ecosystems, in a highly altered, working river. ?? 2010 American Water Resources Association.

  12. Three-dimensional null point reconnection regimes

    SciTech Connect

    Priest, E. R.; Pontin, D. I.

    2009-12-15

    Recent advances in theory and computational experiments have shown the need to refine the previous categorization of magnetic reconnection at three-dimensional null points--points at which the magnetic field vanishes. We propose here a division into three different types, depending on the nature of the flow near the spine and fan of the null. The spine is an isolated field line which approaches the null (or recedes from it), while the fan is a surface of field lines which recede from it (or approach it). So-called torsional spine reconnection occurs when field lines in the vicinity of the fan rotate, with current becoming concentrated along the spine so that nearby field lines undergo rotational slippage. In torsional fan reconnection field lines near the spine rotate and create a current that is concentrated in the fan with a rotational flux mismatch and rotational slippage. In both of these regimes, the spine and fan are perpendicular and there is no flux transfer across spine or fan. The third regime, called spine-fan reconnection, is the most common in practice and combines elements of the previous spine and fan models. In this case, in response to a generic shearing motion, the null point collapses to form a current sheet that is focused at the null itself, in a sheet that locally spans both the spine and fan. In this regime the spine and fan are no longer perpendicular and there is flux transfer across both of them.

  13. Understanding the Early Regime of Drop Spreading.

    PubMed

    Mitra, Surjyasish; Mitra, Sushanta K

    2016-09-01

    We present experimental data to characterize the spreading of a liquid drop on a substrate kept submerged in another liquid medium. They reveal that drop spreading always begins in a regime dominated by drop viscosity where the spreading radius scales as r ∼ t with a nonuniversal prefactor. This initial viscous regime either lasts in its entirety or switches to an intermediate inertial regime where the spreading radius grows with time following the well-established inertial scaling of r ∼ t(1/2). This latter case depends on the characteristic viscous length scale of the problem. In either case, the final stage of spreading, close to equilibrium, follows Tanner's law. Further experiments performed on the same substrate kept in ambient air reveal a similar trend, albeit with limited spatiotemporal resolution, showing the universal nature of the spreading behavior. It is also found that, for early times of spreading, the process is similar to coalescence of two freely suspended liquid drops, making the presence of the substrate and consequently the three-phase contact line insignificant. PMID:27513708

  14. Kinetic studies on novel plasminogen activators. Demonstration of fibrin enhancement for hybrid enzymes comprising the A-chain of plasmin (Lys-78) and B-chain of tissue-type plasminogen activator (Ile-276) or urokinase (Ile-159).

    PubMed Central

    Fears, R; Dodd, I; Ferres, H; Robinson, J H

    1990-01-01

    The activation of plasminogen by two novel hybrid enzymes, constructed from the A-chain of plasmin and the B-chains of tissue-type plasminogen activator (t-PA) or urokinase, was compared with the activation by the parent enzymes. Basal kinetic constants for 'Lys-plasminogen' (human plasminogen with N-terminal lysine) and 'Glu-plasminogen' (human plasminogen with N-terminal glutamic acid) activation were similar to those of the parent activators. The Km for plasminogen turnover for both hybrid enzymes was considerably decreased in the presence of both soluble fibrin and a mimic, a CNBr digest of fibrinogen. These enhancements and the related apparent negative co-operativity are similar to the behaviour of t-PA itself. The results are discussed with regard to the molecular features involved in the mechanism of fibrin stimulation. PMID:2139324

  15. Urokinase plasminogen activator receptor induced non-small cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity

    PubMed Central

    Provost, J.J.; Rastedt, D.; Canine, J.; Ngyuen, T.; Haak, A.; Kutz, C.; Berthesen, N.; Slusser, A.; Anderson, K.; Dorsam, G; Wallert, M.A.

    2012-01-01

    Background Non-small cell lung cancers (NSLC) are aggressive cancers that are insensitive to chemotherapies and accounts for nearly 33% of all cancer deaths in the United States. Two hallmarks of cancer that allow cells to invade and metastasize are sustained proliferation and enhanced motility. In this study we investigate the relationship between urokinase plasminogen activator (uPA)/uPA receptor (uPAR) signaling and Na+/H+ exchanger isoform 1 (NHE1) expression and activity. Methods and Results The addition of 10nM uPA increased the carcinogenic potential of three NSCLC cell lines, NCI-H358, NCI-H460, and NCI-H1299. This included an increase in the rate of cell proliferation 1.6 to 1.9 fold; an increase in the percentage of cells displaying stress fibers 3.05 to 3.17 fold; and an increase in anchorage-independent growth from 1.64 to 2.0 fold. In each of these cases the increase was blocked when the experiments were performed with NHE1 inhibited by 10 μM EIPA (ethylisopropyl amiloride). To further evaluate the role of uPA/uPAR and NHE1 in tumor progression we assessed signaling events using full-length uPA compared to the uPA amino terminal fragment (ATF). Comparing uPA and ATF signaling in H460 cells, we found that both uPA and ATF increased stress fiber formation approximately 2 fold, while uPA increased matrix metalloproteinase 9 (MMP9) activity 5.44 fold compared to 2.81 fold for ATF. To expand this signaling study, two new cell lines were generated, one with reduced NHE1 expression (H460 NHE1 K/D) and one with reduced uPAR expression (H460 uPAR K/D). Using the K/D cell lines we found that neither uPA nor ATF could stimulate stress fiber formation or MMP9 activity in cells with dramatically decreased NHE1 or uPAR expression. Finally, using in vivo tumor formation studies in athymic mice we found that when mice were injected with H460 cells 80% of mice formed tumors with an average volume of 390 mm3. This was compared to 20% of H460 uPAR K/D injected mice

  16. Localization and distribution of tissue type and urokinase type plasminogen activators and their inhibitors Type 1 and 2 in human and rhesus monkey fetal membranes.

    PubMed

    Liu, Y X; Hu, Z Y; Liu, K; Byrne, S; Zou, R J; Ny, T; d'Lacey, C; Ockleford, C D

    1998-01-01

    Fetal membranes consist of 10 distinct layers including components of amnion, chorion and decidua, the latter being of maternal origin. They form mechanically integrated sheets capable of retaining amniotic fluid and play an essential role in protecting fetal growth and development in the pregnant uterus. The extracellular matrix, substrate for plasminogen activators (PAs), is an important supportive framework of the fetal membranes. Fetal membranes from women with preterm premature rupture of membranes may differ in their protease activity compared with normal membranes. To identify the presence of PAs and their inhibitors (PAI) and their possible role in the process of fetal membrane rupture, this study investigated the distribution and localization of both protein and mRNA for tissue (t) and urokinase (u) PA and their inhibitors type 1 (PAI-1) and type 2 (PAI-2) in amniochorion of human and rhesus monkey using conventional and confocal immunofluorescence microscopy. In situ hybridization analysis showed that the distribution and localization of mRNAs for tPA, uPA, PAI-1 and PAI-2 were similar in the fetal membranes of human and rhesus monkey; no obvious species difference was observed. Evidence of tPA mRNA was detected in amniotic epithelium, trophoblast cells and nearly all cells of the decidual layer. Strong expression of uPA mRNA was noted in the decidual cells which increased in intensity as the abscission point was approached. Weak staining in chorion laeve trophoblast was also detected. In situ hybridization experiments showed PAI-1 mRNA to be concentrated mainly in the decidual cells, some of which were interposed into the maternal-facing edge of the chorion laeve. Maximal labelling of the decidua occurred towards the zone of abscission. Weak expression of PAI-1 mRNA was also noted in some cells of the chorion laeve. The distribution of PAI-2 mRNA in amniochorion was also concentrated in the cells of the decidual layer, maximum expression of the mRNA was

  17. FISHER INFORMATION OF DYNAMIC REGIME TRANSITIONS IN ECOLOGICAL SYSTEMS

    EPA Science Inventory

    Ecosystems often exhibit transitions between multiple dynamic regimes (or steady states). As ecosystems experience perturbations of varying regularity and intensity, they may either remain within the state space neighborhood of the current regime, or ?flip? into the neighborhood ...

  18. THE DYNAMIC REGIME CONCEPT FOR ECOSYSTEM MANAGEMENT AND RESTORATION

    EPA Science Inventory

    Dynamic regimes of ecosystems are multidimensional basis of attraction, characterized by particular species communities and ecosystems processes. Ecosystem patterns and processes rarely respond linerarly to disturbances, and the nonlinear cynamic regime concept offers a more real...

  19. Laboratory Exploration of Multiple Zonal Jet Regimes

    NASA Astrophysics Data System (ADS)

    Smith, C. A.; Speer, K. G.; Griffiths, R. W.

    2012-12-01

    The differentially heated, rotating annulus has classically been used to study wave interactions within a single, baroclinic jet. At high rotation rates, the baroclinic instability of the flow leads to a transition to a turbulent, eddy-dominated regime. In the presence of a topographic beta effect, the flow has been observed to produce multiple, meandering zonal jets that are qualitatively similar to those found in planetary atmospheres and in the Antarctic Circumpolar Current (ACC). Our study builds on previous annulus experiments [1] by making observations further within this new regime. We observe with PIV and other techniques how the structure of the flow responds to changes in various parameters such as tank geometry, gradient in the Coriolis parameter, rotation rate, and differential thermal forcing. By not employing the more typical direct forcing of small scales, but by applying a large scale forcing over the annulus gap width, this study allows the varying effects of eddy scale selection, enstrophy cascade, etc. to naturally generate flow that more closely resembles planetary atmospheres and the ACC. We seek nondimensional parameters that significantly control zonation in a real fluid. These observations will provide a metric for the comparison of various theoretical models for multiple zonal jet formation. Other properties of the jets, such as their migration, meandering, bifurcation, and merging, can also be observed in an idealized situation and compared to numerical simulations. Ultimately, this will aid the testing and development of sub-grid-scale parameterizations for the multiple zonal jet regime that remain robust in the face of multiple forcing parameters. [1] Wordsworth, R. D., Read, P. L., & Yamazaki, Y. H. (2008). Turbulence, waves, and jets in a differentially heated rotating annulus experiment Physics of Fluids, 20(12), 126602.Streak photograph of suspended particles visualizing the flow representative of multiple zonal jets

  20. The discrete regime of flame propagation

    NASA Astrophysics Data System (ADS)

    Tang, Francois-David; Goroshin, Samuel; Higgins, Andrew

    The propagation of laminar dust flames in iron dust clouds was studied in a low-gravity envi-ronment on-board a parabolic flight aircraft. The elimination of buoyancy-induced convection and particle settling permitted measurements of fundamental combustion parameters such as the burning velocity and the flame quenching distance over a wide range of particle sizes and in different gaseous mixtures. The discrete regime of flame propagation was observed by substitut-ing nitrogen present in air with xenon, an inert gas with a significantly lower heat conductivity. Flame propagation in the discrete regime is controlled by the heat transfer between neighbor-ing particles, rather than by the particle burning rate used by traditional continuum models of heterogeneous flames. The propagation mechanism of discrete flames depends on the spa-tial distribution of particles, and thus such flames are strongly influenced by local fluctuations in the fuel concentration. Constant pressure laminar dust flames were observed inside 70 cm long, 5 cm diameter Pyrex tubes. Equally-spaced plate assemblies forming rectangular chan-nels were placed inside each tube to determine the quenching distance defined as the minimum channel width through which a flame can successfully propagate. High-speed video cameras were used to measure the flame speed and a fiber optic spectrometer was used to measure the flame temperature. Experimental results were compared with predictions obtained from a numerical model of a three-dimensional flame developed to capture both the discrete nature and the random distribution of particles in the flame. Though good qualitative agreement was obtained between model predictions and experimental observations, residual g-jitters and the short reduced-gravity periods prevented further investigations of propagation limits in the dis-crete regime. The full exploration of the discrete flame phenomenon would require high-quality, long duration reduced gravity environment

  1. Quantum gas mixtures in different correlation regimes

    NASA Astrophysics Data System (ADS)

    Garcia-March, Miguel Angel; Busch, Thomas

    2013-06-01

    We present a many-body description for two-component ultracold bosonic gases when one of the species is in the weakly interacting regime and the other is either weakly or strongly interacting. In the one-dimensional limit the latter is a hybrid in which a Tonks-Girardeau gas is immersed in a Bose-Einstein condensate, which is an example of a class of quantum system involving a tunable, superfluid environment. We describe the process of phase separation microscopically as well as semiclassically in both situations and show that quantum correlations are maintained even in the separated phase.

  2. Imperfect relativistic mirrors in the quantum regime

    SciTech Connect

    Mendonça, J. T.; Serbeto, A.; Galvão, R. M. O.

    2014-05-15

    The collective backscattering of intense laser radiation by energetic electron beams is considered in the relativistic quantum regime. Exact solutions for the radiation field are obtained, for arbitrary electron pulse shapes and laser intensities. The electron beams act as imperfect nonlinear mirrors on the incident laser radiation. This collective backscattering process can lead to the development of new sources of ultra-short pulse radiation in the gamma-ray domain. Numerical examples show that, for plausible experimental conditions, intense pulses of gamma-rays, due to the double Doppler shift of the harmonics of the incident laser radiation, can be produced using the available technology, with durations less than 1 as.

  3. Bose Polarons in the Strongly Interacting Regime.

    PubMed

    Hu, Ming-Guang; Van de Graaff, Michael J; Kedar, Dhruv; Corson, John P; Cornell, Eric A; Jin, Deborah S

    2016-07-29

    When an impurity is immersed in a Bose-Einstein condensate, impurity-boson interactions are expected to dress the impurity into a quasiparticle, the Bose polaron. We superimpose an ultracold atomic gas of ^{87}Rb with a much lower density gas of fermionic ^{40}K impurities. Through the use of a Feshbach resonance and radio-frequency spectroscopy, we characterize the energy, spectral width, and lifetime of the resultant polaron on both the attractive and the repulsive branches in the strongly interacting regime. The width of the polaron in the attractive branch is narrow compared to its binding energy, even as the two-body scattering length diverges. PMID:27517776

  4. Bose polarons in the strongly interacting regime

    NASA Astrophysics Data System (ADS)

    Hu, Ming-Guang; van de Graaff, Michael; Kedar, Dhruv; Cornell, Eric; Jin, Deborah

    Impurities immersed in and interacting with a Bose-Einstein condensate (BEC) are predicted to form quasiparticle excitations called Bose polarons. I will present experimental evidence of Bose polarons in cold atoms obtained using radio-frequency spectroscopy to measure the excitation spectrum of fermionic 40K impurities interacting with a BEC of 87Rb atoms. We use an interspecies Feshbach resonance to tune the interactions between the impurities and the bosons, and we take data in the strongly interacting regime. This work is supported by NSF, NASA and NIST.

  5. Bose Polarons in the Strongly Interacting Regime

    NASA Astrophysics Data System (ADS)

    Hu, Ming-Guang; Van de Graaff, Michael J.; Kedar, Dhruv; Corson, John P.; Cornell, Eric A.; Jin, Deborah S.

    2016-07-01

    When an impurity is immersed in a Bose-Einstein condensate, impurity-boson interactions are expected to dress the impurity into a quasiparticle, the Bose polaron. We superimpose an ultracold atomic gas of 87Rb with a much lower density gas of fermionic 40 impurities. Through the use of a Feshbach resonance and radio-frequency spectroscopy, we characterize the energy, spectral width, and lifetime of the resultant polaron on both the attractive and the repulsive branches in the strongly interacting regime. The width of the polaron in the attractive branch is narrow compared to its binding energy, even as the two-body scattering length diverges.

  6. 22 CFR 120.29 - Missile Technology Control Regime.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Missile Technology Control Regime. 120.29... DEFINITIONS § 120.29 Missile Technology Control Regime. (a) For purposes of this subchapter, Missile Technology Control Regime (MTCR) means the policy statement between the United States, the United...

  7. The relationship between void waves and flow regime transition

    SciTech Connect

    Lahey, R.T. Jr.; Drew, D.A.; Kalkach-Navarro, S.; Park, J.W.

    1992-12-31

    The results of an extensive experimental and analytical study on the relationship between void waves and flow regime transition are presented, in particular, the bubbly/slug flow regime transition. It is shown that void wave instability signals a flow regime transition.

  8. 22 CFR 121.16 - Missile Technology Control Regime Annex.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Missile Technology Control Regime Annex. 121.16... STATES MUNITIONS LIST Enumeration of Articles § 121.16 Missile Technology Control Regime Annex. Some of the items on the Missile Technology Control Regime Annex are controlled by both the Department...

  9. 22 CFR 120.29 - Missile Technology Control Regime.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Missile Technology Control Regime. 120.29... DEFINITIONS § 120.29 Missile Technology Control Regime. (a) For purposes of this subchapter, Missile Technology Control Regime (MTCR) means the policy statement between the United States, the United...

  10. 22 CFR 120.29 - Missile Technology Control Regime.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Missile Technology Control Regime. 120.29... DEFINITIONS § 120.29 Missile Technology Control Regime. (a) For purposes of this subchapter, Missile Technology Control Regime (MTCR) means the policy statement among the United States, the United Kingdom,...

  11. 22 CFR 120.29 - Missile Technology Control Regime.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Missile Technology Control Regime. 120.29... DEFINITIONS § 120.29 Missile Technology Control Regime. (a) For purposes of this subchapter, Missile Technology Control Regime (MTCR) means the policy statement between the United States, the United...

  12. 22 CFR 120.29 - Missile Technology Control Regime.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Missile Technology Control Regime. 120.29... DEFINITIONS § 120.29 Missile Technology Control Regime. (a) For purposes of this subchapter, Missile Technology Control Regime (MTCR) means the policy statement between the United States, the United...

  13. Elastic regimes of subisostatic athermal fiber networks

    NASA Astrophysics Data System (ADS)

    Licup, A. J.; Sharma, A.; MacKintosh, F. C.

    2016-01-01

    Athermal models of disordered fibrous networks are highly useful for studying the mechanics of elastic networks composed of stiff biopolymers. The underlying network architecture is a key aspect that can affect the elastic properties of these systems, which include rich linear and nonlinear elasticity. Existing computational approaches have focused on both lattice-based and off-lattice networks obtained from the random placement of rods. It is not obvious, a priori, whether the two architectures have fundamentally similar or different mechanics. If they are different, it is not clear which of these represents a better model for biological networks. Here, we show that both approaches are essentially equivalent for the same network connectivity, provided the networks are subisostatic with respect to central force interactions. Moreover, for a given subisostatic connectivity, we even find that lattice-based networks in both two and three dimensions exhibit nearly identical nonlinear elastic response. We provide a description of the linear mechanics for both architectures in terms of a scaling function. We also show that the nonlinear regime is dominated by fiber bending and that stiffening originates from the stabilization of subisostatic networks by stress. We propose a generalized relation for this regime in terms of the self-generated normal stresses that develop under deformation. Different network architectures have different susceptibilities to the normal stress but essentially exhibit the same nonlinear mechanics. Such a stiffening mechanism has been shown to successfully capture the nonlinear mechanics of collagen networks.

  14. Vibratory Regime Classification of Infant Phonation

    PubMed Central

    Buder, Eugene H.; Chorna, Lesya B.; Oller, D. Kimbrough; Robinson, Rebecca B.

    2008-01-01

    Infant phonation is highly variable in many respects, including the basic vibratory patterns by which the vocal tissues create acoustic signals. Previous studies have identified the regular occurrence of non-modal phonation types in normal infant phonation. The glottis is like many oscillating systems that, because of non-linear relationships among the elements, may vibrate in ways representing the deterministic patterns classified theoretically within the mathematical framework of non-linear dynamics. The infant’s pre-verbal vocal explorations present such a variety of phonations that it may be possible to find effectively all the classes of vibration predicted by non-linear dynamic theory. The current report defines acoustic criteria for an important subset of such vibratory regimes, and demonstrates that analysts can be trained to reliably use these criteria for a classification that includes all instances of infant phonation in the recorded corpora. The method is thus internally comprehensive in the sense that all phonations are classified, but it is not exhaustive in the sense that all vocal qualities are thereby represented. Using the methods thus developed, this study also demonstrates that the distributions of these phonation types vary significantly across sessions of recording in the first year of life, suggesting developmental changes. The method of regime classification is thus capable of tracking changes that may be indicative of maturation of the mechanism, the learning of categories of phonatory control, and the possibly varying use of vocalizations across social contexts. PMID:17509829

  15. Wavy regime of a viscoplastic film flow

    NASA Astrophysics Data System (ADS)

    Chakraborty, Symphony; Ruyer-Quil, Christian; Dandapat, Bhabani S.

    2010-11-01

    We consider a power-law fluid flowing down an inclined plane under the action of gravity. The divergence of the viscosity of a shear-thinning fluid at zero strain rate is taken care of by introducing a Newtonian plateau at small strain rate. Applying a weighted residual approach, a two-equations model is formulated in terms of two coupled evolution equations for the film thickness h and the local flow rate q within the framework of lubrication theory. The model accounts for the streamwise diffusion of momentum. Consistency of the model is achieved up to first order in the film parameter for inertia terms and up to second order for viscous terms. Comparison to Orr-Sommerfeld stability analysis and to DNS show convincing agreement in both linear and nonlinear regimes. In the case of shear-thinning fluids, lowering the power index has a non-trivial effect on the primary instability of the film: the threshold of the instability occurs at a smaller Reynolds number but the range of instable wavenumber is also reduced. In the nonlinear regime, we have evidenced a subcritical bifurcation of the traveling-wave solutions from marginal stability conditions.

  16. Elastic regimes of subisostatic athermal fiber networks.

    PubMed

    Licup, A J; Sharma, A; MacKintosh, F C

    2016-01-01

    Athermal models of disordered fibrous networks are highly useful for studying the mechanics of elastic networks composed of stiff biopolymers. The underlying network architecture is a key aspect that can affect the elastic properties of these systems, which include rich linear and nonlinear elasticity. Existing computational approaches have focused on both lattice-based and off-lattice networks obtained from the random placement of rods. It is not obvious, a priori, whether the two architectures have fundamentally similar or different mechanics. If they are different, it is not clear which of these represents a better model for biological networks. Here, we show that both approaches are essentially equivalent for the same network connectivity, provided the networks are subisostatic with respect to central force interactions. Moreover, for a given subisostatic connectivity, we even find that lattice-based networks in both two and three dimensions exhibit nearly identical nonlinear elastic response. We provide a description of the linear mechanics for both architectures in terms of a scaling function. We also show that the nonlinear regime is dominated by fiber bending and that stiffening originates from the stabilization of subisostatic networks by stress. We propose a generalized relation for this regime in terms of the self-generated normal stresses that develop under deformation. Different network architectures have different susceptibilities to the normal stress but essentially exhibit the same nonlinear mechanics. Such a stiffening mechanism has been shown to successfully capture the nonlinear mechanics of collagen networks. PMID:26871101

  17. Dynamic regimes of random fuzzy logic networks

    NASA Astrophysics Data System (ADS)

    Wittmann, Dominik M.; Theis, Fabian J.

    2011-01-01

    Random multistate networks, generalizations of the Boolean Kauffman networks, are generic models for complex systems of interacting agents. Depending on their mean connectivity, these networks exhibit ordered as well as chaotic behavior with a critical boundary separating both regimes. Typically, the nodes of these networks are assigned single discrete states. Here, we describe nodes by fuzzy numbers, i.e. vectors of degree-of-membership (DOM) functions specifying the degree to which the nodes are in each of their discrete states. This allows our models to deal with imprecision and uncertainties. Compatible update rules are constructed by expressing the update rules of the multistate network in terms of Boolean operators and generalizing them to fuzzy logic (FL) operators. The standard choice for these generalizations is the Gödel FL, where AND and OR are replaced by the minimum and maximum of two DOMs, respectively. In mean-field approximations we are able to analytically describe the percolation and asymptotic distribution of DOMs in random Gödel FL networks. This allows us to characterize the different dynamic regimes of random multistate networks in terms of FL. In a low-dimensional example, we provide explicit computations and validate our mean-field results by showing that they agree well with network simulations.

  18. 29 CFR 2530.200b-2 - Hour of service.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    .... Under the sick leave policy of E's employer E is paid his normal weekly salary for the first 8 weeks of... sick leave policy under which an employee is entitled to a certain number of hours of sick leave each... 4, 1978. Under the employer's sick leave policy, the employee is entitled to compensation for...

  19. 29 CFR 2530.200b-2 - Hour of service.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... period III, A takes a vacation for a period lasting more than 2 weeks. A is entitled to be credited with 80 hours of service for his vacation in computation period III (40 hours per week multiplied by 2 weeks) even though the vacation lasted more than 2 weeks. (B) Employee B has no regular work...

  20. Classification of Arctic, Mid-Latitude and Tropical Clouds in the Mixed-Phase Temperature Regime

    NASA Astrophysics Data System (ADS)

    Costa, Anja; Afchine, Armin; Luebke, Anna; Meyer, Jessica; Dorsey, James R.; Gallagher, Martin W.; Ehrlich, André; Wendisch, Manfred; Krämer, Martina

    2016-04-01

    The degree of glaciation and the sizes and habits of ice particles formed in mixed-phase clouds remain not fully understood. However, these properties define the mixed clouds' radiative impact on the Earth's climate and thus a correct representation of this cloud type in global climate models is of importance for an improved certainty of climate predictions. This study focuses on the occurrence and characteristics of two types of clouds in the mixed-phase temperature regime (238-275K): coexistence clouds (Coex), in which both liquid drops and ice crystals exist, and fully glaciated clouds that develop in the Wegener-Bergeron-Findeisen regime (WBF clouds). We present an extensive dataset obtained by the Cloud and Aerosol Particle Spectrometer NIXE-CAPS, covering Arctic, mid-latitude and tropical regions. In total, we spent 45.2 hours within clouds in the mixed-phase temperature regime during five field campaigns (Arctic: VERDI, 2012 and RACEPAC, 2014 - Northern Canada; mid-latitude: COALESC, 2011 - UK and ML-Cirrus, 2014 - central Europe; tropics: ACRIDICON, 2014 - Brazil). We show that WBF and Coex clouds can be identified via cloud particle size distributions. The classified datasets are used to analyse temperature dependences of both cloud types as well as range and frequencies of cloud particle concentrations and sizes. One result is that Coex clouds containing supercooled liquid drops are found down to temperatures of -40 deg C only in tropical mixed clouds, while in the Arctic and mid-latitudes no liquid drops are observed below about -20 deg C. In addition, we show that the cloud particles' aspherical fractions - derived from polarization signatures of particles with diameters between 20 and 50 micrometers - differ significantly between WBF and Coex clouds. In Coex clouds, the aspherical fraction of cloud particles is generally very low, but increases with decreasing temperature. In WBF clouds, where all cloud particles are ice, about 20-40% of the cloud

  1. Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part I: main content.

    PubMed

    Orellana, Liliana; Rotnitzky, Andrea; Robins, James M

    2010-01-01

    Dynamic treatment regimes are set rules for sequential decision making based on patient covariate history. Observational studies are well suited for the investigation of the effects of dynamic treatment regimes because of the variability in treatment decisions found in them. This variability exists because different physicians make different decisions in the face of similar patient histories. In this article we describe an approach to estimate the optimal dynamic treatment regime among a set of enforceable regimes. This set is comprised by regimes defined by simple rules based on a subset of past information. The regimes in the set are indexed by a Euclidean vector. The optimal regime is the one that maximizes the expected counterfactual utility over all regimes in the set. We discuss assumptions under which it is possible to identify the optimal regime from observational longitudinal data. Murphy et al. (2001) developed efficient augmented inverse probability weighted estimators of the expected utility of one fixed regime. Our methods are based on an extension of the marginal structural mean model of Robins (1998, 1999) which incorporate the estimation ideas of Murphy et al. (2001). Our models, which we call dynamic regime marginal structural mean models, are specially suitable for estimating the optimal treatment regime in a moderately small class of enforceable regimes of interest. We consider both parametric and semiparametric dynamic regime marginal structural models. We discuss locally efficient, double-robust estimation of the model parameters and of the index of the optimal treatment regime in the set. In a companion paper in this issue of the journal we provide proofs of the main results. PMID:21969994

  2. No Interactions Between Previously Associated 2-Hour Glucose Gene Variants and Physical Activity or BMI on 2-Hour Glucose Levels

    PubMed Central

    Scott, Robert A.; Chu, Audrey Y.; Grarup, Niels; Manning, Alisa K.; Hivert, Marie-France; Shungin, Dmitry; Tönjes, Anke; Yesupriya, Ajay; Barnes, Daniel; Bouatia-Naji, Nabila; Glazer, Nicole L.; Jackson, Anne U.; Kutalik, Zoltán; Lagou, Vasiliki; Marek, Diana; Rasmussen-Torvik, Laura J.; Stringham, Heather M.; Tanaka, Toshiko; Aadahl, Mette; Arking, Dan E.; Bergmann, Sven; Boerwinkle, Eric; Bonnycastle, Lori L.; Bornstein, Stefan R.; Brunner, Eric; Bumpstead, Suzannah J.; Brage, Soren; Carlson, Olga D.; Chen, Han; Chen, Yii-Der Ida; Chines, Peter S.; Collins, Francis S.; Couper, David J.; Dennison, Elaine M.; Dowling, Nicole F.; Egan, Josephine S.; Ekelund, Ulf; Erdos, Michael R.; Forouhi, Nita G.; Fox, Caroline S.; Goodarzi, Mark O.; Grässler, Jürgen; Gustafsson, Stefan; Hallmans, Göran; Hansen, Torben; Hingorani, Aroon; Holloway, John W.; Hu, Frank B.; Isomaa, Bo; Jameson, Karen A.; Johansson, Ingegerd; Jonsson, Anna; Jørgensen, Torben; Kivimaki, Mika; Kovacs, Peter; Kumari, Meena; Kuusisto, Johanna; Laakso, Markku; Lecoeur, Cécile; Lévy-Marchal, Claire; Li, Guo; Loos, Ruth J.F.; Lyssenko, Valeri; Marmot, Michael; Marques-Vidal, Pedro; Morken, Mario A.; Müller, Gabriele; North, Kari E.; Pankow, James S.; Payne, Felicity; Prokopenko, Inga; Psaty, Bruce M.; Renström, Frida; Rice, Ken; Rotter, Jerome I.; Rybin, Denis; Sandholt, Camilla H.; Sayer, Avan A.; Shrader, Peter; Schwarz, Peter E.H.; Siscovick, David S.; Stančáková, Alena; Stumvoll, Michael; Teslovich, Tanya M.; Waeber, Gérard; Williams, Gordon H.; Witte, Daniel R.; Wood, Andrew R.; Xie, Weijia; Boehnke, Michael; Cooper, Cyrus; Ferrucci, Luigi; Froguel, Philippe; Groop, Leif; Kao, W.H. Linda; Vollenweider, Peter; Walker, Mark; Watanabe, Richard M.; Pedersen, Oluf; Meigs, James B.; Ingelsson, Erik; Barroso, Inês; Florez, Jose C.; Franks, Paul W.; Dupuis, Josée; Wareham, Nicholas J.; Langenberg, Claudia

    2012-01-01

    Gene–lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13–0.31], P = 1.63 × 10−6). All SNPs were associated with 2-h glucose (β = 0.06–0.12 mmol/allele, P ≤ 1.53 × 10−7), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene–lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions. PMID:22415877

  3. Institutional design and regime effectiveness in transboundary river management - the Elbe water quality regime

    NASA Astrophysics Data System (ADS)

    Dombrowsky, I.

