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Sample records for focal adhesion kinase-related

  1. Interleukin-2 induces beta2-integrin-dependent signal transduction involving the focal adhesion kinase-related protein B (fakB)

    DEFF Research Database (Denmark)

    Brockdorff, J; Kanner, S B; Nielsen, M

    1998-01-01

    B-tyrosine phosphorylation in beta2-integrin-positive T cells. In parallel experiments, IL-2 does not induce or augment tyrosine phosphorylation of p125(FAK). In conclusion, our data indicate that IL-2 induces beta2-integrin-dependent signal transduction events involving the tyrosine kinase substrate fakB.......beta2 integrin molecules are involved in a multitude of cellular events, including adhesion, migration, and cellular activation. Here, we studied the influence of beta2 integrins on interleukin-2 (IL-2)-mediated signal transduction in human CD4(+) T cell lines obtained from healthy donors...... experiments indicate that the IL-2-induced 125-kDa phosphotyrosine protein is the focal adhesion kinase-related protein B (fakB). Thus, IL-2 induces strong tyrosine phosphorylation of fakB in beta2-integrin-positive but not in beta2-integrin-negative T cells, and CD18 mAb selectively blocks IL-2-induced fak...

  2. Interleukin-2 induces beta2-integrin-dependent signal transduction involving the focal adhesion kinase-related protein B (fakB)

    DEFF Research Database (Denmark)

    Brockdorff, J; Kanner, S B; Nielsen, M;

    1998-01-01

    experiments indicate that the IL-2-induced 125-kDa phosphotyrosine protein is the focal adhesion kinase-related protein B (fakB). Thus, IL-2 induces strong tyrosine phosphorylation of fakB in beta2-integrin-positive but not in beta2-integrin-negative T cells, and CD18 mAb selectively blocks IL-2-induced fakB......-tyrosine phosphorylation in beta2-integrin-positive T cells. In parallel experiments, IL-2 does not induce or augment tyrosine phosphorylation of p125(FAK). In conclusion, our data indicate that IL-2 induces beta2-integrin-dependent signal transduction events involving the tyrosine kinase substrate fakB....... and a leukocyte adhesion deficiency (LAD) patient. We show that IL-2 induces tyrosine phosphorylation of a 125-kDa protein and homotypic adhesion in beta2 integrin (CD18)-positive but not in beta2-integrin-negative T cells. EDTA, an inhibitor of integrin adhesion, blocks IL-2-induced tyrosine phosphorylation...

  3. Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation.

    OpenAIRE

    1996-01-01

    It has been proposed that the focal adhesion kinase (FAK) mediates focal adhesion formation through tyrosine phosphorylation during cell adhesion. We investigated the role of FAK in focal adhesion structure and function. Loading cells with a glutathione-S-transferase fusion protein (GST-Cterm) containing the FAK focal adhesion targeting sequence, but not the kinase domain, decreased the association of endogenous FAK with focal adhesions. This displacement of endogenous FAK in both BALB/c 3T3 ...

  4. Regulation of Cell Adhesion Strength by Peripheral Focal Adhesion Distribution

    OpenAIRE

    2011-01-01

    Cell adhesion to extracellular matrices is a tightly regulated process that involves the complex interplay between biochemical and mechanical events at the cell-adhesive interface. Previous work established the spatiotemporal contributions of adhesive components to adhesion strength and identified a nonlinear dependence on cell spreading. This study was designed to investigate the regulation of cell-adhesion strength by the size and position of focal adhesions (FA). The cell-adhesive interfac...

  5. Focal Adhesion-Independent Cell Migration.

    Science.gov (United States)

    Paluch, Ewa K; Aspalter, Irene M; Sixt, Michael

    2016-10-06

    Cell migration is central to a multitude of physiological processes, including embryonic development, immune surveillance, and wound healing, and deregulated migration is key to cancer dissemination. Decades of investigations have uncovered many of the molecular and physical mechanisms underlying cell migration. Together with protrusion extension and cell body retraction, adhesion to the substrate via specific focal adhesion points has long been considered an essential step in cell migration. Although this is true for cells moving on two-dimensional substrates, recent studies have demonstrated that focal adhesions are not required for cells moving in three dimensions, in which confinement is sufficient to maintain a cell in contact with its substrate. Here, we review the investigations that have led to challenging the requirement of specific adhesions for migration, discuss the physical mechanisms proposed for cell body translocation during focal adhesion-independent migration, and highlight the remaining open questions for the future.

  6. Focal adhesions and cell-matrix interactions

    DEFF Research Database (Denmark)

    Woods, A; Couchman, J R

    1988-01-01

    Focal adhesions are areas of cell surfaces where specializations of cytoskeletal, membrane and extracellular components combine to produce stable cell-matrix interactions. The morphology of these adhesions and the components identified in them are discussed together with possible mechanisms of th...

  7. Syndecan-4 and focal adhesion function

    DEFF Research Database (Denmark)

    Woods, A; Couchman, J R

    2001-01-01

    Two groups have now reported the viability of mice that lack syndecan-4. These mice have wound healing/angiogenesis problems, and fibroblasts from these animals differ in adhesion and migration from normal. This is consistent with recent in vitro data indicating a need for signaling via syndecan-4...... for focal adhesion formation, and reports that overexpression of proteins that bind syndecan-4 can modify cell adhesion and migration....

  8. Molecular Mechanisms of Mechanosensitivity in Focal Adhesions

    OpenAIRE

    2016-01-01

    Physical environment guides tissue regeneration and morphology in both health and disease. In the past three decades, several experiments illustrated that mechanical cues are captured and transduced to biochemical signals in the cellular level (mechanotransduction) mediated by cell adhesion. Cells adhere to their microenvironment through large protein assemblies known as focal adhesions that directly couple intra- and extra-cellular matrices and play a critical role in many vital cell functio...

  9. Regulation of cell adhesion strength by peripheral focal adhesion distribution.

    Science.gov (United States)

    Elineni, Kranthi Kumar; Gallant, Nathan D

    2011-12-21

    Cell adhesion to extracellular matrices is a tightly regulated process that involves the complex interplay between biochemical and mechanical events at the cell-adhesive interface. Previous work established the spatiotemporal contributions of adhesive components to adhesion strength and identified a nonlinear dependence on cell spreading. This study was designed to investigate the regulation of cell-adhesion strength by the size and position of focal adhesions (FA). The cell-adhesive interface was engineered to direct FA assembly to the periphery of the cell-spreading area to delineate the cell-adhesive area from the cell-spreading area. It was observed that redistributing the same adhesive area over a larger cell-spreading area significantly enhanced cell-adhesion strength, but only up to a threshold area. Moreover, the size of the peripheral FAs, which was interpreted as an adhesive patch, did not directly govern the adhesion strength. Interestingly, this is in contrast to the previously reported functional role of FAs in regulating cellular traction where sizes of the peripheral FAs play a critical role. These findings demonstrate, to our knowledge for the first time, that two spatial regimes in cell-spreading area exist that uniquely govern the structure-function role of FAs in regulating cell-adhesion strength.

  10. Focal adhesions and assessment of cytotoxicity

    NARCIS (Netherlands)

    van Kooten, TG; Klein, CL; Wagner, M; Kirkpatrick, CJ

    1999-01-01

    Focal adhesions are highly ordered assemblies of transmembrane receptors, extracellular matrix proteins, and a large number of cytoplasmic proteins, including structural proteins, as well as tyrosine kinases, phosphatases, and their substrates. They are now accepted as a prime component of signal tr

  11. Focal Adhesion Kinases in Adhesion Structures and Disease

    Directory of Open Access Journals (Sweden)

    Pierre P. Eleniste

    2012-01-01

    Full Text Available Cell adhesion to the extracellular matrix (ECM is essential for cell migration, proliferation, and embryonic development. Cells can contact the ECM through a wide range of matrix contact structures such as focal adhesions, podosomes, and invadopodia. Although they are different in structural design and basic function, they share common remodeling proteins such as integrins, talin, paxillin, and the tyrosine kinases FAK, Pyk2, and Src. In this paper, we compare and contrast the basic organization and role of focal adhesions, podosomes, and invadopodia in different cells. In addition, we discuss the role of the tyrosine kinases, FAK, Pyk2, and Src, which are critical for the function of the different adhesion structures. Finally, we discuss the essential role of these tyrosine kinases from the perspective of human diseases.

  12. Focal adhesion kinases in adhesion structures and disease.

    Science.gov (United States)

    Eleniste, Pierre P; Bruzzaniti, Angela

    2012-01-01

    Cell adhesion to the extracellular matrix (ECM) is essential for cell migration, proliferation, and embryonic development. Cells can contact the ECM through a wide range of matrix contact structures such as focal adhesions, podosomes, and invadopodia. Although they are different in structural design and basic function, they share common remodeling proteins such as integrins, talin, paxillin, and the tyrosine kinases FAK, Pyk2, and Src. In this paper, we compare and contrast the basic organization and role of focal adhesions, podosomes, and invadopodia in different cells. In addition, we discuss the role of the tyrosine kinases, FAK, Pyk2, and Src, which are critical for the function of the different adhesion structures. Finally, we discuss the essential role of these tyrosine kinases from the perspective of human diseases.

  13. Focal Adhesion Kinases in Adhesion Structures and Disease

    OpenAIRE

    2012-01-01

    Cell adhesion to the extracellular matrix (ECM) is essential for cell migration, proliferation, and embryonic development. Cells can contact the ECM through a wide range of matrix contact structures such as focal adhesions, podosomes, and invadopodia. Although they are different in structural design and basic function, they share common remodeling proteins such as integrins, talin, paxillin, and the tyrosine kinases FAK, Pyk2, and Src. In this paper, we compare and contrast the basic organiza...

  14. Focal Adhesion Induction at the Tip of a Functionalized Nanoelectrode

    OpenAIRE

    Fuentes, Daniela E.; Bae, Chilman; Peter J Butler

    2011-01-01

    Cells dynamically interact with their physical micro-environment through the assembly of nascent focal contacts and focal adhesions. The dynamics and mechanics of these contact points are controlled by transmembrane integrins and an array of intracellular adaptor proteins. In order to study the mechanics and dynamics of focal adhesion assembly, we have developed a technique for the timed induction of a nascent focal adhesion. Bovine aortic endothelial cells were approached at the apical surfa...

  15. Focal adhesion kinase - the reversible molecular mechanosensor

    CERN Document Server

    Bell, Samuel

    2016-01-01

    Sensors are the first element of the pathways that control the response of cells to their environment. After chemical, the next most important cue is mechanical, and protein complexes that produce or enable a chemical signal in response to a mechanical stimulus are called mechanosensors. There is a sharp distinction between sensing an external force or pressure/tension applied to the cell, and sensing the mechanical stiffness of the environment. We call the first mechanosensitivity of the 1st kind, and the latter mechanosensitivity of the 2nd kind. There are two variants of protein complexes that act as mechanosensors of the 2nd kind: producing the one-off or a reversible action. The latent complex of TGF-beta is an example of the one-off action: on the release of active TGF-beta signal, the complex is discarded and needs to be replaced. In contrast, the focal adhesion kinase (FAK) in a complex with integrin is a reversible mechanosensor, which initiates the chemical signal in its active phosphorylated confor...

  16. Focal Adhesion Induction at the Tip of a Functionalized Nanoelectrode.

    Science.gov (United States)

    Fuentes, Daniela E; Bae, Chilman; Butler, Peter J

    2011-12-01

    Cells dynamically interact with their physical micro-environment through the assembly of nascent focal contacts and focal adhesions. The dynamics and mechanics of these contact points are controlled by transmembrane integrins and an array of intracellular adaptor proteins. In order to study the mechanics and dynamics of focal adhesion assembly, we have developed a technique for the timed induction of a nascent focal adhesion. Bovine aortic endothelial cells were approached at the apical surface by a nanoelectrode whose position was controlled with a resolution of 10s of nanometers using changes in electrode current to monitor distance from the cell surface. Since this probe was functionalized with fibronectin, a focal contact formed at the contact location. Nascent focal adhesion assembly was confirmed using time-lapse confocal fluorescent images of red fluorescent protein (RFP) - tagged talin, an adapter protein that binds to activated integrins. Binding to the cell was verified by noting a lack of change of electrode current upon retraction of the electrode. This study demonstrates that functionalized nanoelectrodes can enable precisely-timed induction and 3-D mechanical manipulation of focal adhesions and the assay of the detailed molecular kinetics of their assembly.

  17. Protein kinase C involvement in focal adhesion formation

    DEFF Research Database (Denmark)

    Woods, A; Couchman, J R

    1992-01-01

    Matrix molecules such as fibronectin can promote cell attachment, spreading and focal adhesion formation. Although some interactions of fibronectin with cell surface receptors have now been identified, the consequent activation of intracellular messenger systems by cell/matrix interactions have...... still to be elucidated. We show here that the kinase inhibitors H7 and HA1004 reduce focal adhesion and stress fiber formation in response to fibronectin in a dose-dependent manner, and that activators of protein kinase C can promote their formation under conditions where they do not normally form....... Fibroblasts spread within 1h on substrata composed of fibronectin and formed focal adhesions by 3h, as monitored by interference reflection microscopy (IRM) and by labeling for talin, vinculin and integrin beta 1 subunits. In addition, stress fibers were visible. When cells were allowed to spread for 1h...

  18. The nanoscale architecture of force-bearing focal adhesions.

    Science.gov (United States)

    van Hoorn, Hedde; Harkes, Rolf; Spiesz, Ewa M; Storm, Cornelis; van Noort, Danny; Ladoux, Benoit; Schmidt, Thomas

    2014-08-13

    The combination of micropillar array technology to measure cellular traction forces with super-resolution imaging allowed us to obtain cellular traction force maps and simultaneously zoom in on individual focal adhesions with single-molecule accuracy. We achieved a force detection precision of 500 pN simultaneously with a mean single-molecule localization precision of 30 nm. Key to the achievement was a two-step etching process that provided an integrated spacer next to the micropillar array that permitted stable and reproducible observation of cells on micropillars within the short working distance of a high-magnification, high numerical aperture objective. In turn, we used the technology to characterize the super-resolved structure of focal adhesions during force exertion. Live-cell imaging on MCF-7 cells demonstrated the applicability of the inverted configuration of the micropillar arrays to dynamics measurements. Forces emanated from a molecular base that was localized on top of the micropillars. What appeared as a single adhesion in conventional microscopy were in fact multiple elongated adhesions emanating from only a small fraction of the adhesion on the micropillar surface. Focal adhesions were elongated in the direction of local cellular force exertion with structural features of 100-280 nm in 3T3 Fibroblasts and MCF-7 cells. The combined measure of nanoscale architecture and force exerted shows a high level of stress accumulation at a single site of adhesion.

  19. Hyperphosphorylated FAK Delocalizes from Focal Adhesions to Membrane Ruffles

    Directory of Open Access Journals (Sweden)

    Abdelkader Hamadi

    2010-01-01

    Full Text Available Cell adhesion and migration are key determinants in tumor metastasis. Adherence of tumor cell to the extracellular matrix is mediated via integrin containing focal adhesions (FAs. Binding of integrins to ECM triggers phosphorylation of two major components of FAs, focal adhesion kinase (FAK and Src, activating downstream signaling pathway which leads to FA disassembly and cell migration. In this paper, we analyze how phosphorylation of FAK regulates its trafficking at FAs in living human astrocytoma cells. Upon pervanadate-induced FAK phosphorylation, phosphorylated FAK appeared highly expressed at newly formed membrane ruffles. This effect was abolished in presence of the specific Src inhibitor PP2. Our findings demonstrate that upon phosphorylation, FAK delocalizes from FAs to membrane ruffles.

  20. Cadherin-11 localizes to focal adhesions and promotes cell–substrate adhesion

    Science.gov (United States)

    Langhe, Rahul P.; Gudzenko, Tetyana; Bachmann, Michael; Becker, Sarah F.; Gonnermann, Carina; Winter, Claudia; Abbruzzese, Genevieve; Alfandari, Dominique; Kratzer, Marie-Claire; Franz, Clemens M.; Kashef, Jubin

    2016-01-01

    Cadherin receptors have a well-established role in cell–cell adhesion, cell polarization and differentiation. However, some cadherins also promote cell and tissue movement during embryonic development and tumour progression. In particular, cadherin-11 is upregulated during tumour and inflammatory cell invasion, but the mechanisms underlying cadherin-11 stimulated cell migration are still incompletely understood. Here, we show that cadherin-11 localizes to focal adhesions and promotes adhesion to fibronectin in Xenopus neural crest, a highly migratory embryonic cell population. Transfected cadherin-11 also localizes to focal adhesions in different mammalian cell lines, while endogenous cadherin-11 shows focal adhesion localization in primary human fibroblasts. In focal adhesions, cadherin-11 co-localizes with β1-integrin and paxillin and physically interacts with the fibronectin-binding proteoglycan syndecan-4. Adhesion to fibronectin mediated by cadherin-11/syndecan-4 complexes requires both the extracellular domain of syndecan-4, and the transmembrane and cytoplasmic domains of cadherin-11. These results reveal an unexpected role of a classical cadherin in cell–matrix adhesion during cell migration. PMID:26952325

  1. Structural Insight into the Mechanisms of Targeting and Signaling of Focal Adhesion Kinase

    OpenAIRE

    2002-01-01

    Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase whose focal adhesion targeting (FAT) domain interacts with other focal adhesion molecules in integrin-mediated signaling. Localization of activated FAK to focal adhesions is indispensable for its function. Here we describe a solution structure of the FAT domain bound to a peptide derived from paxillin, a FAK-binding partner. The FAT domain is composed of four helices that form a “right-turn” elongated bundle; the globular fold is ma...

  2. Stability of focal adhesion enhanced by its inner force fluctuation

    Science.gov (United States)

    Mao, Zhi-Xiu; Chen, Xiao-Feng; Chen, Bin

    2015-08-01

    Cells actively sense and respond to mechanical signals from the extracellular matrix through focal adhesions. By representing a single focal adhesion as a cluster of slip bonds, it has been demonstrated that the cluster often became unstable under fluctuated forces. However, an unusual case was also reported, where the stability of the cluster might be substantially enhanced by a fluctuated force with a relatively low fluctuation frequency and high fluctuation amplitude. Such an observation cannot be explained by the conventional fracture theory of fatigue. Here, we intensively investigate this intriguing observation by carrying out systematic parametric studies. Our intensive simulation results indicate that stability enhancement of this kind is in fact quite robust, which can be affected by the stochastic features of a single bond and the profile of the fluctuated forces such as the average value of bond force. We then suggest that the fluctuation of traction force within a focal adhesion might enhance its stability in a certain way. Project supported by the National Natural Science Foundation of China (Grant No.*11372279).

  3. Focal adhesion kinase maintains, but not increases the adhesion of dental pulp cells.

    Science.gov (United States)

    Qian, Yuyan; Shao, Meiying; Zou, Wenlin; Wang, Linyan; Cheng, Ran; Hu, Tao

    2017-04-01

    Focal adhesion kinase (FAK) functions as a key enzyme in the integrin-mediated adhesion-signalling pathway. Here, we aimed to investigate the effects of FAK on adhesion of human dental pulp (HDP) cells. We transfected lentiviral vectors to silence or overexpress FAK in HDP cells ex vivo. Early cell adhesion, cell survival and focal contacts (FCs)-related proteins (FAK and paxillin) were examined. By using immunofluorescence, the formation of FCs and cytoskeleton was detected, respectively. We found that both adhesion and survival of HDP cells were suppressed by FAK inhibition. However, FAK overexpression slightly inhibited cell adhesion and exhibited no change in cell survival compared with the control. A thick rim of cytoskeleton accumulated and smaller dot-shaped FCs appeared in FAK knockdown cells. Phosphorylation of paxillin (p-paxillin) was inhibited in FAK knockdown cells, verifying that the adhesion was inhibited. Less cytoskeleton and elongated FCs were observed in FAK-overexpressed cells. However, p-paxillin had no significant difference compared with the control. In conclusion, the data suggest that FAK maintains cell adhesion, survival and cytoskeleton formation, but excessive FAK has no positive effects on these aspects.

  4. Exploring the formation of focal adhesions on patterned surfaces using super-resolution imaging.

    Science.gov (United States)

    Chien, Fan-Ching; Kuo, Chiung Wen; Yang, Zong-Han; Chueh, Di-Yen; Chen, Peilin

    2011-10-17

    The formation of focal adhesions on various sizes of fibronectin patterns, ranging from 200 μm to 250 nm, was systematically investigated by total internal reflection fluorescence microscopy and super-resolution imaging. It was found that cells adhered to and spread on these micro/nanopatterns, forming focal adhesions. On a micrometer scale the shape of the focal adhesions was elongated. However, on the nanometer scale, the shape of focal adhesions became dotlike. To further explore the distribution of focal adhesion proteins formed on surfaces, a localization-based super-resolution imaging technique was employed in order to determine the position and density of vinculin proteins. A characteristic distance of 50 nm was found between vinculin molecules in the focal adhesions, which did not depend on the size of the fibronectin nanopatterns. This distance was found to be crucial for the formation of focal adhesions. In addition, the density of vinculin at the focal adhesions formed on the nanopatterns increased as the pattern size decreased. The density of the protein was found to be 425 ± 247, 584 ± 302, and 703 ± 305 proteins μm(-2) on the 600, 400, and 250 nm fibronectin patterns respectively. Whereas 226 ± 77 proteins μm(-2) was measured for the matured focal adhesions on homogeneous fibronectin coated substrates. The increase in vinculin density implies that an increase in mechanical load was applied to the focal adhesions formed on the smaller nanopatterns.

  5. Assembly and mechanosensory function of focal adhesions: experiments and models.

    Science.gov (United States)

    Bershadsky, Alexander D; Ballestrem, Christoph; Carramusa, Letizia; Zilberman, Yuliya; Gilquin, Benoit; Khochbin, Saadi; Alexandrova, Antonina Y; Verkhovsky, Alexander B; Shemesh, Tom; Kozlov, Michael M

    2006-04-01

    Initial integrin-mediated cell-matrix adhesions (focal complexes) appear underneath the lamellipodia, in the regions of the "fast" centripetal flow driven by actin polymerization. Once formed, these adhesions convert the flow behind them into a "slow", myosin II-driven mode. Some focal complexes then turn into elongated focal adhesions (FAs) associated with contractile actomyosin bundles (stress fibers). Myosin II inhibition does not suppress formation of focal complexes but blocks their conversion into mature FAs and further FA growth. Application of external pulling force promotes FA growth even under conditions when myosin II activity is blocked. Thus, individual FAs behave as mechanosensors responding to the application of force by directional assembly. We proposed a thermodynamic model for the mechanosensitivity of FAs, taking into account that an elastic molecular aggregate subject to pulling forces tends to grow in the direction of force application by incorporating additional subunits. This simple model can explain a variety of processes typical of FA behavior. Assembly of FAs is triggered by the small G-protein Rho via activation of two major targets, Rho-associated kinase (ROCK) and the formin homology protein, Dia1. ROCK controls creation of myosin II-driven forces, while Dia1 is involved in the response of FAs to these forces. Expression of the active form of Dia1, allows the external force-induced assembly of mature FAs, even in conditions when Rho is inhibited. Conversely, downregulation of Dia1 by siRNA prevents FA maturation even if Rho is activated. Dia1 and other formins cap barbed (fast growing) ends of actin filaments, allowing insertion of the new actin monomers. We suggested a novel mechanism of such "leaky" capping based on an assumption of elasticity of the formin/barbed end complex. Our model predicts that formin-mediated actin polymerization should be greatly enhanced by application of external pulling force. Thus, the formin-actin complex

  6. Nascent Focal Adhesions Are Responsible for the Generation of Strong Propulsive Forces in Migrating Fibroblasts

    OpenAIRE

    2001-01-01

    Fibroblast migration involves complex mechanical interactions with the underlying substrate. Although tight substrate contact at focal adhesions has been studied for decades, the role of focal adhesions in force transduction remains unclear. To address this question, we have mapped traction stress generated by fibroblasts expressing green fluorescent protein (GFP)-zyxin. Surprisingly, the overall distribution of focal adhesions only partially resembles the distribution of traction stress. In ...

  7. Talin determines the nanoscale architecture of focal adhesions.

    Science.gov (United States)

    Liu, Jaron; Wang, Yilin; Goh, Wah Ing; Goh, Honzhen; Baird, Michelle A; Ruehland, Svenja; Teo, Shijia; Bate, Neil; Critchley, David R; Davidson, Michael W; Kanchanawong, Pakorn

    2015-09-01

    Insight into how molecular machines perform their biological functions depends on knowledge of the spatial organization of the components, their connectivity, geometry, and organizational hierarchy. However, these parameters are difficult to determine in multicomponent assemblies such as integrin-based focal adhesions (FAs). We have previously applied 3D superresolution fluorescence microscopy to probe the spatial organization of major FA components, observing a nanoscale stratification of proteins between integrins and the actin cytoskeleton. Here we combine superresolution imaging techniques with a protein engineering approach to investigate how such nanoscale architecture arises. We demonstrate that talin plays a key structural role in regulating the nanoscale architecture of FAs, akin to a molecular ruler. Talin diagonally spans the FA core, with its N terminus at the membrane and C terminus demarcating the FA/stress fiber interface. In contrast, vinculin is found to be dispensable for specification of FA nanoscale architecture. Recombinant analogs of talin with modified lengths recapitulated its polarized orientation but altered the FA/stress fiber interface in a linear manner, consistent with its modular structure, and implicating the integrin-talin-actin complex as the primary mechanical linkage in FAs. Talin was found to be ∼97 nm in length and oriented at ∼15° relative to the plasma membrane. Our results identify talin as the primary determinant of FA nanoscale organization and suggest how multiple cellular forces may be integrated at adhesion sites.

  8. ADAMTS-10 and -6 differentially regulate cell-cell junctions and focal adhesions

    Science.gov (United States)

    Cain, Stuart A.; Mularczyk, Ewa J.; Singh, Mukti; Massam-Wu, Teresa; Kielty, Cay M.

    2016-01-01

    ADAMTS10 and ADAMTS6 are homologous metalloproteinases with ill-defined roles. ADAMTS10 mutations cause Weill-Marchesani syndrome (WMS), implicating it in fibrillin microfibril biology since some fibrillin-1 mutations also cause WMS. However little is known about ADAMTS6 function. ADAMTS10 is resistant to furin cleavage, however we show that ADAMTS6 is effectively processed and active. Using siRNA, over-expression and mutagenesis, it was found ADAMTS6 inhibits and ADAMTS10 is required for focal adhesions, epithelial cell-cell junction formation, and microfibril deposition. Either knockdown of ADAMTS6, or disruption of its furin processing or catalytic sites restores focal adhesions, implicating its enzyme activity acts on targets in the focal adhesion complex. In ADAMTS10-depleted cultures, expression of syndecan-4 rescues focal adhesions and cell-cell junctions. Recombinant C-termini of ADAMTS10 and ADAMTS6, both of which induce focal adhesions, bind heparin and syndecan-4. However, cells overexpressing full-length ADAMTS6 lack heparan sulphate and focal adhesions, whilst depletion of ADAMTS6 induces a prominent glycocalyx. Thus ADAMTS10 and ADAMTS6 oppositely affect heparan sulphate-rich interfaces including focal adhesions. We previously showed that microfibril deposition requires fibronectin-induced focal adhesions, and cell-cell junctions in epithelial cultures. Here we reveal that ADAMTS6 causes a reduction in heparan sulphate-rich interfaces, and its expression is regulated by ADAMTS10. PMID:27779234

  9. Complementarity of PALM and SOFI for super-resolution live cell imaging of focal adhesions

    CERN Document Server

    Deschout, Hendrik; Sharipov, Azat; Szlag, Daniel; Feletti, Lely; Vandenberg, Wim; Dedecker, Peter; Hofkens, Johan; Leutenegger, Marcel; Lasser, Theo; Radenovic, Aleksandra

    2016-01-01

    Live cell imaging of focal adhesions requires a sufficiently high temporal resolution, which remains a challenging task for super-resolution microscopy. We have addressed this important issue by combining photo-activated localization microscopy (PALM) with super-resolution optical fluctuation imaging (SOFI). Using simulations and fixed cell focal adhesion images, we investigated the complementarity between PALM and SOFI in terms of spatial and temporal resolution. This PALM-SOFI framework was used to image focal adhesions in living cells, while obtaining a temporal resolution below 10 s. We visualized the dynamics of focal adhesions, and revealed local mean velocities around 190 nm per minute. The complementarity of PALM and SOFI was assessed in detail with a methodology that integrates a quantitative resolution and signal-to-noise metric. This PALM and SOFI concept provides an enlarged quantitative imaging framework, allowing unprecedented functional exploration of focal adhesions through the estimation of m...

  10. Complementarity of PALM and SOFI for super-resolution live-cell imaging of focal adhesions

    Science.gov (United States)

    Deschout, Hendrik; Lukes, Tomas; Sharipov, Azat; Szlag, Daniel; Feletti, Lely; Vandenberg, Wim; Dedecker, Peter; Hofkens, Johan; Leutenegger, Marcel; Lasser, Theo; Radenovic, Aleksandra

    2016-12-01

    Live-cell imaging of focal adhesions requires a sufficiently high temporal resolution, which remains a challenge for super-resolution microscopy. Here we address this important issue by combining photoactivated localization microscopy (PALM) with super-resolution optical fluctuation imaging (SOFI). Using simulations and fixed-cell focal adhesion images, we investigate the complementarity between PALM and SOFI in terms of spatial and temporal resolution. This PALM-SOFI framework is used to image focal adhesions in living cells, while obtaining a temporal resolution below 10 s. We visualize the dynamics of focal adhesions, and reveal local mean velocities around 190 nm min-1. The complementarity of PALM and SOFI is assessed in detail with a methodology that integrates a resolution and signal-to-noise metric. This PALM and SOFI concept provides an enlarged quantitative imaging framework, allowing unprecedented functional exploration of focal adhesions through the estimation of molecular parameters such as fluorophore densities and photoactivation or photoswitching kinetics.

  11. Why do receptor-ligand bonds in cell adhesion cluster into discrete focal-adhesion sites?

    Science.gov (United States)

    Gao, Zhiwen; Gao, Yanfei

    2016-10-01

    Cell adhesion often exhibits the clustering of the receptor-ligand bonds into discrete focal-adhesion sites near the contact edge, thus resembling a rosette shape or a contracting membrane anchored by a small number of peripheral forces. The ligands on the extracellular matrix are immobile, and the receptors in the cell plasma membrane consist of two types: high-affinity integrins (that bond to the substrate ligands and are immobile) and low-affinity integrins (that are mobile and not bonded to the ligands). Thus the adhesion energy density is proportional to the high-affinity integrin density. This paper provides a mechanistic explanation for the clustering/assembling of the receptor-ligand bonds from two main points: (1) the cellular contractile force leads to the density evolution of these two types of integrins, and results into a large high-affinity integrin density near the contact edge and (2) the front of a propagating crack into a decreasing toughness field will be unstable and wavy. From this fracture mechanics perspective, the chemomechanical equilibrium is reached when a small number of patches with large receptor-ligand bond density are anticipated to form at the cell periphery, as opposed to a uniform distribution of bonds on the entire interface. Cohesive fracture simulations show that the de-adhesion force can be significantly enhanced by this nonuniform bond density field, but the de-adhesion force anisotropy due to the substrate elastic anisotropy is significantly reduced.

  12. Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration.

    Science.gov (United States)

    Parsons, Sean A; Sharma, Ritu; Roccamatisi, Dawn L; Zhang, Hong; Petri, Björn; Kubes, Paul; Colarusso, Pina; Patel, Kamala D

    2012-02-01

    During an inflammatory response, endothelial cells undergo morphological changes to allow for the passage of neutrophils from the blood vessel to the site of injury or infection. Although endothelial cell junctions and the cytoskeleton undergo reorganization during inflammation, little is known about another class of cellular structures, the focal adhesions. In this study, we examined several focal adhesion proteins during an inflammatory response. We found that there was selective loss of paxillin and focal adhesion kinase (FAK) from focal adhesions in proximity to transmigrating neutrophils; in contrast the levels of the focal adhesion proteins β1-integrin and vinculin were unaffected. Paxillin was lost from focal adhesions during neutrophil transmigration both under static and flow conditions. Down-regulating endothelial paxillin with siRNA blocked neutrophil transmigration while having no effect on rolling or adhesion. As paxillin dynamics are regulated partly by FAK, the role of FAK in neutrophil transmigration was examined using two complementary methods. siRNA was used to down-regulate total FAK protein while dominant-negative, kinase-deficient FAK was expressed to block FAK signaling. Disruption of the FAK protein or FAK signaling decreased neutrophil transmigration. Collectively, these findings reveal a novel role for endothelial focal adhesion proteins paxillin and FAK in regulating neutrophil transmigration.

  13. [Therapeutic effect of focal adhesion kinase gene silence on leukemia].

    Science.gov (United States)

    Xu, Lü-Hong; Fang, Jian-Pei; Weng, Wen-Jun; Xu, Hong-Gui; Zhang, Ya-Ting

    2011-06-01

    This study was aimed to investigate the effects of focal adhesion kinase (FAK) gene silence on leukemia cell growth, leukemogenesis and efficacy of chemotherapy drug. Vector containing lentiviral-FAK-shRNA was constructed and transfected into BCR/ABL-BaF3 leukemic cells, the cell growth and apoptosis were detected in vitro. The effect of FAK shRNA on leukemogenesis was studied in a murine model with leukemia. The apoptosis of leukemia cells and survival of leukemic mice treated by FAK shRNA combined with drug STI571 were monitored. The results showed that FAK gene expression was knocked down by lentiviral-FAK-shRNA. FAK gene silencing inhibited leukemia cell growth in vitro. The apoptosis test results showed that the percentages of Annexin V(+) cells in vector control group and FAK shRNA group were (3.46 ± 0.56)% and (7.3 ± 0.79)%, respectively, and the difference was statistically significant (p silence combined with drug STI571 could enhance the apoptosis of leukemia cells and prolong survival time of leukemic mice. It is concluded that FAK gene silence inhibits leukemogenesis and promotes efficacy of chemotherapy drug on leukemia cells, indicating FAK gene silence may be considered as a new therapeutic strategy for leukemia.

  14. Focal adhesion kinase overexpression and its impact on human osteosarcoma

    Science.gov (United States)

    Chen, Yong; Yang, Aizhen; Chen, Hui; Zhang, Jian; Wu, Sujia; Shi, Xin; Wang, Chen; Sun, Xiaoliang

    2015-01-01

    Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various malignancies. We sought to examine the expression patterns of FAK and the activated form, phosphorylated FAK (pFAK), in human osteosarcoma and to investigate the correlation of FAK expression with clinicopathologic parameters and prognosis. In addition, the functional consequence of manipulating the FAK protein level was investigated in human osteosarcoma cell lines. Immunohistochemical staining was used to detect FAK and pFAK in pathologic archived materials from 113 patients with primary osteosarcoma. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognoses. The role of FAK in the cytological behavior of MG63 and 143B human osteosarcoma cell lines was studied via FAK protein knock down with siRNA. Cell proliferation, migration, invasiveness and apoptosis were assessed using the CCK8, Transwell and Annexin V/PI staining methods. Both FAK and pFAK were overexpressed in osteosarcoma. There were significant differences in overall survival between the FAK-/pFAK- and FAK+/pFAK- groups (P = 0.016), the FAK+/pFAK- and FAK+/pFAK+ groups (P = 0.012) and the FAK-/pFAK- and FAK+/pFAK+ groups (P osteosarcoma cell proliferation and apoptosis. These results collectively suggest that FAK overexpression and phosphorylation might predict more aggressive biologic behavior in osteosarcoma and may be an independent predictor of poor prognosis. PMID:26393679

  15. Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells

    Energy Technology Data Exchange (ETDEWEB)

    Aanei, Carmen Mariana, E-mail: caanei@yahoo.com [Laboratoire Hematologie, CHU de Saint-Etienne, 42055, Saint-Etienne (France); Department of Immunology, Gr. T. Popa University of Medicine and Pharmacy, 700115, Iasi (Romania); Eloae, Florin Zugun [Department of Immunology, Gr. T. Popa University of Medicine and Pharmacy, 700115, Iasi (Romania); Flandrin-Gresta, Pascale [Laboratoire Hematologie, CHU de Saint-Etienne, 42055, Saint-Etienne (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France); Tavernier, Emmanuelle [Service Hematologie Clinique, Institut de Cancerologie de la Loire, 42270, Saint-Priest-en-Jarez (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France); Carasevici, Eugen [Department of Immunology, Gr. T. Popa University of Medicine and Pharmacy, 700115, Iasi (Romania); Guyotat, Denis [Service Hematologie Clinique, Institut de Cancerologie de la Loire, 42270, Saint-Priest-en-Jarez (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France); Campos, Lydia [Laboratoire Hematologie, CHU de Saint-Etienne, 42055, Saint-Etienne (France); CNRS UMR 5239, Universite de Lyon, 42023, Saint-Etienne (France)

    2011-11-01

    Direct cell-cell contact between haematopoietic progenitor cells (HPCs) and their cellular microenvironment is essential to maintain 'stemness'. In cancer biology, focal adhesion (FA) proteins are involved in survival signal transduction in a wide variety of human tumours. To define the role of FA proteins in the haematopoietic microenvironment of myelodysplastic syndromes (MDS), CD73-positive mesenchymal stromal cells (MSCs) were immunostained for paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} and p130CAS, and analysed for reactivity, intensity and cellular localisation. Immunofluorescence microscopy allowed us to identify qualitative and quantitative differences, and subcellular localisation analysis revealed that in pathological MSCs, paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} and enhanced nuclear co-localisation of these proteins correlated with a consistent proliferative advantage in MSCs from patients with refractory anaemia with excess blasts (RAEB) and negatively impacted clonogenicity of HPCs. These results suggest that signalling via FA proteins could be implicated in HPC-MSC interactions. Further, because FAK is an HSP90{alpha}/{beta} client protein, these results suggest the utility of HSP90{alpha}/{beta} inhibition as a target for adjuvant therapy for myelodysplasia.

  16. Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells

    KAUST Repository

    Kadaré, Gress

    2015-01-02

    Focal adhesion (FA) kinase (FAK) regulates cell survival and motility by transducing signals from membrane receptors. The C-terminal FA targeting (FAT) domain of FAK fulfils multiple functions, including recruitment to FAs through paxillin binding. Phosphorylation of FAT on Tyr925 facilitates FA disassembly and connects to the MAPK pathway through Grb2 association, but requires dissociation of the first helix (H1) of the four-helix bundle of FAT. We investigated the importance of H1 opening in cells by comparing the properties of FAK molecules containing wild-type or mutated FAT with impaired or facilitated H1 openings. These mutations did not alter the activation of FAK, but selectively affected its cellular functions, including self-association, Tyr925 phosphorylation, paxillin binding, and FA targeting and turnover. Phosphorylation of Tyr861, located between the kinase and FAT domains, was also enhanced by the mutation that opened the FAT bundle. Similarly phosphorylation of Ser910 by ERK in response to bombesin was increased by FAT opening. Although FAK molecules with the mutation favoring FAT opening were poorly recruited at FAs, they efficiently restored FA turnover and cell shape in FAK-deficient cells. In contrast, the mutation preventing H1 opening markedly impaired FAK function. Our data support the biological importance of conformational dynamics of the FAT domain and its functional interactions with other parts of the molecule.

  17. Actin cap associated focal adhesions and their distinct role in cellular mechanosensing

    Science.gov (United States)

    Kim, Dong-Hwee; Khatau, Shyam B.; Feng, Yunfeng; Walcott, Sam; Sun, Sean X.; Longmore, Gregory D.; Wirtz, Denis

    2012-01-01

    The ability for cells to sense and adapt to different physical microenvironments plays a critical role in development, immune responses, and cancer metastasis. Here we identify a small subset of focal adhesions that terminate fibers in the actin cap, a highly ordered filamentous actin structure that is anchored to the top of the nucleus by the LINC complexes; these differ from conventional focal adhesions in morphology, subcellular organization, movements, turnover dynamics, and response to biochemical stimuli. Actin cap associated focal adhesions (ACAFAs) dominate cell mechanosensing over a wide range of matrix stiffness, an ACAFA-specific function regulated by actomyosin contractility in the actin cap, while conventional focal adhesions are restrictively involved in mechanosensing for extremely soft substrates. These results establish the perinuclear actin cap and associated ACAFAs as major mediators of cellular mechanosensing and a critical element of the physical pathway that transduce mechanical cues all the way to the nucleus. PMID:22870384

  18. Actin cap associated focal adhesions and their distinct role in cellular mechanosensing

    OpenAIRE

    2012-01-01

    The ability for cells to sense and adapt to different physical microenvironments plays a critical role in development, immune responses, and cancer metastasis. Here we identify a small subset of focal adhesions that terminate fibers in the actin cap, a highly ordered filamentous actin structure that is anchored to the top of the nucleus by the LINC complexes; these differ from conventional focal adhesions in morphology, subcellular organization, movements, turnover dynamics, and response to b...

  19. The non-equilibrium thermodynamics and kinetics of focal adhesion dynamics.

    Directory of Open Access Journals (Sweden)

    Joseph E Olberding

    Full Text Available BACKGROUND: We consider a focal adhesion to be made up of molecular complexes, each consisting of a ligand, an integrin molecule, and associated plaque proteins. Free energy changes drive the binding and unbinding of these complexes and thereby controls the focal adhesion's dynamic modes of growth, treadmilling and resorption. PRINCIPAL FINDINGS: We have identified a competition among four thermodynamic driving forces for focal adhesion dynamics: (i the work done during the addition of a single molecular complex of a certain size, (ii the chemical free energy change associated with the addition of a molecular complex, (iii the elastic free energy change associated with deformation of focal adhesions and the cell membrane, and (iv the work done on a molecular conformational change. We have developed a theoretical treatment of focal adhesion dynamics as a nonlinear rate process governed by a classical kinetic model. We also express the rates as being driven by out-of-equilibrium thermodynamic driving forces, and modulated by kinetics. The mechanisms governed by the above four effects allow focal adhesions to exhibit a rich variety of behavior without the need to introduce special constitutive assumptions for their response. For the reaction-limited case growth, treadmilling and resorption are all predicted by a very simple chemo-mechanical model. Treadmilling requires symmetry breaking between the ends of the focal adhesion, and is achieved by driving force (i above. In contrast, depending on its numerical value (ii causes symmetric growth, resorption or is neutral, (iii causes symmetric resorption, and (iv causes symmetric growth. These findings hold for a range of conditions: temporally-constant force or stress, and for spatially-uniform and non-uniform stress distribution over the FA. The symmetric growth mode dominates for temporally-constant stress, with a reduced treadmilling regime. SIGNIFICANCE: In addition to explaining focal adhesion

  20. Focal adhesion kinase is required for actin polymerization and remodeling of the cytoskeleton during sperm capacitation

    Science.gov (United States)

    Roa-Espitia, Ana L.; Hernández-Rendón, Eva R.; Baltiérrez-Hoyos, Rafael; Muñoz-Gotera, Rafaela J.; Cote-Vélez, Antonieta; Jiménez, Irma; González-Márquez, Humberto

    2016-01-01

    ABSTRACT Several focal adhesion proteins are known to cooperate with integrins to link the extracellular matrix to the actin cytoskeleton; as a result, many intracellular signaling pathways are activated and several focal adhesion complexes are formed. However, how these proteins function in mammalian spermatozoa remains unknown. We confirm the presence of focal adhesion proteins in guinea pig spermatozoa, and we explore their role during capacitation and the acrosome reaction, and their relationship with the actin cytoskeleton. Our results suggest the presence of a focal adhesion complex formed by β1-integrin, focal adhesion kinase (FAK), paxillin, vinculin, talin, and α-actinin in the acrosomal region. Inhibition of FAK during capacitation affected the protein tyrosine phosphorylation associated with capacitation that occurs within the first few minutes of capacitation, which caused the acrosome reaction to become increasingly Ca2+ dependent and inhibited the polymerization of actin. The integration of vinculin and talin into the complex, and the activation of FAK and paxillin during capacitation, suggests that the complex assembles at this time. We identify that vinculin and α-actinin increase their interaction with F-actin while it remodels during capacitation, and that during capacitation focal adhesion complexes are structured. FAK contributes to acrosome integrity, likely by regulating the polymerization and the remodeling of the actin cytoskeleton. PMID:27402964

  1. Bacillus cereus Certhrax ADP-ribosylates vinculin to disrupt focal adhesion complexes and cell adhesion.

    Science.gov (United States)

    Simon, Nathan C; Barbieri, Joseph T

    2014-04-11

    Bacillus cereus is often associated with mild to moderate gastroenteritis; however, some recent isolates cause inhalational anthrax-like diseases and death. These potential emerging human pathogens express multiple virulence factors. B. cereus strain G9241 expresses anthrax toxin, several polysaccharide capsules, and the novel ADP-ribosyltransferase, Certhrax. In this study, we show that Certhrax ADP-ribosylates Arg-433 of vinculin, a protein that coordinates actin cytoskeleton and extracellular matrix interactions. ADP-ribosylation of vinculin disrupted focal adhesion complexes and redistributed vinculin to the cytoplasm. Exogenous vinculin rescued these phenotypes. This provides a mechanism for strain G9241 to breach host barrier defenses and promote bacterial growth and spread. Certhrax is the first bacterial toxin to add a post-translational modification to vinculin to disrupt the actin cytoskeleton.

  2. ROCK-2 is associated with focal adhesion maturation during myoblast migration.

    Science.gov (United States)

    Goetsch, K P; Snyman, C; Myburgh, K H; Niesler, C U

    2014-07-01

    Satellite cell migration is critical for skeletal muscle growth and regeneration. Controlled cell migration is dependent on the formation of mature focal adhesions between the cell and the underlying extracellular matrix (ECM). These cell-ECM interactions trigger the activation of signalling events such as the Rho/ROCK pathway. We have previously identified a specific role for ROCK-2 during myoblast migration. In this study we report that ROCK inhibition with Y-27632 increases C2C12 myoblast velocity, but at the expense of directional migration. In response to Y-27632 an increased number of smaller focal adhesions were distributed across adhesion sites that in turn were clearly larger than sites in untreated cells, suggesting a reduction in focal adhesion maturation. We also confirm ROCK-2 localisation to the focal adhesion sites in migrating myoblasts and demonstrate a change in the distribution of these ROCK-2 containing adhesions in response to Y-27632. Taken together, our observations provide further proof that ROCK-2 regulates directional myoblast migration through focal adhesion formation and maturation.

  3. Controlled induction of focal adhesion disassembly and migration in primary fibroblasts

    DEFF Research Database (Denmark)

    Dunlevy, J R; Couchman, J R

    1993-01-01

    Fibroblast migration is an integral component of biological processes such as wound healing and embryogenesis. Previous experiments examining fibroblast locomotion from tissue explants have shown that migrating fibroblasts lack, or contain only transient, focal adhesions (focal contacts). Focal...... adhesions are specialized regions of tight cell-matrix interaction, assembled by a complex process of transmembrane signalling. Although the explant model has been used for studying several aspects of fibroblast locomotion, it is limited by the lack of control over migration, and only a small percentage...

  4. Spatiotemporal Constraints on the Force-Dependent Growth of Focal Adhesions

    Science.gov (United States)

    Stricker, Jonathan; Aratyn-Schaus, Yvonne; Oakes, Patrick W.; Gardel, Margaret L.

    2011-01-01

    Focal adhesions (FAs) are the predominant mechanism by which cells mechanically couple to and exert traction forces on their extracellular matrix (ECM). It is widely presumed that FA size is modulated by force to mediate changes in adhesion strength at different levels of cellular tension. However, previous studies seeking correlations between force and FA morphology have yielded variable and often conflicting results. Here we show that a strong correlation between adhesion size and traction force exists only during the initial stages of myosin-mediated adhesion maturation and growth. For mature adhesions, no correlation between traction stress and size is observed. Rather, the tension that is sustained at mature adhesions is more strongly influenced by proximity to the cell edge, with peripheral adhesions transmitting higher tension than adhesions near the cell center. Finally, we show that mature adhesions can withstand sixfold increases in tension without changes in size. Thus, although a strong correlation between adhesion size and mechanical tension is observed during the initial stages of myosin-mediated adhesion maturation, no correlation is observed in mature, elongated adhesions. This work places spatiotemporal constraints on the force-dependent growth of adhesions and provides insight into the mechanical regulation of cell-ECM adhesion. PMID:21689521

  5. Theory of the mechanical response of focal adhesions to shear flow

    Science.gov (United States)

    Biton, Y. Y.; Safran, S. A.

    2010-05-01

    The response of cells to shear flow is primarily determined by the asymmetry of the external forces and moments that are sensed by each member of a focal adhesion pair connected by a contractile stress fiber. In the theory presented here, we suggest a physical model in which each member of such a pair of focal adhesions is treated as an elastic body subject to both a myosin-activated contractile force and the shear stress induced by the external flow. The elastic response of a focal adhesion complex is much faster than the active cellular processes that determine the size of the associated focal adhesions and the direction of the complex relative to the imposed flow. Therefore, the complex attains its mechanical equilibrium configuration which may change because of the cellular activity. Our theory is based on the experimental observation that focal adhesions modulate their cross-sectional area in order to attain an optimal shear. Using this assumption, our elastic model shows that such a complex can passively change its orientation to align parallel to the direction of the flow.

  6. Theory of the mechanical response of focal adhesions to shear flow

    Energy Technology Data Exchange (ETDEWEB)

    Biton, Y Y; Safran, S A, E-mail: yoav.biton@weizmann.ac.i, E-mail: sam.safran@weizmann.ac.i [Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot 76100 (Israel)

    2010-05-19

    The response of cells to shear flow is primarily determined by the asymmetry of the external forces and moments that are sensed by each member of a focal adhesion pair connected by a contractile stress fiber. In the theory presented here, we suggest a physical model in which each member of such a pair of focal adhesions is treated as an elastic body subject to both a myosin-activated contractile force and the shear stress induced by the external flow. The elastic response of a focal adhesion complex is much faster than the active cellular processes that determine the size of the associated focal adhesions and the direction of the complex relative to the imposed flow. Therefore, the complex attains its mechanical equilibrium configuration which may change because of the cellular activity. Our theory is based on the experimental observation that focal adhesions modulate their cross-sectional area in order to attain an optimal shear. Using this assumption, our elastic model shows that such a complex can passively change its orientation to align parallel to the direction of the flow.

  7. Substrate, focal adhesions, and actin filaments: a mechanical unit with a weak spot for mechanosensitive proteins

    Science.gov (United States)

    Kirchenbüchler, David; Born, Simone; Kirchgeßner, Norbert; Houben, Sebastian; Hoffmann, Bernd; Merkel, Rudolf

    2010-05-01

    Mechanosensing is a vital prerequisite for dynamic remodeling of focal adhesions and cytoskeletal structures upon substrate deformation. For example, tissue formation, directed cell orientation or cell differentiation are regulated by such mechanosensing processes. Focal adhesions and the actin cytoskeleton are believed to be involved in these processes, but where mechanosensing molecules are located and how elastic substrate, focal adhesions and the cytoskeleton couple with each other upon substrate deformation still remains obscure. To approach these questions we have developed a sensitive method to apply defined spatially decaying deformation fields to cells cultivated on ultrasoft elastic substrates and to accurately quantify the resulting displacements of the actin cytoskeleton, focal adhesions, as well as the substrate. Displacement fields were recorded in live cell microscopy by tracking either signals from fluorescent proteins or marker particles in the substrate. As model cell type we used myofibroblasts. These cells are characterized by highly stable adhesion and force generating structures but are still able to detect mechanical signals with high sensitivity. We found a rigid connection between substrate and focal adhesions. Furthermore, stress fibers were found to be barely extendable almost over their whole lengths. Plastic deformation took place only at the very ends of actin filaments close to focal adhesions. As a result, this area became elongated without extension of existing actin filaments by polymerization. Both ends of the stress fibers were mechanically coupled with detectable plastic deformations on either site. Interestingly, traction force dependent substrate deformation fields remained mostly unaffected even when stress fiber elongations were released. These data argue for a location of mechanosensing proteins at the ends of actin stress fibers and describe, except for these domains, the whole system to be relatively rigid for tensile

  8. Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component

    DEFF Research Database (Denmark)

    Woods, A; Couchman, J R

    1994-01-01

    Focal adhesion formation in fibroblasts results from complex transmembrane signaling processes initiated by extracellular matrix molecules. Although a role for integrins with attendant tyrosine kinases has been established, there is evidence that cell surface heparan sulfate proteoglycans (HSPGs......) are also involved with an associated role of protein kinase C. The identity of the proteoglycan has remained elusive, but we now report that syndecan 4 (ryudocan/amphiglycan) is present in focal adhesions of a number of cell types. Affinity-purified antibodies raised against a unique portion...

  9. Focal adhesive arachnoiditis of the spinal cord: Imaging diagnosis and surgical resolution

    Directory of Open Access Journals (Sweden)

    Hiroki Morisako

    2010-01-01

    Full Text Available Background: Although adhesive arachnoiditis of the spinal cord can cause progressive symptoms associated with syringomyelia or myelomalacia, its surgical resolution based on the imaging diagnosis is not well characterized. This study aims to describe the use of imaging for the diagnosis of focal adhesive arachnoiditis of the spinal cord and its surgical resolution using microsurgical arachnoidolysis. Materials and Methods: Four consecutive patients with symptomatic syringomyelia or myelomalacia caused by focal adhesive arachnoiditis underwent microsurgical arachnoidolysis. Comprehensive imaging evaluation using constructive interference in steady-state (CISS magnetic resonance imaging (MRI or myelographic MR imaging using true fast imaging with steady-state precession (TrueFISP sequences was included before surgery to determine the surgical indication. Results: In all four patients a focal adhesion was identified at the cervical or thoracic level of the spinal cord, a consequence of infection or trauma. Three patients showed modest or minor improvement in neurological function, and one patient was unchanged after surgery. The syringomyelia or myelomalacia resolved after surgery and no recurrence was noted within the follow-up period, which ranged from 5 months to 30 months. Conclusions: MRI diagnosis of focal adhesive arachnoiditis is critical to determine the surgical indication. Microsurgical arachnoidolysis appears to be a straightforward method for stabilizing the progressive symptoms, though the procedure is technically demanding.

  10. Combining PALM and SOFI for quantitative imaging of focal adhesions in living cells

    Science.gov (United States)

    Deschout, Hendrik; Lukes, Tomas; Sharipov, Azat; Feletti, Lely; Lasser, Theo; Radenovic, Aleksandra

    2017-02-01

    Focal adhesions are complicated assemblies of hundreds of proteins that allow cells to sense their extracellular matrix and adhere to it. Although most focal adhesion proteins have been identified, their spatial organization in living cells remains challenging to observe. Photo-activated localization microscopy (PALM) is an interesting technique for this purpose, especially since it allows estimation of molecular parameters such as the number of fluorophores. However, focal adhesions are dynamic entities, requiring a temporal resolution below one minute, which is difficult to achieve with PALM. In order to address this problem, we merged PALM with super-resolution optical fluctuation imaging (SOFI) by applying both techniques to the same data. Since SOFI tolerates an overlap of single molecule images, it can improve the temporal resolution compared to PALM. Moreover, an adaptation called balanced SOFI (bSOFI) allows estimation of molecular parameters, such as the fluorophore density. We therefore performed simulations in order to assess PALM and SOFI for quantitative imaging of dynamic structures. We demonstrated the potential of our PALM-SOFI concept as a quantitative imaging framework by investigating moving focal adhesions in living cells.

  11. The regulation of traction force in relation to cell shape and focal adhesions.

    Science.gov (United States)

    Rape, Andrew D; Guo, Wei-Hui; Wang, Yu-Li

    2011-03-01

    Mechanical forces provide critical inputs for proper cellular functions. The interplay between the generation of, and response to, mechanical forces regulate such cellular processes as differentiation, proliferation, and migration. We postulate that adherent cells respond to a number of physical and topographical factors, including cell size and shape, by detecting the magnitude and/or distribution of traction forces under different conditions. To address this possibility we introduce a new simple method for precise micropatterning of hydrogels, and then apply the technique to systematically investigate the relationship between cell geometry, focal adhesions, and traction forces in cells with a series of spread areas and aspect ratios. Contrary to previous findings, we find that traction force is not determined primarily by the cell spreading area but by the distance from cell center to the perimeter. This distance in turn controls traction forces by regulating the size of focal adhesions, such that constraining the size of focal adhesions by micropatterning can override the effect of geometry. We propose that the responses of traction forces to center-periphery distance, possibly through a positive feedback mechanism that regulates focal adhesions, provide the cell with the information on its own shape and size. A similar positive feedback control may allow cells to respond to a variety of physical or topographical signals via a unified mechanism. Copyright © 2010 Elsevier Ltd. All rights reserved.

  12. Redistribution of microfilament-associated proteins during the formation of focal contacts and adhesions in chick fibroblasts

    DEFF Research Database (Denmark)

    Couchman, J R; Badley, R A; Rees, D A

    1983-01-01

    fibroblast system which initially has no such adhesion specializations but then develops them sequentially over a 48 h period. Without exception, all focal contacts and focal adhesions contain both vinculin and alpha-actinin at every stage that we can detect by IRM or by double staining to reveal...... the associated microfilament bundles. Indeed the appearance of small bodies containing alpha-actinin and vinculin is shown to precede focal contact formation in our model system and such structures (not visible by IRM) are proposed to be the precursors of focal contacts and adhesions. Myosin and filamin......The roles of the microfilament-associated proteins vinculin, alpha-actinin, myosin and filamin have been studied by immunofluorescence and double fluorescence in conjunction with interference reflection microscopy (IRM), during the development of focal contacts and focal adhesions in a chick...

  13. The focal adhesion targeting domain of p130Cas confers a mechanosensing function.

    Science.gov (United States)

    Bradbury, Peta M; Turner, Kylie; Mitchell, Camilla; Griffin, Kaitlyn R; Middlemiss, Shiloh; Lau, Loretta; Dagg, Rebecca; Taran, Elena; Cooper-White, Justin; Fabry, Ben; O'Neill, Geraldine M

    2017-04-01

    Members of the Cas family of focal adhesion proteins contain a highly conserved C-terminal focal adhesion targeting (FAT) domain. To determine the role of the FAT domain in these proteins, we compared wild-type exogenous NEDD9 with a hybrid construct in which the NEDD9 FAT domain had been exchanged for the p130Cas (also known as BCAR1) FAT domain. Fluorescence recovery after photobleaching (FRAP) revealed significantly slowed exchange of the fusion protein at focal adhesions and significantly slower two-dimensional migration. No differences were detected in cell stiffness as measured using atomic force microscopy (AFM) and in cell adhesion forces measured with a magnetic tweezer device. Thus, the slowed migration was not due to changes in cell stiffness or adhesion strength. Analysis of cell migration on surfaces of increasing rigidity revealed a striking reduction of cell motility in cells expressing the p130Cas FAT domain. The p130Cas FAT domain induced rigidity-dependent phosphorylation of tyrosine residues within NEDD9. This in turn reduced post-translational cleavage of NEDD9, which we show inhibits NEDD9-induced migration. Collectively, our data therefore suggest that the p130Cas FAT domain uniquely confers a mechanosensing function. © 2017. Published by The Company of Biologists Ltd.

  14. [Study on FAK regulation of migration of vascular endothelial cells depending upon focal adhesion proteins].

    Science.gov (United States)

    Gao, Min; Liu, Xiaoheng; Sun, Heng; Ren, Hongyi; Wang, Lijuan; Shen, Yang

    2013-06-01

    Tumor angiogenesis induced by vascular endothelial cells (VECs) migration is a necessary condition for tumor growth and metastasis. The purpose of this study is to investigate the effect of focal adhesion kinase (FAK) inhibitor (50nmol/mL) on the adhesion and migration of endothelial cells(ECs) and the expression of focal adhesion proteins vinculin, talin and paxillin. Scratch wound migration assay was performed to examine the effect of FAK inhibitor with 50nmol/mL on ECs migration at 0, 5, 10, 30, 60 and 120min, respectively. And immunofluorescence analysis was performed to detect the expression of F-actin in ECs treated with FAK inhibitor within 2h. Western blot was carried out to determine the effect of FAK inhibitor on expression of vinculin, talin and paxillin proteins. The results showed that the migration distance and the expression of F-actin in ECs treated with FAK inhibitor decreased significantly compared with that of the controls, and the level of vinculin showed no significant difference with increasing of treated time of FAK inhibitor. However, the talin and paxillin showed an identical decreasing tendency in 5-10min, but slowly going up in 30min and then after subsequently decreasing. The results of this study proved that blocking phosphorylation of FAK could inhibit VECs adhesion and migration by downregulating focal adhesion proteins so that it may inhibit tumor angiogenesis. This may provide a new approach for tumor therapy.

  15. Lateral shear forces applied to cells with single elastic micropillars to influence focal adhesion dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Heil, Patrick; Spatz, Joachim P, E-mail: spatz@mf.mpg.d [Department of New Materials and Biosystems, Max Planck Institute for Metals Research, Heisenbergstrasse 3, D-70569 Stuttgart (Germany); Department of Biophysical Chemistry, University of Heidelberg, Heisenbergstrasse 3, D-70569 Stuttgart (Germany)

    2010-05-19

    Focal adhesions (FAs) are important adhesion sites between eukaryotic cells and the extracellular matrix, their size depending on the locally applied force. To quantitatively study the mechanosensitivity of FAs, we induce their growth and disassembly by varying the distribution of intracellular stress. We present a novel method for micromanipulation of living cells to explore the dynamics of focal adhesion (FA) assembly under force. Fibroblasts are sheared laterally to their adhesion surface with single PDMS micropillars in order to apply laterally stretch or compression to focal adhesions. This allows for measuring the shear force exerted by the micropillar and correlates it with FA length and growth velocity. Furthermore, we analyze the resulting dynamics of FA molecules (paxillin) and compare intensity profiles along FAs before and after the application of external force. The responses of stretched and relaxed FAs differ fundamentally: relaxed and compressed FAs disassemble isotropically and show no length variation while stretched FAs grow unisotropically in the direction of the applied force and show protein influx only at their front.

  16. Cancer cell metastasis; perspectives from the focal adhesion

    Directory of Open Access Journals (Sweden)

    Lefteris C Zacharia

    2015-10-01

    Full Text Available In almost all cancers, most patients die from metastatic disease and not from the actual primary tumor. That is why addressing the problem of metastasis is of utmost importance for the successful treatment and improved survival of cancer patients. Metastasis is a complex process that ultimately leads to cancer cells spreading from the tumor to distant sites of the body. During this process, cancer cells tend to lose contact with the extracellular matrix (ECM and neighboring cells within the primary tumor, and are thus able to invade surrounding tissues. Hence, ECM, and the ECM-associated adhesion proteins play a critical role in the metastatic process. This review will focus on recent literature regarding interesting and novel molecules at the cell-ECM adhesion sites, namely migfilin, mitogen-inducible gene-2 (Mig-2 and Ras suppressor-1 (RSU-1, that are also critically involved in cancer cell metastasis, emphasizing on data from experiments performed in vitro in breast cancer and hepatocellular carcinoma cell lines as well as human breast cancer tissue samples.

  17. FAK dimerization controls its kinase-dependent functions at focal adhesions

    KAUST Repository

    Brami-Cherrier, Karen

    2014-01-30

    Focal adhesion kinase (FAK) controls adhesion-dependent cell motility, survival, and proliferation. FAK has kinase-dependent and kinase-independent functions, both of which play major roles in embryogenesis and tumor invasiveness. The precise mechanisms of FAK activation are not known. Using x-ray crystallography, small angle x-ray scattering, and biochemical and functional analyses, we show that the key step for activation of FAK\\'s kinase-dependent functions-autophosphorylation of tyrosine-397-requires site-specific dimerization of FAK. The dimers form via the association of the N-terminal FERM domain of FAK and are stabilized by an interaction between FERM and the C-terminal FAT domain. FAT binds to a basic motif on FERM that regulates co-activation and nuclear localization. FAK dimerization requires local enrichment, which occurs specifically at focal adhesions. Paxillin plays a dual role, by recruiting FAK to focal adhesions and by reinforcing the FAT:FERM interaction. Our results provide a structural and mechanistic framework to explain how FAK combines multiple stimuli into a site-specific function. The dimer interfaces we describe are promising targets for blocking FAK activation. © 2014 The Authors.

  18. Targeting Focal Adhesion Assembly by Ethoxyfagaronine Prevents Lymphoblastic Cell Adhesion to Fibronectin

    Directory of Open Access Journals (Sweden)

    F. Ouchani

    2012-01-01

    Full Text Available Background: Leukemic cell adhesion to proteins of the bone marrow microenvironment provides signals which control morphology, motility and cell survival. We described herein the ability of ethoxyfagaronine (etxfag, a soluble synthetic derivative of fagaronine, to prevent leukemic cell adhesion to fibronectin peptide (FN/V.

  19. How to awaken your nanomachines: Site-specific activation of focal adhesion kinases through ligand interactions

    KAUST Repository

    Walkiewicz, Katarzyna Wiktoria

    2015-06-17

    The focal adhesion kinase (FAK) and the related protein-tyrosine kinase 2-beta (Pyk2) are highly versatile multidomain scaffolds central to cell adhesion, migration, and survival. Due to their key role in cancer metastasis, understanding and inhibiting their functions are important for the development of targeted therapy. Because FAK and Pyk2 are involved in many different cellular functions, designing drugs with partial and function-specific inhibitory effects would be desirable. Here, we summarise recent progress in understanding the structural mechanism of how the tug-of-war between intramolecular and intermolecular interactions allows these protein ‘nanomachines’ to become activated in a site-specific manner.

  20. Bidirectional control of the inner dynamics of focal adhesions promotes cell migration

    OpenAIRE

    2009-01-01

    Focal adhesions (FA) are bidirectional mechanical biosensors that allow cells to integrate intracellular and extracellular cues. Their function is tightly regulated by changes in molecular composition and also by variation in the spatio-temporal dynamics of FA components within this structure. A closely regulated turnover of FA proteins within FA sites allows cells to respond appropriately to their environment, thereby impacting on cell shape and function. FA protein dynamics are linked to FA...

  1. Stretch activates human myometrium via ERK, caldesmon and focal adhesion signaling.

    Directory of Open Access Journals (Sweden)

    Yunping Li

    Full Text Available An incomplete understanding of the molecular mechanisms responsible for myometrial activation from the quiescent pregnant state to the active contractile state during labor has hindered the development of effective therapies for preterm labor. Myometrial stretch has been implicated clinically in the initiation of labor and the etiology of preterm labor, but the molecular mechanisms involved in the human have not been determined. We investigated the mechanisms by which gestation-dependent stretch contributes to myometrial activation, by using human uterine samples from gynecologic hysterectomies and Cesarean sections. Here we demonstrate that the Ca requirement for activation of the contractile filaments in human myometrium increases with caldesmon protein content during gestation and that an increase in caldesmon phosphorylation can reverse this inhibitory effect during labor. By using phosphotyrosine screening and mass spectrometry of stretched human myometrial samples, we identify 3 stretch-activated focal adhesion proteins, FAK, p130Cas, and alpha actinin. FAK-Y397, which signals integrin engagement, is constitutively phosphorylated in term human myometrium whereas FAK-Y925, which signals downstream ERK activation, is phosphorylated during stretch. We have recently identified smooth muscle Archvillin (SmAV as an ERK regulator. A newly produced SmAV-specific antibody demonstrates gestation-specific increases in SmAV protein levels and stretch-specific increases in SmAV association with focal adhesion proteins. Thus, whereas increases in caldesmon levels suppress human myometrium contractility during pregnancy, stretch-dependent focal adhesion signaling, facilitated by the ERK activator SmAV, can contribute to myometrial activation. These results suggest that focal adhesion proteins may present new targets for drug discovery programs aimed at regulation of uterine contractility.

  2. The inner workings of stress fibers - from contractile machinery to focal adhesions and back.

    Science.gov (United States)

    Livne, Ariel; Geiger, Benjamin

    2016-04-01

    Ventral stress fibers and focal adhesions are physically coupled structures that play key roles in cellular mechanics and force sensing. The tight functional interdependence between the two is manifested not only by their apparent proximity but also by the fact that ventral stress fibers and focal adhesions are simultaneously diminished upon actomyosin relaxation, and grow when subjected to external stretching. However, whereas the apparent co-regulation of the two structures is well-documented, the underlying mechanisms remains poorly understood. In this Commentary, we discuss some of the fundamental, yet still open questions regarding ventral stress fiber structure, its force-dependent assembly, as well as its capacity to generate force. We also challenge the common approach - i.e. ventral stress fibers are variants of the well-studied striated or smooth muscle machinery - by presenting and critically discussing alternative venues. By highlighting some of the less-explored aspects of the interplay between stress fibers and focal adhesions, we hope that this Commentary will encourage further investigation in this field.

  3. Angiogenin enhances cell migration by regulating stress fiber assembly and focal adhesion dynamics.

    Directory of Open Access Journals (Sweden)

    Saisai Wei

    Full Text Available Angiogenin (ANG acts on both vascular endothelial cells and cancer cells, but the underlying mechanism remains elusive. In this study, we carried out a co-immunoprecipitation assay in HeLa cells and identified 14 potential ANG-interacting proteins. Among these proteins, β-actin, α-actinin 4, and non-muscle myosin heavy chain 9 are stress fiber components and involved in cytoskeleton organization and movement, which prompted us to investigate the mechanism of action of ANG in cell migration. Upon confirmation of the interactions between ANG and the three proteins, further studies revealed that ANG co-localized with β-actin and α-actinin 4 at the leading edge of migrating cells. Down-regulation of ANG resulted in fewer but thicker stress fibers with less dynamics, which was associated with the enlargements of focal adhesions. The focal adhesion kinase activity and cell migration capacity were significantly decreased in ANG-deficient cells. Taken together, our data demonstrated that the existence of ANG in the cytoplasm optimizes stress fiber assembly and focal adhesion formation to accommodate cell migration. The finding that ANG promoted cancer cell migration might provide new clues for tumor metastasis research.