    2007-06-01

    The literature on transboundary river management suggests that institutions play an important role in bringing cooperation about. However, the knowledge on how they should be designed in order to do so remains limited. One way to learn more about adequate institutional design is to assess the effectiveness of existing regimes, and to trace the causal relationships leading to the respective outcomes. In order to gain further insights into the relationship of institutional design and regime effectiveness, this paper presents a study on the water quality regime of the International Commission for the Protection of the Elbe (ICPE). The analysis is based on a review of pertinent documents and ten qualitative interviews with Czech and German Commission members and NGO representatives. Particular emphasis has been put on determining the ICPE's specific contribution and the no-regime counterfactual as well as on the perceived expedience of the institutional arrangements. The study shows that overall due to external as well as internal institutional factors the ICPE proved relatively successful, and as such it also provides insights into how institutions matter: The commission served as platform for joint problem solving by identifying priorities for action. These international obligations increased the power of national administrations and their access to funds. At the same time, the Commission's reporting to the public served as an enforcement mechanism. However, the ICPE's contribution towards achieving the various goals varied significantly between the different areas of activity. It was high where the main responsibility for action was with the public authorities, such as in the area of wastewater treatment and the establishment of an international alarm plan and model. It was practically non existent in the reduction of non-point pollution from agriculture, where the success depended on the behavior of individual private actors (farmers). From a methodological point

  4. The Great Lakes' regional climate regimes

    NASA Astrophysics Data System (ADS)

    Sugiyama, Noriyuki

    For the last couple of decades, the Great Lakes have undergone rapid surface warming. In particular, the magnitude of the summer surface-warming trends of the Great Lakes have been much greater than those of surrounding land (Austin and Colman, 2007). Among the Great Lakes, the deepest Lake Superior exhibited the strongest warming trend in its annual, as well as summer surface water temperature. We find that many aspects of this behavior can be explained in terms of the tendency of deep lakes to exhibit multiple regimes characterized, under the same seasonally varying forcing, by the warmer and colder seasonal cycles exhibiting different amounts of wintertime lake-ice cover and corresponding changes in the summertime lake-surface temperatures. In this thesis, we address the problem of the Great Lakes' warming using one-dimensional lake modeling to interpret diverse observations of the recent lake behavior. (Abstract shortened by ProQuest.).

  5. Stable operating regime for traveling wave devices

    DOEpatents

    Carlsten, Bruce E.

    2000-01-01

    Autophase stability is provided for a traveling wave device (TWD) electron beam for amplifying an RF electromagnetic wave in walls defining a waveguide for said electromagnetic wave. An off-axis electron beam is generated at a selected energy and has an energy noise inherently arising from electron gun. The off-axis electron beam is introduced into the waveguide. The off-axis electron beam is introduced into the waveguide at a second radius. The waveguide structure is designed to obtain a selected detuning of the electron beam. The off-axis electron beam has a velocity and the second radius to place the electron beam at a selected distance from the walls defining the waveguide, wherein changes in a density of the electron beam due to the RF electromagnetic wave are independent of the energy of the electron beam to provide a concomitant stable operating regime relative to the energy noise.

  6. Nonlinear regimes of forced magnetic reconnection

    SciTech Connect

    Vekstein, G.; Kusano, K.

    2015-09-15

    This letter presents a self-consistent description of nonlinear forced magnetic reconnection in Taylor's model of this process. If external boundary perturbation is strong enough, nonlinearity in the current sheet evolution becomes important before resistive effects come into play. This terminates the current sheet shrinking that takes place at the linear stage and brings about its nonlinear equilibrium with a finite thickness. Then, in theory, this equilibrium is destroyed by a finite plasma resistivity during the skin-time, and further reconnection proceeds in the Rutherford regime. However, realization of such a scenario is unlikely because of the plasmoid instability, which is fast enough to develop before the transition to the Rutherford phase occurs. The suggested analytical theory is entirely different from all previous studies and provides proper interpretation of the presently available numerical simulations of nonlinear forced magnetic reconnection.

  7. Supercurrent in the quantum Hall regime

    NASA Astrophysics Data System (ADS)

    Wei, Ming-Tso; Amet, François; Ke, Chung-Ting; Borzenets, Ivan; Wang, Jiyingmei; Watanabe, Keji; Taniguchi, Takashi; Deacon, Russell; Yamamoto, Michihisa; Bomze, Yuriy; Tarucha, Seigo; Finkelstein, Gleb

    Combining superconductivity and the quantum Hall (QH) effect is a promising route for creating new types of topological excitations. Despite this potential, signatures of superconductivity in the quantum Hall regime remain scarce, and a superconducting current through a QH weak link has so far eluded experimental observation. Here we demonstrate the existence of a novel type of Josephson coupling through a QH region at magnetic fields as high as 2 Tesla. The supercurrent is mediated by states encompassing QH edge channels, which are flowing on opposite sides of the sample. The edges are coupled together by the hybrid electron-hole modes at the interfaces between the QH region and the superconducting contacts. These chiral modes, which share some features with Majorana modes, are formed when electron and hole edge states are mixed by the superconductor.

  8. Environment Flow Assessment with Flow Regime Transition

    NASA Astrophysics Data System (ADS)

    Su, J.; Ho, C. C.; Chang, L. C.

    2015-12-01

    To avoid worsen river and estuarine ecosystems cause by overusing water resources, environmental flows conservation is applied to reduce the impact of river environment. Environmental flows refer to water provided within a river, wetland or coastal zone to sustain ecosystems and benefits to human wellbeing. Environment flow assessment is now widely accepted that a naturally variable flow regime, rather than just a minimum low flow. In this study, we propose four methods, experience method, Tenant method, hydraulic method and habitat method to assess the environmental flow of base flow, flush flow and overbank flow with different discharge, frequency and occurrence period. Dahan River has been chosen as a case to demonstrate the assessment mechanism. The alternatives impact analysis of environment and human water used provides a reference for stakeholders when holding an environmental flow consultative meeting.

  9. Deterministic-random separation in nonstationary regime

    NASA Astrophysics Data System (ADS)

    Abboud, D.; Antoni, J.; Sieg-Zieba, S.; Eltabach, M.

    2016-02-01

    In rotating machinery vibration analysis, the synchronous average is perhaps the most widely used technique for extracting periodic components. Periodic components are typically related to gear vibrations, misalignments, unbalances, blade rotations, reciprocating forces, etc. Their separation from other random components is essential in vibration-based diagnosis in order to discriminate useful information from masking noise. However, synchronous averaging theoretically requires the machine to operate under stationary regime (i.e. the related vibration signals are cyclostationary) and is otherwise jeopardized by the presence of amplitude and phase modulations. A first object of this paper is to investigate the nature of the nonstationarity induced by the response of a linear time-invariant system subjected to speed varying excitation. For this purpose, the concept of a cyclo-non-stationary signal is introduced, which extends the class of cyclostationary signals to speed-varying regimes. Next, a "generalized synchronous average'' is designed to extract the deterministic part of a cyclo-non-stationary vibration signal-i.e. the analog of the periodic part of a cyclostationary signal. Two estimators of the GSA have been proposed. The first one returns the synchronous average of the signal at predefined discrete operating speeds. A brief statistical study of it is performed, aiming to provide the user with confidence intervals that reflect the "quality" of the estimator according to the SNR and the estimated speed. The second estimator returns a smoothed version of the former by enforcing continuity over the speed axis. It helps to reconstruct the deterministic component by tracking a specific trajectory dictated by the speed profile (assumed to be known a priori).The proposed method is validated first on synthetic signals and then on actual industrial signals. The usefulness of the approach is demonstrated on envelope-based diagnosis of bearings in variable

  10. Weather Regimes: Recurrence and Quasi Stationarity.

    NASA Astrophysics Data System (ADS)

    Michelangeli, Paul-Antoine; Vautard, Robert; Legras, Bernard

    1995-04-01

    Two different definitions of midlatitude weather regimes are compared. The first seeks recurrent atmospheric patterns. The second seeks quasi-stationary patterns, whose average tendency vanishes. Recurrent patterns are identified by cluster analysis, and quasi-stationary patterns are identified by solving a nonlinear equilibration equation. Both methods are applied on the same dataset: the NMC final analyses of 700-hPa geopotential heights covering 44 winters. The analysis is performed separately over the Atlantic and Pacific sectors.The two methods give the same number of weather regimes-four over the Atlantic sector and three over the Pacific sector. However, the patterns differ significantly. The investigation of the tendency, or drift, of the clusters shows that recurrent flows have a systematic slow evolution, explaining this difference. The patterns are in agreement with the ones obtained from previous studies, but their number differs.The cluster analysis algorithm used here is a partitioning algorithm, which agglomerates data around randomly chosen seeds and iteratively finds the partition that minimizes the variance within clusters, given a prescribed number of clusters. The authors develop a classifiability index, based on the correlation between the cluster centroids obtained from different initial pullings. By comparing the classifiability index of observations with that obtained from a multivariate noise model, an objective definition of the number of clusters present in the data is given. Although the classifiability index is maximal by prescribing two clusters in both sectors, it only differs significantly from that obtained with the noise model using four Atlantic clusters and three Pacific clusters. The partitioning clustering method turns out to give more statistically stable clusters than hierarchical clustering schemes.

  11. Rheological equations in asymptotic regimes of granular flow

    USGS Publications Warehouse

    Chen, C.-L.; Ling, C.-H.

    1998-01-01

    This paper assesses the validity of the generalized viscoplastic fluid (GVF) model in light of the established constitutive relations in two asymptotic flow regimes, namely, the macroviscous and grain-inertia regimes. A comprehensive review of the literature on constitutive relations in both regimes reveals that except for some material constants, such as the coefficient of restitution, the normalized shear stress in both regimes varies only with the grain concentration, C. It is found that Krieger-Dougherty's relative viscosity, ??*(C), is sufficiently coherent among the monotonically nondecreasing functions of C used in describing the variation of the shear stress with C in both regimes. It not only accurately represents the C-dependent relative viscosity of a suspension in the macroviscous regime, but also plays a role of the radial distribution function that describes the statistics of particle collisions in the grain-inertia regime. Use of ??*(C) alone, however, cannot link the two regimes. Another parameter, the shear-rate number, N, is needed in modelling the rheology of neutrally buoyant granular flows in transition between the two asymptotic regimes. The GVF model proves compatible with most established relations in both regimes.

  12. Structural and functional characterization of mutants of recombinant single-chain urokinase-type plasminogen activator obtained by site-specific mutagenesis of Lys158, Ile159 and Ile160.

    PubMed

    Lijnen, H R; Nelles, L; Van Hoef, B; Demarsin, E; Collen, D

    1988-11-15

    Single-chain urokinase-type plasminogen activator (scu-PA) is converted to urokinase by hydrolysis of the Lys158-Ile159 peptide bond. Site-directed mutagenesis of Lys158 to Gly or Glu yields plasmin-resistant mutants with a 10-20-fold reduced catalytic efficiency for the activation of plasminogen [Nelles et al. (1987) J. Biol. Chem. 262, 5682-5689]. In the present study, we have further evaluated the enzymatic properties of derivatives of recombinant scu-PA (rscu-PA), produced by site-directed mutagenesis of Lys158, Ile159 or Ile160, in order to obtain additional information on the structure/function relations underlying the enzymatic properties of the single- and two-chain u-PA moieties. [Arg158]rscu-PA (rscu-PA with Lys158 substituted with Arg) appeared to be indistinguishable from wild-type rscu-PA with respect to plasminogen-activating potential (catalytic efficiency k2/Km = 0.21 mM-1 s-1 versus 0.64 mM-1 s-1), conversion to active two-chain urokinase by plasmin (k2/Km = 0.13 microM-1 s-1 versus 0.28 microM-1 s-1), as well as its specific activity (48,000 IU/mg as compared to 60,000 IU/mg) and its fibrinolytic potential in a plasma medium (50% lysis in 2 h with 2.8 micrograms/ml versus 2.1 micrograms/ml). [Pro159]rscu-PA (Ile159 substituted with Pro) and [Gly159]rscu-PA (Ile159 converted to Gly) are virtually inactive towards plasminogen (k2/Km less than 0.004 mM-1 s-1). They are however converted to inactive two-chain derivatives by plasmin following cleavage of the Arg156-Phe157 peptide bond in [Pro159]rscu-PA and of the Lys158-Gly159 peptide bond in [Gly159]rscu-PA. [Gly158,Lys160]rscu-PA (with Lys158 converted to Gly and Ile160 to Lys) has a low catalytic efficiency towards plasminogen both as a single-chain form (k2/Km = 0.012 mM-1 s-1) and as the two-chain derivative (k2/Km = 0.13 mM-1 s-1) generated by cleavage of both the Arg156-Phe157 and/or the Lys160-Gly161 peptide bonds by plasmin. These findings suggest that the enzymatic properties of rscu-PA are

  13. Human urokinase-type plasminogen activator gene-modified bone marrow-derived mesenchymal stem cells attenuate liver fibrosis in rats by down-regulating the Wnt signaling pathway

    PubMed Central

    Ma, Zhi-Gang; Lv, Xiao-Dan; Zhan, Ling-Ling; Chen, Lan; Zou, Qi-Yuan; Xiang, Ji-Qiao; Qin, Jiao-Li; Zhang, Wei-Wei; Zeng, Zhao-Jing; Jin, Hui; Jiang, Hai-Xing; Lv, Xiao-Ping

    2016-01-01

    AIM: To evaluate the therapeutic effects of bone marrow-derived mesenchymal stem cells (BMSCs) with human urokinase-type plasminogen activator (uPA) on liver fibrosis, and to investigate the mechanism of gene therapy. METHODS: BMSCs transfected with adenovirus-mediated human urokinase plasminogen activator (Ad-uPA) were transplanted into rats with CCl4-induced liver fibrosis. All rats were sacrificed after 8 wk, and their serum and liver tissue were collected for biochemical, histopathologic, and molecular analyzes. The degree of liver fibrosis was assessed by hematoxylin and eosin or Masson’s staining. Western blot and quantitative reverse transcription-polymerase chain reaction were used to determine protein and mRNA expression levels. RESULTS: Serum levels of alanine aminotransferase, aminotransferase, total bilirubin, hyaluronic acid, laminin, and procollagen type III were markedly decreased, whereas the levels of serum albumin were increased by uPA gene modified BMSCs treatment. Histopathology revealed that chronic CCl4-treatment resulted in significant fibrosis while uPA gene modified BMSCs treatment significantly reversed fibrosis. By quantitatively analysing the fibrosis area of liver tissue using Masson staining in different groups of animals, we found that model animals with CCl4-induced liver fibrosis had the largest fibrotic area (16.69% ± 1.30%), while fibrotic area was significantly decreased by BMSCs treatment (12.38% ± 2.27%) and was further reduced by uPA-BMSCs treatment (8.31% ± 1.21%). Both protein and mRNA expression of β-catenin, Wnt4 and Wnt5a was down-regulated in liver tissues following uPA gene modified BMSCs treatment when compared with the model animals. CONCLUSION: Transplantation of uPA gene modified BMSCs suppressed liver fibrosis and ameliorated liver function and may be a new approach to treating liver fibrosis. Furthermore, treatment with uPA gene modified BMSCs also resulted in a decrease in expression of molecules of the Wnt

  14. Evaluating temperature regimes for protection of brown trout

    USGS Publications Warehouse

    Armour, Carl L.

    1994-01-01

    Geographic distribution and population success of brown trout (Salmo trutta) are affected by temperature regimes. Concepts are presented for evaluating alternative temperature regimes for brown trout based on published temperature information and professional judgment. Temperature information from the literature is included for spawning runs, spawning, egg and larval development, growth, and other subjects. The objective is to aid biologists in evaluating alternative temperature regimes so as to select those that will protect and enhance environmental quality for brown trout.

  15. Stability analysis of synchronization regimes of spinning rockets

    NASA Astrophysics Data System (ADS)

    Dron, N. M.

    1993-10-01

    A method is studied for estimating the formation of synchronization regimes in rocket ballistic flight in which the roll rate approaches the pitch rate. Supporting resonance angular motion regimes due to induced moments are analyzed, and the nonlinear second-order differential equation of the rolling motion is addressed. The results permit synchronization regimes to be prevented, which is important for motion stability and trajectory parameter dispersion in sounding rockets.

  16. CSDP: The seismology of continental thermal regimes

    SciTech Connect

    Aki, K.

    1990-05-01

    This is a progress report for the past one year of research (year 3 of 5-year project) under the project titled CSDP: Seismology of Continental Thermal Regime'', in which we proposed to develop seismological interpretation theory and methods applicable to complex structures encountered in continental geothermal areas and apply them to several candidate sites for the Continental Scientific Drilling Project. The past year has been extremely productive especially in the area of interpretation theory, including the following two major break-throughs. One is the derivation of an integral equation for time-dependent power spectra, which unified all the existing theories on seismic scattering (including the radiative transfer theory for total energy and single and multiple scattering theories based on the ray approach) and offers more complete and economical solutions to the problems of seismic scattering and attenuation. The other is the new formula for synthetic seismograms for layered media with irregular interfaces, combining the T-matrix method for an arbitrary shaped inclusion and the method of global generalized reflection/transmission coefficients for layered media. Both breakthroughs will enable us to deal with seismic observations in complex earth structures more efficiently and accurately. In the area of experimental studies, we discovered seismic guided waves trapped in the San Andreas fault near Parkfield, California. 54 refs., 14 figs.

  17. On spinfoam models in large spin regime

    NASA Astrophysics Data System (ADS)

    Han, Muxin

    2014-01-01

    We study the semiclassical behavior of Lorentzian Engle-Pereira-Rovelli-Livine (EPRL) spinfoam model, by taking into account the sum over spins in the large spin regime. We also employ the method of stationary phase analysis with parameters and the so-called, almost analytic machinery, in order to find the asymptotic behavior of the contributions from all possible large spin configurations in the spinfoam model. The spins contributing the sum are written as Jf = λjf, where λ is a large parameter resulting in an asymptotic expansion via stationary phase approximation. The analysis shows that at least for the simplicial Lorentzian geometries (as spinfoam critical configurations), they contribute the leading order approximation of spinfoam amplitude only when their deficit angles satisfy \\gamma \\mathring{\\Theta }_f\\le \\lambda ^{-1/2} mod 4\\pi {Z}. Our analysis results in a curvature expansion of the semiclassical low energy effective action from the spinfoam model, where the UV modifications of Einstein gravity appear as subleading high-curvature corrections.

  18. RF Profile Control for Sustained Plasma Regimes

    NASA Astrophysics Data System (ADS)

    Hosea, J.; Bernabei, S.; Leblanc, B.; Majeski, R.; Menard, J.; Ono, M.; Phillips, C. K.; Schilling, G.; Wilson, J. R.

    1999-11-01

    For advancing plasma operation regimes for AT tokamaks and steady state concepts, as well as for forming and sustaining alternate concepts, it is necessary to provide control of the spatial profiles for the important plasma parameters - pressure, current, etc.. RF techniques offer considerable promise for providing this control and should be further developed as rapidly as possible within the well established tokamak program for forming a basis for application to all confinement concepts. Notably, IBW promises to provide internal transport barrier control if the coupling physics can be understood and efficient antenna coupling to the Bernstein wave can be developed. We will review the IBW experience and discuss possible explanations and solutions for the coupling problems encountered. In particular, the competing roles of parametric decay instability and surface mode excitation will be examined in order to elucidate the increase in surface power losses for the larger devices DIII-D and TFTR. Also, issues which need to be understood for employing ICRF and LH techniques to best advantage, such as antenna bombardment and energetic electron excitation, respectively, will be outlined.

  19. Cluster analysis of multiple planetary flow regimes

    NASA Technical Reports Server (NTRS)

    Mo, Kingtse; Ghil, Michael

    1987-01-01

    A modified cluster analysis method was developed to identify spatial patterns of planetary flow regimes, and to study transitions between them. This method was applied first to a simple deterministic model and second to Northern Hemisphere (NH) 500 mb data. The dynamical model is governed by the fully-nonlinear, equivalent-barotropic vorticity equation on the sphere. Clusters of point in the model's phase space are associated with either a few persistent or with many transient events. Two stationary clusters have patterns similar to unstable stationary model solutions, zonal, or blocked. Transient clusters of wave trains serve as way stations between the stationary ones. For the NH data, cluster analysis was performed in the subspace of the first seven empirical orthogonal functions (EOFs). Stationary clusters are found in the low-frequency band of more than 10 days, and transient clusters in the bandpass frequency window between 2.5 and 6 days. In the low-frequency band three pairs of clusters determine, respectively, EOFs 1, 2, and 3. They exhibit well-known regional features, such as blocking, the Pacific/North American (PNA) pattern and wave trains. Both model and low-pass data show strong bimodality. Clusters in the bandpass window show wave-train patterns in the two jet exit regions. They are related, as in the model, to transitions between stationary clusters.

  20. Flow regimes in a trapped vortex cell

    NASA Astrophysics Data System (ADS)

    Lasagna, D.; Iuso, G.

    2016-03-01

    This paper presents results of an experimental investigation on the flow in a trapped vortex cell, embedded into a flat plate, and interacting with a zero-pressure-gradient boundary layer. The objective of the work is to describe the flow features and elucidate some of the governing physical mechanisms, in the light of recent investigations on flow separation control using vortex cells. Hot-wire velocity measurements of the shear layer bounding the cell and of the boundary layers upstream and downstream are reported, together with spectral and correlation analyses of wall-pressure fluctuation measurements. Smoke flow visualisations provide qualitative insight into some relevant features of the internal flow, namely a large-scale flow unsteadiness and possible mechanisms driving the rotation of the vortex core. Results are presented for two very different regimes: a low-Reynolds-number case where the incoming boundary layer is laminar and its momentum thickness is small compared to the cell opening, and a moderately high-Reynolds-number case, where the incoming boundary layer is turbulent and the ratio between the momentum thickness and the opening length is significantly larger than in the first case. Implications of the present findings to flow control applications of trapped vortex cells are also discussed.

  1. Global fishery prospects under contrasting management regimes.

    PubMed

    Costello, Christopher; Ovando, Daniel; Clavelle, Tyler; Strauss, C Kent; Hilborn, Ray; Melnychuk, Michael C; Branch, Trevor A; Gaines, Steven D; Szuwalski, Cody S; Cabral, Reniel B; Rader, Douglas N; Leland, Amanda

    2016-05-01

    Data from 4,713 fisheries worldwide, representing 78% of global reported fish catch, are analyzed to estimate the status, trends, and benefits of alternative approaches to recovering depleted fisheries. For each fishery, we estimate current biological status and forecast the impacts of contrasting management regimes on catch, profit, and biomass of fish in the sea. We estimate unique recovery targets and trajectories for each fishery, calculate the year-by-year effects of alternative recovery approaches, and model how alternative institutional reforms affect recovery outcomes. Current status is highly heterogeneous-the median fishery is in poor health (overfished, with further overfishing occurring), although 32% of fisheries are in good biological, although not necessarily economic, condition. Our business-as-usual scenario projects further divergence and continued collapse for many of the world's fisheries. Applying sound management reforms to global fisheries in our dataset could generate annual increases exceeding 16 million metric tons (MMT) in catch, $53 billion in profit, and 619 MMT in biomass relative to business as usual. We also find that, with appropriate reforms, recovery can happen quickly, with the median fishery taking under 10 y to reach recovery targets. Our results show that commonsense reforms to fishery management would dramatically improve overall fish abundance while increasing food security and profits. PMID:27035953

  2. Global fishery prospects under contrasting management regimes

    PubMed Central

    Costello, Christopher; Ovando, Daniel; Clavelle, Tyler; Strauss, C. Kent; Hilborn, Ray; Melnychuk, Michael C.; Branch, Trevor A.; Gaines, Steven D.; Szuwalski, Cody S.; Cabral, Reniel B.; Rader, Douglas N.; Leland, Amanda

    2016-01-01

    Data from 4,713 fisheries worldwide, representing 78% of global reported fish catch, are analyzed to estimate the status, trends, and benefits of alternative approaches to recovering depleted fisheries. For each fishery, we estimate current biological status and forecast the impacts of contrasting management regimes on catch, profit, and biomass of fish in the sea. We estimate unique recovery targets and trajectories for each fishery, calculate the year-by-year effects of alternative recovery approaches, and model how alternative institutional reforms affect recovery outcomes. Current status is highly heterogeneous—the median fishery is in poor health (overfished, with further overfishing occurring), although 32% of fisheries are in good biological, although not necessarily economic, condition. Our business-as-usual scenario projects further divergence and continued collapse for many of the world’s fisheries. Applying sound management reforms to global fisheries in our dataset could generate annual increases exceeding 16 million metric tons (MMT) in catch, $53 billion in profit, and 619 MMT in biomass relative to business as usual. We also find that, with appropriate reforms, recovery can happen quickly, with the median fishery taking under 10 y to reach recovery targets. Our results show that commonsense reforms to fishery management would dramatically improve overall fish abundance while increasing food security and profits. PMID:27035953

  3. Institutional design and regime effectiveness in transboundary river management - the Elbe water quality regime

    NASA Astrophysics Data System (ADS)

    Dombrowsky, I.

    2008-02-01

    The literature on transboundary river management suggests that institutions play an important role in bringing about cooperation. However, knowledge about how such institutions should be designed in order to do so remains limited. One way to learn more about adequate institutional design is to assess the effectiveness of existing regimes, and to trace the causal relationships that lead to the respective outcomes. In order to gain further insights into the relationship between institutional design and regime effectiveness, this paper presents a study on the water quality regime of the International Commission for the Protection of the Elbe (ICPE). The analysis is based on a review of pertinent documents and ten qualitative interviews with Czech and German Commission members and NGO representatives. Particular emphasis has been put on determining the ICPE's specific contribution and the no-regime counterfactual as well as on the perceived expediency of the institutional arrangements. The study shows overall that the countries were relatively successful in improving water quality in the Elbe basin. However, this outcome can only partly be attributed to the ICPE itself. Furthermore, the ICPE's contribution towards achieving the various goals varied significantly between the different areas of activity: it was relatively significant where the main responsibility for action lay with the public authorities, such as in the area of wastewater treatment and the establishment of an international alarm plan and model, but was practically non-existent in the reduction of non-point pollution from agriculture, where success depended on the behavior of individual private actors (farmers). The commission contributed towards problem solving by serving as a forum for the joint identification of priorities for action from a basin-wide perspective. The resulting international obligations increased the power of national water administrations and their access to funds. At the same time

  4. Role of Tissue-Specific Transcription Factor LFB3 in a Cyclic AMP-Responsive Enhancer of the Urokinase-Type Plasminogen Activator Gene in LLC-PK1 Cells

    PubMed Central

    Soubt, Mazin Khalil; Marksitzer, René; Menoud, Pierre-Alain; Nagamine, Yoshikuni

    1998-01-01

    A cyclic AMP (cAMP)-inducible enhancer in the pig urokinase-type plasminogen activator gene located 3.4 kb upstream of the transcription initiation site is composed of three protein-binding domains, A, B, and C. Domains A and B each contain a CRE (cAMP response element)-like sequence but require the adjoining C domain for full cAMP responsiveness. A tissue-specific transcription factor, LFB3/HNF1β/vHNF1, binds to the C domain. Mutation analyses suggest that the imperfect CRE and LFB3-binding sequences are required for tight coupling of hormonal and tissue-specific regulation. CREB and ATF1 bind to domains A and B, and this binding is enhanced upon phosphorylation by cAMP-dependent protein kinase (protein kinase A [PKA]). Analysis in a mammalian two-hybrid system revealed that CREB/ATF1 and LFB3 interact and that transactivation potential is enhanced by PKA activation. Interestingly, however, phosphorylation of CREB at Ser-133 does not contribute to its interaction with LFB3. The region of LFB3 involved in its interaction with CREB/ATF1 lies, at least partly, between amino acids 400 and 450. Deletion of this region removed the ability of LFB3 to mediate cAMP induction of the ABC enhancer but did not impair its basal transactivation activity on the albumin promoter. Thus, the two activities are distinct functions of LFB3. PMID:9671480

  5. (±)Equol inhibits invasion in prostate cancer DU145 cells possibly via down-regulation of matrix metalloproteinase-9, matrix metalloproteinase-2 and urokinase-type plasminogen activator by antioxidant activity

    PubMed Central

    Zheng, Wei; Zhang, Yumei; Ma, Defu; Shi, Yuhui; Liu, Changqiu; Wang, Peiyu

    2012-01-01

    Exposure to soy isoflavones has been associated with low mortality of prostate cancer. In this study, we examined the effects of (±)equol and two representative isoflavones, daidzein and genistein, on migration and invasion in human prostate cancer DU145 cells. First of all, the three regents did not show significant growth inhibitive effect in DU145 cells until the treatments last for 72 h. Treatment with 5 µM, 10 µM, 50 µM (±)equol, 0.5 µM, 1 µM, 5 µM daidzein and genistein for 24 h decreased cell migration and invasion significantly. (±)equol activated phosphatase and tensin homologue deleted on chromosome ten at protein level but not mRNA level, which activated antioxidants, including superoxide dismutase and nuclear factor (erythroid-derived 2)-like 2. A reduction of malondialdehyde concentration, the product of lipid per-oxidation, was observed as well. Moreover, matrix metalloproteinase-2, matrix metalloproteinase-9, and urokinase-type plasminogen activator, the crucial members in metastasis, were down-regulated. Overall, our data indicate that (±)equol, daidzein and genistein may have significant anti-invasion effect in DU145 cells (in vitro). The effects induced by (±)equol may relate to its anti-oxidant effect mediated by phosphatase and tensin homologue deleted on chromosome ten. PMID:22798715

  6. Dissipation regimes for short wind waves

    NASA Astrophysics Data System (ADS)

    Caulliez, Guillemette

    2013-02-01

    The dissipation processes affecting short wind waves of centimeter and decimeter scales are investigated experimentally in laboratory. The processes include damping due to molecular viscosity, generation of capillary waves, microbreaking, and breaking. The observations were made in a large wind wave tank for a wide range of fetches and winds, using a laser sheet and a high-resolution video camera. The work aims at constructing a comprehensive picture of dissipative processes in the short wind wave field, to find for which scales particular dissipative mechanism may become important. Four distinct regimes have been identified. For capillary-gravity wave fields, i.e., for dominant waves with scales below 4 cm, viscous damping is found to be the main dissipation mechanism. The gravity-capillary wave fields with dominant wavelength less than 10 cm usually exhibit a train of capillary ripples at the crest wavefront, but no wave breaking. For such waves, the main dissipation process is molecular viscosity occurring through nonlinear energy cascade toward high-frequency motions. Microscale breaking takes place for waves longer than 10 cm and manifests itself in a very localized surface disruption on the forward face of the crest. Such events generate turbulent motions in water and thus enhance wave dissipation. Plunging breaking, characterized by formation of a crest bulge, a microjet hitting the water surface and a splash-up, occurs for short gravity waves of wavelength exceeding 20 cm. Macroscale spilling breaking is also observed for longer waves at high winds. In both cases, the direct momentum transfer from breaking waves to the water flow contributes significantly to wave damping.

  7. The seismology of geothermal regimes. Final report

    SciTech Connect

    Aki, K.

    1997-04-01

    The authors have been developing seismological interpretation theory and methods applicable to complex structures encountered in geothermal areas for a better understanding of the earth`s geothermal regimes. The questions the y have addressed in their research may be summarized as ``What is going on in the earth`s crust under tectonically active regions; what are the structures and processes responsible for such activities as earthquakes and volcanic eruptions; and how can one capture their essence effectively by means of seismological studies?`` First, the authors found clear evidence for localization of scattered seismic energy in the deep magmatic system of the volcano on the island of Reunion in the Indian Ocean. The seismic coda of local earthquakes show concentrated energy in the intrusive zones as late as 30 to 40 seconds after the origin time. This offers a very effective method for defining a zone of strong heterogeneity on a regional scale, complementary to the high resolution study using trapped modes as pursued in the past project. Secondly, the authors identified about 700 long-period events with various frequencies and durations from the data collected during the past 5 years which included three episodes of eruption. They are applying a finite-element method to the simplest event with the longest period and the shortest duration in order to find the location, geometry and physical properties of their source deterministically. The preliminary result described here suggests that their sources may be a horizontally lying magma-filled crack at a shallow depth under the summit area. In addition to the above work on the Reunion data, they have continued the theoretical and observational studies of attenuation and scattering of seismic waves.

  8. CSDP: Seismology of continental thermal regime

    SciTech Connect

    Aki, K.

    1989-04-01

    This is a progress report for the past one year of research (year 2 of 5-year project) under the project titled CSDP: Seismology of Continental Thermal Regime'', in which we proposed to develop seismological interpretation theory and methods applicable to complex structures encountered in continental geothermal areas and apply them to several candidate sites for the Continental Scientific Drilling Project. During the past year, two Ph.D. thesis works were completed under the present project. One is a USC thesis on seismic wave propagation in anisotropic media with application to defining fractures in the earth. The other is a MIT thesis on seismic Q and velocity structure for the magma-hydrothermal system of the Valles Caldera, New Mexico. The P.I. co-organized the first International Workshop on Volcanic Seismology at Capri, Italy in October 1988, and presented the keynote paper on the state-of-art of volcanic seismology''. We presented another paper at the workshop on Assorted Seismic Signals from Kilauea Volcano, Hawaii. Another international meeting, namely, the Chapman Conference on seismic anisotropy in the earth's crust at Berkeley, California in May 1988, was co-organized by the co-P.I. (P.C.L), and we presented our work on seismic waves in heterogeneous and anisotropic media. Adding the publications and presentations made in the past year to the list for the preceding year, the following table lists 21 papers published, submitted or presented in the past two years of the present project. 65 refs., 334 figs., 1 tab.

  9. Magnetised Kelvin-Helmholtz instability in the intermediate regime between subsonic and supersonic regimes

    SciTech Connect

    Henri, P.; Califano, F.; Pegoraro, F.; Faganello, M.

    2012-07-15

    The understanding of the dynamics at play at the Earth's Magnetopause, the boundary separating the Earth's magnetosphere and the solar wind plasmas, is of primary importance for space plasma modeling. We focus our attention on the low latitude flank of the magnetosphere where the velocity shear between the magnetosheath and the magnetospheric plasmas is the energetic source of Kelvin-Helmholtz instability. On the shoulder of the resulting vortex chain, different secondary instabilities are at play depending on the local plasma parameters and compete with the vortex pairing process. Most important, secondary instabilities, among other magnetic reconnection, control the plasma mixing as well as the entry of solar wind plasma in the magnetosphere. We make use of a two-fluid model, including the Hall term and the electron mass in the generalized Ohm's law, to study the 2D non-linear evolution of the Kelvin-Helmholtz instability at the magnetosheath-magnetosphere interface, in the intermediate regime between subsonic and supersonic regimes. We study the saturation mechanisms, depending on the density jump across the shear layer and the magnetic field strength in the plane. In the presence of a weak in-plane magnetic field, the dynamics of the Kelvin-Helmholtz rolled-up vortices self-consistently generates thin current sheets where reconnection instability eventually enables fast reconnection to develop. Such a system enables to study guide field multiple-island collisionless magnetic reconnection as embedded in a large-scale dynamic system, unlike the classical static, ad hoc reconnection setups. In this regime, reconnection is shown to inhibit the vortex pairing process. This study provides a clear example of nonlinear, cross-scale, collisionless plasma dynamics.

  10. Disciplinary Regimes of "Care" and Complementary Alternative Education

    ERIC Educational Resources Information Center

    Thomson, Pat; Pennacchia, Jodie

    2016-01-01

    In schools, the notion of "care" is often synonymous with welfare and disciplinary regimes. Drawing on Foucault, and a study of alternative education (AE) across the UK, and looking in depth at two cases of complementary AE, we identify three types of disciplinary regimes at work in schools: (1) dominant performative reward and…

  11. Bargaining among Nations: Culture, History, and Perceptions in Regime Formation.

    ERIC Educational Resources Information Center

    Lipschutz, Ronnie D.

    1991-01-01

    The formation of regimes (collective international schemes) for managing global problems depends on culture, history, and perceptions. The ways in which these elements affect bargaining among nations over issues of the global commons are discussed. Implications are reviewed for a regime to deal with atmospheric conditions and global warming. (SLD)

  12. IDENTIFICATION OF REGIME SHIFTS IN TIME SERIES USING NEIGHBORHOOD STATISTICS

    EPA Science Inventory

    The identification of alternative dynamic regimes in ecological systems requires several lines of evidence. Previous work on time series analysis of dynamic regimes includes mainly model-fitting methods. We introduce two methods that do not use models. These approaches use state-...

  13. Detection and Assessment of Ecosystem Regime Shifts from Fisher Information

    EPA Science Inventory

    Ecosystem regime shifts, which are long-term system reorganizations, have profound implications for sustainability. There is a great need for indicators of regime shifts, particularly methods that are applicable to data from real systems. We have developed a form of Fisher info...

  14. Plasma Physics Regimes in Tokamaks with Li Walls

    SciTech Connect

    L.E. Zakharo; N.N. Gorelenkov; R.B. White; S.I. Krasheninnikov; G.V. Pereverzev

    2003-08-21

    Low recycling regimes with a plasma limited by a lithium wall surface suggest enhanced stability and energy confinement, both necessary for tokamak reactors. These regimes could make ignition feasible in compact tokamaks. Ignited Spherical Tokamaks (IST), self-sufficient in the bootstrap current, are introduced as a necessary step for development of the physics and technology of power reactors.

  15. Water use regimes: Characterizing direct human interaction with hydrologic systems

    NASA Astrophysics Data System (ADS)

    Weiskel, Peter K.; Vogel, Richard M.; Steeves, Peter A.; Zarriello, Philip J.; Desimone, Leslie A.; Ries, Kernell G.

    2007-04-01

    The sustainability of human water use practices is a rapidly growing concern in the United States and around the world. To better characterize direct human interaction with hydrologic systems (stream basins and aquifers), we introduce the concept of the water use regime. Unlike scalar indicators of anthropogenic hydrologic stress in the literature, the water use regime is a two-dimensional, vector indicator that can be depicted on simple x-y plots of normalized human withdrawals (hout) versus normalized human return flows (hin). Four end-member regimes, natural-flow-dominated (undeveloped), human-flow-dominated (churned), withdrawal-dominated (depleted), and return-flow-dominated (surcharged), are defined in relation to limiting values of hout and hin. For illustration, the water use regimes of 19 diverse hydrologic systems are plotted and interpreted. Several of these systems, including the Yellow River Basin, China, and the California Central Valley Aquifer, are shown to approach particular end-member regimes. Spatial and temporal regime variations, both seasonal and long-term, are depicted. Practical issues of data availability and regime uncertainty are addressed in relation to the statistical properties of the ratio estimators hout and hin. The water use regime is shown to be a useful tool for comparative water resources assessment and for describing both historic and alternative future pathways of water resource development at a range of scales.

  16. Extractive Regimes: Toward a Better Understanding of Indonesian Development

    ERIC Educational Resources Information Center

    Gellert, Paul K.

    2010-01-01

    This article proposes the concept of an extractive regime to understand Indonesia's developmental trajectory from 1966 to 1998. The concept contributes to world-systems, globalization, and commodity-based approaches to understanding peripheral development. An extractive regime is defined by its reliance on extraction of multiple natural resources…

  17. A Tale of Two Regimes: Instrumentality and Commons Access

    ERIC Educational Resources Information Center

    Toly, Noah J.

    2005-01-01

    Technical developments have profound social and environmental impacts. Both are observed in the implications of regimes of instrumentality for commons access regimes. Establishing social, material, ecological, intellectual, and moral infrastructures, technologies are partly constitutive of commons access and may militate against governance…

  18. Global regime shift dynamics of catastrophic sea urchin overgrazing

    PubMed Central

    Ling, S. D.; Scheibling, R. E.; Rassweiler, A.; Johnson, C. R.; Shears, N.; Connell, S. D.; Salomon, A. K.; Norderhaug, K. M.; Pérez-Matus, A.; Hernández, J. C.; Clemente, S.; Blamey, L. K.; Hereu, B.; Ballesteros, E.; Sala, E.; Garrabou, J.; Cebrian, E.; Zabala, M.; Fujita, D.; Johnson, L. E.

    2015-01-01

    A pronounced, widespread and persistent regime shift among marine ecosystems is observable on temperate rocky reefs as a result of sea urchin overgrazing. Here, we empirically define regime-shift dynamics for this grazing system which transitions between productive macroalgal beds and impoverished urchin barrens. Catastrophic in nature, urchin overgrazing in a well-studied Australian system demonstrates a discontinuous regime shift, which is of particular management concern as recovery of desirable macroalgal beds requires reducing grazers to well below the initial threshold of overgrazing. Generality of this regime-shift dynamic is explored across 13 rocky reef systems (spanning 11 different regions from both hemispheres) by compiling available survey data (totalling 10 901 quadrats surveyed in situ) plus experimental regime-shift responses (observed during a total of 57 in situ manipulations). The emergent and globally coherent pattern shows urchin grazing to cause a discontinuous ‘catastrophic’ regime shift, with hysteresis effect of approximately one order of magnitude in urchin biomass between critical thresholds of overgrazing and recovery. Different life-history traits appear to create asymmetry in the pace of overgrazing versus recovery. Once shifted, strong feedback mechanisms provide resilience for each alternative state thus defining the catastrophic nature of this regime shift. Importantly, human-derived stressors can act to erode resilience of desirable macroalgal beds while strengthening resilience of urchin barrens, thus exacerbating the risk, spatial extent and irreversibility of an unwanted regime shift for marine ecosystems.

  19. Water use regimes: Characterizing direct human interaction with hydrologic systems

    USGS Publications Warehouse

    Weiskel, P.K.; Vogel, R.M.; Steeves, P.A.; Zarriello, P.J.; DeSimone, L.A.; Ries, Kernell G., III

    2007-01-01

    [1] The sustainability of human water use practices is a rapidly growing concern in the United States and around the world. To better characterize direct human interaction with hydrologic systems (stream basins and aquifers), we introduce the concept of the water use regime. Unlike scalar indicators of anthropogenic hydrologic stress in the literature, the water use regime is a two-dimensional, vector indicator that can be depicted on simple x-y plots of normalized human withdrawals (hout) versus normalized human return flows (hin). Four end-member regimes, natural-flow-dominated (undeveloped), human-flow-dominated (churned), withdrawal-dominated (depleted), and return-flow-dominated (surcharged), are defined in relation to limiting values of hout and hin. For illustration, the water use regimes of 19 diverse hydrologic systems are plotted and interpreted. Several of these systems, including the Yellow River Basin, China, and the California Central Valley Aquifer, are shown to approach particular end-member regimes. Spatial and temporal regime variations, both seasonal and long-term, are depicted. Practical issues of data availability and regime uncertainty are addressed in relation to the statistical properties of the ratio estimators hout and hin. The water use regime is shown to be a useful tool for comparative water resources assessment and for describing both historic and alternative future pathways of water resource development at a range of scales. Copyright 2007 by the American Geophysical Union.

  20. FISHER INFORMATION AS A METRIC FOR SUSTAINABLE SYSTEM REGIMES

    EPA Science Inventory

    The important question in sustainability is not whether the world is sustainable, but whether a humanly acceptable regime of the world is sustainable. We propose Fisher Information as a metric for the sustainability of dynamic regimes in complex systems. The quantity now known ...

  1. FISHER INFORMATION AS A METRIC FOR SUSTAINABLE REGIMES

    EPA Science Inventory

    The important question in sustainability is not whether the world is sustainable, but whether a humanly acceptable regime of the world is sustainable. We propose Fisher Information as a metric for the sustainability of dynamic regimes in complex systems. The quantity now known ...

  2. Flow regimes in a single dimple on the channel surface

    NASA Astrophysics Data System (ADS)

    Kovalenko, G. V.; Terekhov, V. I.; Khalatov, A. A.

    2010-12-01

    The boundaries of the domains of existence of flow regimes past single dimples made as spherical segments on a flat plate are determined with the use of available experimental results. Regimes of a diffuser-confuser flow, a horseshoe vortex, and a tornado-like vortex in the dimple are considered. Neither a horseshoe vortex nor a tornado-like vortex is observed in dimples with the relative depth smaller than 0.1. Transformations from the diffuser-confuser flow regime to the horseshoe vortex regime and from the horseshoe vortex flow to the tornado-like vortex flow are found to depend not only on the Reynolds number, but also on the relative depth of the spherical segment. Dependences for determining the boundaries of the regime existence domains are proposed, and parameters at which the experimental results can be generalized are given.

  3. Monitoring and diagnostics systems for nuclear power plant operating regimes

    SciTech Connect

    Abagyan, A.A.; Dmitriev, V.M.; Klebanov, L.A.; Kroshilin, A.E.; Larin, E.P.; Morozov, S.K.

    1988-05-01

    The development of new monitoring and diagnostics systems for Soviet reactors is discussed. An experimental test station is described where industrial operation of new experimental systems can be conducted for purposes of bringing their performance to the level of standard Soviet systems for monitoring reactor operation regimes and equipment resources. The requirements and parameters of the systems are described on a unit-by-unit basis, including the sensor reading monitoring unit, the vibroacoustic monitoring unit, the noise monitoring unit, the accident regime identification unit, and the nonstationary regime monitoring unit. Computer hardware and software requirements are discussed. The results of calculational and experimental research on two complex nonstationary regimes of reactor operation are given. The accident regimes identification unit for the VVER-1000 is analyzed in detail.

  4. Human influence on California fire regimes

    USGS Publications Warehouse

    Syphard, A.D.; Radeloff, V.C.; Keeley, J.E.; Hawbaker, T.J.; Clayton, M.K.; Stewart, S.I.; Hammer, R.B.

    2007-01-01

    Periodic wildfire maintains the integrity and species composition of many ecosystems, including the mediterranean-climate shrublands of California. However, human activities alter natural fire regimes, which can lead to cascading ecological effects. Increased human ignitions at the wildland-urban interface (WUI) have recently gained attention, but fire activity and risk are typically estimated using only biophysical variables. Our goal was to determine how humans influence fire in California and to examine whether this influence was linear, by relating contemporary (2000) and historic (1960-2000) fire data to both human and biophysical variables. Data for the human variables included fine-resolution maps of the WUI produced using housing density and land cover data. Interface WUI, where development abuts wildland vegetation, was differentiated from intermix WUI, where development intermingles with wildland vegetation. Additional explanatory variables included distance to WUI, population density, road density, vegetation type, and ecoregion. All data were summarized at the county level and analyzed using bivariate and multiple regression methods. We found highly significant relationships between humans and fire on the contemporary landscape, and our models explained fire frequency (R2 = 0.72) better than area burned (R2 = 0.50). Population density, intermix WUI, and distance to WUI explained the most variability in fire frequency, suggesting that the spatial pattern of development may be an important variable to consider when estimating fire risk. We found nonlinear effects such that fire frequency and area burned were highest at intermediate levels of human activity, but declined beyond certain thresholds. Human activities also explained change in fire frequency and area burned (1960-2000), but our models had greater explanatory power during the years 1960-1980, when there was more dramatic change in fire frequency. Understanding wildfire as a function of the

  5. Mercury's thermal evolution and core crystallization regime

    NASA Astrophysics Data System (ADS)

    Rivoldini, A.; Van Hoolst, T.; Dumberry, M.; Steinle-Neumann, G.

    2015-10-01

    Unlike the Earth, where the liquid core isentrope is shallower than the core liquidus, at the lower pressures inside Mercury's core the isentrope can be steeper than the melting temperature. As a consequence, upon cooling, the isentrope may first enter a solid stability field near the core mantle boundary and produce ironrich snow that sinks under gravity and produces buoyant upwellings of iron depleted fluid. Similar to bottom up crystallization, crystallization initiated near the top might generate sufficient buoyancy flux to drive magnetic field generation by compositional convection.In this study we model Mercury's thermal evolution by taking into account the formation of iron-rich snow to assess when the conditions for an internally magnetic field can be satisfied. We employ a thermodynamic consistent description of the iron high-pressure phase diagram and thermoelastic properties of iron alloys as well as the most recent data about the thermal conductivity of core materials. We use a 1-dimensional parametrized thermal evolution model in the stagnant lid regime for the mantle (e.g. [1]) that is coupled to the core. The model for the mantle takes into account the formation of the crust due to melting at depth. Mantle convection is driven by heat producing radioactive elements, heat loss from secular cooling and from the heat supplied by the core. The heat generated inside the core is mainly provided from secular cooling, from the latent heat released at iron freezing, and from gravitational energy resulting form the release of light elements at the inner core-outer core boundary as well as from the sinking of iron-rich snow and subsequent upwellings of light elements in the snow zone. If the heat flow out of the core is smaller than the heat transported along the core isentrope a thermal boundary will from at the top of the outer core. To determine the extension of the convecting region inside the liquid core we calculate the convective power [2]. Finally, we

  6. Constraints on flow regimes in wide-aperture fractures

    SciTech Connect

    Ghezzehei, Teamrat A.

    2004-02-28

    In recent years, significant advances have been made in our understanding of the complex flow processes in individual fractures, aided by flow visualization experiments and conceptual modeling efforts. These advances have led to the recognition of several flow regimes in individual fractures subjected to different initial and boundary conditions. Of these, the most important regimes are film flow, rivulet flow, and sliding of droplets. The existence of such significantly dissimilar flow regimes has been a major hindrance in the development of self-consistent conceptual models of flow for single fractures that encompass all the flow regimes. The objective of this study is to delineate the existence of the different flow regimes in individual fractures. For steady-state flow conditions, we developed physical constraints on the different flow regimes that satisfy minimum energy configurations, which enabled us to segregate the wide range of fracture transmissivity (volumetric flow rate per fracture width) into several flow regimes. These are, in increasing order of flow rate, flow of adsorbed films, flow of sliding drops, rivulet flow, stable film flow, and unstable (turbulent) film flow. The scope of this study is limited to wide-aperture fractures with the flow on the opposing sides of fracture being independent.

  7. Marine regime shifts: drivers and impacts on ecosystems services

    PubMed Central

    Rocha, J.; Yletyinen, J.; Biggs, R.; Blenckner, T.; Peterson, G.

    2015-01-01

    Marine ecosystems can experience regime shifts, in which they shift from being organized around one set of mutually reinforcing structures and processes to another. Anthropogenic global change has broadly increased a wide variety of processes that can drive regime shifts. To assess the vulnerability of marine ecosystems to such shifts and their potential consequences, we reviewed the scientific literature for 13 types of marine regime shifts and used networks to conduct an analysis of co-occurrence of drivers and ecosystem service impacts. We found that regime shifts are caused by multiple drivers and have multiple consequences that co-occur in a non-random pattern. Drivers related to food production, climate change and coastal development are the most common co-occurring causes of regime shifts, while cultural services, biodiversity and primary production are the most common cluster of ecosystem services affected. These clusters prioritize sets of drivers for management and highlight the need for coordinated actions across multiple drivers and scales to reduce the risk of marine regime shifts. Managerial strategies are likely to fail if they only address well-understood or data-rich variables, and international cooperation and polycentric institutions will be critical to implement and coordinate action across the scales at which different drivers operate. By better understanding these underlying patterns, we hope to inform the development of managerial strategies to reduce the risk of high-impact marine regime shifts, especially for areas of the world where data are not available or monitoring programmes are not in place.

  8. Toward a Physical Characterization of Raindrop Collision Outcome Regimes

    NASA Technical Reports Server (NTRS)

    Testik, F. Y.; Barros, Ana P.; Bilven, Francis L.

    2011-01-01

    A comprehensive raindrop collision outcome regime diagram that delineates the physical conditions associated with the outcome regimes (i.e., bounce, coalescence, and different breakup types) of binary raindrop collisions is proposed. The proposed diagram builds on a theoretical regime diagram defined in the phase space of collision Weber numbers We and the drop diameter ratio p by including critical angle of impact considerations. In this study, the theoretical regime diagram is first evaluated against a comprehensive dataset for drop collision experiments representative of raindrop collisions in nature. Subsequently, the theoretical regime diagram is modified to explicitly describe the dominant regimes of raindrop interactions in (We, p) by delineating the physical conditions necessary for the occurrence of distinct types of collision-induced breakup (neck/filament, sheet, disk, and crown breakups) based on critical angle of impact consideration. Crown breakup is a subtype of disk breakup for lower collision kinetic energy that presents distinctive morphology. Finally, the experimental results are analyzed in the context of the comprehensive collision regime diagram, and conditional probabilities that can be used in the parameterization of breakup kernels in stochastic models of raindrop dynamics are provided.

  9. An Examination of the Nature of Global MODIS Cloud Regimes

    NASA Technical Reports Server (NTRS)

    Oreopoulos, Lazaros; Cho, Nayeong; Lee, Dongmin; Kato, Seiji; Huffman, George J.

    2014-01-01

    We introduce global cloud regimes (previously also referred to as "weather states") derived from cloud retrievals that use measurements by the Moderate Resolution Imaging Spectroradiometer (MODIS) instrument aboard the Aqua and Terra satellites. The regimes are obtained by applying clustering analysis on joint histograms of retrieved cloud top pressure and cloud optical thickness. By employing a compositing approach on data sets from satellites and other sources, we examine regime structural and thermodynamical characteristics. We establish that the MODIS cloud regimes tend to form in distinct dynamical and thermodynamical environments and have diverse profiles of cloud fraction and water content. When compositing radiative fluxes from the Clouds and the Earth's Radiant Energy System instrument and surface precipitation from the Global Precipitation Climatology Project, we find that regimes with a radiative warming effect on the atmosphere also produce the largest implied latent heat. Taken as a whole, the results of the study corroborate the usefulness of the cloud regime concept, reaffirm the fundamental nature of the regimes as appropriate building blocks for cloud system classification, clarify their association with standard cloud types, and underscore their distinct radiative and hydrological signatures.

  10. Past and Future Drought Regimes in Turkey

    NASA Astrophysics Data System (ADS)

    Sen, Burak; Topcu, Sevilay; Turkes, Murat; Sen, Baha

    2010-05-01

    Climate variability in the 20th century was characterized by apparent precipitation variability at both temporal and spatial scales. In addition to the well-known characteristic seasonal and year-to-year variability, some marked and long-term changes in precipitation occurred in Turkey, particularly after the early 1970s. Drought, originating from a deficiency of precipitation over an extended time period (which is usually a season or more) has become a recurring phenomenon in Turkey in the past few decades. Spatially coherent with the significant drought events since early 1970s, water stress and shortages for all water user sectors have also reached their critical points in Turkey. Analyzing the historical occurrence of drought provides an understanding of the range of climate possibilities for a country, resulting in more informed management decision-making. However, future projections about spatial and temporal changes in drought characteristics such as frequency, intensity and duration can be challenging for developing appropriate mitigation and adaptation strategies. Hence, the objectives of this study are (i) to analyze the spatial and temporal dimensions of historical droughts in Turkey, (2) to predict potential intensity, frequency and duration of droughts in Turkey for the future (2070-2100). The Standardized Precipitation Index (SPI) and the Percent to Normal Index (PNI) have been used to assess the drought characteristics. Rainfall datasets for the reference period, 1960-1990, were acquired from 52 stations (representative of all kinds of regions with different rainfall regimes in the country) of the Turkish State Meteorological Service (TSMS). The future rainfall series for the 2070-2100 period were simulated using a regional climate model (RegCM3) for IPCC's SRESS-A2 scenario conditions. For verification of RegCM3 simulations, the model was performed for the reference period and simulated rainfall data were used for computing two drought indices (SPI

  11. Flow regime shifts in the Little Piney creek (US)

    NASA Astrophysics Data System (ADS)

    Botter, G.

    2014-09-01

    Non-stationarity of climate drivers and soil-use strongly affects the hydrologic cycle, producing significant inter-annual and multi-decadal fluctuations of river flow regimes. Understanding the temporal trajectories of hydrologic regimes is a key issue for the management of freshwater ecosystems and the security of human water uses. Here, long-term changes in the seasonal flow regime of the Little Piney creek (US) are analyzed with the aid of a stochastic mechanistic approach that expresses analytically the streamflow distribution in terms of a few measurable hydroclimatic parameters, providing a basis for assessing the impact of climate and landscape modifications on water resources. Mean rainfall and streamflow rates exhibit a pronounced inter-annual variability across the last century, though in the absence of clear sustained drifts. Long-term modifications of streamflow regimes across different periods of 2 and 8 years are likewise significant. The stochastic model is able to reasonably reproduce the observed 2-years and 8-years regimes in the Little Piney creek, as well as the corresponding inter-annual variations of streamflow probability density. The study evidences that a flow regime shift occurred in the Little Piney creek during the last century, with erratic regimes typical of the 30s/40s that had been progressively replaced by persistent flow regimes featured by more dumped streamflow fluctuations. Causal drivers of regime shift are identified as the increase of the frequency of events (a byproduct of climate variability) and the decrease of recession rates (induced by a decrease of cultivated lands). The approach developed offers an objective basis for the analysis and prediction of the impact of climate/landscape change on water resources.

  12. Consequences of regime shifts for marine food webs

    NASA Astrophysics Data System (ADS)

    Alheit, Jürgen

    2009-03-01

    Climate-mediated ecological regime shifts can re-structure entire ecosystems from primary producers to top predators. As a consequence, major trophodynamic pathways change with the altered mix of dominating species. Four cases of ecosystem regime shifts forced by climate variability are presented (North Sea, central Baltic Sea, central North Pacific and Humboldt Current ecosystems) and the effect on food chains is elucidated. Different types of trophodynamic control mechanisms set in motion through the impact of climate variability and the potential impact of regime shifts on biogeochemical cycles are discussed.

  13. Multiple planetary flow regimes in the Southern Hemisphere

    NASA Technical Reports Server (NTRS)

    Yoden, Shigeo; Shiotani, Masato; Hirota, Isamu

    1987-01-01

    Low-frequency variations in the general circulation of the Southern Hemisphere during 1983 were studied using daily geopotential height and temperature analyses for 12 pressure levels from 1000 mb up to 50 mb, performed by the National Meteorological Center of Japan. Results disclosed the presence, in the Southern Hemisphere troposphere, of an irregular fluctuation of two zonal mean geostrophic wind patterns (named single-jet and double-jet regimes) during wintertime. The fluctuation is characterized by the persistence of one geostrophic wind regime, with characteristic duration of a month, followed by a rather rapid transition to another regime.

  14. Raman amplification in the coherent wave-breaking regime.

    PubMed

    Farmer, J P; Pukhov, A

    2015-12-01

    In regimes far beyond the wave-breaking threshold of Raman amplification, we show that significant amplification can occur after the onset of wave breaking, before phase mixing destroys the coherent coupling between pump, probe, and plasma wave. Amplification in this regime is therefore a transient effect, with the higher-efficiency "coherent wave-breaking" (CWB) regime accessed by using a short, intense probe. Parameter scans illustrate the marked difference in behavior between below wave breaking, in which the energy-transfer efficiency is high but total energy transfer is low, wave breaking, in which efficiency is low, and CWB, in which moderate efficiencies allow the highest total energy transfer. PMID:26764840

  15. Boundary between stable and unstable regimes of accretion. Ordered and chaotic unstable regimes

    NASA Astrophysics Data System (ADS)

    Blinova, A. A.; Romanova, M. M.; Lovelace, R. V. E.

    2016-07-01

    We present a new study of the Rayleigh-Taylor unstable regime of accretion on to rotating magnetized stars in a set of high grid resolution three-dimensional magnetohydrodynamic simulations performed in low-viscosity discs. We find that the boundary between the stable and unstable regimes is determined almost entirely by the fastness parameter ωs = Ω⋆/ΩK(rm), where Ω⋆ is the angular velocity of the star and ΩK(rm) is the angular velocity of the Keplerian disc at the disc-magnetosphere boundary r = rm. We found that accretion is unstable if ωs ≲ 0.6. Accretion through instabilities is present in stars with different magnetospheric sizes. However, only in stars with relatively small magnetospheres, rm/R⋆ ≲ 7, do the unstable tongues produce chaotic hotspots on the stellar surface and irregular light curves. At even smaller values of the fastness parameter, ωs ≲ 0.45, multiple irregular tongues merge, forming one or two ordered unstable tongues that rotate with the angular frequency of the inner disc. This transition occurs in stars with even smaller magnetospheres, rm/R⋆ ≲ 4.2. Most of our simulations were performed at a small tilt of the dipole magnetosphere, Θ = 5°, and a small viscosity parameter α = 0.02. Test simulations at higher α values show that many more cases become unstable, and the light curves become even more irregular. Test simulations at larger tilts of the dipole Θ show that instability is present, however, accretion in two funnel streams dominates if Θ ≳ 15°. The results of these simulations can be applied to accreting magnetized stars with relatively small magnetospheres: Classical T Tauri stars, accreting millisecond X-ray pulsars, and cataclysmic variables.