  4. TRPM4 Is a Novel Component of the Adhesome Required for Focal Adhesion Disassembly, Migration and Contractility.

    Directory of Open Access Journals (Sweden)

    Mónica Cáceres

    Full Text Available Cellular migration and contractility are fundamental processes that are regulated by a variety of concerted mechanisms such as cytoskeleton rearrangements, focal adhesion turnover, and Ca2+ oscillations. TRPM4 is a Ca2+-activated non-selective cationic channel (Ca2+-NSCC that conducts monovalent but not divalent cations. Here, we used a mass spectrometry-based proteomics approach to identify putative TRPM4-associated proteins. Interestingly, the largest group of these proteins has actin cytoskeleton-related functions, and among these nine are specifically annotated as focal adhesion-related proteins. Consistent with these results, we found that TRPM4 localizes to focal adhesions in cells from different cellular lineages. We show that suppression of TRPM4 in MEFs impacts turnover of focal adhesions, serum-induced Ca2+ influx, focal adhesion kinase (FAK and Rac activities, and results in reduced cellular spreading, migration and contractile behavior. Finally, we demonstrate that the inhibition of TRPM4 activity alters cellular contractility in vivo, affecting cutaneous wound healing. Together, these findings provide the first evidence, to our knowledge, for a TRP channel specifically localized to focal adhesions, where it performs a central role in modulating cellular migration and contractility.

  5. p38 mitogen-activated protein kinase interacts with vinculin at focal adhesions during fatty acid-stimulated cell adhesion.

    Science.gov (United States)

    George, Margaret D; Wine, Robert N; Lackford, Brad; Kissling, Grace E; Akiyama, Steven K; Olden, Kenneth; Roberts, John D

    2013-12-01

    Arachidonic acid stimulates cell adhesion by activating α2β1 integrins in a process that depends on protein kinases, including p38 mitogen activated protein kinase. Here, we describe the interaction of cytoskeletal components with key signaling molecules that contribute to the spreading of, and morphological changes in, arachidonic acid-treated MDA-MB-435 human breast carcinoma cells. Arachidonic acid-treated cells showed increased attachment and spreading on collagen type IV, as measured by electric cell-substrate impedance sensing. Fatty acid-treated cells displayed short cortical actin filaments associated with an increased number of β1 integrin-containing pseudopodia, whereas untreated cells displayed elongated stress fibers and fewer clusters of β1 integrins. Confocal microscopy of arachidonic acid-treated cells showed that vinculin and phospho-p38 both appeared enriched in pseudopodia and at the tips of actin filaments, and fluorescence ratio imaging indicated the increase was specific for the phospho-(active) form of p38. Immunoprecipitates of phospho-p38 from extracts of arachidonic acid-treated cells contained vinculin, and GST-vinculin fusion proteins carrying the central region of vinculin bound phospho-p38, whereas fusion proteins expressing the terminal portions of vinculin did not. These data suggest that phospho-p38 associates with particular domains on critical focal adhesion proteins that are involved in tumor cell adhesion and spreading, and that this association can be regulated by factors in the tumor microenvironment.

  6. Focal Adhesion Kinase Regulates Expression of Thioredoxin-interacting Protein (TXNIP) in Cancer Cells

    OpenAIRE

    2014-01-01

    Focal Adhesion Kinase (FAK) plays an important role in cancer cell survival. Previous microarray gene profiling study detected inverse regulation between expression of thioredoxin-interacting protein (TXNIP) and FAK, where down-regulation of FAK by siRNA in MCF-7 cells caused up-regulation of TXNIP mRNA level, and in contrast up-regulation of doxycyclin- induced FAK caused repression of TXNIP. In the present report, we show that overexpression of FAK in MCF-7 cells repressed TXNIP promoter ac...

  7. Nanoengineered surfaces for focal adhesion guidance trigger mesenchymal stem cell self-organization and tenogenesis.

    Science.gov (United States)

    Iannone, Maria; Ventre, Maurizio; Formisano, Lucia; Casalino, Laura; Patriarca, Eduardo J; Netti, Paolo A

    2015-03-11

    The initial conditions for morphogenesis trigger a cascade of events that ultimately dictate structure and functions of tissues and organs. Here we report that surface nanopatterning can control the initial assembly of focal adhesions, hence guiding human mesenchymal stem cells (hMSCs) through the process of self-organization and differentiation. This process self-sustains, leading to the development of macroscopic tissues with molecular profiles and microarchitecture reminiscent of embryonic tendons. Therefore, material surfaces can be in principle engineered to set off the hMSC program toward tissuegenesis in a deterministic manner by providing adequate sets of initial environmental conditions.

  8. Focal adhesion kinase modulates activation of NF-κB by flow in endothelial cells

    OpenAIRE

    Petzold, Tobias; Orr, A. Wayne; Hahn, Cornelia; Jhaveri, Krishna A.; Parsons, J Thomas; Schwartz, Martin Alexander

    2009-01-01

    Atherogenesis involves activation of NF-κB in endothelial cells by fluid shear stress. Because this pathway involves integrins, we investigated the involvement of focal adhesion kinase (FAK). We found that FAK was not required for flow-stimulated translocation of the p65 NF-κB subunit to the nucleus but was essential for phosphorylation of p65 on serine 536 and induction of ICAM-1, an NF-κB-dependent gene. NF-κB activation by TNF-α or hydrogen peroxide was FAK independent. Events upstream of ...

  9. The role of focal adhesion complexes in fibroblast mechanotransduction during scar formation.

    Science.gov (United States)

    Rustad, Kristine C; Wong, Victor W; Gurtner, Geoffrey C

    2013-10-01

    Historically, great efforts have been made to elucidate the biochemical pathways that direct the complex process of wound healing; however only recently has there been recognition of the importance that mechanical signals play in the process of tissue repair and scar formation. The body's physiologic response to injury involves a dynamic interplay between mechanical forces and biochemical cues which directs a cascade of signals leading ultimately to the formation of fibrotic scar. Fibroblasts are a highly mechanosensitive cell type and are also largely responsible for the generation of the fibrotic matrix during scar formation and are thus a critical player in the process of mechanotransduction during tissue repair. Mechanotransduction is initiated at the interface between the cell membrane and the extracellular matrix where mechanical signals are first translated into a biochemical response. Focal adhesions are dynamic multi-protein complexes through which the extracellular matrix links to the intracellular cytoskeleton. These focal adhesion complexes play an integral role in the propagation of this initial mechanical cue into an extensive network of biochemical signals leading to widespread downstream effects including the influx of inflammatory cells, stimulation of angiogenesis, keratinocyte migration, fibroblast proliferation and collagen synthesis. Increasing evidence has demonstrated the importance of the biomechanical milieu in healing wounds and suggests that an integrated approach to the discovery of targets to decrease scar formation may prove more clinically efficacious than previous purely biochemical strategies.

  10. The role of focal adhesion kinase in the regulation of cellular mechanical properties

    Science.gov (United States)

    Mierke, Claudia Tanja

    2013-12-01

    The regulation of mechanical properties is necessary for cell invasion into connective tissue or intra- and extravasation through the endothelium of blood or lymph vessels. Cell invasion is important for the regulation of many healthy processes such as immune response reactions and wound healing. In addition, cell invasion plays a role in disease-related processes such as tumor metastasis and autoimmune responses. Until now the role of focal adhesion kinase (FAK) in regulating mechanical properties of cells and its impact on cell invasion efficiency is still not well known. Thus, this review focuses on mechanical properties regulated by FAK in comparison to the mechano-regulating protein vinculin. Moreover, it points out the connection between cancer cell invasion and metastasis and FAK by showing that FAK regulates cellular mechanical properties required for cellular motility. Furthermore, it sheds light on the indirect interaction of FAK with vinculin by binding to paxillin, which then impairs the binding of paxillin to vinculin. In addition, this review emphasizes whether FAK fulfills regulatory functions similar to vinculin. In particular, it discusses the differences and the similarities between FAK and vinculin in regulating the biomechanical properties of cells. Finally, this paper highlights that both focal adhesion proteins, vinculin and FAK, synergize their functions to regulate the mechanical properties of cells such as stiffness and contractile forces. Subsequently, these mechanical properties determine cellular invasiveness into tissues and provide a source sink for future drug developments to inhibit excessive cell invasion and hence, metastases formation.

  11. Myxococcus xanthus gliding motors are elastically coupled to the substrate as predicted by the focal adhesion model of gliding motility

    CERN Document Server

    Balagam, Rajesh; Czerwinski, Fabian; Sun, Mingzhai; Kaplan, Heidi B; Shaevitz, Joshua W; Igoshin, Oleg A

    2014-01-01

    Myxococcus xanthus is a model organism for studying bacterial social behaviors due to its ability to form complex multi-cellular structures. Knowledge of M. xanthus surface gliding motility and the mechanisms that coordinate it are critically important to our understanding of collective cell behaviors. Although the mechanism of gliding motility is still under investigation, recent experiments suggest that there are two possible mechanisms underlying force production for cell motility: the focal adhesion mechanism and the helical rotor mechanism which differ in the biophysics of the cell-substrate interactions. Whereas the focal adhesion model predicts an elastic coupling, the helical rotor model predicts a viscous coupling. Using a combination of computational modeling, imaging, and force microscopy, we find evidence for elastic coupling in support of the focal adhesion model. Using a biophysical model of the M. xanthus cell, we investigated how the mechanical interactions between cells are affected by intera...

  12. Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins.

    Science.gov (United States)

    Seong, Jihye; Tajik, Arash; Sun, Jie; Guan, Jun-Lin; Humphries, Martin J; Craig, Susan E; Shekaran, Asha; García, Andrés J; Lu, Shaoying; Lin, Michael Z; Wang, Ning; Wang, Yingxiao

    2013-11-26

    Matrix mechanics controls cell fate by modulating the bonds between integrins and extracellular matrix (ECM) proteins. However, it remains unclear how fibronectin (FN), type 1 collagen, and their receptor integrin subtypes distinctly control force transmission to regulate focal adhesion kinase (FAK) activity, a crucial molecular signal governing cell adhesion/migration. Here we showed, using a genetically encoded FAK biosensor based on fluorescence resonance energy transfer, that FN-mediated FAK activation is dependent on the mechanical tension, which may expose its otherwise hidden FN synergy site to integrin α5. In sharp contrast, the ligation between the constitutively exposed binding motif of type 1 collagen and its receptor integrin α2 was surprisingly tension-independent to induce sufficient FAK activation. Although integrin α subunit determines mechanosensitivity, the ligation between α subunit and the ECM proteins converges at the integrin β1 activation to induce FAK activation. We further discovered that the interaction of the N-terminal protein 4.1/ezrin/redixin/moesin basic patch with phosphatidylinositol 4,5-biphosphate is crucial during cell adhesion to maintain the FAK activation from the inhibitory effect of nearby protein 4.1/ezrin/redixin/moesin acidic sites. Therefore, different ECM proteins either can transmit or can shield from mechanical forces to regulate cellular functions, with the accessibility of ECM binding motifs by their specific integrin α subunits determining the biophysical mechanisms of FAK activation during mechanotransduction.

  13. Alveolar Type II Cells Escape Stress Failure Caused by Tonic Stretch through Transient Focal Adhesion Disassembly

    Directory of Open Access Journals (Sweden)

    Xiao-Yang Liu, Xiao-Fei Chen, Yan-Hong Ren, Qing-Yuan Zhan, Chen Wang, Chun Yang

    2011-01-01

    Full Text Available Mechanical ventilation-induced excessive stretch of alveoli is reported to induce cellular stress failure and subsequent lung injury, and is therefore an injurious factor to the lung. Avoiding cellular stress failure is crucial to ventilator-induced lung injury (VILI treatment. In the present study, primary rat alveolar type II (ATII cells were isolated to evaluate their viability and the mechanism of their survival under tonic stretch. By the annexin V/ PI staining and flow cytometry assay, we demonstrated that tonic stretch-induced cell death is an immediate injury of mechanical stress. In addition, immunofluorescence and immunoblots assay showed that the cells experienced an expansion-contraction-reexpansion process, accompanied by partial focal adhesion (FA disassembly during contraction. Manipulation of integrin adherent affinity by altering bivalent cation levels in the culture medium and applying an integrin neutralizing antibody showed that facilitated adhesion affinity promoted cell death under tonic stretch, while lower level of adhesion protected the cells from stretch-induced stress failure. Finally, a simplified numerical model was established to reveal that adequate disassembly of FAs reduced the forces transmitting throughout the cell. Taken together, these results indicate that ATII cells escape stress failure caused by tonic stretch via active cell morphological remodeling, during which cells transiently disassemble FAs to unload mechanical forces.

  14. Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoAD⃞

    Science.gov (United States)

    Nelson, Celeste M.; Pirone, Dana M.; Tan, John L.; Chen, Christopher S.

    2004-01-01

    Changes in vascular endothelial (VE)-cadherin–mediated cell-cell adhesion and integrin-mediated cell-matrix adhesion coordinate to affect the physical and mechanical rearrangements of the endothelium, although the mechanisms for such cross talk remain undefined. Herein, we describe the regulation of focal adhesion formation and cytoskeletal tension by intercellular VE-cadherin engagement, and the molecular mechanism by which this occurs. Increasing the density of endothelial cells to increase cell-cell contact decreased focal adhesions by decreasing cell spreading. This contact inhibition of cell spreading was blocked by disrupting VE-cadherin engagement with an adenovirus encoding dominant negative VE-cadherin. When changes in cell spreading were prevented by culturing cells on a micropatterned substrate, VE-cadherin–mediated cell-cell contact paradoxically increased focal adhesion formation. We show that VE-cadherin engagement mediates each of these effects by inducing both a transient and sustained activation of RhoA. Both the increase and decrease in cell-matrix adhesion were blocked by disrupting intracellular tension and signaling through the Rho-ROCK pathway. In all, these findings demonstrate that VE-cadherin signals through RhoA and the actin cytoskeleton to cross talk with cell-matrix adhesion and thereby define a novel pathway by which cell-cell contact alters the global mechanical and functional state of cells. PMID:15075376

  15. The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions.

    OpenAIRE

    1995-01-01

    Focal adhesions are sites of cell-extracellular matrix interactions that function in anchoring stress fibers to the plasma membrane and in adhesion-mediated signal transduction. Both focal adhesion structure and signaling ability involve protein tyrosine phosphorylation. LAR is a broadly expressed transmembrane protein tyrosine phosphatase comprised of a cell adhesion-like ectodomain and two intracellular protein tyrosine phosphatase domains. We have identified a novel cytoplasmic 160 kDa pho...

  16. Up-regulation of Paxillin and Focal Adhesion Signaling follows Dystroglycan Complex deletions and promotes a Hypertensive State of Differentiation

    OpenAIRE

    Sen, Shamik; Tewari, Manorama; Zajac, Allison; Barton, Elisabeth; Sweeney, H. Lee; Discher, Dennis E.

    2011-01-01

    Anchorage to matrix is mediated for many cells not only by integrin-based focal adhesions but also by a parallel assembly of integral and peripheral membrane proteins known as the Dystroglycan Complex. Deficiencies in either dystrophin (mdx mice) or γ-sarcoglycan (γSG−/− mice) components of the Dystroglycan Complex lead to upregulation of numerous focal adhesion proteins, and the phosphoprotein paxillin proves to be among the most prominent. In mdx muscle, paxillin-Y31 and Y118 are both hyper...

  17. Upregulation of paxillin and focal adhesion signaling follows Dystroglycan Complex deletions and promotes a hypertensive state of differentiation.

    Science.gov (United States)

    Sen, Shamik; Tewari, Manorama; Zajac, Allison; Barton, Elisabeth; Sweeney, H Lee; Discher, Dennis E

    2011-01-01

    Anchorage to matrix is mediated for many cells not only by integrin-based focal adhesions but also by a parallel assembly of integral and peripheral membrane proteins known as the Dystroglycan Complex. Deficiencies in either dystrophin (mdx mice) or γ-sarcoglycan (γSG(-/-) mice) components of the Dystroglycan Complex lead to upregulation of numerous focal adhesion proteins, and the phosphoprotein paxillin proves to be among the most prominent. In mdx muscle, paxillin-Y31 and Y118 are both hyper-phosphorylated as are key sites in focal adhesion kinase (FAK) and the stretch-stimulatable pro-survival MAPK pathway, whereas γSG(-/-) muscle exhibits more erratic hyper-phosphorylation. In cultured myotubes, cell tension generated by myosin-II appears required for localization of paxillin to adhesions while vinculin appears more stably integrated. Overexpression of wild-type (WT) paxillin has no obvious effect on focal adhesion density or the physical strength of adhesion, but WT and a Y118F mutant promote contractile sarcomere formation whereas a Y31F mutant shows no effect, implicating Y31 in striation. Self-peeling of cells as well as Atomic Force Microscopy (AFM) probing of cells with or without myosin-II inhibition indicate an increase in cell tension within paxillin-overexpressing cells. However, prednisolone, a first-line glucocorticoid for muscular dystrophies, decreases cell tension without affecting paxillin at adhesions, suggesting a non-linear relationship between paxillin and cell tension. Hypertension that results from upregulation of integrin adhesions is thus a natural and treatable outcome of Dystroglycan Complex down-regulation.

  18. Biphasic function of focal adhesion kinase in endothelial tube formation induced by fibril-forming collagens.

    Science.gov (United States)

    Nakamura, Junko; Shigematsu, Satoshi; Yamauchi, Keishi; Takeda, Teiji; Yamazaki, Masanori; Kakizawa, Tomoko; Hashizume, Kiyoshi

    2008-10-03

    Migration and tube formation of endothelial cells are important in angiogenesis and require a coordinated response to the extra-cellular matrix (ECM) and growth factor. Since focal adhesion kinase (FAK) integrates signals from both ECM and growth factor, we investigated its role in angiogenesis. Type I and II collagens are fibril-forming collagens and stimulate human umbilical vein endothelial cells (HUVECs) to form tube structure. Although knockdown of FAK restrained cell motility and resulted in inhibition of tube formation, FAK degradation and tube formation occurred simultaneously after incubation with fibril-forming collagens. The compensation for the FAK degradation by a calpain inhibitor or transient over-expression of FAK resulted in disturbance of tube formation. These phenomena are specific to fibril-forming collagens and mediated via alpha2beta1 integrin. In conclusion, our data indicate that FAK is functioning in cell migration, but fibril-forming collagen-induced FAK degradation is necessary for endothelial tube formation.

  19. Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation.

    Directory of Open Access Journals (Sweden)

    Tomas Garzon-Muvdi

    Full Text Available Glioblastoma (GB is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na(+-K(+-Cl(- cotransporter 1 (NKCC1 can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF, which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1 through the regulation of focal adhesion dynamics and cell contractility and (2 through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.

  20. Composite resin's adhesive resistance to dentin: influence of Er:YAG laser focal distance variation.

    Science.gov (United States)

    Corona, Silmara Aparecida Milori; Atoui, Juliana Abdallah; Chimello, Daniela Thomazatti; Borsatto, Maria Cristina; Pecora, Jesus Djalma; Dibb, Regina Guenka Palma

    2005-04-01

    The aim of this study was to analyze in vitro the influence of Er:YAG laser focal distance variation on tensile bond strength of a composite resin to dentin. Although there are several studies using the Er:YAG laser for dentin treatment, there is a lack of available literature related to the Er:YAG laser focal distance variation. Sixty vestibular and lingual dentin surfaces from extracted human third molars, kept in a 0.4% azide sodium solution, were ground and assigned to six groups. The control group was conditioned with 35% phosphoric acid (CA). In the lased groups, the dentin surface treatment was performed by irradiation with Er:YAG laser (80 mJ/2 Hz), varying the focal distance (11, 12, 14, 16, and 17 mm), followed by acid etching. The Single Bond/Filtek Z250 (3M) resinous system was used for the specimen manufacture. The tensile bond strength tests were performed in a Universal Testing Machine with 50 kgf load cell and 0.5 mm/min cross head speed. The averages in MPa were: CA: 18.03 (+/-2.09); 11 mm; 9.92 (+/-3.34); 12 mm: 9.49 (+/-2.29); 14 mm: 10.99 (+/-3.45); 16 mm: 10.56 (+/-1.93); and 17 mm: 17.05 (+/-2.31). It was concluded that the application of Er:YAG laser in a defocused mode (17 mm) associated with acid etching was similar to the treatment of acid solely. Er:YAG laser irradiation in a focused (12 mm) and a defocused (11, 14, and 16 mm) mode coupled with acid conditioning produced the lowest values of adhesion.

  1. MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism

    Science.gov (United States)

    Chugh, Seema; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Gupta, Suprit; Seshacharyulu, Parthasarathy; Smith, Lynette M.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2016-01-01

    MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model. Mechanistically, immunoprecipitation and immunofluorescence analyses confirms MUC16 interaction with galectin-3 and mesothelin in PDAC cells. Adhesion assay displayed decreased cell attachment of MUC16 knockdown cells with recombinant galectin-1 and galectin-3 protein. Further, CRISPR/Cas9-mediated MUC16 knockout cells show decreased tumor-associated carbohydrate antigens (T and Tn) in PDAC cells. Importantly, carbohydrate antigens were decreased in the region that corresponds to MUC16 and suggests for the decreased MUC16-galectin interactions. Co-immunoprecipitation also revealed a novel interaction between MUC16 and FAK in PDAC cells. Interestingly, we observed decreased expression of mesenchymal and increased expression of epithelial markers in MUC16-silenced cells. Additionally, MUC16 loss showed a decreased FAK-mediated Akt and ERK/MAPK activation. Altogether, these findings suggest that MUC16-focal adhesion signaling may play a critical role in facilitating PDAC growth and metastasis. PMID:27382435

  2. Decipher the dynamic coordination between enzymatic activity and structural modulation at focal adhesions in living cells

    Science.gov (United States)

    Lu, Shaoying; Seong, Jihye; Wang, Yi; Chang, Shiou-Chi; Eichorst, John Paul; Ouyang, Mingxing; Li, Julie Y.-S.; Chien, Shu; Wang, Yingxiao

    2014-07-01

    Focal adhesions (FAs) are dynamic subcellular structures crucial for cell adhesion, migration and differentiation. It remains an enigma how enzymatic activities in these local complexes regulate their structural remodeling in live cells. Utilizing biosensors based on fluorescence resonance energy transfer (FRET), we developed a correlative FRET imaging microscopy (CFIM) approach to quantitatively analyze the subcellular coordination between the enzymatic Src activation and the structural FA disassembly. CFIM reveals that the Src kinase activity only within the microdomain of lipid rafts at the plasma membrane is coupled with FA dynamics. FA disassembly at cell periphery was linearly dependent on this raft-localized Src activity, although cells displayed heterogeneous levels of response to stimulation. Within lipid rafts, the time delay between Src activation and FA disassembly was 1.2 min in cells seeded on low fibronectin concentration ([FN]) and 4.3 min in cells on high [FN]. CFIM further showed that the level of Src-FA coupling, as well as the time delay, was regulated by cell-matrix interactions, as a tight enzyme-structure coupling occurred in FA populations mediated by integrin αvβ3, but not in those by integrin α5β1. Therefore, different FA subpopulations have distinctive regulation mechanisms between their local kinase activity and structural FA dynamics.

  3. Focal adhesion kinase modulates radial glia-dependent neuronal migration through connexin-26.

    Science.gov (United States)

    Valiente, Manuel; Ciceri, Gabriele; Rico, Beatriz; Marín, Oscar

    2011-08-10

    Focal adhesion kinase (FAK) is an intracellular kinase and scaffold protein that regulates migration in many different cellular contexts but whose function in neuronal migration remains controversial. Here, we have analyzed the function of FAK in two populations of neurons with very distinct migratory behaviors: cortical interneurons, which migrate tangentially and independently of radial glia; and pyramidal cells, which undergo glial-dependent migration. We found that FAK is dispensable for glial-independent migration but is cell-autonomously required for the normal interaction of pyramidal cells with radial glial fibers. Loss of FAK function disrupts the normal morphology of migrating pyramidal cells, delays migration, and increases the tangential dispersion of neurons arising from the same radial unit. FAK mediates this process by regulating the assembly of Connexin-26 contact points in the membrane of migrating pyramidal cells. These results indicate that FAK plays a fundamental role in the dynamic regulation of Gap-mediated adhesions during glial-guided neuronal migration in the mouse.

  4. Integrin-Associated Focal Adhesion Kinase Protects Human Embryonic Stem Cells from Apoptosis, Detachment, and Differentiation

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    Loriana Vitillo

    2016-08-01

    Full Text Available Human embryonic stem cells (hESCs can be maintained in a fully defined niche on extracellular matrix substrates, to which they attach through integrin receptors. However, the underlying integrin signaling mechanisms, and their contribution to hESC behavior, are largely unknown. Here, we show that focal adhesion kinase (FAK transduces integrin activation and supports hESC survival, substrate adhesion, and maintenance of the undifferentiated state. After inhibiting FAK kinase activity we show that hESCs undergo cell detachment-dependent apoptosis or differentiation. We also report deactivation of FAK downstream targets, AKT and MDM2, and upregulation of p53, all key players in hESC regulatory networks. Loss of integrin activity or FAK also induces cell aggregation, revealing a role in the cell-cell interactions of hESCs. This study provides insight into the integrin signaling cascade activated in hESCs and reveals in FAK a key player in the maintenance of hESC survival and undifferentiated state.

  5. PROLACTIN-INDUCED TYROSINE PHOSPHORYLATION, ACTIVATION AND RECEPTOR ASSOCIATION OF FOCAL ADHESION KINASE (FAK) IN MAMMARY EPITHELIAL CELLS

    Science.gov (United States)

    Prolactin-Induced Tyrosine Phosphorylation, Activation and ReceptorAssociation of Focal Adhesion Kinase (FAK) in Mammary Epithelial Cells. Suzanne E. Fenton1 and Lewis G. Sheffield2. 1U.S. Environmental ProtectionAgency, MD-72, Research Triangle Park, NC 27711, and

  6. mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration.

    Science.gov (United States)

    Gupton, Stephanie L; Eisenmann, Kathryn; Alberts, Arthur S; Waterman-Storer, Clare M

    2007-10-01

    Cell migration requires spatial and temporal regulation of filamentous actin (F-actin) dynamics. This regulation is achieved by distinct actin-associated proteins, which mediate polymerization, depolymerization, severing, contraction, bundling or engagement to the membrane. Mammalian Diaphanous-related (mDia) formins, which nucleate, processively elongate, and in some cases bundle actin filaments, have been extensively studied in vitro, but their function in the cell has been less well characterized. Here we study the role of mDia2 activity in the dynamic organization of F-actin in migrating epithelial cells. We find that mDia2 localizes in the lamella of migrating epithelial cells, where it is involved in the formation of a stable pool of cortical actin and in maintenance of polymerization-competent free filament barbed ends at focal adhesions. Specific inhibition of mDia2 alters focal adhesion turnover and reduces migration velocity. We suggest that the regulation of filament assembly dynamics at focal adhesions may be necessary for the formation of a stable pool of cortical lamella actin and the proper assembly and disassembly dynamics of focal adhesions, making mDia2 an important factor in epithelial cell migration.

  7. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling

    NARCIS (Netherlands)

    Ashton, G.H.; Morton, J.P.; Myant, K.; Phesse, T.J.; Ridgway, R.A.; Marsh, V.; Wilkins, J.A.; Athineos, D.; Muncan, V.; Kemp, R.; Neufeld, K.; Clevers, H.; Brunton, V.; Winton, D.J.; Wang, X.; Sears, R.; Clarke, A.R.; Frame, M.C.; Sansom, O.J.

    2010-01-01

    The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration followin

  8. Mammary gland-specific ablation of focal adhesion kinase reduces the incidence of p53-mediated mammary tumour formation.

    NARCIS (Netherlands)

    Miltenburg, van M.H.; Nimwegen, van M.J.; Tijdens, R.B.; Lalai, R.A.; Kuiper, R.; Klarenbeek, S.; Schouten, P.C.; Vries, de A.; Jonkers, J.M.M..; Water, van de B.

    2014-01-01

    BACKGROUND Elevated expression of focal adhesion kinase (FAK) occurs in numerous human cancers including colon-, cervix- and breast cancer. Although several studies have implicated FAK in mammary tumour formation induced by ectopic oncogene expression, evidence supporting a role for FAK in spontaneo

  9. Translucent titanium coating altered the composition of focal adhesions and promoted migration of osteoblast-like MG-63 cells on glass.

    Science.gov (United States)

    Ho, Yi; Kok, Sang-Heng; Wang, Juo-Song; Lin, Li-Deh

    2014-04-01

    "TiGlass" was designed and was known to promote initial adhesion and increase migration of rat calvarial osteoblats. In this article, migration study and a series of epifluorescence microscopic studies were conducted to find out the composition of focal adhesion on titanium surface. The translucent titanium surface was applied in random migration analysis and immunofluorescence cell staining. In the immunofluorescent double staining, phosphorylated focal adhesion kinase was tested with vinculin. Various integrin subunits were then tested with vinculin to study the composition of activated focal adhesions. Integrin subunit α5 and αV were tested against β3; integrin subunits α5, αV, β3, and αVβ3 were tested with F-actin, respectively. The MG-63 cells began migration earlier and migrated faster on "TiGlass." Immunofluorescent double staining revealed that all focal adhesion kinase in the focal adhesions were activated on both the surfaces. The osteoblast was inferred to made adhesion to titanium and glass through integrins. The focal adhesions on glass were found to be composed of integrin subunits αV and β3. However, on "TiGlass," integrin subunits α5 might have supplemented the adhesion to titanium. Results from double staining of integrin subunits α5, αV, β3, and αVβ3 with F-actin also supported integrin subunits α5 might have involved in adhesion of titanium.

  10. Inositol hexaphosphate (IP6) inhibits key events of cancer metastasis: II. Effects on integrins and focal adhesions.

    Science.gov (United States)

    Tantivejkul, Kwanchanit; Vucenik, Ivana; Shamsuddin, Abulkalam M

    2003-01-01

    We have shown that inositol hexaphosphate (IP6), a natural compound and a potent anti-cancer agent, inhibited cancer cell adhesion to the extracellular matrix (ECM) proteins, thereby leading to inhibition of cell migration and invasion. Cell adhesion to ECM is mediated by specific cell surface integrins, which transduce intracellular signals through their interaction and activation of other proteins that are recruited to the focal adhesion. We hypothesize that IP6 decreases cell adhesion by suppressing the integrin receptors and their subsequent signaling pathway. We analyzed integrin expressions of the highly invasive estrogen receptor-negative human breast cancer MDA-MB 231 cells exposed to IP6 by flow cytometry. The expression of focal adhesion proteins was investigated by immunocytochemistry and Western blotting. IP6 treatment caused a significant (P IP6 treatment. When the expression of integrins on the cell surface was assessed, there was a dramatic 82% decrease in the expression of alpha 5 beta 1 on IP6-treated cells (P IP6, was used as a control. Immunocytochemistry showed a lack of clustering of paxillin; tyrosine-phosphorylated proteins in IP6-treated cells were discontinuous and scattered around the cell periphery, whereas the patterns were more dense and localized in control cells. Consistent with these observations, focal adhesion kinase (FAK) autophosphorylation at tyrosine-397 residue was suppressed, albeit modestly, by IP6 treatment, suggesting a down-regulation in the integrin-mediated signaling pathway. The results of this study indicate that IP6-induced inhibition of cancer cell adhesion, migration and invasion may be mediated through the modulation of integrin dimerization, cell surface expression and integrin-associated signaling pathway.

  11. Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis.

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    Duane Delimont

    Full Text Available It has been known for some time that laminins containing α1 and α2 chains, which are normally restricted to the mesangial matrix, accumulate in the glomerular basement membranes (GBM of Alport mice, dogs, and humans. We show that laminins containing the α2 chain, but not those containing the α1 chain activates focal adhesion kinase (FAK on glomerular podocytes in vitro and in vivo. CD151-null mice, which have weakened podocyte adhesion to the GBM rendering these mice more susceptible to biomechanical strain in the glomerulus, also show progressive accumulation of α2 laminins in the GBM, and podocyte FAK activation. Analysis of glomerular mRNA from both models demonstrates significant induction of MMP-9, MMP-10, MMP-12, MMPs linked to GBM destruction in Alport disease models, as well as the pro-inflammatory cytokine IL-6. SiRNA knockdown of FAK in cultured podocytes significantly reduced expression of MMP-9, MMP-10 and IL-6, but not MMP-12. Treatment of Alport mice with TAE226, a small molecule inhibitor of FAK activation, ameliorated fibrosis and glomerulosclerosis, significantly reduced proteinuria and blood urea nitrogen levels, and partially restored GBM ultrastructure. Glomerular expression of MMP-9, MMP-10 and MMP-12 mRNAs was significantly reduced in TAE226 treated animals. Collectively, this work identifies laminin α2-mediated FAK activation in podocytes as an important early event in Alport glomerular pathogenesis and suggests that FAK inhibitors, if safe formulations can be developed, might be employed as a novel therapeutic approach for treating Alport renal disease in its early stages.

  12. Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis.

    Science.gov (United States)

    Delimont, Duane; Dufek, Brianna M; Meehan, Daniel T; Zallocchi, Marisa; Gratton, Michael Anne; Phillips, Grady; Cosgrove, Dominic

    2014-01-01

    It has been known for some time that laminins containing α1 and α2 chains, which are normally restricted to the mesangial matrix, accumulate in the glomerular basement membranes (GBM) of Alport mice, dogs, and humans. We show that laminins containing the α2 chain, but not those containing the α1 chain activates focal adhesion kinase (FAK) on glomerular podocytes in vitro and in vivo. CD151-null mice, which have weakened podocyte adhesion to the GBM rendering these mice more susceptible to biomechanical strain in the glomerulus, also show progressive accumulation of α2 laminins in the GBM, and podocyte FAK activation. Analysis of glomerular mRNA from both models demonstrates significant induction of MMP-9, MMP-10, MMP-12, MMPs linked to GBM destruction in Alport disease models, as well as the pro-inflammatory cytokine IL-6. SiRNA knockdown of FAK in cultured podocytes significantly reduced expression of MMP-9, MMP-10 and IL-6, but not MMP-12. Treatment of Alport mice with TAE226, a small molecule inhibitor of FAK activation, ameliorated fibrosis and glomerulosclerosis, significantly reduced proteinuria and blood urea nitrogen levels, and partially restored GBM ultrastructure. Glomerular expression of MMP-9, MMP-10 and MMP-12 mRNAs was significantly reduced in TAE226 treated animals. Collectively, this work identifies laminin α2-mediated FAK activation in podocytes as an important early event in Alport glomerular pathogenesis and suggests that FAK inhibitors, if safe formulations can be developed, might be employed as a novel therapeutic approach for treating Alport renal disease in its early stages.

  13. The emerin-binding transcription factor Lmo7 is regulated by association with p130Cas at focal adhesions

    Directory of Open Access Journals (Sweden)

    Michele A. Wozniak

    2013-08-01

    Full Text Available Loss of function mutations in the nuclear inner membrane protein, emerin, cause X-linked Emery-Dreifuss muscular dystrophy (X-EDMD. X-EDMD is characterized by contractures of major tendons, skeletal muscle weakening and wasting, and cardiac conduction system defects. The transcription factor Lmo7 regulates muscle- and heart-relevant genes and is inhibited by binding to emerin, suggesting Lmo7 misregulation contributes to EDMD disease. Lmo7 associates with cell adhesions and shuttles between the plasma membrane and nucleus, but the regulation and biological consequences of this dual localization were unknown. We report endogenous Lmo7 also associates with focal adhesions in cells, and both co-localizes and co-immunoprecipitates with p130Cas, a key signaling component of focal adhesions. Lmo7 nuclear localization and transcriptional activity increased significantly in p130Cas-null MEFs, suggesting Lmo7 is negatively regulated by p130Cas-dependent association with focal adhesions. These results support EDMD models in which Lmo7 is a downstream mediator of integrin-dependent signaling that allows tendon cells and muscles to adapt to and withstand mechanical stress.

  14. Diamagnetic levitation causes changes in the morphology, cytoskeleton, and focal adhesion proteins expression in osteocytes.

    Science.gov (United States)

    Qian, A R; Wang, L; Gao, X; Zhang, W; Hu, L F; Han, J; Li, J B; Di, S M; Shang, Peng

    2012-01-01

    Diamagnetic levitation technology is a novel simulated weightless technique and has recently been applied in life-science research. We have developed a superconducting magnet platform with large gradient high magnetic field (LG-HMF), which can provide three apparent gravity levels, namely, μg (diamagnetic levitation), 1g, and 2g for diamagnetic materials. In this study, the effects of LG-HMF on the activity, morphology, and cytoskeleton (actin filament, microtubules, and vimentin intermediate filaments) in osteocyte - like cell line MLO-Y4 were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) methods, hematoxylin-eosin (HE) staining, and laser scanning confocal microscopy (LSCM), respectively. The changes induced by LG-HMF in distribution and expression of focal adhesion (FA) proteins, including vinculin, paxillin, and talin in MLO-Y4 were determined by LSCM and Western blotting. The results showed that LG-HMF produced by superconducting magnet had no lethal effects on MLO-Y4. Compared to control, diamagnetic levitation (μg) affected MLO-Y4 morphology, nucleus size, cytoskeleton architecture, and FA proteins distribution and expression. The study indicates that osteocytes are sensitive to altered gravity and FA proteins (vinculin, paxillin, and talin) may be involved in osteocyte mechanosensation. The diamagnetic levitation may be a novel ground-based space-gravity simulator and can be used for biological experiment at cellular level. © 2011 IEEE

  15. Focal adhesion kinase is involved in the migration of human osteosarcoma cells

    Science.gov (United States)

    FENG, SITAN; SHI, XIN; REN, KE; WU, SUJIA; SUN, XIAOLIANG

    2015-01-01

    The aim of the present study was to analyze the expression of focal adhesion kinase (FAK) in osteosarcoma (OS) cell lines with different migration abilities in order to determine the role of FAK in migration. A number of different 143B subclone cell lines (A1, A2, A3, A4 and A5) were obtained by a limiting dilution method, and the expression of FAK was detected using western blot analysis. The role of FAK in the migration of OS cells was investigated using small interfering RNA (siRNA), and the ratio of the number of lamellipodia was compared by immunofluorescence staining. The A2 and A3 OS 143B subclone cell lines demonstrated a stronger migration ability and exhibited higher FAK expression compared with the A1 cell line (P<0.05). Following transfection with FAK-siRNA, the migration ability of the A3 cells was significantly decreased (P<0.05), and the ratio of the number of lamellipodia formed was reduced from 35 to 11% (P<0.05). In conclusion, the level of FAK expression was higher in the cell lines with a stronger migration ability. FAK affects the migration ability of OS cells by suppressing the formation of lamellipodia. PMID:26137126

  16. High-Content Microscopy Analysis of Subcellular Structures: Assay Development and Application to Focal Adhesion Quantification.

    Science.gov (United States)

    Kroll, Torsten; Schmidt, David; Schwanitz, Georg; Ahmad, Mubashir; Hamann, Jana; Schlosser, Corinne; Lin, Yu-Chieh; Böhm, Konrad J; Tuckermann, Jan; Ploubidou, Aspasia

    2016-07-01

    High-content analysis (HCA) converts raw light microscopy images to quantitative data through the automated extraction, multiparametric analysis, and classification of the relevant information content. Combined with automated high-throughput image acquisition, HCA applied to the screening of chemicals or RNAi-reagents is termed high-content screening (HCS). Its power in quantifying cell phenotypes makes HCA applicable also to routine microscopy. However, developing effective HCA and bioinformatic analysis pipelines for acquisition of biologically meaningful data in HCS is challenging. Here, the step-by-step development of an HCA assay protocol and an HCS bioinformatics analysis pipeline are described. The protocol's power is demonstrated by application to focal adhesion (FA) detection, quantitative analysis of multiple FA features, and functional annotation of signaling pathways regulating FA size, using primary data of a published RNAi screen. The assay and the underlying strategy are aimed at researchers performing microscopy-based quantitative analysis of subcellular features, on a small scale or in large HCS experiments. © 2016 by John Wiley & Sons, Inc.

  17. Focal adhesion kinase regulates expression of thioredoxin-interacting protein (TXNIP) in cancer cells.

    Science.gov (United States)

    Ho, Baotran; Huang, Grace; Golubovskaya, Vita M

    2014-01-01

    Focal Adhesion Kinase (FAK) plays an important role in cancer cell survival. Previous microarray gene profiling study detected inverse regulation between expression of thioredoxin-interacting protein (TXNIP) and FAK, where down-regulation of FAK by siRNA in MCF-7 cells caused up-regulation of TXNIP mRNA level, and in contrast up-regulation of doxycyclin- induced FAK caused repression of TXNIP. In the present report, we show that overexpression of FAK in MCF-7 cells repressed TXNIP promoter activity. Treatment of MCF-7 cells with 1alpha, 25-dihydroxyvitamin D3 (1,25D) down-regulated endogenous FAK and up-regulated TXNIP protein level, and treatment with 5-FU decreased FAK protein expression and up-regulated TXNIP protein expression in 293 cells. Moreover, silencing of FAK with siRNA increased TXNIP protein expression, while overexpression of FAK inhibited TXNIP protein expression in 293 cells. In addition, treatment of DBTRG glioblastoma cells with FAK inhibitor Y15 increased TXNIP mRNA, decreased cancer cell viability and increased apoptosis. These results for the first time demonstrate FAK-regulated TXNIP expression which is important for apoptotic, survival and oxidative stress signaling pathways in cancer cells.

  18. A role for the juxtamembrane cytoplasm in the molecular dynamics of focal adhesions.

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    Haguy Wolfenson

    Full Text Available Focal adhesions (FAs are specialized membrane-associated multi-protein complexes that link the cell to the extracellular matrix and play crucial roles in cell-matrix sensing. Considerable information is available on the complex molecular composition of these sites, yet the regulation of FA dynamics is largely unknown. Based on a combination of FRAP studies in live cells, with in silico simulations and mathematical modeling, we show that the FA plaque proteins paxillin and vinculin exist in four dynamic states: an immobile FA-bound fraction, an FA-associated fraction undergoing exchange, a juxtamembrane fraction experiencing attenuated diffusion, and a fast-diffusing cytoplasmic pool. The juxtamembrane region surrounding FAs displays a gradient of FA plaque proteins with respect to both concentration and dynamics. Based on these findings, we propose a new model for the regulation of FA dynamics in which this juxtamembrane domain acts as an intermediary layer, enabling an efficient regulation of FA formation and reorganization.

  19. GFAP isoforms control intermediate filament network dynamics, cell morphology, and focal adhesions.

    Science.gov (United States)

    Moeton, Martina; Stassen, Oscar M J A; Sluijs, Jacqueline A; van der Meer, Vincent W N; Kluivers, Liselot J; van Hoorn, Hedde; Schmidt, Thomas; Reits, Eric A J; van Strien, Miriam E; Hol, Elly M

    2016-11-01

    Glial fibrillary acidic protein (GFAP) is the characteristic intermediate filament (IF) protein in astrocytes. Expression of its main isoforms, GFAPα and GFAPδ, varies in astrocytes and astrocytoma implying a potential regulatory role in astrocyte physiology and pathology. An IF-network is a dynamic structure and has been functionally linked to cell motility, proliferation, and morphology. There is a constant exchange of IF-proteins with the network. To study differences in the dynamic properties of GFAPα and GFAPδ, we performed fluorescence recovery after photobleaching experiments on astrocytoma cells with fluorescently tagged GFAPs. Here, we show for the first time that the exchange of GFP-GFAPδ was significantly slower than the exchange of GFP-GFAPα with the IF-network. Furthermore, a collapsed IF-network, induced by GFAPδ expression, led to a further decrease in fluorescence recovery of both GFP-GFAPα and GFP-GFAPδ. This altered IF-network also changed cell morphology and the focal adhesion size, but did not alter cell migration or proliferation. Our study provides further insight into the modulation of the dynamic properties and functional consequences of the IF-network composition.

  20. Apigenin Attenuates Melanoma Cell Migration by Inducing Anoikis through Integrin and Focal Adhesion Kinase Inhibition.

    Science.gov (United States)

    Hasnat, Md Abul; Pervin, Mehnaz; Lim, Ji Hong; Lim, Beong Ou

    2015-11-27

    Apigenin, a nonmutagenic flavonoid, has been found to have antitumor properties and is therefore particularly relevant for the development of chemotherapeutic agents for cancers. In this study, time- and dose-dependent cell viability and cytotoxicity were assessed to determine the effects of apigenin on A2058 and A375 melanoma cells. Melanoma cells were pretreated with different concentrations of apigenin and analyzed for morphological changes, anoikis induction, cell migration, and levels of proteins associated with apoptosis. Apigenin reduced integrin protein levels and inhibited the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK1/2), which induce anoikis in human cutaneous melanoma cells. Apigenin exhibited dose-dependent inhibition of melanoma cell migration, unlike untreated controls. Furthermore, apigenin treatment increased apoptotic factors such as caspase-3 and cleaved poly(ADP-ribose) polymerase in a dose-dependent manner, demonstrating the metastasis of melanoma cells. Our results provide a new insight into the mechanisms by which apigenin prevents melanoma metastasis by sensitizing anoikis induced by the loss of integrin proteins in the FAK/ERK1/2 signaling pathway. These findings elucidate the related mechanisms and suggest the potential of apigenin in developing clinical treatment strategies against malignant melanoma.

  1. Force Fluctuations within Focal Adhesions Mediate ECM-Rigidity Sensing to Guide Directed Cell Migration

    Science.gov (United States)

    Plotnikov, Sergey V.; Pasapera, Ana M.; Sabass, Benedikt; Waterman, Clare M.

    2013-01-01

    Summary Cell migration toward areas of higher extracellular matrix (ECM) rigidity via a process called “durotaxis” is thought to contribute to development, immune response, and cancer metastasis. To understand how cells sample ECM rigidity to guide durotaxis, we characterized cell-generated forces on the nanoscale within single mature integrin-based focal adhesions (FAs). We found that individual FAs act autonomously, exhibiting either stable or dynamically fluctuating (“tugging”) traction. We show that a FAK/phosphopaxillin/vinculin pathway is essential for high FA traction and to enable tugging FA traction over a broad range of ECM rigidities. We show that tugging FA traction is dispensable for FA maturation, chemotaxis, and haptotaxis but is critical to direct cell migration toward rigid ECM. We conclude that individual FAs dynamically sample rigidity by applying fluctuating pulling forces to the ECM to act as sensors to guide durotaxis, and that FAK/phosphopaxillin/vinculin signaling defines the rigidity range over which this dynamic sensing process operates. PMID:23260139

  2. Two distinct actin networks mediate traction oscillations to confer mechanosensitivity of focal adhesions

    Science.gov (United States)

    Wu, Zhanghan; Plotnikov, Sergey; Waterman, Clare; Liu, Jian

    Cells sense the mechanical stiffness of their extracellular matrix (ECM) by exerting traction force through focal adhesions (FAs), which are integrin-based protein assemblies. Strikingly, FA-mediated traction forces oscillate in time and space and govern durotaxis - the tendency of most cell types to migrate toward stiffer ECM. The underlying mechanism of this intriguing oscillation of FA traction force is unknown. Combing theory and experiment, we develop a model of FA growth, which integrates coordinated contributions of a branched actin network and stress fibers in the process. We show that retrograde flux of branched actin network contributes to a traction peak near the FA distal tip and that stress fiber-mediated actomyosin Contractility generates a second traction peak near the FA center. Formin-mediated stress fiber elongation negatively feeds back with actomyosin Contractility, resulting in the central traction peak oscillation. This underpins observed spatio-temporal patterns of the FA traction, and broadens the ECM stiffness range, over which FAs could accurately adapt with traction force generation. Our findings shed light on the fundamental mechanism of FA mechanosensing and hence durotaxis.

  3. Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Alicia M. Waters

    2016-08-01

    Full Text Available Despite the tremendous advances in the treatment of childhood solid tumors, rhabdomyosarcoma (RMS continues to provide a therapeutic challenge. Children with metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK is a nonreceptor tyrosine kinase that is important in many facets of tumorigenesis. Signaling pathways both upstream and downstream to FAK have been found to be important in sarcoma tumorigenesis, leading us to hypothesize that FAK would be present in RMS and would impact cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric alveolar and embryonal RMS tumor specimens and cell lines. We also examined the effects of FAK inhibition upon two RMS cell lines utilizing parallel approaches including RNAi and small molecule inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Furthermore, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse RMS xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in RMS and may provide desperately needed novel therapeutic strategies for these difficult-to-treat tumors.

  4. Copper deficiency induced emphysema is associated with focal adhesion kinase inactivation.

    Directory of Open Access Journals (Sweden)

    Shiro Mizuno

    Full Text Available BACKGROUND: Copper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1α dependent vascular endothelial growth factor (VEGF expression, and is also required for the activity of lysyl oxidase (LOX to effect matrix protein cross-linking. Cell detachment from the extracellular matrix can induce apoptosis (anoikis via inactivation of focal adhesion kinase (FAK. METHODOLOGY: To examine the molecular mechanisms whereby copper depletion causes the destruction of the normal alveolar architecture via anoikis, Male Sprague-Dawley rats were fed a copper deficient diet for 6 weeks while being treated with the copper chelator, tetrathiomolybdate. Other groups of rats were treated with the inhibitor of auto-phosphorylation of FAK, 1,2,4,5-benzenetetraamine tetrahydrochloride (1,2,4,5-BT or FAK small interfering RNA (siRNA. PRINCIPAL FINDINGS: Copper depletion caused emphysematous changes, decreased HIF-1α activity, and downregulated VEGF expression in the rat lungs. Cleaved caspase-3, caspase-8 and Bcl-2 interacting mediator of cell death (Bim expression was increased, and the phosphorylation of FAK was decreased in copper depleted rat lungs. Administration of 1,2,4,5-BT and FAK siRNA caused emphysematous lung destruction associated with increased expression of cleaved capase-3, caspase-8 and Bim. CONCLUSIONS: These data indicate that copper-dependent mechanisms contribute to the pathogenesis of emphysema, which may be associated with decreased HIF-1α and FAK activity in the lung.

  5. cAMP-induced Epac-Rap activation inhibits epithelial cell migration by modulating focal adhesion and leading edge dynamics.

    Science.gov (United States)

    Lyle, Karen S; Raaijmakers, Judith H; Bruinsma, Wytse; Bos, Johannes L; de Rooij, Johan

    2008-06-01

    Epithelial cell migration is a complex process crucial for embryonic development, wound healing and tumor metastasis. It depends on alterations in cell-cell adhesion and integrin-extracellular matrix interactions and on actomyosin-driven, polarized leading edge protrusion. The small GTPase Rap is a known regulator of integrins and cadherins that has also been implicated in the regulation of actin and myosin, but a direct role in cell migration has not been investigated. Here, we report that activation of endogenous Rap by cAMP results in an inhibition of HGF- and TGFbeta-induced epithelial cell migration in several model systems, irrespective of the presence of E-cadherin adhesion. We show that Rap activation slows the dynamics of focal adhesions and inhibits polarized membrane protrusion. Importantly, forced integrin activation by antibodies does not mimic these effects of Rap on cell motility, even though it does mimic Rap effects in short-term cell adhesion assays. From these results, we conclude that Rap inhibits epithelial cell migration, by modulating focal adhesion dynamics and leading edge activity. This extends beyond the effect of integrin affinity modulation and argues for an additional function of Rap in controlling the migration machinery of epithelial cells.

  6. Mechanical stimulation of C2C12 cells increases m-calpain expression, focal adhesion plaque protein degradation

    DEFF Research Database (Denmark)

    Grossi, Alberto; Karlsson, Anders H; Lawson, Moira Ann

    2008-01-01

    reorganization due to the activity of the ubiquitous proteolytic enzymes, calpains, has been reported. Whether there is a link between stretch- or load-induced signaling and calpain expression and activation is not known. Using a magnetic bead stimulation assay and C2C12 mouse myoblasts cell population, we have...... demonstrated that mechanical stimulation via laminin receptors leads to an increase in m-calpain expression, but no increase in the expression of other calpain isoforms. Our study revealed that after a short period of stimulation, m-calpain relocates into focal adhesion complexes and is followed by a breakdown...... of specific focal adhesion proteins previously identified as substrates for this enzyme. We show that stimulation also leads to an increase in calpain activity in these cells. These data support the pivotal role for m-calpain in the control of muscle precursor cell differentiation and thus strengthen the idea...

  7. Role of VASP phosphorylation for the regulation of microglia chemotaxis via the regulation of focal adhesion formation/maturation.

    Science.gov (United States)

    Lee, S; Chung, C Y

    2009-12-01

    Microglia activation and migration are known to play crucial roles for the response to brain injuries. Extracellular ADP was reported to induce microglia chemotaxis and membrane ruffles through P2Y12 receptor. In this study, we examined the role of VASP phosphorylation in ADP-induced microglia chemotaxis and membrane ruffle formation. ADP stimulation transiently increased intracellular cAMP level, VASP phosphorylation at Ser153, membrane ruffle formation, and chemotaxis. PKA inhibitor effectively inhibited VASP phosphorylation and chemotaxis, indicating that P2Y12-mediated activation of PKA and subsequent VASP phosphorylation are involved in the regulation of microglia chemotaxis. Forskolin and okadaic acid induced sustained VASP phosphorylation at a high level, causing a significant reduction of the retraction of membrane ruffles and chemotaxis. In forskolin- or okadaic acid-treated cells, phosphorylated VASP remained at the membrane cortex, and size and number of mature focal adhesions were not increased, indicating that prolonged phosphorylation of VASP could inhibit transformation of focal complexes into focal adhesions. VASP knockdown cells showed markedly reduced frequency and distance of membrane ruffling upon ADP stimulation, reinforcing the idea that VASP is required for the ruffle formation. Cells expressing GFP-VASP(S153A) also showed a significant reduction of protrusion distance during ruffle formation, but the frequency and the distance of retraction were not affected by FSK at all. This result suggests that dephosphorylation of VASP might be required for the growth of adhesion strength during membrane retraction. Our results suggest that VASP phosphorylation by PKA plays an important role in membrane ruffle formation and chemotaxis via the regulation of focal adhesion formation/maturation.

  8. Activation of focal adhesion kinase enhances the adhesion of Fusarium solani to human corneal epithelial cells via the tyrosine-specific protein kinase signaling pathway.

    Science.gov (United States)

    Pan, Xiaojing; Wang, Ye; Zhou, Qingjun; Chen, Peng; Xu, Yuanyuan; Chen, Hao; Xie, Lixin

    2011-03-05

    To determine the role of the integrin-FAK signaling pathway triggered by the adherence of F. solani to human corneal epithelial cells (HCECs). After pretreatment with/without genistein, HCECs were incubated with F. solani spores at different times (0-24 h). Cell adhesion assays were performed by optical microscopy. Changes of the ultrastructure were observed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The expression of F-actin and Paxillin (PAX) were detected by immunofluorescence and western blotting to detect the expression of these key proteins with/without genistein treatment. Cell adhesion assays showed that the number of adhered spores began to rise at 6 h after incubation and peaked at 8 h. SEM and TEM showed that the HCECs exhibited a marked morphological alteration induced by the attachment and entry of the spores. The expression of PAX increased, while the expression of F-actin decreased by stimulation with F. solani. The interaction of F. solani with HCECs causes actin rearrangement in HCECs. Genistein strongly inhibited FAK phosphorylation and the activation of the downstream protein (PAX). F. solani-induced enhancement of cell adhesion ability was inhibited along with the inhibition of FAK phosphorylation. Our results suggest that the integrin-FAK signaling pathway is involved in the control of F. solani adhesion to HCECs and that the activation of focal adhesion kinase enhances the adhesion of human corneal epithelial cells to F. solani via the tyrosine-specific protein kinase signaling pathway.

  9. The oncogenic epidermal growth factor receptor variant Xiphophorus melanoma receptor kinase induces motility in melanocytes by modulation of focal adhesions.

    Science.gov (United States)

    Meierjohann, Svenja; Wende, Elisabeth; Kraiss, Anita; Wellbrock, Claudia; Schartl, Manfred

    2006-03-15

    One of the most prominent features of malignant melanoma is the fast generation of metastasizing cells, resulting in the poor prognosis of patients with this tumor type. For this process, cells must gain the ability to migrate. The oncogenic receptor Xmrk (Xiphophorus melanoma receptor kinase) from the Xiphophorus melanoma system is a mutationally activated version of the epidermal growth factor receptor that induces the malignant transformation of pigment cells. Here, we show that the activation of Xmrk leads to a clear increase of pigment cell motility in a fyn-dependent manner. Stimulation of Xmrk induces its interaction with the focal adhesion kinase (FAK) and the interaction of active, receptor-bound fyn with FAK. This results in changes in FAK activity and induces the modulation of stress fibers and focal adhesions. Overexpression of dominant-negative FAK shows that the activity of innate FAK and a receptor-induced focal adhesion turnover are a prerequisite for pigment cell migration. Our findings show that in our system, Xmrk is sufficient for the induction of pigment cell motility and underlines a role of the src family protein tyrosine kinase fyn in melanoma development and progression.

  10. HAb18G/CD147 regulates vinculin-mediated focal adhesion and cytoskeleton organization in cultured human hepatocellular carcinoma cells.

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    Qiang Liang

    Full Text Available Focal adhesions (FAs, integrin-mediated macromolecular complexes located at the cell membrane extracellular interface, have been shown to regulate cell adhesion and migration. Our previous studies have indicated that HAb18G/CD147 (CD147 is involved in cytoskeleton reorganization and FA formation in human hepatocellular carcinoma (HCC cells. However, the precise mechanisms underlying these processes remain unclear. In the current study, we determined that CD147 was involved in vinculin-mediated FA focal adhesion formation in HCC cells. We also found that deletion of CD147 led to reduced vinculin-mediated FA areas (P<0.0001, length/width ratios (P<0.0001, and mean intensities (P<0.0001. CD147 promoted lamellipodia formation by localizing Arp2/3 to the leading edge of the cell. Deletion of CD147 significantly reduced the fluorescence (t1/2 recovery times (22.7±3.3 s of vinculin-mediated focal adhesions (P<0.0001. In cell-spreading assays, CD147 was found to be essential for dynamic focal adhesion enlargement and disassembly. Furthermore, the current data showed that CD147 reduced tyrosine phosphorylation in vinculin-mediated focal adhesions, and enhanced the accumulation of the acidic phospholipid phosphatidylinositol-4, 5-bisphosphate (PIP2. Together, these results revealed that CD147 is involved in vinculin-mediated focal adhesion formation, which subsequently promotes cytoskeleton reorganization to facilitate invasion and migration of human HCC cells.

  11. Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics.

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    Neil Bate

    Full Text Available Talin is a large (∼2540 residues dimeric adaptor protein that associates with the integrin family of cell adhesion molecules in cell-extracellular matrix junctions (focal adhesions; FAs, where it both activates integrins and couples them to the actin cytoskeleton. Calpain2-mediated cleavage of talin between the head and rod domains has previously been shown to be important in FA turnover. Here we identify an additional calpain2-cleavage site that removes the dimerisation domain from the C-terminus of the talin rod, and show that an E2492G mutation inhibits calpain cleavage at this site in vitro, and increases the steady state levels of talin1 in vivo. Expression of a GFP-tagged talin1 E2492G mutant in CHO.K1 cells inhibited FA turnover and the persistence of cell protrusion just as effectively as a L432G mutation that inhibits calpain cleavage between the talin head and rod domains. Moreover, incorporation of both mutations into a single talin molecule had an additive effect clearly demonstrating that calpain cleavage at both the N- and C-terminal regions of talin contribute to the regulation of FA dynamics. However, the N-terminal site was more sensitive to calpain cleavage suggesting that lower levels of calpain are required to liberate the talin head and rod fragments than are needed to clip off the C-terminal dimerisation domain. The talin head and rod liberated by calpain2 cleavage have recently been shown to play roles in an integrin activation cycle important in FA turnover and in FAK-dependent cell cycle progression respectively. The half-life of the talin head is tightly regulated by ubiquitination and we suggest that removal of the C-terminal dimerisation domain from the talin rod may provide a mechanism both for terminating the signalling function of the talin rod and indeed for inactivating full-length talin thereby promoting FA turnover at the rear of the cell.

  12. Orientation-specific responses to sustained uniaxial stretching in focal adhesion growth and turnover

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    Chen, Yun; Pasapera, Ana M.; Koretsky, Alan P.; Waterman, Clare M.

    2013-01-01

    Cells are mechanosensitive to extracellular matrix (ECM) deformation, which can be caused by muscle contraction or changes in hydrostatic pressure. Focal adhesions (FAs) mediate the linkage between the cell and the ECM and initiate mechanically stimulated signaling events. We developed a stretching apparatus in which cells grown on fibronectin-coated elastic substrates can be stretched and imaged live to study how FAs dynamically respond to ECM deformation. Human bone osteosarcoma epithelial cell line U2OS was transfected with GFP-paxillin as an FA marker and subjected to sustained uniaxial stretching. Two responses at different timescales were observed: rapid FA growth within seconds after stretching, and delayed FA disassembly and loss of cell polarity that occurred over tens of minutes. Rapid FA growth occurred in all cells; however, delayed responses to stretch occurred in an orientation-specific manner, specifically in cells with their long axes perpendicular to the stretching direction, but not in cells with their long axes parallel to stretch. Pharmacological treatments demonstrated that FA kinase (FAK) promotes but Src inhibits rapid FA growth, whereas FAK, Src, and calpain 2 all contribute to delayed FA disassembly and loss of polarity in cells perpendicular to stretching. Immunostaining for phospho-FAK after stretching revealed that FAK activation was maximal at 5 s after stretching, specifically in FAs oriented perpendicular to stretch. We hypothesize that orientation-specific activation of strain/stress-sensitive proteins in FAs upstream to FAK and Src promote orientation-specific responses in FA growth and disassembly that mediate polarity rearrangement in response to sustained stretch. PMID:23754369

  13. Two Distinct Actin Networks Mediate Traction Oscillations to Confer Focal Adhesion Mechanosensing.

    Science.gov (United States)

    Wu, Zhanghan; Plotnikov, Sergey V; Moalim, Abdiwahab Y; Waterman, Clare M; Liu, Jian

    2017-02-28

    Focal adhesions (FAs) are integrin-based transmembrane assemblies that connect a cell to its extracellular matrix (ECM). They are mechanosensors through which cells exert actin cytoskeleton-mediated traction forces to sense the ECM stiffness. Interestingly, FAs themselves are dynamic structures that adapt their growth in response to mechanical force. It is unclear how the cell manages the plasticity of the FA structure and the associated traction force to accurately sense ECM stiffness. Strikingly, FA traction forces oscillate in time and space, and govern the cell mechanosensing of ECM stiffness. However, precisely how and why the FA traction oscillates is unknown. We developed a model of FA growth that integrates the contributions of the branched actin network and stress fibers (SFs). Using the model in combination with experimental tests, we show that the retrograde flux of the branched actin network promotes the proximal growth of the FA and contributes to a traction peak near the FA's distal tip. The resulting traction gradient within the growing FA favors SF formation near the FA's proximal end. The SF-mediated actomyosin contractility further stabilizes the FA and generates a second traction peak near the center of the FA. Formin-mediated SF elongation negatively feeds back with actomyosin contractility, resulting in central traction peak oscillation. This underpins the observed FA traction oscillation and, importantly, broadens the ECM stiffness range over which FAs can accurately adapt to traction force generation. Actin cytoskeleton-mediated FA growth and maturation thus culminate with FA traction oscillation to drive efficient FA mechanosensing. Published by Elsevier Inc.

  14. Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase.

    Science.gov (United States)

    Wang, Chunhuai; Xiang, Ru; Zhang, Xiangzhong; Chen, Yunxian

    2015-09-01

    Doxycycline, a tetracycline-based antibiotic, has been reported to attenuate melanoma cell migration through inhibiting the focal adhesion kinase (FAK) signaling pathway. However, it remains to be elucidated whether doxycycline exerts this effect on leukemia cell migration. The present study aimed to examine the role of doxycycline in leukemia cell migration. The invasion capacities of the human leukemia cell lines KG1a (acute myelogenous leukemia) and K562 (chronic myelogenous leukemia) were evaluated using Matrigel® matrix‑coated Transwell® chamber assays; leukemic cell lines treated with doxycycline (1 µg/ml) or anti‑β1‑integrin antibodies were added to the upper chamber, while untreated cells were included as controls. Reverse transcription quantitative polymerase chain reaction was performed in order to further understand the influence of doxycycline treatment on the expression of FAK and gelatinases in the KG1a and K562 leukemic cell lines. In addition, FAK protein expression and phosphorylation were determined using western blot analysis in order to investigate the mechanism by which doxycycline inhibited leukemic cell migration. The results revealed that doxycycline treatment significantly attenuated the migration of KG1a and K562 cells, which was demonstrated to be associated with inhibition of the expression and phosphorylation of FAK. In addition, doxycycline treatment inhibited matrix metalloproteinase (MMP)‑2 and MMP‑9 expression. Furthermore, incubation with blocking anti‑β1‑integrin antibodies had an analogous inhibitory effect on leukemic cell migration to that of doxycycline. In conclusion, the results of the present study suggested that doxycycline attenuated leukemic cell migration through inhibiting the FAK signaling pathway. Therefore, doxycycline may have potential for use as a novel strategy for the treatment of leukemia.

  15. MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression

    Institute of Scientific and Technical Information of China (English)

    WU De-gang; WANG Xi-rui; YOU Yong-ping; LIU Ning; WANG Ying-yi; FAN Li-gang; LUO Hui; HAN Bin; SUN Li-hua; WANG Xie-feng; ZHANG Jun-xia; CAO Lei

    2011-01-01

    Background Invasion growth is the most characteristic biological phenotype of glioblastoma,but the molecular mechanism in glioma cell invasion is poorly understood.Recent data have showed that microRNA plays an essential role in tumor invasion.Our study aimed to explore the mechanism of miR-7 involved in the control of glioblastoma cell invasion.Methods Glioma cell invasion was evaluated by transwell and scratch assays after up-regulation of miR-7 using miR-7 mimics in U87 and U251 cells.Luciferase reporter assay was used to determine focal adhesion kinase (FAK) as a target of miR-7.The levels of miR-7,matrix metalloproteinases (MMP)-2 and MMP-9 mRNA were detected by PCR assay,and the levels of FAK,MMP-2,MMP-9,total and phosphorylation serine/threonine kinase (AKT),and extracellular signal-regulated kinase (ERK) 1/2 were measured by Western blotting analysis.Results Over-expression of miR-7 inhibited the invasion and migration activity of U87 and U251 cells.And up-regulation of miR-7 reduced FAK protein expression,Further,luciferase reporter assay showed that miR-7 modulated FAK expression directly by binding 3'UTR of FAK mRNA.In addition,miR-7 repressed p-ERK1/2 and p-AKT level,MMP-2 and MMP-9 expression.Finally,the inverse relationship between FAK and miR-7 expression was certificated in human glioma tissues.Conclusion To our knowledge,these data indicate for the first time that miR-7 directly regulates cell invasion by targeting FAK in glioblastoma and that miR-7 could be a potential therapeutic target for glioblastoma intervention.

  16. Focal adhesion kinase regulates pathogen-killing capability and life span of neutrophils via mediating both adhesion-dependent and -independent cellular signals.

    Science.gov (United States)

    Kasorn, Anongnard; Alcaide, Pilar; Jia, Yonghui; Subramanian, Kulandayan K; Sarraj, Bara; Li, Yitang; Loison, Fabien; Hattori, Hidenori; Silberstein, Leslie E; Luscinskas, William F; Luo, Hongbo R

    2009-07-15

    Various neutrophil functions such as phagocytosis, superoxide production, and survival are regulated by integrin signaling. Despite the essential role of focal adhesion kinase (FAK) in mediating this signaling pathway, its exact function in neutrophils is ill defined. In this study, we investigated the role of FAK in neutrophils using a myeloid-specific conditional FAK knockout mouse. As reported in many other cell types, FAK is required for regulation of focal adhesion dynamics when neutrophils adhere to fibronectin or ICAM-1. Adhesion on VCAM-1-coated surfaces and chemotaxis after adhesion were not altered in FAK null neutrophils. In addition, we observed significant reduction in NADPH oxidase-mediated superoxide production and complement-mediated phagocytosis in FAK null neutrophils. As a result, these neutrophils displayed decreased pathogen killing capability both in vitro and in vivo in a mouse peritonitis model. In adherent cells, the defects associated with FAK deficiency are likely due to suppression of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) signaling and chemoattractant-elicited calcium signaling. Disruption of FAK also reduced chemoattractant-elicited superoxide production in suspended neutrophils in the absence of cell adhesion. This may be solely caused by suppression of PtdIns(3,4,5)P3 signaling in these cells, because the fMLP-elicited calcium signal was not altered. Consistent with decreased PtdIns(3,4,5)P3/Akt signaling in FAK null neutrophils, we also observed accelerated spontaneous death in these cells. Taken together, our results revealed previously unrecognized roles of FAK in neutrophil function and provided a potential therapeutic target for treatment of a variety of infectious and inflammatory diseases.

  17. Organization and post-transcriptional processing of focal adhesion kinase gene

    Directory of Open Access Journals (Sweden)

    Enslen Hervé

    2006-08-01

    Full Text Available Abstract Background Focal adhesion kinase (FAK is a non-receptor tyrosine kinase critical for processes ranging from embryo development to cancer progression. Although isoforms with specific molecular and functional properties have been characterized in rodents and chicken, the organization of FAK gene throughout phylogeny and its potential to generate multiple isoforms are not well understood. Here, we study the phylogeny of FAK, the organization of its gene, and its post-transcriptional processing in rodents and human. Results A single orthologue of FAK and the related PYK2 was found in non-vertebrate species. Gene duplication probably occurred in deuterostomes after the echinoderma embranchment, leading to the evolution of PYK2 with distinct properties. The amino acid sequence of FAK and PYK2 is conserved in their functional domains but not in their linker regions, with the absence of autophosphorylation site in C. elegans. Comparison of mouse and human FAK genes revealed the existence of multiple combinations of conserved and non-conserved 5'-untranslated exons in FAK transcripts suggesting a complex regulation of their expression. Four alternatively spliced coding exons (13, 14, 16, and 31, previously described in rodents, are highly conserved in vertebrates. Cis-regulatory elements known to regulate alternative splicing were found in conserved alternative exons of FAK or in the flanking introns. In contrast, other reported human variant exons were restricted to Homo sapiens, and, in some cases, other primates. Several of these non-conserved exons may correspond to transposable elements. The inclusion of conserved alternative exons was examined by RT-PCR in mouse and human brain during development. Inclusion of exons 14 and 16 peaked at the end of embryonic life, whereas inclusion of exon 13 increased steadily until adulthood. Study of various tissues showed that inclusion of these exons also occurred, independently from each other, in a

  18. A Site-Specific Phosphorylation of the Focal Adhesion Kinase Controls the Formation of Spheroid Cell Clusters

    DEFF Research Database (Denmark)

    Beck, Hans Christian; Gosau, Martin; Kristensen, Lars Peter

    2014-01-01

    Human dental follicle cells (DFCs) are ectomesenchymal multipotent stem cells that form spheroid cell clusters (SCCs) under serum free medium cell culture conditions (SFM). Until today, molecular mechanisms for the formation of SCCs are unknown. In this study a quantitative phosphoproteomics...... approach revealed regulated phosphorylated proteins in SCCs, which were derived from DFCs after 24 and 48 h in SFM. These regulated proteins were categorized using the Kyoto encyclopedia of genes and genomes program. Here, cellular processes and signaling pathway were identified such as the focal adhesion...

  19. Resveratrol and Estradiol Exert Disparate Effects on Cell Migration, Cell Surface Actin Structures, and Focal Adhesion Assembly in MDA-MB-231 Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Nicolas G. Azios

    2005-02-01

    Full Text Available Resveratrol, a grape polyphenol, is thought to be a cancer preventive, yet its effects on metastatic breast cancer are relatively unknown. Since cancer cell invasion is dependent on cell migration, the chemotactic response of MDA-MB-231 metastatic human breast cancer cells to resveratrol, estradiol (E2, or epidermal growth factor (EGF was investigated. Resveratrol decreased while E2 and EGF increased directed cell migration. Resveratrol may inhibit cell migration by altering the cytoskeleton. Resveratrol induced a rapid global array of filopodia and decreased focal adhesions and focal adhesion kinase (FAK activity. E2 or EGF treatment did not affect filopodia extension but increased lamellipodia and associated focal adhesions that are integral for cell migration. Combined resveratrol and E2 treatment resulted in a filopodia and focal adhesion response similar to resveratrol alone. Combined resveratrol and EGF resulted in a lamellipodia and focal adhesion response similar to EGF alone. E2 and to a lesser extent resveratrol increased EGFR activity. The cytoskeletal changes and EGFR activity in response to E2 were blocked by EGFR1 inhibitor indicating that E2 may increase cell migration via crosstalk with EGFR signaling. These data suggest a promotional role for E2 in breast cancer cell migration but an antiestrogenic, preventative role for resveratrol.

  20. Glycogen synthase kinase 3β dictates podocyte motility and focal adhesion turnover by modulating paxillin activity: implications for the protective effect of low-dose lithium in podocytopathy.

    Science.gov (United States)

    Xu, Weiwei; Ge, Yan; Liu, Zhihong; Gong, Rujun

    2014-10-01

    Aberrant focal adhesion turnover is centrally involved in podocyte actin cytoskeleton disorganization and foot process effacement. The structural and dynamic integrity of focal adhesions is orchestrated by multiple cell signaling molecules, including glycogen synthase kinase 3β (GSK3β), a multitasking kinase lately identified as a mediator of kidney injury. However, the role of GSK3β in podocytopathy remains obscure. In doxorubicin (Adriamycin)-injured podocytes, lithium, a GSK3β inhibitor and neuroprotective mood stabilizer, obliterated the accelerated focal adhesion turnover, rectified podocyte hypermotility, and restored actin cytoskeleton integrity. Mechanistically, lithium counteracted the doxorubicin-elicited GSK3β overactivity and the hyperphosphorylation and overactivation of paxillin, a focal adhesion-associated adaptor protein. Moreover, forced expression of a dominant negative kinase dead mutant of GSK3β highly mimicked, whereas ectopic expression of a constitutively active GSK3β mutant abolished, the effect of lithium in doxorubicin-injured podocytes, suggesting that the effect of lithium is mediated, at least in part, through inhibition of GSK3β. Furthermore, paxillin interacted with GSK3β and served as its substrate. In mice with doxorubicin nephropathy, a single low dose of lithium ameliorated proteinuria and glomerulosclerosis. Consistently, lithium therapy abrogated GSK3β overactivity, blunted paxillin hyperphosphorylation, and reinstated actin cytoskeleton integrity in glomeruli associated with an early attenuation of podocyte foot process effacement. Thus, GSK3β-modulated focal adhesion dynamics might serve as a novel therapeutic target for podocytopathy.

  1. Fluid-flow-induced mesenchymal stem cell migration: role of focal adhesion kinase and RhoA kinase sensors.

    Science.gov (United States)

    Riehl, Brandon D; Lee, Jeong Soon; Ha, Ligyeom; Lim, Jung Yul

    2015-03-01

    The study of mesenchymal stem cell (MSC) migration under flow conditions with investigation of the underlying molecular mechanism could lead to a better understanding and outcome in stem-cell-based cell therapy and regenerative medicine. We used peer-reviewed open source software to develop methods for efficiently and accurately tracking, measuring and processing cell migration as well as morphology. Using these tools, we investigated MSC migration under flow-induced shear and tested the molecular mechanism with stable knockdown of focal adhesion kinase (FAK) and RhoA kinase (ROCK). Under steady flow, MSCs migrated following the flow direction in a shear stress magnitude-dependent manner, as assessed by root mean square displacement and mean square displacement, motility coefficient and confinement ratio. Silencing FAK in MSCs suppressed morphology adaptation capability and reduced cellular motility for both static and flow conditions. Interestingly, ROCK silencing significantly increased migration tendency especially under flow. Blocking ROCK, which is known to reduce cytoskeletal tension, may lower the resistance to skeletal remodelling during the flow-induced migration. Our data thus propose a potentially differential role of focal adhesion and cytoskeletal tension signalling elements in MSC migration under flow shear.

  2. Vimentin contributes to epithelial-mesenchymal transition cancer cell mechanics by mediating cytoskeletal organization and focal adhesion maturation.

    Science.gov (United States)

    Liu, Ching-Yi; Lin, Hsi-Hui; Tang, Ming-Jer; Wang, Yang-Kao

    2015-06-30

    Modulations of cytoskeletal organization and focal adhesion turnover correlate to tumorigenesis and epithelial-mesenchymal transition (EMT), the latter process accompanied by the loss of epithelial markers and the gain of mesenchymal markers (e.g., vimentin). Clinical microarray results demonstrated that increased levels of vimentin mRNA after chemotherapy correlated to a poor prognosis of breast cancer patients. We hypothesized that vimentin mediated the reorganization of cytoskeletons to maintain the mechanical integrity in EMT cancer cells. By using knockdown strategy, the results showed reduced cell proliferation, impaired wound healing, loss of directional migration, and increased large membrane extension in MDA-MB 231 cells. Vimentin depletion also induced reorganization of cytoskeletons and reduced focal adhesions, which resulted in impaired mechanical strength because of reduced cell stiffness and contractile force. In addition, overexpressing vimentin in MCF7 cells increased cell stiffness, elevated cell motility and directional migration, reoriented microtubule polarity, and increased EMT phenotypes due to the increased β1-integrin and the loss of junction protein E-cadherin. The EMT-related transcription factor slug was also mediated by vimentin. The current study demonstrated that vimentin serves as a regulator to maintain intracellular mechanical homeostasis by mediating cytoskeleton architecture and the balance of cell force generation in EMT cancer cells.

  3. Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer*

    Science.gov (United States)

    Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh; Nirujogi, Raja Sekhar; Kim, Min-Sik; Manda, Srikanth S.; Stearns, Vered; Gabrielson, Edward; Sukumar, Saraswati; Pandey, Akhilesh

    2015-01-01

    Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers. PMID:26330541

  4. Protein kinase C, focal adhesions and the regulation of cell migration

    DEFF Research Database (Denmark)

    Fogh, Betina S; Multhaupt, Hinke A B; Couchman, John Robert

    2014-01-01

    Cell adhesion to extracellular matrix is a complex process involving protrusive activity driven by the actin cytoskeleton, engagement of specific receptors, followed by signaling and cytoskeletal organization. Thereafter, contractile and endocytic/recycling activities may facilitate migration...

  5. Silencing of focal adhesion kinase by tumor direct injection of small interfering RNA decreases in vivo tumor growth.

    Science.gov (United States)

    Tsutsumi, Kae; Yamaura, Takeshi; Nakajima, Motowo; Honda, Toshiyuki; Kasaoka, Tatsuhiko

    2009-07-01

    Focal adhesion kinase (FAK) is shown to be frequently correlated with malignancy of the tumor and poor prognosis of the diseases.Because FAK resides immediately downstream of the interaction of cell surface adhesion molecules and extracellular matricies, it is considered to be critical to regulate several cellular processes including growth, differentiation, adhesion, motility and apoptosis. However, the studies on the role of FAK related to cell proliferation have been limited even in vitro. Here, in order to validate the role of FAK in in vivo tumor formation and proliferation, we employed direct intratumoral injection of short hairpin RNA (shRNA) targeting FAK with cationic liposome. Using shRNAs targeting FAK selected from the constructed shRNA library for FAK and by optimization of in vivo delivery conditions, we demonstrated different patterns of the association of FAK inhibition with in vivo tumor formation/proliferation inhibition in two models, PC3M heterotopic xenograft and 4T1 orthotopic syngraft models. These observations indicated that the roles of FAK in tumorigenesis are different among the tumor species. In addition, we showed that ERK is the critical MAP kinase in the signaling pathway down stream of FAK in in vivo proliferation of 4T1 tumor cells.

  6. Therapeutic effects of tyroservatide on metastasis of lung cancer and its mechanism affecting integrin–focal adhesion kinase signal transduction

    Science.gov (United States)

    Huang, Yu-ting; Zhao, Lan; Fu, Zheng; Zhao, Meng; Song, Xiao-meng; Jia, Jing; Wang, Song; Li, Jin-ping; Zhu, Zhi-feng; Lin, Gang; Lu, Rong; Yao, Zhi

    2016-01-01

    Tyroservatide (YSV) can inhibit the growth and metastasis of mouse lung cancer significantly. This study investigated the therapeutic effects of tripeptide YSV on metastasis of human lung cancer cells and explored its possible mechanism that affects integrin–focal adhesion kinase (FAK) signal transduction in tumor cells. YSV significantly inhibited the adhesion and the invasion of highly metastatic human lung cancer cell lines 95D, A549, and NCI-H1299. In addition, YSV significantly inhibited phosphorylation of FAK Tyr397 and FAK Tyr576/577 in the 95D, A549, and NCI-H1299 human lung cancer cells in vitro. And the mRNA level and protein expression of FAK in these human lung cancer cells decreased at the same time. YSV also significantly inhibited mRNA and protein levels of integrin β1 and integrin β3 in the 95D, A549, and NCI-H1299 human lung cancer cells. Our research showed that YSV inhibited adhesion and invasion of human lung cancer cells and exhibited therapeutic effects on metastasis of lung cancer. PMID:27041993

  7. The human papillomavirus E6 oncogene represses a cell adhesion pathway and disrupts focal adhesion through degradation of TAp63β upon transformation.

    Directory of Open Access Journals (Sweden)

    Youcef Ben Khalifa

    2011-09-01

    Full Text Available Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show that the TAp63β isoform of the p63 transcription factor is also a target of E6. The p63 gene plays an essential role in skin homeostasis and is expressed as at least six isoforms. One of these isoforms, ΔNp63α, has been found overexpressed in squamous cell carcinomas and is shown here to be constitutively expressed in Caski cells associated with HPV16. We therefore explored the role of p63 in these cells by performing microarray analyses after repression of endogenous E6/E7 expression. Upon repression of the oncogenes, a large set of p53 target genes was found activated together with many p63 target genes related to cell adhesion. However, through siRNA silencing and ectopic expression of various p63 isoforms we demonstrated that TAp63β is involved in activation of this cell adhesion pathway instead of the constitutively expressed ΔNp63α and β. Furthermore, we showed in cotransfection experiments, combined with E6AP siRNA silencing, that E6 induces an accelerated degradation of TAp63β although not through the E6AP ubiquitin ligase used for degradation of p53. Repression of E6 transcription also induces stabilization of endogenous TAp63β in cervical carcinoma cells that lead to an increased concentration of focal adhesions at the cell surface. Consequently, TAp63β is the only p63 isoform suppressed by E6 in cervical carcinoma as demonstrated previously for p53. Down-modulation of focal adhesions through disruption of TAp63β therefore appears as a novel E6-dependent pathway in transformation. These findings identify a major physiological role for TAp63β in anchorage independent growth that might represent a new critical

  8. A site-specific phosphorylation of the focal adhesion kinase controls the formation of spheroid cell clusters.

    Science.gov (United States)

    Beck, Hans Christian; Gosau, Martin; Kristensen, Lars Peter; Morsczeck, Christian

    2014-07-01

    Human dental follicle cells (DFCs) are ectomesenchymal multipotent stem cells that form spheroid cell clusters (SCCs) under serum free medium cell culture conditions (SFM). Until today, molecular mechanisms for the formation of SCCs are unknown. In this study a quantitative phosphoproteomics approach revealed regulated phosphorylated proteins in SCCs, which were derived from DFCs after 24 and 48 h in SFM. These regulated proteins were categorized using the Kyoto encyclopedia of genes and genomes program. Here, cellular processes and signaling pathway were identified such as the focal adhesion kinase (FAK) signaling pathway. In addition to the phosphoproteomics approach we showed that a specific phosphorylation of FAK (Y397) was required for the formation of SCCs. In conclusion, this study disclosed the phosphoproteome of SCCs for the first time and showed that the FAK signaling pathway is required for the formation of SCCs.

  9. Protective influence of hyaluronic acid on focal adhesion kinase activity in human skin fibroblasts exposed to ethanol

    Directory of Open Access Journals (Sweden)

    Donejko M

    2017-03-01

    Full Text Available Magdalena Donejko,1 Edyta Rysiak,2 Elżbieta Galicka,1 Robert Terlikowski,3 Edyta Katarzyna Głażewska,1 Andrzej Przylipiak1 1Department of Esthetic Medicine, 2Department of Medicinal Chemistry, Faculty of Pharmacy, 3Department of Health Restoration, Medical University of Białystok, Białystok, Poland Aim: The aim of this study was to evaluate the effect of ethanol and hyaluronic acid (HA on cell survival and apoptosis in cultured human skin fibroblasts. Regarding the mechanism of ethanol action on human skin fibroblasts, we investigated cell viability and apoptosis, expression of focal adhesion kinase (FAK, and the influence of HA on those processes. Materials and methods: Studies were conducted in confluent human skin fibroblast cultures that were treated with 25 mM, 50 mM, and 100 mM ethanol or with ethanol and 500 µg/mL HA. Cell viability was examined using methyl thiazolyl tetrazolium (MTT assay and NC-300 Nucleo-Counter. Imaging of the cells using a fluorescence microscope Pathway 855 was performed to measure FAK expression. Results: Depending on the dosage, ethanol decreased cell viability and activated the process of apoptosis in human skin fibroblasts. HA prevented the negative influence of ethanol on cell viability and prevented apoptosis. The analysis of fluorescence imaging using BD Pathway 855 High-Content Bioimager showed the inhibition of FAK migration to the cell nucleus, depending on the increasing concentration of ethanol. Conclusion: This study proves that downregulation of signaling pathway of FAK is involved in ethanol-induced apoptosis in human skin fibroblasts. The work also indicates a protective influence of HA on FAK activity in human skin fibroblasts exposed to ethanol. Keywords: apoptosis, skin fibroblast, focal adhesion kinase, hyaluronic acid, ethanol

  10. Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer.

    Science.gov (United States)

    Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh; Nirujogi, Raja Sekhar; Kim, Min-Sik; Manda, Srikanth S; Stearns, Vered; Gabrielson, Edward; Sukumar, Saraswati; Pandey, Akhilesh

    2015-11-01

    Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation

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    Sophie Béraud-Dufour

    2016-11-01

    Full Text Available The aim of the present review is to unravel the mechanisms of action of the soluble form of the neurotensin (NT receptor-3 (NTSR3, also called Sortilin, in numerous physiopathological processes including cancer development, cardiovascular diseases and depression. Sortilin/NTSR3 is a transmembrane protein thought to exert multiple functions both intracellularly and at the level of the plasma membrane. The Sortilin/NTSR3 extracellular domain is released by shedding from all the cells expressing the protein. Although the existence of the soluble form of Sortilin/NTSR3 (sSortilin/NTSR3 has been evidenced for more than 10 years, the studies focusing on the role of this soluble protein at the mechanistic level remain rare. Numerous cancer cells, including colonic cancer cells, express the receptor family of neurotensin (NT, and particularly Sortilin/NTSR3. This review aims to summarize the functional role of sSortilin/NTSR3 characterized in the colonic cancer cell line HT29. This includes mechanisms involving signaling cascades through focal adhesion kinase (FAK, a key pathway leading to the weakening of cell–cell and cell–extracellular matrix adhesions, a series of events which could be responsible for cancer metastasis. Finally, some future approaches targeting the release of sNTSR3 through the inhibition of matrix metalloproteases (MMPs are suggested.

  12. Focal adhesion kinase is a phospho-regulated repressor of Rac and proliferation in human endothelial cells

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    Patrick W. Bryant

    2012-06-01

    Focal adhesion kinase (FAK is critically positioned to integrate signals from the extracellular matrix and cellular adhesion. It is essential for normal vascular development and has been implicated in a wide range of cellular functions including the regulation of cell proliferation, migration, differentiation, and survival. It is currently being actively targeted therapeutically using different approaches. We have used human endothelial cells as a model system to compare the effects of inhibiting FAK through several different approaches including dominant negatives, kinase inhibitors and shRNA. We find that manipulations of FAK signaling that result in inhibition of FAK 397 phosphorylation inhibit proliferation and migration. However, abolition of FAK expression using stable (shRNA or transient (siRNA approaches does not interfere with these cellular functions. The ability to regulate cell proliferation by FAK manipulation is correlated with the activation status of Rac, an essential signal for the regulation of cyclin-dependent kinase inhibitors. The knockdown of FAK, while not affecting cellular proliferation or migration, dramatically interferes with vascular morphogenesis and survival, mirroring in vivo findings. We propose a novel model of FAK signaling whereby one of the multifunctional roles of FAK as a signaling protein includes FAK as a phospho-regulated repressor of Rac activation, with important implications on interpretation of research experiments and therapeutic development.

  13. Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation

    Science.gov (United States)

    Béraud-Dufour, Sophie; Devader, Christelle; Massa, Fabienne; Roulot, Morgane; Coppola, Thierry; Mazella, Jean

    2016-01-01

    The aim of the present review is to unravel the mechanisms of action of the soluble form of the neurotensin (NT) receptor-3 (NTSR3), also called Sortilin, in numerous physiopathological processes including cancer development, cardiovascular diseases and depression. Sortilin/NTSR3 is a transmembrane protein thought to exert multiple functions both intracellularly and at the level of the plasma membrane. The Sortilin/NTSR3 extracellular domain is released by shedding from all the cells expressing the protein. Although the existence of the soluble form of Sortilin/NTSR3 (sSortilin/NTSR3) has been evidenced for more than 10 years, the studies focusing on the role of this soluble protein at the mechanistic level remain rare. Numerous cancer cells, including colonic cancer cells, express the receptor family of neurotensin (NT), and particularly Sortilin/NTSR3. This review aims to summarize the functional role of sSortilin/NTSR3 characterized in the colonic cancer cell line HT29. This includes mechanisms involving signaling cascades through focal adhesion kinase (FAK), a key pathway leading to the weakening of cell–cell and cell–extracellular matrix adhesions, a series of events which could be responsible for cancer metastasis. Finally, some future approaches targeting the release of sNTSR3 through the inhibition of matrix metalloproteases (MMPs) are suggested. PMID:27834811

  14. Structural and functional assessment of the interaction between focal adhesion kinase and sarcomeric myosin

    OpenAIRE

    Aline Mara dos Santos

    2011-01-01

    Resumo: A tirosino-quinase de adesão focal (FAK) tem papel crítico na mediação da migração, sobrevivência e proliferação celular. Estudos anteriores de nosso laboratório demonstraram que a FAK é ativada pelo estresse mecânico em miócitos cardíacos e que ela se coimunoprecipita com a miosina sarcomérica. No presente trabalho foi demonstrado que o domínio FERM da FAK medeia à interação com a miosina sarcomérica, sendo que esta interação leva a inibição da autofosforilação da FAK, enquanto que a...

  15. PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.

    Science.gov (United States)

    Gari, Hamid H; DeGala, Gregory D; Ray, Rahul; Lucia, M Scott; Lambert, James R

    2016-10-01

    Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells.

  16. Effect of bioactive extruded PLA/HA composite films on focal adhesion formation of preosteoblastic cells.

    Science.gov (United States)

    Persson, Maria; Lorite, Gabriela S; Kokkonen, Hanna E; Cho, Sung-Woo; Lehenkari, Petri P; Skrifvars, Mikael; Tuukkanen, Juha

    2014-09-01

    The quality of the initial cell attachment to a biomaterial will influence any further cell function, including spreading, proliferation, differentiation and viability. Cell attachment is influenced by the material's ability to adsorb proteins, which is related to the surface chemistry and topography of the material. In this study, we incorporated hydroxyapatite (HA) particles into a poly(lactic acid) (PLA) composite and evaluated the surface structure and the effects of HA density on the initial cell attachment in vitro of murine calvarial preosteoblasts (MC3T3-EI). Scanning electron microscopy (SEM), atomic force microscopy (AFM) and infrared spectroscopy (FTIR) showed that the HA particles were successfully incorporated into the PLA matrix and located at the surface which is of importance in order to maintain the bioactive effect of the HA particles. SEM and AFM investigation revealed that the HA density (particles/area) as well as surface roughness increased with HA loading concentration (i.e. 5, 10, 15 and 20wt%), which promoted protein adsorption. Furthermore, the presence of HA on the surface enhanced cell spreading, increased the formation of actin stress fibers and significantly improved the expression of vinculin in MC3T3-E1 cells which is a key player in the regulation of cell adhesion. These results suggest the potential utility of PLA/HA composites as biomaterials for use as a bone substitute material and in tissue engineering applications.

  17. Migration of periodontal ligament fibroblasts on nanometric topographical patterns: influence of filopodia and focal adhesions on contact guidance.

    Directory of Open Access Journals (Sweden)

    Douglas W Hamilton

    Full Text Available Considered to be the "holy grail" of dentistry, regeneration of the periodontal ligament in humans remains a major clinical problem. Removal of bacterial biofilms is commonly achieved using EDTA gels or lasers. One side effect of these treatment regimens is the etching of nanotopographies on the surface of the tooth. However, the response of periodontal ligament fibroblasts to such features has received very little attention. Using laser interference lithography, we fabricated precisely defined topographies with continuous or discontinuous nanogrooves to assess the adhesion, spreading and migration of PDL fibroblasts. PDL fibroblasts adhered to and spread on all tested surfaces, with initial spreading and focal adhesion formation slower on discontinuous nanogrooves. Cells had a significantly smaller planar area on both continuous and discontinuous nanogrooves in comparison with cells on non-patterned controls. At 24 h post seeding, cells on both types of nanogrooves were highly elongated parallel to the groove long axis. Time-lapse video microscopy revealed that PDL fibroblast movement was guided on both types of grooves, but migration velocity was not significantly different from cells cultured on non-patterned controls. Analysis of filopodia formation using time-lapse video microscopy and labeling of vinculin and F-actin revealed that on nanogrooves, filopodia were highly aligned at both ends of the cell, but with increasing time filopodia and membrane protrusions developed at the side of the cell perpendicular to the cell long axis. We conclude that periodontal ligament fibroblasts are sensitive to nanotopographical depths of 85-100 µm, which could be utilized in regeneration of the periodontal ligament.

  18. Progesterone receptor isoforms PRA and PRB differentially contribute to breast cancer cell migration through interaction with focal adhesion kinase complexes.

    Science.gov (United States)

    Bellance, Catherine; Khan, Junaid A; Meduri, Geri; Guiochon-Mantel, Anne; Lombès, Marc; Loosfelt, Hugues

    2013-05-01

    Progesterone receptor (PR) and progestins affect mammary tumorigenesis; however, the relative contributions of PR isoforms A and B (PRA and PRB, respectively) in cancer cell migration remains elusive. By using a bi-inducible MDA-MB-231 breast cancer cell line expressing PRA and/or PRB, we analyzed the effect of conditional PR isoform expression. Surprisingly, unliganded PRB but not PRA strongly enhanced cell migration as compared with PR(-) cells. 17,21-Dimethyl-19-norpregna-4,9-dien-3,20-dione (R5020) progestin limited this effect and was counteracted by the antagonist 11β-(4-dimethyl-amino)-phenyl-17β-hydroxy-17-(1-propynyl)-estra-4,9-dien-3-one (RU486). Of importance, PRA coexpression potentiated PRB-mediated migration, whereas PRA alone was ineffective. PR isoforms differentially regulated expressions of major players of cell migration, such as urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor type 1, uPA receptor (uPAR), and β1-integrin, which affect focal adhesion kinase (FAK) signaling. Moreover, unliganded PRB but not PRA enhanced FAK Tyr397 phosphorylation and colocalized with activated FAK in cell protrusions. Because PRB, as well as PRA, coimmunoprecipitated with FAK, both isoforms can interact with FAK complexes, depending on their respective nucleocytoplasmic trafficking. In addition, FAK degradation was coupled to R5020-dependent turnovers of PRA and PRB. Such an effect of PRB/PRA expression on FAK signaling might thus affect adhesion/motility, underscoring the implication of PR isoforms in breast cancer invasiveness and metastatic evolution with underlying therapeutic outcomes.

  19. STROBE-compliant integrin through focal adhesion involve in cancer stem cell and multidrug resistance of ovarian cancer

    Science.gov (United States)

    Wei, Luwei; Yin, Fuqiang; Zhang, Wei; Li, Li

    2017-01-01

    Abstract Cancer stem cells (CSCs) are considered to be the root of carcinoma relapse and drug resistance in ovarian cancer. Hunting for the potential CSC genes and explain their functions would be a feasible strategy to meet the challenge of the drug resistance in ovarian cancer. In this study, we performed bioinformatic approaches such as biochip data extraction and pathway enrichment analyses to elucidate the mechanism of the CSC genes in regulation of drug resistance. Potential key genes, integrins, were identified to be related to CSC in addition to their associations with drug resistance and prognosis in ovarian cancer. A total of 36 ovarian CSC genes involved in regulation of drug resistance were summarized, and potential drug resistance-related CSC genes were identified based on 3 independent microarrays retrieved from the Gene Expression Omnibus (GEO) Profiles. Pathway enrichment of CSC genes associated with drug resistance in ovarian cancer indicated that focal adhesion signaling might play important roles in CSC genes-mediated drug resistance. Integrins are members of the adhesion molecules family, and integrin subunit alpha 1, integrin subunit alpha 5, and integrin subunit alpha 6 (ITGA6) were identified as central CSC genes and their expression in side population cells, cisplatin-resistant SKOV3 (SKOV3/DDP2) cells, and cisplatin-resistant A2780 (A2780/DDP) cells were dysregulated as measured by real-time quantitative polymerase chain reaction. The high expression of ITGA6 in 287 ovarian cancer patients of TCGA cohort was significantly associated with poorer progression-free survival. This study provide the basis for further understanding of CSC genes in regulation of drug resistance in ovarian cancer, and integrins could be a potential biomarker for prognosis of ovarian cancer. PMID:28328815

  20. Defining central themes in breast cancer biology by differential proteomics: conserved regulation of cell spreading and focal adhesion kinase.

    Science.gov (United States)

    Bateman, Nicholas W; Sun, Mai; Hood, Brian L; Flint, Melanie S; Conrads, Thomas P

    2010-10-01

    Breast cancer is a highly heterogeneous disease, an observation that underscores the importance of elucidating conserved molecular characteristics, such as gene and protein expression, across breast cancer cell types toward providing a greater understanding of context-specific features central to this disease. Motivated by the goal of defining central biological themes across breast cancer cell subtypes, we conducted a global proteomic analysis of three breast cancer cell lines, MCF7, SK-BR-3, and MDA-MB-231, and compared these to a model of nontransformed mammary cells (MCF10A). Our results demonstrate modulation of proteins localized to the extracellular matrix, plasma membrane, and nucleus, along with coordinate decreases in proteins that regulate "cell spreading," a cellular event previously shown to be dysregulated in transformed cells. Protein interaction network analysis revealed the clustering of focal adhesion kinase (FAK), a fundamental regulator of cell spreading, with several proteins identified as mutually, differentially abundant across breast cancer cell lines that impact expression and activity of FAK, such as neprilysin and keratin 19. These analyses provide insights into conservation of protein expression across breast cancer cell subtypes, a subset of which warrants further investigation for their roles in the regulation of cell spreading and FAK in breast cancer.

  1. Down-regulation of integrin β1 and focal adhesion kinase in renal glomeruli under various hemodynamic conditions.

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    Xiaoli Yuan

    Full Text Available Given that integrin β1 is an important component of the connection to maintain glomerular structural integrity, by binding with multiple extracellular matrix proteins and mediating intracellular signaling. Focal adhesion kinase (FAK is the most essential intracellular integrator in the integrin β1-FAK signalling pathway. Here, we investigated the changes of the two molecules and visualized the possible interaction between them under various hemodynamic conditions in podocytes. Mice kidney tissues were prepared using in vivo cryotechnique (IVCT and then were stained and observed using light microscopy, confocal laser scanning microscopy and immunoelectron microscopy. The expression of these molecules were examined by western blot. Under the normal condition, integrin β1 stained continually and evenly at the membrane, and FAK was located in the cytoplasm and nuclei of the podocytes. There were significant colocalized plaques of two molecules. But under acute hypertensive and cardiac arrest conditions, integrin β1 decreased and stained intermittently. Similarly, FAK decreased and appeared uneven. Additionally, FAK translocated to the nuclei of the podocytes. As a result, the colocalization of integrin β1 and FAK reduced obviously under these conditions. Western blot assay showed a consistent result with the immunostaining. Collectively, the abnormal redistribution and decreased expressions of integrin β1 and FAK are important molecular events in regulating the functions of podocytes under abnormal hemodynamic conditions. IVCT could offer considerable advantages for morphological analysis when researching renal diseases.

  2. Protective influence of hyaluronic acid on focal adhesion kinase activity in human skin fibroblasts exposed to ethanol

    Science.gov (United States)

    Donejko, Magdalena; Rysiak, Edyta; Galicka, Elżbieta; Terlikowski, Robert; Głażewska, Edyta Katarzyna; Przylipiak, Andrzej

    2017-01-01

    Aim The aim of this study was to evaluate the effect of ethanol and hyaluronic acid (HA) on cell survival and apoptosis in cultured human skin fibroblasts. Regarding the mechanism of ethanol action on human skin fibroblasts, we investigated cell viability and apoptosis, expression of focal adhesion kinase (FAK), and the influence of HA on those processes. Materials and methods Studies were conducted in confluent human skin fibroblast cultures that were treated with 25 mM, 50 mM, and 100 mM ethanol or with ethanol and 500 µg/mL HA. Cell viability was examined using methyl thiazolyl tetrazolium (MTT) assay and NC-300 Nucleo-Counter. Imaging of the cells using a fluorescence microscope Pathway 855 was performed to measure FAK expression. Results Depending on the dosage, ethanol decreased cell viability and activated the process of apoptosis in human skin fibroblasts. HA prevented the negative influence of ethanol on cell viability and prevented apoptosis. The analysis of fluorescence imaging using BD Pathway 855 High-Content Bioimager showed the inhibition of FAK migration to the cell nucleus, depending on the increasing concentration of ethanol. Conclusion This study proves that downregulation of signaling pathway of FAK is involved in ethanol-induced apoptosis in human skin fibroblasts. The work also indicates a protective influence of HA on FAK activity in human skin fibroblasts exposed to ethanol. PMID:28293103

  3. Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth*♦

    Science.gov (United States)

    Cheng, Zhaokang; Zhu, Qiang; Dee, Rachel; Opheim, Zachary; Mack, Christopher P.; Cyr, Douglas M.; Taylor, Joan M.

    2017-01-01

    Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophy in vivo. Collectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux. PMID:27994061

  4. Heat shock protein 90β stabilizes focal adhesion kinase and enhances cell migration and invasion in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Xiangyang [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China); Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330006 (China); State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047 (China); Wang, Yao [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China); Liu, Chengmei [State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi 330047 (China); Lu, Quqin [Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi 330006 (China); Liu, Tao [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China); Chen, Guoan [Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006 (China); Rao, Hai [Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229 (United States); Luo, Shiwen, E-mail: shiwenluo@ncu.edu.cn [Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Donghu District, Nanchang, Jiangxi 330006 (China)

    2014-08-01

    Focal adhesion kinase (FAK) acts as a regulator of cellular signaling and may promote cell spreading, motility, invasion and survival in malignancy. Elevated expression and activity of FAK frequently correlate with tumor cell metastasis and poor prognosis in breast cancer. However, the mechanisms by which the turnover of FAK is regulated remain elusive. Here we report that heat shock protein 90β (HSP90β) interacts with FAK and the middle domain (amino acids 233–620) of HSP90β is mainly responsible for this interaction. Furthermore, we found that HSP90β regulates FAK stability since HSP90β inhibitor 17-AAG triggers FAK ubiquitylation and subsequent proteasome-dependent degradation. Moreover, disrupted FAK-HSP90β interaction induced by 17-AAG contributes to attenuation of tumor cell growth, migration, and invasion. Together, our results reveal how HSP90β regulates FAK stability and identifies a potential therapeutic strategy to breast cancer. - Highlights: • HSP90β protects FAK from degradation by the ubiquitin-proteasome pathway. • Inhibition of HSP90β or FAK attenuates tumorigenesis of breast cancer cells. • Genetic repression of HSP90β or FAK inhibits tumor cell migration and proliferation. • Inhibition of HSP90β or FAK interferes cell invasion and cytoskeleton.

  5. Homozygous mutation of focal adhesion kinase in embryonic stem cell derived neurons: normal electrophysiological and morphological properties in vitro

    Directory of Open Access Journals (Sweden)

    Komiyama NH

    2006-06-01

    Full Text Available Abstract Background Genetically manipulated embryonic stem (ES cell derived neurons (ESNs provide a powerful system with which to study the consequences of gene manipulation in mature, synaptically connected neurons in vitro. Here we report a study of focal adhesion kinase (FAK, which has been implicated in synapse formation and regulation of ion channels, using the ESN system to circumvent the embryonic lethality of homozygous FAK mutant mice. Results Mouse ES cells carrying homozygous null mutations (FAK-/- were generated and differentiated in vitro into neurons. FAK-/- ESNs extended axons and dendrites and formed morphologically and electrophysiologically intact synapses. A detailed study of NMDA receptor gated currents and voltage sensitive calcium currents revealed no difference in their magnitude, or modulation by tyrosine kinases. Conclusion FAK does not have an obligatory role in neuronal differentiation, synapse formation or the expression of NMDA receptor or voltage-gated calcium currents under the conditions used in this study. The use of genetically modified ESNs has great potential for rapidly and effectively examining the consequences of neuronal gene manipulation and is complementary to mouse studies.

  6. Vascular growth responses to chronic arterial occlusion are unaffected by myeloid specific focal adhesion kinase (FAK) deletion

    Science.gov (United States)

    Heuslein, Joshua L.; Murrell, Kelsey P.; Leiphart, Ryan J.; Llewellyn, Ryan A.; Meisner, Joshua K.; Price, Richard J.

    2016-05-01

    Arteriogenesis, or the lumenal expansion of pre-existing arterioles in the presence of an upstream occlusion, is a fundamental vascular growth response. Though alterations in shear stress stimulate arteriogenesis, the migration of monocytes into the perivascular space surrounding collateral arteries and their differentiation into macrophages is critical for this vascular growth response to occur. Focal adhesion kinase’s (FAK) role in regulating cell migration has recently been expanded to primary macrophages. We therefore investigated the effect of the myeloid-specific conditional deletion of FAK on vascular remodeling in the mouse femoral arterial ligation (FAL) model. Using laser Doppler perfusion imaging, whole mount imaging of vascular casted gracilis muscles, and immunostaining for CD31 in gastrocnemius muscles cross-sections, we found that there were no statistical differences in perfusion recovery, arteriogenesis, or angiogenesis 28 days after FAL. We therefore sought to determine FAK expression in different myeloid cell populations. We found that FAK is expressed at equally low levels in Ly6Chi and Ly6Clo blood monocytes, however expression is increased over 2-fold in bone marrow derived macrophages. Ultimately, these results suggest that FAK is not required for monocyte migration to the perivascular space and that vascular remodeling following arterial occlusion occurs independently of myeloid specific FAK.

  7. Three-dimensional cell body shape dictates the onset of traction force generation and growth of focal adhesions.

    Science.gov (United States)

    Fouchard, Jonathan; Bimbard, Célian; Bufi, Nathalie; Durand-Smet, Pauline; Proag, Amsha; Richert, Alain; Cardoso, Olivier; Asnacios, Atef

    2014-09-09

    Cell shape affects proliferation and differentiation, which are processes known to depend on integrin-based focal adhesion (FA) signaling. Because shape results from force balance and FAs are mechanosensitive complexes transmitting tension from the cell structure to its mechanical environment, we investigated the interplay between 3D cell shape, traction forces generated through the cell body, and FA growth during early spreading. Combining measurements of cell-scale normal traction forces with FA monitoring, we show that the cell body contact angle controls the onset of force generation and, subsequently, the initiation of FA growth at the leading edge of the lamella. This suggests that, when the cell body switches from convex to concave, tension in the apical cortex is transmitted to the lamella where force-sensitive FAs start to grow. Along this line, increasing the stiffness resisting cell body contraction led to a decrease of the lag time between force generation and FA growth, indicating mechanical continuity of the cell structure and force transmission from the cell body to the leading edge. Remarkably, the overall normal force per unit area of FA increased with stiffness, and its values were similar to those reported for local tangential forces acting on individual FAs. These results reveal how the 3D cell shape feeds back on its internal organization and how it may control cell fate through FA-based signaling.

  8. Focal adhesion kinase is involved in type III group B streptococcal invasion of human brain microvascular endothelial cells.

    Science.gov (United States)

    Shin, Sooan; Paul-Satyaseela, Maneesh; Maneesh, Paul-Satyaseela; Lee, Jong-Seok; Romer, Lewis H; Kim, Kwang Sik

    2006-01-01

    Group B streptococcus (GBS), the leading cause of neonatal meningitis, has been shown to invade human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier. GBS invasion of HBMEC has been shown to require the host cell actin cytoskeleton rearrangements. The present study examined the mechanisms underlying actin cytoskeleton rearrangements that are involved in type III GBS invasion of HBMEC. We showed that type III GBS invasion was inhibited by genistein, a general tyrosine kinase inhibitor (mean 54% invasion decrease at 100 microM), and LY294002, a phosphatidylinositol 3 (PI3) kinase inhibitor (mean 70% invasion decrease at 50 microM), but not by PP2, an inhibitor of the Src family tyrosine kinases. We subsequently showed that the focal adhesion kinase (FAK) was the one of the host proteins tyrosine phosphorylated by type III GBS. Over-expression of a dominant negative form of the FAK C-terminal domain significantly decreased type III GBS invasion of HBMEC (mean 51% invasion decrease). In addition, we showed that FAK phosphorylation correlated with its association of paxillin, an adapter protein of actin filament, and PI3-kinase subunit p85. This is the first demonstration that FAK phosphorylation and its association with paxillin and PI3 kinase play a key role in type III GBS invasion of HBMEC.

  9. Inhibition of Focal Adhesion Kinase (FAK) Leads to Abrogation of the Malignant Phenotype in Aggressive Pediatric Renal Malignancies

    Science.gov (United States)

    Megison, Michael L.; Gillory, Lauren A.; Stewart, Jerry E.; Nabers, Hugh C.; Mrozcek-Musulman, Elizabeth; Beierle, Elizabeth A.

    2014-01-01

    Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and non-osseous renal Ewing sarcoma. Children with advanced, metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading us to hypothesize that FAK would be present in pediatric kidney tumors and would impact their cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric kidney tumor specimens. We also examined the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines utilizing a number of parallel approaches to block FAK including RNAi and small molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Further, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse SK-NEP-1 xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in rare pediatric renal tumors, and may provide desperately needed novel therapeutic strategies and targets for these rare, but difficult to treat, malignancies. PMID:24464916

  10. Exploring the interaction between human focal adhesion kinase and inhibitors: a molecular dynamic simulation and free energy calculations.

    Science.gov (United States)

    Zhan, Jiu-Yu; Zhang, Ji-Long; Wang, Yan; Li, Ye; Zhang, Hong-Xing; Zheng, Qing-Chuan

    2016-11-01

    Focal adhesion kinase is an important target for the treatment of many kinds of cancers. Inhibitors of FAK are proposed to be the anticancer agents for multiple tumors. The interaction characteristic between FAK and its inhibitors is crucial to develop new inhibitors. In the present article, we used Molecular Dynamic (MD) simulation method to explore the characteristic of interaction between FAK and three inhibitors (PHM16, TAE226, and ligand3). The MD simulation results together with MM-GB/SA calculations show that the combinations are enthalpy-driven process. Cys502 and Asp564 are both essential residues due to the hydrogen bond interactions with inhibitors, which was in good agreement with experimental data. Glu500 can form a non-classical hydrogen bond with each inhibitor. Arg426 can form electrostatic interactions with PHM16 and ligand3, while weaker with TAE226. The electronic static potential was employed, and we found that the ortho-position methoxy of TAE226 has a weaker negative charge than the meta-position one in PHM16 or ligand3. Ile428, Val436, Ala452, Val484, Leu501, Glu505, Glu506, Leu553, Gly563 Leu567, Ser568 are all crucial residues in hydrophobic interactions. The key residues in this work will be available for further inhibitor design of FAK and also give assistance to further research of cancer.

  11. Annexin A6 contributes to the invasiveness of breast carcinoma cells by influencing the organization and localization of functional focal adhesions

    Energy Technology Data Exchange (ETDEWEB)

    Sakwe, Amos M., E-mail: asakwe@mmc.edu [Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208 (United States); Koumangoye, Rainelli; Guillory, Bobby [Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208 (United States); Ochieng, Josiah [Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208 (United States); Center for Aids Health Disparity Research, Meharry Medical College, Nashville, TN 37208 (United States); Department of Cancer Biology, Vanderbilt University, Nashville, TN (United States)

    2011-04-01

    The interaction of annexin A6 (AnxA6) with membrane phospholipids and either specific extracellular matrix (ECM) components or F-actin suggests that it may influence cellular processes associated with rapid plasma membrane reorganization such as cell adhesion and motility. Here, we examined the putative roles of AnxA6 in adhesion-related cellular processes that contribute to breast cancer progression. We show that breast cancer cells secrete annexins via the exosomal pathway and that the secreted annexins are predominantly cell surface-associated. Depletion of AnxA6 in the invasive BT-549 breast cancer cells is accompanied by enhanced anchorage-independent cell growth but cell-cell cohesion, cell adhesion/spreading onto collagen type IV or fetuin-A, cell motility and invasiveness were strongly inhibited. To explain the loss in adhesion/motility, we show that vinculin-based focal adhesions in the AnxA6-depleted BT-549 cells are elongated and randomly distributed. These focal contacts are also functionally defective because the activation of focal adhesion kinase and the phosphoinositide-3 kinase/Akt pathway were strongly inhibited while the MAP kinase pathway remained constitutively active. Compared with normal human breast tissues, reduced AnxA6 expression in breast carcinoma tissues correlates with enhanced cell proliferation. Together this suggests that reduced AnxA6 expression contributes to breast cancer progression by promoting the loss of functional cell-cell and/or cell-ECM contacts and anchorage-independent cell proliferation.

  12. Mechanical Stimulation of C2C12 Cells Increases m-Calpain Expression and Activity, Focal Adhesion Plaque Degradation and Cell Fusion

    DEFF Research Database (Denmark)

    Grossi, Alberto; Lawson, Moira Ann; Karlsson, Anders H

    Abstract Mechanical Stimulation of C2C12 Cells Increases m-calpain Expression and Activity, Focal Adhesion Plaque Degradation and Cell Fusion A. Grossi, A. H. Karlsson, M. A. Lawson; Department of Dairy and Food Science, Royal Veterinary and Agricultural University, Frederiksberg C, Denmark...... to the activity of ubiquitous proteolytic enzymes known as calpains has been reported. Whether there is a link between stretch- or load induced signaling and calpain expression and activation is not known. Using a magnetic bead stimulation assay and C2C12 mouse myoblasts cell population, we have demonstrated...... that mechanical stimulation via laminin receptors leads to an increase in m-calpain expression, but no increase in the expression of other calpain isoforms. Our study revealed that after a short period of stimulation, m-calpain relocates into focal adhesion complexes and is followed by a breakdown of specific...

  13. Suppression of β3-integrin in mice triggers a neuropilin-1-dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis

    Directory of Open Access Journals (Sweden)

    Tim S. Ellison

    2015-09-01

    Full Text Available Anti-angiogenic treatments against αvβ3-integrin fail to block tumour growth in the long term, which suggests that the tumour vasculature escapes from angiogenesis inhibition through αvβ3-integrin-independent mechanisms. Here, we show that suppression of β3-integrin in mice leads to the activation of a neuropilin-1 (NRP1-dependent cell migration pathway in endothelial cells via a mechanism that depends on NRP1's mobilisation away from mature focal adhesions following VEGF-stimulation. The simultaneous genetic targeting of both molecules significantly impairs paxillin-1 activation and focal adhesion remodelling in endothelial cells, and therefore inhibits tumour angiogenesis and the growth of already established tumours. These findings provide a firm foundation for testing drugs against these molecules in combination to treat patients with advanced cancers.

  14. The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity

    Energy Technology Data Exchange (ETDEWEB)

    Gustafsson, Karin [Department of Medical Cell Biology, Uppsala University, Uppsala 751 23 (Sweden); Heffner, Garrett; Wenzel, Pamela L.; Curran, Matthew [HHMI, Children' s Hospital Boston, Harvard Medical School, Boston, 02115 MA (United States); Grawé, Jan [Department of Genetics and Pathology, Uppsala University, Uppsala 75185 (Sweden); McKinney-Freeman, Shannon L. [Department of Hematology, St. Jude Children' s Research Hospital, Memphis, TN 38105 (United States); Daley, George Q. [HHMI, Children' s Hospital Boston, Harvard Medical School, Boston, 02115 MA (United States); Welsh, Michael, E-mail: michael.welsh@mcb.uu.se [Department of Medical Cell Biology, Uppsala University, Uppsala 751 23 (Sweden)

    2013-07-15

    The widely expressed adaptor protein Shb has previously been reported to contribute to T cell function due to its association with the T cell receptor and furthermore, several of Shb's known interaction partners are established regulators of blood cell development and function. In addition, Shb deficient embryonic stem cells displayed reduced blood cell colony formation upon differentiation in vitro. The aim of the current study was therefore to explore hematopoietic stem and progenitor cell function in the Shb knockout mouse. Shb deficient bone marrow contained reduced relative numbers of long-term hematopoietic stem cells (LT-HSCs) that exhibited lower proliferation rates. Despite this, Shb knockout LT-HSCs responded promptly by entering the cell cycle in response to genotoxic stress by 5-fluorouracil treatment. In competitive LT-HSC transplantations, Shb null cells initially engrafted as well as the wild-type cells but provided less myeloid expansion over time. Moreover, Shb knockout bone marrow cells exhibited elevated basal activities of focal adhesion kinase/Rac1/p21-activated kinase signaling and reduced responsiveness to Stem Cell Factor stimulation. Consequently, treatment with a focal adhesion kinase inhibitor increased Shb knockout LT-HSC proliferation. The altered signaling characteristics thus provide a plausible mechanistic explanation for the changes in LT-HSC proliferation since these signaling intermediates have all been shown to participate in LT-HSC cell cycle control. In summary, the loss of Shb dependent signaling in bone marrow cells, resulting in elevated focal adhesion kinase activity and reduced proliferative responses in LT-HSCs under steady state hematopoiesis, confers a disadvantage to the maintenance of LT-HSCs over time. -- Highlights: • Shb is an adaptor protein operating downstream of tyrosine kinase receptors. • Shb deficiency reduces hematopoietic stem cell proliferation. • The proliferative effect of Shb occurs via

  15. A novel type 3 secretion system effector, YspI of Yersinia enterocolitica, induces cell paralysis by reducing total focal adhesion kinase.

    Science.gov (United States)

    LeGrand, Karen; Matsumoto, Hiroyuki; Young, Glenn M

    2015-05-01

    Some of the world's most important diseases are caused by bacterial pathogens that deliver toxic effector proteins directly into eukaryotic cells using type III secretion systems. The myriad of pathological outcomes caused by these pathogens is determined, in part, by the manipulation of host cell physiology due to the specific activities of individual effectors among the unique suite each pathogen employs. YspI was found to be an effector, delivered by Yersinia enterocolitica Biovar 1B, that inhibits host cell motility. The action of YspI comes about through its specific interaction with focal adhesion kinase, FAK, which is a fulcrum of focal adhesion complexes for controlling cellular motility. The interaction was defined by a specific domain of YspI that bound to the FAK kinase domain. Further examination revealed that YspI-FAK interaction leads to a reduction of FAK steady-state levels without altering its phosphorylation state. This collection of observations and results showed YspI displays unique functionality by targeting the key regulator of focal adhesion complexes to inhibit cellular movement.

  16. Recruitment of focal adhesion kinase and paxillin to β1 integrin promotes cancer cell migration via mitogen activated protein kinase activation

    Directory of Open Access Journals (Sweden)

    Ohannessian Arthur

    2004-05-01

    Full Text Available Abstract Background Integrin-extracellular matrix interactions activate signaling cascades such as mitogen activated protein kinases (MAPK. Integrin binding to extracellular matrix increases tyrosine phosphorylation of focal adhesion kinase (FAK. Inhibition of FAK activity by expression of its carboxyl terminus decreases cell motility, and cells from FAK deficient mice also show reduced migration. Paxillin is a focal adhesion protein which is also phosphorylated on tyrosine. FAK recruitment of paxillin to the cell membrane correlates with Shc phosphorylation and activation of MAPK. Decreased FAK expression inhibits papilloma formation in a mouse skin carcinogenesis model. We previously demonstrated that MAPK activation was required for growth factor induced in vitro migration and invasion by human squamous cell carcinoma (SCC lines. Methods Adapter protein recruitment to integrin subunits was examined by co-immunoprecipitation in SCC cells attached to type IV collagen or plastic. Stable clones overexpressing FAK or paxillin were created using the lipofection technique. Modified Boyden chambers were used for invasion assays. Results In the present study, we showed that FAK and paxillin but not Shc are recruited to the β1 integrin cytoplasmic domain following attachment of SCC cells to type IV collagen. Overexpression of either FAK or paxillin stimulated cancer cell migration on type IV collagen and invasion through reconstituted basement membrane which was dependent on MAPK activity. Conclusions We concluded that recruitment of focal adhesion kinase and paxillin to β1 integrin promoted cancer cell migration via the mitogen activated protein kinase pathway.

  17. Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing.

    Science.gov (United States)

    Wong, Victor W; Garg, Ravi K; Sorkin, Michael; Rustad, Kristine C; Akaishi, Satoshi; Levi, Kemal; Nelson, Emily R; Tran, Misha; Rennert, Robert; Liu, Wei; Longaker, Michael T; Dauskardt, Reinhold H; Gurtner, Geoffrey C

    2014-12-01

    To investigate how epithelial mechanotransduction pathways impact wound repair. Mechanical forces are increasingly recognized to influence tissue repair, but their role in chronic wound pathophysiology remains unknown. Studies have shown that chronic wounds exhibit high levels of matrix metalloproteinase 9 (MMP9), a key proteolytic enzyme that regulates wound remodeling. We hypothesized that epithelial mechanosensory pathways regulated by keratinocyte-specific focal adhesion kinase (FAK) control dermal remodeling via MMP9. A standard wound model was applied to keratinocyte-specific FAK knockout (KO) and control mice. Rates of wound healing were measured and tissue was obtained for histologic and molecular analyses. Transcriptional and immunoblot assays were used to assess the activation of FAK, intracellular kinases, and MMP9 in vitro. A cell suspension model was designed to validate the importance of FAK mechanosensing, p38, and MMP9 secretion in human cells. Biomechanical testing was utilized to evaluate matrix tensile properties in FAK KO and control wounds. Wound healing in FAK KO mice was significantly delayed compared with controls (closure at 15 days compared with 20 days, P = 0.0003). FAK KO wounds demonstrated decreased dermal thickness and collagen density. FAK KO keratinocytes exhibited overactive p38 and MMP9 signaling in vitro, findings recapitulated in human keratinocytes via the deactivation of FAK in the cell suspension model. Functionally, FAK KO wounds were significantly weaker and more brittle than control wounds, results consistent with the histologic and molecular analyses. Keratinocyte FAK is highly responsive to mechanical cues and may play a critical role in matrix remodeling via regulation of p38 and MMP9. These findings suggest that aberrant epithelial mechanosensory pathways may contribute to pathologic dermal proteolysis and wound chronicity.

  18. Cell invasion by Neisseria meningitidis requires a functional interplay between the focal adhesion kinase, Src and cortactin.

    Directory of Open Access Journals (Sweden)

    Heiko Slanina

    Full Text Available Entry of Neisseria meningitidis (the meningococcus into human brain microvascular endothelial cells (HBMEC is mediated by fibronectin or vitronectin bound to the surface protein Opc forming a bridge to the respective integrins. This interaction leads to cytoskeletal rearrangement and uptake of meningococci. In this study, we determined that the focal adhesion kinase (FAK, which directly associates with integrins, is involved in integrin-mediated internalization of N. meningitidis in HBMEC. Inhibition of FAK activity by the specific FAK inhibitor PF 573882 reduced Opc-mediated invasion of HBMEC more than 90%. Moreover, overexpression of FAK mutants that were either impaired in the kinase activity or were not capable of autophosphorylation or overexpression of the dominant-negative version of FAK (FRNK blocked integrin-mediated internalization of N. meningitidis. Importantly, FAK-deficient fibroblasts were significantly less invaded by N. meningitidis. Furthermore, N. meningitidis induced tyrosine phosphorylation of several host proteins including the FAK/Src complex substrate cortactin. Inhibition of cortactin expression by siRNA silencing and mutation of critical amino acid residues within cortactin, that encompass Arp2/3 association and dynamin binding, significantly reduced meningococcal invasion into eukaryotic cells suggesting that both domains are critical for efficient uptake of N. meningitidis into eukaryotic cells. Together, these results indicate that N. meningitidis exploits the integrin signal pathway for its entry and that FAK mediates the transfer of signals from activated integrins to the cytoskeleton. A cooperative interplay between FAK, Src and cortactin then enables endocytosis of N. meningitidis into host cells.

  19. Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1.

    Science.gov (United States)

    Diaz, Jorge; Aranda, Evelyn; Henriquez, Soledad; Quezada, Marisol; Espinoza, Estefanía; Bravo, Maria Loreto; Oliva, Bárbara; Lange, Soledad; Villalon, Manuel; Jones, Marius; Brosens, Jan J; Kato, Sumie; Cuello, Mauricio A; Knutson, Todd P; Lange, Carol A; Leyton, Lisette; Owen, Gareth I

    2012-08-01

    Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mechanisms are still not fully understood. The protease-activated receptors (PARs) are a family of membrane receptors that are activated by serine proteases in the blood coagulation cascade. PAR1 (F2R) has been reported to be involved in cancer cell migration and overexpressed in breast cancer. We herein demonstrate that PAR1 mRNA and protein are upregulated by progesterone treatment of the breast cancer cell lines ZR-75 and T47D. This regulation is dependent on the progesterone receptor (PR) but does not require PR phosphorylation at serine 294 or the PR proline-rich region mPRO. The increase in PAR1 mRNA was transient, being present at 3  h and returning to basal levels at 18  h. The addition of a PAR1-activating peptide (aPAR1) to cells treated with progesterone resulted in an increase in focal adhesion (FA) formation as measured by the cellular levels of phosphorylated FA kinase. The combined but not individual treatment of progesterone and aPAR1 also markedly increased stress fiber formation and the migratory capacity of breast cancer cells. In agreement with in vitro findings, data mining from the Oncomine platform revealed that PAR1 expression was significantly upregulated in PR-positive breast tumors. Our observation that PAR1 expression and signal transduction are modulated by progesterone provides new insight into how the progestin component in hormone therapies increases the risk of breast cancer in postmenopausal women.

  20. MVL-PLA2, a snake venom phospholipase A2, inhibits angiogenesis through an increase in microtubule dynamics and disorganization of focal adhesions.

    Directory of Open Access Journals (Sweden)

    Amine Bazaa

    Full Text Available Integrins are essential protagonists of the complex multi-step process of angiogenesis that has now become a major target for the development of anticancer therapies. We recently reported and characterized that MVL-PLA2, a novel phospholipase A2 from Macrovipera lebetina venom, exhibited anti-integrin activity. In this study, we show that MVL-PLA2 also displays potent anti-angiogenic properties. This phospholipase A2 inhibited adhesion and migration of human microvascular-endothelial cells (HMEC-1 in a dose-dependent manner without being cytotoxic. Using Matrigel and chick chorioallantoic membrane assays, we demonstrated that MVL-PLA2, as well as its catalytically inactivated form, significantly inhibited angiogenesis both in vitro and in vivo. We have also found that the actin cytoskeleton and the distribution of alphav beta3 integrin, a critical regulator of angiogenesis and a major component of focal adhesions, were disturbed after MVL-PLA2 treatment. In order to further investigate the mechanism of action of this protein on endothelial cells, we analyzed the dynamic instability behavior of microtubules in living endothelial cells. Interestingly, we showed that MVL-PLA2 significantly increased microtubule dynamicity in HMEC-1 cells by 40%. We propose that the enhancement of microtubule dynamics may explain the alterations in the formation of focal adhesions, leading to inhibition of cell adhesion and migration.

  1. alpha2-Adrenoceptor stimulation promotes actin polymerization and focal adhesion in 3T3F442A and BFC-1beta preadipocytes.

    Science.gov (United States)

    Bétuing, S; Daviaud, D; Valet, P; Bouloumié, A; Lafontan, M; Saulnier-Blache, J S

    1996-12-01

    We previously demonstrated that in white fat cell precursors alpha2-adrenoceptor stimulation lead to the phosphorylation of p44 and p42 mitogen-activated protein kinases and an increase in cell number. Regulation of cell adhesion and cell cytoskeleton plays a crucial role in the control of cell growth by various growth factors. Here, we report that in mouse 3T3F442A preadipocytes expressing 2500 fmol/mg protein of the human alpha2C10-adrenoceptor (alpha2AF2 cells), alpha2-adrenergic stimulation rapidly restored the spreading of cells previously retracted by serum withdrawal. This effect was pertussis toxin sensitive and was blocked by pretreatment of the cells with dihydrocytochalasin B (a blocker of actin polymerization), genistein (a tyrosine kinase inhibitor), or agents that increase cell cAMP content. Spreading was accompanied by cell membrane ruffling, formation of lamelipodia and filipodia, appearance of focal adhesion plaques, and induction of actin stress fibers. alpha2-Adrenergic stimulation also lead to a rapid Gi- and actin-dependent tyrosine phosphorylation of the pp125 focal adhesion kinase (FAK) as well as of the p42 and p44 mitogen-activated protein kinases. alpha2-Adrenergic-dependent spreading and FAK and mitogen-activated protein kinase phosphorylation were also observed in 3T3F442A preadipocytes permanently expressing 20 fmol/mg protein of the human alpha2C10-adrenoceptor (alpha2AF3 cells) as well as in BFC-1beta preadipocytes, which constitutively express 25 fmol/mg protein of mouse alpha2A-adrenoceptors. In BFC-1beta preadipocytes, alpha2-adrenergic-dependent spreading and pp125FAK phosphorylation were counteracted by beta-adrenergic stimulation. Our results suggest that alpha2-adrenergic control of actin polymerization and focal adhesion assembly could play a crucial role in the regulation of preadipocyte growth by the sympathetic nervous system.

  2. CEACAM6 cross-linking induces caveolin-1-dependent, Src-mediated focal adhesion kinase phosphorylation in BxPC3 pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Duxbury, Mark S; Ito, Hiromichi; Ashley, Stanley W; Whang, Edward E

    2004-05-28

    Despite lacking transmembrane or intracellular domains, glycosylphosphatidylinositol-anchored proteins can modulate intracellular signaling events, in many cases through aggregation within membrane "lipid raft" microdomains. CEACAM6 is a glycosylphosphatidylinositol-linked cell surface protein of importance in the anchorage-independent survival and metastasis of pancreatic adenocarcinoma cells. We examined the effects of antibody-mediated cross-linking of CEACAM6 on intracellular signaling events and anchorage-independent survival of the CEACAM6-overexpressing pancreatic ductal adenocarcinoma cell line, BxPC3. CEACAM6 cross-linking increased c-Src activation and induced tyrosine phosphorylation of p125(FAK) focal adhesion kinase. Focal adhesion kinase phosphorylation was dependent on c-Src kinase activation, for which caveolin-1 was required. CEACAM6 cross-linking induced a significant increase in cellular resistance to anoikis. These observations represent the first characterization of the mechanism through which this important cell surface oncoprotein influences intracellular signaling events and hence malignant cellular behavior.

  3. Substrate Elastic Modulus Regulates the Morphology, Focal Adhesions, and alpha-Smooth Muscle Actin Expression of Retinal Muller Cells

    NARCIS (Netherlands)

    Bu, Shao-Chong; Kuijer, Roel; van der Worp, Roelofje J.; van Putten, Sander M.; Wouters, Olaf; Li, Xiao-Rong; Hooymans, Johanna M. M.; Los, Leonoor I.

    PURPOSE. The stiffness of the extracellular matrix has been shown to regulate cell adhesion, migration, and transdifferentiation in fibrotic processes. Retinal Muller cells have been shown to be mechanosensitive; they are involved in fibrotic vitreoretinal diseases. Since fibrosis increases the

  4. Cellular adhesome screen identifies critical modulators of focal adhesion dynamics, cellular traction forces and cell migration behaviour.

    Science.gov (United States)

    Fokkelman, Michiel; Balcıoğlu, Hayri E; Klip, Janna E; Yan, Kuan; Verbeek, Fons J; Danen, Erik H J; van de Water, Bob

    2016-08-17

    Cancer cells migrate from the primary tumour into surrounding tissue in order to form metastasis. Cell migration is a highly complex process, which requires continuous remodelling and re-organization of the cytoskeleton and cell-matrix adhesions. Here, we aimed to identify genes controlling aspects of tumour cell migration, including the dynamic organization of cell-matrix adhesions and cellular traction forces. In a siRNA screen targeting most cell adhesion-related genes we identified 200+ genes that regulate size and/or dynamics of cell-matrix adhesions in MCF7 breast cancer cells. In a subsequent secondary screen, the 64 most effective genes were evaluated for growth factor-induced cell migration and validated by tertiary RNAi pool deconvolution experiments. Four validated hits showed significantly enlarged adhesions accompanied by reduced cell migration upon siRNA-mediated knockdown. Furthermore, loss of PPP1R12B, HIPK3 or RAC2 caused cells to exert higher traction forces, as determined by traction force microscopy with elastomeric micropillar post arrays, and led to considerably reduced force turnover. Altogether, we identified genes that co-regulate cell-matrix adhesion dynamics and traction force turnover, thereby modulating overall motility behaviour.

  5. Substrate Elastic Modulus Regulates the Morphology, Focal Adhesions, and α-Smooth Muscle Actin Expression of Retinal Müller Cells.

    Science.gov (United States)

    Bu, Shao-Chong; Kuijer, Roel; van der Worp, Roelofje J; van Putten, Sander M; Wouters, Olaf; Li, Xiao-Rong; Hooymans, Johanna M M; Los, Leonoor I

    2015-09-01

    The stiffness of the extracellular matrix has been shown to regulate cell adhesion, migration, and transdifferentiation in fibrotic processes. Retinal Müller cells have been shown to be mechanosensitive; they are involved in fibrotic vitreoretinal diseases. Since fibrosis increases the rigidity of the extracellular matrix, our aim was to develop an in vitro model for studying Müller cell morphology and differentiation state in relation to matrix stiffness. A spontaneously immortalized human Müller cell line (MIO-M1) was cultured on type I collagen-coated polyacrylamide gels with Young's moduli ranging from 2 to 92 kPa. Cell surface area, focal adhesion, and the expression and morphology of α-smooth muscle actin induced by transforming growth factor β (TGF-β [10 ng/mL for 48 hours]) were analyzed by immunocytology. The images were documented by using fluorescence microscopy and confocal scanning laser microscopy. MIO-M1 cells cultured on stiff substrates exhibited a significant increase in cell surface area, stress fiber, and mature focal adhesion formation. Furthermore, Müller cells treated with TGF-β1 and TGF-β2 and cultured on stiff substrates showed an increased incorporation of α-smooth muscle actin into stress fibers when compared to those grown on soft surfaces. Compliance of the surrounding matrix seems to influence the morphology and contraction of retinal Müller cells in fibrotic conditions. Development of an in vitro model simulating both the normally compliant retinal tissue and the rigid retinal fibrotic tissue helps fill the gap between the results of petri-dish cell culture with rigid surfaces and in vivo findings.

  6. Cell adhesion to fibrillin-1: identification of an Arg-Gly-Asp-dependent synergy region and a heparin-binding site that regulates focal adhesion formation

    DEFF Research Database (Denmark)

    Bax, Daniel V; Mahalingam, Yashithra; Cain, Stuart;

    2007-01-01

    We have defined the molecular basis of cell adhesion to fibrillin-1, the major structural component of extracellular microfibrils that are associated with elastic fibres. Using human dermal fibroblasts, and recombinant domain swap fragments containing the Arg-Gly-Asp motif, we have demonstrated a...

  7. A synthetic peptide from the COOH-terminal heparin-binding domain of fibronectin promotes focal adhesion formation

    DEFF Research Database (Denmark)

    Woods, A; McCarthy, J B; Furcht, L T

    1993-01-01

    Cell adhesion to extracellular matrix molecules such as fibronectin involves complex transmembrane signaling processes. Attachment and spreading of primary fibroblasts can be promoted by interactions of cell surface integrins with RGD-containing fragments of fibronectin, but the further process o...

  8. Substrate Elastic Modulus Regulates the Morphology, Focal Adhesions, and alpha-Smooth Muscle Actin Expression of Retinal Muller Cells

    NARCIS (Netherlands)

    Bu, Shao-Chong; Kuijer, Roel; van der Worp, Roelofje J.; van Putten, Sander M.; Wouters, Olaf; Li, Xiao-Rong; Hooymans, Johanna M. M.; Los, Leonoor I.

    2015-01-01

    PURPOSE. The stiffness of the extracellular matrix has been shown to regulate cell adhesion, migration, and transdifferentiation in fibrotic processes. Retinal Muller cells have been shown to be mechanosensitive; they are involved in fibrotic vitreoretinal diseases. Since fibrosis increases the rigi

  9. cAMP-induced Epac-Rap activation inhibits epithelial cell migration by modulating focal adhesion and leading edge dynamics

    NARCIS (Netherlands)

    Lyle, Karen S.; Raaijmakers, J.H.; Bruinsma, Wytse; Bos, Johannes L.; Rooij, J. de

    2008-01-01

    Epithelial cell migration is a complex process crucial for embryonic development, wound healing and tumor metastasis. It depends on alterations in cell–cell adhesion and integrin–extracellular matrix interactions and on actomyosin-driven, polarized leading edge protrusion. The small GTPase Rap is a

  10. Mild hypothermia effects on intercellular adhesion molecule-1 and serum interleukin-6 expression in brain tissues of a rat focal ischemia model

    Institute of Scientific and Technical Information of China (English)

    Shengqi Fu; Lei Yang; Shuling Zhang; Shilong Sun; Xingai Mao

    2008-01-01

    BACKGROUND: Previous studies have confirmed the neuroprotective effect of mild hypothermia on ischemic brain injury.OBJECTIVE: To investigate the effects of mild hypothermia on intercellular adhesion molecule-1 expression and serum interleukin-6 levels in ischemic brain tissues of focal brain ischemia rats, and to explore the neuroprotective effects of mild hypothermia on ischemic brain injury.DESIGN, TIME AND SETTING: A randomized, controlled, neurobiological experiment was performed at the Central Laboratory, First Affiliated Hospital, Xinxiang Medical College, China from February to July 2006.MATERIALS: Thirty healthy, adult, Sprague Dawley rats were used to establish middle cerebral artery occlusion models using the suture method. The immunohistochemistry (streptavidin-biotin-peroxidase complex method) kit was purchased from Boster, China. Interleukin-6 radioimmunoassay was supplied by Institute of Radioimmunity, Technology Development Center, General Hospital of Chinese PLA. METHODS: The rats were equally and randomly assigned into mild hypothermia and control groups, and middle cerebral artery occlusion models were established. The rectal temperature was maintained at (37 ± 0.5)℃ in the control group. In the mild hypothermia group, the rectal temperature was maintained at (33±1)℃.MAIN OUTCOME MEASURES: At 12 hours after model establishment, the ischemic brain hemispheres were coronally sliced at the level of the optic chiasm. The number of intercellular adhesion molecule- 1 -positive vessels per high-power field was observed with an optical microscope. Serum interleukin-6 levels were measured by radioimmunoassay.RESULTS: Compared with the control group, intercellular adhesion molecule-I and serum interleukin-6 expressions were significantly decreased in ischemic brain tissues of the mild hypothermia group (P < 0.01).CONCLUSION: Mild hypothermia exhibits a neuroprotective effect by reducing serum interleukin-6 and intercellular adhesion molecule- 1

  11. E-cadherin-dependent stimulation of traction force at focal adhesions via the Src and PI3K signaling pathways.

    Science.gov (United States)

    Jasaitis, Audrius; Estevez, Maruxa; Heysch, Julie; Ladoux, Benoit; Dufour, Sylvie

    2012-07-18

    The interplay between cadherin- and integrin-dependent signals controls cell behavior, but the precise mechanisms that regulate the strength of adhesion to the extracellular matrix remains poorly understood. We deposited cells expressing a defined repertoire of cadherins and integrins on fibronectin (FN)-coated polyacrylamide gels (FN-PAG) and on FN-coated pillars used as a micro-force sensor array (μFSA), and analyzed the functional relationship between these adhesion receptors to determine how it regulates cell traction force. We found that cadherin-mediated adhesion stimulated cell spreading on FN-PAG, and this was modulated by the substrate stiffness. We compared S180 cells with cells stably expressing different cadherins on μFSA and found that traction forces were stronger in cells expressing cadherins than in parental cells. E-cadherin-mediated contact and mechanical coupling between cells are required for this increase in cell-FN traction force, which was not observed in isolated cells, and required Src and PI3K activities. Traction forces were stronger in cells expressing type I cadherins than in cells expressing type II cadherins, which correlates with our previous observation of a higher intercellular adhesion strength developed by type I compared with type II cadherins. Our results reveal one of the mechanisms whereby molecular cross talk between cadherins and integrins upregulates traction forces at cell-FN adhesion sites, and thus provide additional insight into the molecular control of cell behavior. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  12. Osthole Suppresses the Migratory Ability of Human Glioblastoma Multiforme Cells via Inhibition of Focal Adhesion Kinase-Mediated Matrix Metalloproteinase-13 Expression

    Directory of Open Access Journals (Sweden)

    Cheng-Fang Tsai

    2014-03-01

    Full Text Available Glioblastoma multiforme (GBM is the most common type of primary and malignant tumor occurring in the adult central nervous system. GBM often invades surrounding regions of the brain during its early stages, making successful treatment difficult. Osthole, an active constituent isolated from the dried C. monnieri fruit, has been shown to suppress tumor migration and invasion. However, the effects of osthole in human GBM are largely unknown. Focal adhesion kinase (FAK is important for the metastasis of cancer cells. Results from this study show that osthole can not only induce cell death but also inhibit phosphorylation of FAK in human GBM cells. Results from this study show that incubating GBM cells with osthole reduces matrix metalloproteinase (MMP-13 expression and cell motility, as assessed by cell transwell and wound healing assays. This study also provides evidence supporting the potential of osthole in reducing FAK activation, MMP-13 expression, and cell motility in human GBM cells.