  16. The effect of refrigerants in the mixed lubrication regime

    SciTech Connect

    Mizuhara, Kazuyuki; Tomimoto, Makoto

    1997-12-31

    Because of environmental concerns, CFC (chlorofluorocarbon) refrigerants must be replaced with HFCs (hydrofluorocarbons). As a result, many tribological problems are caused especially in rotary piston compressors. To solve the problem, the effects of refrigerants on friction and wear characteristics of the oil and refrigerant mixtures at the mixed lubrication regime are investigated. The difference in refrigerants are clearly observed not only in boundary but also in the mixed lubrication regime. The effects of operating conditions on sliding conditions and experimental results are also discussed. It is concluded that for practical application where long life is essential, experiments must be conducted under the mixed lubrication regime. Also, the importance of defining the lubrication regime in terms of film parameter is emphasized.

  17. Nonlinear Trapped Electron Mode Pinch in Strong Turbulence Regime

    NASA Astrophysics Data System (ADS)

    Hatch, David; Terry, P. W.

    2006-10-01

    Recent work has shown that there is an inward flux component in collisionless trapped electron mode turbulence produced by a nonlinear cross phase^2. The result was obtained for a weak turbulence regime, consistent with near threshold conditions. We extend this work to the strong turbulence regime, applying asymptotic analysis to the nonlinear frequency expressions generated from self-consistent statistical closure theory. We first check to see if there is a consistent strong turbulence regime for the previously considered threshold ordering^2, and examine the properties and scalings of the inward flux components. We then examine other orderings that are further above the instability threshold. The orderings will be compared with experimental profiles to determine likely regimes and nonlinear pinch properties. ^2P.W. Terry and R. Gatto, Phys. Plasmas 13, 062309 (2006).

  18. FISHER INFORMATION AND DYNAMIC REGIME CHANGES IN ECOLOGICAL SYTEMS

    EPA Science Inventory

    Ecosystems often exhibit transitions between dynamic regimes (or steady states), such as the conversion of oligotrophic to eutrophic conditions and associated aquatic ecological communities, due to natural (or increasingly) anthropogenic disturbances. As ecosystems experience per...

  19. Regime shifts and resilience in China's coastal ecosystems.

    PubMed

    Zhang, Ke

    2016-02-01

    Regime shift often results in large, abrupt, and persistent changes in the provision of ecosystem services and can therefore have significant impacts on human wellbeing. Understanding regime shifts has profound implications for ecosystem recovery and management. China's coastal ecosystems have experienced substantial deterioration within the past decades, at a scale and speed the world has never seen before. Yet, information about this coastal ecosystem change from a dynamics perspective is quite limited. In this review, I synthesize existing information on coastal ecosystem regime shifts in China and discuss their interactions and cascading effects. The accumulation of regime shifts in China's coastal ecosystems suggests that the desired system resilience has been profoundly eroded, increasing the potential of abrupt shifts to undesirable states at a larger scale, especially given multiple escalating pressures. Policy and management strategies need to incorporate resilience approaches in order to cope with future challenges and avoid major losses in China's coastal ecosystem services. PMID:26286204

  20. Fixed points, stable manifolds, weather regimes, and their predictability

    DOE PAGESBeta

    Deremble, Bruno; D'Andrea, Fabio; Ghil, Michael

    2009-10-27

    In a simple, one-layer atmospheric model, we study the links between low-frequency variability and the model’s fixed points in phase space. The model dynamics is characterized by the coexistence of multiple ''weather regimes.'' To investigate the transitions from one regime to another, we focus on the identification of stable manifolds associated with fixed points. We show that these manifolds act as separatrices between regimes. We track each manifold by making use of two local predictability measures arising from the meteorological applications of nonlinear dynamics, namely, ''bred vectors'' and singular vectors. These results are then verified in the framework of ensemblemore » forecasts issued from clouds (ensembles) of initial states. The divergence of the trajectories allows us to establish the connections between zones of low predictability, the geometry of the stable manifolds, and transitions between regimes.« less

  1. Fixed points, stable manifolds, weather regimes, and their predictability

    SciTech Connect

    Deremble, Bruno; D'Andrea, Fabio; Ghil, Michael

    2009-10-27

    In a simple, one-layer atmospheric model, we study the links between low-frequency variability and the model’s fixed points in phase space. The model dynamics is characterized by the coexistence of multiple ''weather regimes.'' To investigate the transitions from one regime to another, we focus on the identification of stable manifolds associated with fixed points. We show that these manifolds act as separatrices between regimes. We track each manifold by making use of two local predictability measures arising from the meteorological applications of nonlinear dynamics, namely, ''bred vectors'' and singular vectors. These results are then verified in the framework of ensemble forecasts issued from clouds (ensembles) of initial states. The divergence of the trajectories allows us to establish the connections between zones of low predictability, the geometry of the stable manifolds, and transitions between regimes.

  2. Stochastic regimes in very-low-frequency fluidic oscillator

    NASA Astrophysics Data System (ADS)

    Tesař, Václav

    2016-03-01

    Paper discusses interesting unexpected stochastic regimes discovered in a fluidic oscillator designed for operation at very low oscillation frequencies - without the inconvenience of the long feedback loops needed in standard low-frequency oscillator designs. The new oscillator contains a pair of bistable turn-down active valves operating in anti-parallel — essentially analogous to Abraham & Bloch electric "multibrateur" invented in 1919. Three different self-excited oscillation regimes were found. In the order of increasing supplied flow rate, these regimes are characterised by: (A) generation of stochastic-duration multi-pulse packs, (B) generation of individual pulses with a degree of periodicity, and (C) regime with randomly appearing flow pulses separated by intervals of the order of seconds.

  3. The Hadley and Rossby regimes in a spherical atmosphere

    NASA Technical Reports Server (NTRS)

    Feldstein, S. B.; Clark, J. H. E.

    1985-01-01

    The properties of the steady Hadley and Rossby regimes for a thermally forced rotating fluid on a sphere are studied. The two layer modified geostrophic model is employed which allows for thermal advection by the divergent wind and time dependent static stability. Heating processes are parameterized using the Newtonian approximation and Rayleigh friction is accounted for. The equations are transformed to spectral form using spherical harmonics and then truncated retaining a simple axisymmetric state and initial, one wave. A time independent Hadley circulation is obtained which is neutral to axisymmetric disturbances but unstable to wave like perturbations for intermediate values of the meridional temperature gradient, indicating the existence of both an upper and lower symmetric Hadley regime. An analytical solution for the steady Rossby circulation is determined for values of the meridional temperature gradient where the Hadley regime is unstable. Linear perturbation theory is used to show that within the steady Rossby regime two or more waves cannot exist simultaneously.

  4. The role of transients in weather regimes and transitions

    SciTech Connect

    Reinhold, B.; Yang, Shuting )

    1993-05-01

    Transition of weather regimes is examined in a highly simplified model. Two completely distinct internal methods of transition are identified. The first is a synoptically triggered large-scale instability, while the second is an energy inconsistency between the large-scale and synoptic scales that does not allow the two scales to equilibrate. In the atmosphere, the first case appears as a sudden propagation and damping (or vice versa) of the large-scale pattern with no obvious warning, while the second is consistent with the synoptician's description of a regime being disrupted by a single catastrophic event such as explosive cyclogenesis. The first method is always fast (on a synoptic time scale), while the second does not have to be, though often is. By examining what causes the regimes to fail, one can better understand the role of the transients during all phases of weather regimes. 27 refs., 5 figs.

  5. Urokinase-type Plasminogen Activator (uPA) Promotes Angiogenesis by Attenuating Proline-rich Homeodomain Protein (PRH) Transcription Factor Activity and De-repressing Vascular Endothelial Growth Factor (VEGF) Receptor Expression.

    PubMed

    Stepanova, Victoria; Jayaraman, Padma-Sheela; Zaitsev, Sergei V; Lebedeva, Tatiana; Bdeir, Khalil; Kershaw, Rachael; Holman, Kelci R; Parfyonova, Yelena V; Semina, Ekaterina V; Beloglazova, Irina B; Tkachuk, Vsevolod A; Cines, Douglas B

    2016-07-15

    Urokinase-type plasminogen activator (uPA) regulates angiogenesis and vascular permeability through proteolytic degradation of extracellular matrix and intracellular signaling initiated upon its binding to uPAR/CD87 and other cell surface receptors. Here, we describe an additional mechanism by which uPA regulates angiogenesis. Ex vivo VEGF-induced vascular sprouting from Matrigel-embedded aortic rings isolated from uPA knock-out (uPA(-/-)) mice was impaired compared with vessels emanating from wild-type mice. Endothelial cells isolated from uPA(-/-) mice show less proliferation and migration in response to VEGF than their wild type counterparts or uPA(-/-) endothelial cells in which expression of wild type uPA had been restored. We reported previously that uPA is transported from cell surface receptors to nuclei through a mechanism that requires its kringle domain. Intranuclear uPA modulates gene transcription by binding to a subset of transcription factors. Here we report that wild type single-chain uPA, but not uPA variants incapable of nuclear transport, increases the expression of cell surface VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) by translocating to the nuclei of ECs. Intranuclear single-chain uPA binds directly to and interferes with the function of the transcription factor hematopoietically expressed homeodomain protein or proline-rich homeodomain protein (HHEX/PRH), which thereby lose their physiologic capacity to repress the activity of vehgr1 and vegfr2 gene promoters. These studies identify uPA-dependent de-repression of vegfr1 and vegfr2 gene transcription through binding to HHEX/PRH as a novel mechanism by which uPA mediates the pro-angiogenic effects of VEGF and identifies a potential new target for control of pathologic angiogenesis. PMID:27151212

  6. Dioscorea nipponica Attenuates Migration and Invasion by Inhibition of Urokinase-Type Plasminogen Activator through Involving PI3K/Akt and Transcriptional Inhibition of NF-[Formula: see text]B and SP-1 in Hepatocellular Carcinoma.

    PubMed

    Hsieh, Ming-Ju; Yeh, Chao-Bin; Chiou, Hui-Ling; Hsieh, Ming-Chang; Yang, Shun-Fa

    2016-01-01

    High mortality and morbidity rates for hepatocellular carcinoma (HCC) in Taiwan primarily result from uncontrolled tumor metastasis. In our previous studies, we have reported that Dioscorea nipponica Makino extract (DNE) has anti-metastasis effects on human oral cancer cells. However, the effect of DNE on hepatoma metastasis have not been thoroughly investigated and remains poorly understood. To determine the effects of DNE on the migration and invasion in HCC cells we used a wound healing model, Boyden chamber assays, gelatin/casein zymography and Western blotting. Transcriptional levels of matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (u-PA) were detected by real-time PCR and promoter assays. In this study, DNE treatment significantly inhibited the migration/invasion capacities of Huh7 cell lines. The results of gelatin/casein zymography and Western blotting revealed that the activities and protein levels of the MMP-9 and u-PA were inhibited by DNE. Tests of the mRNA levels, real-time PCR, and promoter assays evaluated the inhibitory effects of DNE on u-PA expression in human hepatoma cells. A chromatin immunoprecipitation (ChIP) assay showed not only that DNE inhibits u-PA expression, but also the inhibitory effects were associated with the down-regulation of the transcription factors of NF-[Formula: see text]B and SP-1 signaling pathways. Western blot analysis also showed that DNE inhibits PI3K and phosphorylation of Akt. In conclusion, these results show that u-PA expression may be a potent therapeutic target in the DNE-mediated suppression of HCC invasion/migration. DNE may have potential use as a chemo-preventive agent against liver cancer metastasis. PMID:26916922

  7. The soluble form of LR11 protein is a regulator of hypoxia-induced, urokinase-type plasminogen activator receptor (uPAR)-mediated adhesion of immature hematological cells.

    PubMed

    Nishii, Keigo; Nakaseko, Chiaki; Jiang, Meizi; Shimizu, Naomi; Takeuchi, Masahiro; Schneider, Wolfgang J; Bujo, Hideaki

    2013-04-26

    A key property of hematopoietic stem and progenitor cells (HSPCs) regarding differentiation from the self-renewing quiescent to the proliferating stage is their adhesion to the bone marrow (BM) niche. An important molecule involved in proliferation and pool size of HSPCs in the BM is the hypoxia-induced urokinase-type plasminogen activator receptor (uPAR). Here, we show that the soluble form (sLR11) of LR11 (also called SorLA or SORL1) modulates the uPAR-mediated attachment of HSPCs under hypoxic conditions. Immunohistochemical and mRNA expression analyses revealed that hypoxia increased LR11 expression in hematological c-Kit(+) Lin(-) cells. In U937 cells, hypoxia induced a transient rise in LR11 transcription, production of cellular protein, and release of sLR11. Attachment to stromal cells of c-Kit(+) Lin(-) cells of lr11(-/-) mice was reduced by hypoxia much more than of lr11(+/+) animals. sLR11 induced the adhesion of U937 and c-Kit(+) Lin(-) cells to stromal cells. Cell attachment was increased by sLR11 and reduced in the presence of anti-uPAR antibodies. Furthermore, the fraction of uPAR co-immunoprecipitated with LR11 in membrane extracts of U937 cells was increased by hypoxia. CoCl2, a chemical inducer of HIF-1α, enhanced the levels of LR11 and sLR11 in U937 cells. The decrease in hypoxia-induced attachment of HIF-1α-knockdown cells was largely prevented by exogenously added sLR11. Finally, hypoxia induced HIF-1α binding to a consensus binding site in the LR11 promoter. Thus, we conclude that sLR11 regulates the hypoxia-enhanced adhesion of HSPCs via an uPAR-mediated pathway that stabilizes the hematological pool size by controlling cell attachment to the BM niche. PMID:23486467

  8. Plasma confinement regimes and collective modes characterizing them

    SciTech Connect

    Coppi, B.; Zhou, T.

    2012-10-15

    A unified theory is presented for the modes that are excited at the edge of the plasma column and are important signatures of the advanced confinement regimes into which magnetically confined plasmas can be driven. In particular, the so-called EDA H-Regime, the Elmy H-Regime, and the I-Regime are considered. The modes that are identified theoretically have characteristics that are consistent with or have anticipated those of the modes observed experimentally for each of the investigated regimes. The phase velocities, the produced transport processes, the frequencies, the wavelengths, and the consistency with the direction of spontaneous rotation are the factors considered for comparison with the relevant experiments. The quasi-coherent mode [I. Cziegler, Ph.D. dissertation, Massachusetts Institute of Technology, Cambridge, MA, 2011] that is present in the EDA H-Regime has a phase velocity in the direction of the ion diamagnetic velocity in the plasma reference frame. Consequently, this is identified as a ballooning mode near finite Larmor radius marginal stability involving the effects of transverse ion viscosity and other dissipative effects. In this regime, impurities are driven outward by the combined effects of the local temperature gradients of the impurities and their thermal conductivity, while in the Elmy H-Regime impurities are driven toward the center of the plasma column. In the I-Regimes, the excited 'Heavy Particle' modes [B. Coppi and T. Zhou, Phys. Plasmas 19, 012302 (2012); Phys. Lett. A 375, 2916 (2011)] are not of the ballooning kind and are shown to expel the impurities toward the plasma edge in the presence of significant fluctuations. These modes can have a finite frequency of oscillation with a phase velocity in the direction of the electron diamagnetic velocity or they can be nearly purely growing, explaining why there are I-Regimes where fluctuations are not observed. Instead, the modes considered for the Elmy H-Regime are of the ballooning

  9. Longitudinal dunes on Mars: Relation to current wind regimes

    NASA Technical Reports Server (NTRS)

    Lee, Pascal; Thomas, Peter C.

    1995-01-01

    Longitudinal dunes are extremely rare on Mars, but constitute a substantial fraction of terrestrial desert dunes. We report finding isolated examples of longitudinal dunes on Mars and relate their occurence to expected sand transport regimes. Terrestrial longitudinal dunes form in bimodal and multimodal transport regimes. General circulation models and streak data indicate that bimodal and multimodal transport of sand should be very rare on Mars. Thus the dearth of longitudinal dunes on Mars is consistant with their apparent formation conditions on Earth.

  10. Longitudinal dunes on Mars: Relation to current wind regimes

    NASA Technical Reports Server (NTRS)

    Lee, Pascal; Thomas, Peter C.

    1995-01-01

    Longitudinal dunes are extremely rare on Mars, but constitute a substantial fraction of terrestrial desert dunes. We report finding isolated examples of longitudinal dunes on Mars and relate their occurrence to expected sand transport regimes. Terrestrial longitudinal dunes form in bimodal and multimodal transport regimes. General circulation models and streak data indicate that bimodal and multimodal transport of sand should be very rare on Mars. Thus the dearth of longitudinal dunes on Mars is consistent with their apparent formation conditions on Earth.

  11. Laboratory experiment on boundaries of upper stage plane bed regime

    NASA Astrophysics Data System (ADS)

    Zrostlík, Štěpán; Matoušek, Václav

    2016-04-01

    Results are discussed of laboratory experiments on criteria determining the transition between the regime of dunes and the upper stage plane bed (UPB) regime and the transition between the UPB regime and the regime of wavy flow. The experiments were carried for 3 fractions of plastic material and two fractions of glass beads in a broad range of flow conditions (different discharges of water and solids and longitudinal bed slopes) in a tilting flume. The experiments reveal that, contrary to expectations, a constant value of the Shields parameter is not an appropriate criterion for the transition between the dune regime and the UPB regime. Furthermore, the transition appears to be insensitive to the total discharge of solids and water. Instead, the criterion seems to be well represented by a constant value of the average transport concentration of sediment (the ratio of volumetric discharge of solids and volumetric discharge of mixture). The experimental results exhibit a very tight correlation between the transport concentration and the longitudinal bed slope. Hence, a constant value of the bed slope can be considered an appropriate criterion for the transition. The transition between the UPB regime and the wavy regime (significant waves develop but they are not always standing waves) is found at a constant value of Froude number, which is in agreement with literature, although it is found at a higher value than the literature usually suggests (Fr = 1.2 instead of 1.0). Hence, the transition occurs in the super-critical flow but it is not necessarily associated with the critical flow.

  12. Brownian colloids in underdamped and overdamped regimes with nonhomogeneous temperature

    NASA Astrophysics Data System (ADS)

    Sancho, J. M.

    2015-12-01

    The motion of Brownian particles when temperature is spatially dependent is studied by stochastic simulations and theoretical analysis. Nonequilibrium steady probability distributions Ps t(z ,v ) for both underdamped and overdamped regimes are analyzed. The existence of local kinetic energy equipartition theorem is also discussed. The transition between both regimes is characterized by a dimensionless friction parameter. This study is applied to three physical systems of colloidal particles.

  13. Brownian colloids in underdamped and overdamped regimes with nonhomogeneous temperature.

    PubMed

    Sancho, J M

    2015-12-01

    The motion of Brownian particles when temperature is spatially dependent is studied by stochastic simulations and theoretical analysis. Nonequilibrium steady probability distributions P(st)(z,v) for both underdamped and overdamped regimes are analyzed. The existence of local kinetic energy equipartition theorem is also discussed. The transition between both regimes is characterized by a dimensionless friction parameter. This study is applied to three physical systems of colloidal particles. PMID:26764635

  14. Evaluation of interregional variability in MODIS cloud regimes

    NASA Astrophysics Data System (ADS)

    Leinonen, J. S.; Lebsock, M. D.; Oreopoulos, L.; Cho, N.

    2015-12-01

    Clustering techniques have been used in the last few decades to classify cloud types automatically from satellite observations, most commonly using cloud top pressure and cloud optical depth. The underlying assumption is that the resulting clusters, called "cloud regimes" or "weather states", represent some type of basic states of the atmosphere, and thus that their occurrence can be used as a proxy for related variables such as radiative balance or precipitation. We have examined the validity of these assumptions by using independent measurements from the CloudSat and CALIPSO satellites. The CloudSat radar yields a reflectivity product that is sensitive to many aspects of the physics of the clouds, while CloudSat together with the CALIPSO lidar can retrieve the vertical structure of the cloud column, including multi-layer clouds. These observations have been separated into groups according to the recently published cloud regimes based on data from the MODIS instrument, deployed on the Aqua satellite orbiting in the same constellation with CloudSat and CALIPSO. The distributions of these observations have been constructed both globally and in a number of regions in different parts of the Earth. By analyzing the differences in the distributions between these regions, we can evaluate the usefulness of the cloud regimes as a proxy for the measured variables. Some cloud regimes have been found to be rather stable between regions, while others display considerable variability. Moreover, some cloud regimes appear much more similar to each other in CloudSat observations than they do using the MODIS regimes. We analyze the implications of these differences for the usability of the cloud regimes as climate indicators. We also explore various filtering techniques and different clustering methods that can potentially be used to reduce these differences, and thus to improve the universality of the cloud regimes.

  15. Equatorial atmospheric weather regimes: Their structure and role

    SciTech Connect

    Connors, V.S.

    1991-01-01

    Infrared radiance measurements by the Geostationary Operational Environmental Satellite (GOES-6) from April 1986 through April 1987 are used to characterize and identify distinct regimes of persistent, large-scale cloudiness patterns over the Amazon Basin. These tropical weather regimes are responsible for the continental-scale atmospheric processes that transport air, trace gases, and heat from the Amazon Basin. The cloud patterns are represented by both scene-scale parameters, such as the cloud-free area and the value of the 'clear sky peak' in a histogram, and textural measures, such as contrast of cloudy area and homogeneity or cloudy area. Correlation analyses of the attribute arrays determined that only 9 of the original 15 cloud pattern descriptors are required for the cluster analyses. Seventy-six percent of the satellite images are classified into 1 of 14 weather regimes which persist for periods that range from 3 to 15 days each. The dominant weather regimes are described by the recurrence and duration of the events, by the rainfall produced and energy released to the tropical atmosphere, and by the composite kinematic and thermodynamic analyses. While the classification analyses identified a range of organized weather conditions in the Amazon Basin, two weather regimes, each occurring in separate seasons, dominate the year. The prominent dry season regime (A) occurs 11 times, persists for 25 percent of the year, produces 81 percent of the dry season rainfall, and 7 percent of the energy export necessary to balance the global heat budget. The prominent wet season regime (B) occurs 8 times, persists for 18 percent of the year, delivers about 30 percent of the wet season rainfall, and 16 percent of the energy export requirement. Because the dry season regime (A) draws nearly half of its water vapor supply from local sources, a vital link may exist between the rainforest ecosystem and the dry season rainfall.

  16. Synchronous marine pelagic regime shifts in the Northern Hemisphere

    PubMed Central

    Beaugrand, G.; Conversi, A.; Chiba, S.; Edwards, M.; Fonda-Umani, S.; Greene, C.; Mantua, N.; Otto, S. A.; Reid, P. C.; Stachura, M. M.; Stemmann, L.; Sugisaki, H.

    2015-01-01

    Regime shifts are characterized by sudden, substantial and temporally persistent changes in the state of an ecosystem. They involve major biological modifications and often have important implications for exploited living resources. In this study, we examine whether regime shifts observed in 11 marine systems from two oceans and three regional seas in the Northern Hemisphere (NH) are synchronous, applying the same methodology to all. We primarily infer marine pelagic regime shifts from abrupt shifts in zooplankton assemblages, with the exception of the East Pacific where ecosystem changes are inferred from fish. Our analyses provide evidence for quasi-synchronicity of marine pelagic regime shifts both within and between ocean basins, although these shifts lie embedded within considerable regional variability at both year-to-year and lower-frequency time scales. In particular, a regime shift was detected in the late 1980s in many studied marine regions, although the exact year of the observed shift varied somewhat from one basin to another. Another regime shift was also identified in the mid- to late 1970s but concerned less marine regions. We subsequently analyse the main biological signals in relation to changes in NH temperature and pressure anomalies. The results suggest that the main factor synchronizing regime shifts on large scales is NH temperature; however, changes in atmospheric circulation also appear important. We propose that this quasi-synchronous shift could represent the variably lagged biological response in each ecosystem to a large-scale, NH change of the climatic system, involving both an increase in NH temperature and a strongly positive phase of the Arctic Oscillation. Further investigation is needed to determine the relative roles of changes in temperature and atmospheric pressure patterns and their resultant teleconnections in synchronizing regime shifts at large scales.

  17. Assessing the Institution of the Nuclear Nonproliferation Regime

    SciTech Connect

    Toomey, Christopher

    2010-05-14

    The nuclear nonproliferation regime is facing a crisis of effectiveness. During the Cold War, the regime was relatively effective in stemming the proliferation of nuclear weapons and building an institutional structure that could, under certain conditions, ensure continued success. However, in the evolving global context, the traditional approaches are becoming less appropriate. Globalization has introduced new sets of stresses on the nonproliferation regime, such as the rise of non-state actors, broadening extensity and intensity of supply chains, and the multipolarization of power. This evolving global context demands an analytical and political flexibility in order to meet future threats. Current institutional capabilities established during the Cold War are now insufficient to meet the nonproliferation regime’s current and future needs. The research was based on information gathered through interviews and reviews of the relevant literature, and two dominant themes emerged. First, that human security should be integrated into the regime to account for the rise of non-state actors and networked violence. Second, confidence in the regime’s overall effectiveness has eroded at a time where verification-based confidence is becoming more essential. The research postulates that a critical analysis of the regime that fully utilizes institutional theory, with its focus on rules, normative structures, and procedures will be essential to adapting the regime to the current global context, building mechanisms for generating trust, creating better enforcement, and providing flexibility for the future.

  18. Modeling of a Two-Regime Crystallization in a Multicomponent

    SciTech Connect

    Mazzanti, G.; Marangoni, A; Idziak, S

    2008-01-01

    The kinetics of phase transitions of milk fat triacylglycerols, as model multicomponent lipid systems, were studied under shear in a Couette cell at 17 C, 17.5 C and 20 C under shear rates ranging from 0 to 2880s-1 using synchrotron X-ray diffraction. Two-dimensional diffraction patterns were captured during the crystallization process. No effect of shear on onset time for phase a from the liquid was observed. Afterwards a two-regime crystallization process was observed. During the first regime, as observed in other systems, shear reduced the onset time of the phase transition from phase a to 2880s-. The model previously developed for palm oil (ODE model) worked well to describe this regime, confirming the general value of the proposed ODE model. However, the ODE model did not satisfactorily describe the second regime. We found that, as the system gets closer to equilibrium, the growth regime becomes controlled by diffusion, manifested by the kinetics following a {radical}t dependence. This regime was found to be consistent with a mechanism combining step growth at a kink with progressive selection of the crystallizing moieties. This mechanism is in agreement with the displacement of the diffraction peak positions, which revealed how increased shear rate promotes the crystallization of the higher melting fraction affecting the composition of the crystallites.

  19. Trends in the hydrologic regime of Alpine rivers

    NASA Astrophysics Data System (ADS)

    Bard, Antoine; Renard, Benjamin; Lang, Michel; Giuntoli, Ignazio; Korck, Jane; Koboltschnig, Gernot; Janža, Mitja; d'Amico, Michele; Volken, David

    2015-10-01

    This paper describes a trend analysis performed on 177 streamflow time series collected over the Alps in Central Europe. The analysis covers several facets of the Alpine hydrologic regimes, including winter droughts and spring snowmelt flows, both in terms of severity and timing of occurrence. Statistical trend tests are applied at a local scale (i.e. on a site-by-site basis) and at a regional scale (seeking a common trend for sites within the same hydro-climatic region). The overall results indicate a trend toward less severe winter droughts, and consistent changes in the timing of snowmelt flows. However, a more in-depth analysis at the scale of hydro-climatic regimes reveals more contrasted changes. While most glacial- and snowmelt-dominated regimes show a decreasing trend in the severity of winter droughts, contrasted trends are found for mixed snowmelt-rainfall regimes in the Southeastern Alps. Changes in the timing of snowmelt flows (earlier start and increased duration of the snowmelt season) mostly affect glacial- and snowmelt-dominated regimes. Lastly, glacial regimes show an increase in the volume and the peak of snowmelt flows.

  20. Regimes of the magnetized Rayleigh{endash}Taylor instability

    SciTech Connect

    Winske, D.

    1996-11-01

    Hybrid simulations with kinetic ions and massless fluid electrons are used to investigate the linear and nonlinear behavior of the magnetized Rayleigh{endash}Taylor instability in slab geometry with the plasma subject to a constant gravity. Three regimes are found, which are determined by the magnitude of the complex frequency {omega}={omega}{sub {ital r}}+{ital i}{gamma}. For {vert_bar}{omega}{vert_bar}{lt}{Omega}{sub {ital i}}({Omega}{sub {ital i}}= ion gyrofrequency), one finds the typical behavior of the usual fluid regime, namely the development of {open_quote}{open_quote}mushroom-head{close_quote}{close_quote} spikes and bubbles in the density and a strongly convoluted boundary between the plasma and magnetic field, where the initial gradient is not relaxed much. A second regime, where {vert_bar}{omega}{vert_bar}{approximately}0.1{Omega}{sub {ital i}}, is characterized by the importance of the Hall term. Linearly, the developing flute modes are more finger-like and tilted along the interface; nonlinearly, clump-like structures form, leading to a significant broadening of the interface. The third regime is characterized by unmagnetized ion behavior, with {vert_bar}{omega}{vert_bar}{approximately}{Omega}{sub {ital i}}. Density clumps, rather than flutes, form in the linear stage, while nonlinearly, longer-wavelength modes that resemble those in fluid regime dominate. Finite Larmor radius stabilization of short-wavelength modes is observed in each regime. {copyright} {ital 1996 American Institute of Physics.}

  1. Do family policy regimes matter for children's well-being?

    PubMed

    Engster, Daniel; Stensöta, Helena Olofsdotter

    2011-01-01

    Researchers have studied the impact of different welfare state regimes, and particularly family policy regimes, on gender equality. Very little research has been conducted, however, on the association between different family policy regimes and children's well-being. This article explores how the different family policy regimes of twenty OECD countries relate to children's well-being in the areas of child poverty, child mortality, and educational attainment and achievement. We focus specifically on three family policies: family cash and tax benefits, paid parenting leaves, and public child care support. Using panel data for the years 1995, 2000, and 2005, we test the association between these policies and child well-being while holding constant for a number of structural and policy variables. Our analysis shows that the dual-earner regimes, combining high levels of support for paid parenting leaves and public child care, are strongly associated with low levels of child poverty and child mortality. We find little long-term effect of family policies on educational achievement, but a significant positive correlation between high family policy support and higher educational attainment. We conclude that family policies have a significant impact on improving children's well-being, and that dual-earner regimes represent the best practice for promoting children's health and development. PMID:21692245

  2. Numerical simulation of transitions between back discharge regimes

    NASA Astrophysics Data System (ADS)

    Jánský, Jaroslav; Bessières, Delphine; Paillol, Jean; Lemont, Florent

    2014-11-01

    This paper presents numerical simulations of transitions between back discharge regimes. Back discharge refers to any discharge initiated at or near a dielectric layer covering a passive electrode. In this work, a pinhole in a dielectric layer on a plane anode serves as a model for back discharge activity. We have studied transitions between back discharge regimes by varying the surface charge density on the dielectric layer and the electric field in front of the pinhole. From the variation of these two independent parameters, the back discharge regimes have been depicted as a mode diagram inspired by the experimental study of Masuda and Mizuno. The resulting diagram includes the different discharge regimes that are commonly observed in experiments. The propagation of a positive ionizing wave inside the pinhole toward its edge, and the resulting formation of a plasma zone at its exit constitute the onset stage of back discharge. From this stage, the transitions to volume discharge or surface discharge can occur. The volume discharge regime consists of the propagation of a discharge in space toward the cathode which can be superimposed with the propagation of a discharge above the dielectric layer surface. The diagram reveals the conditions for transitions between back discharge regimes.