  13. Direct binding of syndecan-4 cytoplasmic domain to the catalytic domain of protein kinase C alpha (PKC alpha) increases focal adhesion localization of PKC alpha

    DEFF Research Database (Denmark)

    Lim, Ssang-Taek; Longley, Robert L; Couchman, John R

    2003-01-01

    Syndecan-4 is a transmembrane heparan sulfate proteoglycan that acts as a coreceptor with integrins in focal adhesion formation. The central region of syndecan-4 cytoplasmic domain (4V; LGKKPIYKK) binds phosphatidylinositol 4,5-bisphosphate, and together they regulate protein kinase C alpha (PKC...... alpha) activity. Syndecan 4V peptide directly potentiates PKC alpha activity, leading to "superactivation" of the enzyme, apparently through an interaction with its catalytic domain. We now have performed yeast two-hybrid and in vitro binding assays to determine the interaction sites between 4V and PKC...... alpha. Full-length PKC alpha weakly interacted with 4V by yeast two-hybrid assays, but PKC alpha constructs that lack the pseudosubstrate region or constructs of the whole catalytic domain interacted more strongly. A mutated 4V sequence (4V(YF): LGKKPIFKK) did not interact with PKC alpha, indicating...

  14. Mechanical stimulation of C2C12 cells increases m-calpain expression, focal adhesion plaque protein degradation and cell differentiation

    DEFF Research Database (Denmark)

    Grossi, Alberto; Lawson, Moira Ann

    Abstract Mechanical stimulation of C2C12 cells increases m-calpain expression, focal adhesion plaque protein degradation and cell differentiation. A. Grossi, M. A. Lawson; Department of Food Science, Royal Veterinary and Agricultural University, Frederiksberg C, Denmark The process of muscle...... documented and has been shown to affect transcription of specific gene sequences, protein synthesis, the immune system and increase in Ca2+ influx. The past 10 years has seen a dramatic increase in the understanding of how proteolytic enzymes such as calpains can affect the growth of muscle. In vivo studies...... have shown that m-calpain is necessary for myoblast fusion leading to the formation of muscle fibers and that inhibition of this enzyme restricts myotube formation. Whether there is a link between stretchor load induced signaling and m-calpain expression and activation is not known. Using a magnetic...

  15. Mechanical stimulation of C2C12 cells increases m-calpain expression, focal adhesion plaque protein degradation and cell differentiation

    DEFF Research Database (Denmark)

    Grossi, Alberto; Lawson, Moira Ann

    Abstract Mechanical stimulation of C2C12 cells increases m-calpain expression, focal adhesion plaque protein degradation and cell differentiation. A. Grossi, M. A. Lawson; Department of Food Science, Royal Veterinary and Agricultural University, Frederiksberg C, Denmark The process of muscle...... development and growth is a complex sequence of events whereby muscle cells respond to a number of stimuli in order to form organised muscle tissue. Increase in muscle mass is greatly influenced by the rate of skeletal muscle protein synthesis and degradation, processes that can be altered by mechanical...... forces. Stretch- or load-induced signaling is now beginning to be understood as a factor which affects the mass and phenotype of muscles as well as the expression of a number of proteins within muscle cells. Use of magnetic field to produce mechanical forces to stimulate cell populations has been well...

  16. Impact of extracellular matrix derived from osteoarthritis subchondral bone osteoblasts on osteocytes: role of integrinβ1 and focal adhesion kinase signaling cues.

    Science.gov (United States)

    Prasadam, Indira; Farnaghi, Saba; Feng, Jian Q; Gu, Wenyi; Perry, Samuel; Crawford, Ross; Xiao, Yin

    2013-10-09

    Our recent study indicated that subchondral bone pathogenesis in osteoarthritis (OA) is associated with osteocyte morphology and phenotypic abnormalities. However, the mechanism underlying this abnormality needs to be identified. In this study we investigated the effect of extracellular matrix (ECM) produced from normal and OA bone on osteocytic cells function. De-cellularized matrices, resembling the bone provisional ECM secreted from primary human subchondral bone osteoblasts (SBOs) of normal and OA patients were used as a model to study the effect on osteocytic cells. Osteocytic cells (MLOY4 osteocyte cell line) cultured on normal and OA derived ECMs were analyzed by confocal microscopy, scanning electron microscopy (SEM), cell attachment assays, zymography, apoptosis assays, qRT-PCR and western blotting. The role of integrinβ1 and focal adhesion kinase (FAK) signaling pathways during these interactions were monitored using appropriate blocking antibodies. The ECM produced by OA SBOs contained less mineral content, showed altered organization of matrix proteins and matrix structure compared with the matrices produced by normal SBOs. Culture of osteocytic cells on these defective OA ECM resulted in a decrease of integrinβ1 expression and the de-activation of FAK cell signaling pathway, which subsequently affected the initial osteocytic cell's attachment and functions including morphological abnormalities of cytoskeletal structures, focal adhesions, increased apoptosis, altered osteocyte specific gene expression and increased Matrix metalloproteinases (MMP-2) and -9 expression. This study provides new insights in understanding how altered OA bone matrix can lead to the abnormal osteocyte phenotypic changes, which is typical in OA pathogenesis.

  17. Crk adaptor protein-induced phosphorylation of Gab1 on tyrosine 307 via Src is important for organization of focal adhesions and enhanced cell migration

    Institute of Scientific and Technical Information of China (English)

    Takuya Watanabe; Masumi Tsuda; Yoshinori Makino; Tassos Konstantinou; Hiroshi Nishihara; Tokifumi Majima; Akio Minami; Stephan M Feller; Shinya Tanaka

    2009-01-01

    Upon growth factor stimulation, the scaffold protein, Gabl, is tyrosine phosphorylated and subsequently the adaptor protein, Crk, transmits signals from Gabl. We have previously shown that Crk overexpression, which is detectable in various human cancers, induces tyrosine phosphorylation of Gab1 without extraceilular stimuli. In the present study, the underlying mechanisms were further investigated. Mutational analyses of Crkll demonstrated that the SH2 domain, but not the SH3(N) or the regulatory Y221 residue of Crkll, is critical for the induction of Gabl-Y307 phosphorylation. SH2 mutation of Crkll also decreased the interaction with Gab1. In GST pull-down assay, Crk-SH2 bound to wild-type Gabl, whereas Crk-SH3(N) interacted with the Gabl mutant, which lacks the clus-tered tyrosine region (residues 242-410). Tyrosine phosphorylation of Gabl was induced by all Crk family proteins, but not other SH2-containing signalling adaptors. Src-family kinase inhibitor, PP2, abrogates Crk-induced tyrosine phosphorylations of Gabl. Y307 phosphorylation was undetectable in fibroblasts lacking Src, Yes, and Fyn, even upon overexpression of Crk, whereas cells lacking only Yes and Fyn still contained Gabl with phosphorylated Y307. Furthermore, Crk induced the phosphorylation of Src-Y416; accordingly the interaction between Crk and Csk was increased. The GabI-Y307F mutant failed to localize near the plasma membrane even upon HGF stimulation and decreased cell migration. Moreover, Gabl-Y307F disturbed the localization of Crk, FAK, and paxiilin, which are the typical components of focal adhesions. Taken together, these results indicate that Crk facilitates tyrosine phosphory-lation of Gabl-Y307 through Src, contributing to the organization of focal adhesions and enhanced cell migration, thereby possibly promoting human cancer development.

  18. Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment.

    Science.gov (United States)

    Gemba, Takefumi; Valbracht, Jean; Alsalameh, Saifeddin; Lotz, Martin

    2002-01-11

    The 29-kDa amino-terminal fibronectin fragment (FN-f) has a potent chondrolytic effect and is thought to be involved in cartilage degradation in arthritis. However, little is known about signal transduction pathways that are activated by FN-f. Here we demonstrated that FN-f induced nitric oxide (NO) production from human articular chondrocytes. Expression of inducible nitric-oxide synthase (iNOS) mRNA and NO production were observed at 6 and 48 h after FN-f treatment, respectively. Interleukin-1beta (IL-1beta) mRNA up-regulation was stimulated by FN-f in human chondrocytes. To address the possibility that FN-f-induced NO release is mediated by IL-1beta production, the effect of IL-1 receptor antagonist (IL-1ra) was determined. IL-1ra partially inhibited FN-f-induced NO release although it almost completely inhibited IL-1beta-induced NO release. Tyrosine phosphorylation of focal adhesion kinase was induced transiently by FN-f treatment. Blocking antibodies to alpha(5) or beta(1) integrin and Arg-Gly-Asp-containing peptides did not inhibit FN-f-induced NO production. PP2, a Src family kinase inhibitor, or cytochalasin D, which selectively disrupts the network of actin filaments, inhibited both FAK phosphorylation and NO production induced by FN-f, but the phosphatidylinositol 3-kinase inhibitor wortmannin had no effect. Analysis of mitogen-activated protein kinases (MAPK) showed activation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase, and p38 MAPK. High concentrations of SB203580, which inhibit both JNK and p38 MAPK, and PD98059 a selective inhibitor of MEK1/2 that blocks ERK activation, inhibited FN-f induced NO production. These data suggest that focal adhesion kinase and MAPK mediate FN-f induced activation of human articular chondrocytes.

  19. Research progress on focal adhesion kinase in malignant tumors%FAK 在恶性肿瘤中的研究进展

    Institute of Scientific and Technical Information of China (English)

    赵美娜(综述); 陈公琰(审校)

    2016-01-01

    Focal adhesion kinase( FAK) ,a cytoplasmic non-receptor protein tyrosine kinase,serves as both a molecular scaffold and a mediator participating in multiple signal transduction pathways.FAK is involved in tumor cell survival,proliferation,migration and metastasis.Recent studies have shown that FAK is expressed in many tumor cells.Currently,FAK has been regarded as a potential target for cancer therapy.This review is to summarize the relationship between FAK and tumor progression.%黏着斑激酶( Focal adhesion kinase,FAK)是细胞内重要的骨架蛋白,属于一种非受体型酪氨酸蛋白激酶,也是多种信号通路的关键性分子。在肿瘤发生、发展、迁移以及侵袭的各个阶段FAK都具有重要作用。近年来,人们对FAK的研究越来越多,综合国内外研究资料表明,FAK在许多肿瘤组织中表达增高,提示FAK可能与肿瘤的发生发展密切相关,可能是肿瘤治疗的潜在靶点。该综述将对FAK分子结构及功能特点,与肿瘤的关系进行系统阐述。

  20. Manganese-induced integrin affinity maturation promotes recruitment of alpha V beta 3 integrin to focal adhesions in endothelial cells: evidence for a role of phosphatidylinositol 3-kinase and Src.

    Science.gov (United States)

    Dormond, Olivier; Ponsonnet, Lionel; Hasmim, Meriem; Foletti, Alessandro; Rüegg, Curzio

    2004-07-01

    Integrin activity is controlled by changes in affinity (i.e. ligand binding) and avidity (i.e. receptor clustering). Little is known, however, about the effect of affinity maturation on integrin avidity and on the associated signaling pathways. To study the effect of affinity maturation on integrin avidity, we stimulated human umbilical vein endothelial cells (HUVEC) with MnCl(2) to increase integrin affinity and monitored clustering of beta 1 and beta 3 integrins. In unstimulated HUVEC, beta 1 integrins were present in fibrillar adhesions, while alpha V beta 3 was detected in peripheral focal adhesions. Clustered beta 1 and beta 3 integrins expressed high affinity/ligand-induced binding site (LIBS) epitopes. MnCl(2)-stimulation promoted focal adhesion and actin stress fiber formation at the basal surface of the cells, and strongly enhanced mAb LM609 staining and expression of beta 3 high affinity/LIBS epitopes at focal adhesions. MnCl(2)-induced alpha V beta 3 clustering was blocked by a soluble RGD peptide, by wortmannin and LY294002, two pharmacological inhibitors of phosphatidylinositol 3-kinase (PI 3-K), and by over-expressing a dominant negative PI 3-K mutant protein. Conversely, over-expression of active PI 3-K and pharmacological inhibiton of Src with PP2 and CGP77675, enhanced basal and manganese-induced alpha V beta 3 clustering. Transient increased phosphorylation of protein kinase B/Akt, a direct target of PI 3K, occurred upon manganese stimulation. MnCl(2) did not alter beta 1 integrin distribution or beta1 high-affinity/LIBS epitope expression. Based on these results, we conclude that MnCl(2)-induced alpha V beta 3 integrin affinity maturation stimulates focal adhesion and actin stress fiber formation, and promotes recruitment of high affinity alpha V beta 3 to focal adhesions. Affinity-modulated alpha V beta 3 clustering requires PI3-K signaling and is negatively regulate by Src.

  1. Focal uptake at the rotator interval or inferior capsule of shoulder on {sup 18}F-FDG PET/CT is associated with adhesive capsulitis

    Energy Technology Data Exchange (ETDEWEB)

    Sridharan, Radhika [Universiti Kebangsaan Malaysia Medical Centre, Department of Diagnostic Imaging, Kuala Lumpur (Malaysia); Engle, Mitchell Philip [The University of Texas M.D. Anderson Cancer Center, Department of Pain Medicine, Houston, TX (United States); Garg, Naveen [The University of Texas M.D. Anderson Cancer Center, Department of Diagnostic Imaging, Houston, TX (United States); Wei, Wei; Amini, Behrang [The University of Texas M.D. Anderson Cancer Center, Department of Biostatistics, Houston, TX (United States)

    2017-04-15

    To determine if focal increased uptake at the rotator interval (RI) and/or inferior capsule (IC) on{sup 18}F-FDG PET/CT (''positive PET'') predicts the presence of adhesive capsulitis (AC). Three populations were retrospectively examined. Group 1 included 1,137 consecutive {sup 18}F-FDG PET/CT studies and was used to determine the prevalence of focal uptake at the RI or IC. Group 2 included 361 cases from a 10-year period with {sup 18}F-FDG PET/CT and MRI of shoulder performed within 45 days of each other and was used to enrich the study group. Group 3 included 109 randomly selected patients from the same time frame as groups 1 and 2 and was used to generate the control group. The study group consisted of 15 cases from the three groups, which had positive PET findings. PET/CT images were assessed in consensus by two musculoskeletal radiologists. The reference standard for a diagnosis of AC was clinical and was made by review of the medical record by a pain medicine physician. The prevalence of focal activity at either the RI or IC (''positive PET'') was 0.53%. Nine patients had a clinical diagnosis of AC and 15 patients had a positive PET. The sensitivity and specificity of PET for detection of AC was 56% and 87%, respectively. PET/CT had a positive likelihood ratio for AC of 6.3 (95% CI: 2.8-14.6). Increased uptake at the RI or IC on PET/CT confers a moderate increase in the likelihood of AC. (orig.)

  2. Focal nodular hyperplasia of the liver: composition of the extracellular matrix and expression of cell-cell and cell-matrix adhesion molecules.

    Science.gov (United States)

    Scoazec, J Y; Flejou, J F; D'Errico, A; Couvelard, A; Kozyraki, R; Fiorentino, M; Grigioni, W F; Feldmann, G

    1995-10-01

    We studied by immunohistochemistry 25 cases of focal nodular hyperplasia (FNH) to evaluate the composition of the extracellular matrix and the expression and distribution of endothelial cell-cell adhesion molecules and integrin receptors. The extracellular matrix of FNH retained the overall organization of that of normal liver. The matrix of central scars resembled that of portal tracts. The main difference was the presence of large vitronectin deposits, which might indicate the existence of local hemodynamic disturbances. The matrix lining the sinusoid-like vessels running in the hyperplastic parenchyma retained characteristic features of the normal perisinusoidal matrix, such as the presence of tenascin. In the zone surrounding the central scars, it contained large amounts of laminin, von Willebrand factor, and thrombospondin, suggesting the development of perisinusoidal fibrosis. Laminin deposition was accompanied by the induction of cell-cell adhesion molecules on adjacent endothelial cells and by the up-regulation of specific integrin receptors on both hepatocytes and sinusoidal endothelial cells. In conclusion, our study: (1) reinforces the hypothesis that FNH is merely a hyperplastic response of liver parenchyma to local vascular abnormalities, and (2) shows that the lesions of perisinusoidal fibrosis associated with FNH are accompanied by the induction of integrin receptors on hepatocytes and sinusoidal endothelial cells.

  3. Heterogeneous response of traction force at focal adhesions of vascular smooth muscle cells subjected to macroscopic stretch on a micropillar substrate.

    Science.gov (United States)

    Nagayama, Kazuaki; Adachi, Akifumi; Matsumoto, Takeo

    2011-10-13

    Traction force generated at focal adhesions (FAs) of cells plays an essential role in regulating cellular functions. However, little is known about how the traction force at each FA changes during cell stretching. Here we investigated dynamic changes in traction force at FAs during macroscopic stretching of porcine aortic smooth muscle cells (SMCs) cultured on elastic micropillar substrates. SMCs were cultured on polydimethylsiloxane (PDMS)-based substrates with a micropillar array, and stretched approximately in the direction of their major axis and then released by stretching and relaxing the substrates. This stretch-release cycle was repeated twice with cell strain rates of 0.3%/15s up to a 3% strain, and the deflection of the PDMS micropillars was measured simultaneously to obtain the traction force at each FA F, total force in the cell's major axis direction F(all), and whole-cell strain ε(cell). Traction forces of SMCs during stretching varied widely with location: their changes at some pillars synchronized well with the applied strain ε(cell), but others did not synchronized. Whole-cell stiffness estimated as the slope of the loading limb of the F(all)-ε(cell) curves was ∼10nN/%, which was the same order of magnitude of the reported stiffness of cultured SMCs obtained in a tensile test. Interestingly, F(all) at a zero-strain state (pretension at the whole-cell level) actively increased in some cells following the loading/unloading process, as did whole-cell stiffness. Such a change did not occur in cultured SMCs in the tensile test in which cells were held with a pair of micropipettes coated with nonspecific adhesive. These results indicate that SMCs showed a myogenic response when stretched through their multiple FAs, but not through nonspecific adhesions on their membrane. SMCs may behave differently depending on the sites through which they are stretched. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. The relative roles of collagen adhesive receptor DDR2 activation and matrix stiffness on the downregulation of focal adhesion kinase in vascular smooth muscle cells.

    Science.gov (United States)

    Bhadriraju, Kiran; Chung, Koo-Hyun; Spurlin, Tighe A; Haynes, Ross J; Elliott, John T; Plant, Anne L

    2009-12-01

    Cells within tissues derive mechanical anchorage and specific molecular signals from the insoluble extracellular matrix (ECM) that surrounds them. Understanding the role of different cues that extracellular matrices provide cells is critical for controlling and predicting cell response to scaffolding materials. Using an engineered extracellular matrix of Type I collagen we examined how the stiffness, supramolecular structure, and glycosylation of collagen matrices influence the protein levels of cellular FAK and the activation of myosin II. Our results show that (1) cellular FAK is downregulated on collagen fibrils, but not on a non-fibrillar monolayer of collagen, (2) the downregulation of FAK is independent of the stiffness of the collagen fibrils, and (3) FAK levels are correlated with levels of tyrosine phosphorylation of the collagen adhesion receptor DDR2. Further, siRNA depletion of DDR2 blocks FAK downregulation. Our results suggest that the collagen receptor DDR2 is involved in the regulation of FAK levels in vSMC adhered to Type I collagen matrices, and that regulation of FAK levels in these cells appears to be independent of matrix stiffness.

  5. Correlation between {sup 99m}Tc-(V)-DMSA uptake and constitutive level of phosphorylated focal adhesion kinase in an in vitro model of cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Denoyer, Delphine; Perek, Nathalie; Jeune, Nathalie Le; Dubois, Francis [University of Saint-Etienne, Department of Biophysics and Radiopharmaceuticals, ' ' Cell Survival and Adhesion' ' Research Group, Jacques Lisfranc Faculty of Medicine, Saint-Etienne (France); Cornillon, Jerome [University of Saint-Etienne, Department of Haematology, ' ' Cell Survival and Adhesion' ' Research Group, Jacques Lisfranc Faculty of Medicine, Saint-Etienne (France)

    2005-07-01

    Although a number of prognostic indicators have been developed, it is still difficult to predict the biological behaviour of all cancer types. {sup 99m}Tc-(V)-DMSA (V DMSA) uptake and focal adhesion kinase (FAK) expression and activation level could be potential agents for this purpose. We hypothesised the existence of a correlation between V DMSA, whose uptake is linked to phosphate ions, essential compounds for tumour growth and cell proliferation, and the adhesion protein FAK, whose elevated expression and level of constitutive activation are implicated in cancer progression. The aim of this study was to assess the relationship between V DMSA incorporation rate and FAK expression and activation by phosphorylation on tyrosine 397 residue. We determined V DMSA uptake in six different cancer cell lines and we measured FAK expression and activation by using Western Blotting analysis. Correlations with factors known to be associated with poor prognosis, such as invasive potential, resistance to chemotherapy and proliferation rate, were also investigated. The cell lines exhibited different V DMSA incorporation rates. In addition, these cells showed the same FAK expression, but various degrees of activation. A correlation was observed between V DMSA uptake and level of FAK phosphorylation and between V DMSA or constitutive FAK activation and proliferation rate. However, no correlation was shown between these parameters and the other factors tested, i.e. invasive potential and anticancer drug resistance. The results of this in vitro study clearly demonstrate that phosphorylation of FAK, proliferation rate and V DMSA uptake are closely related. Because proliferation and a high level of constitutive FAK activation are linked to cancer progression, it can be assumed that in vivo V DMSA uptake reflects tumour aggressiveness. (orig.)

  6. MicroRNA-151 and its hosting gene FAK (focal adhesion kinase) regulate tumor cell migration and spreading of hepatocellular carcinoma.

    Science.gov (United States)

    Luedde, Tom

    2010-09-01

    Recurrent chromosomal aberrations are often observed in hepatocellular carcinoma (HCC), but little is known about the functional non-coding sequences, particularly microRNAs (miRNAs), at the chromosomal breakpoints in HCC. Here we show that 22 miRNAs are often amplified or deleted in HCC. MicroRNA-151 (miR-151), a frequently amplified miRNA on 8q24.3, is correlated with intrahepatic metastasis of HCC. We further show that miR-151, which is often expressed together with its host gene FAK, encoding focal adhesion kinase, significantly increases HCC cell migration and invasion in vitro and in vivo, mainly through miR-151-5p, but not through miR-151-3p. Moreover, miR-151 exerts this function by directly targeting RhoGDIA, a putative metastasis suppressor in HCC, thus leading to the activation of Rac1, Cdc42 and Rho GTPases. In addition, miR-151 can function synergistically with FAK to enhance HCC cell motility and spreading. Thus, our findings indicate that chromosome gain of miR-151 is a crucial stimulus for tumour invasion and metastasis of HCC.

  7. Focal adhesion kinase activation is required for TNF-α-induced production of matrix metalloproteinase-2 and proinflammatory cytokines in cultured human periodontal ligament fibroblasts.

    Science.gov (United States)

    Zhang, Peng; Li, Ya-jing; Guo, Liu-yun; Wang, Guo-fang; Lu, Ke; Yue, Er-li

    2015-08-01

    Since focal adhesion kinase (FAK) was proposed as a mediator of the inflammatory response, we have investigated the role of this molecule in the release of inflammatory cytokines by cultured human periodontal ligament fibroblasts (HPDLFs), cells that are thought to be important in the patient's response to periodontal infection. Human periodontal ligament fibroblasts were stimulated by tumor necrosis factor alpha (TNF-α) and its effects on interleukin (IL)-6 and IL-8 release were measured by ELISA. Expression of matrix metalloproteinase 2 (MMP-2) protein was analysed by western blotting. The levels of IL6, IL8, and MMP2 mRNA were evaluated by real-time PCR. Tumor necrosis factor alpha dose-dependently induced the phosphorylation of FAK, whereas small interfering FAK (siFAK) inhibited TNF-α-induced FAK phosphorylation. Tumor necrosis factor alpha also stimulated the production of IL-6, IL-8, and MMP-2 in a dose-dependent manner. Knockdown of FAK significantly suppressed TNF-α-induced expression of IL6 and IL8 mRNA and release of IL-6 and IL-8 protein in HPDLFs. Similarly, MMP-2 down-regulation was significantly prevented by siFAK. Our results strongly suggest that knockdown of FAK can decrease the production of TNF-α-induced IL-6, IL-8, and MMP-2 in HPDLFs. These effects may help in understanding the mechanisms that control expression of inflammatory cytokines in the pathogenesis of periodontitis.

  8. Focal adhesion kinase-mediated activation of glycogen synthase kinase 3β regulates IL-33 receptor internalization and IL-33 signaling.

    Science.gov (United States)

    Zhao, Jing; Wei, Jianxin; Bowser, Rachel K; Traister, Russell S; Fan, Ming-Hui; Zhao, Yutong

    2015-01-15

    IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. Long form ST2 (ST2L), the receptor for IL-33, is expressed on immune effector cells and lung epithelia and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system; however, its upstream internalization has not been studied. In this study, we demonstrate that glycogen synthase kinase 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, and an effect was attenuated by inhibition or downregulation of GSK3β. GSK3β was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3β binding site mutant (ST2L(S446A)) and phosphorylation site mutant (ST2L(S442A)) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3β activation and ST2L internalization. Furthermore, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3β might serve as a unique strategy to lessen pulmonary inflammation.

  9. Antitumor effect of focal adhesion kinase inhibitor PF562271 against human osteosarcoma in vitro and in vivo.

    Science.gov (United States)

    Hu, Chuanzhen; Chen, Xu; Wen, Junxiang; Gong, Liangzhi; Liu, Zhuochao; Wang, Jun; Liang, Jing; Hu, Fangqiong; Zhou, Qi; Wei, Li; Shen, Yuhui; Zhang, Weibin

    2017-07-01

    Focal adhesion kinase (FAK) overexpression is related to invasive and metastatic properties in different kinds of cancers. Target therapy by inhibiting FAK has achieved promising effect in some cancer treatments, but its effect in human osteosarcoma has not been well studied. In the present study, we analyzed the antitumor efficacy of PF562271, an FAK inhibitor, against osteosarcoma in vitro and in vivo. Phosphorylated FAK (Y397) was highly expressed in primary human osteosarcoma tumor samples and was associated with osteosarcoma prognosis and lung metastasis. PF562271 greatly suppressed proliferation and colony formation in human osteosarcoma cell lines. In addition, treatment of osteosarcoma cell lines with PF562271 induced apoptosis and downregulated the activity of the protein kinase B/mammalian target of rapamycin pathway. PF562271 also impaired the tube formation ability of endothelial cells in vitro. Finally, oral treatment with PF562271 in mice dramatically reduced tumor volume, weight, and angiogenesis of osteosarcoma xenografts in vivo. These results indicate that FAK inhibitor PF562271 can potentially be effectively used for the treatment of osteosarcoma. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  10. Mycosporine-Like Amino Acids Promote Wound Healing through Focal Adhesion Kinase (FAK and Mitogen-Activated Protein Kinases (MAP Kinases Signaling Pathway in Keratinocytes

    Directory of Open Access Journals (Sweden)

    Yun-Hee Choi

    2015-11-01

    Full Text Available Mycosporine-like amino acids (MAAs are secondary metabolites found in diverse marine, freshwater, and terrestrial organisms. Evidence suggests that MAAs have several beneficial effects on skin homeostasis such as protection against UV radiation and reactive oxygen species (ROS. In addition, MAAs are also involved in the modulation of skin fibroblasts proliferation. However, the regulatory function of MAAs on wound repair in human skin is not yet clearly elucidated. To investigate the roles of MAAs on the wound healing process in human keratinocytes, three MAAs, Shinorine (SH, Mycosporine-glycine (M-Gly, and Porphyra (P334 were purified from Chlamydomonas hedlyei and Porphyra yezoensis. We found that SH, M-Gly, and P334 have significant effects on the wound healing process in human keratinocytes and these effects were mediated by activation of focal adhesion kinases (FAK, extracellular signal-regulated kinases (ERK, and c-Jun N-terminal kinases (JNK. These results suggest that MAAs accelerate wound repair by activating the FAK-MAPK signaling pathways. This study also indicates that MAAs can act as a new wound healing agent and further suggests that MAAs might be a novel biomaterial for wound healing therapies.

  11. Dynamics of Actin Stress Fibers and Focal Adhesions during Slow Migration in Swiss 3T3 Fibroblasts: Intracellular Mechanism of Cell Turning

    Directory of Open Access Journals (Sweden)

    Michiko Sugawara

    2016-01-01

    Full Text Available To understand the mechanism regulating the spontaneous change in polarity that leads to cell turning, we quantitatively analyzed the dynamics of focal adhesions (FAs coupling with the self-assembling actin cytoskeletal structure in Swiss 3T3 fibroblasts. Fluorescent images were acquired from cells expressing GFP-actin and RFP-zyxin by laser confocal microscopy. On the basis of the maximum area, duration, and relocation distance of FAs extracted from the RFP-zyxin images, the cells could be divided into 3 regions: the front region, intermediate lateral region, and rear region. In the intermediate lateral region, FAs appeared close to the leading edge and were stabilized gradually as its area increased. Simultaneously, bundled actin stress fibers (SFs were observed vertically from the positions of these FAs, and they connected to the other SFs parallel to the leading edge. Finally, these connecting SFs fused to form a single SF with matured FAs at both ends. This change in SF organization with cell retraction in the first cycle of migration followed by a newly formed protrusion in the next cycle is assumed to lead to cell turning in migrating Swiss 3T3 fibroblasts.

  12. A small physiological electric field mediated responses of extravillous trophoblasts derived from HTR8/SVneo cells: involvement of activation of focal adhesion kinase signaling.

    Directory of Open Access Journals (Sweden)

    Juan Zhang

    Full Text Available Moderate invasion of trophoblast cells into endometrium is essential for the placental development and normal pregnancy. Electric field (EF-induced effects on cellular behaviors have been observed in many cell types. This study was to investigate the effect of physiological direct current EF (dc EF on cellular responses such as elongation, orientation and motility of trophoblast cells. Immortalized first trimester extravillous trophoblast cells (HTR-8/SVneo were exposed to the dc EF at physiological magnitude. Cell images were recorded and analyzed by image analyzer. Cell lysates were used to detect protein expression by Western blot. Cultured in the dc EFs the cells showed elongation, orientation and enhanced migration rate compared with non-EF stimulated cells at field strengths of 100 mV/mm to 200 mV/mm. EF exposure increased focal adhesion kinase (FAK phosphorylation in a time-dependent manner and increased expression levels of MMP-2. Pharmacological inhibition of FAK impaired the EF-induced responses including motility and abrogated the elevation of MMP-2 expression. However, the expression levels of integrins like integrin α1, α5, αV and β1 were not affected by EF stimulation. Our results demonstrate the importance of FAK activation in migration/motility of trophobalst cells driven by EFs. In addition, it raises the feasibility of using applied EFs to promote placentation through effects on trophoblast cells.

  13. A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

    Science.gov (United States)

    Brethour, Dylan; Mehrabian, Mohadeseh; Williams, Declan; Wang, Xinzhu; Ghodrati, Farinaz; Ehsani, Sepehr; Rubie, Elizabeth A.; Woodgett, James R.; Sevalle, Jean; Xi, Zhengrui; Rogaeva, Ekaterina; Schmitt-Ulms, Gerold

    2017-01-01

    The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs 5, 6 and 10, raising the prospect that the study of these ZIPs may reveal insights relevant for understanding the function of PrP. Building on data which suggested PrP and ZIP6 are critical during epithelial-to-mesenchymal transition (EMT), we investigated ZIP6 in an EMT paradigm using ZIP6 knockout cells, mass spectrometry and bioinformatic methods. Reminiscent of PrP, ZIP6 levels are five-fold upregulated during EMT and the protein forms a complex with NCAM1. ZIP6 also interacts with ZIP10 and the two ZIP transporters exhibit interdependency during their expression. ZIP6 contributes to the integration of NCAM1 in focal adhesion complexes but, unlike cells lacking PrP, ZIP6 deficiency does not abolish polysialylation of NCAM1. Instead, ZIP6 mediates phosphorylation of NCAM1 on a cluster of cytosolic acceptor sites. Substrate consensus motif features and in vitro phosphorylation data point toward GSK3 as the kinase responsible, and interface mapping experiments identified histidine-rich cytoplasmic loops within the ZIP6/ZIP10 heteromer as a novel scaffold for GSK3 binding. Our data suggests that PrP and ZIP6 inherited the ability to interact with NCAM1 from their common ZIP ancestors but have since diverged to control distinct posttranslational modifications of NCAM1. PMID:28098160

  14. Focal adhesion kinase antisense oligodeoxynucleotides inhibit human pulmonary artery smooth muscle cells proliferation and promote human pulmonary artery smooth muscle cells apoptosis

    Institute of Scientific and Technical Information of China (English)

    LIN Chun-long; ZHANG Zhen-xiang; XU Yong-jian; NI Wang; CHEN Shi-xin

    2005-01-01

    Background Pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in pulmonary vessel structural remodelling. At present, the mechanisms related to proliferation of PASMCs are not clear. Focal adhesion kinase (FAK) is a widely expressed nonreceptor protein tyrosine kinase. Recent research indicates that FAK is implicated in signalling pathways which regulate cytoskeletal organization, adhesion, migration, survival and proliferation of cells. Furthermore, there are no reports about the role of FAK in human pulmonary artery smooth muscle cells (HPASMCs). We investigated whether FAK takes part in the intracellular signalling pathway involved in HPASMCs proliferation and apoptosis, by using antisense oligodeoxynucleotides (ODNs) to selectively suppress the expression of FAK protein.Methods Cultured HPASMCs stimulated by fibronectin (40 μg/ml) were passively transfected with ODNs, sense FAK, mismatch sense and antisense-FAK respectively. Expression of FAK, Jun NH2-terminal kinase (JNK), cyclin-dependent kinase 2 (CDK 2) and caspase-3 proteins were detected by immunoprecipitation and Western blots. Cell cycle and cell apoptosis were analysed by flow cytometry. In addition, cytoplasmic FAK expression was detected by immunocytochemical staining.Results When compared with mismatch sense group, the protein expressions of FAK, JNK and CDK 2 in HPASMCs decreased in antisense-FAK ODNs group and increased in sense-FAK ODNs group significantly. Caspase-3 expression upregulated in HPASMCs when treated with antisense ODNs and downregulated when treated with sense ODNs. When compared with mismatch sense ODNs group, the proportion of cells at G1 phase decreased significantly in sense ODNs group, while the proportion of cells at S phase increased significantly. In contrast, compared with mismatch sense ODNs group, the proportion of cells at G1 phase was increased significantly in antisense-FAK ODNs group. The level of cell apoptosis in antisense-FAK group

  15. Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin-332/α3 integrin axis recovery of focal adhesion kinase ubiquitination.

    Science.gov (United States)

    Azzariti, Amalia; Mancarella, Serena; Porcelli, Letizia; Quatrale, Anna Elisa; Caligiuri, Alessandra; Lupo, Luigi; Dituri, Francesco; Giannelli, Gianluigi

    2016-12-01

    In patients with hepatocellular carcinoma (HCC) receiving sorafenib, drug resistance is common. HCC develops in a microenvironment enriched with extracellular matrix proteins including laminin (Ln)-332, produced by hepatic stellate cells (HSCs). Ln-332 is the ligand of α3β1 and α6β4 integrins, differently expressed on the HCC cell surface, that deliver intracellular pathways. The aim of this study was to investigate the effect of Ln-332 on sorafenib's effectiveness. HCC cells were challenged with sorafenib in the presence of Ln-332 and of HSC conditioned medium (CM). Sorafenib impaired HCC cell proliferation and induced apoptosis. HSC-CM or Ln-332 inhibited sorafenib's effectiveness in HCC cells expressing both α3β1 and α6β4. Inhibiting α3 but not α6 integrin subunit using blocking antibodies or small interfering RNA abrogated the protection induced by Ln-332 and HSC-CM. Hep3B cells expressing α6β4 but lacking the α3 integrin were insensitive to Ln-332 and HSC-CM protective effects. Hep3B α3-positive, but not wild-type and scramble transfected, cells acquired protection by sorafenib when plated on Ln-332-CM or HSCs. Sorafenib dephosphorylated focal adhesion kinase (FAK) and extracellular signal-regulated kinases 1/2, whereas Ln-332 and HSC-CM partially restored the pathways. Silencing FAK, but not extracellular signal-regulated kinases 1/2, abrogated the protection induced by Ln-332 and HSC-CM, suggesting a specific role for FAK. Sorafenib down-regulated total FAK, inducing its proteasomal degradation, while Ln-332 and HSC-CM promoted the escape of FAK from ubiquitination, probably inducing a preferential membrane localization.

  16. Synopsis and meta-analysis of genetic association studies in osteoporosis for the focal adhesion family genes: the CUMAGAS-OSTEOporosis information system

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    Kastanis Alkibiadis

    2011-01-01

    Full Text Available Abstract Background Focal adhesion (FA family genes have been studied as candidate genes for osteoporosis, but the results of genetic association studies (GASs are controversial. To clarify these data, a systematic assessment of GASs for FA genes in osteoporosis was conducted. Methods We developed Cumulative Meta-Analysis of GAS-OSTEOporosis (CUMAGAS-OSTEOporosis, a web-based information system that allows the retrieval, analysis and meta-analysis (for allele contrast, recessive, dominant, additive and codominant models of data from GASs on osteoporosis with the capability of update. GASs were identified by searching the PubMed and HuGE PubLit databases. Results Data from 72 studies involving 13 variants of 6 genes were analyzed and catalogued in CUMAGAS-OSTEOporosis. Twenty-two studies produced significant associations with osteoporosis risk under any genetic model. All studies were underpowered (1 (COL1A1 G2046T (all genetic models, COL1A1 G-1997T (allele contrast and dominant model and integrin β-chain β3 (ITGB3 T176C (recessive and additive models. In COL1A1 G2046T, subgroup analysis has shown significant associations for Caucasians, adults, females, males and postmenopausal women. A differential magnitude of effect in large versus small studies (that is, indication of publication bias was detected for the variant COL1A1 G2046T. Conclusion There is evidence of an implication of FA family genes in osteoporosis. CUMAGAS-OSTEOporosis could be a useful tool for current genomic epidemiology research in the field of osteoporosis.

  17. A novel orally available inhibitor of focal adhesion signaling increases survival in a xenograft model of diffuse large B-cell lymphoma with central nervous system involvement.

    Science.gov (United States)

    Bosch, Rosa; Moreno, María José; Dieguez-Gonzalez, Rebeca; Céspedes, María Virtudes; Gallardo, Alberto; Trias, Manuel; Grañena, Albert; Sierra, Jorge; Casanova, Isolda; Mangues, Ramon

    2013-08-01

    Central nervous system dissemination is a relatively uncommon but almost always fatal complication in diffuse large B-cell lymphoma patients. Optimal therapy for central nervous involvement in this malignancy has not been established. In this paper, we aimed to evaluate the therapeutic effect of E7123, a celecoxib derivative that inhibits focal adhesion signaling, in a novel xenograft model of diffuse large B-cell lymphoma with central nervous system involvement. Cells obtained after disaggregation of HT subcutaneous tumors (HT-SC cells) were intravenously injected in NOD/SCID mice. These mice received oral vehicle or 75 mg/kg of E7123 daily until they were euthanized for weight loss or signs of sickness. The antitumor effect of E7123 was validated in an independent experiment using a bioluminescent mouse model. Intravenously injected HT-SC cells showed higher take rate and higher central nervous system tropism (associated with increased expression of β1-integrin and p130Cas proteins) than HT cells. The oral administration of E7123 significantly increased survival time in 2 independent experiments using mice injected with unmodified or bioluminescent HT-SC cells. We have developed a new xenograft model of diffuse large B-cell lymphoma with central nervous system involvement that can be used in the pre-clinical evaluation of new drugs for this malignancy. E7123 is a new, well-tolerated and orally available therapeutic agent that merits further investigation since it may improve current management of diffuse large B-cell lymphoma patients with central nervous system involvement.

  18. Matriptase is required for the active form of hepatocyte growth factor induced Met, focal adhesion kinase and protein kinase B activation on neural stem/progenitor cell motility.

    Science.gov (United States)

    Fang, Jung-Da; Lee, Sheau-Ling

    2014-07-01

    Hepatocyte growth factor (HGF) is a chemoattractant and inducer for neural stem/progenitor (NS/P) cell migration. Although the type II transmembrane serine protease, matriptase (MTP) is an activator of the latent HGF, MTP is indispensable on NS/P cell motility induced by the active form of HGF. This suggests that MTP's action on NS/P cell motility involves mechanisms other than proteolytic activation of HGF. In the present study, we investigate the role of MTP in HGF-stimulated signaling events. Using specific inhibitors of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) or focal adhesion kinase (FAK), we demonstrated that in NS/P cells HGF-activated c-Met induces PI3k-Akt signaling which then leads to FAK activation. This signaling pathway ultimately induces MMP2 expression and NS/P cell motility. Knocking down of MTP in NS/P cells with specific siRNA impaired HGF-stimulation of c-Met, Akt and FAK activation, blocked HGF-induced production of MMP2 and inhibited HGF-stimulated NS/P cell motility. MTP-knockdown NS/P cells cultured in the presence of recombinant protein of MTP protease domain or transfected with the full-length wild-type but not the protease-defected MTP restored HGF-responsive events in NS/P cells. In addition to functioning as HGF activator, our data revealed novel function of MTP on HGF-stimulated c-Met signaling activation.

  19. A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors.

    Science.gov (United States)

    Jones, Suzanne F; Siu, Lillian L; Bendell, Johanna C; Cleary, James M; Razak, Albiruni R A; Infante, Jeffrey R; Pandya, Shuchi S; Bedard, Philippe L; Pierce, Kristen J; Houk, Brett; Roberts, W Gregory; Shreeve, S Martin; Shapiro, Geoffrey I

    2015-10-01

    VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.

  20. Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase.

    Science.gov (United States)

    Lee, L F; Guan, J; Qiu, Y; Kung, H J

    2001-12-01

    The bombesin/gastrin-releasing peptide (GRP) family of neuropeptides has been implicated in various in vitro and in vivo models of human malignancies including prostate cancers. It was previously shown that bombesin and/or neurotensin (NT) acts as a survival and migratory factor(s) for androgen-independent prostate cancers. However, a role in the transition from an androgen-dependent to -refractory state has not been addressed. In this study, we investigate the biological effects and signal pathways of bombesin and NT on LNCaP, a prostate cancer cell line which requires androgen for growth. We show that both neurotrophic factors can induce LNCaP growth in the absence of androgen. Concurrent transactivation of reporter genes driven by the prostate-specific antigen promoter or a promoter carrying an androgen-responsive element (ARE) indicate that growth stimulation is accompanied by androgen receptor (AR) activation. Furthermore, neurotrophic factor-induced gene activation was also present in PC3 cells transfected with the AR but not in the parental line which lacks the AR. Given that bombesin does not directly bind to the AR and is known to engage a G-protein-coupled receptor, we investigated downstream signaling events that could possibly interact with the AR pathway. We found that three nonreceptor tyrosine kinases, focal adhesion kinase (FAK), Src, and Etk/BMX play important parts in this process. Etk/Bmx activation requires FAK and Src and is critical for neurotrophic factor-induced growth, as LNCaP cells transfected with a dominant-negative Etk/BMX fail to respond to bombesin. Etk's activation requires FAK, Src, but not phosphatidylinositol 3-kinase. Likewise, bombesin-induced AR activation is inhibited by the dominant-negative mutant of either Src or FAK. Thus, in addition to defining a new G-protein pathway, this report makes the following points regarding prostate cancer. (i) Neurotrophic factors can activate the AR, thus circumventing the normal growth

  1. Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer.

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    Grant A Howe

    Full Text Available Blockade of epidermal growth factor receptor (EGFR activity has been a primary therapeutic target for non-small cell lung cancers (NSCLC. As patients with wild-type EGFR have demonstrated only modest benefit from EGFR tyrosine kinase inhibitors (TKIs, there is a need for additional therapeutic approaches in patients with wild-type EGFR. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs. As such, EGFR TKI-resistant NSCLC cells (A549, H1299, H1975 were treated with the EGFR TKI erlotinib and FAK inhibitors (PF-573,228 or PF-562,271 both as single agents and in combination. We determined cell viability, apoptosis and 3-dimensional growth in vitro and assessed tumor growth in vivo. Treatment of EGFR TKI-resistant NSCLC cells with FAK inhibitor alone effectively inhibited cell viability in all cell lines tested; however, its use in combination with the EGFR TKI erlotinib was more effective at reducing cell viability than either treatment alone when tested in both 2- and 3-dimensional assays in vitro, with enhanced benefit seen in A549 cells. This increased efficacy may be due in part to the observed inhibition of Akt phosphorylation when the drugs were used in combination, where again A549 cells demonstrated the most inhibition following treatment with the drug combination. Combining erlotinib with FAK inhibitor was also potent in vivo as evidenced by reduced tumor growth in the A549 mouse xenograft model. We further ascertained that the enhanced sensitivity was irrespective of the LKB1 mutational status. In summary, we demonstrate the effectiveness of combining erlotinib and FAK inhibitors for use in known EGFR wild-type, EGFR TKI resistant cells, with the potential that a subset of cell types, which includes A549, could be

  2. Cellular prion protein is required for neuritogenesis: fine-tuning of multiple signaling pathways involved in focal adhesions and actin cytoskeleton dynamics

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    Alleaume-Butaux A

    2013-07-01

    Full Text Available Aurélie Alleaume-Butaux,1,2 Caroline Dakowski,1,2 Mathéa Pietri,1,2 Sophie Mouillet-Richard,1,2 Jean-Marie Launay,3,4 Odile Kellermann,1,2 Benoit Schneider1,2 1INSERM, UMR-S 747, 2Paris Descartes University, Sorbonne Paris Cité, UMR-S 747, 3Public Hospital of Paris, Department of Biochemistry, INSERM UMR-S 942, Lariboisière Hospital, Paris, France; 4Pharma Research Department, Hoffmann La Roche Ltd, Basel, Switzerland Abstract: Neuritogenesis is a dynamic phenomenon associated with neuronal differentiation that allows a rather spherical neuronal stem cell to develop dendrites and axon, a prerequisite for the integration and transmission of signals. The acquisition of neuronal polarity occurs in three steps: (1 neurite sprouting, which consists of the formation of buds emerging from the postmitotic neuronal soma; (2 neurite outgrowth, which represents the conversion of buds into neurites, their elongation and evolution into axon or dendrites; and (3 the stability and plasticity of neuronal polarity. In neuronal stem cells, remodeling and activation of focal adhesions (FAs associated with deep modifications of the actin cytoskeleton is a prerequisite for neurite sprouting and subsequent neurite outgrowth. A multiple set of growth factors and interactors located in the extracellular matrix and the plasma membrane orchestrate neuritogenesis by acting on intracellular signaling effectors, notably small G proteins such as RhoA, Rac, and Cdc42, which are involved in actin turnover and the dynamics of FAs. The cellular prion protein (PrPC, a glycosylphosphatidylinositol (GPI-anchored membrane protein mainly known for its role in a group of fatal neurodegenerative diseases, has emerged as a central player in neuritogenesis. Here, we review the contribution of PrPC to neuronal polarization and detail the current knowledge on the signaling pathways fine-tuned by PrPC to promote neurite sprouting, outgrowth, and maintenance. We emphasize that Pr

  3. The Sal-like 4 - integrin α6β1 network promotes cell migration for metastasis via activation of focal adhesion dynamics in basal-like breast cancer cells.

    Science.gov (United States)

    Itou, Junji; Tanaka, Sunao; Li, Wenzhao; Iida, Atsuo; Sehara-Fujisawa, Atsuko; Sato, Fumiaki; Toi, Masakazu

    2017-01-01

    During metastasis, cancer cell migration is enhanced. However, the mechanisms underlying this process remain elusive. Here, we addressed this issue by functionally analyzing the transcription factor Sal-like 4 (SALL4) in basal-like breast cancer cells. Loss-of-function studies of SALL4 showed that this transcription factor is required for the spindle-shaped morphology and the enhanced migration of cancer cells. SALL4 also up-regulated integrin gene expression. The impaired cell migration observed in SALL4 knockdown cells was restored by overexpression of integrin α6 and β1. In addition, we clarified that integrin α6 and β1 formed a heterodimer. At the molecular level, loss of the SALL4 - integrin α6β1 network lost focal adhesion dynamics, which impairs cell migration. Over-activation of Rho is known to inhibit focal adhesion dynamics. We observed that SALL4 knockdown cells exhibited over-activation of Rho. Aberrant Rho activation was suppressed by integrin α6β1 expression, and pharmacological inhibition of Rho activity restored cell migration in SALL4 knockdown cells. These results indicated that the SALL4 - integrin α6β1 network promotes cell migration via modulation of Rho activity. Moreover, our zebrafish metastasis assays demonstrated that this gene network enhances cell migration in vivo. Our findings identify a potential new therapeutic target for the prevention of metastasis, and provide an improved understanding of cancer cell migration. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. 局部黏着斑激酶作为肿瘤治疗靶点的研究进展%Focal adhesion kinase, a novel target for cancer therapy

    Institute of Scientific and Technical Information of China (English)

    张文静; 黄启来; 华子春

    2011-01-01

    局部黏着斑激酶(focal adhesion kinase,FAK)是一种非受体型酪氨酸蛋白激酶,是细胞内重要的骨架蛋白与多种信号通路的关键分子.FAK在肿瘤发生、发展、迁移和侵袭的各个阶段都具有重要作用,FAK己经被当作潜在的肿瘤治疗靶点来研究.该综述将对FAK与肿瘤的关系以及FAK作为肿瘤治疗靶点的研究进展进行探讨.%Focal adhesion kinase (FAK), a cytoplasmic non-receptor protein tyrosine kinase, serves as both a molecular scaffold and a mediator participating in multiple signal transduction pathways. FAK is involved in tumor cell survival, proliferation, migration and metastasis. Currently, FAK has been regarded as a potential target for cancer therapy. This review is to summarize the relationship between FAK and tumor progression, and to discuss the strategies targeting FAK for cancer treatment.

  5. Green Tea Epigallocatechin Gallate Exhibits Anticancer Effect in Human Pancreatic Carcinoma Cells via the Inhibition of Both Focal Adhesion Kinase and Insulin-Like Growth Factor-I Receptor

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    Hoang Anh Vu

    2010-01-01

    Full Text Available The exact molecular mechanism by which epigallocatechin gallate (EGCG suppresses human pancreatic cancer cell proliferation is unclear. We show here that EGCG-treated pancreatic cancer cells AsPC-1 and BxPC-3 decrease cell adhesion ability on micro-pattern dots, accompanied by dephosphorylations of both focal adhesion kinase (FAK and insulin-like growth factor-1 receptor (IGF-1R whereas retained the activations of mitogen-activated protein kinase and mammalian target of rapamycin. The growth of AsPC-1 and BxPC-3 cells can be significantly suppressed by EGCG treatment alone in a dose-dependent manner. At a dose of 100 μM which completely abolishes activations of FAK and IGF-1R, EGCG suppresses more than 50% of cell proliferation without evidence of apoptosis analyzed by PARP cleavage. Finally, the MEK1/2 inhibitor U0126 enhances growth-suppressive effect of EGCG. Our data suggests that blocking FAK and IGF-1R by EGCG could prove valuable for targeted therapy, which can be used in combination with other therapies, for pancreatic cancer.

  6. Focal adhesion kinase (FAK) mediates the induction of pro-oncogenic and fibrogenic phenotypes in hepatitis C virus (HCV)-infected cells.

    Science.gov (United States)

    Alisi, Anna; Arciello, Mario; Petrini, Stefania; Conti, Beatrice; Missale, Gabriele; Balsano, Clara

    2012-01-01

    Hepatitis C Virus (HCV) infection is one of the most common etiological factors involved in fibrosis development and its progression to hepatocellular carcinoma (HCC). The pivotal role of hepatic stellate cells (HCSs) and extracellular matrix (ECM) in fibrogenesis is now certainly accepted, while the network of molecular interactions connecting HCV is emerging as a master regulator of several biological processes including proliferation, inflammation, cytoskeleton and ECM remodeling. In this study, the effects of HCV proteins expression on liver cancer cells, both pro-invasive and pro-fibrogenic phenotypes were explored. As a model of HCV infection, we used permissive Huh7.5.1 hepatoma cells infected with JFH1-derived ccHCV. Conditioned medium from these cells was used to stimulate LX-2 cells, a line of HSCs. We found that the HCV infection of Huh7.5.1 cells decreased adhesion, increased migration and caused the delocalization of alpha-actinin from plasma membrane to cytoplasm and increased expression levels of paxillin. The treatment of LX-2 cells, with conditioned medium from HCV-infected Huh7.5.1 cells, caused an increase in cell proliferation, expression of alpha-smooth muscle actin, hyaluronic acid release and apoptosis rate measured as cleaved poly ADP-ribose polymerase (PARP). These effects were accompanied in Huh7.5.1 cells by an HCV-dependent increasing of FAK activation that physically interacts with phosphorylated paxillin and alpha-actinin, and a rising of tumor necrosis factor alpha production/release. Silencing of FAK by siRNA reverted all effects of HCV infection, both those directed on Huh7.5.1 cells, and those indirect effects on the LX-2 cells. Moreover and interestingly, FAK inhibition enhances apoptosis in HCV-conditioned LX-2 cells. In conclusion, our findings demonstrate that HCV, through FAK activation, may promote cytoskeletal reorganization and a pro-oncogenic phenotype in hepatocyte-like cells, and a fibrogenic phenotype in HSCs.

  7. The direct effect of Focal Adhesion Kinase (FAK, dominant-negative FAK, FAK-CD and FAK siRNA on gene expression and human MCF-7 breast cancer cell tumorigenesis

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    Zhang Li

    2009-08-01

    Full Text Available Abstract Background Focal adhesion kinase (FAK is a non-receptor tyrosine kinase that plays an important role in survival signaling. FAK has been shown to be overexpressed in breast cancer tumors at early stages of tumorigenesis. Methods To study the direct effect of FAK on breast tumorigenesis, we developed Tet-ON (tetracycline-inducible system of MCF-7 breast cancer cells stably transfected with FAK or dominant-negative, C-terminal domain of FAK (FAK-CD, and also FAKsiRNA with silenced FAK MCF-7 stable cell line. Increased expression of FAK in isogenic Tet-inducible MCF-7 cells caused increased cell growth, adhesion and soft agar colony formation in vitro, while expression of dominant-negative FAK inhibitor caused inhibition of these cellular processes. To study the role of induced FAK and FAK-CD in vivo, we inoculated these Tet-inducible cells in nude mice to generate tumors in the presence or absence of doxycycline in the drinking water. FAKsiRNA-MCF-7 cells were also injected into nude mice to generate xenograft tumors. Results Induction of FAK resulted in significant increased tumorigenesis, while induced FAK-CD resulted in decreased tumorigenesis. Taq Man Low Density Array assay demonstrated specific induction of FAKmRNA in MCF-7-Tet-ON-FAK cells. DMP1, encoding cyclin D binding myb-like protein 1 was one of the genes specifically affected by Tet-inducible FAK or FAK-CD in breast xenograft tumors. In addition, silencing of FAK in MCF-7 cells with FAK siRNA caused increased cell rounding, decreased cell viability in vitro and inhibited tumorigenesis in vivo. Importantly, Affymetrix microarray gene profiling analysis using Human Genome U133A GeneChips revealed >4300 genes, known to be involved in apoptosis, cell cycle, and adhesion that were significantly down- or up-regulated (p Conclusion Thus, these data for the first time demonstrate the direct effect of FAK expression and function on MCF-7 breast cancer tumorigenesis in vivo and reveal

  8. Focal adhesion kinase (FAK mediates the induction of pro-oncogenic and fibrogenic phenotypes in hepatitis C virus (HCV-infected cells.

    Directory of Open Access Journals (Sweden)

    Anna Alisi

    Full Text Available Hepatitis C Virus (HCV infection is one of the most common etiological factors involved in fibrosis development and its progression to hepatocellular carcinoma (HCC. The pivotal role of hepatic stellate cells (HCSs and extracellular matrix (ECM in fibrogenesis is now certainly accepted, while the network of molecular interactions connecting HCV is emerging as a master regulator of several biological processes including proliferation, inflammation, cytoskeleton and ECM remodeling. In this study, the effects of HCV proteins expression on liver cancer cells, both pro-invasive and pro-fibrogenic phenotypes were explored. As a model of HCV infection, we used permissive Huh7.5.1 hepatoma cells infected with JFH1-derived ccHCV. Conditioned medium from these cells was used to stimulate LX-2 cells, a line of HSCs. We found that the HCV infection of Huh7.5.1 cells decreased adhesion, increased migration and caused the delocalization of alpha-actinin from plasma membrane to cytoplasm and increased expression levels of paxillin. The treatment of LX-2 cells, with conditioned medium from HCV-infected Huh7.5.1 cells, caused an increase in cell proliferation, expression of alpha-smooth muscle actin, hyaluronic acid release and apoptosis rate measured as cleaved poly ADP-ribose polymerase (PARP. These effects were accompanied in Huh7.5.1 cells by an HCV-dependent increasing of FAK activation that physically interacts with phosphorylated paxillin and alpha-actinin, and a rising of tumor necrosis factor alpha production/release. Silencing of FAK by siRNA reverted all effects of HCV infection, both those directed on Huh7.5.1 cells, and those indirect effects on the LX-2 cells. Moreover and interestingly, FAK inhibition enhances apoptosis in HCV-conditioned LX-2 cells. In conclusion, our findings demonstrate that HCV, through FAK activation, may promote cytoskeletal reorganization and a pro-oncogenic phenotype in hepatocyte-like cells, and a fibrogenic phenotype in

  9. Smooth muscle hyperplasia due to loss of smooth muscle α-actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor-β.

    Science.gov (United States)

    Papke, Christina L; Cao, Jiumei; Kwartler, Callie S; Villamizar, Carlos; Byanova, Katerina L; Lim, Soon-Mi; Sreenivasappa, Harini; Fischer, Grant; Pham, John; Rees, Meredith; Wang, Miranda; Chaponnier, Christine; Gabbiani, Giulio; Khakoo, Aarif Y; Chandra, Joya; Trache, Andreea; Zimmer, Warren; Milewicz, Dianna M

    2013-08-01

    Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α-actin (α-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown. Here, we show that the loss of Acta2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. Acta2(-/-) mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of α-SMA induced hyperplasia through focal adhesion (FA) rearrangement, FA kinase activation, re-localization of p53 from the nucleus to the cytoplasm and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-β). Disruption of α-SMA in wild-type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-β activation and Acta2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-β, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.

  10. Inhibition of tumor vasculogenic mimicry and prolongation of host survival in highly aggressive gallbladder cancers by norcantharidin via blocking the ephrin type a receptor 2/focal adhesion kinase/paxillin signaling pathway.

    Directory of Open Access Journals (Sweden)

    Hui Wang

    Full Text Available Vasculogenic mimicry (VM is a newly-defined tumor microcirculation pattern in highly aggressive malignant tumors. We recently reported tumor growth and VM formation of gallbladder cancers through the contribution of the ephrin type a receptor 2 (EphA2/focal adhesion kinase (FAK/Paxillin signaling pathways. In this study, we further investigated the anti-VM activity of norcantharidin (NCTD as a VM inhibitor for gallbladder cancers and the underlying mechanisms. In vivo and in vitro experiments to determine the effects of NCTD on tumor growth, host survival, VM formation of GBC-SD nude mouse xenografts, and vasculogenic-like networks, malignant phenotypes i.e., proliferation, apoptosis, invasion and migration of GBC-SD cells. Expression of VM signaling-related markers EphA2, FAK and Paxillin in vivo and in vitro were examined by immunofluorescence, western blotting and real-time polymerase chain reaction (RT-PCR, respectively. The results showed that after treatment with NCTD, GBC-SD cells were unable to form VM structures when injecting into nude mouse, growth of the xenograft was inhibited and these observations were confirmed by facts that VM formation by three-dimensional (3-D matrix, proliferation, apoptosis, invasion, migration of GBC-SD cells were affected; and survival time of the xenograft mice was prolonged. Furthermore, expression of EphA2, FAK and Paxillin proteins/mRNAs of the xenografts was downregulated. Thus, we concluded that NCTD has potential anti-VM activity against human gallbladder cancers; one of the underlying mechanisms may be via blocking the EphA2/FAK/Paxillin signaling pathway.

  11. The β5/focal adhesion kinase/glycogen synthase kinase 3β integrin pathway in high-grade osteosarcoma: a protein expression profile predictive of response to neoadjuvant chemotherapy.

    Science.gov (United States)

    Le Guellec, Sophie; Moyal, Elizabeth Cohen-Jonathan; Filleron, Thomas; Delisle, Marie-Bernadette; Chevreau, Christine; Rubie, Hervé; Castex, Marie-Pierre; de Gauzy, Jerome Sales; Bonnevialle, Paul; Gomez-Brouchet, Anne

    2013-10-01

    To date, chemosensitivity to neoadjuvant chemotherapy of patients with high-grade osteosarcoma is evaluated on surgical resection by evaluation of the percentage of necrotic cells. As yet, no predictive profile of response to chemotherapy has been used in clinical practice. Because we have previously shown that the integrin pathway controls genotoxic-induced cell death and hypoxia, we hypothesized that in primary biopsies, expression of proteins involved in this pathway could be associated with sensitivity to neoadjuvant chemotherapy in high-grade osteosarcoma. We studied β1, β3, and β5 integrin expression and integrin-linked kinase, focal adhesion kinase (FAK), glycogen synthase kinase 3β (GSK3β), Rho B, angiopoietin-2, β-catenin, and ezrin expression by immunohistochemistry in 36 biopsies of osteosarcomas obtained before treatment. All patients received a chemotherapy regimen in the neoadjuvant setting. An immunoreactive score was assessed, combining the percentage of positive tumor cells and staining intensity. We evaluated the correlation of the biomarkers with response to chemotherapy, metastasis-free survival, and overall survival. A combination of 3 biomarkers (β5 integrin, FAK, and GSK3β) discriminated good and poor responders to chemotherapy, with the highest area under the curve (89.9%; 95% confidence interval, 77.4-1.00) and a diagnostic accuracy of 90.3%. Moreover, high expression of ezrin was associated with an increased risk of metastasis (hazard ratio, 3.93; 95% confidence interval, 1.19-12.9; P = .024). We report a protein expression profile in high-grade osteosarcoma associating β5 integrin, FAK, and GSK3β that significantly correlates with poor response to neoadjuvant chemotherapy. This biomarker profile could help select patients for whom an alternative protocol using inhibitors of this pathway can be proposed.

  12. A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors.

    Science.gov (United States)

    Shimizu, Toshio; Fukuoka, Kazuya; Takeda, Masayuki; Iwasa, Tutomu; Yoshida, Takeshi; Horobin, Joanna; Keegan, Mitchell; Vaickus, Lou; Chavan, Ajit; Padval, Mahesh; Nakagawa, Kazuhiko

    2016-05-01

    VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.

  13. Prednisone inhibits the focal adhesion kinase/receptor activator of NF-κB ligand/mitogen-activated protein kinase signaling pathway in rats with adriamycin-induced nephropathy.

    Science.gov (United States)

    Ye, Minyuan; Zheng, Jing; Chen, Xiaoying; Chen, Xuelan; Wu, Xinhong; Lin, Xiuqin; Liu, Yafang

    2015-11-01

    The aim of the present study was to investigate the mechanisms underlying the effects of prednisone on adriamycin-induced nephritic rat kidney damage via the focal adhesion kinase (FAK)/receptor activator of nuclear factor-κB ligand (RANKL)/mitogen‑activated protein kinase (MAPK) signaling pathway. An adriamycin‑induced nephritic rat model was established to investigate these mechanisms. A total of 30 healthy male Sprague‑Dawley rats were randomly assigned to the normal, model or prednisone group. Samples of urine were collected over the course of 24 h at days 7, 14, and 28, and renal cortex tissue samples were harvested at days 14, and 28 following nephritic rat model establishment. The total urinary protein content was measured by biuret colorimetry. Pathological changes in the kidney tissue samples were observed using an electron microscope. The mRNA expressions levels of FAK, RANKL, p38, extracellular signal‑regulated kinase (ERK), c‑Jun N‑terminal kinase (JNK), and nephrin were then quantified by reverse transcription‑quantitative polymerase chain reaction. In addition, the protein expressions levels of FAK, RANKL, p38, ERK, JNK, phosphorylated (p)‑FAK, p‑ERK, and p‑JNK were quantified by western blotting. As compared with the normal group, the protein expression levels of FAK, RANKL, p-FAK, p38 and p-ERK in the model group were increased. In the prednisone group, the protein expression levels of p-ERK decreased, as compared with the normal group. In the prednisone group, the urinary protein levels, the protein expression levels of FAK, RANKL, p38, p-FAK, p-p38 and the mRNA expression levels of FAK, p38, RANKL, ERK, JNK decreased, as compared with the model group. In the prednisone group, the mRNA and protein expression levels of nephrin and the serum expression levels of RANKL increased, the serum expression levels of osteoprotegerin (OPG) were decreased, as compared with the model group. No significant changes in the protein expression

  14. Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase.

    Science.gov (United States)

    Chikumi, Hiroki; Fukuhara, Shigetomo; Gutkind, J Silvio

    2002-04-05

    A recently identified family of guanine nucleotide exchange factors for Rho that includes PDZ-RhoGEF, LARG, and p115RhoGEF exhibits a unique structural feature consisting in the presence of area of similarity to regulators of G protein signaling (RGS). This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho. Recently available data suggest, however, that tyrosine kinases can regulate the ability of G protein-coupled receptors (GPCRs) to stimulate Rho, although the underlying molecular mechanisms are still unknown. Here, we found that the activation of thrombin receptors endogenously expressed in HEK-293T cells leads to a remarkable increase in the levels of GTP-bound Rho within 1 min (11-fold) and a more limited but sustained activation (4-fold) thereafter, which lasts even for several hours. Interestingly, tyrosine kinase inhibitors did not affect the early phase of Rho activation, immediately after thrombin addition, but diminished the levels of GTP-bound Rho during the delayed phase. As thrombin receptors stimulate focal adhesion kinase (FAK) potently, we explored whether this non-receptor tyrosine kinase participates in the activation of Rho by GPCRs. We obtained evidence that FAK can be activated by thrombin, Galpha(12), Galpha(13), and Galpha(q) through both Rho-dependent and Rho-independent mechanisms and that PDZ-RhoGEF and LARG can in turn be tyrosine-phosphorylated through FAK in response to thrombin, thereby enhancing the activation of Rho in vivo. These data indicate that FAK may act as a component of a positive feedback loop that results in the sustained activation of Rho by GPCRs, thus providing evidence of the existence of a novel biochemical route by which tyrosine kinases may regulate the activity of Rho through

  15. Inhibition on Apoptosis Induced by Elevated Hydrostatic Pressure in Retinal Ganglion Cell-5 via Laminin Upregulating β1-integrin/Focal Adhesion Kinase/Protein Kinase B Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    Yi Li; Yan-Ming Chen; Ming-Ming Sun; Xiao-Dan Guo; Ya-Chen Wang; Zhong-Zhi Zhang

    2016-01-01

    Background:Glaucoma is a progressive optic neuropathy characterized by degeneration of neurons due to loss of retinal ganglion cells (RGCs).High intraocular pressure (HIOP),the main risk factor,causes the optic nerve damage.However,the precise mechanism of HIOP-induced RGC death is not yet completely understood.This study was conducted to determine apoptosis of RGC-5 cells induced by elevated hydrostatic pressures,explore whether laminin is associated with apoptosis under pressure,whether laminin can protect RGCs from apoptosis and affirm the mechanism that regulates the process of RGCs survival.Methods:RGC-5 cells were exposed to 0,20,40,and 60 mmHg in a pressurized incubator for 6,12,and 24 h,respectively.The effect of elevated hydrostatic pressure on RGC-5 cells was measured by Annexin V-fluorescein isothiocyanate/propidium iodide staining,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,and Western blotting of cleaved caspase-3 protein.Location and expression oflaminin were detected by immunofluorescence.The expression of β 1-integrin,phosphorylation of focal adhesion kinase (FAK) and protein kinase B (PKB,or AKT) were investigated with real-time polymerase chain reaction and Western blotting analysis.Results:Elevated hydrostatic pressure induced apoptosis in cultured RGC-5 cells.Pressure with 40 mmHg for 24 h induced a maximum apoptosis.Laminin was declined in RGC-5 cells after exposing to 40 mmHg for 24 h.After pretreating with laminin,RGC-5 cells survived from elevated pressure.Furthermore,β1-integrin and phosphorylation of FAK and AKT were increased compared to 40 mmHg group.Conclusions:The data show apoptosis tendency of RGC-5 cells with elevated hydrostatic pressure.Laminin can protect RGC-5 cells against high pressure via β 1-integrin/FAK/AKT signaling pathway.These results suggest that the decreased laminin of RGC-5 cells might be responsible for apoptosis induced by elevated hydrostatic pressure,and laminin or activating β1

  16. Breast cancer metastasis suppressor 1 (BRMS1) suppresses attachment and spreading of breast cancer cells on 2D and 3D extracellular matrix components by altering focal adhesion-associated signaling

    Science.gov (United States)

    Metastatic dissemination of cancer cells from primary tumor to secondary sites is a multi-step process that depends heavily on the ability of cancer cells to respond to the microenvironmental cues, such as changes in composition of surrounding extracellular matrix (ECM), by adapting their adhesion a...