  3. Sensitivity of streamflows to hydroclimatic fluctuations: resilience and regime shifts

    NASA Astrophysics Data System (ADS)

    Botter, Gianluca; Basso, Stefano; Rodriguez-Iturbe, Ignacio; Rinaldo, Andrea

    2016-04-01

    Landscape and climate alterations foreshadow global-scale shifts of river flow regimes. However, a theory that identifies the range of foreseen impacts on streamflows resulting from inhomogeneous forcings and sensitivity gradients across diverse regimes is lacking. In this contribution, we use a dimensionless index embedding simple climate and landscape attributes (the ratio of the mean interarrival of streamflow-producing rainfall events and the mean catchment response time) to discriminate erratic regimes with enhanced intra-seasonal streamflow variability from persistent regimes endowed with regular flow patterns. The proposed classification is successfully applied to 110 seasonal streamflow distributions observed in 44 catchments of the Alps and the United States, allowing the identification of emerging patterns in space and time. In the same framework, the impact of multi-scale fluctuations of the underlying climatic drivers (temperature, precipitation) on the streamflow distributions can be analyzed. Theoretical and empirical data show that erratic regimes, typical of rivers with low mean discharges, are highly resilient in that they hold a reduced sensitivity to variations in the external forcing. Specific temporal trajectories of streamflow distributions and flow regime shifts driven by land-cover change and rainfall patterns can be also evidenced. The approach developed offers an objective basis for the analysis and prediction of the impact of climate/landscape change on water resources.

  4. Triggered dynamics in a model of different fault creep regimes

    PubMed Central

    Kostić, Srđan; Franović, Igor; Perc, Matjaž; Vasović, Nebojša; Todorović, Kristina

    2014-01-01

    The study is focused on the effect of transient external force induced by a passing seismic wave on fault motion in different creep regimes. Displacement along the fault is represented by the movement of a spring-block model, whereby the uniform and oscillatory motion correspond to the fault dynamics in post-seismic and inter-seismic creep regime, respectively. The effect of the external force is introduced as a change of block acceleration in the form of a sine wave scaled by an exponential pulse. Model dynamics is examined for variable parameters of the induced acceleration changes in reference to periodic oscillations of the unperturbed system above the supercritical Hopf bifurcation curve. The analysis indicates the occurrence of weak irregular oscillations if external force acts in the post-seismic creep regime. When fault motion is exposed to external force in the inter-seismic creep regime, one finds the transition to quasiperiodic- or chaos-like motion, which we attribute to the precursory creep regime and seismic motion, respectively. If the triggered acceleration changes are of longer duration, a reverse transition from inter-seismic to post-seismic creep regime is detected on a larger time scale. PMID:24954397

  5. Dynamic regime marginal structural mean models for estimation of optimal dynamic treatment regimes, Part II: proofs of results.

    PubMed

    Orellana, Liliana; Rotnitzky, Andrea; Robins, James M

    2010-01-01

    In this companion article to "Dynamic Regime Marginal Structural Mean Models for Estimation of Optimal Dynamic Treatment Regimes, Part I: Main Content" [Orellana, Rotnitzky and Robins (2010), IJB, Vol. 6, Iss. 2, Art. 7] we present (i) proofs of the claims in that paper, (ii) a proposal for the computation of a confidence set for the optimal index when this lies in a finite set, and (iii) an example to aid the interpretation of the positivity assumption. PMID:20405047

  6. North Sea wind climate in changing weather regimes

    NASA Astrophysics Data System (ADS)

    Anders, Ivonne; Rockel, Burkhardt

    2015-04-01

    Results from regional climate models (RCMs) are getting more and more important in future wind climate assessment. From RCMs often only the daily wind speed is available, but no information on prevailing wind direction of each day. Weather regime classification can close this gap and models ability of simulating surface wind speed can be analysed in detail. Several objective regime classifications have been investigated to be a sufficient diagnostic tool to evaluate the present wind climate at the German and Dutch coastal area of the North Sea. The classification by Jenkinson and Collison (1977) uses values for mean sea level pressure at 16 locations centered over the North Sea. Beside the predefined 8 prevailed wind directions and the two possibilities on cyclonic or anticyclonic turbulence, 2x8 hybrid weather types can be defined. In this way 27 different regimes can be distinguished including a class of non-classifiable cases. The 27 regimes could be reduced to a number of 11 by allotting the hybrid types to the directional or the centered types. As the classification is carried out for the North Sea based on ERA40 mean sea level pressure the different regimes clearly reflect the mean wind characteristics at the stations. Comparing the wind roses for the individual observations leads to the assumption that the regime classification described before fits the requirements to carry out the regime dependent evaluation of the RCMs with a focus on the German and Dutch coast. Trends in the occurrence of the regimes in the winter period of 1961 to 2000 show an increase of the regimes with Western and Southwestern wind directions and a decrease of wind events from Eastern directions in the North Sea. The trend is dominated by the strong positive phase of the NAO especially in the months January to March starting in the beginning of the 1980s. Due to the applied method ERA40 and the RCMs do not necessarily show the same regime at each day. The agreement among the RCM

  7. AN INDEX TO DETECT EXTERNALLY-FORCED DYNAMIC REGIME SHIFTS IN ECOSYSTEMS

    EPA Science Inventory

    The concept of dynamic regimes, and nonlinear shifts between regimes, has gained acceptance and importance in ecosystem research. Regimes in ecosystems are identified as states with characteristic species abundances and abiotic conditions. Ecosystems are maintained in particular ...

  8. USING FISHER INFORMATION TO DETECT GRADUAL AND RAPID ECOSYSTEM REGIME SHIFTS

    EPA Science Inventory

    As ecosystems experience perturbations of varying regularity and intensity, they may either remain within the state space neighborhood of the current regime, or "flip" into the neighborhood of a regime with different characteristics. Although the possibility of such regime shifts...

  9. Dynamically strained ferroelastics: Statistical behavior in elastic and plastic regimes

    NASA Astrophysics Data System (ADS)

    Ding, X.; Lookman, T.; Zhao, Z.; Saxena, A.; Sun, J.; Salje, E. K. H.

    2013-03-01

    The dynamic evolution in ferroelastic crystals under external shear is explored by computer simulation of a two-dimensional model. The characteristic geometrical patterns obtained during shear deformation include dynamic tweed in the elastic regime as well as interpenetrating needle domains in the plastic regime. As a result, the statistics of jerk energy differ in the elastic and plastic regimes. In the elastic regime the distributions of jerk energy are sensitive to temperature and initial configurations. However, in the plastic regime the jerk distributions are rather robust and do not depend much on the details of the configurations, although the geometrical pattern formed after yield is strongly influenced by the elastic constants of the materials and the configurations we used. Specifically, for all geometrical configurations we studied, the energy distribution of jerks shows a power-law noise pattern P(E)˜E-(γ-1)(γ-1=1.3-2) at low temperatures and a Vogel-Fulcher distribution P(E) ˜ exp-(E/E0) at high temperatures. More complex behavior occurs at the crossover between these two regimes where our simulated jerk distributions are very well described by a generalized Poisson distributions P(E)˜E-(γ-1) exp-(E/E0)n with n = 0.4-0.5 and γ-1 ≈ 0 (Kohlrausch law). The geometrical mechanisms for the evolution of the ferroelastic microstructure under strain deformation remain similar in all thermal regimes, whereas their thermodynamic behavior differs dramatically: on heating, from power-law statistics via the Kohlrausch law to a Vogel-Fulcher law. There is hence no simple way to predict the local evolution of the twin microstructure from just the observed statistical behavior of a ferroelastic crystal. It is shown that the Poisson distribution is a convenient way to describe the crossover behavior contained in all the experimental data without recourse to specific scaling functions or temperature-dependent cutoff lengths.

  10. Electronic structure in the crossover regimes in lower dimensional structures

    NASA Astrophysics Data System (ADS)

    Batabyal, R.; Dev, B. N.

    2014-11-01

    Modern growth and fabrication techniques can produce lower dimensional structures in the crossover regimes. Such structures in the crossover regimes can provide tunability of various properties of materials. For example, a zero-dimensional (0-D) structure (quantum dot) evolving towards a 3-D structure (bulk) shows electronic structure, which is neither 0-D-like, nor 3-D-like in the dimensional crossover regime. Within the crossover regime the electronic density of states (DOS) at Fermi level (Ef) keeps on changing as the size of the system changes. DOS at Ef determines many properties of materials, such as electronic specific heat, spin susceptibility, etc. Such properties can be tuned by controlling the size of the system in the crossover regimes. Keeping the importance of DOS at Ef in mind, we determine their values and other details of electronic structure of lower dimensional structures, in the 0-D to 1-D, 1-D to 2-D, 2-D to 3-D, 0-D to 2-D, 0-D to 3-D and 1-D to 3-D crossover regimes, in a simple free electron model. We compare our results with analytical theory and experimental results, wherever available. We also present some results obtained by scanning tunneling spectroscopy measurements on Ag islands on Si(1 1 1) substrates evolving from a 0-D to a 2-D structure. This simple model is quite useful in understanding lower dimensional structures in the crossover regimes and, in general, in nanoscale science. Fabrication of such structures would provide control on materials properties.

  11. Transient response of Salix cuttings to changing water level regimes

    NASA Astrophysics Data System (ADS)

    Gorla, L.; Signarbieux, C.; Turberg, P.; Buttler, A.; Perona, P.

    2015-03-01

    Sustainable water management requires an understanding of the effects of flow regulation on riparian ecomorphological processes. We investigated the transient response of Salix viminalis by examining the effect of water-level regimes on its above-ground and below-ground biomass. Four sets of Salix cuttings, three juveniles (in the first growing season) and one mature (1 year old), were planted and initially grown under the same water-level regime for 1 month. We imposed three different water-level regime treatments representing natural variability, a seasonal trend with no peaks, and minimal flow (characteristic of hydropower) consisting of a constant water level and natural flood peaks. We measured sap flux, stem water potential, photosynthesis, growth parameters, and final root architecture. The mature cuttings were not affected by water table dynamics, but the juveniles displayed causal relationships between the changing water regime, plant growth, and root distribution during a 2 month transient period. For example, a 50% drop in mean sap flux corresponded with a -1.5 Mpa decrease in leaf water potential during the first day after the water regime was changed. In agreement with published field observations, the cuttings concentrated their roots close to the mean water table of the corresponding treatment, allowing survival under altered conditions and resilience to successive stress events. Juvenile development was strongly impacted by the minimum flow regime, leading to more than 60% reduction of both above-ground and below-ground biomass, with respect to the other treatments. Hence, we suggest avoiding minimum flow regimes where Salix restoration is prioritized.

  12. Stochastic Parametrisations and Regime Behaviour of Atmospheric Models

    NASA Astrophysics Data System (ADS)

    Arnold, Hannah; Moroz, Irene; Palmer, Tim

    2013-04-01

    The presence of regimes is a characteristic of non-linear, chaotic systems (Lorenz, 2006). In the atmosphere, regimes emerge as familiar circulation patterns such as the El-Nino Southern Oscillation (ENSO), the North Atlantic Oscillation (NAO) and Scandinavian Blocking events. In recent years there has been much interest in the problem of identifying and studying atmospheric regimes (Solomon et al, 2007). In particular, how do these regimes respond to an external forcing such as anthropogenic greenhouse gas emissions? The importance of regimes in observed trends over the past 50-100 years indicates that in order to predict anthropogenic climate change, our climate models must be able to represent accurately natural circulation regimes, their statistics and variability. It is well established that representing model uncertainty as well as initial condition uncertainty is important for reliable weather forecasts (Palmer, 2001). In particular, stochastic parametrisation schemes have been shown to improve the skill of weather forecast models (e.g. Berner et al., 2009; Frenkel et al., 2012; Palmer et al., 2009). It is possible that including stochastic physics as a representation of model uncertainty could also be beneficial in climate modelling, enabling the simulator to explore larger regions of the climate attractor including other flow regimes. An alternative representation of model uncertainty is a perturbed parameter scheme, whereby physical parameters in subgrid parametrisation schemes are perturbed about their optimal value. Perturbing parameters gives a greater control over the ensemble than multi-model or multiparametrisation ensembles, and has been used as a representation of model uncertainty in climate prediction (Stainforth et al., 2005; Rougier et al., 2009). We investigate the effect of including representations of model uncertainty on the regime behaviour of a simulator. A simple chaotic model of the atmosphere, the Lorenz '96 system, is used to study

  13. Positron acceleration in doughnut wakefields in the blowout regime

    NASA Astrophysics Data System (ADS)

    Vieira, Jorge; Mendonca, Jose; Fonseca, Ricardo; Silva, Luis

    2014-10-01

    Most important plasma acceleration results were reached in the so called bubble or blowout regime. Although ideally suited for electron acceleration, it has been recognized that non-linear regimes are not adequate to accelerate positrons. New configurations enabling positron acceleration in non-linear regimes would therefore open new research paths for future plasma based collider configurations. In this work, we explore, analytically and through 3D OSIRIS simulations, a novel configuration for positron acceleration in strongly non-linear laser wakefield excitation regimes using Laguerre-Gaussian laser drivers to drive doughnut shaped wakefields with positron focusing and accelerating fields. We demonstrate that positron focusing-fields can be up to an order of magnitude larger than electron focusing in the spherical blowout regime. The amplitude of the accelerating fields is similar to the spherical blowout. Simulations demonstrate laser self-guiding and stable positron acceleration until the laser energy has been exhausted to the plasma. Other realisations of the scheme, using two Gaussian laser pulses, will also be explored. FCT Grant No EXPL/FIS-PLA/0834/2012 and European Research Council ERC-2010-AdG Grant No. 267841.

  14. Contrasting convective regimes over the Amazon: Implications for cloud electrification

    NASA Astrophysics Data System (ADS)

    Williams, E.; Rosenfeld, D.; Madden, N.; Gerlach, J.; Gears, N.; Atkinson, L.; Dunnemann, N.; Frostrom, G.; Antonio, M.; Biazon, B.; Camargo, R.; Franca, H.; Gomes, A.; Lima, M.; Machado, R.; Manhaes, S.; Nachtigall, L.; Piva, H.; Quintiliano, W.; Machado, L.; Artaxo, P.; Roberts, G.; Renno, N.; Blakeslee, R.; Bailey, J.; Boccippio, D.; Betts, A.; Wolff, D.; Roy, B.; Halverson, J.; Rickenbach, T.; Fuentes, J.; Avelino, E.

    2002-10-01

    Four distinct meteorological regimes in the Amazon basin have been examined to distinguish the contributions from boundary layer aerosol and convective available potential energy (CAPE) to continental cloud structure and electrification. The lack of distinction in the electrical parameters (peak flash rate, lightning yield per unit rainfall) between aerosol-rich October and aerosol-poor November in the premonsoon regime casts doubt on a primary role for the aerosol in enhancing cloud electrification. Evidence for a substantial role for the aerosol in suppressing warm rain coalescence is identified in the most highly polluted period in early October. The electrical activity in this stage is qualitatively peculiar. During the easterly and westerly wind regimes of the wet season, the lightning yield per unit of rainfall is positively correlated with the aerosol concentration, but the electrical parameters are also correlated with CAPE, with a similar degree of scatter. Here cause and effect are difficult to establish with available observations. This ambiguity extends to the "green ocean" westerly regime, a distinctly maritime regime over a major continent with minimum aerosol concentration, minimum CAPE, and little if any lightning.

  15. Are there multiple scaling regimes in Holocene temperature records?

    NASA Astrophysics Data System (ADS)

    Nilsen, Tine; Rypdal, Kristoffer; Fredriksen, Hege-Beate

    2016-04-01

    The concept of multiple scaling regimes in temperature time series is examined, with emphasis on the question whether or not a monoscaling model with one single scaling regime can be rejected from observation data from the Holocene. A model for internal variability with only one regime is simpler and allows more certain predictions on timescales of centuries when combined with existing knowledge of radiative forcing. Our analysis of spectra from stable isotope ratios from Greenland and Antarctica ice cores shows that a scale break around centennial timescales is evident for the last glacial period, but not for the Holocene. Spectra from a number of late Holocene multiproxy temperature reconstructions, and one from the entire Holocene, have also been analysed, without identifying a significant scale break. Our results indicate that a single-regime scaling climate noise, with some non-scaling fluctuations on a millennial timescale superposed, cannot be rejected as a null model for the Holocene climate. The scale break observed from the glacial time ice-core records is likely caused by the influence of Dansgaard-Oeschger events and teleconnections to the Southern Hemisphere on centennial timescales. From our analysis we conclude that the two-regime model is not sufficiently justified for the Holocene to be used for temperature prediction on centennial timescales.

  16. Defining pyromes and global syndromes of fire regimes.

    PubMed

    Archibald, Sally; Lehmann, Caroline E R; Gómez-Dans, Jose L; Bradstock, Ross A

    2013-04-16

    Fire is a ubiquitous component of the Earth system that is poorly understood. To date, a global-scale understanding of fire is largely limited to the annual extent of burning as detected by satellites. This is problematic because fire is multidimensional, and focus on a single metric belies its complexity and importance within the Earth system. To address this, we identified five key characteristics of fire regimes--size, frequency, intensity, season, and extent--and combined new and existing global datasets to represent each. We assessed how these global fire regime characteristics are related to patterns of climate, vegetation (biomes), and human activity. Cross-correlations demonstrate that only certain combinations of fire characteristics are possible, reflecting fundamental constraints in the types of fire regimes that can exist. A Bayesian clustering algorithm identified five global syndromes of fire regimes, or pyromes. Four pyromes represent distinctions between crown, litter, and grass-fueled fires, and the relationship of these to biomes and climate are not deterministic. Pyromes were partially discriminated on the basis of available moisture and rainfall seasonality. Human impacts also affected pyromes and are globally apparent as the driver of a fifth and unique pyrome that represents human-engineered modifications to fire characteristics. Differing biomes and climates may be represented within the same pyrome, implying that pathways of change in future fire regimes in response to changes in climate and human activity may be difficult to predict. PMID:23559374

  17. THE IMPACT OF THE GLOBAL NUCLEAR SAFETY REGIME IN BRAZIL

    SciTech Connect

    Almeida, C.

    2004-10-06

    A turning point of the world nuclear industry with respect to safety occurred due to the accident at Chernobyl, in 1986. A side from the tragic personal losses and the enormous financial damage, the Chernobyl accident has literally demonstrated that ''a nuclear accident anywhere is an accident everywhere''. The impact was felt immediately by the nuclear industry, with plant cancellations (e.g. Austria), elimination of national programs (e.g. Italy) and general construction delays. However, the reaction of the nuclear industry was equally immediate, which led to the proposal and establishment of a Global Nuclear Safety Regime. This regime is composed of biding international safety conventions, globally accepted safety standard, and a voluntary peer review system. In a previous work, the author has presented in detail the components of this Regime, and briefly discussed its impact in the Brazilian nuclear power organizations, including the Regulatory Body. This work, on the opposite, briefly reviews the Global Nuclear Safety Regime, and concentrates in detail in the discussion of its impact in Brazil, showing how it has produced some changes, and where the peer pressure regime has failed to produce real results.

  18. Early regimes of water capillary flow in slit silica nanochannels.

    PubMed

    Oyarzua, Elton; Walther, Jens H; Mejía, Andrés; Zambrano, Harvey A

    2015-06-14

    Molecular dynamics simulations are conducted to investigate the initial stages of spontaneous imbibition of water in slit silica nanochannels surrounded by air. An analysis is performed for the effects of nanoscopic confinement, initial conditions of liquid uptake and air pressurization on the dynamics of capillary filling. The results indicate that the nanoscale imbibition process is divided into three main flow regimes: an initial regime where the capillary force is balanced only by the inertial drag and characterized by a constant velocity and a plug flow profile. In this regime, the meniscus formation process plays a central role in the imbibition rate. Thereafter, a transitional regime takes place, in which, the force balance has significant contributions from both inertia and viscous friction. Subsequently, a regime wherein viscous forces dominate the capillary force balance is attained. Flow velocity profiles identify the passage from an inviscid flow to a developing Poiseuille flow. Gas density profiles ahead of the capillary front indicate a transient accumulation of air on the advancing meniscus. Furthermore, slower capillary filling rates computed for higher air pressures reveal a significant retarding effect of the gas displaced by the advancing meniscus. PMID:25976034

  19. Ballooning filament growth in the intermediate nonlinear regime

    SciTech Connect

    Zhu, P.; Hegna, C. C.

    2008-09-15

    A theory is developed for the description of ballooning instability in the intermediate nonlinear regime for general magnetic configurations including toroidal systems such as tokamaks. The evolution equations for the plasma filament growth induced by the ballooning instability are derived accounting for the dominant nonlinear effects in an ideal magnetohydrodynamic description. The intermediate nonlinear regime of ballooning modes is defined by the ordering that the plasma filament displacement across the magnetic surface is comparable to the linear mode width in the same direction. In the tokamak case, this regime could become particularly relevant for a transport barrier as the width of the barrier (or pedestal) region approaches the mode width of the dominant ballooning mode. A remarkable feature of the nonlinear ballooning equations is that solutions of the associated local linear ballooning mode equations continue to be valid solutions into the intermediate nonlinear regime. The filament growth equations for the intermediate nonlinear ballooning regime may be applicable to the precursor and precollapse phase of edge localized modes observed in both simulations and experiments.

  20. Decoherence induced by a dynamic spin environment: The universal regime

    SciTech Connect

    Cormick, Cecilia; Paz, Juan Pablo

    2008-02-15

    This paper analyzes the decoherence induced on a single qubit by the interaction with a spin chain with nontrivial internal dynamics (XY-type interactions). The aim of the paper is to study the existence and properties of the so-called universal regime, in which the decoherence time scale becomes independent of the strength of the coupling with the environment. It is shown that, although such a regime does exist, as previously established by Cucchietti et al. [Phys. Rev. A 75, 032337 (2007)], it is not a clear signature of a quantum phase transition in the environment. In fact, this kind of universality also exists in the absence of quantum phase transitions. A universal regime can be related to the existence of an energy scale separation between the Hamiltonian of the environment and the one characterizing the system-environment interaction. The results presented also indicate that in the strong-coupling regime the quantum phase transition does not produce an enhancement of decoherence (as opposed to what happens in the weak-coupling regime)

  1. Aerodynamic Optimization of Supersonic Transport at Near-Sonic Regime

    NASA Astrophysics Data System (ADS)

    Yamazaki, Wataru; Matsushima, Kisa; Obayashi, Shigeru; Nakahashi, Kazuhiro

    Recently, an airplane cruising at near-sonic regime is watched with keen interest. The Sonic-Cruiser, of which the Boeing Company has examined and challenged the development, is the most remarkable case. In this paper, motivated by this trend, aerodynamic performance optimization for an airplane cruising at near-sonic regime is discussed based on CFD simulations. NAL’s experimental supersonic airplane, called NEXST-1, was employed as the baseline model for optimization. Aerodynamic performance was evaluated by solving the Euler equations with the unstructured grid method. It was confirmed that the performance Euler simulation predicted was qualitatively correct. By the evaluation to select a baseline model for optimization, NEXST-1 was accepted as a candidate of sonic plane because of the existence of drag bucket at near-sonic regime. In the optimization, Genetic Algorithm was used with Euler simulations. The objective was to reduce drag keeping lift constant, at the flying speed of Mach 0.98. The optimized result showed L/D improvement not only for near-sonic regime but also for transonic regime. The mechanism of design to reduce drag force was found through the analysis and comparison of the geometries and aerodynamic phenomena about the baseline model and the optimized one.

  2. Burning plasma regime for Fussion-Fission Research Facility

    NASA Astrophysics Data System (ADS)

    Zakharov, Leonid E.

    2010-11-01

    The basic aspects of burning plasma regimes of Fusion-Fission Research Facility (FFRF, R/a=4/1 m/m, Ipl=5 MA, Btor=4-6 T, P^DT=50-100 MW, P^fission=80-4000 MW, 1 m thick blanket), which is suggested as the next step device for Chinese fusion program, are presented. The mission of FFRF is to advance magnetic fusion to the level of a stationary neutron source and to create a technical, scientific, and technology basis for the utilization of high-energy fusion neutrons for the needs of nuclear energy and technology. FFRF will rely as much as possible on ITER design. Thus, the magnetic system, especially TFC, will take advantage of ITER experience. TFC will use the same superconductor as ITER. The plasma regimes will represent an extension of the stationary plasma regimes on HT-7 and EAST tokamaks at ASIPP. Both inductive discharges and stationary non-inductive Lower Hybrid Current Drive (LHCD) will be possible. FFRF strongly relies on new, Lithium Wall Fusion (LiWF) plasma regimes, the development of which will be done on NSTX, HT-7, EAST in parallel with the design work. This regime will eliminate a number of uncertainties, still remaining unresolved in the ITER project. Well controlled, hours long inductive current drive operation at P^DT=50-100 MW is predicted.

  3. Soil magnetic susceptibility reflects soil moisture regimes and the adaptability of tree species to these regimes

    USGS Publications Warehouse

    Wang, J.-S.; Grimley, D.A.; Xu, C.; Dawson, J.O.

    2008-01-01

    Flooded, saturated or poorly drained soils are frequently anaerobic, leading to dissolution of the strongly magnetic minerals, magnetite and maghemite, and a corresponding decrease in soil magnetic susceptibility (MS). In this study of five temperate deciduous forests in east-central Illinois, USA, mean surface soil MS was significantly higher adjacent to upland tree species (31 ?? 10-5 SI) than adjacent to floodplain or lowland tree species (17 ?? 10-5 SI), when comparing regional soils with similar parent material of loessal silt. Although the sites differ in average soil MS for each tree species, the relative order of soil MS means for associated tree species at different locations is similar. Lowland tree species, Celtis occidentalis L., Ulmus americana L., Acer saccharinum L., Carya laciniosa (Michx. f.) Loud., and Fraxinus pennsylvanica Marsh. were associated with the lowest measured soil MS mean values overall and at each site. Tree species' flood tolerance rankings increased significantly, as soil MS values declined, the published rankings having significant correlations with soil MS values for the same species groups. The three published classifications of tree species' flood tolerance were significantly correlated with associated soil MS values at all sites, but most strongly at Allerton Park, the site with the widest range of soil drainage classes and MS values. Using soil MS measurements in forests with soil parent material containing similar initial levels of strongly magnetic minerals can provide a simple, rapid and quantitative method to classify soils according to hydric regimes, including dry conditions, and associated plant composition. Soil MS values thus have the capacity to quantify the continuum of hydric tolerances of tree species and guide tree species selection for reforestation. ?? 2007 Elsevier B.V. All rights reserved.

  4. Laser Wakefield Acceleration in the PetaWatt Regime

    NASA Astrophysics Data System (ADS)

    Katsouleas, Tom; Tsung, Frank; Mori, Warren

    2002-11-01

    Laser wakefield acceleration with multi-terawatt lasers has demonstrated impressive results in experiments around the world-- e.g., energy gains up to 200 MeV in mm-scale gas jets. With the prospects good for a number of petawatt class lasers in the near future, we examine with 2-D and 3-D PIC simulations the potential energy gain and new physics of laser wakefield acceleration in this regime. Prospects for producing GeV electron beams in underdense plasmas will be described. In addition, the differences in physics between terawatt and petawatt regimes will be explored. Preliminary results indicate that there are two acceleration stages in the petawatt regime -- with the early electrons dephasing due to elongation of the laser wake as the laser pump evolves. The later stage produces a long beam of electrons several times the initial plasma wake wavelength with a fairly defined energy in the GeV range.

  5. Coarsening foams robustly reach a self-similar growth regime.

    PubMed

    Lambert, Jérôme; Mokso, Rajmund; Cantat, Isabelle; Cloetens, Peter; Glazier, James A; Graner, François; Delannay, Renaud

    2010-06-18

    Dry liquid foams coarsen like other diphasic systems governed by interfacial energy: gas slowly diffuses across liquid films, resulting in large bubbles growing at the expense of smaller ones which eventually shrink and disappear. A foam scatters light very effectively, preventing direct optical observation of bubble sizes and shapes in large foams. Using high speed x-ray tomography, we have produced 4D movies (i.e., 3D + time) of up to 30,000 bubbles. After a transient regime, the successive images look alike, except that the average bubble size increases as the square root of time: This scaling state is the long sought self-similar growth regime. The bubble size and face-number distributions in this regime are compared with experimental distributions for grains in crystals and with numerical simulations of foams. PMID:20867343

  6. Rough-wall turbulent boundary layers in the transition regime

    NASA Technical Reports Server (NTRS)

    Bandyopadhyay, Promode R.

    1987-01-01

    An experimental investigation of turbulent boundary layers over two-dimensional spanwise groove and three-dimensional sandgrain roughnesses in the transition regime between hydraulically smooth and fully rough conditions is presented. It is found that a self-preserving state can be reached in boundary layers developing over both d-type groove and sandgrain roughnesses, and that the drag of a k-type rough wall can be reduced by lowering the spanwise aspect ratio of the roughness elements. The two roughness Reynolds numbers defining the boundaries of the transition regime of the k-type roughnesses are shown to decrease with increasing roughness-element spanwise aspect ratio, and the upper critical transition Reynolds number is shown to determine the roughness behavior in both the transition and fully rough regime.

  7. Gas flow through rough microchannels in the transition flow regime.

    PubMed

    Deng, Zilong; Chen, Yongping; Shao, Chenxi

    2016-01-01

    A multiple-relaxation-time lattice Boltzmann model of Couette flow is developed to investigate the rarified gas flow through microchannels with roughness characterized by fractal geometry, especially to elucidate the coupled effects of roughness and rarefaction on microscale gas flow in the transition flow regime. The results indicate that the surface roughness effect on gas flow behavior becomes more significant in rarefied gas flow with the increase of Knudsen number. We find the gas flow behavior in the transition flow regime is more sensitive to roughness height than that in the slip flow regime. In particular, the influence of fractal dimension on rarefied gas flow behavior is less significant than roughness height. PMID:26871175

  8. Optimization of electrodynamic acceleration regimes for cylindrical conductors

    NASA Astrophysics Data System (ADS)

    Kalikhman, S. A.

    1985-11-01

    At the present time electromagnetic accelerators which use the action of an impulsive electromagnetic field on a current-carrying conductor appear to be promising devices for the study of high-speed collisions. In the regime using separate sources for the accelerating magnetic field and the current in the conductor being accelerated it is possible to bring cylindrical conductors up to velocities exceeding 12 km/sec [1]. Acceleration regimes have been calculated previously [2] assuming independence of the current density in the conductor from the accelerating magnetic field. However, as analysis of transient electromagnetic processes occurring in the interaction of an impulsive electromagnetic field with a cylindrical conductor shows [3], the maximum current density, limited by heating conditions, depends significantly on the induction of the accelerating magnetic field. In the present study we will analyze regimes for electrodynamic acceleration of cylindrical conductors with consideration of diffusion of both the intrinsic and the external impulsive magnetic field within the conductor.

  9. Shifts in fisheries management: adapting to regime shifts

    PubMed Central

    King, Jacquelynne R.; McFarlane, Gordon A.; Punt, André E.

    2015-01-01

    For many years, fisheries management was based on optimizing yield and maintaining a target biomass, with little regard given to low-frequency environmental forcing. However, this policy was often unsuccessful. In the last two to three decades, fisheries science and management have undergone a shift towards balancing sustainable yield with conservation, with the goal of including ecosystem considerations in decision-making frameworks. Scientific understanding of low-frequency climate–ocean variability, which is manifested as ecosystem regime shifts and states, has led to attempts to incorporate these shifts and states into fisheries assessment and management. To date, operationalizing these attempts to provide tactical advice has met with limited success. We review efforts to incorporate regime shifts and states into the assessment and management of fisheries resources, propose directions for future investigation and outline a potential framework to include regime shifts and changes in ecosystem states into fisheries management.

  10. Nonlinear-optical frequency-doubling metareflector: pulsed regime

    NASA Astrophysics Data System (ADS)

    Popov, A. K.; Myslivets, S. A.

    2016-01-01

    The properties of backward-wave second-harmonic metareflector operating in pulse regime are investigated. It is made of metamaterial which enables phase matching of contra-propagating fundamental and second-harmonic waves. References are given to the works that prove such a possibility. Physical principles underlying differences in the proposed and standard settings as well as between continuous-wave and pulsed regimes are discussed. Pulsed regime is more practicable and has a broader scope of applications. A set of partial differential equations which describe such a reflector with the account for losses are solved numerically. It is shown that unlike second-harmonic generation in standard settings, contra-propagating pulse of second harmonic may become much longer than the incident fundamental one and the difference grows with decrease in the input pulse length as compared to thickness of the metaslab. The revealed properties are important for applications and may manifest themselves beyond the optical wavelength range.

  11. Laser-nucleus interactions: The quasi-adiabatic regime

    NASA Astrophysics Data System (ADS)

    Pálffy, Adriana; Buss, Oliver; Hoefer, Axel; Weidenmüller, Hans A.

    2015-10-01

    The interaction between nuclei and a strong zeptosecond laser pulse with coherent MeV photons is investigated theoretically. We provide a first semiquantitative study of the quasi-adiabatic regime where the photon absorption rate is comparable to the nuclear equilibration rate. In that regime, multiple photon absorption leads to the formation of a compound nucleus in the so-far unexplored regime of excitation energies several hundred MeV above the yrast line. The temporal dynamics of the process is investigated by means of a set of master equations that account for dipole absorption, stimulated dipole emission, neutron decay, and induced fission in a chain of nuclei. That set is solved numerically by means of state-of-the-art matrix exponential methods also used in nuclear fuel burn-up and radioactivity transport calculations. Our quantitative estimates predict the excitation path and range of nuclei reached by neutron decay and provide relevant information for the layout of future experiments.

  12. Living dangerously on borrowed time during slow, unrecognized regime shifts.

    PubMed

    Hughes, Terry P; Linares, Cristina; Dakos, Vasilis; van de Leemput, Ingrid A; van Nes, Egbert H

    2013-03-01

    Regime shifts from one ecological state to another are often portrayed as sudden, dramatic, and difficult to reverse. Yet many regime shifts unfold slowly and imperceptibly after a tipping point has been exceeded, especially at regional and global scales. These long, smooth transitions between equilibrium states are easy to miss, ignore, or deny, confounding management and governance. However, slow responses by ecosystems after transgressing a dangerous threshold also affords borrowed time - a window of opportunity to return to safer conditions before the new state eventually locks in and equilibrates. In this context, the most important challenge is a social one: convincing enough people to confront business-as-usual before time runs out to reverse unwanted regime shifts even after they have already begun. PMID:22995893

  13. Theoretical study of the crossover into hydrodynamic regime in graphene

    NASA Astrophysics Data System (ADS)

    Ho, Derek; Yudhistira, Indra; Hu, Ben Yu-Kuang; Adam, Shaffique

    Experiments on graphene have recently succeeded in entering the hydrodynamic regime, as demonstrated by successful observations of strong violation of Wiedemann-Franz law, the Gurzhi effect and electronic Poiseuille flow. It is known that electronic systems enter the hydrodynamic regime when electron-electron scattering dominates over electron-impurity and electron-phonon scattering. However, a quantitative study of this transition from the Fermi liquid to hydrodynamic regime is still lacking. In view of this, we quantitatively analyze the electron-electron, electron-impurity and electron-phonon scattering rates as a function of temperature, charge doping and disorder (charge puddle) strength. This yields a quantitative understanding of the onset of hydrodynamic electronic behavior in graphene samples. This work is supported by the National Research Foundation of Singapore under its Fellowship program (NRF-NRFF2012-01) and by the Singapore Ministry of Education and Yale-NUS College through Grant No. R-607-265-01312.

  14. Rearrangements in Sheared Disordered Solids: Low and High Pressure Regimes

    NASA Astrophysics Data System (ADS)

    Wijtmans, Sven; van Deen, Merlijn; van Hecke, Martin; Manning, M. Lisa

    We study contact changes and rearrangements in quasistatic shear of disordered jammed packings at a range of pressures. We distinguish rearrangements where particle positions are discontinuous, leading to energy and stress discontinuities, from more frequent network events where contacts change but particle positions remain continuous. Moreover, we introduce two distinct protocols to unambiguously distinguish line reversible, loop reversible and irreversible events. The prevalence and spatial extension of five distinct event types (there are no loop reversible network events) evidence two distinct regimes: a low pressure regime dominated by irreversible extended events and a high pressure regime dominated by reversible localized ones. These trends indicate a crossover in the qualitative nature of plastic behavior in disordered solids near and far from jamming.

  15. Supercurrent in the quantum Hall regime, part II

    NASA Astrophysics Data System (ADS)

    Amet, Francois; Ke, Chung Ting; Borzenets, Ivan; Wang, Jiyingmei; Watanabe, Kenji; Taniguchi, Takashi; Deacon, Russel; Yamamoto, Michihisa; Bomze, Yuriy; Tarucha, Seigo; Finkelstein, Gleb

    A novel promising route for creating topological states and excitations is to combine superconductivity and the quantum Hall effect. Despite this potential, signatures of superconductivity in the quantum Hall regime remain scarce, and a superconducting current through a Landau-quantized two-dimensional electron gas has so far eluded experimental observation. High-mobility graphene/BN heterostructures exhibit the quantum Hall effect at relatively low field and are therefore particularly suitable to study the fate of the Josephson effect in that regime. Here, we report the observation of a superconducting current through graphene at fields as high as 2 Tesla. In that regime, the normal-state resistance is quantized but pockets of superconductivity still persist at small current bias. We will describe their bias and temperature dependence. Magnetic field interference patterns in the supercurrent inform on possible mechanisms mediating this supercurrent.

  16. The Isolated Bubble Regime in Pool Nucleate Boiling

    NASA Technical Reports Server (NTRS)

    Buyevich, Y. A.; Webbon, Bruce W.; Callaway, Robert (Technical Monitor)

    1995-01-01

    We consider an isolated bubble boiling regime in which vapour bubbles are intermittently produced at a prearranged set of nucleation site on an upward facing overheated wall plane. In this boiling regime, the bubbles depart from the wall and move as separate entities. Except in the matter of rise velocity, the bubbles do not interfere and are independent of one another. However, the rise velocity is dependent on bubble volume concentration in the bulk. Heat transfer properties specific to this regime cannot be described without bubble detachment size, and we apply our previously developed dynamic theory of vapour bubble growth and detachment to determine this size. Bubble growth is presumed to be thermally controlled. Two limiting cases of bubble evolution are considered: the one in which buoyancy prevails in promoting bubble detachment and the one in which surface tension prevails. We prove termination of the isolated regime of pool nucleate boiling to result from one of the four possible causes, depending on relevant parameters values. The first cause consists in the fact that the upward flow of rising bubbles hampers the downward liquid flow, and under certain conditions, prevents the liquid from coming to the wall in an amount that would be sufficient to compensate for vapour removal from the wall. The second cause is due to the lateral coalescence of growing bubbles that are attached to their corresponding nucleation sites, with ensuing generation of larger bubbles and extended vapour patches near the wall. The other two causes involve longitudinal coalescence either 1) immediately in the wall vicinity, accompanied by the establishment of the multiple bubble boiling regime, or 2) in the bulk, with the formation of vapour columns. The longitudinal coalescence in the bulk is shown to be the most important cause. The critical wall temperature and the heat flux density associated with isolated bubble regime termination are found to be functions of the physical and

  17. Temporal evolution of flow regimes in urbanizing basins

    NASA Astrophysics Data System (ADS)

    Mejia, A.; Rossel, F.; Gironas, J. A.; Jovanovic, T.

    2014-12-01

    We characterize the temporal evolution of the flow regime of urbanizing basins. By urbanizing basins, we mean basins that have experienced urban growth during their observation period. To represent the flow regime, we use flow duration curves (FDCs). We compute the FDCs using a stochastic model of daily streamflow for urban basins. In this case, the model aids in discerning the influence of key factors (e.g., climate, land use change, stormwater managenment conditions, and the slow and fast properties of the hydrologic response) on streamflow. To implement the model, we first divide the complete observation period of a given urban basin into intervals of equal duration, e.g. 5 years. Subsequently, we apply the model to each interval and this is how we capture the influence of land use changes and climatic fluctuations on the flow regime. We apply this modeling framework to 14 urbanizing basins in the Baltimore-Washington DC region. Results from this application indicate consistent changes in the temporal evolution of the altered flow regimes, which can largely be explained by the progressive redistribution with urban growth of water from slow subsurface runoff and evapotranspiration to fast urban runoff. We also use the modeling framework to determine indicators of ecohydrological alteration for urbanizing basins. The application of these indicators to our study area suggests that the flow regime is sensitive to alterations up to a certain level of urbanization after which sensitivity seems to level off. The flow regime also seems to be relatively more resistant to alterations for both the smaller and larger levels of urbanization considered. In the future, we would like to extend the application of the proposed modeling framework to other metropolitan areas.

  18. Energy regimes and the development of the European Community

    SciTech Connect

    Hadjilambrinos, C.J.

    1993-01-01

    Energy policy has historically played an important role in the development of the European Community (EC). This study examines the reasons for the choice of coal and atomic energy as regimes of integration, analyzes their impact on the institutions and political traditions of the EC, and evaluates their consistency with the principles of democratic governance. Functionalist theory has provided the idealogical foundations for the European Coal and Steel Community and the European Atomic Energy Community. Functionalist theorists advocate technocracy as the means for overcoming the conflicts inherent in traditional political processes. Coal and atomic energy were chosen as regimes of integration because of their technocratic character and the importance attached to them as the dominant energy source of the time and the perceived source of energy abundance in the near future. Energy regimes could not be removed from the political context of national governance. Hard energy regimes, which include coal and atomic energy, are technocratic policies which exclude ordinary citizens from the exercise of power and intensify international conflict. An institutional analysis of the French and Danish electricity regimes demonstrates that their political characteristics are incompatible with the principles of democratic governance. It is also demonstrated that the characteristics of soft energy regimes (e.g., conservation and renewables) are compatible with these principles and are based on cooperation. An analysis of the EC's energy policy demonstrates that a soft energy path represents a concept of integration which distributes decision-making power among various levels of governance. A hard energy path would concentrate power in the hands of a technocratic elite. The pursuit of a soft energy path by the EC would enhance significantly the opportunities for political integration.

  19. Dynamic regimes of local homogeneous population model with time lag

    NASA Astrophysics Data System (ADS)

    Neverova, Galina; Frisman, Efim

    2016-06-01

    We investigated Moran - Ricker model with time lag 1. It is made analytical and numerical study of the model. It is shown there is co-existence of various dynamic regimes under the same values of parameters. The model simultaneously possesses several different limit regimes: stable state, periodic fluctuations, and chaotic attractor. The research results show if present population size substantially depends on population number of previous year then it is observed quasi-periodic oscillations. Fluctuations with period 2 occur when the growth of population size is regulated by density dependence in the current year.

  20. Ocean Wave Energy Regimes of the Circumpolar Coastal Zones

    NASA Astrophysics Data System (ADS)

    Atkinson, D. E.

    2004-12-01

    Ocean wave activity is a major enviromental forcing agent of the ice-rich sediments that comprise large sections of the arctic coastal margins. While it is instructive to possess information about the wind regimes in these regions, direct application to geomorphological and engineering needs requires knowledge of the resultant wave-energy regimes. Wave energy information has been calculated at the regional scale using adjusted reanalysis model windfield data. Calculations at this scale are not designed to account for local-scale coastline/bathymetric irregularities and variability. Results will be presented for the circumpolar zones specified by the Arctic Coastal Dynamics Project.

  1. Strong and moderate nonlinear El Niño regimes

    NASA Astrophysics Data System (ADS)

    Takahashi, Ken; Dewitte, Boris

    2016-03-01

    It has been previously proposed that two El Niño (EN) regimes, strong and moderate, exist but the historical observational record is too short to establish this conclusively. Here, 1200 years of simulations with the GFDL CM2.1 model allowed us to demonstrate their existence in this model and, by showing that the relevant dynamics are also evident in observations, we present a stronger case for their existence in nature. In CM2.1, the robust bimodal probability distribution of equatorial Pacific sea surface temperature (SST) indices during EN peaks provides evidence for the existence of the regimes, which is also supported by a cluster analysis of these same indices. The observations agree with this distribution, with the EN of 1982-1983 and 1997-1998 corresponding to the strong EN regime and all the other observed EN to the moderate regime. The temporal evolution of various indices during the observed strong EN agrees very well with the events in CM2.1, providing further validation of this model as a proxy for nature. The two regimes differ strongly in the magnitude of the eastern Pacific warming but not much in the central Pacific. Observations and model agree in the existence of a finite positive threshold in the SST anomaly above which the zonal wind response to warming is strongly enhanced. Such nonlinearity in the Bjerknes feedback, which increases the growth rate of EN events if they reach sufficiently large amplitude, is very likely the essential mechanism that gives rise to the existence of the two EN regimes. Oceanic nonlinear advection does not appear essential for the onset of strong EN. The threshold nonlinearity could make the EN regimes very sensitive to stochastic forcing. Observations and model agree that the westerly wind stress anomaly in the central equatorial Pacific in late boreal summer has a substantial role determining the EN regime in the following winter and it is suggested that a stochastic component at this time was key for the

  2. Explicit mapping of acoustic regimes for wind instruments

    NASA Astrophysics Data System (ADS)

    Missoum, Samy; Vergez, Christophe; Doc, Jean-Baptiste

    2014-09-01

    This paper proposes a methodology to map the various acoustic regimes of wind instruments. The maps can be generated in a multidimensional space consisting of design, control parameters, and initial conditions. The boundaries of the maps are obtained explicitly in terms of the parameters using a Support Vector Machine (SVM) classifier as well as a dedicated adaptive sampling scheme. The approach is demonstrated on a simplified clarinet model for which several maps are generated based on different criteria. Examples of computation of the probability of occurrence of a specific acoustic regime are also provided. In addition, the approach is demonstrated on a design optimization example for optimal intonation.

  3. Phase contrast and operation regimes in multifrequency atomic force microscopy

    SciTech Connect

    Santos, Sergio

    2014-04-07

    In amplitude modulation atomic force microscopy the attractive and the repulsive force regimes induce phase shifts above and below 90°, respectively. In the more recent multifrequency approach, however, multiple operation regimes have been reported and the theory should be revisited. Here, a theory of phase contrast in multifrequency atomic force microscopy is developed and discussed in terms of energy transfer between modes, energy dissipation and the kinetic energy and energy transfer associated with externally driven harmonics. The single frequency virial that controls the phase shift might undergo transitions in sign while the average force (modal virial) remains positive (negative)

  4. Using Clustering to Establish Climate Regimes from PCM Output

    NASA Technical Reports Server (NTRS)

    Oglesby, Robert; Arnold, James E. (Technical Monitor); Hoffman, Forrest; Hargrove, W. W.; Erickson, D.

    2002-01-01

    A multivariate statistical clustering technique--based on the k-means algorithm of Hartigan has been used to extract patterns of climatological significance from 200 years of general circulation model (GCM) output. Originally developed and implemented on a Beowulf-style parallel computer constructed by Hoffman and Hargrove from surplus commodity desktop PCs, the high performance parallel clustering algorithm was previously applied to the derivation of ecoregions from map stacks of 9 and 25 geophysical conditions or variables for the conterminous U.S. at a resolution of 1 sq km. Now applied both across space and through time, the clustering technique yields temporally-varying climate regimes predicted by transient runs of the Parallel Climate Model (PCM). Using a business-as-usual (BAU) scenario and clustering four fields of significance to the global water cycle (surface temperature, precipitation, soil moisture, and snow depth) from 1871 through 2098, the authors' analysis shows an increase in spatial area occupied by the cluster or climate regime which typifies desert regions (i.e., an increase in desertification) and a decrease in the spatial area occupied by the climate regime typifying winter-time high latitude perma-frost regions. The patterns of cluster changes have been analyzed to understand the predicted variability in the water cycle on global and continental scales. In addition, representative climate regimes were determined by taking three 10-year averages of the fields 100 years apart for northern hemisphere winter (December, January, and February) and summer (June, July, and August). The result is global maps of typical seasonal climate regimes for 100 years in the past, for the present, and for 100 years into the future. Using three-dimensional data or phase space representations of these climate regimes (i.e., the cluster centroids), the authors demonstrate the portion of this phase space occupied by the land surface at all points in space and time

  5. Terahertz Quantum Plasmonics of Nanoslot Antennas in Nonlinear Regime.

    PubMed

    Kim, Joon-Yeon; Kang, Bong Joo; Park, Joohyun; Bahk, Young-Mi; Kim, Won Tae; Rhie, Jiyeah; Jeon, Hyeongtag; Rotermund, Fabian; Kim, Dai-Sik

    2015-10-14

    Quantum tunneling in plasmonic nanostructures has presented an interesting aspect of incorporating quantum mechanics into classical optics. However, the study has been limited to the subnanometer gap regime. Here, we newly extend quantum plasmonics to gap widths well over 1 nm by taking advantage of the low-frequency terahertz regime. Enhanced electric fields of up to 5 V/nm induce tunneling of electrons in different arrays of ring-shaped nanoslot antennas of gap widths from 1.5 to 10 nm, which lead to a significant nonlinear transmission decrease. These observations are consistent with theoretical calculations considering terahertz-funneling-induced electron tunneling across the gap. PMID:26372787

  6. Simple bounds from the perturbative regime of inflation

    SciTech Connect

    Leblond, Louis; Shandera, Sarah E-mail: sarah@phys.columbia.edu

    2008-08-15

    We examine the conditions under which a perturbative expansion around an inflating background is valid. When inflation is driven by a single field with a general sound speed, we find a lower limit on the sound speed related to the amplitude of the inflationary power spectrum. Generalizing the sound speed constraints to include scale dependence can limit the number of e-folds obtained in the perturbative regime and restrict otherwise apparently viable models. We also show that, for models with a low sound speed, eternal inflation cannot occur in the perturbative regime.

  7. Predictive mapping of the natural flow regimes of France

    NASA Astrophysics Data System (ADS)

    Snelder, Ton H.; Lamouroux, Nicolas; Leathwick, John R.; Pella, Hervé; Sauquet, Eric; Shankar, Ude

    2009-06-01

    SummaryHydrologic variability is important in sustaining a variety of ecological processes in streams and rivers. Natural flow regime classifications group streams and rivers that are relatively homogeneous with respect to flow variability and have been promoted as a method of defining units for management of river flows. Although there has been considerable interest in classifying natural flow regimes, there has been less emphasis given to developing accurate methods of extrapolating these classifications to locations without flow data. We developed a method of mapping flow regime classes using boosted regression trees (BRT) that automatically fits non-linear functions and interactions between explanatory variables of flow regimes, both of which can be expected when comparing responses between complex systems such as watersheds. A natural flow regimes classification of continental France was developed from cluster analysis of 157 hydrological indices derived from 763 gauging stations representing unmodified flows. BRT models were used to predict the likelihood of gauging stations belonging to each class based on the watershed characteristics. These models were used to extrapolate the natural flow regime classification to all segments of a national river network. The performance of the BRT models were compared with other methods of assigning locations to flow regime classes, including the use of geographically contiguous regions, linear discriminant analysis (LDA) and classification and regression trees (CART). The "fitted" misclassification rate (associated with model fits) for assignment based on the BRT models was 13% whereas the fitted misclassification rates for geographically contiguous regions, LDA and CART were 52%, 44% and 39% respectively. A "predictive" misclassification rate (calculated for new cases) was estimated for assignments based on the BRT, LDA and CART models using cross validation analysis. For assignment based on the BRT models, the mean

  8. The transition between the niche and neutral regimes in ecology

    PubMed Central

    Fisher, Charles K.; Mehta, Pankaj

    2014-01-01

    An ongoing debate in ecology concerns the impacts of ecological drift and selection on community assembly. Here, we show that there is a transition in diverse ecological communities between a selection-dominated regime (the niche phase) and a drift-dominated regime (the neutral phase). Simulations and analytic arguments show that the niche phase is favored in communities with large population sizes and relatively constant environments, whereas the neutral phase is favored in communities with small population sizes and fluctuating environments. Our results demonstrate how apparently neutral populations may arise even in communities inhabited by species with varying traits. PMID:25157131

  9. Geothermal regimes at Clearlake California: A preliminary review

    SciTech Connect

    Burns, K.L.; Potter, R.M.; Zyvoloski, G.

    1992-08-01

    Three distinct geothermal regimes are inferred in the vicinity of the city of Clearlake, California. The first is a conductive heat flow regime, the second is a fault-controlled hot spring flow of ``magmatic`` fluids, and the third is a resurgent flow of meteoric warm water. The conductive heat flow results in flat, horizontal isotherms. The hot spring generates a localized spike in the isotherms. The advective disturbance carries heat laterally to a fault-line resurgence, lowering the apparent heat flow at the surface.

  10. Ranking Regime and the Future of Vernacular Scholarship

    ERIC Educational Resources Information Center

    Ishikawa, Mayumi

    2014-01-01

    World university rankings and their global popularity present a number of far-reaching impacts for vernacular scholarship. This article employs a multidimensional approach to analyze the ranking regime's threat to local scholarship and knowledge construction through a study of Japanese research universities. First, local conditions that have…

  11. PULSE ENERGIZATION IN THE TUFT CORONA REGIME OF NEGATIVE CORONA

    EPA Science Inventory

    The paper discusses pulse energization in the tuft corona regime of negative corona. Fabric filtration, with integral particle charging and collection in a combined electric and flow field, is sensitive to maldistribution of current among bags energized by one power source, espec...

  12. Political Regime and Human Capital: A Cross-Country Analysis

    ERIC Educational Resources Information Center

    Klomp, Jeroen; de Haan, Jakob

    2013-01-01

    We examine the relationship between different dimensions of the political regime in place and human capital using a two-step structural equation model. In the first step, we employ factor analysis on 16 human capital indicators to construct two new human capital measures (basic and advanced human capital). In the second step, we estimate the…

  13. Defining pyromes and global syndromes of fire regimes

    PubMed Central

    Archibald, Sally; Lehmann, Caroline E. R.; Gómez-Dans, Jose L.; Bradstock, Ross A.

    2013-01-01

    Fire is a ubiquitous component of the Earth system that is poorly understood. To date, a global-scale understanding of fire is largely limited to the annual extent of burning as detected by satellites. This is problematic because fire is multidimensional, and focus on a single metric belies its complexity and importance within the Earth system. To address this, we identified five key characteristics of fire regimes—size, frequency, intensity, season, and extent—and combined new and existing global datasets to represent each. We assessed how these global fire regime characteristics are related to patterns of climate, vegetation (biomes), and human activity. Cross-correlations demonstrate that only certain combinations of fire characteristics are possible, reflecting fundamental constraints in the types of fire regimes that can exist. A Bayesian clustering algorithm identified five global syndromes of fire regimes, or pyromes. Four pyromes represent distinctions between crown, litter, and grass-fueled fires, and the relationship of these to biomes and climate are not deterministic. Pyromes were partially discriminated on the basis of available moisture and rainfall seasonality. Human impacts also affected pyromes and are globally apparent as the driver of a fifth and unique pyrome that represents human-engineered modifications to fire characteristics. Differing biomes and climates may be represented within the same pyrome, implying that pathways of change in future fire regimes in response to changes in climate and human activity may be difficult to predict. PMID:23559374

  14. Search Regimes and the Industrial Dynamics of Science

    ERIC Educational Resources Information Center

    Bonaccorsi, Andrea

    2008-01-01

    The article addresses the issue of dynamics of science, in particular of new sciences born in twentieth century and developed after the Second World War (information science, materials science, life science). The article develops the notion of search regime as an abstract characterization of dynamic patterns, based on three dimensions: the rate of…

  15. Dynamic Financial Constraints: Distinguishing Mechanism Design from Exogenously Incomplete Regimes*

    PubMed Central

    Karaivanov, Alexander; Townsend, Robert M.

    2014-01-01

    We formulate and solve a range of dynamic models of constrained credit/insurance that allow for moral hazard and limited commitment. We compare them to full insurance and exogenously incomplete financial regimes (autarky, saving only, borrowing and lending in a single asset). We develop computational methods based on mechanism design, linear programming, and maximum likelihood to estimate, compare, and statistically test these alternative dynamic models with financial/information constraints. Our methods can use both cross-sectional and panel data and allow for measurement error and unobserved heterogeneity. We estimate the models using data on Thai households running small businesses from two separate samples. We find that in the rural sample, the exogenously incomplete saving only and borrowing regimes provide the best fit using data on consumption, business assets, investment, and income. Family and other networks help consumption smoothing there, as in a moral hazard constrained regime. In contrast, in urban areas, we find mechanism design financial/information regimes that are decidedly less constrained, with the moral hazard model fitting best combined business and consumption data. We perform numerous robustness checks in both the Thai data and in Monte Carlo simulations and compare our maximum likelihood criterion with results from other metrics and data not used in the estimation. A prototypical counterfactual policy evaluation exercise using the estimation results is also featured. PMID:25246710

  16. Redox regime shifts in microbially mediated biogeochemical cycles

    NASA Astrophysics Data System (ADS)

    Bush, T.; Butler, I. B.; Free, A.; Allen, R. J.

    2015-06-01

    Understanding how the Earth's biogeochemical cycles respond to environmental change is a prerequisite for the prediction and mitigation of the effects of anthropogenic perturbations. Microbial populations mediate key steps in these cycles, yet they are often crudely represented in biogeochemical models. Here, we show that microbial population dynamics can qualitatively affect the response of biogeochemical cycles to environmental change. Using simple and generic mathematical models, we find that nutrient limitations on microbial population growth can lead to regime shifts, in which the redox state of a biogeochemical cycle changes dramatically as the availability of a redox-controlling species, such as oxygen or acetate, crosses a threshold (a "tipping point"). These redox regime shifts occur in parameter ranges that are relevant to the present-day sulfur cycle in the natural environment and the present-day nitrogen cycle in eutrophic terrestrial environments. These shifts may also have relevance to iron cycling in the iron-containing Proterozoic and Archean oceans. We show that redox regime shifts also occur in models with physically realistic modifications, such as additional terms, chemical states, or microbial populations. Our work reveals a possible new mechanism by which regime shifts can occur in nutrient-cycling ecosystems and biogeochemical cycles, and highlights the importance of considering microbial population dynamics in models of biogeochemical cycles.

  17. FISHER INFORMATION AND DYNAMIC REGIME CHANGES IN ECOLOGICAL SYSTEMS

    EPA Science Inventory

    Fisher Information and Dynamic Regime Changes in Ecological Systems
    Abstract for the 3rd Conference of the International Society for Ecological Informatics
    Audrey L. Mayer, Christopher W. Pawlowski, and Heriberto Cabezas

    The sustainable nature of particular dynamic...

  18. Microgravity Flow Regime Data: Buoyancy and Mixing Apparatus Effects

    NASA Astrophysics Data System (ADS)

    Shephard, Adam; Best, Frederick

    2010-01-01

    Zero-g two-phase flow data set qualification and flight experiment design have not been standardized and as a result, agreement among researchers has not been reached regarding what experimental conditions adequately approximate those of microgravity. The effects of buoyancy forces and mixing apparatus on the flow regime transitions are presented in this study. The gravity conditions onboard zero-g aircraft are at best 10-3 g which is used to approximate the 10-5 g conditions of microgravity, thus the buoyancy forces present on zero-g aircraft can become significantly large and unrepresentative of microgravity. When buoyancy forces approach those of surface tension forces, buoyancy induced coalescence occurs. When discussing flow regime transitions, these large buoyancy forces lead to flow regime transitions which otherwise would not occur. The buoyancy attributes of the two-phase flow data sets available in the literature are evaluated to determine which data sets exhibit buoyancy induced transitions. Upon comparison of the representative data sets, the affects of different mixing apparatus can be seen in the superficial velocity flow regime maps.

  19. Shear-driven Dynamo Waves in the Fully Nonlinear Regime

    NASA Astrophysics Data System (ADS)

    Pongkitiwanichakul, P.; Nigro, G.; Cattaneo, F.; Tobias, S. M.