  17. Pathogenesis of Focal Segmental Glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Beom Jin Lim

    2016-11-01

    Full Text Available Focal segmental glomerulosclerosis (FSGS is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. FSGS is classified as collapsing, tip, cellular, perihilar and not otherwise specified variants according to the location and character of the sclerotic lesion. Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. FSGS may also be caused by genetic alterations. These genes are mainly those regulating slit diaphragm structure, actin cytoskeleton of podocytes, and foot process structure. The mode of inheritance and age of onset are different according to the gene involved. Recently, the role of parietal epithelial cells (PECs has been highlighted. Podocytes and PECs have common mesenchymal progenitors, therefore, PECs could be a source of podocyte repopulation after podocyte injury. Activated PECs migrate along adhesion to the glomerular tuft and may also contribute to the progression of sclerosis. Markers of activated PECs, including CD44, could be used to distinguish FSGS from minimal change disease. The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice.

  18. Beamlet focal plane diagnostic

    Energy Technology Data Exchange (ETDEWEB)

    Caird, J.A.; Nielsen, N.D.; Patton, H.G.; Seppala, L.G.; Thompson, C.E.; Wegner, P.J.

    1996-12-01

    This paper describes the major optical and mechanical design features of the Beamlet Focal Plane Diagnostic system as well as measurements of the system performance, and typical data obtained to date. We also discuss the NIF requirements on the focal spot that we are interested in measuring, and some of our plans for future work using this system.

  19. Bimaxillary Oral Focal Mucinosis.

    Science.gov (United States)

    Yadav, Sunil; Malik, Sunita; Mittal, Hitesh Chander; Singh, Gurdarshan; Kamra, Hemlata

    2016-10-01

    Oral focal mucinosis is considered as oral counterpart of cutaneous focal mucinosis. The preoperative diagnosis of mucinosis is almost impossible because of its rarity and clinical similarity to other lesions of various etiologies. The histological diagnosis of oral mucinosis is important to better understand the etiopathogenesis, treatment modalities, and any recurrence of the lesion besides differentiating from the other soft tissue lesions.The purpose of this paper is to report the first case of bimaxillary involvement with dome-shaped elevated, rounded, asymptomatic, normally colored swelling in left posterior palatal mucosa and left mandibular posterior region in a 25-year old woman who was diagnosed as oral focal mucinosis histopathologically.

  20. Focal neurological deficits

    Science.gov (United States)

    ... Other examples of focal loss of function include: Horner syndrome : small pupil on one side, one-sided ... 403. Read More Alertness - decreased Fine motor control Horner syndrome Hypotonia Movement - uncoordinated Muscle function loss Neurologic ...

  1. Adhesive Categories

    DEFF Research Database (Denmark)

    Lack, Stephen; Sobocinski, Pawel

    2003-01-01

    We introduce adhesive categories, which are categories with structure ensuring that pushouts along monomorphisms are well-behaved. Many types of graphical structures used in computer science are shown to be examples of adhesive categories. Double-pushout graph rewriting generalises well...... to rewriting on arbitrary adhesive categories....

  2. ERK kinases modulate the activation of PI3 kinase related kinases (PIKKs) in DNA damage response.

    Science.gov (United States)

    Lin, Xiaozeng; Yan, Judy; Tang, Damu

    2013-12-01

    DNA damage response (DDR) is the critical surveillance mechanism in maintaining genome integrity. The mechanism activates checkpoints to prevent cell cycle progression in the presence of DNA lesions, and mediates lesion repair. DDR is coordinated by three apical PI3 kinase related kinases (PIKKs), including ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), and DNA-PKcs (the catalytic subunit of the DNA dependent protein kinase). These kinases are activated in response to specific DNA damage or lesions, resulting in checkpoint activation and DNA lesion repair. While it is clear that the pathways of ATM, ATR, and DNA-PK are the core components of DDR, there is accumulating evidence revealing the involvement of other cellular pathways in regulating DDR; this is in line with the concept that in addition to being a nuclear event DDR is also a cellular process. One of these pathways is the extracellular signal-regulated kinase (ERK) MAPK (mitogen-activated protein kinase) pathway. ERK is a converging point of multiple signal transduction pathways involved in cell proliferation, differentiation, and apoptosis. Adding to this list of pathways is the recent development of ERK in DDR. The ERK kinases (ERK1 and ERK2) contribute to the proper execution of DDR in terms of checkpoint activation and the repair of DNA lesions. This review summarizes the contributions of ERK to DDR with emphasis on the relationship of ERK kinases with the activation of ATM, ATR, and DNA-PKcs.

  3. Kartagener syndrome with focal segmental glomerulosclerosis.

    Science.gov (United States)

    Momeni, Ali; Doroushi, Behzad; Taheri, Nadia

    2013-11-01

    Primary ciliary dyskinesia is characterized by congenital impairment of mucociliary clearance. Kartagener syndrome (KS) is a clinical variant of primary ciliary dyskinesia which is involved in situs inversus associated with chronic respiratory infections. In addition, glomerular disease in KS syndrome is rare and reported cases are limited. We had a 27-year-old female patient with KS who presented with proteinuria, hematuria, normal kidney function, and a family history of systemic lupus erythematosus. Kidney biopsy showed segmental scar with adhesion to Bowman capsule, which was indicative of focal segmental glomerulosclerosis.

  4. [Focal epithelial hyperplasia].

    Science.gov (United States)

    Vera-Iglesias, E; García-Arpa, M; Sánchez-Caminero, P; Romero-Aguilera, G; Cortina de la Calle, P

    2007-11-01

    Focal epithelial hyperplasia is a rare disease of the oral mucosa caused by the human papilloma virus (HPV). It appears as a benign epithelial growth, usually in the mucosa of the lower lip. It is mainly associated with HPV serotypes 13 and 32 and there is a clear racial predilection for the disease in Native Americans and Eskimos. We describe the case of a 17-year-old girl from Ecuador with multiple papular lesions in both lips that were clinically and histologically consistent with focal epithelial hyperplasia. Analysis by polymerase chain reaction detected HPV serotype 13.

  5. SNAP focal plane

    Energy Technology Data Exchange (ETDEWEB)

    Lampton, Michael L.; Kim, A.; Akerlof, C.W.; Aldering, G.; Amanullah, R.; Astier, P.; Barrelet, E.; Bebek, C.; Bergstrom, L.; Berkovitz, J.; Bernstein, G.; Bester, M.; Bonissent, A.; Bower, C.; Carithers Jr., W.C.; Commins, E.D.; Day, C.; Deustua, S.E.; DiGennaro,R.; Ealet, A.; Ellis, R.S.; Eriksson, M.; Fruchter, A.; Genat, J.-F.; Goldhaber, G.; Goobar, A.; Groom, D.; Harris, S.E.; Harvey, P.R.; Heetderks, H.D.; Holland, S.E.; Huterer, D.; Karcher, A.; Kolbe, W.; Krieger, B.; Lafever, R.; Lamoureux, J.; Levi, M.E.; Levin, D.S.; Linder,E.V.; Loken, S.C.; Malina, R.; Massey, R.; McKay, T.; McKee, S.P.; Miquel, R.; Mortsell, E.; Mostek, N.; Mufson, S.; Musser, J.; Nugent, P.; Oluseyi, H.; Pain, R.; Palaio, N.; Pankow, D.; Perlmutter, S.; Pratt, R.; Prieto, E.; Refregier, A.; Rhodes, J.; Robinson, K.; Roe, N.; Sholl, M.; Schubnell, M.; Smadja, G.; Smoot, G.; Spadafora, A.; Tarle, G.; Tomasch,A.; von der Lippe, H.; Vincent, R.; Walder, J.-P.; Wang, G.

    2002-07-29

    The proposed SuperNova/Acceleration Probe (SNAP) mission will have a two-meter class telescope delivering diffraction-limited images to an instrumented 0.7 square-degree field sensitive in the visible and near-infrared wavelength regime. We describe the requirements for the instrument suite and the evolution of the focal plane design to the present concept in which all the instrumentation--visible and near-infrared imagers, spectrograph, and star guiders--share one common focal plane.

  6. Adhesive Categories

    DEFF Research Database (Denmark)

    Lack, Stephen; Sobocinski, Pawel

    2004-01-01

    We introduce adhesive categories, which are categories with structure ensuring that pushouts along monomorphisms are well-behaved. Many types of graphical structures used in computer science are shown to be examples of adhesive categories. Double-pushout graph rewriting generalises well to rewrit...

  7. Focal and generalized alopecia.

    Science.gov (United States)

    O'Dair, H A; Foster, A P

    1995-07-01

    Focal or generalized alopecia is defined as hair loss affecting the ventral, lateral, perineal, and dorsal aspects of the trunk of the cat, usually in a symmetric pattern. This may be attributable to failure of hair coat production, excess loss of hair due to self trauma, or excess shedding of whole hairs. Self trauma is the most common cause of hair loss and is associated particularly with flea allergy dermatitis. Other causes of hair loss are reviewed.

  8. Proximal Focal Femoral Deficiency

    OpenAIRE

    Vishal Kalia, Vibhuti

    2008-01-01

    Proximal focal femoral deficiency (PFFD) is a developmental disorder of the proximal segment of thefemur and of acetabulum resulting in shortening of the affected limb and impairment of the function. It isa spectrum of congenital osseous anomalies characterized by a deficiency in the structure of the proximalfemur. The diagnosis is often made by radiological evaluation which includes identification and descriptionof PFFD and evaluation of associated limb anomalies by plain radiographs. Contra...

  9. Oral focal epithelial hyperplasia.

    Science.gov (United States)

    López-Jornet, Pía; Camacho-Alonso, Fabio; Berdugo, Lucero

    2010-01-01

    Focal epithelial hyperplasia (FEH) is a benign, asymptomatic disease. It appears as papules, principally on the lower lip, although it can also be found on the retro-commissural mucosa and tongue and, less frequently, on the upper lip, gingiva and palate. FEH is caused by human papillomavirus subtype 13 or 32. The condition occurs in many populations and ethnic groups. We present the clinical case of a 31-year-old male with lesions that clinically and histologically corresponded to FEH.

  10. Microtubule-dependent modulation of adhesion complex composition.

    Science.gov (United States)

    Ng, Daniel H J; Humphries, Jonathan D; Byron, Adam; Millon-Frémillon, Angélique; Humphries, Martin J

    2014-01-01

    The microtubule network regulates the turnover of integrin-containing adhesion complexes to stimulate cell migration. Disruption of the microtubule network results in an enlargement of adhesion complex size due to increased RhoA-stimulated actomyosin contractility, and inhibition of adhesion complex turnover; however, the microtubule-dependent changes in adhesion complex composition have not been studied in a global, unbiased manner. Here we used label-free quantitative mass spectrometry-based proteomics to determine adhesion complex changes that occur upon microtubule disruption with nocodazole. Nocodazole-treated cells displayed an increased abundance of the majority of known adhesion complex components, but no change in the levels of the fibronectin-binding α5β1 integrin. Immunofluorescence analyses confirmed these findings, but revealed a change in localisation of adhesion complex components. Specifically, in untreated cells, α5-integrin co-localised with vinculin at peripherally located focal adhesions and with tensin at centrally located fibrillar adhesions. In nocodazole-treated cells, however, α5-integrin was found in both peripherally located and centrally located adhesion complexes that contained both vinculin and tensin, suggesting a switch in the maturation state of adhesion complexes to favour focal adhesions. Moreover, the switch to focal adhesions was confirmed to be force-dependent as inhibition of cell contractility with the Rho-associated protein kinase inhibitor, Y-27632, prevented the nocodazole-induced conversion. These results highlight a complex interplay between the microtubule cytoskeleton, adhesion complex maturation state and intracellular contractile force, and provide a resource for future adhesion signaling studies. The proteomics data have been deposited in the ProteomeXchange with identifier PXD001183.

  11. Focal cortical dysplasia - review.

    Science.gov (United States)

    Kabat, Joanna; Król, Przemysław

    2012-04-01

    Focal cortical dysplasia is a malformation of cortical development, which is the most common cause of medically refractory epilepsy in the pediatric population and the second/third most common etiology of medically intractable seizures in adults.Both genetic and acquired factors are involved in the pathogenesis of cortical dysplasia. Numerous classifications of the complex structural abnormalities of focal cortical dysplasia have been proposed - from Taylor et al. in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized.Type I focal cortical dysplasia with mild symptomatic expression and late onset, is more often seen in adults, with changes present in the temporal lobe.Clinical symptoms are more severe in type II of cortical dysplasia usually seen in children. In this type, more extensive changes occur outside the temporal lobe with predilection for the frontal lobes.New type III is one of the above dysplasias with associated another principal lesion as hippocampal sclerosis, tumor, vascular malformation or acquired pathology during early life.Brain MRI imaging shows abnormalities in the majority of type II dysplasias and in only some of type I cortical dysplasias.THE MOST COMMON FINDINGS ON MRI IMAGING INCLUDE: focal cortical thickening or thinning, areas of focal brain atrophy, blurring of the gray-white junction, increased signal on T2- and FLAIR-weighted images in the gray and subcortical white matter often tapering toward the ventricle. On the basis of the MRI findings, it is possible to differentiate between type I and type II cortical dysplasia. A complete resection of the epileptogenic zone is required for seizure-free life. MRI imaging is very helpful to identify those patients who are likely to benefit from surgical treatment in a group of patients with drug-resistant epilepsy.However, in type I cortical dysplasia, MR imaging is often normal, and also in both types

  12. Systemic focal epileptogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Remler, M.P.; Marcussen, W.H.

    1986-01-01

    Rats that receive radiation to 0.25 cc of one cerebral hemisphere are clinically and electroencephalographically normal until there is a breakdown of the blood-brain barrier (BBB) at 3 to 6 months postradiation. This BBB lesion can be detected by transient focal seizure activity produced by the BBB-excluded systemic convulsant bicuculline methiodide. In two rats the seizure activity induced by this one injection was self-sustaining. In seven of 15 other rats tested, the subsequent administration of repeated 2 mg/kg injections created a chronic focus that continued to spike with great frequency for 3 weeks or more without further administration of any convulsant. In three of eight other rats, implanted minipumps delivering 180 micrograms/h of bicuculline methiodide produced self-sustaining epileptic activity.

  13. Focal femoral condyle resurfacing.

    LENUS (Irish Health Repository)

    Brennan, S A

    2013-03-01

    Focal femoral inlay resurfacing has been developed for the treatment of full-thickness chondral defects of the knee. This technique involves implanting a defect-sized metallic or ceramic cap that is anchored to the subchondral bone through a screw or pin. The use of these experimental caps has been advocated in middle-aged patients who have failed non-operative methods or biological repair techniques and are deemed unsuitable for conventional arthroplasty because of their age. This paper outlines the implant design, surgical technique and biomechanical principles underlying their use. Outcomes following implantation in both animal and human studies are also reviewed. Cite this article: Bone Joint J 2013;95-B:301-4.

  14. Extensive focal epithelial hyperplasia.

    Science.gov (United States)

    Hashemipour, Maryam Alsadat; Shoryabi, Ali; Adhami, Shahrzad; Mehrabizadeh Honarmand, Hoda

    2010-01-01

    Heck's disease or focal epithelial hyperplasia is a benign contagious disease caused by human papillomavirus types 13 or 32. It occurs with low frequency in the Iranian population. This condition is characterized by the occurrence of multiple, small papules or nodules in the oral cavity, especially on the labial and buccal mucosa and tongue. In some populations, up to 39% of children are affected. Conservative surgical excision of lesions may be performed for diagnostic or aesthetic purposes. The risk of recurrence after this therapy is minimal, and there seems to be no malignant transformation potential. In the present work, we presented the clinical case of a 12-year-old Iranian girl with oral lesions that clinically and histologically correspond to Heck's disease.

  15. Proximal Focal Femoral Deficiency

    Directory of Open Access Journals (Sweden)

    Vishal Kalia, Vibhuti

    2008-01-01

    Full Text Available Proximal focal femoral deficiency (PFFD is a developmental disorder of the proximal segment of thefemur and of acetabulum resulting in shortening of the affected limb and impairment of the function. It isa spectrum of congenital osseous anomalies characterized by a deficiency in the structure of the proximalfemur. The diagnosis is often made by radiological evaluation which includes identification and descriptionof PFFD and evaluation of associated limb anomalies by plain radiographs. Contrast arthrography orMagnetic Resonance Imaging is indicated when radiological features are questionable and to disclose thepresence and location of the femoral head and any cartilagenous anlage. The disorder is more commonlyunilateral and is apparent at birth. However, bilateral involvement is rarely seen. Therapy of the disorder isdirected towards satisfactory ambulation and specific treatment depending on the severity of dysplasia.

  16. Bacterial Adhesion & Blocking Bacterial Adhesion

    DEFF Research Database (Denmark)

    Vejborg, Rebecca Munk

    2008-01-01

    tract to the microbial flocs in waste water treatment facilities. Microbial biofilms may however also cause a wide range of industrial and medical problems, and have been implicated in a wide range of persistent infectious diseases, including implantassociated microbial infections. Bacterial adhesion...... is the first committing step in biofilm formation, and has therefore been intensely scrutinized. Much however, still remains elusive. Bacterial adhesion is a highly complex process, which is influenced by a variety of factors. In this thesis, a range of physico-chemical, molecular and environmental parameters......, which influence the transition from a planktonic lifestyle to a sessile lifestyle, have been studied. Protein conditioning film formation was found to influence bacterial adhesion and subsequent biofilm formation considerable, and an aqueous extract of fish muscle tissue was shown to significantly...

  17. Role of dystrophins and utrophins in platelet adhesion process.

    Science.gov (United States)

    Cerecedo, Doris; Mondragón, Ricardo; Cisneros, Bulmaro; Martínez-Pérez, Francisco; Martínez-Rojas, Dalila; Rendón, Alvaro

    2006-07-01

    Platelets are crucial at the site of vascular injury, adhering to the sub-endothelial matrix through receptors on their surface, leading to cell activation and aggregation to form a haemostatic plug. Platelets display focal adhesions as well as stress fibres to contract and facilitate expulsion of growth and pro-coagulant factors contained in the granules and to constrict the clot. The interaction of F-actin with different actin-binding proteins determines the properties and composition of the focal adhesions. Recently, we demonstrated the presence of dystrophin-associated protein complex corresponding to short dystrophin isoforms (Dp71d and Dp71) and the uthophin gene family (Up400 and Up71), which promote shape change, adhesion, aggregation, and granule centralisation. To elucidate participation of both complexes during the platelet adhesion process, their potential association with integrin beta-1 fraction and the focal adhesion system (alpha-actinin, vinculin and talin) was evaluated by immunofluorescence and immunoprecipitation assays. It was shown that the short dystrophin-associated protein complex participated in stress fibre assembly and in centralisation of cytoplasmic granules, while the utrophin-associated protein complex assembled and regulated focal adhesions. The simultaneous presence of dystrophin and utrophin complexes indicates complementary structural and signalling mechanisms to the actin network, improving the platelet haemostatic role.

  18. Statistical earthquake focal mechanism forecasts

    CERN Document Server

    Kagan, Yan Y

    2013-01-01

    Forecasts of the focal mechanisms of future earthquakes are important for seismic hazard estimates and Coulomb stress and other models of earthquake occurrence. Here we report on a high-resolution global forecast of earthquake rate density as a function of location, magnitude, and focal mechanism. In previous publications we reported forecasts of 0.5 degree spatial resolution, covering the latitude range magnitude, and focal mechanism. In previous publications we reported forecasts of 0.5 degree spatial resolution, covering the latitude range from -75 to +75 degrees, based on the Global Central Moment Tensor earthquake catalog. In the new forecasts we've improved the spatial resolution to 0.1 degree and the latitude range from pole to pole. Our focal mechanism estimates require distance-weighted combinations of observed focal mechanisms within 1000 km of each grid point. Simultaneously we calculate an average rotation angle between the forecasted mechanism and all the surrounding mechanisms, using the method ...

  19. Adhesive plasters

    Science.gov (United States)

    Holcombe, Jr., Cressie E.; Swain, Ronald L.; Banker, John G.; Edwards, Charlene C.

    1978-01-01

    Adhesive plaster compositions are provided by treating particles of Y.sub.2 O.sub.3, Eu.sub.2 O.sub.3, Gd.sub.2 O.sub.3 or Nd.sub.2 O.sub.3 with dilute acid solutions. The resulting compositions have been found to spontaneously harden into rigid reticulated masses resembling plaster of Paris. Upon heating, the hardened material is decomposed into the oxide, yet retains the reticulated rigid structure.

  20. Actomyosin organisation for adhesion, spreading, growth and movement in chick fibroblasts

    DEFF Research Database (Denmark)

    Couchman, J R; Rees, D A

    1979-01-01

    Examination of the actomyosin structures and their relation to adhesion, movement and growth in the first fibroblasts migrating from chick heart explants shows striking differences with fibroblasts adapted to grow in culture. The latter have focal adhesions which seem to immobilize them for ancho......Examination of the actomyosin structures and their relation to adhesion, movement and growth in the first fibroblasts migrating from chick heart explants shows striking differences with fibroblasts adapted to grow in culture. The latter have focal adhesions which seem to immobilize them...

  1. Cell adhesion to cathodic arc plasma deposited CrAlSiN thin films

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Kyu, E-mail: skim@ulsan.ac.kr [School of Materials Science and Engineering, University of Ulsan, Ulsan 680-749 (Korea, Republic of); Pham, Vuong-Hung [Department of Materials Science and Engineering, Seoul National University, Seoul 151-744 (Korea, Republic of); Kim, Chong-Hyun [Department of Food Science, Cornell University, Ithaca, NY 14853 (United States)

    2012-07-01

    Osteoblast cell response (cell adhesion, actin cytoskeleton and focal contact adhesion as well as cell proliferation) to CrN, CrAlSiN and Ti thin films was evaluated in vitro. Cell adhesion and actin stress fibers organization depended on the film composition significantly. Immunofluorescent staining of vinculin in osteoblast cells showed good focal contact adhesion on the CrAlSiN and Ti thin films but not on the CrN thin films. Cell proliferation was significantly greater on the CrAlSiN thin films as well as on Ti thin films than on the CrN thin films.

  2. FOCAL MOTOR SEIZURES WITH TYPICAL AUTOMATISMS (FOCAL AUTOMOTOR SEIZURES

    Directory of Open Access Journals (Sweden)

    M. B. Mironov

    2014-01-01

    Full Text Available The paper deals with the study of a group of patients with focal automotor seizures, by taking into consideration their nosological, anamnestic, clinical, electroencephalographic, and neuroimaging features.

  3. Genetics Home Reference: focal dermal hypoplasia

    Science.gov (United States)

    ... Home Health Conditions focal dermal hypoplasia focal dermal hypoplasia Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Focal dermal hypoplasia is a genetic disorder that primarily affects the ...

  4. The computed cranial focal point

    NARCIS (Netherlands)

    Jong, G.A. de; Maal, T.J.J.; Delye, H.

    2015-01-01

    INTRODUCTION: Stereophotogrammetry is a radiation-free method for monitoring skull development after craniosynostosis repair. Lack of clear fixed reference points complicate longitudinal comparison of 3D photographs. Therefore we developed the 'computed cranial focal point' (CCFP). METHODS: The CCFP

  5. Adhesion and cohesion.

    Science.gov (United States)

    von Fraunhofer, J Anthony

    2012-01-01

    The phenomena of adhesion and cohesion are reviewed and discussed with particular reference to dentistry. This review considers the forces involved in cohesion and adhesion together with the mechanisms of adhesion and the underlying molecular processes involved in bonding of dissimilar materials. The forces involved in surface tension, surface wetting, chemical adhesion, dispersive adhesion, diffusive adhesion, and mechanical adhesion are reviewed in detail and examples relevant to adhesive dentistry and bonding are given. Substrate surface chemistry and its influence on adhesion, together with the properties of adhesive materials, are evaluated. The underlying mechanisms involved in adhesion failure are covered. The relevance of the adhesion zone and its importance with regard to adhesive dentistry and bonding to enamel and dentin is discussed.

  6. Adhesion and Cohesion

    Directory of Open Access Journals (Sweden)

    J. Anthony von Fraunhofer

    2012-01-01

    Full Text Available The phenomena of adhesion and cohesion are reviewed and discussed with particular reference to dentistry. This review considers the forces involved in cohesion and adhesion together with the mechanisms of adhesion and the underlying molecular processes involved in bonding of dissimilar materials. The forces involved in surface tension, surface wetting, chemical adhesion, dispersive adhesion, diffusive adhesion, and mechanical adhesion are reviewed in detail and examples relevant to adhesive dentistry and bonding are given. Substrate surface chemistry and its influence on adhesion, together with the properties of adhesive materials, are evaluated. The underlying mechanisms involved in adhesion failure are covered. The relevance of the adhesion zone and its importance with regard to adhesive dentistry and bonding to enamel and dentin is discussed.

  7. Flexible nanopillars to regulate cell adhesion and movement

    Science.gov (United States)

    Chien, Fan-Ching; Dai, Yang-Hong; Kuo, Chiung Wen; Chen, Peilin

    2016-11-01

    Flexible polymer nanopillar substrates were used to systematically demonstrate cell alignment and migration guided by the directional formation of focal adhesions. The polymer nanopillar substrates were constructed to various height specifications to provide an extensive variation of flexibility; a rectangular arrangement created spatial confinement between adjacent nanopillars, providing less spacing in the horizontal and vertical directions. Three polymer nanopillar substrates with the diameter of 400 nm and the heights of 400, 800, and 1200 nm were fabricated. Super-resolution localization imaging and protein pair-distance analysis of vinculin proteins revealed that Chinese hamster ovary (CHO) cells formed mature focal adhesions on 1200 nm high nanopillar substrates by bending adjacent nanopillars to link dot-like adhesions. The spacing confinement of the adjacent nanopillars enhanced the orthogonal directionality of the formation tendency of the mature focal adhesions. The directional formation of the mature focal adhesions also facilitated the organization of actin filaments in the horizontal and vertical directions. Moreover, 78% of the CHO cells were aligned in these two directions, in conformity with the flexibility and nanotopographical cues of the nanopillars. Biased cell migration was observed on the 1200 nm high nanopillar substrates.

  8. Bacterial Adhesion & Blocking Bacterial Adhesion

    DEFF Research Database (Denmark)

    Vejborg, Rebecca Munk

    2008-01-01

    tract to the microbial flocs in waste water treatment facilities. Microbial biofilms may however also cause a wide range of industrial and medical problems, and have been implicated in a wide range of persistent infectious diseases, including implantassociated microbial infections. Bacterial adhesion...... in the formation of highly complex sessile communities, referred to as biofilms. Such microbial communities are often highly dynamic and heterogeneous in nature. Microbial biofilms are of great importance in a wide range of natural processes and industrial settings, from the commensal flora of the gastrointestinal...

  9. Dynamic monitoring of changes in endothelial cell-substrate adhesiveness during leukocyte adhesion by microelectrical impedance assay

    Institute of Scientific and Technical Information of China (English)

    Yakun Ge; Tongle Deng; Xiaoxiang Zheng

    2009-01-01

    Adhesion of leukocytes to endothelial cells in inflammation processes leads to changes of endothelial cell-substrate adhesiveness, and understanding of such changes will provide us with important information of inflammation processes. In this study, we used a non-invasive biosensor system referred to as real-time cell electronic sensor (RT-CES) system to monitor the changes in endothelial cell-substrate adhesiveness induced by human monoblastic cell line U937 cell adhesion in a dynamic and quantitative manner. This assay, which is based on cell-substrate impedance readout, is able to monitor transient changes in cell-substrate adhesiveness as a result of U937 cell adhesion. The U937 cell adhesion to endothelial cells was induced by lipopolysaccharide (LPS) in a dose-dependent manner. Although the number of adherent U937 cells to the endothelial cells was verified by a standard assay, the adhesiveness of endothelial cells after addition of U937 cells was monitored by the RT-CES system. Furthermore, focal adhesion kinase protein decrease and F-actin rearrangement in endothelial cells were observed after addition of U937 cells. Our results indicated that the adhesion of U937 cells to LPS-treated endothelial cells reduced the cell adhesiveness to the substrate, and such reduction might facilitate infiltration of leukocytes.

  10. Grupo Focal em Pesquisas Sociais

    OpenAIRE

    Maria Lúcia Silva Servo; Pricila Oliveira Araújo

    2012-01-01

    Este artigo tem como objetivo discutir a técnica de grupo focal em pesquisas sociais. Apresenta-se as concepções sobre grupo focal. Traz-se os postulados de Pichon-Rivière sobre grupo operativo, os instrumentos de planificação, os vetores do campo grupal para nortear a dinâmica e a observação do campo grupal, bem como a organização, a operacionalização e a análise dos dados das sessões de grupo focal. Através desta técnica de coleta de dados em pesquisas sociais, é possível a construção do EC...

  11. Grupo Focal em Pesquisas Sociais

    OpenAIRE

    Maria Lúcia Silva Servo; Pricila Oliveira Araújo

    2012-01-01

    Este artigo tem como objetivo discutir a técnica de grupo focal em pesquisas sociais. Apresenta-se as concepções sobre grupo focal. Traz-se os postulados de Pichon-Rivière sobre grupo operativo, os instrumentos de planificação, os vetores do campo grupal para nortear a dinâmica e a observação do campo grupal, bem como a organização, a operacionalização e a análise dos dados das sessões de grupo focal. Através desta técnica de coleta de dados em pesquisas sociais, é possível a construção do EC...

  12. Advanced adhesives in electronics

    CERN Document Server

    Bailey, C

    2011-01-01

    Adhesives are widely used in the manufacture of electronic devices to act as passive and active components. Recently there has been considerable interest in the use of conductive adhesives. This book reviews key types of conductive adhesives, processing methods, properties and the way they can be modelled as well as potential applications.$bAdhesives for electronic applications serve important functional and structural purposes in electronic components and packaging, and have developed significantly over the last few decades. Advanced adhesives in electronics reviews recent developments in adhesive joining technology, processing and properties. The book opens with an introduction to adhesive joining technology for electronics. Part one goes on to cover different types of adhesive used in electronic systems, including thermally conductive adhesives, isotropic and anisotropic conductive adhesives and underfill adhesives for flip-chip applications. Part two focuses on the properties and processing of electronic ...

  13. Syndecans promote integrin-mediated adhesion of mesenchymal cells in two distinct pathways

    DEFF Research Database (Denmark)

    Whiteford, James; Behrends, Volker; Kirby, Hishani;

    2007-01-01

    to form focal adhesions in response to fibronectin. Consistent with actin cytoskeleton organization, the process required Rho-GTP and Rho kinase. While syndecan-2 and -4 ectodomains could both promote integrin-mediated adhesion, their pathways were distinct, as shown by competition assays. Evidence...

  14. Focal epithelial hyperplasia: Case report.

    Science.gov (United States)

    Puriene, Alina; Rimkevicius, Arunas; Gaigalas, Mindaugas

    2011-01-01

    The purpose of the present article is to present a 15 year-old patient with focal epithelial hyperplasia and to review the references on the subject-related etiological, pathological, diagnostic and treatment aspects. Focal epithelial hyperplasia is a rare human papilloma virus (HPV) related to oral lesion with very low frequency within our population. Surgical treatment with a biopsy was performed, acanthosis and parakeratosis are consistent histopathological features, since the patient had no history of sexual contact and HIV infection, the virus was probably acquired from environmental sources.

  15. Patterned hybrid nanohole array surfaces for cell adhesion and migration.

    Science.gov (United States)

    Westcott, Nathan P; Lou, Yi; Muth, John F; Yousaf, Muhammad N

    2009-10-06

    We report the fabrication of hybrid nanohole array surfaces to study the role of the surface nanoevironment on cell adhesion and cell migration. We use polystyrene beads and reactive ion etching to control the size and the spacing between nanoholes on a tailored self-assembled monolayer inert gold surface. The arrays were characterized by scanning electron microscopy and brightfield microscopy. For cell adhesion studies, cells were seeded to these substrates to study the effect of ligand spacing on cell spreading, stress fiber formation, and focal adhesion structure and size. Finally, comparative cell migration rates were examined on the various nanohole array surfaces using time-lapse microscopy.

  16. Focal fits during chlorambucil therapy

    Science.gov (United States)

    Naysmith, A.; Robson, R. H.

    1979-01-01

    An elderly man receiving chlorambucil for chronic lymphatic leukaemia developed focal fits. The onset and frequency were dose related. There was no evidence of metabolic disturbance or of meningeal leukaemia. Although reported in children and well recognized in animals, chlorambucil-induced fits in an adult have not been previously recorded. PMID:118440

  17. Focal lesions of the patella

    Energy Technology Data Exchange (ETDEWEB)

    Hedayati, B. [Royal national Orthopaedic Hospital Stanmore, Brockley Hill Stanmore, Department of Radiology, Middlesex (United Kingdom); Lewisham Hospital NHS Trust, Department of Radiology, London (United Kingdom); Saifuddin, A. [Royal national Orthopaedic Hospital Stanmore, Brockley Hill Stanmore, Department of Radiology, Middlesex (United Kingdom)

    2009-08-15

    Focal lesions of the patella may be identified during the investigation of anterior knee pain or as an incidental finding on radiological images. This pictorial review describes the radiographic appearances of a wide range of conditions that have been seen in this sesamoid bone. Where appropriate, computed tomography and magnetic resonance features have been included. (orig.)

  18. Adhesion in microelectronics

    CERN Document Server

    Mittal, K L

    2014-01-01

    This comprehensive book will provide both fundamental and applied aspects of adhesion pertaining to microelectronics in a single and easily accessible source. Among the topics to be covered include; Various theories or mechanisms of adhesionSurface (physical or chemical) characterization of materials as it pertains to adhesionSurface cleaning as it pertains to adhesionWays to improve adhesionUnraveling of interfacial interactions using an array of pertinent techniquesCharacterization of interfaces / interphasesPolymer-polymer adhesionMetal-polymer adhesion  (metallized polymers)Polymer adhesi

  19. Focal rigidity of flat tori

    Directory of Open Access Journals (Sweden)

    Ferry Kwakkel

    2011-12-01

    Full Text Available Given a closed Riemannian manifold (M, g, i.e. compact and boundaryless, there is a partition of its tangent bundle TM = ∪iΣi called the focal decomposition of TM. The sets Σi are closely associated to focusing of geodesics of (M, g, i.e. to the situation where there are exactly i geodesic arcs of the same length joining points p and q in M. In this note, we study the topological structure of the focal decomposition of a closed Riemannian manifold and its relation with the metric structure of the manifold. Our main result is that flat n-tori, n > 2, are focally rigid in the sense that if two flat tori are focally equivalent then the tori are isometric up to rescaling. The case n = 2 was considered before by F. Kwakkel.Dada uma variedade Riemanniana (M, g fechada, isto é, compacta e sem bordo, existe uma partição de seu fibrado tangente TM = ∪iΣi chamada decomposição focal de TM. Os conjuntos Σi estão intimamente associados ao modo como focalizam as geodésicas de (M,g, isto é, à situação em que existem exatamente i arcos de geodésica de mesmo comprimento unindo pontos p e q em M. Nesta nota, estudamos a estrutura topológica da decomposição focal de uma variedade Riemanniana fechada e sua relação com a estrutura métrica de M. Nosso principal resultado é que n-toros planos, n > 2, são focalmente rigidos, isto é, se dois toros planos são focalmente equivalentes, então os dois toros são isométricos módulo mudança de escala. O caso n = 2 foi considerado anteriormente por F. Kwakkel.

  20. Effect of H2O2,extracellular matrix and out segment of photoreceptor on expression of focal adhesion kinase in RPE cell%氧化衰老、细胞外基质和光感受器外节膜盘对RPE细胞中黏着斑激酶表达的影响

    Institute of Scientific and Technical Information of China (English)

    朱洁; 王雨生; 赵炜; 杨秀梅; 李夏; 姜廷帅

    2011-01-01

    Background The underlying mechanism of choroidal neovascularization(CNV) is multifactorial and complex.Focal adhesion kinase(FAK) plays a crucial role in controlling essential cellular processes and influencing distinct steps of the angiogenic response.But to our knowledge,seldom study on the effect of FAK on CNV formation has been reported previously.Objective In this study,the effect of several CNV risk factors on the expression of FAK in cultured retinal pigment epithelium(RPE) cells was investigated to illuminate effect of FAK on CNV.Methods Human RPE cells were isolated from donor eyes and exposed to H2O2,swallow of outer segment of photoreceptors(POS) and extracellular matrix(ECM) separately with the treating as follows:RPE cells were co-cultured with 10,20,50 and 100μmol/L H2O2 for 20 days;POS(1×106/ml) were co-cultivated with RPE cells for 20 days(setting control group,POS group,hypoxia group with 200μmol/L CoCl2,and POS+hyoxia group);RPE cells were cultured on the plates coated with 100mg/L fibronectin(FN),laminin(LN) or collagen typeⅠfor 30minutes or 1 hour.The expression of FAK and pFAK in RPE cells were examined by Western blot analysis.Results FAK was highly expressed in the 20μmol/L and 50μmol/L H2O2 groups compared with control group(P<0.01);while he expression level of pFAK was reduced after treated with H2O2 in comparison with the control group(P<0.01).After cultured with POS for 20 days,the undigested lysosome could be observed in RPE cells.The expressions of FAK and pFAK in RPE cells were not significantly changed between control group and POS groups(P>0.05),but those in hypoxia group were significantly up-regulated in comparison with control group(P<0.01).Compared with the hypoxia group,the expression amount of pFAK was elevated in POS+hyoxia group(P<0.01).In comparison with control group,the increased pFAK expression was seen in FN,LN and collagen typeⅠtreating for 1-hour groups(P<0.05,P<0.01).Conclusion FAK pathway

  1. [Asterixis in focal brain lesions].

    Science.gov (United States)

    Velasco, F; Gomez, J C; Zarranz, J J; Lambarri, I; Ugalde, J

    2004-05-01

    Asterixis is a motor control disorder characterized by the presence of abnormal movements of the lower limbs in the vertical plane during posture maintenance. Asterixis is usually bilateral and associated with toxic-metabolic metabolic encephalopathies. Unilateral asterixis is less frequent and it normally indicates focal brain damage. We report the cases of four patients (two males/two females), aged 57 to 83 years, suffering from uni or bilateral asterixis associated with focal brain damage. All patients underwent CT brain scan and a neurophysiological study (parietal EMG and/or PES). In addition, any toxic-metabolic cause that could be produced by this clinical phenomenon was ruled out with the appropriate testing. Unilateral asterixis is a clinical symptom that may indicate the presence of focal brain damage. Often, it is ignored or overlooked during routine neurological examinations. On the other hand, the presence of a bilateral asterixis is not always indicative of a toxic-metabolic encephalopathy.Rarely, such as in one of the cases herein presented, bilateral asterixis can also appear associated with structural brain lesions. Although asterixis diagnosis is fundamentally clinical, the neurophysiological study contributes to verify the diagnosis.

  2. Focal cortical dysplasia – review

    Science.gov (United States)

    Kabat, Joanna; Król, Przemysław

    2012-01-01

    Summary Focal cortical dysplasia is a malformation of cortical development, which is the most common cause of medically refractory epilepsy in the pediatric population and the second/third most common etiology of medically intractable seizures in adults. Both genetic and acquired factors are involved in the pathogenesis of cortical dysplasia. Numerous classifications of the complex structural abnormalities of focal cortical dysplasia have been proposed – from Taylor et al. in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized. Type I focal cortical dysplasia with mild symptomatic expression and late onset, is more often seen in adults, with changes present in the temporal lobe. Clinical symptoms are more severe in type II of cortical dysplasia usually seen in children. In this type, more extensive changes occur outside the temporal lobe with predilection for the frontal lobes. New type III is one of the above dysplasias with associated another principal lesion as hippocampal sclerosis, tumor, vascular malformation or acquired pathology during early life. Brain MRI imaging shows abnormalities in the majority of type II dysplasias and in only some of type I cortical dysplasias. The most common findings on MRI imaging include: focal cortical thickening or thinning, areas of focal brain atrophy, blurring of the gray-white junction, increased signal on T2- and FLAIR-weighted images in the gray and subcortical white matter often tapering toward the ventricle. On the basis of the MRI findings, it is possible to differentiate between type I and type II cortical dysplasia. A complete resection of the epileptogenic zone is required for seizure-free life. MRI imaging is very helpful to identify those patients who are likely to benefit from surgical treatment in a group of patients with drug-resistant epilepsy. However, in type I cortical dysplasia, MR imaging is often normal, and also

  3. Differential regulation of adhesion complex turnover by ROCK1 and ROCK2.

    Directory of Open Access Journals (Sweden)

    Frances E Lock

    Full Text Available BACKGROUND: ROCK1 and ROCK2 are serine/threonine kinases that function downstream of the small GTP-binding protein RhoA. Rho signalling via ROCK regulates a number of cellular functions including organisation of the actin cytoskeleton, cell adhesion and cell migration. METHODOLOGY/PRINCIPAL FINDINGS: In this study we use RNAi to specifically knockdown ROCK1 and ROCK2 and analyse their role in assembly of adhesion complexes in human epidermal keratinocytes. We observe that loss of ROCK1 inhibits signalling via focal adhesion kinase resulting in a failure of immature adhesion complexes to form mature stable focal adhesions. In contrast, loss of ROCK2 expression results in a significant reduction in adhesion complex turnover leading to formation of large, stable focal adhesions. Interestingly, loss of either ROCK1 or ROCK2 expression significantly impairs cell migration indicating both ROCK isoforms are required for normal keratinocyte migration. CONCLUSIONS: ROCK1 and ROCK2 have distinct and separate roles in adhesion complex assembly and turnover in human epidermal keratinocytes.

  4. Cell substratum adhesion during early development of Dictyostelium discoideum.

    Directory of Open Access Journals (Sweden)

    Marco Tarantola

    Full Text Available Vegetative and developed amoebae of Dictyostelium discoideum gain traction and move rapidly on a wide range of substrata without forming focal adhesions. We used two independent assays to quantify cell-substrate adhesion in mutants and in wild-type cells as a function of development. Using a microfluidic device that generates a range of hydrodynamic shear stress, we found that substratum adhesion decreases at least 10 fold during the first 6 hr of development of wild type cells. This result was confirmed using a single-cell assay in which cells were attached to the cantilever of an atomic force probe and allowed to adhere to untreated glass surfaces before being retracted. Both of these assays showed that the decrease in substratum adhesion was dependent on the cAMP receptor CAR1 which triggers development. Vegetative cells missing talin as the result of a mutation in talA exhibited slightly reduced adhesive properties compared to vegetative wild-type cells. In sharp contrast to wild-type cells, however, these talA mutant cells did not show further reduction of adhesion during development such that after 5 hr of development they were significantly more adhesive than developed wild type cells. In addition, both assays showed that substrate adhesion was reduced in 0 hr cells when the actin cytoskeleton was disrupted by latrunculin. Consistent with previous observations, substrate adhesion was also reduced in 0 hr cells lacking the membrane proteins SadA or SibA as the result of mutations in sadA or sibA. However, there was no difference in the adhesion properties between wild type AX3 cells and these mutant cells after 6 hr of development, suggesting that neither SibA nor SadA play an essential role in substratum adhesion during aggregation. Our results provide a quantitative framework for further studies of cell substratum adhesion in Dictyostelium.

  5. PH dependent adhesive peptides

    Science.gov (United States)

    Tomich, John; Iwamoto, Takeo; Shen, Xinchun; Sun, Xiuzhi Susan

    2010-06-29

    A novel peptide adhesive motif is described that requires no receptor or cross-links to achieve maximal adhesive strength. Several peptides with different degrees of adhesive strength have been designed and synthesized using solid phase chemistries. All peptides contain a common hydrophobic core sequence flanked by positively or negatively charged amino acids sequences.

  6. Interferon Induced Focal Segmental Glomerulosclerosis

    Science.gov (United States)

    Bayram Kayar, Nuket; Alpay, Nadir; Hamdard, Jamshid; Emegil, Sebnem; Bag Soydas, Rabia; Baysal, Birol

    2016-01-01

    Behçet's disease is an inflammatory disease of unknown etiology which involves recurring oral and genital aphthous ulcers and ocular lesions as well as articular, vascular, and nervous system involvement. Focal segmental glomerulosclerosis (FSGS) is usually seen in viral infections, immune deficiency syndrome, sickle cell anemia, and hyperfiltration and secondary to interferon therapy. Here, we present a case of FSGS identified with kidney biopsy in a patient who had been diagnosed with Behçet's disease and received interferon-alpha treatment for uveitis and presented with acute renal failure and nephrotic syndrome associated with interferon. PMID:27847659

  7. Focal epithelial hyperplasia: Heck disease.

    Science.gov (United States)

    Cohen, P R; Hebert, A A; Adler-Storthz, K

    1993-09-01

    Two sisters of Mexican ancestry had focal epithelial hyperplasia (FEH). The lesions on the oral mucosa of the older child were initially misinterpreted as representing sexual abuse. Microscopic evaluation of a hematoxylin and eosin-stained section from a lower lip papule demonstrated the histologic features of FEH. Although human papillomavirus (HPV) type 13 and HPV32 have been most consistently present in FEH lesions, types 6, 11, 13, and 32 were not detected in the paraffin-embedded tissue specimen of our patient using an in situ hybridization technique. The lesions persisted or recurred during management using destructive modalities; subsequently, they completely resolved spontaneously.

  8. Focal epithelial hyperplasia (Heck's disease

    Directory of Open Access Journals (Sweden)

    Parichehr Gheliani

    2011-11-01

    Full Text Available Focal epithelial hyperplasia (Heck is a rare lesion caused by human papilloma virus subtype 13 or 32 and presents as multiple small white or pink papules on the mucosal surface of lips, buccal mucosa and tongue usually seen in children and adolescent of American Indian and Eskimo background. This disease has a genetic basis. The site of new lesions and recurrence are unpredictable. Continued follow up of the patient is often necessary. In this report, a 50-year-old woman is described with benign papillomatous lesions on dorsal surface of tongue for 15 years

  9. SNAP Satellite Focal Plane Development

    Energy Technology Data Exchange (ETDEWEB)

    Bebek, C.; Akerlof, C.; Aldering, G.; Amanullah, R.; Astier, P.; Baltay, C.; Barrelet, E.; Basa, S.; Bercovitz, J.; Bergstrom, L.; Berstein, G.P.; Bester, M.; Bohlin, R.; Bonissent, A.; Bower, C.; Campbell, M.; Carithers, W.; Commins, E.; Day, C.; Deustua, S.; DiGennaro, R.; Ealet, A.; Ellis, R.; Emmett, W.; Eriksson, M.; Fouchez,D.; Fruchter, A.; Genat, J-F.; Goldhaber, G.; Goobar, A.; Groom, D.; Heetderks, H.; Holland, S.; Huterer, D.; Johnson, W.; Kadel, R.; Karcher,A.; Kim, A.; Kolbe, W.; Lafever, R.; Lamoureaux, J.; Lampton, M.; Lefevre, O.; Levi, M.; Levin, D.; Linder, E.; Loken, S.; Malina, R.; Mazure, A.; McKay, T.; McKee, S.; Miquel, R.; Morgan, N.; Mortsell, E.; Mostek, N.; Mufson, S.; Musser, J.; Roe, N.; Nugent, P.; Oluseyi, H.; Pain, R.; Palaio, N.; Pankow, D.; Perlmutter, S.; Prieto, E.; Rabinowitz,D.; Refregier, A.; Rhodes, J.; Schubnell, M.; Sholl, M.; Smadja, G.; Smith, R.; Smoot, G.; Snyder, J.; Spadafora, A.; Szymkowiak, A.; Tarle,G.; Taylor, K.; Tilquin, A.; Tomasch, A.; Vincent, D.; von der Lippe, H.; Walder, J-P.; Wang, G.

    2003-07-07

    The proposed SuperNova/Acceleration Probe (SNAP) mission will have a two-meter class telescope delivering diffraction-limited images to an instrumented 0.7 square degree field in the visible and near-infrared wavelength regime. The requirements for the instrument suite and the present configuration of the focal plane concept are presented. A two year R&D phase, largely supported by the Department of Energy, is just beginning. We describe the development activities that are taking place to advance our preparedness for mission proposal in the areas of detectors and electronics.

  10. Understanding adhesive dentistry.

    Science.gov (United States)

    Burrow, Michael

    2010-03-01

    This review paper firstly provides an outline of the development of resin-based adhesives. A simple classification method is described based on whether an acid etching agent requiring a washing and drying step is used. These systems are called etch and rinse systems. The other adhesives that do not have the washing and drying steps are referred to as self-etching adhesives. The advantages and disadvantages of these groups of adhesives are discussed. Methods of adhering to the tooth surface are provided, especially where the resin-based adhesive reliability is difficult to control.

  11. Particle adhesion and removal

    CERN Document Server

    Mittal, K L

    2015-01-01

    The book provides a comprehensive and easily accessible reference source covering all important aspects of particle adhesion and removal.  The core objective is to cover both fundamental and applied aspects of particle adhesion and removal with emphasis on recent developments.  Among the topics to be covered include: 1. Fundamentals of surface forces in particle adhesion and removal.2. Mechanisms of particle adhesion and removal.3. Experimental methods (e.g. AFM, SFA,SFM,IFM, etc.) to understand  particle-particle and particle-substrate interactions.4. Mechanics of adhesion of micro- and  n

  12. Thermography Examination of Abdominal Area Skin Temperatures in Individuals With and Without Focal-Onset Epilepsy.

    Science.gov (United States)

    King, Hollis H; Cayce, Charles Thomas; Herrin, Jeph

    Early osteopathic theory and practice, and the work of the medical intuitive Edgar Cayce suggested that the abdominal areas of individuals with epilepsy would manifest "cold spots." The etiology for this phenomenon was thought to be abdominal adhesions caused by inflammation and viscero-somatic reflexes caused by adhesions or injury to visceral or musculoskeletal system structures. Indeed, until that advent of electroencephalography in the 1930s, medical practice regarding epilepsy focused on abdominal neural and visceral structures. Following two hypotheses were formulated to evaluate any abdominal temperature phenomena: (1) an abdominal quadrant division analysis would find one or more quadrants "colder" in the focal-onset epilepsy group (ICD9-CM 345.4 and 345.5) compared to controls. (2) Total abdominal areas of individuals with focal-onset epilepsy wound be colder than a control group.

  13. Multi-focal multiphoton lithography.

    Science.gov (United States)

    Ritschdorff, Eric T; Nielson, Rex; Shear, Jason B

    2012-03-01

    Multiphoton lithography (MPL) provides unparalleled capabilities for creating high-resolution, three-dimensional (3D) materials from a broad spectrum of building blocks and with few limitations on geometry, qualities that have been key to the design of chemically, mechanically, and biologically functional microforms. Unfortunately, the reliance of MPL on laser scanning limits the speed at which fabrication can be performed, making it impractical in many instances to produce large-scale, high-resolution objects such as complex micromachines, 3D microfluidics, etc. Previously, others have demonstrated the possibility of using multiple laser foci to simultaneously perform MPL at numerous sites in parallel, but use of a stage-scanning system to specify fabrication coordinates resulted in the production of identical features at each focal position. As a more general solution to the bottleneck problem, we demonstrate here the feasibility for performing multi-focal MPL using a dynamic mask to differentially modulate foci, an approach that enables each fabrication site to create independent (uncorrelated) features within a larger, integrated microform. In this proof-of-concept study, two simultaneously scanned foci produced the expected two-fold decrease in fabrication time, and this approach could be readily extended to many scanning foci by using a more powerful laser. Finally, we show that use of multiple foci in MPL can be exploited to assign heterogeneous properties (such as differential swelling) to micromaterials at distinct positions within a fabrication zone.

  14. Polymeric flat focal field arrayed waveguide grating using electron-beam direct wiring

    Institute of Scientific and Technical Information of China (English)

    Si Lu(陆思); Yingbai Yan(严瑛白); Guofan Jin(金国藩); W.H.Wong(黄咏娴); E.Y.B.Pun(潘裕斌)

    2004-01-01

    A four-channel 400-GHz spacing flat focal field arrayed waveguide grating (AWG) demultiplexer is designed based on polymeric optical waveguide. The waveguide core-layer material is a newly developed negative tone epoxy Novolak resin (ENR) polymer with ultravoilet (UV) cured resin Norland optical adhesive 61(NOA61) as the cladding layer. The device is fabricated using electron-beam direct writing, which has less processing steps than the reported polymeric AWGs. The experimental result is presented.

  15. RF/Optical Demonstration: Focal Plane Assembly

    Science.gov (United States)

    Hoppe, D. J.; Chung, S.; Kovalik, J.; Gama, E.; Fernandez, M. M.

    2016-11-01

    In this article, we describe the second-generation focal plane optical assembly employed in the RF/optical demonstration at DSS-13. This assembly receives reflected light from the two mirror segments mounted on the RF primary. The focal plane assembly contains a fast steering mirror (FSM) to stabilize the focal plane spot, a pupil camera to aid in aligning the two segments, and several additional cameras for receiving the optical signal prior to as well as after the FSM loop.

  16. Periodontitis in patients with focal tuberculosis

    Directory of Open Access Journals (Sweden)

    Alexandrova Е.А.

    2010-12-01

    Full Text Available The research goal is to investigate the mechanisms of formation and peculiarities of periodontitis in patients with focal tuberculosis. Patients with periodontitis and focal tuberculosis are proved to develop local inflammatory reaction with increased infection and activation of proinflammatory cytokines in parodontal pockets fluid. The main risk factor of frequent and durable recurrence of parodontal pathology in case of focal tuberculosis was the development of pathologic process as a cause of disbalance of lipid peroxidation and antioxidant system, endotoxicosis syndrome

  17. Focal properties of geodesic waveguide lenses

    Science.gov (United States)

    Verber, C. M.; Vahey, D. W.; Wood, V. E.

    1976-01-01

    The focal properties of uncorrected geodesic lenses in ion-exchanged glass waveguides are reported. A 13.8-mm-focal-length lens resolved beams with an angular separation of 27.6 mrad, while a 28-mm-focal-length lens resolved beams with an angular separation of only 3.3 mrad. Intensity profiles of the focal region of the former lens revealed a 40-micron spot size when the input aperture was 5 mm, and a spot size of 7.7 microns when the aperture was reduced to 1 mm. This value is close to the diffraction-limited spot size of 5.7 microns.

  18. Large Format Uncooled Focal Plane Array Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Black Forest Engineering has identified innovative modifications in uncooled focal plane array (UFPA) architecture and processing that allows development of large...

  19. Focal epithelial hyperplasia - an update.

    Science.gov (United States)

    Said, Ahmed K; Leao, Jair C; Fedele, Stefano; Porter, Stephen R

    2013-07-01

    Focal epithelial hyperplasia (FEH) is an asymptomatic benign mucosal disease, which is mostly observed in specific groups in certain geographical regions. FEH is usually a disease of childhood and adolescence and is generally associated with people who live in poverty and of low socioeconomic status. Clinically, FEH is typically characterized by multiple, painless, soft, sessile papules, plaques or nodules, which may coalesce to give rise to larger lesions. Human papillomavirus (HPV), especially genotypes 13 and 32, have been associated and detected in the majority of FEH lesions. The clinical examination and social history often allow diagnosis, but histopathological examination of lesional tissue is usually required to confirm the exact diagnosis. FEH sometimes resolves spontaneously however, treatment is often indicated as a consequence of aesthetic effects or any interference with occlusion. There remains no specific therapy for FEH, although surgical removal, laser excision or possibly topical antiviral agents may be of benefit. There remains no evidence that FEH is potentially malignant.

  20. Focal fatty infiltra- tion and focal fatty sparing of the liver

    African Journals Online (AJOL)

    Enrique

    Focal fatty infiltration of the liver is caused by focal ... has also been described in children.1. The most common cause is alcohol abuse, although diabetes, obesity, cer- tain drugs, toxins ... infiltration was not initially consid- ered are reported.

  1. Adhesives, silver amalgam.

    Science.gov (United States)

    1995-09-01

    The most recent advancement in silver amalgam is use of resin formulations to bond metal to tooth both chemically &/or physically, Since, historically, amalgam has been used successfully without adhesion to tooth, obvious clinical question is: Why is bonding now desirable? Two major clinical reasons to bond are: (1) Adhesive can increase fracture resistance of amalgam restored teeth & decrease cusp fractures; & (2) Seal provided by adhesive can greatly decrease, & often eliminate post-operative sensitivity. Following report summarizes CRA laboratory study of shear bond strength & sealing capability of 23 commercial adhesives used to bond 2 types of silver amalgam to tooth structure.

  2. More automation, more adhesives

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, Jens-Peter

    2012-07-01

    Although aluminium has become established as an absorber plate material, it is still seldom used for piping. Moreover, adhesive processes are becoming increasingly important in collector production. (orig.)

  3. Reversible Thermoset Adhesives

    Science.gov (United States)

    Mac Murray, Benjamin C. (Inventor); Tong, Tat H. (Inventor); Hreha, Richard D. (Inventor)

    2016-01-01

    Embodiments of a reversible thermoset adhesive formed by incorporating thermally-reversible cross-linking units and a method for making the reversible thermoset adhesive are provided. One approach to formulating reversible thermoset adhesives includes incorporating dienes, such as furans, and dienophiles, such as maleimides, into a polymer network as reversible covalent cross-links using Diels Alder cross-link formation between the diene and dienophile. The chemical components may be selected based on their compatibility with adhesive chemistry as well as their ability to undergo controlled, reversible cross-linking chemistry.

  4. Electro-dry-adhesion.

    Science.gov (United States)

    Krahn, Jeffrey; Menon, Carlo

    2012-03-27

    This work presents novel conductive bioinspired dry adhesives with mushroom caps that enable the use of a synergistic combination of electrostatic and van der Waals forces (electro-dry-adhesion). An increase in shear adhesion bond strength of up to 2046% on a wide range of materials is measured when a maximum electrical field of 36.4 V μm(-1) is applied. A suction effect, due to the shape of the dry adhesive fibers, on overall adhesion was not noted for electro-dry-adhesives when testing was performed at both atmospheric and reduced pressure. Utilization of electrostatics to apply a preloading force to dry adhesive fiber arrays allows increased adhesion even after electrostatic force generation has been halted by ensuring the close contact necessary for van der Waals forces to be effective. A comparison is made between self-preloading of the electro-dry-adhesives and the direct application of a normal preloading pressure resulting in nearly the same shear bond strength with an applied voltage of 3.33 kV on the same sample.

  5. Integrin activation and focal complex formation in cardiac hypertrophy

    Science.gov (United States)

    Laser, M.; Willey, C. D.; Jiang, W.; Cooper, G. 4th; Menick, D. R.; Zile, M. R.; Kuppuswamy, D.

    2000-01-01

    Cardiac hypertrophy is characterized by both remodeling of the extracellular matrix (ECM) and hypertrophic growth of the cardiocytes. Here we show increased expression and cytoskeletal association of the ECM proteins fibronectin and vitronectin in pressure-overloaded feline myocardium. These changes are accompanied by cytoskeletal binding and phosphorylation of focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, c-Src at Tyr-416, recruitment of the adapter proteins p130(Cas), Shc, and Nck, and activation of the extracellular-regulated kinases ERK1/2. A synthetic peptide containing the Arg-Gly-Asp (RGD) motif of fibronectin and vitronectin was used to stimulate adult feline cardiomyocytes cultured on laminin or within a type-I collagen matrix. Whereas cardiocytes under both conditions showed RGD-stimulated ERK1/2 activation, only collagen-embedded cells exhibited cytoskeletal assembly of FAK, c-Src, Nck, and Shc. In RGD-stimulated collagen-embedded cells, FAK was phosphorylated only at Tyr-397 and c-Src association occurred without Tyr-416 phosphorylation and p130(Cas) association. Therefore, c-Src activation is not required for its cytoskeletal binding but may be important for additional phosphorylation of FAK. Overall, our study suggests that multiple signaling pathways originate in pressure-overloaded heart following integrin engagement with ECM proteins, including focal complex formation and ERK1/2 activation, and many of these pathways can be activated in cardiomyocytes via RGD-stimulated integrin activation.

  6. Integrin activation and focal complex formation in cardiac hypertrophy

    Science.gov (United States)

    Laser, M.; Willey, C. D.; Jiang, W.; Cooper, G. 4th; Menick, D. R.; Zile, M. R.; Kuppuswamy, D.

    2000-01-01

    Cardiac hypertrophy is characterized by both remodeling of the extracellular matrix (ECM) and hypertrophic growth of the cardiocytes. Here we show increased expression and cytoskeletal association of the ECM proteins fibronectin and vitronectin in pressure-overloaded feline myocardium. These changes are accompanied by cytoskeletal binding and phosphorylation of focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, c-Src at Tyr-416, recruitment of the adapter proteins p130(Cas), Shc, and Nck, and activation of the extracellular-regulated kinases ERK1/2. A synthetic peptide containing the Arg-Gly-Asp (RGD) motif of fibronectin and vitronectin was used to stimulate adult feline cardiomyocytes cultured on laminin or within a type-I collagen matrix. Whereas cardiocytes under both conditions showed RGD-stimulated ERK1/2 activation, only collagen-embedded cells exhibited cytoskeletal assembly of FAK, c-Src, Nck, and Shc. In RGD-stimulated collagen-embedded cells, FAK was phosphorylated only at Tyr-397 and c-Src association occurred without Tyr-416 phosphorylation and p130(Cas) association. Therefore, c-Src activation is not required for its cytoskeletal binding but may be important for additional phosphorylation of FAK. Overall, our study suggests that multiple signaling pathways originate in pressure-overloaded heart following integrin engagement with ECM proteins, including focal complex formation and ERK1/2 activation, and many of these pathways can be activated in cardiomyocytes via RGD-stimulated integrin activation.

  7. Fast & Furious focal-plane wavefront sensing

    NARCIS (Netherlands)

    Korkiakoski, V.A.; Keller, C.U.; Doelman, N.; Kenworthy, M.; Otten, G.; Verhaegen, M.H.G.

    2014-01-01

    We present two complementary algorithms suitable for using focal-plane measurements to control a wavefront corrector with an extremely high-spatial resolution. The algorithms use linear approximations to iteratively minimize the aberrations seen by the focal-plane camera. The first algorithm, Fast &

  8. Focal-plane sensor-processor chips

    CERN Document Server

    Zarándy, Ákos

    2011-01-01

    Focal-Plane Sensor-Processor Chips explores both the implementation and application of state-of-the-art vision chips. Presenting an overview of focal plane chip technology, the text discusses smart imagers and cellular wave computers, along with numerous examples of current vision chips.

  9. Soy protein adhesives

    Science.gov (United States)

    Charles R. Frihart

    2010-01-01

    In the quest to manufacture and use building materials that are more environmentally friendly, soy adhesives can be an important component. Trees fix and store carbon dioxide in the atmosphere. After the trees are harvested, machinery converts the wood into strands, which are then bonded together with adhesives to form strandboard, used in constructing long-lasting...

  10. Instant acting adhesive system

    Science.gov (United States)

    Davis, T. R.; Haines, R. C.

    1971-01-01

    Adhesive developes 80 percent of minimum bond strength of 250 psi less than 30 sec after activation is required. Adhesive is stable, handles easily, is a low toxic hazard, and is useful in industrial and domestic prototype bonding and clamping operations.

  11. Focal brain inflammation and autism.

    Science.gov (United States)

    Theoharides, Theoharis C; Asadi, Shahrzad; Patel, Arti B

    2013-04-09

    Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Autism spectrum disorders (ASD) are characterized by social and learning disabilities that affect as many as 1/80 children in the USA. There is still no definitive pathogenesis or reliable biomarkers for ASD, thus significantly curtailing the development of effective therapies. Many children with ASD regress at about age 3 years, often after a specific event such as reaction to vaccination, infection, stress or trauma implying some epigenetic triggers, and may constitute a distinct phenotype. ASD children respond disproportionally to stress and are also affected by food and skin allergies. Corticotropin-releasing hormone (CRH) is secreted under stress and together with neurotensin (NT) stimulates mast cells and microglia resulting in focal brain inflammation and neurotoxicity. NT is significantly increased in serum of ASD children along with mitochondrial DNA (mtDNA). NT stimulates mast cell secretion of mtDNA that is misconstrued as an innate pathogen triggering an auto-inflammatory response. The phosphatase and tensin homolog (PTEN) gene mutation, associated with the higher risk of ASD, which leads to hyper-active mammalian target of rapamycin (mTOR) signalling that is crucial for cellular homeostasis. CRH, NT and environmental triggers could hyperstimulate the already activated mTOR, as well as stimulate mast cell and microglia activation and proliferation. The natural flavonoid luteolin inhibits mTOR, mast cells and microglia and could have a significant benefit in ASD.

  12. Focal Plane Instrumentation of VERITAS

    CERN Document Server

    Nagai, T; Sleege, G; Petry, D

    2007-01-01

    VERITAS is a new atmospheric Cherenkov imaging telescope array to detect very high energy gamma rays above 100 GeV. The array is located in southern Arizona, USA, at an altitude of 1268m above sea level. The array consists of four 12-m telescopes of Davies-Cotton design and structurally resembling the Whipple 10-m telescope. The four focal plane instruments are equipped with high-resolution (499 pixels) fast photo-multiplier-tube (PMT) cameras covering a 3.5 degree field of view with 0.15 degree pixel separation. Light concentrators reduce the dead-space between PMTs to 25% and shield the PMTs from ambient light. The PMTs are connected to high-speed preamplifiers allowing operation at modest anode current and giving good single photoelectron peaks in situ. Electronics in the focus box provides real-time monitoring of the anode currents for each pixel and ambient environmental conditions. A charge injection subsystem installed in the focus box allows daytime testing of the trigger and data acquisition system b...

  13. Early vision and focal attention

    Science.gov (United States)

    Julesz, Bela

    1991-07-01

    At the thirty-year anniversary of the introduction of the technique of computer-generated random-dot stereograms and random-dot cinematograms into psychology, the impact of the technique on brain research and on the study of artificial intelligence is reviewed. The main finding-that stereoscopic depth perception (stereopsis), motion perception, and preattentive texture discrimination are basically bottom-up processes, which occur without the help of the top-down processes of cognition and semantic memory-greatly simplifies the study of these processes of early vision and permits the linking of human perception with monkey neurophysiology. Particularly interesting are the unexpected findings that stereopsis (assumed to be local) is a global process, while texture discrimination (assumed to be a global process, governed by statistics) is local, based on some conspicuous local features (textons). It is shown that the top-down process of "shape (depth) from shading" does not affect stereopsis, and some of the models of machine vision are evaluated. The asymmetry effect of human texture discrimination is discussed, together with recent nonlinear spatial filter models and a novel extension of the texton theory that can cope with the asymmetry problem. This didactic review attempts to introduce the physicist to the field of psychobiology and its problems-including metascientific problems of brain research, problems of scientific creativity, the state of artificial intelligence research (including connectionist neural networks) aimed at modeling brain activity, and the fundamental role of focal attention in mental events.

  14. Focal liver lesions found incidentally

    Institute of Scientific and Technical Information of China (English)

    Abdullah; A; Algarni; Abdullah; H; Alshuhri; Majed; M; Alonazi; Moustafa; Mabrouk; Mourad; Simon; R; Bramhal

    2016-01-01

    Incidentally found focal liver lesions are a commonfinding and a reason for referral to hepatobiliary service.They are often discovered in patients with history of liver cirrhosis,colorectal cancer,incidentally during work up for abdominal pain or in a trauma setting.Specific points should considered during history taking such as risk factors of liver cirrhosis;hepatitis,alcohol consumption,substance exposure or use of oral con-traceptive pills and metabolic syndromes.Full blood count,liver function test and tumor markers can act as a guide to minimize the differential diagnosis and to categorize the degree of liver disease.Imaging should start with B-mode ultrasound.If available,contrast enhanced ultrasound is a feasible,safe,cost effective option and increases the ability to reach a diagnosis.Contrast enhanced computed tomography should be considered next.It is more accurate in diagnosis and better to study anatomy for possible operation.Contrast enhanced magnetic resonance is the gold standard with the highest sensitivity.If doubt still remains,the options are biopsy or surgical excision.

  15. Tissue adhesives in otorhinolaryngology

    Directory of Open Access Journals (Sweden)

    Schneider, Gerlind

    2009-01-01

    Full Text Available The development of medical tissue adhesives has a long history without finding an all-purpose tissue adhesive for clinical daily routine. This is caused by the specific demands which are made on a tissue adhesive, and the different areas of application. In otorhinolaryngology, on the one hand, this is the mucosal environment as well as the application on bones, cartilage and periphery nerves. On the other hand, there are stressed regions (skin, oral cavity, pharynx, oesophagus, trachea and unstressed regions (middle ear, nose and paranasal sinuses, cranial bones. But due to the facts that adhesives can have considerable advantages in assuring surgery results, prevention of complications and so reduction of medical costs/treatment expenses, the search for new adhesives for use in otorhinolaryngology will be continued intensively. In parallel, appropriate application systems have to be developed for microscopic and endoscopic use.

  16. Prevention of bacterial adhesion

    DEFF Research Database (Denmark)

    Klemm, Per; Vejborg, Rebecca Munk; Hancock, Viktoria

    2010-01-01

    Management of bacterial infections is becoming increasingly difficult due to the emergence and increasing prevalence of bacterial pathogens that are resistant to available antibiotics. Conventional antibiotics generally kill bacteria by interfering with vital cellular functions, an approach...... that imposes selection pressure for resistant bacteria. New approaches are urgently needed. Targeting bacterial virulence functions directly is an attractive alternative. An obvious target is bacterial adhesion. Bacterial adhesion to surfaces is the first step in colonization, invasion, and biofilm formation....... As such, adhesion represents the Achilles heel of crucial pathogenic functions. It follows that interference with adhesion can reduce bacterial virulence. Here, we illustrate this important topic with examples of techniques being developed that can inhibit bacterial adhesion. Some of these will become...