    2016-07-01

    Large-scale dynamo action is well understood when the magnetic Reynolds number (Rm) is small, but becomes problematic in the astrophysically relevant large Rm limit since the fluctuations may control the operation of the dynamo, obscuring the large-scale behavior. Recent works by Tobias & Cattaneo demonstrated numerically the existence of large-scale dynamo action in the form of dynamo waves driven by strongly helical turbulence and shear. Their calculations were carried out in the kinematic regime in which the back-reaction of the Lorentz force on the flow is neglected. Here, we have undertaken a systematic extension of their work to the fully nonlinear regime. Helical turbulence and large-scale shear are produced self-consistently by prescribing body forces that, in the kinematic regime, drive flows that resemble the original velocity used by Tobias & Cattaneo. We have found four different solution types in the nonlinear regime for various ratios of the fluctuating velocity to the shear and Reynolds numbers. Some of the solutions are in the form of propagating waves. Some solutions show large-scale helical magnetic structure. Both waves and structures are permanent only when the kinetic helicity is non-zero on average.

  20. Production regimes for Self-Interacting Dark Matter

    NASA Astrophysics Data System (ADS)

    Bernal, Nicolás; Chu, Xiaoyong; Garcia-Cely, Camilo; Hambye, Thomas; Zaldivar, Bryan

    2016-03-01

    In the context of Self-Interacting Dark Matter as a solution for the small-scale structure problems, we consider the possibility that Dark Matter could have been produced without being in thermal equilibrium with the Standard Model bath. We discuss one by one the following various dark matter production regimes of this kind: freeze-in, reannihilation and dark freeze-out. We exemplify how these mechanisms work in the context of the particularly simple Hidden Vector Dark Matter model. In contrast to scenarios where there is thermal equilibrium with the Standard Model bath, we find two regimes which can easily satisfy all the laboratory and cosmological constraints. These are dark freeze-out with 3-to-2 annihilations and freeze-in via a light mediator. In the first regime, different temperatures in the visible and the Dark Matter sectors allow us to avoid the constraints coming from cosmic structure formation as well as the use of non-perturbative couplings to reproduce the observed relic density. For the second regime, different couplings are responsible for Dark Matter relic density and self-interactions, permitting to surpass BBN, X-ray, CMB and direct detection constraints.

  1. Welfare Regimes and Educational Inequality: A Cross-National Exploration

    ERIC Educational Resources Information Center

    Peter, Tracey; Edgerton, Jason D.; Roberts, Lance W.

    2010-01-01

    Research on welfare state regimes and research on educational policy share a common concern for the reduction of social inequality. On one hand, welfare state research is typically designed within a comparative approach where scholars investigate similarities and differences in social institutions across selected countries. On the other hand, the…

  2. Transport processes in magnetically confined plasmas in the nonlinear regime

    SciTech Connect

    Sonnino, Giorgio

    2006-06-15

    A field theory approach to transport phenomena in magnetically confined plasmas is presented. The thermodynamic field theory (TFT), previously developed for treating the generic thermodynamic system out of equilibrium, is applied to plasmas physics. Transport phenomena are treated here as the effect of the field linking the thermodynamic forces with their conjugate flows combined with statistical mechanics. In particular, the Classical and the Pfirsch-Schlueter regimes are analyzed by solving the thermodynamic field equations of the TFT in the weak-field approximation. We found that, the TFT does not correct the expressions of the ionic heat fluxes evaluated by the neoclassical theory in these two regimes. On the other hand, the fluxes of matter and electronic energy (heat flow) is further enhanced in the nonlinear Classical and Pfirsch-Schlueter regimes. These results seem to be in line with the experimental observations. The complete set of the electronic and ionic transport equations in the nonlinear Banana regime, is also reported. A paper showing the comparison between our theoretic results and the experimental observations in the JET machine is currently in preparation.

  3. Nonlinear transport processes in tokamak plasmas. I. The collisional regimes

    SciTech Connect

    Sonnino, Giorgio; Peeters, Philippe

    2008-06-15

    An application of the thermodynamic field theory (TFT) to transport processes in L-mode tokamak plasmas is presented. The nonlinear corrections to the linear ('Onsager') transport coefficients in the collisional regimes are derived. A quite encouraging result is the appearance of an asymmetry between the Pfirsch-Schlueter (P-S) ion and electron transport coefficients: the latter presents a nonlinear correction, which is absent for the ions, and makes the radial electron coefficients much larger than the former. Explicit calculations and comparisons between the neoclassical results and the TFT predictions for Joint European Torus (JET) plasmas are also reported. It is found that the nonlinear electron P-S transport coefficients exceed the values provided by neoclassical theory by a factor that may be of the order 10{sup 2}. The nonlinear classical coefficients exceed the neoclassical ones by a factor that may be of order 2. For JET, the discrepancy between experimental and theoretical results for the electron losses is therefore significantly reduced by a factor 10{sup 2} when the nonlinear contributions are duly taken into account but, there is still a factor of 10{sup 2} to be explained. This is most likely due to turbulence. The expressions of the ion transport coefficients, determined by the neoclassical theory in these two regimes, remain unaltered. The low-collisional regimes, i.e., the plateau and the banana regimes, are analyzed in the second part of this work.

  4. Globalisation, the "Idea of a University" and Its Ethical Regimes

    ERIC Educational Resources Information Center

    Marginson, Simon

    2007-01-01

    This paper sketches the impact of globalisation and internationalisation on the terrain of values and ethics in higher education. The first part of the paper discusses values and ethics in higher education in relation to the "Idea of a University", and identifies the ethical regimes essential to the functioning of HEIs as knowledge-forming…

  5. The two-antidot system in the ballistic regime

    NASA Astrophysics Data System (ADS)

    Sachrajda, A. S.; Gould, C.; Kirczenow, G.; Johnson, B.; Feng, Y.; Kelly, P. J.; Delage, A.

    1998-01-01

    A tunable two-antidot device is studied in the cyclotron-trapping regime. Periodic quantum oscillations are found to be superimposed on the peaks reminiscent of those observed in antidot lattices. The results are compared to quantum and classical simulations and Feynman path integral analysis. Published by Elsevier Science B.V.

  6. Syria: The Consolidation of the Asad Regime, 1970-1975.

    ERIC Educational Resources Information Center

    Olson, Robert W.

    1982-01-01

    Up to 1975-76, Syria's Hafiz al-Asad was successful in consolidating his power, securing the maintenance of his regime, and broadening his base of political power. His system started weakening in 1975 due to increased opposition stemming from Syria's intervention in the Lebanese civil war. (AM)

  7. Towards an Orderly Exit Regime in English Higher Education

    ERIC Educational Resources Information Center

    Fisher, Andrew

    2016-01-01

    In a competitive market, the exit of those suppliers who cannot offer an attractive product at an attractive price is seen as desirable. However, the consequences for consumers when their own supplier leaves the market in an unplanned or disorderly way may be undesirable. Exit regimes exist in regulated markets to ensure that consumers are not…

  8. Accessing Imagined Communities and Reinscribing Regimes of Truth

    ERIC Educational Resources Information Center

    Carroll, Sherrie; Motha, Suhanthie; Price, Jeremy N.

    2008-01-01

    In this article, we explore the complex and nebulous terrain between two theoretical concepts, imagined communities (Norton, 2000, 2001), that is, individuals' imagined affiliations with certain groups, and regimes of truth (Foucault, 1980), dominant images inscribed and reinscribed into individual consciousness until they become normative. Using…

  9. Local-field correction in the strong-coupling regime

    SciTech Connect

    Hien, Tran Minh; Dung, Ho Trung; Welsch, Dirk-Gunnar

    2011-04-15

    The influence of the local-field correction on the strong atom-field coupling regime are investigated using the real-cavity model. The atom is positioned at the center of a multilayer sphere. Three types of mirrors are considered: perfectly reflecting, Lorentz band gap, and Bragg-distributed ones, with special emphasis on experimental practicability. In particular, the influence of the local field on the spectral resonance lines, the Rabi oscillation frequency and decay rate, and the condition indicating the occurrence of the strong-coupling regime are studied in detail. It is shown that the local-field correction gives rise to a structureless plateau in the density of states of the electromagnetic field. The level of the plateau rises with increasing material density and/or absorption, which may eventually destroy the strong-coupling regime. The effect of the local field is especially pronounced at high-material densities due to direct energy transfer from the guest atom to the medium. At lower material density and/or absorption, variation of the material density does not seem to affect much the strong-coupling regime, except for a small shift in the resonance frequency.

  10. 31 CFR 576.305 - Former Iraqi regime.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Former Iraqi regime. 576.305 Section 576.305 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY IRAQ STABILIZATION AND INSURGENCY SANCTIONS REGULATIONS General Definitions § 576.305 Former...

  11. Electron Transport Dominated Regimes in Alcator C-Mod

    NASA Astrophysics Data System (ADS)

    Porkolab, M.; Dorris, J.; Bonoli, P. T.; Ennever, P.; Fiore, C.; Greenwald, M.; Hubbard, A.; Ma, Y.; Reinke, M. L.; Rice, J.; Rost, J.; Tsujii, N.; Lin, L.; Candy, J.; Waltz, R.; Diamond, P.; Lee, C. J.

    2010-11-01

    In ohmically heated low density plasmas where τE ne, the so-called neo-Alcator regime, TRANSP results indicate that χi<< χe, while nonlinear gyrokinetic analysis for the measured profiles predicts the opposite inequality [1]. This regime is of great interest for transport studies since Ti < Te, and the electron and ion transport channels can be separated and studied separately. At the same time, measurements of turbulent fluctuations with Phase Contrast Imaging diagnostic (PCI) indicated reasonable agreement with GYRO predictions at frequencies 80-250 kHz, corresponding to core ITG turbulence. The turbulent spectrum at lower frequencies could not be identified since the PCI technique does not allow separation of the core plasma fluctuations from those at the edge. Here we present measurements and analysis from a more extensive set of plasma regimes than previously. Of particular current interest is the role of electron drift wave turbulence driven by ohmic electron drift, U [2], since in these low density regimes U/Cs <= 6, and experimentally we find that the global confinement τE Cs/U where Cs = (Te/mi)^1/2. [1] L. Lin, Invited talk, APS-DPP, 11, 2009, Atlanta, GA. [2] C.J. Lee, P. Diamond, M. Porkolab, presented at TTF workshop, 2010.

  12. Dynamics of liquid drops coalescing in the inertial regime.

    PubMed

    Sprittles, James E; Shikhmurzaev, Yulii D

    2014-06-01

    We examine the dynamics of two coalescing liquid drops in the "inertial regime," where the effects of viscosity are negligible and the propagation of the front of the bridge connecting the drops can be considered as "local." The solution fully computed in the framework of classical fluid mechanics allows this regime to be identified, and the accuracy of the approximating scaling laws proposed to describe the propagation of the bridge to be established. It is shown that the scaling law known for this regime has a very limited region of accuracy, and, as a result, in describing experimental data it has frequently been applied outside its limits of applicability. The origin of the scaling law's shortcoming appears to be the fact that it accounts for the capillary pressure due only to the longitudinal curvature of the free surface as the driving force for the process. To address this deficiency, the scaling law is extended to account for both the longitudinal and azimuthal curvatures at the bridge front, which, fortuitously, still results in an explicit analytic expression for the front's propagation speed. This expression is shown to offer an excellent approximation for both the fully computed solution and for experimental data from a range of flow configurations for a remarkably large proportion of the coalescence process. The derived formula allows one to predict the speed at which drops coalesce for the duration of the inertial regime, which should be useful for the analysis of experimental data. PMID:25019880

  13. Dynamics of liquid drops coalescing in the inertial regime

    NASA Astrophysics Data System (ADS)

    Sprittles, James E.; Shikhmurzaev, Yulii D.

    2014-06-01

    We examine the dynamics of two coalescing liquid drops in the "inertial regime," where the effects of viscosity are negligible and the propagation of the front of the bridge connecting the drops can be considered as "local." The solution fully computed in the framework of classical fluid mechanics allows this regime to be identified, and the accuracy of the approximating scaling laws proposed to describe the propagation of the bridge to be established. It is shown that the scaling law known for this regime has a very limited region of accuracy, and, as a result, in describing experimental data it has frequently been applied outside its limits of applicability. The origin of the scaling law's shortcoming appears to be the fact that it accounts for the capillary pressure due only to the longitudinal curvature of the free surface as the driving force for the process. To address this deficiency, the scaling law is extended to account for both the longitudinal and azimuthal curvatures at the bridge front, which, fortuitously, still results in an explicit analytic expression for the front's propagation speed. This expression is shown to offer an excellent approximation for both the fully computed solution and for experimental data from a range of flow configurations for a remarkably large proportion of the coalescence process. The derived formula allows one to predict the speed at which drops coalesce for the duration of the inertial regime, which should be useful for the analysis of experimental data.

  14. Regimes of flow induced vibration for tandem, tethered cylinders

    NASA Astrophysics Data System (ADS)

    Nave, Gary; Stremler, Mark

    2015-11-01

    In the wake of a bluff body, there are a number of dynamic response regimes that exist for a trailing bluff body depending on spacing, structural restoring forces, and the mass-damping parameter m* ζ . For tandem cylinders with low values of m* ζ , two such regimes of motion are Gap Flow Switching and Wake Induced Vibration. In this study, we consider the dynamics of a single degree-of-freedom rigid cylinder in the wake of another in these regimes for a variety of center-to-center cylinder spacings (3-5 diameters) and Reynolds numbers (4,000-11,000). The system consists of a trailing cylinder constrained to a circular arc around a fixed leading cylinder, which, for small angle displacements, bears a close resemblance to the transversely oscillating cylinders found more commonly in existing literature. From experiments on this system, we compare and contrast the dynamic response within these two regimes. Our results show sustained oscillations in the absence of a structural restoring force in all cases, providing experimental support for the wake stiffness assumption, which is based on the mean lift toward the center line of flow.

  15. Two regimes in the regularity of sunspot number

    SciTech Connect

    Shapoval, A.; Shnirman, M.

    2013-12-20

    Sunspot numbers WN display quasi-periodical variations that undergo regime changes. These irregularities could indicate a chaotic system and be measured by Lyapunov exponents. We define a functional λ (an 'irregularity index') that is close to the (maximal) Lyapunov exponent for dynamical systems and well defined for series with a random component: this allows one to work with sunspot numbers. We compute λ for the daily WN from 1850 to 2012 within 4 yr sliding windows: λ exhibit sharp maxima at solar minima and secondary maxima at solar maxima. This pattern is reflected in the ratio R of the amplitudes of the main versus secondary peaks. Two regimes have alternated in the past 150 yr, R1 from 1850 to 1915 (large λ and R values) and R2 from 1935 to 2005 (shrinking difference between main and secondary maxima, R values between 1 and 2). We build an autoregressive model consisting of Poisson noise plus an 11 yr cycle and compute its irregularity index. The transition from R1 to R2 can be reproduced by strengthening the autocorrelation a of the model series. The features of the two regimes are stable for model and WN with respect to embedding dimension and delay. Near the time of the last solar minimum (∼2008), the irregularity index exhibits a peak similar to the peaks observed before 1915. This might signal a regime change back from R2 to R1 and the onset of a significant decrease of solar activity.

  16. Root response of Jerusalem artichoke genotypes to different water regimes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to determine effects of drought on selected root growth parameters and develop relationships between root parameters and tuber yield for selected Jerusalem artichoke (JA) genotypes. Three water regimes (Field capacity, 50% available water (AW) and 25% AW) and five JA...

  17. ECOLOGICALLY-RELEVANT QUANTIFICATION OF STREAMFLOW REGIMES IN WESTERN STREAMS

    EPA Science Inventory

    This report describes the rationale for and application of a protocol for estimation of ecologically-relevant streamflow metrics that quantify streamflow regime for ungaged sites subject to a range of human impact. The analysis presented here is focused on sites sampled by the U....

  18. The Harrison Diffusion Kinetics Regimes in Solute Grain Boundary Diffusion

    SciTech Connect

    Belova, Irina; Fiedler, T; Kulkarni, Nagraj S; Murch, Prof. Graeme

    2012-01-01

    Knowledge of the limits of the principal Harrison kinetics regimes (Type-A, B and C) for grain boundary diffusion is very important for the correct analysis of the depth profiles in a tracer diffusion experiment. These regimes for self-diffusion have been extensively studied in the past by making use of the phenomenological Lattice Monte Carlo (LMC) method with the result that the limits are now well established. The relationship of those self-diffusion limits to the corresponding ones for solute diffusion in the presence of solute segregation to the grain boundaries remains unclear. In the present study, the influence of solute segregation on the limits is investigated with the LMC method for the well-known parallel grain boundary slab model by showing the equivalence of two diffusion models. It is shown which diffusion parameters are useful for identifying the limits of the Harrison kinetics regimes for solute grain boundary diffusion. It is also shown how the measured segregation factor from the diffusion experiment in the Harrison Type-B kinetics regime may differ from the global segregation factor.

  19. Welfare Attitudes and Social Expenditure: Do Regimes Shape Public Opinion?

    ERIC Educational Resources Information Center

    Jakobsen, Tor Georg

    2011-01-01

    This article examines the link between regime types, social expenditure, and welfare attitudes. By employing data on 19 countries taken from the World Values Survey, the main aim is to see to what degree the institutions of a country affect the attitudes of its citizens. According to Esping-Andersen ("The three worlds of welfare capitalism".…

  20. Connectivity, regime shifts and the resilience of coral reefs

    NASA Astrophysics Data System (ADS)

    Elmhirst, Toby; Connolly, Sean R.; Hughes, Terry P.

    2009-12-01

    Connectivity of larvae among metapopulations in open marine systems can be a double-edged sword, allowing for the colonization and replenishment of both desirable and undesirable elements of interacting species-rich assemblages. This article studies the effect of recruitment by coral and macroalgae on the resilience of grazed reef ecosystems. In particular, we focus on how larval connectivity affects regime shifts between alternative assemblages that are dominated either by corals or by macroalgae. Using a model with bistability dynamics, we show that recruitment of coral larvae erodes the resilience of a macroalgae-dominated ecosystem when grazing is high, but has negligible effect when grazing is low. Conversely, recruitment by macroalgae erodes the resilience of a coral-dominated ecosystem when grazing is low, leading to a regime shift to macroalgae. Thus, spillover of coral recruits from highly protected areas will not restore coral cover or prevent flips to macroalgae in the surrounding seascape if grazing levels in these areas are depleted, but may be pivotal for re-building coral populations if grazing is high. Fishing restrictions and the re-introduction of herbivores should therefore be a prime conservation objective for preventing undesirable regime shifts. Connectivity by some components of coral reef assemblages (e.g., macroalgae, pathogens, crown-of-thorns starfish) may be detrimental to sustaining reefs, especially where overfishing and other drivers have eroded their resilience, making them more vulnerable to a regime shift.

  1. Consequences of more extreme precipitation regimes for terrestrial ecosystems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Amplification of the hydrological cycle, as a consequence of global warming, will be manifest not only by alterations in total annual precipitation, but also through more extreme precipitation regimes characterized by fewer, but larger rainfall events and more severe intervening drought periods. Ba...

  2. Civic Capacity in Educational Reform Efforts: Emerging and Established Regimes in Rust Belt Cities

    ERIC Educational Resources Information Center

    Mitra, Dana L.; Frick, William C.

    2011-01-01

    Using urban regime theory, the article examines two Rust Belt cities that tried to break the cycle of social reproduction in their communities by reforming their schools. The article contributes to the development of urban regime theory by comparing an "emerging" regime to an "established" regime. The comparison highlights the interdependent…

  3. TRMM Observations of Convective Regimes in the Amazon

    NASA Technical Reports Server (NTRS)

    Petersen, W. A.; Nesbitt, S. W.; Blakeslee, Robert J.; Hein, P.; Cifelli, R.; Rutledge, S. A.; Arnold, James E. (Technical Monitor)

    2001-01-01

    This study utilizes TRMM satellite precipitation radar, lightning imaging sensor, and passive microwave imager data together with ground-based lightning data to investigate the vertical structure, lightning, and rainfall characteristics of Amazonian and central South American convection for three separate wet-seasons. These characteristics are partitioned as a function of 850 mb zonal wind direction, motivated by observations collected during the six-week TRMM-LBA field campaign. The TRMM-LBA field campaign observations suggest that systematic variations in Amazonian convective vertical structure, lightning, and rainfall are all linked to bimodal variations in the low-level zonal wind (e.g., easterly and westerly regimes). The more spatially and temporally comprehensive TRMM dataset used in this study extends the TRMM-LBA observations by examining regime variability in Amazonian and South American convective structure over a continental scale domain. On a continental-scale, patterns of east and west regime 850 mb winds combined with LIS lightning flash densities suggest the presence of synoptic-scale controls (e.g., intrusion of extratropical frontal systems and interaction with the SACZ) on regional-scale variability in convective vertical structure. TRMM PR, TMI and ground-based lightning data suggest that regional variability in wet-season convective structure is most evident over the southern Amazon, Mato Grosso, Altiplano, southern Brazil, and eastern coastal regions of central and southern South America. Convective vertical structure, rain fall rates, and lightning activity are all more pronounced during easterly (westerly) regimes over the southern Amazon and Mato Grosso (Altiplano, and southern Brazil). Importantly, when considered with case-study results from TRMM-LBA, the systematic differences in convective structure that occur as a function of regime suggest that associated regime-differences may exist in the vertical distribution of diabatic heating

  4. Classification of river regimes: A context for hydroecology

    USGS Publications Warehouse

    Osterkamp, W.R.; Friedman, J.M.

    2000-01-01

    Over the past 30 years, ecologists have demostrated the importance of flow and temperature as primary variables in driving running water, riparian and floodplain ecosystems. As it is important to assess the size and timing of discharge variations in relation to those in temperature, a method is proposed that uses multivariate techniques to separately classify annual discharge and temperature regimes according to their 'shape' and 'magnitude', and which then combines the classifications. This paper: (i) describes a generally applicable method; (ii) tests the method by applying it to riparian systems on four British rivers using a 20-year record (1977-97) of flow and air temperature: (iii) proposes a hydroecological interpretation of the classification; (iv) considers the degree to which the methodology might provide information to support the design of ecologically acceptable flow regimes. 'Regimes' are defined for discharge and air temperature using monthly mean data. The results of applying the classification procedure to four British rivers indicates that the 'typical' regimes for each of the four catchments are composite features produced by a small number of clearly defined annual types that reflect interannual variability in hydroclimatological conditions. Annual discharge patterns are dominated by three 'shape' classes (accounting for 94% of the station years: class A, early (November) peak; class B, intermediate (December-January) peak; and class C, late (March) peak) and one 'magnitude' class (70% of the station years fall into class 3, intermediate), with two subordinate 'magnitude' classes: low-flow years (18%) and high flow years (12%). For air temperature, annual patterns are classified evenly into three 'shape' and four 'magnitude' classes. It is argued that this variety of flow-temperature patterns is important for sustaining ecosystem integrity and for establishing benchmark flow regimes and associated frequencies to aid river management. Copyright

  5. Towards a dynamical understanding of flood regime changes

    NASA Astrophysics Data System (ADS)

    Perdigão, Rui A. P.; Hall, Julia; Blöschl, Günter

    2014-05-01

    Flood regime changes can be analysed and statistically attributed by disentangling a whole network of driving processes and interactions, from ocean-atmospheric processes to land-related changes. However, such approaches do not provide dynamical dependence necessary to tackle changes in the process network itself, namely variations in the causal hierarchy. The present study addresses this issue by introducing a cross-platform mathematical framework aimed at the retrieval, analysis and modelling of dynamical features from hydrological datasets representing continuous and discrete physical processes of different nature. In doing so, a unified approach is devised for a more systematic and consistent analysis of hydrological processes and their interactions irrespective of whether they are governed by continuous, semi-discrete or fully discrete dynamical systems. The novel methodological developments are then used to investigate emerging behaviours in climate and hydrological regimes not resolved by any of the individual classes of dynamical systems. In the present study we are particularly interested in addressing flood regime changes, including seasonality changes and shifts between flood rich and flood poor periods. The new framework reveals that these changes may be associated to physical features emerging from nonlinear interactions in low-order dynamical models involving climate and land-related drivers. The spatiotemporal variability and nonlinear twists of the causal relationships are also investigated, noting that drivers of flood change have different impacts on different spatial and temporal scales. In this regard, multilateral interactions, feedbacks and structural causal changes are found among oceanic, atmospheric and land-related processes, and their combined influence is seen to explain flood change patterns that could not be explained by linear superposition of individual drivers or static causal hierarchies. In conclusion, investigating dynamical

  6. Detecting regime shifts in the ocean: Data considerations [review article

    NASA Astrophysics Data System (ADS)

    deYoung, B.; Harris, R.; Alheit, J.; Beaugrand, G.; Mantua, N.; Shannon, L.

    2004-02-01

    We review observational data sets that have been used to detect regime shifts in the ocean. Through exploration of data time series we develop a definition of a regime shift from a pragmatic perspective, in which a shift is considered as an abrupt change from a quantifiable ecosystem state. We conclude that such changes represent a restructuring of the ecosystem state in some substantial sense that persists for long enough that a new quasi-equilibrium state can be observed. The abruptness of the shift is relative to the life-scale or the reproductive time-scale of the higher predators that are influenced by the shift. In general, the event-forcing is external to the biological ecosystem, usually the physical climate system, but we also identify shifts that can be ascribed to anthropogenic forcing, in our examples fishing. This pragmatic definition allows for several different types of regime shift ranging from simple biogeographic shifts to non-linear state changes. In practice it is quite difficult to determine whether observed changes in an oceanic ecosystem are primarily spatial or temporally regulated. The determination of ecosystem state remains an unresolved, and imprecise, oceanographic problem. We review observations and interpretation from several different oceanic regions as examples to illustrate this pragmatic definition of a regime shift: the Northeast Pacific, the Northwest and Northeast Atlantic, and Eastern Boundary Currents. For each region, different types of data (biological and physical) are available for differing periods of time, and we conclude, with varying degrees of certainty, whether a regime shift is in fact detectable in the data.

  7. The human dimension of fire regimes on Earth.

    PubMed

    Bowman, David M J S; Balch, Jennifer; Artaxo, Paulo; Bond, William J; Cochrane, Mark A; D'Antonio, Carla M; Defries, Ruth; Johnston, Fay H; Keeley, Jon E; Krawchuk, Meg A; Kull, Christian A; Mack, Michelle; Moritz, Max A; Pyne, Stephen; Roos, Christopher I; Scott, Andrew C; Sodhi, Navjot S; Swetnam, Thomas W; Whittaker, Robert

    2011-12-01

    Humans and their ancestors are unique in being a fire-making species, but 'natural' (i.e. independent of humans) fires have an ancient, geological history on Earth. Natural fires have influenced biological evolution and global biogeochemical cycles, making fire integral to the functioning of some biomes. Globally, debate rages about the impact on ecosystems of prehistoric human-set fires, with views ranging from catastrophic to negligible. Understanding of the diversity of human fire regimes on Earth in the past, present and future remains rudimentary. It remains uncertain how humans have caused a departure from 'natural' background levels that vary with climate change. Available evidence shows that modern humans can increase or decrease background levels of natural fire activity by clearing forests, promoting grazing, dispersing plants, altering ignition patterns and actively suppressing fires, thereby causing substantial ecosystem changes and loss of biodiversity. Some of these contemporary fire regimes cause substantial economic disruptions owing to the destruction of infrastructure, degradation of ecosystem services, loss of life, and smoke-related health effects. These episodic disasters help frame negative public attitudes towards landscape fires, despite the need for burning to sustain some ecosystems. Greenhouse gas-induced warming and changes in the hydrological cycle may increase the occurrence of large, severe fires, with potentially significant feedbacks to the Earth system. Improved understanding of human fire regimes demands: (1) better data on past and current human influences on fire regimes to enable global comparative analyses, (2) a greater understanding of different cultural traditions of landscape burning and their positive and negative social, economic and ecological effects, and (3) more realistic representations of anthropogenic fire in global vegetation and climate change models. We provide an historical framework to promote understanding

  8. Early warning of atmospheric regime transitions using transfer operators

    NASA Astrophysics Data System (ADS)

    Tantet, Alexis; Dijkstra, Henk

    2015-04-01

    The existence of persistent midlatitude atmospheric regimes, such as blocking events, with time scales larger than 5-10 days and indications of preferred transition paths between them motivates the development of early-warning indicators of regime transitions. Here, we use a barotropic model of the northern midlatitudes winter flow to study such meta-stable regimes. We look at estimates of transfer operators acting on densities evolving on a reduced phase space spanned by the first Empirical Orthogonal Functions of the streamfunction and develop an early-warning indicator of zonal to blocked flow transition. The study of the spectra of transfer operators estimated for different lags reveals a multi-level structure in the flow as well as the effect of memory on the reduced dynamics due to past interactions between the resolved and unresolved variables. The slowest motions in the reduced phase space are thereby found to have time scales larger than 8 days and to behave as Markovian for larger lags. These motions are associated with meta-stable regimes and their transitions and can be detected as almost-invariant sets of the transfer operator. The early-warning indicator is based on the action on an initial density of products of the transfer operators estimated for sufficiently long lags, making use of the semi-group property of these operators and shows relatively good Peirce skill score. From the energy budget of the model, we are able to explain the meta-stability of the regimes and the existence of preferred transition paths as the manifestation of barotropic instability. Finally, even though the model is highly simplified, the skill of the early warning indicator is promising, suggesting that the transfer operator approach can be used in parallel to an operational deterministic model for stochastic prediction or to assess forecast uncertainty.

  9. Quantifying Floods of a Flood Regime in Space and Time

    NASA Astrophysics Data System (ADS)

    Whipple, A. A.; Fleenor, W. E.; Viers, J. H.

    2015-12-01

    Interaction between a flood hydrograph and floodplain topography results in spatially and temporally variable conditions important for ecosystem process and function. Individual floods whose frequency and dimensionality comprise a river's flood regime contribute to that variability and in aggregate are important drivers of floodplain ecosystems. Across the globe, water management actions, land use changes as well as hydroclimatic change associated with climate change have profoundly affected natural flood regimes and their expression within the floodplain landscape. Homogenization of riverscapes has degraded once highly diverse and productive ecosystems. Improved understanding of the range of flood conditions and spatial variability within floodplains, or hydrospatial conditions, is needed to improve water and land management and restoration activities to support the variable conditions under which species adapted. This research quantifies the flood regime of a floodplain site undergoing restoration through levee breaching along the lower Cosumnes River of California. One of the few lowland alluvial rivers of California with an unregulated hydrograph and regular floodplain connectivity, the Cosumnes River provides a useful test-bed for exploring river-floodplain interaction. Representative floods of the Cosumnes River are selected from previously-established flood types comprising the flood regime and applied within a 2D hydrodynamic model representing the floodplain restoration site. Model output is analyzed and synthesized to quantify and compare conditions in space and time, using metrics such as depth and velocity. This research establishes methods for quantifying a flood regime's floodplain inundation characteristics, illustrates the role of flow variability and landscape complexity in producing heterogeneous floodplain conditions, and suggests important implications for managing more ecologically functional floodplains.

  10. Image quality assessment in the low quality regime

    NASA Astrophysics Data System (ADS)

    Pinto, Guilherme O.; Hemami, Sheila S.

    2012-03-01

    Traditionally, image quality estimators have been designed and optimized to operate over the entire quality range of images in a database, from very low quality to visually lossless. However, if quality estimation is limited to a smaller quality range, their performances drop dramatically, and many image applications only operate over such a smaller range. This paper is concerned with one such range, the low-quality regime, which is defined as the interval of perceived quality scores where there exists a linear relationship between the perceived quality scores and the perceived utility scores and exists at the low-quality end of image databases. Using this definition, this paper describes a subjective experiment to determine the low-quality regime for databases of distorted images that include perceived quality scores but not perceived utility scores, such as CSIQ and LIVE. The performances of several image utility and quality estimators are evaluated in the low-quality regime, indicating that utility estimators can be successfully applied to estimate perceived quality in this regime. Omission of the lowestfrequency image content is shown to be crucial to the performances of both kinds of estimators. Additionally, this paper establishes an upper-bound for the performances of quality estimators in the LQR, using a family of quality estimators based on VIF. The resulting optimal quality estimator indicates that estimating quality in the low-quality regime is robust to exact frequency pooling weights, and that near-optimal performance can be achieved by a variety of estimators providing that they substantially emphasize the appropriate frequency content.

  11. Vegetation management with fire modifies peatland soil thermal regime.

    PubMed

    Brown, Lee E; Palmer, Sheila M; Johnston, Kerrylyn; Holden, Joseph

    2015-05-01

    Vegetation removal with fire can alter the thermal regime of the land surface, leading to significant changes in biogeochemistry (e.g. carbon cycling) and soil hydrology. In the UK, large expanses of carbon-rich upland environments are managed to encourage increased abundance of red grouse (Lagopus lagopus scotica) by rotational burning of shrub vegetation. To date, though, there has not been any consideration of whether prescribed vegetation burning on peatlands modifies the thermal regime of the soil mass in the years after fire. In this study thermal regime was monitored across 12 burned peatland soil plots over an 18-month period, with the aim of (i) quantifying thermal dynamics between burned plots of different ages (from <2 to 15 + years post burning), and (ii) developing statistical models to determine the magnitude of thermal change caused by vegetation management. Compared to plots burned 15 + years previously, plots recently burned (<2-4 years) showed higher mean, maximum and range of soil temperatures, and lower minima. Statistical models (generalised least square regression) were developed to predict daily mean and maximum soil temperature in plots burned 15 + years prior to the study. These models were then applied to predict temperatures of plots burned 2, 4 and 7 years previously, with significant deviations from predicted temperatures illustrating the magnitude of burn management effects. Temperatures measured in soil plots burned <2 years previously showed significant statistical disturbances from model predictions, reaching +6.2 °C for daily mean temperatures and +19.6 °C for daily maxima. Soil temperatures in plots burnt 7 years previously were most similar to plots burned 15 + years ago indicating the potential for soil temperatures to recover as vegetation regrows. Our findings that prescribed peatland vegetation burning alters soil thermal regime should provide an impetus for further research to understand the consequences of thermal regime

  12. The human dimension of fire regimes on Earth

    USGS Publications Warehouse

    Bowman, David M.J.S.; Balch, Jennifer; Artaxo, Paulo; Bond, William J.; Cochrane, Mark A.; D'Antonio, Carla M.; DeFries, Ruth; Johnston, Fay H.; Keeley, Jon E.; Krawchuk, Meg A.; Kull, Christian A.; Michelle, Mack; Moritz, Max A.; Pyne, Stephen; Roos, Christopher I.; Scott, Andrew C.; Sodhi, Navjot S.; Swetnam, Thomas W.

    2011-01-01

    Humans and their ancestors are unique in being a fire-making species, but 'natural' (i.e. independent of humans) fires have an ancient, geological history on Earth. Natural fires have influenced biological evolution and global biogeochemical cycles, making fire integral to the functioning of some biomes. Globally, debate rages about the impact on ecosystems of prehistoric human-set fires, with views ranging from catastrophic to negligible. Understanding of the diversity of human fire regimes on Earth in the past, present and future remains rudimentary. It remains uncertain how humans have caused a departure from 'natural' background levels that vary with climate change. Available evidence shows that modern humans can increase or decrease background levels of natural fire activity by clearing forests, promoting grazing, dispersing plants, altering ignition patterns and actively suppressing fires, thereby causing substantial ecosystem changes and loss of biodiversity. Some of these contemporary fire regimes cause substantial economic disruptions owing to the destruction of infrastructure, degradation of ecosystem services, loss of life, and smoke-related health effects. These episodic disasters help frame negative public attitudes towards landscape fires, despite the need for burning to sustain some ecosystems. Greenhouse gas-induced warming and changes in the hydrological cycle may increase the occurrence of large, severe fires, with potentially significant feedbacks to the Earth system. Improved understanding of human fire regimes demands: (1) better data on past and current human influences on fire regimes to enable global comparative analyses, (2) a greater understanding of different cultural traditions of landscape burning and their positive and negative social, economic and ecological effects, and (3) more realistic representations of anthropogenic fire in global vegetation and climate change models. We provide an historical framework to promote understanding

  13. Climate change and future fire regimes: Examples from California

    USGS Publications Warehouse

    Keeley, Jon E.; Syphard, Alexandra D.

    2016-01-01

    Climate and weather have long been noted as playing key roles in wildfire activity, and global warming is expected to exacerbate fire impacts on natural and urban ecosystems. Predicting future fire regimes requires an understanding of how temperature and precipitation interact to control fire activity. Inevitably this requires historical analyses that relate annual burning to climate variation. Fuel structure plays a critical role in determining which climatic parameters are most influential on fire activity, and here, by focusing on the diversity of ecosystems in California, we illustrate some principles that need to be recognized in predicting future fire regimes. Spatial scale of analysis is important in that large heterogeneous landscapes may not fully capture accurate relationships between climate and fires. Within climatically homogeneous subregions, montane forested landscapes show strong relationships between annual fluctuations in temperature and precipitation with area burned; however, this is strongly seasonal dependent; e.g., winter temperatures have very little or no effect but spring and summer temperatures are critical. Climate models that predict future seasonal temperature changes are needed to improve fire regime projections. Climate does not appear to be a major determinant of fire activity on all landscapes. Lower elevations and lower latitudes show little or no increase in fire activity with hotter and drier conditions. On these landscapes climate is not usually limiting to fires but these vegetation types are ignition-limited. Moreover, because they are closely juxtaposed with human habitations, fire regimes are more strongly controlled by other direct anthropogenic impacts. Predicting future fire regimes is not rocket science; it is far more complicated than that. Climate change is not relevant to some landscapes, but where climate is relevant, the relationship will change due to direct climate effects on vegetation trajectories, as well as

  14. Numerical simulation of flows from free molecular regime to continuum regime by a DVM with streaming and collision processes

    NASA Astrophysics Data System (ADS)

    Yang, L. M.; Shu, C.; Wu, J.; Wang, Y.

    2016-02-01

    A discrete velocity method (DVM) with streaming and collision processes is presented in this work for simulation of flows from free molecular regime to continuum regime. The present scheme can be considered as a semi-Lagrangian like scheme. At first, we follow the conventional DVM to discretize the phase velocity space by a number of discrete velocities. Then, for each discrete velocity, the kinetic equation with BGK-Shakhov model is integrated in space and time within one time step. As a result, a simple algebraic formulation can be obtained, and its solution can be marched in time by the streaming and collision processes. However, differently from the conventional semi-Lagrangian scheme, the present scheme uses the MUSCL approach with van Albada limiter in the process of reconstructing the distribution function at the surrounding points of the cell center, and the transport distance is controlled in order to avoid extrapolation. This makes the present scheme be capable of simulating the hypersonic rarefied flows. In addition, as compared to the unified gas kinetic scheme (UGKS), the present scheme is simpler and easier for implementation. Thus, the computational efficiency can be improved accordingly. To validate the proposed numerical scheme, test examples from free molecular regime to continuum regime are simulated. Numerical results showed that the present scheme can predict the flow properties accurately even for hypersonic rarefied flows.

  15. Disorder-assisted quantum transport in suboptimal decoherence regimes

    PubMed Central

    Novo, Leonardo; Mohseni, Masoud; Omar, Yasser

    2016-01-01

    We investigate quantum transport in binary tree structures and in hypercubes for the disordered Frenkel-exciton Hamiltonian under pure dephasing noise. We compute the energy transport efficiency as a function of disorder and dephasing rates. We demonstrate that dephasing improves transport efficiency not only in the disordered case, but also in the ordered one. The maximal transport efficiency is obtained when the dephasing timescale matches the hopping timescale, which represent new examples of the Goldilocks principle at the quantum scale. Remarkably, we find that in weak dephasing regimes, away from optimal levels of environmental fluctuations, the average effect of increasing disorder is to improve the transport efficiency until an optimal value for disorder is reached. Our results suggest that rational design of the site energies statistical distributions could lead to better performances in transport systems at nanoscale when their natural environments are far from the optimal dephasing regime. PMID:26726133

  16. Couette flow regimes with heat transfer in rarefied gas

    SciTech Connect

    Abramov, A. A. Butkovskii, A. V.

    2013-06-15

    Based on numerical solution of the Boltzmann equation by direct statistic simulation, the Couette flow with heat transfer is studied in a broad range of ratios of plate temperatures and Mach numbers of a moving plate. Flow regime classification by the form of the dependences of the energy flux and friction stress on the Knudsen number Kn is proposed. These dependences can be simultaneously monotonic and nonmonotonic and have maxima. Situations are possible in which the dependence of the energy flux transferred to a plate on Kn has a minimum, while the dependence of the friction stress is monotonic or even has a maximum. Also, regimes exist in which the dependence of the energy flux on Kn has a maximum, while the dependence of the friction stress is monotonic, and vice versa.

  17. The single-channel regime of transport through random media

    PubMed Central

    Peña, A.; Girschik, A.; Libisch, F.; Rotter, S.; Chabanov, A. A.

    2014-01-01

    The propagation of light through samples with random inhomogeneities can be described by way of transmission eigenchannels, which connect incoming and outgoing external propagating modes. Although the detailed structure of a disordered sample can generally not be fully specified, these transmission eigenchannels can nonetheless be successfully controlled and used for focusing and imaging light through random media. Here we demonstrate that in deeply localized quasi-1D systems, the single dominant transmission eigenchannel is formed by an individual Anderson-localized mode or by a ‘necklace state’. In this single-channel regime, the disordered sample can be treated as an effective 1D system with a renormalized localization length, coupled through all the external modes to its surroundings. Using statistical criteria of the single-channel regime and pulsed excitations of the disordered samples allows us to identify long-lived localized modes and short-lived necklace states at long and short time delays, respectively. PMID:24663028

  18. Disorder-assisted quantum transport in suboptimal decoherence regimes

    NASA Astrophysics Data System (ADS)

    Novo, Leonardo; Mohseni, Masoud; Omar, Yasser

    2016-01-01

    We investigate quantum transport in binary tree structures and in hypercubes for the disordered Frenkel-exciton Hamiltonian under pure dephasing noise. We compute the energy transport efficiency as a function of disorder and dephasing rates. We demonstrate that dephasing improves transport efficiency not only in the disordered case, but also in the ordered one. The maximal transport efficiency is obtained when the dephasing timescale matches the hopping timescale, which represent new examples of the Goldilocks principle at the quantum scale. Remarkably, we find that in weak dephasing regimes, away from optimal levels of environmental fluctuations, the average effect of increasing disorder is to improve the transport efficiency until an optimal value for disorder is reached. Our results suggest that rational design of the site energies statistical distributions could lead to better performances in transport systems at nanoscale when their natural environments are far from the optimal dephasing regime.

  19. Quarks with Twisted Boundary Conditions in the Epsilon Regime

    SciTech Connect

    Thomas Mehen; Brian C. Tiburzi

    2005-05-01

    We study the effects of twisted boundary conditions on the quark fields in the epsilon regime of chiral perturbation theory. We consider the SU(2){sub L} x SU(2){sub R} chiral theory with non-degenerate quarks and the SU(3){sub L} x SU(3){sub R} chiral theory with massless up and down quarks and massive strange quarks. The partition function and condensate are derived for each theory. Because flavor-neutral Goldstone bosons are unaffected by twisted boundary conditions chiral symmetry is still restored in finite volumes. The dependence of the condensate on the twisting parameters can be used to extract the pion decay constant from simulations in the epsilon regime. The relative contribution to the partition function from sectors of different topological charge is numerically insensitive to twisted boundary conditions.

  20. Nondiffusive transport regimes for suprathermal ions in turbulent plasmas.

    PubMed

    Bovet, A; Fasoli, A; Ricci, P; Furno, I; Gustafson, K

    2015-04-01

    The understanding of the transport of suprathermal ions in the presence of turbulence is important for fusion plasmas in the burning regime that will characterize reactors, and for space plasmas to understand the physics of particle acceleration. Here, three-dimensional measurements of a suprathermal ion beam in the toroidal plasma device TORPEX are presented. These measurements demonstrate, in a turbulent plasma, the existence of subdiffusive and superdiffusive transport of suprathermal ions, depending on their energy. This result stems from the unprecedented combination of uniquely resolved measurements and first-principles numerical simulations that reveal the mechanisms responsible for the nondiffusive transport. The transport regime is determined by the interaction of the suprathermal ion orbits with the turbulent plasma dynamics, and is strongly affected by the ratio of the suprathermal ion energy to the background plasma temperature. PMID:25974432

  1. Mechanical surface treatment of steel-Optimization parameters of regime

    NASA Astrophysics Data System (ADS)

    Laouar, L.; Hamadache, H.; Saad, S.; Bouchelaghem, A.; Mekhilef, S.

    2009-11-01

    Mechanical treatment process by superficial plastic deformation is employed for finished mechanical part surface. It introduces structural modifications that offer to basic material new properties witch give a high quality of physical and geometrical on superficial layers. This study focuses on the application of burnishing treatment (ball burnishing) on XC48 steel and parameters optimisation of treatment regime. Three important parameters were considered: burnishing force ' Py', burnishing feed 'f' and ball radius 'r'. An empirical model has been developed to illustrate the relationship between these parameters and superficial layer characteristics defined by surface roughness ' Ra' and superficial hardness ' Hv'. A program was developed in order to determine the optimum treatment regimes for each characteristic.

  2. The case for regime-based water quality standards

    USGS Publications Warehouse

    Poole, Geoffrey C.; Dunham, J.B.; Keenan, D.M.; Sauter, S.T.; McCullough, D.A.; Mebane, Christopher; Lockwood, Jeffrey C.; Essig, Don A.; Hicks, Mark P.; Sturdevant, Debra J.; Materna, E.J.; Spalding, M.; Risley, John; Deppman, Marianne

    2004-01-01

    Conventional water quality standards have been successful in reducing the concentration of toxic substances in US waters. However, conventional standards are based on simple thresholds and are therefore poorly structured to address human-caused imbalances in dynamic, natural water quality parameters, such as nutrients, sediment, and temperature. A more applicable type of water quality standarda??a a??regime standarda??a??would describe desirable distributions of conditions over space and time within a stream network. By mandating the protection and restoration of the aquatic ecosystem dynamics that are required to support beneficial uses in streams, well-designed regime standards would facilitate more effective strategies for management of natural water quality parameters.

  3. Giant magnetoresistance in the variable-range hopping regime

    SciTech Connect

    Ioffe, L. B.; Spivak, B. Z.

    2013-09-15

    We predict the universal power-law dependence of the localization length on the magnetic field in the strongly localized regime. This effect is due to the orbital quantum interference. Physically, this dependence shows up in an anomalously large negative magnetoresistance in the hopping regime. The reason for the universality is that the problem of the electron tunneling in a random media belongs to the same universality class as the directed polymer problem even in the case of wave functions of random sign. We present numerical simulations that prove this conjecture. We discuss the existing experiments that show anomalously large magnetoresistance. We also discuss the role of localized spins in real materials and the spin polarizing effect of the magnetic field.

  4. Brittle failure mode plots for compressional and extensional tectonic regimes

    NASA Astrophysics Data System (ADS)

    Sibson, Richard H.

    1998-05-01

    Equations governing different macroscopic modes of brittle rock failure (extensional fracturing, extensional-shear fracturing, compressional shear failure and reshear of existing faults) can be represented on plots of differential stress vs effective vertical stress for a set of material properties. Such plots can be constructed for different tectonic regimes and correlated to depth for particular fluid pressure conditions, allowing easy evaluation of the physical controls on brittle rock failure, and ready comparison of the fields occupied by the three failure modes in different tectonic settings. They emphasize the relative ease, in terms of differential stress and fluid-pressure levels, of deforming a rock mass by brittle fracturing and faulting in extensional regimes compared with compressional. Aside from their relevance to general structural mechanics, these generic failure plots have wide-ranging application to understanding the initial development and progressive evolution of fault-fracture systems, both in sedimentary basins and as hosting structures for hydrothermal mineralization in different tectonic settings.

  5. Critical Josephson current in the dynamical Coulomb blockade regime

    NASA Astrophysics Data System (ADS)

    Jäck, Berthold; Eltschka, Matthias; Assig, Maximilian; Etzkorn, Markus; Ast, Christian R.; Kern, Klaus

    2016-01-01

    The current-voltage characteristics of a voltage-biased Josephson junction in the low conductance regime of an ultra-low temperature scanning tunneling microscope (STM) is dominated by sequential charge tunneling. Using P (E ) theory we show that the Josephson coupling energy, experimentally determined in this regime, is in good agreement with the critical current I0 calculated from the Ambegaokar-Baratoff formula. In this way, we can determine the critical current values of a Josephson junction in an STM. Furthermore, we experimentally determine a range of validity for P (E ) theory, which is in accordance with theoretical predictions. In this way, we establish an optimal parameter range, in which Josephson STM can be performed.

  6. Spectator effects during Leptogenesis in the strong washout regime

    SciTech Connect

    Garbrecht, Björn; Schwaller, Pedro E-mail: pedro.schwaller@cern.ch

    2014-10-01

    By including spectator fields into the Boltzmann equations for Leptogenesis, we show that partially equilibrated spectator interactions can have a significant impact on the freeze-out value of the asymmetry in the strong washout regime. The final asymmetry is typically increased, since partially equilibrated spectators ''hide'' a part of the asymmetry from washout. We study examples with leptonic and non-leptonic spectator processes, assuming thermal initial conditions, and find up to 50% enhanced asymmetries compared to the limit of fully equilibrated spectators. Together with a comprehensive overview of the equilibration temperatures for various Standard Model processes, the numerical results indicate the ranges when the limiting cases of either fully equilibrated or negligible spectator fields are applicable and when they are not. Our findings also indicate an increased sensitivity to initial conditions and finite density corrections even in the strong washout regime.

  7. Regimes of strong light-matter coupling under incoherent excitation

    SciTech Connect

    Valle, E. del; Laussy, F. P.

    2011-10-15

    We study a two-level system (atom, superconducting qubit, or quantum dot) strongly coupled to a single photonic mode of a cavity, in the presence of incoherent pumping and including detuning and dephasing. This system displays a striking quantum-to-classical transition. On the grounds of several approximations that reproduce to various degrees exact results obtained numerically, we separate five regimes of operations, that we term ''linear,''''quantum,''''lasing,''''quenching,'' and ''thermal.'' In the fully quantized picture, the lasing regime arises as a condensation of dressed states and manifests itself as a Mollow triplet structure in the direct emitter photoluminescence spectrum, which embeds fundamental features of the full-field quantization description of light-matter interaction.

  8. A new climate regime in northeast pacific ecosystems

    NASA Astrophysics Data System (ADS)

    Peterson, William T.; Schwing, Franklin B.

    2003-09-01

    Following a strong El Niño, the climate of the North Pacific underwent a rapid and striking transition in late 1998. Upwelling-favorable winds strengthened over the California Current (CC), and winds weakened in the Gulf of Alaska (GOA). Coastal waters of the CC and GOA cooled by several degrees, and the Pacific Decadal Oscillation (PDO) reversed sign and remained negative through summer 2002. Zooplankton biomass in the northern CC doubled and switched from warm to cold water species dominance, coho and chinook salmon stocks rebounded, and anchovy and osmeriids increased. Persistent changes in atmosphere and upper ocean fields and ecosystem structure suggest a climate regime shift has occurred, similar (opposite) to shifts observed in 1947 (1925 and 1976). If the 1998 regime shift in the northern CC is completely analogous to earlier shifts, then ecosystem structure should have changed in the GOA. Recent surveys indicate this ecosystem has transformed as well.

  9. A Cold-Strontium Laser in the Superradiant Crossover Regime

    NASA Astrophysics Data System (ADS)

    Norcia, Matthew; Thompson, James

    2016-05-01

    We demonstrate and study a laser based on the 7.5 kHz linewidth dipole forbidden 3 P1 to 1 S0 transition in laser-cooled and tightly confined 88 Sr. We can operate this laser in the bad-cavity or superradiant regime, where coherence is primarily stored in the atoms, or continuously tune to the more conventional good-cavity regime, where coherence is primarily stored in the light field. We show that the cold-atom gain medium can be repumped to achieve quasi steady-state lasing. We also demonstrate up to an order of magnitude suppression in the sensitivity of laser frequency to changes in cavity length, verifying a key feature of proposed narrow linewidth lasers based on dipole-forbidden transitions in alkaline earth atoms.

  10. Computer Language Choices in Arms Control and Nonproliferation Regimes

    SciTech Connect

    White, G K

    2005-06-10

    The U.S. and Russian Federation continue to make substantive progress in the arms control and nonproliferation transparency regimes. We are moving toward an implementation choice for creating radiation measurement systems that are transparent in both their design and in their implementation. In particular, the choice of a programming language to write software for such regimes can decrease or significantly increase the costs of authentication. In this paper, we compare procedural languages with object-oriented languages. In particular, we examine the C and C++ languages; we compare language features, code generation, implementation details, and executable size and demonstrate how these attributes aid or hinder authentication and backdoor threats. We show that programs in lower level, procedural languages are more easily authenticated than are object-oriented ones. Potential tools and methods for authentication are covered. Possible mitigations are suggested for using object-oriented programming languages.

  11. Biphoton spectroscopy in a strongly nondegenerate regime of SPDC

    NASA Astrophysics Data System (ADS)

    Kalachev, A. A.; Kalashnikov, D. A.; Kalinkin, A. A.; Mitrofanova, T. G.; Shkalikov, A. V.; Samartsev, V. V.

    2008-08-01

    The absorption spectrum of Cr3+ ions in Al2O3 crystal in the range from 691 nm to 697 nm was measured at the room temperature using the biphoton light generated by nondegenerate spontaneous parametric down-conversion of the He-Cd laser radiation (325 nm) in the LiIO3 crystal. The spectrum of the sample was measured by counting the coincidences when signal photons go through the impurity crystal, whilst the wavelength of the idler photons is resolved by a monochromator. A strongly nondegenerate regime of SPDC, when the difference in frequencies of correlated photons exceeds significantly their spectral width, was used in the biphoton spectroscopy for the first time. Such a regime allows one to obtain an absorption spectrum by measuring the wavelength in a completely different spectral range.

  12. Giant magnetoresistance in the variable-range hopping regime

    NASA Astrophysics Data System (ADS)

    Ioffe, L. B.; Spivak, B. Z.

    2013-09-01

    We predict the universal power-law dependence of the localization length on the magnetic field in the strongly localized regime. This effect is due to the orbital quantum interference. Physically, this dependence shows up in an anomalously large negative magnetoresistance in the hopping regime. The reason for the universality is that the problem of the electron tunneling in a random media belongs to the same universality class as the directed polymer problem even in the case of wave functions of random sign. We present numerical simulations that prove this conjecture. We discuss the existing experiments that show anomalously large magnetoresistance. We also discuss the role of localized spins in real materials and the spin polarizing effect of the magnetic field.

  13. The superradiant instability regime of the spinning Kerr black hole

    NASA Astrophysics Data System (ADS)

    Hod, Shahar

    2016-07-01

    Spinning Kerr black holes are known to be superradiantly unstable to massive scalar perturbations. We here prove that the instability regime of the composed Kerr-black-hole-massive-scalar-field system is bounded from above by the dimensionless inequality Mμ < m ṡ√{2 (1 + γ)/(1 -√1 -γ2 ) -γ2 4γ2 , where { μ , m } are respectively the proper mass and azimuthal harmonic index of the scalar field and γ ≡r- /r+ is the dimensionless ratio between the horizon radii of the black hole. It is further shown that this analytically derived upper bound on the superradiant instability regime of the spinning Kerr black hole agrees with recent numerical computations of the instability resonance spectrum.

  14. On the heat capacity of elements in WMD regime

    NASA Astrophysics Data System (ADS)

    Hamel, Sebatien

    2014-03-01

    Once thought to get simpler with increasing pressure, elemental systems have been discovered to exhibit complex structures and multiple phases at high pressure. For carbon, QMD/PIMC simulations have been performed and the results are guiding alternative modelling methodologies for constructing a carbon equation-of-state covering the warm dense matter regime. One of the main results of our new QMD/PIMC carbon equation of state is that the decay of the ion-thermal specific heat with temperature is much faster than previously expected. An important question is whether this is only found in carbon and not other element. In this presentation, based on QMD calculations for several elements, we explore trends in the transition from condensed matter to warm dense matter regime.

  15. Narrowband biphoton generation in the group delay regime

    NASA Astrophysics Data System (ADS)

    Zhao, Luwei; Su, Yumian; Du, Shengwang

    2016-03-01

    We study narrowband biphoton generation from spontaneous four-wave mixing with electromagnetically induced transparency in a laser-cooled atomic ensemble. We compare two formalisms in the interaction and Heisenberg pictures and find that they agree in the low-gain regime but disagree in the high-gain regime. We extend both formalisms to account for the nonuniformity of the atomic density and the driving laser fields. We find that for a fixed optical depth and a weak and far-detuned pump laser beam, the two-photon waveform is independent of the atomic density distribution. However, the spatial profiles of the two driving laser beams have significant effects on the biphoton temporal waveform. We predict that waveform shaping in the time domain can be achieved by controlling the spatial profiles of the driving laser fields.

  16. Modeling of drop breakup in the bag breakup regime

    NASA Astrophysics Data System (ADS)

    Wang, C.; Chang, S.; Wu, H.; Xu, J.

    2014-04-01

    Several analytic models for predicting the drop deformation and breakup have been developed over the last three decades, but modeling drop breakup in the bag-type regime is less reported. In this Letter, a breakup model has been proposed to predict the drop deformation length and breakup time in the bag-type breakup regime in a more accurate manner. In the present model, the drop deformation which is approximately as the displacement of the centre of mass (c. m.) along the axis located at the centre of the drop, and the movement of c. m. is obtained by solving the pressure balance equation. The effects of the drop deformation on the drop external aerodynamic force are considered in this model. Drop breakup occurs when the deformation length reaches the maximum value and the maximum deformation length is a function of Weber number. The performance and applicability of the proposed breakup model are tested against the published experimental data.

  17. A new plasma regime in the distant geomagnetic tail

    NASA Technical Reports Server (NTRS)

    Hardy, D. A.; Hills, H. K.; Freeman, J. W.

    1975-01-01

    Observations are reported of an extensive region of low-energy plasma particles (LEP) flowing antisunward along the ordered field lines in the lobes of the geomagnetic tail at lunar distances. The flow was detected by three suprathermal ion detectors deployed on the lunar surface during the Apollo 12, 14, and 15 missions. This particle regime is found to be similar to the 'boundary layer' and 'plasma mantle' observed at smaller geocentric distances and to an interior flow region parallel to the magnetopause in the dayside magnetosphere. It is located exterior to the plasma sheet across essentially the entire tail and adjacent to the magnetopause on both the dawn and dusk sides of the magnetosphere. Variations in the integral flux, temperature, and number density are described. It is suggested that this flow and the three similar regimes are simply connected along the inner surface of the magnetopause and are, in fact, the same phenomenon.

  18. Optically Pumped NMR in the Fractional Quantum Hall Regime

    NASA Astrophysics Data System (ADS)

    Barrett, S. E.; Kuzma, N. N.; Khandelwal, P.; Pfeiffer, L. N.; West, K. W.

    1998-03-01

    Optically Pumped Nuclear Magnetic Resonance measurements are a local probe of the electron spin degree of freedom in n-type GaAs quantum wells.(S.E.Barrett et al.,Phys.Rev.Lett.72),1368(1994).^, footnote S. E. Barrett et al., Phys. Rev. Lett. 74, 5112 (1995)^, footnote R. Tycko et al., Science 268, 1460 (1995). We have recently shown that this OPNMR technique can be carried out in fields up to B=12 Tesla and temperatures down to T=0.3 K, making this technique a viable new probe of the Fractional Quantum Hall regime. We will discuss our latest measurements in these conditions, and compare our new results with previous measurements and the existing theoretical models for this regime.

  19. When do jammed sphere packings have a valid linear regime?

    NASA Astrophysics Data System (ADS)

    Goodrich, Carl; Liu, Andrea; Nagel, Sidney

    2014-03-01

    The physics of jamming can be studied in its purest form in packings of soft spheres at zero temperature. One of the successes of this approach is that bulk material properties, such as the elastic moduli or density of normal modes, can be predicted solely from the distance of the system to the jamming transition. Such properties are both defined and measured in the linear-response regime. It is thus tacitly assumed that the harmonic approximation to the local energy landscape can capture the meaningful physics, and it is therefore essential to delineate when this assumption is valid. We will examine the regime of validity of the harmonic approximation in jammed sphere packings as a function of system size and density. We will also discuss the crossover from linear response of the zero-temperature jammed solid to thermal behavior at nonzero temperatures.

  20. Scalable quantum memory in the ultrastrong coupling regime.

    PubMed

    Kyaw, T H; Felicetti, S; Romero, G; Solano, E; Kwek, L-C

    2015-01-01

    Circuit quantum electrodynamics, consisting of superconducting artificial atoms coupled to on-chip resonators, represents a prime candidate to implement the scalable quantum computing architecture because of the presence of good tunability and controllability. Furthermore, recent advances have pushed the technology towards the ultrastrong coupling regime of light-matter interaction, where the qubit-resonator coupling strength reaches a considerable fraction of the resonator frequency. Here, we propose a qubit-resonator system operating in that regime, as a quantum memory device and study the storage and retrieval of quantum information in and from the Z2 parity-protected quantum memory, within experimentally feasible schemes. We are also convinced that our proposal might pave a way to realize a scalable quantum random-access memory due to its fast storage and readout performances. PMID:25727251