  17. Effects of Alcohol on Postoperative Adhesion Formation in Ischemic Myocardium and Pericardium.

    Science.gov (United States)

    Elmadhun, Nassrene Y; Sabe, Ashraf A; Lassaletta, Antonio D; Dalal, Rahul S; Sellke, Frank W

    2017-08-01

    Postoperative formation of adhesions increases risk of complications during cardiac reoperations. We previously demonstrated that swine supplemented with vodka had a significant reduction in adhesions at sternotomy after previous thoracotomy. This follow-up study was conducted to determine reproducibility and the mechanism for adhesion reduction in swine supplemented with ethanol. An ameroid constrictor was placed in the left circumflex in 14 male Yorkshire swine to induce chronic myocardial ischemia through left minithoracotomy. Animals were supplemented postoperatively with ethanol (45 g ETOH, n = 7) or sucrose (80 g SUC, n = 7) for 7 weeks, followed by a reoperative median sternotomy. The ETOH group had significantly fewer adhesions, thinner pericardial thickness, decreased intramyocardial fibrosis, and decreased myocardial collagen deposition compared with the SUC group. In the myocardium, ETOH animals had decreased expression of proadhesion proteins focal adhesion kinase, paxillin, integrin-β1, transforming growth factor-β1 and phosphorylated SMAD and increased expression of adhesion breakdown proteins matrix metalloproteinase (MMP) 1, MMP2, MMP3, and MMP9 compared with SUC animals. However in the pericardium, ETOH animals had increased expression of proadhesion proteins focal adhesion kinase, paxillin, phosphorylated paxillin, vinculin, integrin-β1, tumor necrosis factor-α, transforming growth factor-β, and phosphorylated SMAD3, and decreased expression of adhesion breakdown proteins MMP1, MMP3, MMP9, and plasmin compared with SUC animals. Alcohol supplementation substantially reduced postoperative pericardial adhesion formation, attenuated pericardial thickening, and reduced myocardial fibrosis in response to chronic ischemia. Alcohol supplementation modulates adhesion protein and MMP/tissue inhibitor of metalloproteinase expression, favoring a profile associated with reduced pericardial adhesions. These results suggest that the myocardium is the

  18. The Role of the Composition of Adhesive Systems on Adhesive System-Tooth Surface Adhesion

    National Research Council Canada - National Science Library

    Yeliz GÜVEN; Oya AKTÖREN

    2014-01-01

    .... Keeping an updated knowledge of the composition, characteristics and mechanisms of adhesion of the currently available adhesive systems as well as knowing how the dental substrates interact with...

  19. [Endothelial cell adhesion molecules].

    Science.gov (United States)

    Ivanov, A N; Norkin, I A; Puchin'ian, D M; Shirokov, V Iu; Zhdanova, O Iu

    2014-01-01

    The review presents current data concerning the functional role of endothelial cell adhesion molecules belonging to different structural families: integrins, selectins, cadherins, and the immunoglobulin super-family. In this manuscript the regulatory mechanisms and factors of adhesion molecules expression and distribution on the surface of endothelial cells are discussed. The data presented reveal the importance of adhesion molecules in the regulation of structural and functional state of endothelial cells in normal conditions and in pathology. Particular attention is paid to the importance of these molecules in the processes of physiological and pathological angiogenesis, regulation of permeability of the endothelial barrier and cell transmigration.

  20. Lactobacillus Adhesion to Mucus

    Directory of Open Access Journals (Sweden)

    Maxwell L. Van Tassell

    2011-05-01

    Full Text Available Mucus provides protective functions in the gastrointestinal tract and plays an important role in the adhesion of microorganisms to host surfaces. Mucin glycoproteins polymerize, forming a framework to which certain microbial populations can adhere, including probiotic Lactobacillus species. Numerous mechanisms for adhesion to mucus have been discovered in lactobacilli, including partially characterized mucus binding proteins. These mechanisms vary in importance with the in vitro models studied, which could significantly affect the perceived probiotic potential of the organisms. Understanding the nature of mucus-microbe interactions could be the key to elucidating the mechanisms of probiotic adhesion within the host.

  1. Large Format Uncooled Focal Plane Array Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Uncooled focal plane arrays have improved dramatically and array sizes of 320x240 elements in a 50-?m pitch are commercially available at affordable cost. Black...

  2. Focal skin defect, limb anomalies and microphthalmia.

    NARCIS (Netherlands)

    Jackson, K.E.; Andersson, H.C.

    2004-01-01

    We describe two unrelated female patients with congenital single focal skin defects, unilateral microphthalmia and limb anomalies. Growth and psychomotor development were normal and no brain malformation was detected. Although eye and limb anomalies are commonly associated, clinical anophthalmia and

  3. Snake beam: a paraxial arbitrary focal line

    OpenAIRE

    Rosen, Joseph; Yariv, Amnon

    1995-01-01

    The creation of paraxial arbitrary focal lines by a Fourier computer-generated hologram is demonstrated. The desired focal line is represented by a series of connected straight line segments, each of which is implemented by a radial harmonic function located on a different radial portion of the entire hologram. Each subhologram is multiplied by appropriate linear and quadratic phase functions and is shifted by some distance from the center. The two phase factors determine the location of each...

  4. An uncommon focal epithelial hyperplasia manifestation.

    Science.gov (United States)

    dos Santos-Pinto, Lourdes; Giro, Elisa Maria Aparecida; Pansani, Cyneu Aguiar; Ferrari, Junia; Massucato, Elaine Maria Sgavioli; Spolidório, Luis Carlos

    2009-01-01

    Focal epithelial hyperplasia is a rare, contagious disease associated with infection of the oral mucosa by human papillomavirus types 13 or 32, characterized by multiple soft papules of the same color as the adjacent normal mucosa. It mainly affects the lower lip, buccal mucosa, and tongue. The purpose of this case report was to describe a rare verrucal lesion located in the upper gingiva that was clinically and histologically consistent with focal epithelial hyperplasia.

  5. Cell adhesion property of cathodic arc plasma deposited CrN thin film

    Science.gov (United States)

    Kim, Sun Kyu; Pham, Vuong Hung

    2009-09-01

    The interaction between human osteoblast cells and CrN thin film was studied in vitro. CrN thin films were produced by cathodic arc plasma deposition. The surface was characterized by atomic force microscopy. Cell adhesion on the coatings was assessed by MTT assay and visualization. Cell cytoskeleton organization was studied by analyzing microtubule and actin cytoskeleton organization. Focal contact adhesion was monitored by analyzing vinculin density. The study found that the CrN thin film is a potential candidate as a protective coating on implantable devices that require minimal cellular adhesion.

  6. Prolactin stimulates integrin-mediated adhesion of circulating mononuclear cells to endothelial cells.

    Science.gov (United States)

    Montes de Oca, Pável; Macotela, Yazmín; Nava, Gabriel; López-Barrera, Fernando; de la Escalera, Gonzalo Martínez; Clapp, Carmen

    2005-05-01

    Attachment of leukocytes to endothelial cells is an essential step for the extravasation and recruitment of cells at sites of inflammation. The pituitary hormone prolactin (PRL) is involved in the inflammatory process. Here, we show that treatment with PRL of human peripheral blood mononuclear cells (PBMC) stimulates their adhesion to human umbilical vein endothelial cells (HUVEC) activated by interleukin-1beta. Stimulation of adhesion by PRL is mediated via integrins leukocyte functional antigen-1 (LFA-1) and very late antigen-4 (VLA-4), because immunoneutralization of both integrins prevents PRL action. Also, PRL promotes the adhesion of PBMC to immobilized intercellular adhesion molecule-1 and fibronectin, ligands for LFA-1 and VLA-4, respectively. Stimulation of integrin-mediated cell adhesion by PRL may involve the activation of chemokine receptors, because PRL upregulates the expression of the G-protein-coupled chemokine receptor CXCR3 in PBMC, and pertussis toxin, a specific G-protein inhibitor, blocks PRL stimulation of PBMC adhesion to HUVEC. In addition, PRL stimulates tyrosine phosphorylation pathways leading to leukocyte adhesion. PRL triggered the tyrosine phosphorylation of Janus kinase-2, of signal transducer and activator of transcription-3 and 5, and of the focal adhesion protein paxillin. Furthermore, genistein, a tyrosine kinase inhibitor, blocked PRL-stimulated adhesion of PBMC and Jurkat T-cells to HUVEC. These results suggest that PRL promotes integrin-mediated leukocyte adhesion to endothelial cells via chemokine receptors and tyrosine phosphorylation signaling pathways.

  7. Cohesion and Adhesion with Proteins

    Science.gov (United States)

    Charles R. Frihart

    2016-01-01

    With increasing interest in bio-based adhesives, research on proteins has expanded because historically they have been used by both nature and humans as adhesives. A wide variety of proteins have been used as wood adhesives. Ancient Egyptians most likely used collagens tobond veneer to wood furniture, then came casein (milk), blood, fish scales, and soy adhesives, with...

  8. Adhesion to porcelain and metal.

    Science.gov (United States)

    Bertolotti, Raymond L

    2007-04-01

    Some compelling clinical benefits of porcelain and metal adhesion are presented. Current concepts for metal adhesion are reviewed, including modifications of metal surface and resin chemistry. Porcelain adhesion is reviewed, including little-known methods that use silane but no hydrofluoric acid etching. Clinical protocols for use of metal and porcelain adhesives are presented.

  9. Bioinspired pressure actuated adhesive system

    NARCIS (Netherlands)

    Paretkar, D.R.; Kamperman, M.M.G.; Schneider, A.S.; Martina, D.; Creton, C.; Arzt, E.

    2011-01-01

    We developed a dry synthetic adhesive system inspired by gecko feet adhesion that can switch reversibly from adhesion to non-adhesion with applied pressure as external stimulus. Micropatterned polydimethylsiloxane (PDMS) surfaces with pillars of 30 µm length and 10 µm diameter were fabricated using

  10. Bioinspired pressure actuated adhesive system

    NARCIS (Netherlands)

    Paretkar, D.R.; Kamperman, M.M.G.; Schneider, A.S.; Martina, D.; Creton, C.; Arzt, E.

    2011-01-01

    We developed a dry synthetic adhesive system inspired by gecko feet adhesion that can switch reversibly from adhesion to non-adhesion with applied pressure as external stimulus. Micropatterned polydimethylsiloxane (PDMS) surfaces with pillars of 30 µm length and 10 µm diameter were fabricated using

  11. Sighting optics including an optical element having a first focal length and a second focal length

    Science.gov (United States)

    Crandall, David Lynn

    2011-08-01

    One embodiment of sighting optics according to the teachings provided herein may include a front sight and a rear sight positioned in spaced-apart relation. The rear sight includes an optical element having a first focal length and a second focal length. The first focal length is selected so that it is about equal to a distance separating the optical element and the front sight and the second focal length is selected so that it is about equal to a target distance. The optical element thus brings into simultaneous focus, for a user, images of the front sight and the target.

  12. Alpha9beta1 integrin in melanoma cells can signal different adhesion states for migration and anchorage

    DEFF Research Database (Denmark)

    Lydolph, Magnus C; Morgan-Fisher, Marie; Høye, Anette M

    2009-01-01

    Cell surface integrins are the primary receptors for cell migration on extracellular matrix, and exist in several activation states regulated in part by ectodomain conformation. The alpha9 integrin subunit, which pairs only with beta1, has specific roles in the immune system and may regulate cell...... migration. Melanoma cells express abundant alpha9beta1 integrin, and its role in cell migration was assessed. Ligands derived from Tenascin-C and ADAM12 supported alpha9beta1 integrin-mediated cell attachment and GTP-Rac dependent migration, but not focal adhesion formation. Manganese ions induced alpha9......beta1 integrin- and Rho kinase-dependent focal adhesion and stress fibre formation, suggesting that the activation status of alpha9beta1 integrin was altered. The effect of manganese ions in promoting focal adhesion formation was reproduced by beta1 integrin activating antibody. The alpha9beta1...

  13. A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes.

    Science.gov (United States)

    Smith, Andrew; Carrasco, Yolanda R; Stanley, Paula; Kieffer, Nelly; Batista, Facundo D; Hogg, Nancy

    2005-07-01

    Cells such as fibroblasts and endothelial cells migrate through the coordinated responses of discrete integrin-containing focal adhesions and complexes. In contrast, little is known about the organization of integrins on the highly motile T lymphocyte. We have investigated the distribution, activity, and cytoskeletal linkage of the integrin lymphocyte function associated antigen-1 (LFA-1) on human T lymphocytes migrating on endothelial cells and on ligand intercellular adhesion molecule-1 (ICAM-1). The pattern of total LFA-1 varies from low expression in the lamellipodia to high expression in the uropod. However, high affinity, clustered LFA-1 is restricted to a mid-cell zone that remains stable over time and over a range of ICAM-1 densities. Talin is essential for the stability and formation of the LFA-1 zone. Disruption of the talin-integrin link leads to loss of zone integrity and a substantial decrease in speed of migration on ICAM-1. This adhesive structure, which differs from the previously described integrin-containing attachments displayed by many other cell types, we have termed the "focal zone."

  14. Integrin-Matrix Clusters Form Podosome-like Adhesions in the Absence of Traction Forces

    Directory of Open Access Journals (Sweden)

    Cheng-han Yu

    2013-12-01

    Full Text Available Matrix-activated integrins can form different adhesion structures. We report that nontransformed fibroblasts develop podosome-like adhesions when spread on fluid Arg-Gly-Asp peptide (RGD-lipid surfaces, whereas they habitually form focal adhesions on rigid RGD glass surfaces. Similar to classic macrophage podosomes, the podosome-like adhesions are protrusive and characterized by doughnut-shaped RGD rings that surround characteristic core components including F-actin, N-WASP, and Arp2/Arp3. Furthermore, there are 18 podosome markers in these adhesions, though they lack matrix metalloproteinases that characterize invadopodia and podosomes of Src-transformed cells. When nontransformed cells develop force on integrin-RGD clusters by pulling RGD lipids to prefabricated rigid barriers (metal lines spaced by 1–2 μm, these podosomes fail to form and instead form focal adhesions. The formation of podosomes on fluid surfaces is mediated by local activation of phosphoinositide 3-kinase (PI3K and the production of phosphatidylinositol-(3,4,5-triphosphate (PIP3 in a FAK/PYK2-dependent manner. Enrichment of PIP3 precedes N-WASP activation and the recruitment of RhoA-GAP ARAP3. We propose that adhesion structures can be modulated by traction force development and that production of PIP3 stimulates podosome formation and subsequent RhoA downregulation in the absence of traction force.

  15. Amygdalin influences bladder cancer cell adhesion and invasion in vitro.

    Science.gov (United States)

    Makarević, Jasmina; Rutz, Jochen; Juengel, Eva; Kaulfuss, Silke; Tsaur, Igor; Nelson, Karen; Pfitzenmaier, Jesco; Haferkamp, Axel; Blaheta, Roman A

    2014-01-01

    The cyanogenic diglucoside amygdalin, derived from Rosaceae kernels, is employed by many patients as an alternative anti-cancer treatment. However, whether amygdalin indeed acts as an anti-tumor agent is not clear. Metastasis blocking properties of amygdalin on bladder cancer cell lines was, therefore, investigated. Amygdalin (10 mg/ml) was applied to UMUC-3, TCCSUP or RT112 bladder cancer cells for 24 h or for 2 weeks. Tumor cell adhesion to vascular endothelium or to immobilized collagen as well as tumor cell migration was examined. Effects of drug treatment on integrin α and β subtypes, on integrin-linked kinase (ILK) and total and activated focal adhesion kinase (FAK) were also determined. Integrin knock-down was carried out to evaluate integrin influence on migration and adhesion. A 24 h or 2 week amygdalin application distinctly reduced tumor cell adhesion and migration of UMUC-3 and RT112 cells. TCCSUP adhesion was also reduced, but migration was elevated under amygdalin. Integrin subtype expression was significantly and specifically altered by amygdalin depending on the cell line. ILK was moderately, and activated FAK strongly, lost in all tumor cell lines in the presence of amygdalin. Knock down of β1 integrin caused a significant decrease in both adhesion and migration of UMUC-3 cells, but a significant increase in TCCSUP adhesion. Knock down of β4 integrin caused a significant decrease in migration of RT112 cells. Since the different actions of amygdalin on the different cell lines was mirrored by β1 or β4 knock down, it is postulated that amygdalin influences adhesion and migratory properties of bladder cancer cells by modulating β1 or β4 integrin expression. The amygdalin induced increase in TCCSUP migratory behavior indicates that any anti-tumor benefits from amygdalin (seen with the other two cell lines) may depend upon the cancer cell type.

  16. Amygdalin influences bladder cancer cell adhesion and invasion in vitro.

    Directory of Open Access Journals (Sweden)

    Jasmina Makarević

    Full Text Available The cyanogenic diglucoside amygdalin, derived from Rosaceae kernels, is employed by many patients as an alternative anti-cancer treatment. However, whether amygdalin indeed acts as an anti-tumor agent is not clear. Metastasis blocking properties of amygdalin on bladder cancer cell lines was, therefore, investigated. Amygdalin (10 mg/ml was applied to UMUC-3, TCCSUP or RT112 bladder cancer cells for 24 h or for 2 weeks. Tumor cell adhesion to vascular endothelium or to immobilized collagen as well as tumor cell migration was examined. Effects of drug treatment on integrin α and β subtypes, on integrin-linked kinase (ILK and total and activated focal adhesion kinase (FAK were also determined. Integrin knock-down was carried out to evaluate integrin influence on migration and adhesion. A 24 h or 2 week amygdalin application distinctly reduced tumor cell adhesion and migration of UMUC-3 and RT112 cells. TCCSUP adhesion was also reduced, but migration was elevated under amygdalin. Integrin subtype expression was significantly and specifically altered by amygdalin depending on the cell line. ILK was moderately, and activated FAK strongly, lost in all tumor cell lines in the presence of amygdalin. Knock down of β1 integrin caused a significant decrease in both adhesion and migration of UMUC-3 cells, but a significant increase in TCCSUP adhesion. Knock down of β4 integrin caused a significant decrease in migration of RT112 cells. Since the different actions of amygdalin on the different cell lines was mirrored by β1 or β4 knock down, it is postulated that amygdalin influences adhesion and migratory properties of bladder cancer cells by modulating β1 or β4 integrin expression. The amygdalin induced increase in TCCSUP migratory behavior indicates that any anti-tumor benefits from amygdalin (seen with the other two cell lines may depend upon the cancer cell type.

  17. Dry adhesives with sensing features

    Science.gov (United States)

    Krahn, J.; Menon, C.

    2013-08-01

    Geckos are capable of detecting detachment of their feet. Inspired by this basic observation, a novel functional dry adhesive is proposed, which can be used to measure the instantaneous forces and torques acting on an adhesive pad. Such a novel sensing dry adhesive could potentially be used by climbing robots to quickly realize and respond appropriately to catastrophic detachment conditions. The proposed torque and force sensing dry adhesive was fabricated by mixing Carbon Black (CB) and Polydimethylsiloxane (PDMS) to form a functionalized adhesive with mushroom caps. The addition of CB to PDMS resulted in conductive PDMS which, when under compression, tension or torque, resulted in a change in the resistance across the adhesive patch terminals. The proposed design of the functionalized dry adhesive enables distinguishing an applied torque from a compressive force in a single adhesive pad. A model based on beam theory was used to predict the change in resistance across the terminals as either a torque or compressive force was applied to the adhesive patch. Under a compressive force, the sensing dry adhesive was capable of measuring compression stresses from 0.11 Pa to 20.9 kPa. The torque measured by the adhesive patch ranged from 2.6 to 10 mN m, at which point the dry adhesives became detached. The adhesive strength was 1.75 kPa under an applied preload of 1.65 kPa for an adhesive patch with an adhesive contact area of 7.07 cm2.

  18. "Focal thyroid inferno" on color Doppler ultrasonography: a specific feature of focal Hashimoto's thyroiditis.

    Science.gov (United States)

    Fu, Xianshui; Guo, Limei; Zhang, Huabin; Ran, Weiqiang; Fu, Peng; Li, Zhiqiang; Chen, Wen; Jiang, Ling; Wang, Jinrui; Jia, Jianwen

    2012-11-01

    To evaluate color-Doppler features predictive of focal Hashimoto's thyroiditis. A total of 521 patients with 561 thyroid nodules that underwent surgeries or gun biopsies were included in this study. These nodules were divided into three groups: focal Hashimoto's thyroiditis (104 nodules in 101 patients), benignity other than focal Hashimoto's thyroiditis (73 nodules in 70 patients), and malignancy (358 nodules in 350 patients). On color Doppler sonography, four vascularity types were determined as: hypovascularity, marked internal flow, marked peripheral flow and focal thyroid inferno. The χ2 test was performed to seek the potential vascularity type with the predictive ability of certain thyroid pathology. Furthermore, the gray-scale features of each nodule were also studied. The vascularity type I (hypovascularity) was more often seen in focal Hashimoto's thyroiditis than other benignity and malignancy (46% vs. 20.5% and 19%). While the type II (marked internal flow) showed the opposite tendency (26.9% [focal Hashimoto's thyroiditis] vs. 45.2% [other benignity] and 52.8% [malignancy]). However, type III (marked peripheral flow) was unable to predict any thyroid pathology. Importantly, type IV (focal thyroid inferno) was exclusive to focal Hashimoto's thyroiditis. All 8 type IV nodules appeared to be solid, hypoechoic, and well-defined. Using "focal thyroid inferno" as an indicator of FHT, the diagnostic sensitivity and specificity were 7.7% and 100% respectively. The vascularity type of "focal thyroid inferno" is specific for focal Hashimoto thyroiditis. Recognition of this particular feature may avoid unnecessary interventional procedures for some solid hypoechoic thyroid nodules suspicious of malignancy. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. Transparent meta-analysis: does aging spare prospective memory with focal vs. non-focal cues?

    Directory of Open Access Journals (Sweden)

    Bob Uttl

    Full Text Available BACKGROUND: Prospective memory (ProM is the ability to become aware of a previously-formed plan at the right time and place. For over twenty years, researchers have been debating whether prospective memory declines with aging or whether it is spared by aging and, most recently, whether aging spares prospective memory with focal vs. non-focal cues. Two recent meta-analyses examining these claims did not include all relevant studies and ignored prevalent ceiling effects, age confounds, and did not distinguish between prospective memory subdomains (e.g., ProM proper, vigilance, habitual ProM (see Uttl, 2008, PLoS ONE. The present meta-analysis focuses on the following questions: Does prospective memory decline with aging? Does prospective memory with focal vs. non-focal cues decline with aging? Does the size of age-related declines with focal vs. non-focal cues vary across ProM subdomains? And are age-related declines in ProM smaller than age-related declines in retrospective memory? METHODS AND FINDINGS: A meta-analysis of event-cued ProM using data visualization and modeling, robust count methods, and conventional meta-analysis techniques revealed that first, the size of age-related declines in ProM with both focal and non-focal cues are large. Second, age-related declines in ProM with focal cues are larger in ProM proper and smaller in vigilance. Third, age-related declines in ProM proper with focal cues are as large as age-related declines in recall measures of retrospective memory. CONCLUSIONS: The results are consistent with Craik's (1983 proposal that age-related declines on ProM tasks are generally large, support the distinction between ProM proper vs. vigilance, and directly contradict widespread claims that ProM, with or without focal cues, is spared by aging.

  20. Intraosseous transcutaneous amputation prostheses versus dental implants: a comparison between keratinocyte and gingival epithelial cell adhesion in vitro.

    Science.gov (United States)

    Pendegrass, C J; Lancashire, H T; Fontaine, C; Chan, G; Hosseini, P; Blunn, G W

    2015-04-19

    Infection is the primary failure modality for transcutaneous implants because the skin breach provides a route for pathogens to enter the body. Intraosseous transcutaneous amputation prostheses (ITAP) are being developed to overcome this problem by creating a seal at the skin-implant interface. Oral gingival epithelial cell attachment creates an infection-free seal around dental implants. However, this has yet to be achieved consistently outside of the oral environment. Epithelial cells attach to metal substrates by means of hemidesmosomes and focal adhesions. Their density per unit cell is an indicator of attachment strength. We postulate that gingival epithelial cells express more hemidesmosomes and focal adhesions at earlier time points, compared with epidermal keratinocytes, and this increased speed and strength of attachment may be the reason why an infection-free seal is often achieved around dental implants but less frequently around ITAP. The aim of this study was to compare epidermal keratinocyte with oral gingival cell attachment on titanium alloy in vitro, to determine whether these two cell types differ in their speed and strength of attachment. We aimed to test the hypothesis that gingival cells up-regulate focal adhesion and hemidesmosome formation at earlier time points compared with extra-oral keratinocytes. To test this hypothesis we cultured epidermal keratinocytes and oral gingival cells on titanium alloy substrates and assessed cell attachment by focal adhesions and hemidesmosome expression at 4, 24, 48 and 72 hours. Formation and expression of hemidesmosomes temporally lagged behind that of focal adhesions in both cell types. Gingival derived cells up-regulated focal adhesion and hemidesmosome expression at earlier time points compared with epidermal keratinocytes. Hemidesmosome expression in oral gingival cells was 3 times greater compared with epidermal keratinocytes at 4 hours. Our findings indicate that earlier attachment may be key to the

  1. Polymeric Nanoelectrodes for Investigating Cellular Adhesion

    Science.gov (United States)

    Thapa, Prem; Paneru, Govind; Flanders, Bret

    2011-03-01

    Polyethylene dioxythiophene nano-filaments were grown on lithographic electrode arrays by the recently developed directed electrochemical nanowire assembly technique. These filaments are firmly attached to the electrode but are not attached to the glass substrate. Hence, they behave like cantilevered rods (with one free end). Individual cells of the slime mold Dictystolium discoideum initiate contact by extending pseudopods to the nanoelectrodes when cultured on the electrode arrays. Scanning electron micrographs of the interfaces show the contact area to be of the order of 0.1 μ m 2 . Confocal images reveal the focal adhesions in the cell-electrode contact region. Deflection of the nanoelectrode by an individual cell can be used to measure the force exerted by the cell. Recent results on this innovative force sensing approach will be discussed. NSF.

  2. Non-uniform breaking of molecular bonds, peripheral morphology and releasable adhesion by elastic anisotropy in bio-adhesive contacts.

    Science.gov (United States)

    Liu, Yan; Gao, Yanfei

    2015-01-01

    Biological adhesive contacts are usually of hierarchical structures, such as the clustering of hundreds of sub-micrometre spatulae on keratinous hairs of gecko feet, or the clustering of molecular bonds into focal contacts in cell adhesion. When separating these interfaces, releasable adhesion can be accomplished by asymmetric alignment of the lowest scale discrete bonds (such as the inclined spatula that leads to different peeling force when loading in different directions) or by elastic anisotropy. However, only two-dimensional contact has been analysed for the latter method (Chen & Gao 2007 J. Mech. Phys. Solids 55, 1001-1015 (doi:10.1016/j.jmps.2006.10.008)). Important questions such as the three-dimensional contact morphology, the maximum to minimum pull-off force ratio and the tunability of releasable adhesion cannot be answered. In this work, we developed a three-dimensional cohesive interface model with fictitious viscosity that is capable of simulating the de-adhesion instability and the peripheral morphology before and after the onset of instability. The two-dimensional prediction is found to significantly overestimate the maximum to minimum pull-off force ratio. Based on an interface fracture mechanics analysis, we conclude that (i) the maximum and minimum pull-off forces correspond to the largest and smallest contact stiffness, i.e. 'stiff-adhere and compliant-release', (ii) the fracture toughness is sensitive to the crack morphology and the initial contact shape can be designed to attain a significantly higher maximum-to-minimum pull-off force ratio than a circular contact, and (iii) since the adhesion is accomplished by clustering of discrete bonds or called bridged crack in terms of fracture mechanics terminology, the above conclusions can only be achieved when the bridging zone is significantly smaller than the contact size. This adhesion-fracture analogy study leads to mechanistic predictions that can be readily used to design biomimetics and

  3. I Focalize, You Focalize, We All Focalize Together: Audience Participation in Persepolis

    Directory of Open Access Journals (Sweden)

    Lizzie Nixon

    2010-06-01

    Full Text Available

    Abstract (E: This article combines theories of cognition and empathy with focalization theory to examine how and why different forms of audience engagement in fictional worlds are cued. The article argues that critics should examine the differences between engagement that encourages audiences to apply their own frames to the world presented and type engagement cued by means of point-of-view shots and close-ups of facial expressions.

    Abstract (F: Cet article combine les théories de la cognition et de l’empathie avec la théorie de la focalisation afin d’analyser comment et pourquoi certaines œuvres construisent la manière dont le public est invité à s’investir dans des mondes fictionnels. Il défend l

  4. Magnetic field switchable dry adhesives.

    Science.gov (United States)

    Krahn, Jeffrey; Bovero, Enrico; Menon, Carlo

    2015-02-01

    A magnetic field controllable dry adhesive device is manufactured. The normal adhesion force can be increased or decreased depending on the presence of an applied magnetic field. If the magnetic field is present during the entire normal adhesion test cycle which includes both applying a preloading force and measuring the pulloff pressure, a decrease in adhesion is observed when compared to when there is no applied magnetic field. Similarly, if the magnetic field is present only during the preload portion of the normal adhesion test cycle, a decrease in adhesion is observed because of an increased stiffness of the magnetically controlled dry adhesive device. When the applied magnetic field is present during only the pulloff portion of the normal adhesion test cycle, either an increase or a decrease in normal adhesion is observed depending on the direction of the applied magnetic field.

  5. Mapping cell surface adhesion by rotation tracking and adhesion footprinting

    Science.gov (United States)

    Li, Isaac T. S.; Ha, Taekjip; Chemla, Yann R.

    2017-03-01

    Rolling adhesion, in which cells passively roll along surfaces under shear flow, is a critical process involved in inflammatory responses and cancer metastasis. Surface adhesion properties regulated by adhesion receptors and membrane tethers are critical in understanding cell rolling behavior. Locally, adhesion molecules are distributed at the tips of membrane tethers. However, how functional adhesion properties are globally distributed on the individual cell’s surface is unknown. Here, we developed a label-free technique to determine the spatial distribution of adhesive properties on rolling cell surfaces. Using dark-field imaging and particle tracking, we extract the rotational motion of individual rolling cells. The rotational information allows us to construct an adhesion map along the contact circumference of a single cell. To complement this approach, we also developed a fluorescent adhesion footprint assay to record the molecular adhesion events from cell rolling. Applying the combination of the two methods on human promyelocytic leukemia cells, our results surprisingly reveal that adhesion is non-uniformly distributed in patches on the cell surfaces. Our label-free adhesion mapping methods are applicable to the variety of cell types that undergo rolling adhesion and provide a quantitative picture of cell surface adhesion at the functional and molecular level.

  6. Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

    Directory of Open Access Journals (Sweden)

    David G. Menter

    2012-01-01

    Full Text Available Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1 are upregulated in inflammation and cancer. This results in the production of prostaglandin E2 (PGE2, which binds to and activates G-protein-coupled prostaglandin E1-4 receptors (EP1-4. Selectively targeting the COX-2/mPGES-1/PGE2/EP1-4 axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM. Interactions with the ECM are mediated by cell surface integrins by “outside-in signaling” through Src and focal adhesion kinase (FAK and/or “inside-out signaling” through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE2/EP1-4 axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy.

  7. Focal Cryoablation of Prostate: A Review

    Directory of Open Access Journals (Sweden)

    Duke K. Bahn

    2008-01-01

    Full Text Available Current treatment options for men with early localized prostate cancer are either some form of radical therapy or active surveillance. Radical therapy is usually associated with significant adverse effects that might jeopardize a man's quality of life. Some observers believe that PSA screening has resulted in the over diagnosis and over treatment of prostate cancer. Many men are being diagnosed with an early stage, small volume, unifocal or unilateral prostate cancer but are reluctant to accept watchful waiting or active surveillance. Focal cryoablation is the less than complete ablation of the gland with ice. Based on review of the limited amount of material available in the current literature, focal cryoablation can provide acceptable cancer control while preserving sexual potency and urinary continence. Focal cryoablation may fill a void in the therapeutic options available to patients with unifocal or unilateral prostate cancer who have a strong desire to maintain their quality of life.

  8. Measuring microfocus focal spots using digital radiography

    Energy Technology Data Exchange (ETDEWEB)

    Fry, David A [Los Alamos National Laboratory

    2009-01-01

    Measurement of microfocus spot size can be important for several reasons: (1) Quality assurance during manufacture of microfocus tubes; (2) Tracking performance and stability of microfocus tubes; (3) Determining magnification (especially important for digital radiography where the native spatial resolution of the digital system is not adequate for the application); (4) Knowledge of unsharpness from the focal spot alone. The European Standard EN 12543-5 is based on a simple geometrical method of calculating focal spot size from unsharpness of high magnification film radiographs. When determining microfocus focal spot dimensions using unsharpness measurements both signal-to-noise (SNR) and magnification can be important. There is a maximum accuracy that is a function of SNR and therefore an optimal magnification. Greater than optimal magnification can be used but it will not increase accuracy.

  9. Solid-state curved focal plane arrays

    Science.gov (United States)

    Nikzad, Shouleh (Inventor); Hoenk, Michael (Inventor); Jones, Todd (Inventor)

    2010-01-01

    The present invention relates to curved focal plane arrays. More specifically, the present invention relates to a system and method for making solid-state curved focal plane arrays from standard and high-purity devices that may be matched to a given optical system. There are two ways to make a curved focal plane arrays starting with the fully fabricated device. One way, is to thin the device and conform it to a curvature. A second way, is to back-illuminate a thick device without making a thinned membrane. The thick device is a special class of devices; for example devices fabricated with high purity silicon. One surface of the device (the non VLSI fabricated surface, also referred to as the back surface) can be polished to form a curved surface.

  10. Adhesive particle shielding

    Science.gov (United States)

    Klebanoff, Leonard Elliott; Rader, Daniel John; Walton, Christopher; Folta, James

    2009-01-06

    An efficient device for capturing fast moving particles has an adhesive particle shield that includes (i) a mounting panel and (ii) a film that is attached to the mounting panel wherein the outer surface of the film has an adhesive coating disposed thereon to capture particles contacting the outer surface. The shield can be employed to maintain a substantially particle free environment such as in photolithographic systems having critical surfaces, such as wafers, masks, and optics and in the tools used to make these components, that are sensitive to particle contamination. The shield can be portable to be positioned in hard-to-reach areas of a photolithography machine. The adhesive particle shield can incorporate cooling means to attract particles via the thermophoresis effect.

  11. Expansive focal cemento-osseous dysplasia.

    Science.gov (United States)

    Bulut, Emel Uzun; Acikgoz, Aydan; Ozan, Bora; Zengin, Ayse Zeynep; Gunhan, Omer

    2012-01-01

    To present a case of expansive focal cemento-osseous dysplasia and emphasize the importance of differential diagnosis. Cemento-osseous dysplasia is categorized into three subtypes on the basis of the clinical and radiographic features: Periapical, focal and florid. The focal type exhibits a single site of involvement in any tooth-bearing or edentulous area of the jaws. These lesions are usually asymptomatic; therefore, they are frequently diagnosed incidentally during routine radiographic examinations. Lesions are usually benign, show limited growth, and do not require further surgical intervention, but periodic follow-up is recommended because occasionally, this type of dysplasia progresses into florid osseous dysplasia and simple bone cysts are formed. A 24-year-old female patient was referred to our clinic for swelling in the left edentulous mandibular premolarmolar region and felt discomfort when she wore her prosthetics. She had no pain, tenderness or paresthesia. Clinical examination showed that the swelling in the posterior mandible that was firm, nonfluctuant and covered by normal mucosa. On panoramic radiography and computed tomography, a well defined lesion of approximately 1.5 cm in diameter of mixed density was observed. The swelling increased slightly in size over 2 years making it difficult to use prosthetics and, therefore, the lesion was totally excised under local anesthesia, and surgical specimens were submitted for histopathological examination. The histopathological diagnosis was focal cemento-osseous dysplasia. In the present case, because of the increasing size of the swelling making it difficult to use prosthetics, young age of the patient and localization of the lesion, in the initial examination, cemento-ossifying fibroma was suspected, and the lesion was excised surgically; the histopathological diagnosis confirmed it as focal cemento-osseous dysplasia. We present a case of expansive focal cemento-osseous dysplasia. Differential diagnosis

  12. Adhesion in hydrogel contacts

    Science.gov (United States)

    Torres, J. R.; Jay, G. D.; Kim, K.-S.; Bothun, G. D.

    2016-05-01

    A generalized thermomechanical model for adhesion was developed to elucidate the mechanisms of dissipation within the viscoelastic bulk of a hyperelastic hydrogel. Results show that in addition to the expected energy release rate of interface formation, as well as the viscous flow dissipation, the bulk composition exhibits dissipation due to phase inhomogeneity morphological changes. The mixing thermodynamics of the matrix and solvent determines the dynamics of the phase inhomogeneities, which can enhance or disrupt adhesion. The model also accounts for the time-dependent behaviour. A parameter is proposed to discern the dominant dissipation mechanism in hydrogel contact detachment.

  13. [Antiperspirants for the therapy of focal hyperhidrosis].

    Science.gov (United States)

    Streker, M; Kerscher, M

    2012-06-01

    In Europe often no clear distinction is made between deodorant and antiperspirant. Particularly in Germany, the labeling "deo" is used for both. Only antiperspirants are capable of influencing the activity of eccrine sweat glands. In the treatment of focal hyperhidrosis, the use of aluminum chloride solutions represents the first choice. The efficacy is well documented in a variety of studies. Subjective side effects include pruritus and - less often - irritant dermatitis, which can be treated symptomatically and usually does not require discontinuation of the treatment. Rare variants of focal hyperhidrosis like auriculotemporal syndrome, Ross syndrome and nevus sudoriferus also are suitable for treatment with topical aluminum chloride hexahydrate solutions.

  14. Rasmussen's encephalitis presenting as focal cortical dysplasia

    Directory of Open Access Journals (Sweden)

    D.J. O'Rourke

    2014-01-01

    Full Text Available Rasmussen's encephalitis is a rare syndrome characterized by intractable seizures, often associated with epilepsia partialis continua and symptoms of progressive hemispheric dysfunction. Seizures are usually the hallmark of presentation, but antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua, which often requires surgical intervention. Co-occurrence of focal cortical dysplasia has only rarely been described and may have implications regarding pathophysiology and management. We describe a rare case of dual pathology of Rasmussen's encephalitis presenting as a focal cortical dysplasia (FCD and discuss the literature on this topic.

  15. Ambroxol-induced focal epileptic seizure.

    Science.gov (United States)

    Lapenta, Leonardo; Morano, Alessandra; Fattouch, Jinane; Casciato, Sara; Fanella, Martina; Giallonardo, Anna Teresa; Di Bonaventura, Carlo

    2014-01-01

    It is well known that in epileptic patients some compounds and different drugs used for the treatment of comorbidities can facilitate or provoke seizures, this evidence regarding a wide spectrum of pharmacological categories. The potential facilitating factors usually include direct toxic effects or pharmacological interactions of either active ingredients or excipients. We report the case of a patient with drug-resistant epilepsy who experienced focal epileptic seizures, easily and constantly reproducible, after each administration of a cough syrup. This is, to our knowledge, the first electroencephalogram-documented case of focal epileptic seizures induced by cough syrup containing ambroxol as active ingredient.

  16. Extensive Focal Epithelial Hyperplasia: A Case Report

    OpenAIRE

    Mansouri, Zahra; Bakhtiari, Sedigheh; Noormohamadi, Robab

    2015-01-01

    Focal epithelial hyperplasia (FEH) or Heck’s disease is a rare viral infection of the oral mucosa caused by human papilloma virus especially subtypes 13 or 32. The frequency of this disease varies widely from one geographic region and ethnic groups to another. This paper reports an Iranian case of extensive focal epithelial hyperplasia. A 35-year-old man with FEH is described, in whom the lesions had persisted for more than 25 years. The lesion was diagnosed according to both clinical and his...

  17. Extensive Focal Epithelial Hyperplasia: A Case Report.

    Science.gov (United States)

    Mansouri, Zahra; Bakhtiari, Sedigheh; Noormohamadi, Robab

    2015-01-01

    Focal epithelial hyperplasia (FEH) or Heck's disease is a rare viral infection of the oral mucosa caused by human papilloma virus especially subtypes 13 or 32. The frequency of this disease varies widely from one geographic region and ethnic groups to another. This paper reports an Iranian case of extensive focal epithelial hyperplasia. A 35-year-old man with FEH is described, in whom the lesions had persisted for more than 25 years. The lesion was diagnosed according to both clinical and histopathological features. Dental practitioner should be aware of these types of lesions and histopathological examination together and a careful clinical observation should be carried out for a definitive diagnosis.

  18. Actinic Granuloma with Focal Segmental Glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Ruedee Phasukthaworn

    2016-02-01

    Full Text Available Actinic granuloma is an uncommon granulomatous disease, characterized by annular erythematous plaque with central clearing predominately located on sun-damaged skin. The pathogenesis is not well understood, ultraviolet radiation is recognized as precipitating factor. We report a case of a 52-year-old woman who presented with asymptomatic annular erythematous plaques on the forehead and both cheeks persisting for 2 years. The clinical presentation and histopathologic findings support the diagnosis of actinic granuloma. During that period of time, she also developed focal segmental glomerulosclerosis. The association between actinic granuloma and focal segmental glomerulosclerosis needs to be clarified by further studies.

  19. A simple method for focal length measurement

    Science.gov (United States)

    Ma, Hua; Ren, Huan; Zhang, Lin; Shi, Zhengdong; Yuan, Quan; Yang, Yi

    2016-09-01

    A simple method for focal length measurement based on image processing is demonstrated and discussed. The collimated beam, detector, motorized translation stage and computer make up of this test system. The two spots pass through the tested lens is accepted by detector, which is transferred twice by motorized translation stage. By acquired the difference of two spots by image processing, the focal length of the tested lens can be gained. The error sources in the measurement are analyzed. Then the results of experiment show that the relative error was 0.1%. This method can be used in workshop and labs for its convenience and low cost.

  20. Tibia Vara due to Focal Fibrocartilaginous Dysplasia

    Directory of Open Access Journals (Sweden)

    A Tavakoli

    2004-06-01

    Full Text Available We present a case of unilateral tibia vara associated with an area of focal fibrocartilaginous dysplasia in the medial aspect of the right proximal tibia. Such a case has not been described previously. The affected child was 8 months old. Deformity resolved without aggressive treatment. The pathogenesis of the focal lesion remains controversial. The most likely explanation is that the mesenchymal anlage of the tibial metaphysis has for unknown reasons, developed abnormality at the insertion of the pes anserinus. Keywords: Tibia Vara, Pes Anserinus

  1. Switchable Adhesion in Vacuum Using Bio-Inspired Dry Adhesives

    OpenAIRE

    Purtov, Julia; Frensemeier, Mareike; Kroner, Elmar

    2015-01-01

    Suction based attachment systems for pick and place handling of fragile objects like glass plates or optical lenses are energy-consuming and noisy and fail at reduced air pressure, which is essential, e.g., in chemical and physical vapor deposition processes. Recently, an alternative approach toward reversible adhesion of sensitive objects based on bioinspired dry adhesive structures has emerged. There, the switching in adhesion is achieved by a reversible buckling of adhesive pillar structur...

  2. Switchable bio-inspired adhesives

    Science.gov (United States)

    Kroner, Elmar

    2015-03-01

    Geckos have astonishing climbing abilities. They can adhere to almost any surface and can run on walls and even stick to ceilings. The extraordinary adhesion performance is caused by a combination of a complex surface pattern on their toes and the biomechanics of its movement. These biological dry adhesives have been intensely investigated during recent years because of the unique combination of adhesive properties. They provide high adhesion, allow for easy detachment, can be removed residue-free, and have self-cleaning properties. Many aspects have been successfully mimicked, leading to artificial, bio-inspired, patterned dry adhesives, and were addressed and in some aspects they even outperform the adhesion capabilities of geckos. However, designing artificial patterned adhesion systems with switchable adhesion remains a big challenge; the gecko's adhesion system is based on a complex hierarchical surface structure and on advanced biomechanics, which are both difficult to mimic. In this paper, two approaches are presented to achieve switchable adhesion. The first approach is based on a patterned polydimethylsiloxane (PDMS) polymer, where adhesion can be switched on and off by applying a low and a high compressive preload. The switch in adhesion is caused by a reversible mechanical instability of the adhesive silicone structures. The second approach is based on a composite material consisting of a Nickel- Titanium (NiTi) shape memory alloy and a patterned adhesive PDMS layer. The NiTi alloy is trained to change its surface topography as a function of temperature, which results in a change of the contact area and of alignment of the adhesive pattern towards a substrate, leading to switchable adhesion. These examples show that the unique properties of bio-inspired adhesives can be greatly improved by new concepts such as mechanical instability or by the use of active materials which react to external stimuli.

  3. Syringomyelia associated with adhesive spinal arachnoiditis: MRI

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Y.; Nemoto, Y.; Daikokuya, H.; Tashiro, T.; Shakudo, M.; Nakayama, K.; Yamada, R. [Dept. of Radiology, Osaka City University Medical School (Japan); Ohata, K.; Hakuba, A.; Nagai, K. [Dept. of Neurosurgery, Osaka City University Medical School (Japan)

    2001-04-01

    We reviewed the MRI of seven patients with syringomyelia associated with surgically proven adhesive spinal arachnoiditis to describe clinical and MRI findings in this condition. Using 0.5, 1.0 or 1.5 tesla units, we obtained sagittal T1- and T2-weighted spin-echo and axial T1-weighted images. Additional sagittal T2-weighted images were obtained without using motion-artefact suppression. Contrast medium was given intravenously to five patients. The syrinx cavities were thoracic in five cases, cervicothoracic in one, and extended from C4 to L1 in one. No Chiari malformation or craniovertebral junction anomaly was demonstrated. Meningeal thickening was seen on T2-weighted sagittal images only in one case. Cord deformity due to adhesion or displacement due to an associated arachnoid cyst was seen in all cases best demonstrated on axial images. Focal blurring of the syrinx wall on axial images was seen in six patients. Flow voids were seen in the syrinx fluid in all cases on T2-weighted images obtained without motion-artefact suppression. No abnormal contrast enhancement was demonstrated. (orig.)

  4. Switchable Adhesion in Vacuum Using Bio-Inspired Dry Adhesives.

    Science.gov (United States)

    Purtov, Julia; Frensemeier, Mareike; Kroner, Elmar

    2015-11-01

    Suction based attachment systems for pick and place handling of fragile objects like glass plates or optical lenses are energy-consuming and noisy and fail at reduced air pressure, which is essential, e.g., in chemical and physical vapor deposition processes. Recently, an alternative approach toward reversible adhesion of sensitive objects based on bioinspired dry adhesive structures has emerged. There, the switching in adhesion is achieved by a reversible buckling of adhesive pillar structures. In this study, we demonstrate that these adhesives are capable of switching adhesion not only in ambient air conditions but also in vacuum. Our bioinspired patterned adhesive with an area of 1 cm(2) provided an adhesion force of 2.6 N ± 0.2 N in air, which was reduced to 1.9 N ± 0.2 N if measured in vacuum. Detachment was induced by buckling of the structures due to a high compressive preload and occurred, independent of air pressure, at approximately 0.9 N ± 0.1 N. The switch in adhesion was observed at a compressive preload between 5.6 and 6.0 N and was independent of air pressure. The difference between maximum adhesion force and adhesion force after buckling gives a reasonable window of operation for pick and place processes. High reversibility of the switching behavior is shown over 50 cycles in air and in vacuum, making the bioinspired switchable adhesive applicable for handling operations of fragile objects.

  5. Redundant control of migration and adhesion by ERM proteins in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Baeyens, Nicolas; Latrache, Iman; Yerna, Xavier [Laboratory of Cell Physiology, IoNS, Université Catholique de Louvain (Belgium); Noppe, Gauthier; Horman, Sandrine [Pôle de Recherche Cardiovasculaire, IREC, Université Catholique de Louvain (Belgium); Morel, Nicole, E-mail: nicole.morel@uclouvain.be [Laboratory of Cell Physiology, IoNS, Université Catholique de Louvain (Belgium)

    2013-11-22

    Highlights: •The three ERM proteins are expressed in vascular smooth muscle cell. •ERM depletion inhibited PDGF-evoked migration redundantly. •ERM depletion increased cell adhesion redundantly. •ERM depletion did not affect PDGF-evoked Ca signal, Rac1 activation, proliferation. •ERM proteins control PDGF-induced migration by regulating adhesion. -- Abstract: Ezrin, radixin, and moesin possess a very similar structure with a C-terminal actin-binding domain and a N-terminal FERM interacting domain. They are known to be involved in cytoskeleton organization in several cell types but their function in vascular smooth muscle cells (VSMC) is still unknown. The aim of this study was to investigate the role of ERM proteins in cell migration induced by PDGF, a growth factor involved in pathophysiological processes like angiogenesis or atherosclerosis. We used primary cultured VSMC obtained from rat aorta, which express the three ERM proteins. Simultaneous depletion of the three ERM proteins with specific siRNAs abolished the effects of PDGF on cell architecture and migration and markedly increased cell adhesion and focal adhesion size, while these parameters were only slightly affected by depletion of ezrin, radixin or moesin alone. Rac1 activation, cell proliferation, and Ca{sup 2+} signal in response to PDGF were unaffected by ERM depletion. These results indicate that ERM proteins exert a redundant control on PDGF-induced VSMC migration by regulating focal adhesion turn-over and cell adhesion to substrate.

  6. Underwater adhesion: The barnacle way

    Digital Repository Service at National Institute of Oceanography (India)

    Khandeparker, L.; Anil, A.C.

    of substrates in aqueous environment. The adhesive properties of the barnacle adhesive proteins have been utilized for various dental and medical purposes. These polyphenolic proteins are currently in demand as they are non-toxic biomaterial, highly effective...

  7. Bio-Inspired Dry Adhesives

    Science.gov (United States)

    2013-02-01

    of mask respirators with bio -inspired adhesive integrated into their peripheral seals; and (2) assessment of the competitive position of the new bio -inspired adhesives in broader fields of application.

  8. Biological adhesion of Parthenocissus tricuspidata

    Directory of Open Access Journals (Sweden)

    He Tianxian

    2011-01-01

    Full Text Available Parthenocissus tricuspidata is a climbing plant of the grape family. It can climb with its adhesive discs on different substrates such as stone mountains, roadside stone banks, exterior walls of buildings, thereby withstanding strong winds and storms without detachment. The details about the adhesion process of Parthenocissus tricuspidata are not yet entirely understood. We studied the component-structure-property relationship of the adhesive discs in detail and propose a twostage model to describe the biological adhesion: (i structural contact and (ii adhesive action. These two stages and their variations play an important role for the attaching of the adhesive disc to different structural surfaces. We believe that in Parthenocissus tricuspidata different mechanisms work together to allow the adhesive disc to climb on various vertical substrates and reveal strong adhesive properties.

  9. [Dentin adhesives. An update].

    Science.gov (United States)

    Grandini, R; Novelli, C; Pierleoni, P

    1991-11-01

    Even if mechanical bonding to enamel utilizing the acid-etch technique has been very successful, adhesion to dentin is still a challenge to researchers and clinicians. Dentin is a vital tissue and differs in composition from enamel: acid-etching does not enhance the bond strength of composite resins to dentin and may elicit a severe pulpal response. For an effective bond to occur, a dentin bonding system has to be used. The first generation of methacrylate-based dentin adhesives was capable of chemical bonding to the inorganic phase of dentin. The chemical basis for this resin-dentin adhesive was the interaction between a phosphate group attached to the methacrylate and the calcium ions on the dentin surface. This system yielded rather low bond strengths which were clinically unsatisfying. The second generation of dentin adhesives became available to the profession recently. Each of these new bonding systems use similar chemical composition for the same purpose of bonding with physicochemical interaction to the hard tooth tissues. All these systems contain a mild acid dentin conditioner to remove the smear layer and an aqueous resin containing primer to improve monomer penetration into the hydrophilic dentin surface. The second generation dentin bonding systems are extremely sensitive to variations upon the completeness of instructions and how accurately these are followed by dental practitioners.

  10. Adhesive tape exfoliation

    DEFF Research Database (Denmark)

    Bohr, Jakob

    2015-01-01

    Single-crystal graphite can be cleaved by the use of an adhesive tape. This was also the initial route for obtaining graphene, a one-layer thick graphite slab. In this letter a few simple and fun considerations are presented in an attempt to shed some light on why this procedure is successful...

  11. Chest pain in focal musculoskeletal disorders

    DEFF Research Database (Denmark)

    Stochkendahl, Mette Jensen; Christensen, Henrik Wulff

    2010-01-01

    overlapping conditions and syndromes of focal disorders, including Tietze syndrome, costochondritis, chest wall syndrome, muscle tenderness, slipping rib, cervical angina, and segmental dysfunction of the cervical and thoracic spine, have been reported to cause pain. For most of these syndromes, evidence...

  12. Focal dermal hypoplasia: A rare case report

    Directory of Open Access Journals (Sweden)

    Sahana M Srinivas

    2015-01-01

    Full Text Available Focal dermal hypoplasia (Goltz syndrome is a rare genetic multisystem disorder primarily involving the skin, skeletal system, eyes, and face. We report the case of an eight-month-old female child who presented with multiple hypopigmented atrophic macules along the lines of blaschko, skeletal anomalies, umbilical hernia, developmental delay, hypoplastic nails, syndactyly, and lobster claw deformity characteristic of Goltz syndrome.

  13. Optical interconnections to focal plane arrays

    Energy Technology Data Exchange (ETDEWEB)

    Rienstra, J.L.; Hinckley, M.K.

    2000-11-01

    The authors have successfully demonstrated an optical data interconnection from the output of a focal plane array to the downstream data acquisition electronics. The demonstrated approach included a continuous wave laser beam directed at a multiple quantum well reflectance modulator connected to the focal plane array analog output. The output waveform from the optical interconnect was observed on an oscilloscope to be a replica of the input signal. They fed the output of the optical data link to the same data acquisition system used to characterize focal plane array performance. Measurements of the signal to noise ratio at the input and output of the optical interconnection showed that the signal to noise ratio was reduced by a factor of 10 or more. Analysis of the noise and link gain showed that the primary contributors to the additional noise were laser intensity noise and photodetector receiver noise. Subsequent efforts should be able to reduce these noise sources considerably and should result in substantially improved signal to noise performance. They also observed significant photocurrent generation in the reflectance modulator that imposes a current load on the focal plane array output amplifier. This current loading is an issue with the demonstrated approach because it tends to negate the power saving feature of the reflectance modulator interconnection concept.

  14. Ketogenic Diet for Epilepsy and Focal Malformation

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2008-09-01

    Full Text Available The efficacy and long-term treatment outcome of a classic ketogenic diet (KD addon treatment (4:1 lipid/nonlipid ratio, without initial fasting and fluid restriction were evaluated retrospectively in 47 children with intractable epilepsy and focal malformation of cortical development, in a study at Severance Children’s and Sanggye Park Hospitals, Seoul, Korea.

  15. MTI Focal Plane Assembly Design and Performance

    Energy Technology Data Exchange (ETDEWEB)

    Ballard, M.; Rienstra, J.L.

    1999-06-17

    The focal plane assembly for the Multispectral Thermal Imager (MTI) consists of sensor chip assemblies, optical filters, and a vacuum enclosure. Sensor chip assemblies, composed of linear detector arrays and readout integrated circuits, provide spatial resolution in the cross-track direction for the pushbroom imager. Optical filters define 15 spectral bands in a range from 0.45 {micro}m to 10.7 {micro}m. All the detector arrays are mounted on a single focal plane and are designed to operate at 75 K. Three pairs of sensor chip assemblies (SCAs) are required to provide cross-track coverage in all 15 spectral bands. Each pair of SCAs includes detector arrays made from silicon, iridium antimonide, and mercury cadmium telluride. Read out integrated circuits multiplex the signals from the detectors to 18 separate video channels. Optical filter assemblies defining the spectral bands are mounted over the linear detector arrays. Each filter assembly consists of several filter strips bonded together side-by-side. The MTI focal plane assembly has been integrated with the rest of the payload and has undergone detailed testing and calibration. This paper includes representative test data for the various spectral bands and the overall performance of the focal plane assembly.

  16. [Focal epithelial hyperplasia. An unusual clinical aspect].

    Science.gov (United States)

    Bodokh, I; Lacour, J P; Rainero, C; Orth, G; Perrin, C; Hoffman, P; Santini, J; Ortonne, J P

    1993-01-01

    We report a case of focal epithelial hyperplasia in a child born in France of Algerian parents. The clinical appearance was unusual in that certain lesions were verrucous and pediculate. A virological study revealed the presence of papillomavirus 32, one of the two types of HPV specifically associated with this entity.

  17. Atypical focal nodular hyperplasia of the liver

    Institute of Scientific and Technical Information of China (English)

    Muhammad Rizwan Khan; Taimur Saleem; Tanveer Ul Haq; Kanwal Aftab

    2011-01-01

    BACKGROUND: Focal nodular hyperplasia, a benign hepatic tumor, is usually asymptomatic. However, rarely the entity can cause symptoms, mandating intervention. METHOD: We present a case of focal nodular hyperplasia of the liver, which caused a considerable diagnostic dilemma due to its atypical presentation. RESULTS: A 29-year-old woman presented with a 15-year history of a progressively increasing mass in the right upper quadrant which was associated with pain and emesis. Examination showed a firm, mobile mass palpable below the right subcostal margin. A computed tomography scan of the abdomen showed an exophytic mass arising from hepatic segments III and IVb. Trucut biopsy of the hepatic mass was equivocal. Angiography showed a vascular tumor that was supplied by a tortuous branch of the proper hepatic artery. Surgical intervention for removal of the mass was undertaken. Intra-operatively, two large discrete tumors were found and completely resected. Histopathological examination showed features consistent with focal nodular hyperplasia. CONCLUSION: This description of an unusual case of focal nodular hyperplasia of the liver highlights the point that the diagnosis of otherwise benign hepatic tumors may be difficult despite extensive work-up in some cases.

  18. Pure Gerstmann's syndrome from a focal lesion.

    Science.gov (United States)

    Roeltgen, D P; Sevush, S; Heilman, K M

    1983-01-01

    It is controversial whether a focal lesion can specifically induce Gerstmann's syndrome (dyscalculia, left-right disorientation, finger agnosia, and agraphia). Also, Gerstmann's tetrad has been attributed to other cerebral symptoms, particularly aphasia. We examined a patient who had all four symptoms of Gerstmann's syndrome, without other symptoms or signs, and who had a discrete left parietal lesion.

  19. Laser Dazzling of Focal Plane Array Cameras

    NARCIS (Netherlands)

    Schleijpen, H.M.A.; Dimmeler, A.; Eberle, B; Heuvel, J.C. van den; Mieremet, A.L.; Bekman, H.H.P.T.; Mellier, B.

    2007-01-01

    Laser countermeasures against infrared focal plane array cameras aim to saturate the full camera image. In this paper we will discuss the results of dazzling experiments performed with MWIR lasers. In the “low energy” pulse regime we observe an increasing saturated area with increasing power. The si

  20. Pathogenesis of postoperative adhesion formation

    NARCIS (Netherlands)

    Hellebrekers, B.W.J.; Kooistra, T.

    2011-01-01

    Background: Current views on the pathogenesis of adhesion formation are based on the "classical concept of adhesion formation", namely that a reduction in peritoneal fibrinolytic activity following peritoneal trauma is of key importance in adhesion development. Methods: A non-systematic literature

  1. Mesenchymal stem cell adhesion but not plasticity is affected by high substrate stiffness

    Directory of Open Access Journals (Sweden)

    Janice Kal Van Tam, Koichiro Uto, Mitsuhiro Ebara, Stefania Pagliari, Giancarlo Forte and Takao Aoyagi

    2012-01-01

    Full Text Available The acknowledged ability of synthetic materials to induce cell-specific responses regardless of biological supplies provides tissue engineers with the opportunity to find the appropriate materials and conditions to prepare tissue-targeted scaffolds. Stem and mature cells have been shown to acquire distinct morphologies in vitro and to modify their phenotype when grown on synthetic materials with tunable mechanical properties. The stiffness of the substrate used for cell culture is likely to provide cells with mechanical cues mimicking given physiological or pathological conditions, thus affecting the biological properties of cells. The sensitivity of cells to substrate composition and mechanical properties resides in multiprotein complexes called focal adhesions, whose dynamic modification leads to cytoskeleton remodeling and changes in gene expression. In this study, the remodeling of focal adhesions in human mesenchymal stem cells in response to substrate stiffness was followed in the first phases of cell–matrix interaction, using poly-ε-caprolactone planar films with similar chemical composition and different elasticity. As compared to mature dermal fibroblasts, mesenchymal stem cells showed a specific response to substrate stiffness, in terms of adhesion, as a result of differential focal adhesion assembly, while their multipotency as a bulk was not significantly affected by matrix compliance. Given the sensitivity of stem cells to matrix mechanics, the mechanobiology of such cells requires further investigations before preparing tissue-specific scaffolds.

  2. Focal adhesion kinase regulates collagen I-induced airway smooth muscle phenotype switching

    NARCIS (Netherlands)

    Dekkers, Bart G J; Spanjer, Anita I R; van der Schuyt, Robert D; Kuik, Willem Jan; Zaagsma, Johan; Meurs, Herman

    2013-01-01

    Increased extracellular matrix (ECM) deposition and airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma. Recently, we demonstrated that the ECM protein collagen I, which is increased surrounding asthmatic ASM, induces a proliferative, hypocontractile ASM phenotype.

  3. Interleukin-8 induces motile behavior and loss of focal adhesions in primary fibroblasts

    DEFF Research Database (Denmark)

    Dunlevy, J R; Couchman, J R

    1995-01-01

    Interleukin-8 (IL-8) is a proinflammatory cytokine that promotes neutrophil migration. Although fibroblasts are known to secrete IL-8, the actions of this cytokine on fibroblasts have not been previously reported. We have found that in subconfluent populations of cultured primary fibroblasts, IL-8....... Additionally, video microscopy assays using heart conditioned medium depleted with the IL-8 antibody show an increase in the percentage of stationary cells, a consequent decrease in the percentage of migrating cells, and a twofold increase in the mitotic rate. Interleukin-1 alpha and tumor necrosis factor...

  4. Focal Adhesion-Chromatin Linkage Controls Tumor Cell Resistance to Radio- and Chemotherapy

    Directory of Open Access Journals (Sweden)

    Katja Storch

    2012-01-01

    Full Text Available Cancer resistance to therapy presents an ongoing and unsolved obstacle, which has clear impact on patient's survival. In order to address this problem, novel in vitro models have been established and are currently developed that enable data generation in a more physiological context. For example, extracellular-matrix- (ECM- based scaffolds lead to the identification of integrins and integrin-associated signaling molecules as key promoters of cancer cell resistance to radio- and chemotherapy as well as modern molecular agents. In this paper, we discuss the dynamic nature of the interplay between ECM, integrins, cytoskeleton, nuclear matrix, and chromatin organization and how this affects the response of tumor cells to various kinds of cytotoxic anticancer agents.

  5. The Regulation of Traction Force in Relation to Cell Shape and Focal Adhesions

    OpenAIRE

    Rape, Andrew; Guo, Wei-hui; Wang, Yu-Li

    2010-01-01

    Mechanical forces provide critical inputs for proper cellular functions. The interplay between the generation of, and response to, mechanical forces regulate such cellular processes as differentiation, proliferation, and migration. We postulate that adherent cells respond to a number of physical and topographical factors, including cell size and shape, by detecting the magnitude and/or distribution of traction forces under different conditions. To address this possibility we introduce a new s...

  6. Modulation of FAK and Src adhesion signaling occurs independently of adhesion complex composition

    DEFF Research Database (Denmark)

    Horton, Edward R.; Humphries, Jonathan D.; Stutchbury, Ben

    2016-01-01

    of the key IAC signaling components focal adhesion kinase (FAK) and Src. FAK inhibition using AZ13256675 blocked FAKY397 phosphorylation but did not alter IAC composition, as reported by mass spectrometry. IAC composition was also insensitive to Src inhibition using AZD0530 alone or in combination with FAK...... inhibition. In contrast, kinase inhibition substantially reduced phosphorylation within IACs, cell migration and proliferation. Furthermore using fluorescence recovery after photobleaching, we found that FAK inhibition increased the exchange rate of a phosphotyrosine (pY) reporter (dSH2) at IACs. These data...... demonstrate that kinase-dependent signal propagation through IACs is independent of gross changes in IAC composition. Together, these findings demonstrate a general separation between the composition of IACs and their ability to relay pY-dependent signals....

  7. Cell adhesive behavior on thin polyelectrolyte multilayers: cells attempt to achieve homeostasis of its adhesion energy.

    Science.gov (United States)

    Mehrotra, Sumit; Hunley, S Christopher; Pawelec, Kendell M; Zhang, Linxia; Lee, Ilsoon; Baek, Seungik; Chan, Christina

    2010-08-03

    Linearly growing ultrathin polyelectrolyte multilayer (PEM) films of strong polyelectrolytes, poly(diallyldimethylammonium chloride) (PDAC), and sulfonated polystyrene, sodium salt (SPS) exhibit a gradual shift from cytophilic to cytophobic behavior, with increasing thickness for films of less than 100 nm. Previous explanations based on film hydration, swelling, and changes in the elastic modulus cannot account for the cytophobicity observed with these thin films as the number of bilayers increases. We implemented a finite element analysis to help elucidate the observed trends in cell spreading. The simulation results suggest that cells maintain a constant level of energy consumption (energy homeostasis) during active probing and thus respond to changes in the film stiffness as the film thickness increases by adjusting their morphology and the number of focal adhesions recruited and thereby their attachment to a substrate.

  8. Adhesion behaviors on superhydrophobic surfaces.

    Science.gov (United States)

    Zhu, Huan; Guo, Zhiguang; Liu, Weimin

    2014-04-18

    The adhesion behaviors of superhydrophobic surfaces have become an emerging topic to researchers in various fields as a vital step in the interactions between materials and organisms/materials. Controlling the chemical compositions and topological structures via various methods or technologies is essential to fabricate and modulate different adhesion properties, such as low-adhesion, high-adhesion and anisotropic adhesion on superhydrophobic surfaces. We summarize the recent developments in both natural superhydrophobic surfaces and artificial superhydrophobic surfaces with various adhesions and also pay attention to superhydrophobic surfaces switching between low- and high-adhesion. The methods to regulate or translate the adhesion of superhydrophobic surfaces can be considered from two perspectives. One is to control the chemical composition and change the surface geometric structure on the surfaces, respectively or simultaneously. The other is to provide external stimulations to induce transitions, which is the most common method for obtaining switchable adhesions. Additionally, adhesion behaviors on solid-solid interfaces, such as the behaviors of cells, bacteria, biomolecules and icing on superhydrophobic surfaces are also noticeable and controversial. This review is aimed at giving a brief and crucial overview of adhesion behaviors on superhydrophobic surfaces.

  9. Management of adhesive capsulitis

    Directory of Open Access Journals (Sweden)

    Stupay KL

    2015-08-01

    Full Text Available Kristen L Stupay,1 Andrew S Neviaser2 1Tulane University School of Medicine, New Orleans, LA, USA; 2George Washington University Medical Faculty Associates, Washington, DC, USA Abstract: Adhesive capsulitis of the shoulder is a condition of capsular contracture that reduces both active and passive glenohumeral motion. The cause of adhesive capsulitis is not known but it is strongly associated with endocrine abnormalities such as diabetes. Diverse terminology and the absence of definitive criteria for diagnosis make evaluating treatment modalities difficult. Many treatment methods have been reported, most with some success, but few have been proved to alter the natural course of this disease. Most afflicted patients will achieve acceptable shoulder function without surgery. Those who remain debilitated after 8–12 months are reasonable candidates for invasive treatments. Here, the various treatment methods and the data to support their use are reviewed. Keywords: frozen shoulder, stiff shoulder, periarthritis, painful shoulder 

  10. Syndecans and cell adhesion

    DEFF Research Database (Denmark)

    Couchman, J R; Chen, L; Woods, A

    2001-01-01

    Now that transmembrane signaling through primary cell-matrix receptors, integrins, is being elucidated, attention is turning to how integrin-ligand interactions can be modulated. Syndecans are transmembrane proteoglycans implicated as coreceptors in a variety of physiological processes, including...... cell adhesion, migration, response to growth factors, development, and tumorigenesis. This review will describe this family of proteoglycans in terms of their structures and functions and their signaling in conjunction with integrins, and indicate areas for future research....

  11. PI3K{gamma} activation by CXCL12 regulates tumor cell adhesion and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Monterrubio, Maria; Mellado, Mario; Carrera, Ana C. [Department of Immunology and Oncology, Centro Nacional de Biotecnologia/CSIC, Campus de Cantoblanco, E-28049 Madrid (Spain); Rodriguez-Frade, Jose Miguel, E-mail: jmrfrade@cnb.csic.es [Department of Immunology and Oncology, Centro Nacional de Biotecnologia/CSIC, Campus de Cantoblanco, E-28049 Madrid (Spain)

    2009-10-16

    Tumor dissemination is a complex process, in which certain steps resemble those in leukocyte homing. Specific chemokine/chemokine receptor pairs have important roles in both processes. CXCL12/CXCR4 is the most commonly expressed chemokine/chemokine receptor pair in human cancers, in which it regulates cell adhesion, extravasation, metastatic colonization, angiogenesis, and proliferation. All of these processes require activation of signaling pathways that include G proteins, phosphatidylinositol-3 kinase (PI3K), JAK kinases, Rho GTPases, and focal adhesion-associated proteins. We analyzed these pathways in a human melanoma cell line in response to CXCL12 stimulation, and found that PI3K{gamma} regulates tumor cell adhesion through mechanisms different from those involved in cell invasion. Our data indicate that, following CXCR4 activation after CXCL12 binding, the invasion and adhesion processes are regulated differently by distinct downstream events in these signaling cascades.

  12. The physiological substrates of fructosamine-3-kinase-related-protein (FN3KRP) are intermediates of nonenzymatic reactions between biological amines and ketose sugars (fructation products).

    Science.gov (United States)

    Szwergold, Benjamin S; Bunker, Richard D; Loomes, Kerry M

    2011-11-01

    The physiological function of fructosamine-3-kinase (FN3K) is relatively well understood. As shown in several studies, most conclusively by data on the FN3K-KO mouse, this enzyme breaks down compounds produced by the non-enzymatic glycation of proteins by D-glucose. In contrast with FN3K, very little is known about the function of the fructosamine-3-kinase-related-protein (FN3KRP) even though it has a 65% amino-acid sequence identity with FN3K. We do know that this enzyme is a kinase as evidenced by its ability to phosphorylate non-physiological compounds such a psicosamines, ribulosamines, erythrulosamines, and glucitolamines. However, FN3KRP does not phosphorylate any of the numerous Amadori products that are the physiological substrates of FN3K. The fact that FN3KRP is highly conserved in all vertebrates and present throughout nature suggests that it plays an important role in cellular metabolism and makes identification of its physiological substrates an important objective. In this paper, we propose that FN3KRP phosphorylates products resulting from a non-enzymatic glycation of amines by ketoses (fructation) that involves a 2,3-enolization and produces the stable Amadori intermediate, 2-amino-2-deoxy-D-ribo-hex-3-ulose (ADRH). This ketosamine is then phosphorylated to 2-amino-2-deoxy-D-ribo-hex-3-ulose-4-phosphate (ADRH-4-P). Since phosphates are much better leaving groups than hydroxyls, this destabilizes the C-2 amine bond and results in a spontaneous β-elimination of the phosphate to regenerate an unmodified amine with the concomitant production of 4-deoxy-2,3-diulose. Consequently, we postulate that the principal physiological function of FN3KRP is the breakdown of nonenzymatic fructation products. If confirmed in future studies, this hypothesis opens up new perspectives for an improved understanding of biological Maillard reactions and mechanisms for their control and/or reversal. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Hemorrhagc focal nodular hyperplasia in young men: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jin Hyun; Kwon, Hee Jin; Cho, Jin Han; Oh, Jong Yeong; Nam, Kyung Jin; Roh, Young Hoon; Jeong, Jin Sook [College of Medicine, Dong-A University, Busan (Korea, Republic of)

    2014-04-15

    In general, focal nodular hyperplasia is a hepatic lesion that most frequently affects the healthy women of reproductive age. Focal nodular hyperplasia lesions have a benign natural course; the majority of the cases remain asymptomatic and complications are rare. Spontaneous hemorrhage of focal nodular hyperplasia is a rare disease, and the hemorrhage in young men is even more uncommon. We report a rare case of spontaneous hemorrhage of focal nodular hyperplasia in a 19-year-old man.

  14. Likelihood analysis of earthquake focal mechanism distributions

    CERN Document Server

    Kagan, Y Y

    2014-01-01

    In our paper published earlier we discussed forecasts of earthquake focal mechanism and ways to test the forecast efficiency. Several verification methods were proposed, but they were based on ad-hoc, empirical assumptions, thus their performance is questionable. In this work we apply a conventional likelihood method to measure a skill of forecast. The advantage of such an approach is that earthquake rate prediction can in principle be adequately combined with focal mechanism forecast, if both are based on the likelihood scores, resulting in a general forecast optimization. To calculate the likelihood score we need to compare actual forecasts or occurrences of predicted events with the null hypothesis that the mechanism's 3-D orientation is random. For double-couple source orientation the random probability distribution function is not uniform, which complicates the calculation of the likelihood value. To better understand the resulting complexities we calculate the information (likelihood) score for two rota...

  15. Dynamic reactive astrocytes after focal ischemia

    Institute of Scientific and Technical Information of China (English)

    Shinghua Ding

    2014-01-01

    Astrocytes are specialized and most numerous glial cell type in the central nervous system and play important roles in physiology. Astrocytes are also critically involved in many neural disor-ders including focal ischemic stroke, a leading cause of brain injury and human death. One of the prominent pathological features of focal ischemic stroke is reactive astrogliosis and glial scar for-mation associated with morphological changes and proliferation. This review paper discusses the recent advances in spatial and temporal dynamics of morphology and proliferation of reactive astrocytes after ischemic stroke based on results from experimental animal studies. As reactive astrocytes exhibit stem cell-like properties, knowledge of dynamics of reactive astrocytes and glial scar formation will provide important insights for astrocyte-based cell therapy in stroke.

  16. Membership Functions for Fuzzy Focal Elements

    Directory of Open Access Journals (Sweden)

    Porębski Sebastian

    2016-09-01

    Full Text Available The paper presents a study on data-driven diagnostic rules, which are easy to interpret by human experts. To this end, the Dempster-Shafer theory extended for fuzzy focal elements is used. Premises of the rules (fuzzy focal elements are provided by membership functions which shapes are changing according to input symptoms. The main aim of the present study is to evaluate common membership function shapes and to introduce a rule elimination algorithm. Proposed methods are first illustrated with the popular Iris data set. Next experiments with five medical benchmark databases are performed. Results of the experiments show that various membership function shapes provide different inference efficiency but the extracted rule sets are close to each other. Thus indications for determining rules with possible heuristic interpretation can be formulated.

  17. Focal Plane Image Assembly of Subpixel

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    This paper describes the scanning assembly principle and construction of scanning assembly sample.The factors that affect assembly accuracy are analyzed.There are two steps in CCD focal plane scanning assembly.The first is rough assembly,and the second is accurate assembly.In this paper,the moiré fringe is introduced in judging assembly accuracy directly and accurately.The equation for optical transmission characteristics of CCD Moiré fringes is presented.The measurement of Moiré fringes can be completed when some conditions are satisfied.2D-assembly error can be obtained by using digital correlation filtering technique.Finally,the result of focal plane scanning assembly is presented.The result is in good accordance with theory.

  18. Single and collective cell migration: the mechanics of adhesions

    Science.gov (United States)

    De Pascalis, Chiara; Etienne-Manneville, Sandrine

    2017-01-01

    Chemical and physical properties of the environment control cell proliferation, differentiation, or apoptosis in the long term. However, to be able to move and migrate through a complex three-dimensional environment, cells must quickly adapt in the short term to the physical properties of their surroundings. Interactions with the extracellular matrix (ECM) occur through focal adhesions or hemidesmosomes via the engagement of integrins with fibrillar ECM proteins. Cells also interact with their neighbors, and this involves various types of intercellular adhesive structures such as tight junctions, cadherin-based adherens junctions, and desmosomes. Mechanobiology studies have shown that cell–ECM and cell–cell adhesions participate in mechanosensing to transduce mechanical cues into biochemical signals and conversely are responsible for the transmission of intracellular forces to the extracellular environment. As they migrate, cells use these adhesive structures to probe their surroundings, adapt their mechanical properties, and exert the appropriate forces required for their movements. The focus of this review is to give an overview of recent developments showing the bidirectional relationship between the physical properties of the environment and the cell mechanical responses during single and collective cell migration. PMID:28684609

  19. Friction-controlled traction force in cell adhesion.

    Science.gov (United States)

    Pompe, Tilo; Kaufmann, Martin; Kasimir, Maria; Johne, Stephanie; Glorius, Stefan; Renner, Lars; Bobeth, Manfred; Pompe, Wolfgang; Werner, Carsten

    2011-10-19

    The force balance between the extracellular microenvironment and the intracellular cytoskeleton controls the cell fate. We report a new (to our knowledge) mechanism of receptor force control in cell adhesion originating from friction between cell adhesion ligands and the supporting substrate. Adherent human endothelial cells have been studied experimentally on polymer substrates noncovalently coated with fluorescent-labeled fibronectin (FN). The cellular traction force correlated with the mobility of FN during cell-driven FN fibrillogenesis. The experimental findings have been explained within a mechanistic two-dimensional model of the load transfer at focal adhesion sites. Myosin motor activity in conjunction with sliding of FN ligands noncovalently coupled to the surface of the polymer substrates is shown to result in a controlled traction force of adherent cells. We conclude that the friction of adhesion ligands on the supporting substrate is important for mechanotransduction and cell development of adherent cells in vitro and in vivo. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  20. Adhesion, growth, and matrix production by fibroblasts on laminin substrates

    DEFF Research Database (Denmark)

    Couchman, J R; Höök, M; Rees, D A;

    1983-01-01

    Human embryonic skin fibroblasts have been shown to attach and spread on laminin substrates in the absence of protein synthesis and presence of fibronectin-depleted serum and anti-fibronectin antibodies. Rates of attachment and the type of spreading are virtually identical on fibronectin and lami......Human embryonic skin fibroblasts have been shown to attach and spread on laminin substrates in the absence of protein synthesis and presence of fibronectin-depleted serum and anti-fibronectin antibodies. Rates of attachment and the type of spreading are virtually identical on fibronectin...... and laminin-coated substrates with the development of microfilament bundles and focal adhesions. Antibodies to laminin, but not fibronectin, will prevent or reverse fibroblast adhesion to laminin, whereas antibodies to fibronectin but not laminin will give similar results on fibronectin-coated substrates....... These and other results indicate that fibroblasts possess distinct receptors for laminin and fibronectin which on contact with suitable substrates promote adhesion through interaction with common intermediates. This type of adhesion is compatible with subsequent growth and extracellular matrix production....

  1. Focal epileptic seizures mimicking sleep paralysis.

    Science.gov (United States)

    Galimberti, Carlo Andrea; Ossola, Maria; Colnaghi, Silvia; Arbasino, Carla

    2009-03-01

    Sleep paralysis (SP) is a common parasomnia. The diagnostic criteria for SP, as reported in the International Classification of Sleep Disorders, are essentially clinical, as electroencephalography (EEG)-polysomnography (PSG) is not mandatory. We describe a subject whose sleep-related events fulfilled the diagnostic criteria for SP, even though her visual hallucinations were elementary, repetitive and stereotyped, thus differing from those usually reported by patients with SP. Video/EEG-PSG documented the focal epileptic nature of the SP-like episodes.

  2. Staring Focal Plane Array System Modeling

    Science.gov (United States)

    1989-12-01

    mod- eling. This chapter presents background material needed to understand basic Focal Plane Array technology, the linear systems theory commonly... Linear systems theory is commonly used to assess the performance of imaging systems by describing the system’s response to different spatial frequencies...account for the nonlinearities (edge enhancement, adaptive spatial filtering) intro- duced by the eye/brain is not clear. How far can linear systems theory and

  3. Characterization of LIL laser UV focal spot

    Energy Technology Data Exchange (ETDEWEB)

    Mangeant, M.; Dubois, J.L.; Behar, G.; Arroyo, P.; Durand, V.; Lahonde, C. [CEA - Centre d' Etudes Scientifiques et Techniques d' Aquitaine, CESTA/DLP, 33 - Le Barp (France)

    2006-06-15

    One way to get the fusion of hydrogen in laboratory consists in heating and compressing a DT fuel capsule by using a laser. To reach this aim requires a new generation of high power laser facility. Cea (French board for atomic energy) is developing for this purpose a new 240 laser line facility, the LMJ facility. The LIL which is the prototype of four LMJ laser lines is operational now. In order to confirm the technical choices, a systematic characterization of LIL was carried out. A particular effort has been provided to measure the 3{omega} high energy focal spot (1.5 kJ/700 ps and 5 ns for one beam) and the synchronization of laser beams onto the target, which are key issues for the plasma production. An experimental device, SAT-3{omega} (a 3{omega} laser focal spot analysis) has been designed to perform these measures. That diagnostic which is located at the end of the laser lines delivered its first results during the 2004 quadruplet qualification campaigns. The near field imaging showed no diaphony and vignetting. Low power spots allowed us to control we had no ghost. The energy measurement quality showed the photometric transfer function was perfectly known. Our caustic image are given with an average dynamic range of 800, a spatial resolution of 10 {mu}m and diameter accuracy about 1% for 50% and 3% for 90% of encircled energy. The high energy focal spot diameters are in agreement with low and very low energy diameters. The phase plate and 14 GHz effects are similar to what we had expected. For a laser shot completed with a continuous phase plate at 14 GHz, and for an energy level of 1.5 kJ per beam at 351 nm, the focal beam diameter at 3% of the peak level is (875 {+-} 45) {mu}m.

  4. FOCAL EPITHELIAL HYPERPLASIA: HECK’S DISEASE

    OpenAIRE

    Brzeziński Piotr

    2010-01-01

    Heck's disease (focal epithelial hyperplasia) (FEH) is clinically characterized by multiple circumscribed, soft elevated nodules of the oral mucosa. Papules and plaques are usually the color of normal mucosa, but may be pale or, rarely, white. Disease may persist for years, producing a significant reduction in quality of life. Lessions may be located in the area of mucous membranes of the lips, cheeks and tongue. It is believed that the two virus types are responsible for the FEH, are: HPV 1...

  5. Extensive focal epithelial hyperplasia: case report.

    Science.gov (United States)

    Durso, Braz Campos; Pinto, José Marcelo Vargas; Jorge, Jacks; de Almeida, Oslei Paes

    2005-11-01

    Focal epithelial hyperplasia (FEH) is a rare benign lesion caused by human papillomavirus subtype 13 or 32. The condition occurs in numerous populations and ethnic groups. A higher incidence in close communities and among family members indicates infectious pathogenesis. A 21-year-old woman with FEH is described, in whom the lesions had persisted for 10 years. A literature review is also presented, with emphasis on manifestations in the oral mucosa and histopathological features.

  6. Focal epithelial hyperplasia in a Turkish family.

    Science.gov (United States)

    Gökahmetoğlu, Selma; Ferahbaş, Ayten; Canöz, Özlem

    2014-12-01

    Focal epithelial hyperplasia (FEH) is a benign proliferative condition that is more frequently found in children of certain ethnic groups. Human papillomavirus (HPV) 13 and 32 genotypes has been consistently detected in these lesions. In this study a daughter, mother and father had FEH, and HPV 13 was shown by sequence analysis in the lesions of these patients. Cryotherapy was applied to the lesions and the lesions improved, but did not recover properly. In conclusion, HPV genotyping should be performed in FEH cases.

  7. Dynamics of Focal Fibrillation Waves during Persistent Atrial Fibrillation.

    Science.gov (United States)

    Lanters, Eva A H; Allessie, Maurits A; DE Groot, Natasja M S

    2016-04-01

    The incidence and appearance of focal fibrillation waves on the right and left atrial epicardial surface were visualized during 10 seconds of persistent atrial fibrillation in a 71-year-old woman with valvular heart disease. The frequent, nonrepetitive, widespread, and capricious distribution of focal waves suggests that transmural conduction of fibrillation waves is most likely the mechanism underlying focal fibrillation waves.

  8. Sonographic features of focal Hashimoto's thyroiditis.

    Science.gov (United States)

    Fu, Xian-shui; Li, Zhi-qiang; Zhang, Hua-bin; Wang, Jin-rui

    2014-06-01

    To evaluate the diagnostic values of gray-scale and color Doppler ultrasound in the diagnosis of focal Hashimoto's thyroiditis (FHT). The gray-scale and colour Doppler ultrasound data of 120 patients with histopathologically confirmed FHT were retrospectively studied. The background of thyroid parenchyma was subjectively evaluated as absence or presence of diffuse Hashimoto's thyroiditis. The vascular types of thyroid nodules were determined as follows: hypovascularity, marked internal flow, marked peripheral flow, and focal thyroid inferno. Among all 120 nodules, 71 (59.2%) were located in normal thyroid parenchyma, 49 (40.8%) in the background of diffuse Hashimoto's thyroiditis. In the normal thyroid background, hypoechoic nodules accounted for 85.9% (61/71), and only 14.1% (10/71)nodules were isoechoic or hyperechoic. However, in the background of diffuse Hashimoto's thyroiditis, 40.8% were hypoechoic and 59.2% were isoechoic or hyperechoic. The difference was statistically significant (Pinferno accounted for 45 %, 25.9%, 20.8%, and 8.3%, respectively. The "focal inferno" is a relative specific color Doppler feature of FHT.

  9. Focal Conic Flower Textures at Curved Interfaces

    Directory of Open Access Journals (Sweden)

    Daniel A. Beller

    2013-12-01

    Full Text Available Focal conic domains (FCDs in smectic-A liquid crystals have drawn much attention, both for their exquisitely structured internal form and for their ability to direct the assembly of micromaterials and nanomaterials in a variety of patterns. A key to directing FCD assembly is control over the eccentricity of the domain. Here, we demonstrate a new paradigm for creating spatially varying FCD eccentricity by confining a hybrid-aligned smectic with curved interfaces. In particular, we manipulate interface behavior with colloidal particles in order to experimentally produce two examples of what has recently been dubbed the flower texture [C. Meyer et al., Focal Conic Stacking in Smectic A Liquid Crystals: Smectic Flower and Apollonius Tiling, Materials 2, 499, 2009MATEG91996-194410.3390/ma2020499], where the focal hyperbolæ diverge radially outward from the center of the texture, rather than inward as in the canonical éventail or fan texture. We explain how this unconventional assembly can arise from appropriately curved interfaces. Finally, we present a model for this system that applies the law of corresponding cones, showing how FCDs may be embedded smoothly within a “background texture” of large FCDs and concentric spherical layers, in a manner consistent with the qualitative features of the smectic flower. Such understanding could potentially lead to disruptive liquid-crystal technologies beyond displays, including patterning, smart surfaces, microlens arrays, sensors, and nanomanufacturing.

  10. Smart focal plane technologies for ELT instruments

    Science.gov (United States)

    Cunningham, Colin R.; Ramsay-Howat, Suzanne K.; Garzon, Francisco; Parry, Ian R.; Prieto, Eric; Robertson, David J.; Zamkotsian, Frederic

    2004-07-01

    Smart Focal Planes are devices that enable the efficient sampling of a telescope's focal plane to feed spectroscopic and imaging instruments. Examples are integral field units (fiber and image slicers), cryogenic beam manipulators, and MOEMS (micro-opto-electromechanical systems) such as miniature slit shutters. These technologies are critical in making best use of the current 8m class telescopes for key science goals such as spectroscopic surveys of high redshift galaxies, and will be even more important for Extremely Large Telescope (ELT) instruments. In fact, the density of pixels in an ELT focal plane with several milliarcsecond resolution will mean that sub-sampling of the field will be needed even for imaging. We have proposed a joint European project to develop these technologies, building on expertise from partners in the UK, France, the Netherlands, Spain, Germany and others, and led by the UK. We describe the current status of these technologies, showing how they will contribute to the feasibility and performance of proposed instruments for ELTs, and concentrating on capabilities within Europe. We then outline the proposed future developments, highlighting the technical challenges, such as the difficulties of manufacturing and verifying complex image slicers with thousands of optical surfaces, and building highly reliable cryogenic mechanisms such as pick-off arms, beam steering mirrors and reconfigurble slit mechanisms.

  11. Altering FAK-paxillin interactions reduces adhesion, migration and invasion processes.

    Directory of Open Access Journals (Sweden)

    Thérèse B Deramaudt

    Full Text Available Focal adhesion kinase (FAK plays an important role in signal transduction pathways initiated at sites of integrin-mediated cell adhesion to the extracellular matrix. Thus, FAK is involved in many aspects of the metastatic process including adhesion, migration and invasion. Recently, several small molecule inhibitors which target FAK catalytic activity have been developed by pharmaceutical companies. The current study was aimed at addressing whether inhibiting FAK targeting to focal adhesions (FA represents an efficient alternative strategy to inhibit FAK downstream pathways. Using a mutagenesis approach to alter the targeting domain of FAK, we constructed a FAK mutant that fails to bind paxillin. Inhibiting FAK-paxillin interactions led to a complete loss of FAK localization at FAs together with reduced phosphorylation of FAK and FAK targets such as paxillin and p130Cas. This in turn resulted in altered FA dynamics and inhibition of cell adhesion, migration and invasion. Moreover, the migration properties of cells expressing the FAK mutant were reduced as compared to FAK-/- cells. This was correlated with a decrease in both phospho-Src and phospho-p130Cas levels at FAs. We conclude that targeting FAK-paxillin interactions is an efficient strategy to reduce FAK signalling and thus may represent a target for the development of new FAK inhibitors.

  12. Altering FAK-paxillin interactions reduces adhesion, migration and invasion processes.

    Science.gov (United States)

    Deramaudt, Thérèse B; Dujardin, Denis; Noulet, Fanny; Martin, Sophie; Vauchelles, Romain; Takeda, Ken; Rondé, Philippe

    2014-01-01

    Focal adhesion kinase (FAK) plays an important role in signal transduction pathways initiated at sites of integrin-mediated cell adhesion to the extracellular matrix. Thus, FAK is involved in many aspects of the metastatic process including adhesion, migration and invasion. Recently, several small molecule inhibitors which target FAK catalytic activity have been developed by pharmaceutical companies. The current study was aimed at addressing whether inhibiting FAK targeting to focal adhesions (FA) represents an efficient alternative strategy to inhibit FAK downstream pathways. Using a mutagenesis approach to alter the targeting domain of FAK, we constructed a FAK mutant that fails to bind paxillin. Inhibiting FAK-paxillin interactions led to a complete loss of FAK localization at FAs together with reduced phosphorylation of FAK and FAK targets such as paxillin and p130Cas. This in turn resulted in altered FA dynamics and inhibition of cell adhesion, migration and invasion. Moreover, the migration properties of cells expressing the FAK mutant were reduced as compared to FAK-/- cells. This was correlated with a decrease in both phospho-Src and phospho-p130Cas levels at FAs. We conclude that targeting FAK-paxillin interactions is an efficient strategy to reduce FAK signalling and thus may represent a target for the development of new FAK inhibitors.

  13. Adhesion defective BHK cell mutant has cell surface heparan sulfate proteoglycan of altered properties

    DEFF Research Database (Denmark)

    Couchman, J R; Austria, R; Woods, A;

    1988-01-01

    In the light of accumulating data that implicate cell surface heparan sulfate proteoglycans (HSPGs) with a role in cell interactions with extracellular matrix molecules such as fibronectin, we have compared the properties of these molecules in wild-type BHK cells and an adhesion-defective ricin......-resistant mutant (RicR14). Our results showed that the mutant, unlike BHK cells, cannot form focal adhesions when adherent to planar substrates in the presence of serum. Furthermore, while both cell lines possess similar amounts of cell surface HSPG with hydrophobic properties, that of RicR14 cells had decreased...

  14. Cellular adhesion responses to the heparin-binding (HepII) domain of fibronectin require heparan sulfate with specific properties

    DEFF Research Database (Denmark)

    Mahalingam, Yashithra; Gallagher, John T; Couchman, John R

    2006-01-01

    Cell surface heparan sulfate (HS) proteoglycans are required in development and postnatal repair. Important classes of ligands for HS include growth factors and extracellular matrix macromolecules. For example, the focal adhesion component syndecan-4 interacts with the III(12-14) region of fibron......Cell surface heparan sulfate (HS) proteoglycans are required in development and postnatal repair. Important classes of ligands for HS include growth factors and extracellular matrix macromolecules. For example, the focal adhesion component syndecan-4 interacts with the III(12-14) region...... trap mutation in one of the two major glucosaminoglycan polymerases (EXT1). Several separate, specific properties of cell surface HS are therefore required in cell adhesion responses to the fibronectin HepII domain....

  15. [Adhesive cutaneous pharmaceutical forms].

    Science.gov (United States)

    Gafiţanu, E; Matei, I; Mungiu, O C; Pavelescu, M; Mîndreci, I; Apostol, I; Ionescu, G

    1989-01-01

    The adhesive cutaneous pharmaceutical forms aimed to local action release the drug substance in view of a dermatological, traumatological, antirheumatic, cosmetic action. Two such preparations were obtained and their stability, consistency and pH were determined. The "in vitro" tests of their bioavailability revealed the dynamics of calcium ions release according to the associations of each preparation. The bioavailability determined by evaluating the pharmacological response demonstrated the antiinflammatory action obtained by the association of calcium ions with the components extracted from poplar muds. The therapeutical efficiency of the studied preparations has proved in the treatment of some sport injuries.

  16. Adhesive tape exfoliation

    DEFF Research Database (Denmark)

    Bohr, Jakob

    2015-01-01

    cleaving of a single chunk of graphite. For both cases, parallel and serial exfoliation, it is investigated how many generations of cleavages are needed. An approximate model with the probability distribution expressed as a simple closed form is presented and compared with the simulations.......Single-crystal graphite can be cleaved by the use of an adhesive tape. This was also the initial route for obtaining graphene, a one-layer thick graphite slab. In this letter a few simple and fun considerations are presented in an attempt to shed some light on why this procedure is successful...

  17. Syndecan proteoglycans and cell adhesion

    DEFF Research Database (Denmark)

    Woods, A; Oh, E S; Couchman, J R

    1998-01-01

    It is now becoming clear that a family of transmembrane proteoglycans, the syndecans, have important roles in cell adhesion. They participate through binding of matrix ligand to their glycosaminoglycan chains, clustering, and the induction of signaling cascades to modify the internal microfilament...... organization. Syndecans can modulate the type of adhesive responses induced by other matrix ligand-receptor interactions, such as those involving the integrins, and so contribute to the control of cell morphology, adhesion and migration....

  18. Adhesion properties of gecko setae

    Science.gov (United States)

    Hill, Ginel; Peattie, Anne; Daniels, Roxanne; Full, Robert; Kenny, Thomas

    2005-03-01

    Millions of keratin hairs on gecko feet, called setae, act as a spectacular dry adhesive. Each seta branches into hundreds of smaller fibers that terminate in spatula-shaped ends. Morphological differences between the setae from different gecko species are suspected to affect both single-seta and whole-animal adhesion properties. Single-seta adhesive force measurements made using a MEMS piezoresistive cantilever capable of two-axis measurements are presented.

  19. The neural cell adhesion molecule

    DEFF Research Database (Denmark)

    Berezin, V; Bock, E; Poulsen, F M

    2000-01-01

    During the past year, the understanding of the structure and function of neural cell adhesion has advanced considerably. The three-dimensional structures of several of the individual modules of the neural cell adhesion molecule (NCAM) have been determined, as well as the structure of the complex...... between two identical fragments of the NCAM. Also during the past year, a link between homophilic cell adhesion and several signal transduction pathways has been proposed, connecting the event of cell surface adhesion to cellular responses such as neurite outgrowth. Finally, the stimulation of neurite...

  20. Phosphoproteome reveals an atlas of protein signaling networks during osteoblast adhesion.

    Science.gov (United States)

    Milani, Renato; Ferreira, Carmen V; Granjeiro, José M; Paredes-Gamero, Edgar J; Silva, Rodrigo A; Justo, Giselle Z; Nader, Helena B; Galembeck, Eduardo; Peppelenbosch, Maikel P; Aoyama, Hiroshi; Zambuzzi, Willian F

    2010-04-01

    Cell adhesion on surfaces is a fundamental process in the emerging biomaterials field and developmental events as well. However, the mechanisms regulating this biological process in osteoblasts are not fully understood. Reversible phosphorylation catalyzed by kinases is probably the most important regulatory mechanism in eukaryotes. Therefore, the goal of this study is to assess osteoblast adhesion through a molecular prism under a peptide array technology, revealing essential signaling proteins governing adhesion-related events. First, we showed that there are main morphological changes on osteoblast shape during adhesion up to 3 h. Second, besides classical proteins activated upon integrin activation, our results showed a novel network involving signaling proteins such as Rap1A, PKA, PKC, and GSK3beta during osteoblast adhesion on polystyrene. Third, these proteins were grouped in different signaling cascades including focal adhesion establishment, cytoskeleton rearrangement, and cell-cycle arrest. We have thus provided evidence that a global phosphorylation screening is able to yield a systems-oriented look at osteoblast adhesion, providing new insights for understanding of bone formation and improvement of cell-substratum interactions. Altogether, these statements are necessary means for further intervention and development of new approaches for the progress of tissue engineering.

  1. Efficacy of lacosamide by focal seizure subtype.

    Science.gov (United States)

    Sperling, Michael R; Rosenow, Felix; Faught, Edward; Hebert, David; Doty, Pamela; Isojärvi, Jouko

    2014-10-01

    The purpose of this post hoc exploratory analysis was to determine the effects of the antiepileptic drug, lacosamide, on focal (partial-onset) seizure subtypes. Patient data from the three lacosamide pivotal trials were grouped and pooled by focal seizure subtype at Baseline: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized partial seizures (SGPS). Both efficacy outcomes (median percent change from Baseline to Maintenance Phase in seizure frequency per 28 days and the proportion of patients experiencing at least a 50% reduction in seizures) were evaluated by lacosamide dose (200, 400, or 600 mg/day) compared to placebo for each seizure subtype. An additional analysis was performed to determine whether a shift from more severe focal seizure subtypes to less severe occurred upon treatment with lacosamide. In patients with CPS or SGPS at Baseline, lacosamide 400 mg/day (maximum recommended daily dose) and 600 mg/day reduced the frequency of CPS and SGPS compared to placebo. Likewise, a proportion of patients with CPS and SGPS at Baseline experienced at least a 50% reduction in the frequency of CPS and SGPS (≥50% responder rate) in the lacosamide 400 and 600 mg/day groups compared with placebo. For both outcomes, numerically greatest responses were observed in the lacosamide 600 mg/day group among patients with SGPS at Baseline. In patients with SPS at Baseline, no difference between placebo and lacosamide was observed for either efficacy outcome. An additional exploratory analysis suggests that in patients with SPS at Baseline, CPS and SGPS may have been shifted to less severe SPS upon treatment with lacosamide. The results of these exploratory analyses revealed reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment.

  2. Ultrasonographic features of focal xanthogranulomatous pyelonephritis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jong Chul [Chungnam National University Hospital, Daejeon (Korea, Republic of)

    2003-09-15

    To analyze ultrasonographic (US) features of focal xanthogranulomatous pyelonephritis (XGP). US features of 15 patients with pathologically proven focal XGP were retrospectively analyzed by two radiologists who reached a consensus, in terms of the location, margin, size, and echo texture of the mass-like lesion, and presence or absence of associated calculi, lymphadenopathy, or local extension. These US findings were compared with CT findings. The patients were checked for the clinical symptom and sign through the review of hospital records. Thirteen of 15 patients were adults and 2 were children, and 10 were males. Their age ranged from 6 to 57 (mean, 39) years at presentation. Eight of 15 cases (53%) were in right kidney, and on US scan 12 cases (80%) were well circumscribed. The size of the mass ranged from 2.5 to 5.8 (mean, 3.8) cm. Of 15 masses, 13 (87%) were solid and two were cystic. Thirteen solid masses were composed of 10 masses (77%) with inner hypo- or anechoic foci and the other three masses without inner hypo- or anechoic foci, and the preoperative diagnosis was either renal cell carcinoma (n=11) or Wilms' tumor (n=2). The preoperative diagnosis in two cystic lesions (13%) was renal abscess. Renal calculi were found in one case, but lymphadenopathy or local extension was not depicted. Clinical symptoms and signs of flank pain, fever, leukocytosis, or anemia were found in 11 of 15 patients. Focal XGP revealed US features of solid or cystic masses confined within the renal outline mimicking renal tumor or abscess. US features, however, in association with clinical findings and other imaging findings (such as CT or MR imaging) may help the differential diagnosis of this lesion.

  3. The fibronectin-binding integrins alpha5beta1 and alphavbeta3 differentially modulate RhoA-GTP loading, organization of cell matrix adhesions, and fibronectin fibrillogenesis

    DEFF Research Database (Denmark)

    Danen, Erik H J; Sonneveld, Petra; Brakebusch, Cord

    2002-01-01

    We have studied the formation of different types of cell matrix adhesions in cells that bind to fibronectin via either alpha5beta1 or alphavbeta3. In both cases, cell adhesion to fibronectin leads to a rapid decrease in RhoA activity. However, alpha5beta1 but not alphavbeta3 supports high levels...... of RhoA activity at later stages of cell spreading, which are associated with a translocation of focal contacts to peripheral cell protrusions, recruitment of tensin into fibrillar adhesions, and fibronectin fibrillogenesis. Expression of an activated mutant of RhoA stimulates alphavbeta3-mediated...... fibrillogenesis. Despite the fact that alpha5beta1-mediated adhesion to the central cell-binding domain of fibronectin supports activation of RhoA, other regions of fibronectin are required for the development of alpha5beta1-mediated but not alphavbeta3-mediated focal contacts. Using chimeras of beta1 and beta3...

  4. Pressure sensitive adhesives from renewable resources

    OpenAIRE

    Maaßen, Wiebke

    2015-01-01

    Pressure-sensitive adhesives (PSAs) represent an important segment of the adhesives market. In this work, novel insights into the adhesive performance of bio-based pressure sensitive adhesives are presented. Three different homopolymers based on fatty acids derived from native vegetable oils as renewable feedstock were characterized in terms of their mechanical and adhesive properties.

  5. Characterization of DECam focal plane detectors

    Energy Technology Data Exchange (ETDEWEB)

    Diehl, H.Thomas; Angstadt, Robert; Campa, Julia; Cease, Herman; Derylo, Greg; Emes, John H.; Estrada, Juan; Kibik, Donna; Flaugher, Brenna L.; Holland, Steve E.; Jonas, Michelle; /Fermilab /Madrid, CIEMAT /LBL, Berkeley /Argonne /Pennsylvania U.

    2008-06-01

    DECam is a 520 Mpix, 3 square-deg FOV imager being built for the Blanco 4m Telescope at CTIO. This facility instrument will be used for the 'Dark Energy Survey' of the southern galactic cap. DECam has chosen 250 ?m thick CCDs, developed at LBNL, with good QE in the near IR for the focal plane. In this work we present the characterization of these detectors done by the DES team, and compare it to the DECam technical requirements. The results demonstrate that the detectors satisfy the needs for instrument.

  6. Characterization of DECam focal plane detectors

    Energy Technology Data Exchange (ETDEWEB)

    Diehl, H.Thomas; Angstadt, Robert; Campa, Julia; Cease, Herman; Derylo, Greg; Emes, John H.; Estrada, Juan; Kibik, Donna; Flaugher, Brenna L.; Holland, Steve E.; Jonas, Michelle; /Fermilab /Madrid, CIEMAT /LBL, Berkeley /Argonne /Pennsylvania U.

    2008-06-01

    DECam is a 520 Mpix, 3 square-deg FOV imager being built for the Blanco 4m Telescope at CTIO. This facility instrument will be used for the 'Dark Energy Survey' of the southern galactic cap. DECam has chosen 250 ?m thick CCDs, developed at LBNL, with good QE in the near IR for the focal plane. In this work we present the characterization of these detectors done by the DES team, and compare it to the DECam technical requirements. The results demonstrate that the detectors satisfy the needs for instrument.

  7. Focal inflammatory diseases of the liver

    Energy Technology Data Exchange (ETDEWEB)

    Oto, Aytekin; Akhan, Okan; Oezmen, Mustafa

    1999-10-01

    Inflammatory lesions constitute an important subgroup of focal liver lesions. They may mimic primary or metastatic neoplastic lesions and their differentiation from neoplasia is clinically very important since management of the patient significantly changes. Radiologists should have an important role in both the diagnosis and therapy of these lesions by performing percutaneous aspirations and drainages. In this review we discussed the radiological findings of pyogenic abscesses, amebic abscesses, candidiasis, tuberculosis, hydatic cysts, fascioliasis, ascariasis, schistosomiasis, and sarcoidosis with a special emphasis on US, CT and MR characteristics.

  8. Focal epithelial hyperplasia (Heck’s disease)

    OpenAIRE

    Parichehr Gheliani; Atefe Tavangar; Nakissa Torabinia; Laleh Maleki; Tahereh Nosratzehi

    2013-01-01

    Focal epithelial hyperplasia (Heck) is a rare lesion caused by human papilloma virus subtype 13 or 32 and presents as multiple small white or pink papules on the mucosal surface of lips, buccal mucosa and tongue usually seen in children and adolescent of American Indian and Eskimo background. This disease has a genetic basis. The site of new lesions and recurrence are unpredictable. Continued follow up of the patient is often necessary. In this report, a 50-year-old woman is described with be...

  9. FOCAL EPITHELIAL HYPERPLASIA: HECK’S DISEASE

    Directory of Open Access Journals (Sweden)

    Brzeziński Piotr

    2010-10-01

    Full Text Available Heck's disease (focal epithelial hyperplasia (FEH is clinically characterized by multiple circumscribed, soft elevated nodules of the oral mucosa. Papules and plaques are usually the color of normal mucosa, but may be pale or, rarely, white. Disease may persist for years, producing a significant reduction in quality of life. Lessions may be located in the area of mucous membranes of the lips, cheeks and tongue. It is believed that the two virus types are responsible for the FEH, are: HPV 13 and HPV 32. Different therapeutic procedures have been reported: surgical excision, laser ablation, cryotherapy, electrocauterization, interferon, retinoic acid, 5% immiquimod.

  10. Focal xanthogranulomatous pyelonephritis: reports of 2 cases

    Energy Technology Data Exchange (ETDEWEB)

    Han, Dae Hee; Jeong, Young Ki; Kim, Seung Hyup [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    1996-07-01

    Xanthogranulomatous pyelonephritis is a chronic inflammatory condition which in most cases involves either an entire non-duplicated kidney or a moiety of a duplicated kidney. These cases present with quite characteristic radiologic findings including an enlarged nonfunctioning kidney and renal stones. However, when the condition involves only a part of a non-duplicated kidney and especially where there is an absence of the specific findings described above, differentiation from cystic neoplasm may be difficult. We report the radiologic findings of two such cases of focal xanthogranulomatous pyelonephritis.

  11. Improved Adhesion and Compliancy of Hierarchical Fibrillar Adhesives.

    Science.gov (United States)

    Li, Yasong; Gates, Byron D; Menon, Carlo

    2015-08-01

    The gecko relies on van der Waals forces to cling onto surfaces with a variety of topography and composition. The hierarchical fibrillar structures on their climbing feet, ranging from mesoscale to nanoscale, are hypothesized to be key elements for the animal to conquer both smooth and rough surfaces. An epoxy-based artificial hierarchical fibrillar adhesive was prepared to study the influence of the hierarchical structures on the properties of a dry adhesive. The presented experiments highlight the advantages of a hierarchical structure despite a reduction of overall density and aspect ratio of nanofibrils. In contrast to an adhesive containing only nanometer-size fibrils, the hierarchical fibrillar adhesives exhibited a higher adhesion force and better compliancy when tested on an identical substrate.

  12. Stretchable, adhesion-tunable dry adhesive by surface wrinkling.

    Science.gov (United States)

    Jeong, Hoon Eui; Kwak, Moon Kyu; Suh, Kahp Y

    2010-02-16

    We introduce a simple yet robust method of fabricating a stretchable, adhesion-tunable dry adhesive by combining replica molding and surface wrinkling. By utilizing a thin, wrinkled polydimethyl siloxane (PDMS) sheet with a thickness of 1 mm with built-in micropillars, active, dynamic control of normal and shear adhesion was achieved. Relatively strong normal (approximately 10.8 N/cm(2)) and shear adhesion (approximately 14.7 N/cm(2)) forces could be obtained for a fully extended (strained) PDMS sheet (prestrain of approximately 3%), whereas the forces could be rapidly reduced to nearly zero once the prestrain was released (prestrain of approximately 0.5%). Moreover, durability tests demonstrated that the adhesion strength in both the normal and shear directions was maintained over more than 100 cycles of attachment and detachment.

  13. Effect of adhesive thickness on adhesively bonded T-joint

    Science.gov (United States)

    Abdullah, A. R.; Afendi, Mohd; Majid, M. S. Abdul

    2013-12-01

    The aim of this work is to analyze the effect of adhesive thickness on tensile strength of adhesively bonded stainless steel T-joint. Specimens were made from SUS 304 Stainless Steel plate and SUS 304 Stainless Steel perforated plate. Four T-joint specimens with different adhesive thicknesses (0.5, 1.0, 1.5 and 2.0 mm) were made. Experiment result shows T-joint specimen with adhesive thickness of 1.0 mm yield highest maximum load. Identical T-joint specimen jointed by spot welding was also tested. Tensile test shows welded T-Joint had eight times higher tensile load than adhesively bonded T-joint. However, in low pressure application such as urea granulator chamber, high tensile strength is not mandatory. This work is useful for designer in fertilizer industry and others who are searching for alternative to spot welding.

  14. Stretchable, Adhesion-Tunable Dry Adhesive by Surface Wrinkling

    KAUST Repository

    Jeong, Hoon Eui

    2010-02-16

    We introduce a simple yet robust method of fabricating a stretchable, adhesion-tunable dry adhesive by combining replica molding and surface wrinkling. By utilizing a thin, wrinkled polydimethyl siloxane (PDMS) sheet with a thickness of 1 mm with built-in micropillars, active, dynamic control of normal and shear adhesion was achieved. Relatively strong normal (∼10.8 N/cm2) and shear adhesion (∼14.7 N/cm2) forces could be obtained for a fully extended (strained) PDMS sheet (prestrain of∼3%), whereas the forces could be rapidly reduced to nearly zero once the prestrain was released (prestrain of ∼0.5%). Moreover, durability tests demonstrated that the adhesion strength in both the normal and shear directions was maintained over more than 100 cycles of attachment and detachment. © 2010 American Chemical Society.

  15. 21 CFR 880.5240 - Medical adhesive tape and adhesive bandage.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Medical adhesive tape and adhesive bandage. 880... Personal Use Therapeutic Devices § 880.5240 Medical adhesive tape and adhesive bandage. (a) Identification. A medical adhesive tape or adhesive bandage is a device intended for medical purposes that...

  16. Focal liver lesions: Practical magnetic resonance imagingapproach

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    With the widespread of cross-sectional imaging, a growthof incidentally detected focal liver lesions (FLL) hasbeen observed. A reliable detection and characterizationof FLL is critical for optimal patient management.Maximizing accuracy of imaging in the context ofFLL is paramount in avoiding unnecessary biopsies,which may result in post-procedural complications. Atremendous development of new imaging techniqueshas taken place during these last years. Nowadays,Magnetic resonance imaging (MRI) plays a key rolein management of liver lesions, using a radiation-freetechnique and a safe contrast agent profile. MRI playsa key role in the non-invasive correct characterizationof FLL. MRI is capable of providing comprehensiveand highly accurate diagnostic information, withthe additional advantage of lack of harmful ionizingradiation. These properties make MRI the mainstay forthe noninvasive evaluation of focal liver lesions. In thispaper we review the state-of-the-art MRI liver protocol,briefly discussing different sequence types, the uniquecharacteristics of imaging non-cooperative patients anddiscuss the role of hepatocyte-specific contrast agents.A review of the imaging features of the most commonbenign and malignant FLL is presented, supplementedby a schematic representation of a simplistic practicalapproach on MRI.

  17. The Piriform Cortex and Human Focal Epilepsy

    Directory of Open Access Journals (Sweden)

    David eVaughan

    2014-12-01

    Full Text Available It is surprising that the piriform cortex, when compared to the hippocampus, has been given relatively little significance in human epilepsy. Like the hippocampus, it has a phylogenetically preserved three-layered cortex that is vulnerable to excitotoxic injury, has broad connections to both limbic and cortical areas, and is highly epileptogenic - being critical to the kindling process. The well-known phenomenon of early olfactory auras in temporal lobe epilepsy highlights its clinical relevance in humans. Perhaps because it is anatomically indistinct and difficult to approach surgically, as it clasps the middle cerebral artery, it has, until now, been understandably neglected. In this review we emphasize how its unique anatomical and functional properties, as primary olfactory cortex, predispose it to involvement in focal epilepsy. From recent convergent findings in human neuroimaging, clinical epileptology and experimental animal models, we make the case that the piriform cortex is likely to play a facilitating and amplifying role in human focal epileptogenesis, and may influence progression to epileptic intractability.

  18. The piriform cortex and human focal epilepsy.

    Science.gov (United States)

    Vaughan, David N; Jackson, Graeme D

    2014-01-01

    It is surprising that the piriform cortex, when compared to the hippocampus, has been given relatively little significance in human epilepsy. Like the hippocampus, it has a phylogenetically preserved three-layered cortex that is vulnerable to excitotoxic injury, has broad connections to both limbic and cortical areas, and is highly epileptogenic - being critical to the kindling process. The well-known phenomenon of early olfactory auras in temporal lobe epilepsy highlights its clinical relevance in human beings. Perhaps because it is anatomically indistinct and difficult to approach surgically, as it clasps the middle cerebral artery, it has, until now, been understandably neglected. In this review, we emphasize how its unique anatomical and functional properties, as primary olfactory cortex, predispose it to involvement in focal epilepsy. From recent convergent findings in human neuroimaging, clinical epileptology, and experimental animal models, we make the case that the piriform cortex is likely to play a facilitating and amplifying role in human focal epileptogenesis, and may influence progression to epileptic intractability.

  19. Musical anhedonia after focal brain damage.

    Science.gov (United States)

    Belfi, Amy M; Evans, Erin; Heskje, Jonah; Bruss, Joel; Tranel, Daniel

    2017-03-01

    People listen to music because it is pleasurable. However, there are individual differences in the reward value of music. At the extreme low end of this continuum, individuals who derive no pleasure from music are said to have 'musical anhedonia.' Cases of acquired musical anhedonia following focal brain damage are rare, with only a handful having been reported in the scientific literature. Here, we surveyed a large sample of patients with focal brain damage to identify the frequency, specificity, and neural correlates of acquired musical anhedonia. Participants completed the Musical anhedonia Questionnaire and the Barcelona Music Reward Questionnaire (Mas-Herrero et al., 2013) to assess changes in musical enjoyment and reward following brain injury. Neuroanatomical data were analyzed with a proportional MAP-3 method to create voxelwise lesion proportion difference maps. No clear or consistent neuroanatomical correlates of musical anhedonia were identified. One patient with damage to the right-hemisphere putamen and internal capsule displayed specific and severe acquired musical anhedonia. These findings indicate that acquired musical anhedonia is very uncommon, a result which is consistent with the fact that only a small number of such cases have been reported in the literature. This rarity could have positive implications for the therapeutic potentialities of music in patients with severe neurological disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Fast & Furious focal-plane wavefront sensing

    CERN Document Server

    Korkiakoski, Visa; Doelman, Niek; Kenworthy, Matthew; Otten, Gilles; Verhaegen, Michel

    2014-01-01

    We present two complementary algorithms suitable for using focal-plane measurements to control a wavefront corrector with an extremely high spatial resolution. The algorithms use linear approximations to iteratively minimize the aberrations seen by the focal-plane camera. The first algorithm, Fast & Furious (FF), uses a weak-aberration assumption and pupil symmetries to achieve fast wavefront reconstruction. The second algorithm, an extension to FF, can deal with an arbitrary pupil shape; it uses a Gerchberg-Saxton style error reduction to determine the pupil amplitudes. Simulations and experimental results are shown for a spatial light modulator controlling the wavefront with a resolution of 170 x 170 pixels. The algorithms increase the Strehl ratio from ~0.75 to 0.98-0.99, and the intensity of the scattered light is reduced throughout the whole recorded image of 320 x 320 pixels. The remaining wavefront rms error is estimated to be ~0.15 rad with FF and ~0.10 rad with FF-GS.

  1. Clinical and Morphological Features of Focal Adenomyosis

    Directory of Open Access Journals (Sweden)

    Yuliya B. Kurashvili

    2013-09-01

    Full Text Available Background: Adenomyosis is a very real problem encountered in modern gynecology due to the increase in the incidence, severity of the disease, and absence of effective methods of conservative treatment. The aim of the study was to investigate the clinical and morphological features of the focal and diffuse forms of adenomyosis. Methods and Results: The study involved 70 women who applied to the Center with the diagnosis of ‘adenomyosis’. Examination included transvaginal sonography (TVS, magnetic resonance spectroscopy (MRS, and morphological study of the adenomyotic foci. With a probability of 99%, one can argue that focal adenomyosis (FA in its clinical features is different from diffuse adenomyosis (DA in all its major manifestations. Conclusion: FA has unique morphological characteristics and clinical features. The diagnosis of FA should be based on a complex of clinical and instrumental data in conjunction with morphological process verification. Besides, there are difficulties in the diagnosis of FA, which is a major reason for the incorrect determination of the treatment tactic for patients. However, the application of MRS allows the preoperative identification of the biochemical structure of the focus and determination of its borders, and in the postoperative period, selection of optimal treatment tactics based on the identified morphological features of the removed adenomyotic foci.

  2. Cleaning properties of dry adhesives

    Institute of Scientific and Technical Information of China (English)

    J.; P.; DíAZ; TéLLEZ; D.; SAMEOTO; C.; MENON

    2010-01-01

    In this paper we present a study into the cleaning properties of synthetic dry adhesives. We have manufactured the adhesive micro-fibres through a low-cost, high yield fabrication method using Sylgard 184 Polydimethylsiloxane (PDMS) as the structural material. We deliberately contaminated the adhesive samples with different sized particles in the micro and macro scales and tested different cleaning methods for their efficacy with respect to each particle size. We investigated different cleaning methods, which included the use of wax moulding, vibration and pressure sensitive adhesives. For adhesion testing we used a custom system with a linear stage and a force sensor indenting a hemispherical probe into the adhesive surface and measuring the pull-off force. To characterize the cleaning efficacy we visually inspected each sample in a microscope and weighed the samples with a microgram-accuracy analytical balance. Results showed that the moulding method induced adhesion recovery in a greater percentage than the other cleaning methods and even helped with the recovery of collapsed posts in some cases. On the other hand pressure sensitive adhesives seem to have the upper hand with regards to certain particle sizes that can potentially pose problems with the moulding method.

  3. Idiopathic focal epilepsies: the "lost tribe".

    Science.gov (United States)

    Pal, Deb K; Ferrie, Colin; Addis, Laura; Akiyama, Tomoyuki; Capovilla, Giuseppe; Caraballo, Roberto; de Saint-Martin, Anne; Fejerman, Natalio; Guerrini, Renzo; Hamandi, Khalid; Helbig, Ingo; Ioannides, Andreas A; Kobayashi, Katsuhiro; Lal, Dennis; Lesca, Gaetan; Muhle, Hiltrud; Neubauer, Bernd A; Pisano, Tiziana; Rudolf, Gabrielle; Seegmuller, Caroline; Shibata, Takashi; Smith, Anna; Striano, Pasquale; Strug, Lisa J; Szepetowski, Pierre; Valeta, Thalia; Yoshinaga, Harumi; Koutroumanidis, Michalis

    2016-09-01

    The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., 2010), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many "treats" for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age-related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow-wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro-temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau-Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro-clinical features warranting inclusion. In addition, a number of less well-defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence. The

  4. Alterations in ovarian cancer cell adhesion drive taxol resistance by increasing microtubule dynamics in a FAK-dependent manner.

    Science.gov (United States)

    McGrail, Daniel J; Khambhati, Niti N; Qi, Mark X; Patel, Krishan S; Ravikumar, Nithin; Brandenburg, Chandler P; Dawson, Michelle R

    2015-04-17

    Chemorefractory ovarian cancer patients show extremely poor prognosis. Microtubule-stabilizing Taxol (paclitaxel) is a first-line treatment against ovarian cancer. Despite the close interplay between microtubules and cell adhesion, it remains unknown if chemoresistance alters the way cells adhere to their extracellular environment, a process critical for cancer metastasis. To investigate this, we isolated Taxol-resistant populations of OVCAR3 and SKOV3 ovarian cancer cell lines. Though Taxol-resistant cells neither effluxed more drug nor gained resistance to other chemotherapeutics, they did display increased microtubule dynamics. These changes in microtubule dynamics coincided with faster attachment rates and decreased adhesion strength, which correlated with increased surface β1-integrin expression and decreased focal adhesion formation, respectively. Adhesion strength correlated best with Taxol-sensitivity, and was found to be independent of microtubule polymerization but dependent on focal adhesion kinase (FAK), which was up-regulated in Taxol-resistant cells. FAK inhibition also decreased microtubule dynamics to equal levels in both populations, indicating alterations in adhesive signaling are up-stream of microtubule dynamics. Taken together, this work demonstrates that Taxol-resistance dramatically alters how ovarian cancer cells adhere to their extracellular environment causing down-stream increases in microtubule dynamics, providing a therapeutic target that may improve prognosis by not only recovering drug sensitivity, but also decreasing metastasis.

  5. Universal adhesives: the next evolution in adhesive dentistry?

    Science.gov (United States)

    Alex, Gary

    2015-01-01

    Every so often a new material, technique, or technological breakthrough spurs a paradigm shift in the way dentistry is practiced. The development and evolution of reliable enamel and dentin bonding agents is one such example. Indeed, the so-called "cosmetic revolution" in dentistry blossomed in large part due to dramatic advances in adhesive technology. It is the ability to bond various materials in a reasonably predictable fashion to both enamel and dentin substrates that enables dentists to routinely place porcelain veneers, direct and indirect composites, and a plethora of other restorative and esthetic materials. In fact, the longevity and predictability of many (if not most) current restorative procedures is wholly predicated on the dentist's ability to bond various materials to tooth tissues. Adhesive systems have progressed from the largely ineffective systems of the 1970s and early 1980s to the relatively successful total- and self-etching systems of today. The latest players in the adhesive marketplace are the so-called "universal adhesives." In theory, these systems have the potential to significantly simplify and expedite adhesive protocols and may indeed represent the next evolution in adhesive dentistry. But what defines a universal system, and are all these new systems truly "universal" and everything they are claimed to be? This article will examine the origin, chemistry, strengths, weaknesses, and clinical relevance of this new genre of dental adhesives.

  6. MRI-guided focal therapy of prostate cancer.

    Science.gov (United States)

    Mathew, Melvy Sarah; Oto, Aytekin

    2017-03-01

    With the advent of focal therapy as a recognized treatment option for men with prostate cancer, there are a host of emerging interventions that take advantage of MRI for image guidance. Focal therapy affords a middleground option for patients with low- to intermediate-grade prostate cancer by providing a means of keeping their cancer at bay while avoiding the negative consequences of radical therapies. However, the practice of focal treatment is far from straightforward, with some believing focal treatment errs on the side of overtreatment among patients with low-grade cancer; others worry it is undertreatment in potentially significant multifocal disease. Further research is necessary, both relating to focal therapy in general and to the utility of each MRI-guided focal treatment discussed.

  7. The Adhesion Modulating Properties of Tenascin-W

    Directory of Open Access Journals (Sweden)

    Florence Brellier, Enrico Martina, Matthias Chiquet, Jacqueline Ferralli, Michael van der Heyden, Gertraud Orend, Johannes C. Schittny, Ruth Chiquet-Ehrismann, Richard P. Tucker

    2012-01-01

    Full Text Available Tenascins are extracellular matrix glycoproteins associated with cell motility, proliferation and differentiation. Tenascin-C inhibits cell spreading by binding to fibronectin; tenascin-R and tenascin-X also have anti-adhesive properties in vitro. Here we have studied the adhesion modulating properties of the most recently characterized tenascin, tenascin-W. C2C12 cells, a murine myoblast cell line, will form broad lamellipodia with stress fibers and focal adhesion complexes after culture on fibronectin. In contrast, C2C12 cells cultured on tenascin-W fail to spread and form stress fibers or focal adhesion complexes, and instead acquire a multipolar shape with short, actin-tipped pseudopodia. The same stellate morphology is observed when C2C12 cells are cultured on a mixture of fibronectin and tenascin-W, or on fibronectin in the presence of soluble tenascin-W. Tenascin-W combined with fibronectin also inhibits the spreading of mouse embryo fibroblasts when compared with cells cultured on fibronectin alone. The similarity between the adhesion modulating effects of tenascin-W and tenascin-C in vitro led us to study the possibility of tenascin-W compensating for tenascin-C in tenascin-C knockout mice, especially during epidermal wound healing. Dermal fibroblasts harvested from a tenascin-C knockout mouse express tenascin-W, but dermal fibroblasts taken from a wild type mouse do not. However, there is no upregulation of tenascin-W in the dermis of tenascin-C knockout mice, or in the granulation tissue of skin wounds in tenascin-C knockout animals. Similarly, tenascin-X is not upregulated in early wound granulation tissue in the tenascin-C knockout mice. Thus, tenascin-W is able to inhibit cell spreading in vitro and it is upregulated in dermal fibroblasts taken from the tenascin-C knockout mouse, but neither it nor tenascin-X are likely to compensate for missing tenascin-C during wound healing.

  8. Physical Activity Performance of Focal Middle School Students

    Science.gov (United States)

    Erfle, Stephen E.; Gelbaugh, Corey M.

    2013-01-01

    Histograms of push-ups and curl-ups from a sample of more than 9,000 students show periodic spikes at five and 10 unit intervals. This article argues that these spikes are related to focal points, a game theoretic concept popularized by Nobel Laureate Thomas Schelling. Being focal on one test makes one more likely to be focal on the other. Focal…

  9. Pharmacological response of systemically derived focal epileptic lesions

    Energy Technology Data Exchange (ETDEWEB)

    Remler, M.P.; Sigvardt, K.; Marcussen, W.H.

    1986-11-01

    Focal epileptic lesions were made in rats by systemic focal epileptogenesis. In this method, a focal lesion of the blood-brain barrier (BBB) is produced by focal alpha irradiation followed by repeated systemic injection of a convulsant drug that cannot cross the normal BBB, resulting in a chronic epileptic focus. Changes in the spike frequency of these foci in response to various drugs was recorded. The controls, saline and chlorpromazine, produced no change. Phenytoin, phenobarbital, chlordiazepoxide, and valproic acid produced the expected decrease in spike frequency. Pentobarbital and diazepam produced a paradoxical increase in spike frequency.

  10. Prevalence and Clinical Features of Focal Takotsubo Cardiomyopathy.

    Science.gov (United States)

    Kato, Ken; Kitahara, Hideki; Fujimoto, Yoshihide; Sakai, Yoshiaki; Ishibashi, Iwao; Himi, Toshiharu; Kobayashi, Yoshio

    2016-07-25

    Because it is difficult to distinguish between focal takotsubo cardiomyopathy and aborted myocardial infarction, there is little information about the prevalence and clinical features of focal takotsubo cardiomyopathy. Our cardiac catheterization databases were queried to identify patients with focal takotsubo cardiomyopathy and other types of takotsubo cardiomyopathy. We defined focal takotsubo cardiomyopathy as hypo-, a- or dyskinesis in both anterolateral and septal segments without obstructive coronary artery disease explaining the wall motion abnormality. A total of 10 patients were diagnosed with focal takotsubo cardiomyopathy. The control group comprised patients with takotsubo cardiomyopathy with apical, mid-ventricular, or basal ballooning. Clinical features and in-hospital outcomes were compared between patients with focal takotsubo cardiomyopathy and those with other types of takotsubo cardiomyopathy. Among the 144 patients with takotsubo cardiomyopathy, the apical, mid-ventricular, basal, and focal types occurred in 85 (59.0%), 49 (34.0%), 0 (0%), and 10 patients (6.9%), respectively. The left ventricular ejection fraction was significantly higher in the focal group compared with the apical and mid-ventricular group (56±13 vs. 45±13 vs. 46±12%, P=0.03). In-hospital outcome was not significantly different among the 3 groups. Focal takotsubo cardiomyopathy is not rare. Biplane left ventriculography is useful for its diagnosis. (Circ J 2016; 80: 1824-1829).

  11. Botulinum toxin physiology in focal hand and cranial dystonia.

    Science.gov (United States)

    Karp, Barbara Illowsky

    2012-11-20

    The safety and efficacy of botulinum toxin for the treatment of focal hand and cranial dystonias are well-established. Studies of these adult-onset focal dystonias reveal both shared features, such as the dystonic phenotype of muscle hyperactivity and overflow muscle contraction and divergent features, such as task specificity in focal hand dystonia which is not a common feature of cranial dystonia. The physiologic effects of botulinum toxin in these 2 disorders also show both similarities and differences. This paper compares and contrasts the physiology of focal hand and cranial dystonias and of botulinum toxin in the management of these disorders.

  12. Botulinum Toxin Physiology in Focal Hand and Cranial Dystonia

    Directory of Open Access Journals (Sweden)

    Barbara Illowsky Karp

    2012-11-01

    Full Text Available The safety and efficacy of botulinum toxin for the treatment of focal hand and cranial dystonias are well-established. Studies of these adult-onset focal dystonias reveal both shared features, such as the dystonic phenotype of muscle hyperactivity and overflow muscle contraction and divergent features, such as task specificity in focal hand dystonia which is not a common feature of cranial dystonia. The physiologic effects of botulinum toxin in these 2 disorders also show both similarities and differences. This paper compares and contrasts the physiology of focal hand and cranial dystonias and of botulinum toxin in the management of these disorders.

  13. Focal Length Affects Depicted Shape and Perception of Facial Images.

    Science.gov (United States)

    Třebický, Vít; Fialová, Jitka; Kleisner, Karel; Havlíček, Jan

    2016-01-01

    Static photographs are currently the most often employed stimuli in research on social perception. The method of photograph acquisition might affect the depicted subject's facial appearance and thus also the impression of such stimuli. An important factor influencing the resulting photograph is focal length, as different focal lengths produce various levels of image distortion. Here we tested whether different focal lengths (50, 85, 105 mm) affect depicted shape and perception of female and male faces. We collected three portrait photographs of 45 (22 females, 23 males) participants under standardized conditions and camera setting varying only in the focal length. Subsequently, the three photographs from each individual were shown on screen in a randomized order using a 3-alternative forced-choice paradigm. The images were judged for attractiveness, dominance, and femininity/masculinity by 369 raters (193 females, 176 males). Facial width-to-height ratio (fWHR) was measured from each photograph and overall facial shape was analysed employing geometric morphometric methods (GMM). Our results showed that photographs taken with 50 mm focal length were rated as significantly less feminine/masculine, attractive, and dominant compared to the images taken with longer focal lengths. Further, shorter focal lengths produced faces with smaller fWHR. Subsequent GMM revealed focal length significantly affected overall facial shape of the photographed subjects. Thus methodology of photograph acquisition, focal length in this case, can significantly affect results of studies using photographic stimuli perhaps due to different levels of perspective distortion that influence shapes and proportions of morphological traits.

  14. The Molecular Architecture of Cell Adhesion: Dynamic Remodeling Revealed by Videonanoscopy

    Directory of Open Access Journals (Sweden)

    Arnauld eSergé

    2016-05-01

    Full Text Available The plasma membrane delimits the cell, which is the basic unit of living organisms, and is also a privileged site for cell communication with the environment. Cell adhesion can occur through cell-cell and cell-matrix contacts. Adhesion proteins such as integrins and cadherins also constitute receptors for inside-out and outside-in signaling within proteolipidic platforms. Adhesion molecule targeting and stabilization relies on specific features such as preferential segregation by the sub-membrane cytoskeleton meshwork and within membrane proteolipidic microdomains. This review presents an overview of the recent insights brought by the latest developments in microscopy, to unravel the molecular remodeling occurring at cell contacts. The dynamic aspect of cell adhesion was recently highlighted by super-resolution videomicroscopy, also named videonanoscopy. By circumventing the diffraction limit of light, nanoscopy has allowed the monitoring of molecular localization and behavior at the single-molecule level, on fixed and living cells. Accessing molecular-resolution details such as quantitatively monitoring components entering and leaving cell contacts by lateral diffusion and reversible association has revealed an unexpected plasticity. Adhesion structures can be highly specialized, such as focal adhesion in motile cells, as well as immune and neuronal synapses. Spatiotemporal reorganization of adhesion molecules, receptors and adaptors directly relates to structure/function modulation. Assembly of these supramolecular complexes is continuously balanced by dynamic events, remodeling adhesions on various timescales, notably by molecular conformation switches, lateral diffusion within the membrane and endo/exocytosis. Pathological alterations in cell adhesion are involved in cancer evolution, through cancer stem cell interaction with stromal niches, growth, extravasation and metastasis.

  15. The Molecular Architecture of Cell Adhesion: Dynamic Remodeling Revealed by Videonanoscopy.

    Science.gov (United States)

    Sergé, Arnauld

    2016-01-01

    The plasma membrane delimits the cell, which is the basic unit of living organisms, and is also a privileged site for cell communication with the environment. Cell adhesion can occur through cell-cell and cell-matrix contacts. Adhesion proteins such as integrins and cadherins also constitute receptors for inside-out and outside-in signaling within proteolipidic platforms. Adhesion molecule targeting and stabilization relies on specific features such as preferential segregation by the sub-membrane cytoskeleton meshwork and within membrane proteolipidic microdomains. This review presents an overview of the recent insights brought by the latest developments in microscopy, to unravel the molecular remodeling occurring at cell contacts. The dynamic aspect of cell adhesion was recently highlighted by super-resolution videomicroscopy, also named videonanoscopy. By circumventing the diffraction limit of light, nanoscopy has allowed the monitoring of molecular localization and behavior at the single-molecule level, on fixed and living cells. Accessing molecular-resolution details such as quantitatively monitoring components entering and leaving cell contacts by lateral diffusion and reversible association has revealed an unexpected plasticity. Adhesion structures can be highly specialized, such as focal adhesion in motile cells, as well as immune and neuronal synapses. Spatiotemporal reorganization of adhesion molecules, receptors, and adaptors directly relates to structure/function modulation. Assembly of these supramolecular complexes is continuously balanced by dynamic events, remodeling adhesions on various timescales, notably by molecular conformation switches, lateral diffusion within the membrane and endo/exocytosis. Pathological alterations in cell adhesion are involved in cancer evolution, through cancer stem cell interaction with stromal niches, growth, extravasation, and metastasis.

  16. Smart trigger logic for focal plane arrays

    Science.gov (United States)

    Levy, James E; Campbell, David V; Holmes, Michael L; Lovejoy, Robert; Wojciechowski, Kenneth; Kay, Randolph R; Cavanaugh, William S; Gurrieri, Thomas M

    2014-03-25

    An electronic device includes a memory configured to receive data representing light intensity values from pixels in a focal plane array and a processor that analyzes the received data to determine which light values correspond to triggered pixels, where the triggered pixels are those pixels that meet a predefined set of criteria, and determines, for each triggered pixel, a set of neighbor pixels for which light intensity values are to be stored. The electronic device also includes a buffer that temporarily stores light intensity values for at least one previously processed row of pixels, so that when a triggered pixel is identified in a current row, light intensity values for the neighbor pixels in the previously processed row and for the triggered pixel are persistently stored, as well as a data transmitter that transmits the persistently stored light intensity values for the triggered and neighbor pixels to a data receiver.

  17. Focal Epithelial Hyperplasia. A Case Report

    Directory of Open Access Journals (Sweden)

    Rafael Pila Pérez

    2014-02-01

    Full Text Available Focal epithelial hyperplasia, also known as Heck's disease, is relatively rare, occurring mostly in children and adolescents. A case of a 20 year-old female patient treated at the Manuel Ascunce Domenech University Hospital in Camagüey due to papular lesions, which had evolved for ten months, is presented. Other viral diseases were ruled out; however based on histological studies, it was concluded that she suffered from Heck disease, which is frequently treated by dentists, but little known among pediatricians, internists and dermatologists. Because of its etiology, many cases are related to human papilloma virus infection. When the disease evolves, treatment can involve excision, laser surgery or cryotherapy. The latter method was used in this patient with satisfactory results, as she is completely asymptomatic.

  18. Focal cemento-osseous dysplasia of mandible.

    Science.gov (United States)

    Cankaya, Abdülkadir Burak; Erdem, Mehmet Ali; Olgac, Vakur; Firat, Deniz Refia

    2012-09-03

    Fibro-osseous lesions are disturbances in bone metabolism in which normal bone is replaced by a connective tissue matrix that then gradually develops into cemento-osseous tissue. Typically, the lesion is asymptomatic and is detected on routine radiographic examination. Radiologically, this lesion has three stages of maturation: pure radiolucent, radiopaque/mixed radiolucent, and radiopaque appearance. During these stages the lesion can be misdiagnosed. In this case report a 69-year- old patient with a a complaint of painless swelling of the left mandibular molar and premolar area is presented along with a review of the differential diagnoses considered in order to reach a final diagnosis of focal cemento-osseous dysplasia.

  19. Focal epilepsy in the Belgian shepherd

    DEFF Research Database (Denmark)

    Berendt, Mette; Gulløv, Christina Hedal; Fredholm, Merete

    2009-01-01

    OBJECTIVES: To establish the mode of inheritance and describe the clinical features of epilepsy in the Belgian shepherd, taking the outset in an extended Danish dog family (199 individuals) of Groenendael and Tervueren with accumulated epilepsy. METHODS: Epilepsy positive individuals (living...... and deceased) were ascertained through a telephone interview using a standardised questionnaire regarding seizure history and phenomenology. Living dogs were invited to a detailed clinical evaluation. Litters more than five years of age, or where epilepsy was present in all offspring before the age of five......, were included in the calculations of inheritance. results: Out of 199 family members, 66 dogs suffered from epilepsy. The prevalence of epilepsy in the family was 33%. Fifty-five dogs experienced focal seizures with or without secondary generalisation, while four dogs experienced primary generalised...

  20. Tunable focalizers: axicons, lenses, and axilenses

    Science.gov (United States)

    Ojeda-Castañeda, Jorge; Gómez-Sarabia, Cristina M.; Ledesma, Sergio

    2013-09-01

    We propose the use of a pair of phase masks, which have both radial and angular variations, for implementing several varifocal devices. One mask of the proposed pair has a complex amplitude transmittance that is the complex conjugate of the other member of the pair. We show that the overall complex amplitude transmittance has only a radial variation after introducing an in-plane rotation, say by an angle β, between the members of the pair. However, we note that the optical power is proportional to the rotation angle β. As examples of the proposed method, we show that the refractive pair is useful for implementing varifocal lenses, tunable axicons, controllable axilenses, as well as annularly distributed focalizers.

  1. Design of large aperture focal plane shutter

    Science.gov (United States)

    Hu, Jia-wen; Ma, Wen-li; Huang, Jin-long

    2012-09-01

    To satisfy the requirement of large telescope, a large aperture focal plane shutter with aperture size of φ200mm was researched and designed to realize, which could be started and stopped in a relative short time with precise position, and also the blades could open and close at the same time at any orientation. Timing-belts and stepper motors were adopted as the drive mechanism. Velocity and position of the stepper motors were controlled by the PWM pulse generated by DSP. Exponential curve is applied to control the velocity of the stepper motors to make the shutter start and stop in a short time. The closing/open time of shutter is 0.2s, which meets the performance requirements of large telescope properly.

  2. Focal cerebral lesions and painting abilities.

    Science.gov (United States)

    Mazzucchi, Anna; Sinforiani, Elena; Boller, François

    2013-01-01

    Focal lesions such as strokes significantly affect painting production in the vast majority of artists. In particular, painters, when they resume painting, show changes in their painting style. In exceptional cases, there may be an apparent improvement in style, but in most cases, the changes represent nothing short of deterioration. This, however, varies according to the hemisphere affected. Painters with left-hemisphere lesions tend to show an inability to deal adequately with perspective and also tend to use simplified colors with fewer nuances. One often witnesses an evolution toward simpler, often "naïve" techniques, and at times rigid geometric repetitive features. Painters with right-hemisphere lesions also become unable to represent tridimensionality. In addition, their figures are often drawn in very summary fashion, with lack of coordination between volumes and space and a chromatic impoverishment; their main problem, however, is visuospatial, leading to neglect of the left side of the canvas.

  3. [Improving adhesion to antiretroviral treatment].

    Science.gov (United States)

    2008-01-01

    To facilitate unified criteria for health professionals to improve adhesion to antiretroviral therapy. The recommendations were drawn up and agreed upon by an expert panel from the SPNS, GESIDA and SEFH, after an exhaustive review of the latest relevant epidemiological and clinical studies that have been published in the medical literature and/or presented at congresses and scientific forums. The factors related to adhesion with antiretroviral therapy came from individuals, health care professionals and treatment variables. Current available methods for measuring adhesion are diverse and classified as direct and indirect. The ideal method is shown to be one which is highly sensitive and specific, enables quantitative and continuous measurement and is reliable, reproducible, economical and quick. The doctor, nurse and pharmacist play a key role in the strategies for adhesion improvement. Specific programmes based on exhaustive knowledge of individualized variables from patients and their antiretroviral therapy should be developed. The use of combined methods which are adapted to healthcare facility characteristics for adhesion improvement is recommended. The structured support to interpersonal adhesion developed by trained healthcare professionals and individualized strategies has been demonstrated as being the most effective intervention strategy to improve adhesion with antiretroviral treatment.

  4. Focal cerebral hyperemia in postconcussive amnesia.

    Science.gov (United States)

    Nariai, T; Suzuki, R; Ohta, Y; Ohno, K; Hirakawa, K

    2001-12-01

    Transient amnesia caused by minor head injury is commonly encountered in daily neurosurgical practice, but the mechanism of such amnesia has not been extensively studied. We measured the regional cerebral blood flow (rCBF) of patients with postconcussive amnesia with Xe/CT CBF to examine whether a focal disturbance of CBF exists. The Xe/CT CBF study was performed in eight patients with closed head injury without organic cerebral lesion while they were suffering from posttraumatic amnesia (concussion group). The time interval between accident and CBF measurement was less than 2 h in three patients, 5-6 h in two, 8-9 h in two, and 18 in one. The results were compared with those of nine normal volunteers and eight other age-matched patients who recovered without any neurological deficit despite the presence of hemorrhagic regions (mild hemorrhage group). The rCBF of the concussion group was significantly elevated in the bilateral mesial temporal cortex in comparison to the normal group. The rCBF in the mild hemorrhage group was lower than that of normal controls in all regions. The analysis of right-left difference in CBF indicated that there was significant asymmetry (right > left) in the frontal and temporal cortex in the concussion group, but not in the normal and mild hemorrhage group. This Xe/CT CBF study in acute stages of cerebral concussion, in which patients were amnestic, detected focal cerebral hyperemia. Such hyperemia in regions closely related to human memory function may be the result of vasoparalysis or the compensatory activation of memory circuits after denervation injury.

  5. Pneumatic release of focal vitreomacular traction.

    Science.gov (United States)

    Claus, M G; Feron, E; Veckeneer, M

    2017-03-01

    PurposeTo study the efficacy of a single intravitreal injection of expansile gas as a valuable alternative to current treatment options (conservative, pharmacological, and surgical) in patients with symptomatic, focal vitreomacular traction (VMT).Patients and methodsThis study comprises a retrospective, interventional case series of patients. Twenty eyes in seventeen patients with symptomatic and persisting focal VMT were treated in an outpatient setting with an intravitreal gas injection of 0.2 ml. In 19 eyes, 100% hexafluoroethane (C2F6) was used. One eye received sulfur hexafluoride (SF6). To all but three patients posturing advice was given. Patients were reviewed with a full-eye examination and ocular coherence tomography (OCT) after 14 days and later. The primary outcome measure was the release of VMT on OCT.ResultsIn 17 of the 20 (85.0%) treated eyes, a release of VMT was achieved as documented on OCT. The release of VMT was diagnosed during the first month after injection in 11 eyes of 11 patients and within 3 months in 16 eyes of 15 patients. In all but five of our patients, best corrected visual acuity (BCVA) remained stable or improved. In four patients, the progression or development of cataract was the probable cause of the decrease in BCVA. One patient developed a stage II macular hole after injection and needed vitrectomy. None of the treated patients developed retinal breaks.ConclusionIntravitreal expansile gas injection could offer a minimally invasive, low-cost alternative treatment in patients with symptomatic, persisting VMT. Additional studies on a larger number of patients are required.

  6. FOCAL EPILEPTIC MYOCLONUS: DIFFERENTIAL DIAGNOSIS AND PROGNOSIS

    Directory of Open Access Journals (Sweden)

    N. E. Kvaskova

    2014-01-01

    Full Text Available The paper describes the clinical, electroencephalographic (EEG, and neuroimaging features of focal epileptic myoclonus (FEM and the results of therapy in patients with this type of seizure. The latter was identified in 2.5 % of the cases of epilepsy with onset beyond the age of 18 years (n = 1261. The age of onset of FЕМ was from 5 months to 23 years (mean 8.1 ± 1.6 years. The addition of secondary generalized seizures was stated in 90.3% of cases; that of focal motor seizures, epileptic aura, and negative FЕМ was seen in 64.5, 25.8, and 12.8 %, respectively. FЕМ was most commonly located in the flexor muscles of the upper extremities (22.6 % and facial and upper limb muscles (25.6 %. The regional epileptoformactivity maximally located in the frontocentroparietal leads is a typical EEG pattern of FЕМ in all the patients. Magnetic resonance imaging most frequently revealed diffuse cortical and subcortical atrophy (29 % and total cortical hemiatrophy (32 %. There was no case of complete remission of FЕМ. Monotherapy with antiepileptic drugs (AEDs resulted in reduction of FЕМ in only 6.4 % of cases. During duo therapy, there was more than a 50 % reduction in FЕМ in 67.7 %. Our investigation has indicated that active FЕМ is a seizure type resistant to AEDs. This fact necessitates the detection of FЕМ at its early stages in order to predict the course of the disease and search for new therapies for epileptic syndromes associated with this type of seizures.

  7. Association of membrane/lipid rafts with the platelet cytoskeleton and the caveolin PY14: participation in the adhesion process.

    Science.gov (United States)

    Cerecedo, Doris; Martínez-Vieyra, Ivette; Maldonado-García, Deneb; Hernández-González, Enrique; Winder, Steve J

    2015-11-01

    Platelets are the most prominent elements of blood tissue involved in hemostasis at sites of blood vessel injury. Platelet cytoskeleton is responsible for their shape modifications observed during activation and adhesion to the substratum; therefore the interactions between cytoskeleton and plasma membrane are critical to modulate blood platelet functions. Several cytoskeletal components and binding partners, as well as enzymes that regulate the cytoskeleton, localize to membrane/lipid rafts (MLR) and regulate lateral diffusion of membrane proteins and lipids. Resting, thrombin-activated, and adherent human platelets were processed for biochemical studies including western-blot and immunprecipitation assays and confocal analysis were performed to characterize the interaction of MLR with the main cytoskeleton elements and β-dystroglycan as well as with the association of caveolin-1 PY14 with focal adhesion proteins. We transfected a megakaryoblast cell line (Meg-01) to deplete β-dystroglycan, subsequent to their differentiation to the platelet progenitors. Our data showed a direct interaction of the MLR with cytoskeleton to regulate platelet shape, while an association of caveolin-1 PY14 with vinculin is needed to establish focal adhesions, which are modulated for β-dystroglycan. In conclusion, caveolin-1 PY14 in association with platelet cytoskeleton participate in focal adhesions dynamics.

  8. Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells.

    Science.gov (United States)

    Liu, Yan-Jun; Le Berre, Maël; Lautenschlaeger, Franziska; Maiuri, Paolo; Callan-Jones, Andrew; Heuzé, Mélina; Takaki, Tohru; Voituriez, Raphaël; Piel, Matthieu

    2015-02-12

    The mesenchymal-amoeboid transition (MAT) was proposed as a mechanism for cancer cells to adapt their migration mode to their environment. While the molecular pathways involved in this transition are well documented, the role of the microenvironment in the MAT is still poorly understood. Here, we investigated how confinement and adhesion affect this transition. We report that, in the absence of focal adhesions and under conditions of confinement, mesenchymal cells can spontaneously switch to a fast amoeboid migration phenotype. We identified two main types of fast migration--one involving a local protrusion and a second involving a myosin-II-dependent mechanical instability of the cell cortex that leads to a global cortical flow. Interestingly, transformed cells are more prone to adopt this fast migration mode. Finally, we propose a generic model that explains migration transitions and predicts a phase diagram of migration phenotypes based on three main control parameters: confinement, adhesion, and contractility.

  9. Coupling of cytoplasm and adhesion dynamics determines cell polarization and locomotion

    CERN Document Server

    Bock, Martin; Möhl, Christoph

    2009-01-01

    Observations of single epidermal cells on flat adhesive substrates have revealed two distinct morphological and functional states, namely a non-migrating symmetric unpolarized state and a migrating asymmetric polarized state. These states are characterized by different spatial distributions and dynamics of important biochemical cell components: F-actin and myosin-II form the contractile part of the cytoskeleton, and integrin receptors in the plasma membrane connect F-actin filaments to the substratum. In this way, focal adhesion complexes are assembled, which determine cytoskeletal force transduction and subsequent cell locomotion. So far, physical models have reduced this phenomenon either to gradients in regulatory control molecules or to different mechanics of the actin filament system in different regions of the cell. Here we offer an alternative and self-organizational model incorporating polymerization, pushing and sliding of filaments, as well as formation of adhesion sites and their force dependent ki...

  10. TANNIN ADHESIVES AS AN ALTENATIVE TO THE SYNTHETIC PHENOLIC ADHESIVES

    Directory of Open Access Journals (Sweden)

    Semra Çolak

    2003-04-01

    Full Text Available Recently, increasing attention has been paid industrially to the use of tannin formaldehyde adhesives in production of wood based panel products such as particleboard, fiber board and plywood. The researches on the use of tannin extracts as a wood adhesive started in 1950, however, they proceeded very slowly since the problems associated with the application of them. The idea which tannin extract can be used replace the oil-based phenolic adhesive was the base of several studies after the oil crisis of the 1970s. In the past, the economical aspects were important in the researches on the tannin-based adhesives. Nowadays, however, both economical and ecological factors should have taken into consideration in wood bonding.

  11. Cell adhesion molecules regulate contractile ring-independent cytokinesis in Dictyostelium discoideum

    Institute of Scientific and Technical Information of China (English)

    Akira Nagasaki; Masamitsu Kanada; Taro QP Uyeda

    2009-01-01

    To investigate the roles of substrate adhesion in cytokinesis, we established cell lines lacking paxiUin (PAXB) or vinculin (VINA), and those expressing the respective GFP fusion proteins in Dictyostelium discoideum. As in mammalian cells, GFP-PAXB and GFP-VINA formed focal adhesion-like complexes on the cell bottom, paxB cells in suspension grew normally, but on substrates, often failed to divide after regression of the furrow. The efficient cytokinesis of paxB cells in suspension is not because of shear forces to assist abscission, as they divided normally in static suspension culture as well. Double knockout strains lacking mhcA, which codes for myosin I1, and paxB or vinA displayed more severe cytokinetic defects than each single knockout strain. In mitotic wild-type cells, GFP-PAXB was diffusely distributed on the basal membrane, but was strikingly condensed along the polar edges in mitotic mhcA cells. These results are consistent with our idea that Dictyostelium displays two forms of cytokinesis, one that is contractile ringdependent and adhesion-independent, and the other that is contractile ring-independent and adhesion-dependent, and that the latter requires PAXB and VINA. Furthermore, that paxB cells fail to divide normally in the presence of substrate adhesion suggests that this adhesion molecule may play additional signaling roles.

  12. Adhesives from modified soy protein

    Science.gov (United States)

    Sun, Susan [Manhattan, KS; Wang, Donghai [Manhattan, KS; Zhong, Zhikai [Manhattan, KS; Yang, Guang [Shanghai, CN

    2008-08-26

    The present invention provides useful adhesive compositions having similar adhesive properties to conventional UF and PPF resins. The compositions generally include a protein portion and modifying ingredient portion selected from the group consisting of carboxyl-containing compounds, aldehyde-containing compounds, epoxy group-containing compounds, and mixtures thereof. The composition is preferably prepared at a pH level at or near the isoelectric point of the protein. In other preferred forms, the adhesive composition includes a protein portion and a carboxyl-containing group portion.

  13. Photovoltaic module with adhesion promoter

    Science.gov (United States)

    Xavier, Grace

    2013-10-08

    Photovoltaic modules with adhesion promoters and methods for fabricating photovoltaic modules with adhesion promoters are described. A photovoltaic module includes a solar cell including a first surface and a second surface, the second surface including a plurality of interspaced back-side contacts. A first glass layer is coupled to the first surface by a first encapsulating layer. A second glass layer is coupled to the second surface by a second encapsulating layer. At least a portion of the second encapsulating layer is bonded directly to the plurality of interspaced back-side contacts by an adhesion promoter.

  14. Sighting optics including an optical element having a first focal length and a second focal length and methods for sighting

    Science.gov (United States)

    Crandall, David Lynn

    2011-08-16

    Sighting optics include a front sight and a rear sight positioned in a spaced-apart relation. The rear sight includes an optical element having a first focal length and a second focal length. The first focal length is selected so that it is about equal to a distance separating the optical element and the front sight and the second focal length is selected so that it is about equal to a target distance. The optical element thus brings into simultaneous focus for a user images of the front sight and the target.

  15. Enhanced cell adhesion on bioinert ceramics mediated by the osteogenic cell membrane enzyme alkaline phosphatase.

    Science.gov (United States)

    Aminian, Alieh; Shirzadi, Bahareh; Azizi, Zahra; Maedler, Kathrin; Volkmann, Eike; Hildebrand, Nils; Maas, Michael; Treccani, Laura; Rezwan, Kurosch

    2016-12-01

    Functional bone and dental implant materials are required to guide cell response, offering cues that provide specific instructions to cells at the implant/tissue interface while maintaining full biocompatibility as well as the desired structural requirements and functions. In this work we investigate the influence of covalently immobilized alkaline phosphatase (ALP), an enzyme involved in bone mineralization, on the first contact and initial cell adhesion. To this end, ALP is covalently immobilized by carbodiimide-mediated chemoligation on two highly bioinert ceramics, alpha-alumina (Al2O3) and yttria-stabilized zirconia (Y-TZP) that are well-established for load-bearing applications. The physicochemical surface properties are evaluated by profilometry, zeta potential and water contact angle measurements. The initial cell adhesion of human osteoblasts (HOBs), human osteoblast-like cells (MG-63) and mesenchymal stromal cells (hMSCs) was investigated. Cell adhesion was assessed at serum free condition via quantification of percentage of adherent cells, adhesion area and staining of the focal adhesion protein vinculin. Our findings show that after ALP immobilization, the Al2O3 and Y-TZP surfaces gained a negative charge and their hydrophilicity was increased. In the presence of surface-immobilized ALP, a higher cell adhesion, more pronounced cell spreading and a higher number of focal contact points were found. Thereby, this work gives evidence that surface functionalization with ALP can be utilized to modify inert materials for biological conversion and faster bone regeneration on inert and potentially load-bearing implant materials. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions.

    Science.gov (United States)

    Himmel, Mirko; Ritter, Anett; Rothemund, Sven; Pauling, Björg V; Rottner, Klemens; Gingras, Alexandre R; Ziegler, Wolfgang H

    2009-05-15

    In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.

  17. Adhesion Transition of Flexible Filaments

    Science.gov (United States)

    Evans, Arthur; Lauga, Eric

    2009-03-01

    As forays into fabrication and self-assembly venture to increasingly small length scales, the role of adhesion events between material elements of the system must be closely scrutinized. This area of study is typically dominated by investigations into capillary adhesion, but relatively recent interest in carbon nanotubes and biomimetic devices have spurred interest in intermolecular forces as another source of micro- and nano-scale adhesion. We present here a far-field model for ``dry'' adhesion. We consider a small number N of flexible beams interacting with each other via a typical Lennard-Jones 6-12 potential, and describe the behavior of the system as the ratio of bending rigidity to beam-beam attraction is reduced. Applications ranging from fibrillar systems to the comparatively stiff carbon nanotubes are discussed.

  18. Radiologic manifestations of focal cerebral hyperemia in acute stroke

    DEFF Research Database (Denmark)

    Olsen, Tom Skyhøj; Skriver, E B; Herning, M

    1991-01-01

    In 16 acute stroke patients with focal cerebral hyperemia angiography and regional cerebral blood flow (rCBF) were studied 1 to 4 days post stroke. CT was performed twice with and without contrast enhancement 3 +/- 1 days and 16 +/- 4 days post stroke. Angiographic evidence of focal cerebral hype...

  19. Focal sampling of cow lying behaviour for automated welfare assessment

    NARCIS (Netherlands)

    Mattachini, G.; Riva, E.; Bisaglia, C.; Pompe, J.C.A.M.; Provolo, G.

    2013-01-01

    the objective of the current study was to determine the number of focal animals required to represent the daily lying behaviour of a herd of lactating dairy cows. the study was carried out at 3 commercial dairy farms. the lying time (h/d) and number of lying bouts (n/d) of 15 ± 3 focal dairy cows,

  20. Focal epithelial hyperplasia caused by human papillomavirus 13.

    Science.gov (United States)

    Saunders, Natasha R; Scolnik, Dennis; Rebbapragada, Anuradha; Koelink, Eric; Craw, Lindsey; Roth, Sherryn; Aronson, Leya; Perusini, Stephen; Silverman, Michael S

    2010-06-01

    Focal epithelial hyperplasia is a benign, papulo-nodular disease of the oral cavity. It is rare, affecting primarily Native American populations during childhood. It is closely associated with human papillomavirus 13 and 32. This report describes the diagnosis of 2 cases of focal epithelial hyperplasia in children from southern Guyana. The diagnosis was made using clinical criteria, polymerase chain reaction, and DNA sequencing.

  1. Focal decompositions for linear differential equations of the second order

    Directory of Open Access Journals (Sweden)

    L. Birbrair

    2003-01-01

    two-points problems to itself such that the image of the focal decomposition associated to the first equation is a focal decomposition associated to the second one. In this paper, we present a complete classification for linear second-order equations with respect to this equivalence relation.

  2. Mechanisms of adhesion in geckos.

    Science.gov (United States)

    Autumn, Kellar; Peattie, Anne M

    2002-12-01

    The extraordinary adhesive capabilities of geckos have challenged explanation for millennia, since Aristotle first recorded his observations. We have discovered many of the secrets of gecko adhesion, yet the millions of dry, adhesive setae on the toes of geckos continue to generate puzzling new questions and valuable answers. Each epidermally-derived, keratinous seta ends in hundreds of 200 nm spatular tips, permitting intimate contact with rough and smooth surfaces alike. Prior studies suggested that adhesive force in gecko setae was directly proportional to the water droplet contact angle (θ) , an indicator of the free surface energy of a substrate. In contrast, new theory suggests that adhesion energy between a gecko seta and a surface (W(GS)) is in fact proportional to (1 + cosθ), and only for θ > 60°. A reanalysis of prior data, in combination with our recent study, support the van der Waals hypothesis of gecko adhesion, and contradict surface hydrophobicity as a predictor of adhesion force. Previously, we and our collaborators measured the force production of a single seta. Initial efforts to attach a seta failed because of improper 3D orientation. However, by simulating the dynamics of gecko limbs during climbing (based on force plate data) we discovered that, in single setae, a small normal preload, combined with a 5 μm displacement yielded a very large adhesive force of 200 microNewton (μN), 10 times that predicted by whole-animal measurements. 6.5 million setae of a single tokay gecko attached maximally could generate 130 kg force. This raises the question of how geckos manage to detach their feet in just 15 ms. We discovered that simply increasing the angle that the setal shaft makes with the substrate to 30° causes detachment. Understanding how simultaneous attachment and release of millions of setae are controlled will require an approach that integrates levels ranging from molecules to lizards.

  3. Laser surface modification and adhesion

    CERN Document Server

    Mittal, K L

    2014-01-01

    The book provides a unique overview on laser techniques and applications for the purpose of improving adhesion by altering surface chemistry and topography/morphology of the substrate. It details laser surface modification techniques for a wide range of industrially relevant materials (plastics, metals, ceramics, composites) with the aim to improve and enhance their adhesion to other materials. The joining of different materials is of critical importance in the fabrication of many and varied products.

  4. 21 CFR 878.4010 - Tissue adhesive.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Tissue adhesive. 878.4010 Section 878.4010 Food... DEVICES GENERAL AND PLASTIC SURGERY DEVICES Surgical Devices § 878.4010 Tissue adhesive. (a) Tissue adhesive for the topical approximation of skin—(1) Identification. A tissue adhesive for the...

  5. Fibrillar Adhesive for Climbing Robots

    Science.gov (United States)

    Pamess, Aaron; White, Victor E.

    2013-01-01

    A climbing robot needs to use its adhesive patches over and over again as it scales a slope. Replacing the adhesive at each step is generally impractical. If the adhesive or attachment mechanism cannot be used repeatedly, then the robot must carry an extra load of this adhesive to apply a fresh layer with each move. Common failure modes include tearing, contamination by dirt, plastic deformation of fibers, and damage from loading/ unloading. A gecko-like fibrillar adhesive has been developed that has been shown useful for climbing robots, and may later prove useful for grasping, anchoring, and medical applications. The material consists of a hierarchical fibrillar structure that currently contains two levels, but may be extended to three or four levels in continuing work. The contacting level has tens of thousands of microscopic fibers made from a rubberlike material that bend over and create intimate contact with a surface to achieve maximum van der Waals forces. By maximizing the real area of contact that these fibers make and minimizing the bending energy necessary to achieve that contact, the net amount of adhesion has been improved dramatically.

  6. A review of adhesion science.

    Science.gov (United States)

    Marshall, Sally J; Bayne, Stephen C; Baier, Robert; Tomsia, Antoni P; Marshall, Grayson W

    2010-02-01

    Adhesion or cohesion includes an adherend, adhesive, and intervening interface. Adhesive joints may include one or more interfaces. Adhesion science focuses on understanding the materials properties associated with formation of the interfaces, changes in the interfaces with time, and events associated with failure of the interfaces. The key principles for good interface formation are creation of a clean surface, generation of a rough surface for interfacial interlocking, good wetting of the substratum by the adhesive/cohesive materials, adequate flow and adaptation for intimate interaction, and acceptable curing when phase changes are required for final joint formation. Much more effort is needed in the future to carefully assess each of these using available testing methods that attempt to characterize the energetics of the interfaces. Bonding involves potential contributions from physical, chemical, and mechanical sources but primarily relies on micro-mechanical interaction for success. Characterization of the interface before adhesion, during service, and after failure would be much more useful for future investigations and remains as a great challenge. Scientists should more rigorously apply techniques such as comprehensive contact angle analysis (rather than simple water wettability) for surface energy determination, and AFM in addition to SEM for surface texture analysis. Copyright 2009 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  7. An Overview of Dental Adhesive Systems and the Dynamic Tooth-Adhesive Interface.

    Science.gov (United States)

    Bedran-Russo, Ana; Leme-Kraus, Ariene A; Vidal, Cristina M P; Teixeira, Erica C

    2017-10-01

    From the conception of resin-enamel adhesion to today's contemporary dental adhesive systems, clinicians are no longer afraid of exploring the many advantages brought by adhesive restorative concepts. To maximize the performance of adhesive-based restorative procedures, practitioners must be familiar with the mechanism of adhesion, clinical indications, proper handling, the inherent limitations of the materials and the biological challenges. This review provides an overview of the current status of restorative dental adhesives, their mechanism of adhesion, mechanisms of degradation of dental adhesive interfaces, how to maximize performance, and future trends in adhesive dentistry. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Laser differential confocal ultra-long focal length measurement.

    Science.gov (United States)

    Zhao, Weiqian; Sun, Ruoduan; Qiu, Lirong; Sha, Dingguo

    2009-10-26

    A new laser differential confocal focal-length measurement method is proposed for the measurement of an ultra-long focal-length. The approach proposed uses the property of an axial intensity curve that the absolute zero precisely corresponds to the focus of the objective in a differential confocal focusing system (DCFS) to measure the variation in position of DCFS focus with and without a measured ultra-long focal-length lens (UFL), uses the distance between the two focuses to obtain the UFL focal-length, and thereby achieving the precise measurement of ultra-long focal-length. The method has a high focusing precision, a strong anti-interference capability and a short measurement light-path. The theoretical analyses and preliminary experimental results indicate that the relative measurement error is about 0.01% when the method is used for the measurement of back-focus-distance (BFD).

  9. [Color Doppler sonography of focal abdominal lesions].

    Science.gov (United States)

    Licanin, Zoran; Lincender, Lidija; Djurović, V; Salihefendić, Nizama; Smajlović, Fahrudin

    2004-01-01

    Color Doppler sonography (CDS--spectral, color and power), harmonic imaging techniques (THI, PHI), possibility of 3D analysis of picture, usage of contrast agents, have raised the values of ultrasound as a diagnostic method to a very high level. THI--non-linear gray scale modality, is based on the processing of higher reflected frequencies, that has improved a picture resolution, which is presented with less artifacts and limiting effects of obesity and gases. Ultrasound contrast agents improve analysis of micro and macro circulation of the examined area, and with the assessment of velocity of supply in ROI (wash in), distribution and time of signal weakening (wash out), are significantly increasing diagnostic value of ultrasound. Besides the anatomical and topographic presentation of examined region (color, power), Color Doppler sonography gives us haemodynamic-functional information on vascularisation of that region, as well as on pathologic vascularisation if present. Avascular aspect of a focal pathologic lesion corresponds to a cyst or haematoma, while coloration and positive spectral curve discover that anechogenic lesions actually represents aneurysms, pseudoaneurysms or AVF. In local inflammatory lesion, abscess in an acute phase, CDS shows first increased, and then decreased central perfusion, while in a chronic phase, a pericapsular vascularisation is present. Contribution of CDS in differentiation of hepatic tumors (hemangioma, HCC and metastasis) is very significant. Central color dots along the peripheral blood vessels and the blush phenomenon are characteristics of capillary hemangioma, peritumoral vascular ring "basket" of HCC, and "detour" sign of metastasis. The central artery, RI from 0.45 to 0.60 and radial spreading characterize FNH. Hepatic adenoma is characterized by an intratumoral vein, and rarely by a vascular hallo. Further on, blood velocity in tumor defined by Color Doppler, distinguishes malignant from benign lesion, where 40 cm/s is a

  10. Bond strength of adhesive resin cement with different adhesive systems

    Science.gov (United States)

    Lorenzoni e Silva, Fabrizio; Pamato, Saulo; Kuga, Milton-Carlos; Só, Marcus-Vinicius-Reis

    2017-01-01

    Background To assess the immediate bond strength of a dual-cure adhesive resin cement to the hybridized dentin with different bonding systems. Material and Methods Fifty-six healthy human molars were randomly divided into 7 groups (n=8). After 3 longitudinal sections, the central cuts were included in PVC matrix and were submitted to dentin hybridization according to the groups: G1 - etch & rinse system with 3-step (Apder™ Scotchbond™ Multi-Purpose, 3M ESPE), G2 - etch & rinse system with 3-step (Optibond™ FL, Kerr), G3 - etch & rinse system with 3-step (All-Bond 3®, Bisco), G4 - etch & rinse simplified system (Adper™ Single Bond 2, 3M ESPE), G5 - self-etching system with one step (Bond Force, Tokuyama), G6 - universal system in moist dentin (Single Bond Universal, 3M ESPE), G7 - universal system in dry dentin (Single Bond Universal, 3M ESPE). Then all groups received the cementing of a self-adhesive resin cement cylinder (Duo-link, Bisco) made from a polypropylene matrix. In the evaluation of bond strength, the samples were subjected to the microshear test and evaluated according to the fracture pattern by optical microscopy. Results The Kruskal-Wallis test suggests a statistically significant difference between groups (p=0,039), and Tukey for multiple comparisons, indicating a statistically significant difference between G3 and G4 (p<0.05). It was verified high prevalence of adhesive failures, followed by mixed failure and cohesive in dentin. Conclusions The technique and the system used to dentin hybridization are able to affect the immediate bond strength of resin cement dual adhesive. Key words:Adhesion, adhesive resin cement, adhesive systems, microshear. PMID:28149471

  11. Proteomic dataset of the sea urchin Paracentrotus lividus adhesive organs and secreted adhesive

    NARCIS (Netherlands)

    Lebesgue, Nicolas; da Costa, Gonçalo; Ribeiro, Raquel Mesquita; Ribeiro-Silva, Cristina; Martins, Gabriel G; Matranga, Valeria; Scholten, Arjen; Cordeiro, Carlos; Heck, Albert J R; Santos, Romana

    2016-01-01

    Sea urchins have specialized adhesive organs called tube feet, which mediate strong but reversible adhesion. Tube feet are composed by a disc, producing adhesive and de-adhesive secretions for substratum attachment, and a stem for movement. After detachment the secreted adhesive remains bound to the

  12. An empirical assessment of the focal species hypothesis.

    Science.gov (United States)

    Lindenmayer, D B; Lane, P W; Westgate, M J; Crane, M; Michael, D; Okada, S; Barton, P S

    2014-12-01

    Biodiversity surrogates and indicators are commonly used in conservation management. The focal species approach (FSA) is one method for identifying biodiversity surrogates, and it is underpinned by the hypothesis that management aimed at a particular focal species will confer protection on co-occurring species. This concept has been the subject of much debate, in part because the validity of the FSA has not been subject to detailed empirical assessment of the extent to which a given focal species actually co-occurs with other species in an assemblage. To address this knowledge gap, we used large-scale, long-term data sets of temperate woodland birds to select focal species associated with threatening processes such as habitat isolation and loss of key vegetation attributes. We quantified co-occurrence patterns among focal species, species in the wider bird assemblage, and species of conservation concern. Some, but not all, focal species were associated with high levels of species richness. One of our selected focal species was negatively associated with the occurrence of other species (i.e., it was an antisurrogate)-a previously undescribed property of nominated focal species. Furthermore, combinations of focal species were not associated with substantially elevated levels of bird species richness, relative to levels associated with individual species. Our results suggest that although there is some merit to the underpinning concept of the FSA, there is also a need to ensure that actions are sufficiently flexible because management tightly focused on a given focal species may not benefit some other species, including species of conservation concern, such of which might not occur in species-rich assemblages. © 2014 Society for Conservation Biology.

  13. Control of mesenchymal stem cell phenotype and differentiation depending on cell adhesion mechanism

    Directory of Open Access Journals (Sweden)

    J Kang

    2014-11-01

    Full Text Available Control of cell-matrix adhesion has become an important issue in the regulation of stem cell function. In this study, a maltose-binding protein (MBP-linked basic fibroblast growth factor (FGF2-immobilised polystyrene surface (PS-MBP-FGF2 was applied as an artificial matrix to regulate integrin-mediated signalling. We sought to characterise human mesenchymal-stem cell (hMSC behaviour in response to two different mechanisms of cell adhesion; (i FGF2-heparan sulphate proteoglycan (HSPG-mediated adhesion vs. (ii fibronectin (FN-integrin-mediated adhesion. Heparin inhibited hMSC adhesion to PS-MBP-FGF2 but not to FN-coated surface. The phosphorylation of focal adhesion kinase, cytoskeletal re-organisation, and cell proliferation were restricted in hMSCs adhering to PS-MBP-FGF2 compared to FN-coated surface. Expression of MSC markers, such as CD105, CD90 and CD166, decreased in hMSCs expanded on PS-MBP-FGF2 compared to expression in cells expanded on FN-coated surface. hMSCs that were expanded on FN-coated surface differentiated into osteogenic and adipogenic cells more readily than those that were expanded on PS-MBP-FGF2. Furthermore, we characterised the N-linked glycan structures of hMSCs depending on the cell adhesion mechanism using mass spectrometry (MS-based quantitative techniques. MS analysis revealed that 2,3-sialylated glycans, a potential marker of stem cell function, were more abundant on hMSCs expanded on FN-coated surface than on those expanded on PS-MBP-FGF2. Thus, the differentiation potential of hMSCs is controlled by the type of adhesion substrate that might provide an idea for the design of biomaterials to control stem cell fate. Elucidation of the glycan structure on the cell membrane may help characterise hMSC function.

  14. Control of mesenchymal stem cell phenotype and differentiation depending on cell adhesion mechanism.

    Science.gov (United States)

    Kang, J; Park, H M; Kim, Y W; Kim, Y H; Varghese, S; Seok, H K; Kim, Y G; Kim, S H

    2014-11-25

    Control of cell-matrix adhesion has become an important issue in the regulation of stem cell function. In this study, a maltose-binding protein (MBP)-linked basic fibroblast growth factor (FGF2)-immobilised polystyrene surface (PS-MBP-FGF2) was applied as an artificial matrix to regulate integrin-mediated signalling. We sought to characterise human mesenchymal-stem cell (hMSC) behaviour in response to two different mechanisms of cell adhesion; (i) FGF2-heparan sulphate proteoglycan (HSPG)-mediated adhesion vs. (ii) fibronectin (FN)-integrin-mediated adhesion. Heparin inhibited hMSC adhesion to PS-MBP-FGF2 but not to FN-coated surface. The phosphorylation of focal adhesion kinase, cytoskeletal re-organisation, and cell proliferation were restricted in hMSCs adhering to PS-MBP-FGF2 compared to FN-coated surface. Expression of MSC markers, such as CD105, CD90 and CD166, decreased in hMSCs expanded on PS-MBP-FGF2 compared to expression in cells expanded on FN-coated surface. hMSCs that were expanded on FN-coated surface differentiated into osteogenic and adipogenic cells more readily than those that were expanded on PS-MBP-FGF2. Furthermore, we characterised the N-linked glycan structures of hMSCs depending on the cell adhesion mechanism using mass spectrometry (MS)-based quantitative techniques. MS analysis revealed that 2,3-sialylated glycans, a potential marker of stem cell function, were more abundant on hMSCs expanded on FN-coated surface than on those expanded on PS-MBP-FGF2. Thus, the differentiation potential of hMSCs is controlled by the type of adhesion substrate that might provide an idea for the design of biomaterials to control stem cell fate. Elucidation of the glycan structure on the cell membrane may help characterise hMSC function.

  15. Focal Points on Constructing News Stories

    Directory of Open Access Journals (Sweden)

    Elena Yuryevna Ilyinova

    2015-11-01

    Full Text Available The issues stated in the article line with the current interest to pragmatic value of news releases in modern media. The news is thought to be a verbalized focal reflection of some event that was chosen by media professionals for setting the current information agenda. Having generated the opinions on the newsworthiness the authors present a set of values that may be used for measurement of relevance and clarity of an event reflection in the news content with frequency, clarity, predictability, unexpectedness, amplitude, cultural proximity, elite nations, elite people, personification, negativity among them. The novelty of the research is that the newsworthiness is checked with the focus to lexical (thematic representation of the news in a diachronic approach: the empirical base of the research was taken from the archives of UK national and local media sources (18–20th cent. and implied comparison of lexical means that reflected an event itself and some values of human interest potential in the news stories written in defined periods. The article states the trend for dynamics in the way the event is reflected in the news stories – the information core of the story is merged with detailed reporting parts, and their content is conditioned by social and moral values.

  16. Visual agnosia and focal brain injury.

    Science.gov (United States)

    Martinaud, O

    Visual agnosia encompasses all disorders of visual recognition within a selective visual modality not due to an impairment of elementary visual processing or other cognitive deficit. Based on a sequential dichotomy between the perceptual and memory systems, two different categories of visual object agnosia are usually considered: 'apperceptive agnosia' and 'associative agnosia'. Impaired visual recognition within a single category of stimuli is also reported in: (i) visual object agnosia of the ventral pathway, such as prosopagnosia (for faces), pure alexia (for words), or topographagnosia (for landmarks); (ii) visual spatial agnosia of the dorsal pathway, such as cerebral akinetopsia (for movement), or orientation agnosia (for the placement of objects in space). Focal brain injuries provide a unique opportunity to better understand regional brain function, particularly with the use of effective statistical approaches such as voxel-based lesion-symptom mapping (VLSM). The aim of the present work was twofold: (i) to review the various agnosia categories according to the traditional visual dual-pathway model; and (ii) to better assess the anatomical network underlying visual recognition through lesion-mapping studies correlating neuroanatomical and clinical outcomes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Acquired agraphia caused by focal brain damage.

    Science.gov (United States)

    Anderson, S W; Saver, J; Tranel, D; Damasio, H

    1993-03-01

    Motor and linguistic aspects of writing were evaluated in 31 subjects with focal damage in 1 of 3 regions of the left hemisphere: (1) dorsolateral frontal lobe sparing primary motor cortex (group FL), (2) parietal lobe (group PL), or (3) temporal lobe (group TL). A standard procedure was used to evaluate writing for grapheme formation, spatial arrangement, spelling, word selection, grammar, and perseveration. It was predicted that agraphia would be observed in all 3 groups, and that the most severe impairments would be associated with frontal lobe damage, particularly in aspects of writing dependent on sequencing (grapheme formation, spelling, and grammar). It was found that agraphia was common in all groups, particularly in the acute epoch, and that all groups showed considerable recovery of writing by the chronic epoch. Few differences were found between groups. However, the FL group was impaired on spelling and grammar relative to the PL group in the acute epoch and impaired on grammar relative to the TL group in the chronic epoch. The findings are consistent with the notion that writing relies on a distributed neuroanatomical network, which acts in concert to link fragments of visuomotor activity with component linguistic elements.

  18. Medical image of the week: focal myopericaditis

    Directory of Open Access Journals (Sweden)

    Meenakshisundaram C

    2015-07-01

    Full Text Available No abstract available. Article truncated at 150 words. A 44-year-old man with no significant past medical history was admitted with a history of two episodes of substernal chest pain unrelated to exertion which had resolved spontaneously. Admission vital signs were within normal limits and physical examination was unremarkable. Basic lab tests were normal and urine toxicology was negative. Electrocardiogram was unremarkable with no ST/T changes. Troponin I was elevated at 4.19 which trended up to 6.57. An urgent cardiac angiogram was done which revealed normal patent coronaries. His transthoracic echocardiogram was also reported to be normal. He continued to have intermittent episodes of chest pain that was partially relieved by morphine. Erythrocyte sedimentation rate and C-reactive protein were elevated. Work up for autoimmune diseases, vasculitis, myocarditis panel were insignificant. Later, magnetic resonance imaging (MRI with gadolinium enhanced contrast (Figure 1 was obtained which showed abnormal epicardial/subepicardial myocardial enhancement within the inferolateral wall and cardiac apex consistent with focal ...

  19. Novel PORCN mutations in focal dermal hypoplasia.

    Science.gov (United States)

    Froyen, G; Govaerts, K; Van Esch, H; Verbeeck, J; Tuomi, M-L; Heikkilä, H; Torniainen, S; Devriendt, K; Fryns, J-P; Marynen, P; Järvelä, I; Ala-Mello, S

    2009-12-01

    Focal dermal hypoplasia (FDH), Goltz or Goltz-Gorlin syndrome, is an X-linked dominant multisystem disorder characterized primarily by involvement of the skin, skeletal system and eyes. We screened for mutations in the PORCN gene in eight patients of Belgian and Finnish origin with firm clinical suspicion of FDH. First, we performed quantitative PCR (qPCR) analysis to define the copy number at this locus. Next, we sequenced the coding regions and flanking intronic sequences of the PORCN gene. Three de novo mutations were identified in our patients with FDH: a 150-kb deletion removing six genes including PORCN, as defined by qPCR and X-array-CGH, and two heterozygous missense mutations; c.992T>G (p.L331R) in exon 11 and c.1094G>A (p.R365Q) in exon 13 of the gene. Both point mutations changed highly conserved amino acids and were not found in 300 control X chromosomes. The three patients in whom mutations were identified all present with characteristic dermal findings together with limb manifestations, which were not seen in our mutation-negative patients. The clinical characteristics of our patients with PORCN mutations were compared with the previously reported mutation-positive cases. In this report, we summarize the literature on PORCN mutations and associated phenotypes.

  20. Pathogenetic mechanisms of focal cortical dysplasia.

    Science.gov (United States)

    Marin-Valencia, Isaac; Guerrini, Renzo; Gleeson, Joseph G

    2014-07-01

    Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecular, and electrophysiologic aspects of FCDs was conducted. Disruption of the mammalian target of rapamycin (mTOR) signaling comprises a common pathway underlying the structural and electrical disturbances of some FCDs. Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD. Encouraging progress has been achieved on the molecular and electrophysiologic basis of constitutive cells in the dysplastic tissue. Despite the promising results of mTOR inhibitors, large-scale randomized trials are in need to evaluate their efficacy and side effects, along with additional mechanistic studies for the development of novel, molecular-based diagnostic and therapeutic approaches. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

  1. Optimizing Adhesive Design by Understanding Compliance.

    Science.gov (United States)

    King, Daniel R; Crosby, Alfred J

    2015-12-23

    Adhesives have long been designed around a trade-off between adhesive strength and releasability. Geckos are of interest because they are the largest organisms which are able to climb utilizing adhesive toepads, yet can controllably release from surfaces and perform this action over and over again. Attempting to replicate the hierarchical, nanoscopic features which cover their toepads has been the primary focus of the adhesives field until recently. A new approach based on a scaling relation which states that reversible adhesive force capacity scales with (A/C)(1/2), where A is the area of contact and C is the compliance of the adhesive, has enabled the creation of high strength, reversible adhesives without requiring high aspect ratio, fibrillar features. Here we introduce an equation to calculate the compliance of adhesives, and utilize this equation to predict the shear adhesive force capacity of the adhesive based on the material components and geometric properties. Using this equation, we have investigated important geometric parameters which control force capacity and have shown that by controlling adhesive shape, adhesive force capacity can be increased by over 50% without varying pad size. Furthermore, we have demonstrated that compliance of the adhesive far from the interface still influences shear adhesive force capacity. Utilizing this equation will allow for the production of adhesives which are optimized for specific applications in commercial and industrial settings.

  2. Denture adhesives: a systematic review.

    Science.gov (United States)

    Papadiochou, Sofia; Emmanouil, Ioannis; Papadiochos, Ioannis

    2015-05-01

    Denture adhesives have been the objective of scientific research for over half a century. Although they are used by denture wearers worldwide, investigations of their effectiveness and biocompatibility have led to controversial conclusions. The purpose of this study was to review the literature data with regard to the effectiveness and biocompatibility of denture adhesives as well as the attitudes of both patients and dental professionals toward these materials. An electronic search of English peer-reviewed dental literature in the Medline database was conducted to evaluate the effectiveness and biocompatibility of denture adhesives. There was no limitation in publication year, so the search included all the available scientific evidence included in that particular database until March 2014. Specific inclusion criteria were used for the selection of the appropriate articles. A manual search of the citations of the obtained articles followed to extend the electronic search. A full text review was carried out for only 32 articles. Of the 32 articles, 21 examined the efficacy of denture adhesives in terms of retention and stability and masticatory performance, 6 evaluated the issue of the biocompatibility of denture adhesives, and 5 presented the attitudes of either professionals or patients toward these materials. The majority of clinical studies supported the fact that denture adhesives enhance the retention, stability, and masticatory performance of a removable prosthesis. In terms of biocompatibility, long-term in vivo studies to investigate potential harmful effects were lacking. Patients are satisfied with denture adhesives that meet their needs. Copyright © 2015 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

  3. Innovative Electrostatic Adhesion Technologies

    Science.gov (United States)

    Gagliano, L.; Bryan, T.; Williams, S.; McCoy, B.; MacLeod, T.

    Developing specialized Electro-Static grippers (commercially used in Semiconductor Manufacturing and in package handling) will allow gentle and secure Capture, Soft Docking, and Handling of a wide variety of materials and shapes (such as upper-stages, satellites, arrays, and possibly asteroids) without requiring physical features or cavities for a pincher or probe or using harpoons or nets. Combined with new rigid boom mechanisms or small agile chaser vehicles, flexible, high speed Electro-Static Grippers can enable compliant capture of spinning objects starting from a safe stand-off distance. Electroadhesion (EA) can enable lightweight, ultra-low-power, compliant attachment in space by using an electrostatic force to adhere similar and dissimilar surfaces. A typical EA enabled device is composed of compliant space-rated materials, such as copper-clad polyimide encapsulated by polymers. Attachment is induced by strong electrostatic forces between any substrate material, such as an exterior satellite panel and a compliant EA surface. When alternate positive and negative charges are induced in adjacent planar electrodes in an EA surface, the electric fields set up opposite charges on the substrate and cause an electrostatic adhesion between the electrodes and the induced charges on the substrate. Since the electrodes and the polymer are compliant and can conform to uneven or rough surfaces, the electrodes can remain intimately close to the entire surface, enabling high clamping pressures. Clamping pressures of more than 3 N/cm2 in shear can be achieved on a variety of substrates with ultra-low holding power consumption (measured values are less than 20 microW/Newton weight held). A single EA surface geometry can be used to clamp both dielectric and conductive substrates, with slightly different physical mechanisms. Furthermore EA clamping requires no normal force be placed on the substrate, as conventional docking requires. Internally funded research and development

  4. Innovative Electrostatic Adhesion Technologies

    Science.gov (United States)

    Bryan, Tom; Macleod, Todd; Gagliano, Larry; Williams, Scott; McCoy, Brian

    2015-01-01

    Developing specialized Electro-Static grippers (commercially used in Semiconductor Manufacturing and in package handling) will allow gentle and secure Capture, Soft Docking, and Handling of a wide variety of materials and shapes (such as upper-stages, satellites, arrays, and possibly asteroids) without requiring physical features or cavities for a pincher or probe or using harpoons or nets. Combined with new rigid boom mechanisms or small agile chaser vehicles, flexible, high speed Electro-Static Grippers can enable compliant capture of spinning objects starting from a safe stand-off distance. Electroadhesion (EA) can enable lightweight, ultra-low-power, compliant attachment in space by using an electrostatic force to adhere similar and dissimilar surfaces. A typical EA enabled device is composed of compliant space-rated materials, such as copper-clad polyimide encapsulated by polymers. Attachment is induced by strong electrostatic forces between any substrate material, such as an exterior satellite panel and a compliant EA gripper pad surface. When alternate positive and negative charges are induced in adjacent planar electrodes in an EA surface, the electric fields set up opposite charges on the substrate and cause an electrostatic adhesion between the electrodes and the induced charges on the substrate. Since the electrodes and the polymer are compliant and can conform to uneven or rough surfaces, the electrodes can remain intimately close to the entire surface, enabling high clamping pressures. Clamping pressures of more than 3 N/cm2 in shear can be achieved on a variety of substrates with ultra-low holding power consumption (measured values are less than 20 microW/Newton weight held). A single EA surface geometry can be used to clamp both dielectric and conductive substrates, with slightly different physical mechanisms. Furthermore EA clamping requires no normal force be placed on the substrate, as conventional docking requires. Internally funded research and

  5. Elastocapilllarity in insect adhesion: the case of beetle adhesive hair

    Science.gov (United States)

    Gernay, Sophie; Gilet, Tristan; Lambert, Pierre; Federle, Walter

    2014-11-01

    The feet of many insects are covered with dense arrays of hair-like structures called setae. Liquid capillary bridges at the tip of these micrometric structures are responsible for the controlled adhesion of the insect on a large variety of substrates. The resulting adhesion force can exceed several times the body weight of the insect. The high aspect-ratio of setae suggests that flexibility is a key ingredient in this capillary-based adhesion mechanism. There is indeed a strong coupling between their elastic deformation and the shape of the liquid meniscus. In this experimental work, we observe and quantify the local deflection of dock beetle seta tips under perpendicular loading using interference microscopy. Our results are then interpreted in the light of an analytic model of elastocapillarity. This research has been funded by the FRIA/FNRS and the Interuniversity Attraction Poles Programme (IAP 7/38 MicroMAST) initiated by the Belgian Science Policy Office.

  6. Assessing the impact of modifications neoprene adhesives amine-containing compounds the mechanisms to improve adhesion

    OpenAIRE

    KABLOV V.F.; KEYBAL N.A.; S. N. Bondarenko; RUDENKO K.U.; Zaikov, G. E.

    2015-01-01

    Possible mechanisms for an increase in the adhesion parameters of neopren-based adhesive compositions modified with adhesion promoters on the basis of epoxy compounds and aniline derivatives are studied.

  7. The semiology of febrile seizures: Focal features are frequent.

    Science.gov (United States)

    Takasu, Michihiko; Kubota, Tetsuo; Tsuji, Takeshi; Kurahashi, Hirokazu; Numoto, Shingo; Watanabe, Kazuyoshi; Okumura, Akihisa

    2017-08-01

    To clarify the semiology of febrile seizures (FS) and to determine the frequency of FS with symptoms suggestive of focal onset. FS symptoms in children were reported within 24h of seizure onset by the parents using a structured questionnaire consisting principally of closed-ended questions. We focused on events at seizure commencement, including changes in behavior and facial expression, and ocular and oral symptoms. We also investigated the autonomic and motor symptoms developing during seizures. The presence or absence of focal and limbic features was determined for each patient. The associations of certain focal and limbic features with patient characteristics were assessed. Information was obtained on FS in 106 children. Various events were recorded at seizure commencement. Behavioral changes were observed in 35 children, changes in facial expression in 53, ocular symptoms in 78, and oral symptoms in 90. In terms of events during seizures, autonomic symptoms were recognized in 78, and convulsive motor symptoms were recognized in 68 children. Focal features were evident in 81 children; 38 children had two or more such features. Limbic features were observed in 44 children, 9 of whom had two or more such features. There was no significant relationship between any patient characteristic and the numbers of focal or limbic features. The semiology of FS varied widely among children, and symptoms suggestive of focal onset were frequent. FS of focal onset may be more common than is generally thought. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Focal spot measurements using a digital flat panel detector

    Science.gov (United States)

    Jain, Amit; Panse, A.; Bednarek, Daniel R.; Rudin, Stephen

    2014-03-01

    Focal spot size is one of the crucial factors that affect the image quality of any x-ray imaging system. It is, therefore, important to measure the focal spot size accurately. In the past, pinhole and slit measurements of x-ray focal spots were obtained using direct exposure film. At present, digital detectors are replacing film in medical imaging so that, although focal spot measurements can be made quickly with such detectors, one must be careful to account for the generally poorer spatial resolution of the detector and the limited usable magnification. For this study, the focal spots of a diagnostic x-ray tube were measured with a 10-μm pinhole using a 194-μm pixel flat panel detector (FPD). The twodimensional MTF, measured with the Noise Response (NR) Method was used for the correction for the detector blurring. The resulting focal spot sizes based on the FWTM (Full Width at Tenth Maxima) were compared with those obtained with a very high resolution detector with 8-μm pixels. This study demonstrates the possible effect of detector blurring on the focal spot size measurements with digital detectors with poor resolution and the improvement obtained by deconvolution. Additionally, using the NR method for measuring the two-dimensional MTF, any non-isotropies in detector resolution can be accurately corrected for, enabling routine measurement of non-isotropic x-ray focal spots. This work presents a simple, accurate and quick quality assurance procedure for measurements of both digital detector properties and x-ray focal spot size and distribution in modern x-ray imaging systems.

  9. Focal Length Affects Depicted Shape and Perception of Facial Images.

    Directory of Open Access Journals (Sweden)

    Vít Třebický

    Full Text Available Static photographs are currently the most often employed stimuli in research on social perception. The method of photograph acquisition might affect the depicted subject's facial appearance and thus also the impression of such stimuli. An important factor influencing the resulting photograph is focal length, as different focal lengths produce various levels of image distortion. Here we tested whether different focal lengths (50, 85, 105 mm affect depicted shape and perception of female and male faces. We collected three portrait photographs of 45 (22 females, 23 males participants under standardized conditions and camera setting varying only in the focal length. Subsequently, the three photographs from each individual were shown on screen in a randomized order using a 3-alternative forced-choice paradigm. The images were judged for attractiveness, dominance, and femininity/masculinity by 369 raters (193 females, 176 males. Facial width-to-height ratio (fWHR was measured from each photograph and overall facial shape was analysed employing geometric morphometric methods (GMM. Our results showed that photographs taken with 50 mm focal length were rated as significantly less feminine/masculine, attractive, and dominant compared to the images taken with longer focal lengths. Further, shorter focal lengths produced faces with smaller fWHR. Subsequent GMM revealed focal length significantly affected overall facial shape of the photographed subjects. Thus methodology of photograph acquisition, focal length in this case, can significantly affect results of studies using photographic stimuli perhaps due to different levels of perspective distortion that influence shapes and proportions of morphological traits.

  10. Polyurethane adhesives in flat roofs

    Directory of Open Access Journals (Sweden)

    Bogárová Markéta

    2017-01-01

    Full Text Available It is necessary to stabilize individual layers of flat roofs, mainly because of wind suction. Apart from anchoring and surcharge, these layers can be secured by bonding. At present gluing is an indispensable and widely used stabilization method. On our market we can found many types of adhesives, most widely used are based on polyurethane. This paper focuses on problematic about stabilization thermal insulation from expanded polystyrene to vapor barrier from bitumen. One of the main issues is to calculate the exact amount of adhesive, which is required to guarantee the resistance against wind suction. In this problematic we can not find help neither in technical data sheets provided by the manufactures. Some of these data sheets contain at least information about amount of adhesive depending on location in roof plane and building height, but they do not specify the strength of such connection. It was therefore resorted to select several representatives polyurethane adhesives and their subsequent testing on specimens simulating the flat roof segment. The paper described the test methodology and results for two types of polyurethane adhesives.

  11. Capillarity-based switchable adhesion.

    Science.gov (United States)

    Vogel, Michael J; Steen, Paul H

    2010-02-23

    Drawing inspiration from the adhesion abilities of a leaf beetle found in nature, we have engineered a switchable adhesion device. The device combines two concepts: The surface tension force from a large number of small liquid bridges can be significant (capillarity-based adhesion) and these contacts can be quickly made or broken with electronic control (switchable). The device grabs or releases a substrate in a fraction of a second via a low-voltage pulse that drives electroosmotic flow. Energy consumption is minimal because both the grabbed and released states are stable equilibria that persist with no energy added to the system. Notably, the device maintains the integrity of an array of hundreds to thousands of distinct interfaces during active reconfiguration from droplets to bridges and back, despite the natural tendency of the liquid toward coalescence. We demonstrate the scaling of adhesion strength with the inverse of liquid contact size. This suggests that strengths approaching those of permanent bonding adhesives are possible as feature size is scaled down. In addition, controllability is fast and efficient because the attachment time and required voltage also scale down favorably. The device features compact size, no solid moving parts, and is made of common materials.

  12. Differences between diffuse and focal autoimmune pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Taku Tabata; Terumi Kamisawa; Kensuke Takuma; Seiichi Hara; Sawako Kuruma; Yoshihiko Inaba

    2012-01-01

    AIM:To investigate differences in clinical features between diffuse-and focal-type autoimmune pancreatitis (AIP).METHODS:Based on radiological findings by computed tomography and/or magnetic resonance imaging,we divided 67 AIP patients into diffuse type (D type)and focal type (F type).We further divided F type into head type (H type) and body and/or tail type (B/T type)according to the location of enlargement.Finally,we classified the 67 AIP patients into three groups:D type,H type and B/F type.We compared the three types of AIP in terms of clinical,laboratory,radiological,functional and histological findings and clinical course.RESULTS:There were 34 patients with D-type,19 with H-type and 14 with B/T-type AIP.Although obstructive jaundice was frequently detected in D-type patients (88%) and H-type patients (68%),no B/T-type patients showed jaundice as an initial symptom (P < 0.001).There were no differences in frequency of abdominal pain,but acute pancreatitis was associated more frequently in B/T-type patients (36%) than in D-type patients (3%) (P =0.017).Serum immunoglobulin G (IgG)4 levels were significantly higher in D-type patients (median 309 mg/dL) than in B/T-type patients (133.5 mg/dL) (P =0.042).Serum amylase levels in B/T-type patients (median:114 IU/L) were significantly greater than in H-type patients (72 IU/L) (P =0.049).Lymphoplasmacytic sclerosing pancreatitis (LPSP) was histologically confirmed in 6 D-type,7 H-type and 4 B/T-type patients; idiopathic duct-centric pancreatitis was observed in no patients.Marked fibrosis and abundant infiltration of CD20-positive B lymphocytes with few IgG4-positive plasma cells were detected in 2 B/T-type patients.Steroid therapy was effective in all 50 patients (31 D type,13 H type and 6 B/T type).Although AIP relapsed during tapering or after stopping steroids in 3 D-type and 3 H-type patients,no patients relapsed in B/T type.During follow-up,radiological features of 6 B/T-type patients were not changed

  13. Recovery of Deep Moonquake Focal Mechanisms

    Science.gov (United States)

    Weber, Renee C.; Knapmeyer, Martin

    2012-01-01

    Deep moonquakes are clustered not only in space but also in time: their recurrence times correspond to the durations of the anomalistic and draconic months, with some clusters preferring one of the two periods, while others are active with both periods. A key constraint for the understanding of the connection between the orbital motion of the Moon and its seismic activity is the focal mechanism: the orientation of the fault surface on which failure occurs during the quake. Due to the small aperture of the Apollo seismic network and the strong scattering of seismic waves within the lunar crust, the evaluation of P wave first motions to constrain the strike and dip of the fault planes is not feasible. Instead we evaluate the amplitude ratios of P and S waves. Seismograms are rotated into the P-SV-SH coordinate frame and amplitudes are determined as averages over short time windows after the arrival to reduce the impact of the scattering coda, which is independent of the source orientation. We allow for reversals of the fault motion, as observed for some clusters in previous studies, by taking into account the absolute amplitude only, without sign. An empirical site correction factor is applied to correct for amplitude distortions in the crust. We construct ensembles of fault plane solutions using an exhaustive grid search by accepting all orientations that reproduce the measured amplitude ratios within the observed standard deviations. Since all events of a given cluster are supposed to share the same fault plane, the combination of the individual inversion results further constrains the orientation. We evaluate 106 events from 25 different moonquake clusters. The most active cluster A001 contributes 37 events, while others contribute 1 to 9 events per cluster. Comparison of fault orientations with the variation of the tidal stress results in preferred orientations.

  14. Focal cemento-osseous dysplasia: review and a case report.

    Science.gov (United States)

    Salem, Y M Y; Osman, Y I; Norval, E J G

    2010-10-01

    Focal cemento-osseous dysplasia is a benign fibro-osseous condition that can be seen in dentate and edentulous patients. It is an asymptomatic lesion and needs no treatment; however follow-up is essential due to the possibility that focal cemento-osseous dysplasia can progress to a condition called florid osseous dysplasia that involves multiple sites. A case report is presented here, along with a review of the differential diagnoses considered in order to reach a final diagnosis of focal cemento-osseous dysplasia.

  15. Involvement of rho-gtpases in fibroblast adhesion and fibronectine fibrillogenesis under stretch

    Science.gov (United States)

    Guignandon, A.; Lambert, C.; Rattner, A.; Servotte, S.; Lapiere, C.; Nusgens, B.; Vico, L.

    The Rho family small GTPases play a crucial role in mediating cellular adaptation to mechanical stimulation (MS), and possibly to microgravity (μg), through effects on the cytoskeleton and cell adhesion which is, in turn, mainly regulated by fibronectin fibrillogenesis (FnF). It remains unclear how mechanical stimulation is transduced to the Rho signaling pathways and how it impacts on fibronectin (fbn) fibrillogenesis (FnF). μg (2 days, mission STS-095) led to de-adhesion of fibroblasts and modification of the underlying extracellular matrix. To determine whether GTPases modulated FnF, we generated stable cell lines expressing high level of activated RhoA and Rac1 (QL) as compared to wild type (WI26-WT). After MS application [8% deformation, 1Hz, 15 min., 3 times/day for 1-2 days], we quantified focal adhesion (vinculin, paxillin, FAKY397), f-actin stress fibers (Sf) and FnF with home-developed softwares. We reported that after MS, Sf are more rapidly (30min) formed under the nucleus in Wi26-WT (+100%) and Rac1 (+200%) than in RhoA (+20%). Vinculin & paxillin were only restricted to the cell edge in static conditions and homogeneously distributed after MS in WT and Rac1. The relative area of contacts (vinculin & paxillin) was more dramatically enhanced by MS in Rac1 (+80%) than in WT (+40%) and RhoA (+25%) indicating that new focal contacts are formed under MS and supported the presence of Sf. MS Activation of FAK (FAKY397) was clear in WT and Rac1 and reduced in RhoA. FnF was restricted to cell-cell contacts zone without any change in the relative area of fbn after a 2-days MS. However we found more numerous spots of fbn at the cell center in Rac1 as compared with RhoA & WT suggesting that these fibrillar contacts will grow upon maturation and modulate FnF. The results indicate that MS induces formation of Sf and focal adhesions and enhances FF. RhoA has been shown to induce the formation of Sf and focal adhesions, and Rac1 activation decreases Rho activity in

  16. Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma

    Science.gov (United States)

    Konen, Jessica; Koo, Junghui; Robinson, Brian S.; Wiles, Walter Guy; Huang, Chunzi; Martin, W. David; Behera, Madhusmita; Smith, Geoffrey H.; Hill, Charles E.; Rossi, Michael R.; Sica, Gabriel L.; Rupji, Manali; Chen, Zhengjia; Kowalski, Jeanne; Kasinski, Andrea L.; Ramalingam, Suresh S.; Khuri, Fadlo R.; Marcus, Adam I.

    2017-01-01

    Loss of LKB1 activity is prevalent in KRAS mutant lung adenocarcinoma and promotes aggressive and treatment-resistant tumors. Previous studies have shown that LKB1 is a negative regulator of the focal adhesion kinase (FAK), but in vivo studies testing the efficacy of FAK inhibition in LKB1 mutant cancers are lacking. Here, we took a pharmacologic approach to show that FAK inhibition is an effective early-treatment strategy for this high-risk molecular subtype. We established a lenti-Cre–induced Kras and Lkb1 mutant genetically engineered mouse model (KLLenti) that develops 100% lung adenocarcinoma and showed that high spatiotemporal FAK activation occurs in collective invasive cells that are surrounded by high levels of collagen. Modeling invasion in 3D, loss of Lkb1, but not p53, was sufficient to drive collective invasion and collagen alignment that was highly sensitive to FAK inhibition. Treatment of early, stage-matched KLLenti tumors with FAK inhibitor monotherapy resulted in a striking effect on tumor progression, invasion, and tumor-associated collagen. Chronic treatment extended survival and impeded local lymph node spread. Lastly, we identified focally upregulated FAK and collagen-associated collective invasion in KRAS and LKB1 comutated human lung adenocarcinoma patients. Our results suggest that patients with LKB1 mutant tumors should be stratified for early treatment with FAK inhibitors.

  17. Role of cell adhesion signal molecules in hepatocellular carcinoma cell apoptosis

    Institute of Scientific and Technical Information of China (English)

    Jian-Min Su; Li-Ying Wang; Yu-Long Liang; Xi-Liang Zha

    2005-01-01

    AIM: Cell adhesion molecules and their signal molecules play a very important role in carcinogenesis. The aim of this study is to elucidate the role of these molecules and the signal molecules of integrins and E-cadherins, such as (focal adhesion kinase) FAK, (integrin linked kinase)ILK, and β-catenin in hepatocellular carcinoma cell apoptosis.METHODS: We first synthesized the small molecular compound, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and identified it, by element analysis and 1H NMR. To establish the apoptosis model of the SMMC-7721 hepatocellular carcinoma cell, we treated cells with DCVC in EBSS for different concentrations or for various length times in the presence of 20 μmol/L N,N-diphenyl-p-phenylenediamine,which blocks necrotic cell death and identified this model by flow cytometry and DNA ladder. Then we studied the changes of FAK, ILK, β-catenin, and PKB in this apoptotic model by Western blot.RESULTS: We found that the loss or decrease of cell adhesion signal molecules is an important reason in apoptosis of SMMC-7721 hepatocellular carcinoma cell and the apoptosis of SMMC-7721 cell was preceded by the loss or decrease of FAK, ILK, PKB, and β-catenin or the damage of cell-matrix and cell-cell adhesion.CONCLUSION: Our results suggested that the decrease of adhesion signal molecules, FAK, ILK, PKB, and β-catenin,could induce hepatocellular carcinoma cell apoptosis.

  18. Increasing mouse embryonic fibroblast cells adhesion on superhydrophilic vertically aligned carbon nanotube films

    Energy Technology Data Exchange (ETDEWEB)

    Lobo, A.O., E-mail: loboao@yahoo.com [Laboratory of Biomedical Nanotechnology (NanoBio), Instituto de Pesquisa e Desenvolvimento (IP and D), Universidade do Vale do Paraiba UniVap, Avenida Shishima Hifumi 2911, Sao Jose dos Campos, 12244-000, SP (Brazil) and Laboratory of Biomedical Vibrational Spectroscopy (LEVB), Instituto de Pesquisa e Desenvolvimento (IP and D), Universidade do Vale do Paraiba UniVap, Avenida Shishima Hifumi 2911, Sao Jose dos Campos, 12244-000, SP (Brazil); Marciano, F.R. [Laboratory of Biomedical Nanotechnology (NanoBio), Instituto de Pesquisa e Desenvolvimento (IP and D), Universidade do Vale do Paraiba UniVap, Avenida Shishima Hifumi 2911, Sao Jose dos Campos, 12244-000, SP (Brazil); Laboratory of Biomedical Vibrational Spectroscopy LEVB, Instituto de Pesquisa e Desenvolvimento (IP and D), Universidade do Vale do Paraiba (UniVap), Avenida Shishima Hifumi 2911, Sao Jose dos Campos, 12244-000, SP (Brazil); Ramos, S.C. [Laboratorio Associado de Sensores e Materiais (LAS), Instituto Nacional de Pesquisas Espaciais (INPE), Avenida dos Astronautas 1758, Sao Jose dos Campos, 12.245-970, SP (Brazil); Machado, M.M. [Centro Multidisciplinar para Investigacao Biologica na Area da Ciencia em Animais de Laboratorio (CEMIB), Universidade Estadual de Campinas (UNICAMP), Rua 05 de Junho s/no, Cidade Universitaria ' Zeferino Vaz' , 13083-877, Campinas (Brazil); Corat, E.J. [Laboratorio Associado de Sensores e Materiais (LAS), Instituto Nacional de Pesquisas Espaciais (INPE), Avenida dos Astronautas 1758, Sao Jose dos Campos, 12.245-970, SP (Brazil); Corat, M.A.F. [Centro Multidisciplinar para Investigacao Biologica na Area da Ciencia em Animais de Laboratorio (CEMIB), Universidade Estadual de Campinas (UNICAMP), Rua 05 de Junho s/no, Cidade Universitaria ' Zeferino Vaz' , 13083-877, Campinas (Brazil)

    2011-10-10

    We have analyzed the adhesion of mouse embryonic fibroblasts (MEFs) genetically modified by green fluorescence protein (GFP) gene cultured on vertically-aligned carbon nanotubes (VACNTs) after 6 days. The VACNTs films grown on Ti were obtained by microwave plasma chemical vapor deposition process using Fe catalyst and submitted to an oxygen plasma treatment, for 2 min, at 400 V and 80 mTorr, to convert them to superhydrophilic. Cellular adhesion and morphology were analyzed by scanning electron, fluorescence microscopy, and thermodynamics analysis. Characterizations of superhydrophilic VACNTs films were evaluated by contact angle and X-Ray Photoelectron Spectroscopy. Differences of crowd adhered cells, as well as their spreading on superhydrophilic VACNTs scaffolds, were evaluated using focal adhesion analysis. This study was the first to demonstrate, in real time, that the wettability of VACNTs scaffolds might have enhanced and differential adherence patterns to the MEF-GFP on VACNTs substrates. Highlights: {yields} A simple oxygen plasma treatment was used to obtain superhydrophilic CNT films. {yields} Superhydrophilic CNTs films were successfully produced by incorporation of carboxylic groups. {yields} Cellular adhesion on superhydrophilic VACNT films was analyzed in real time. {yields} Wettability of CNT films directly affects the cellular migration, proliferation and adhesion.

  19. Cell adhesion in embryo morphogenesis.

    Science.gov (United States)

    Barone, Vanessa; Heisenberg, Carl-Philipp

    2012-02-01

    Visualizing and analyzing shape changes at various scales, ranging from single molecules to whole organisms, are essential for understanding complex morphogenetic processes, such as early embryonic development. Embryo morphogenesis relies on the interplay between different tissues, the properties of which are again determined by the interaction between their constituent cells. Cell interactions, on the other hand, are controlled by various molecules, such as signaling and adhesion molecules, which in order to exert their functions need to be spatiotemporally organized within and between the interacting cells. In this review, we will focus on the role of cell adhesion functioning at different scales to organize cell, tissue and embryo morphogenesis. We will specifically ask how the subcellular distribution of adhesion molecules controls the formation of cell-cell contacts, how cell-cell contacts determine tissue shape, and how tissue interactions regulate embryo morphogenesis.

  20. Liposome adhesion generates traction stress

    Science.gov (United States)

    Murrell, Michael P.; Voituriez, Raphaël; Joanny, Jean-François; Nassoy, Pierre; Sykes, Cécile; Gardel, Margaret L.

    2014-02-01

    Mechanical forces generated by cells modulate global shape changes required for essential life processes, such as polarization, division and spreading. Although the contribution of the cytoskeleton to cellular force generation is widely recognized, the role of the membrane is considered to be restricted to passively transmitting forces. Therefore, the mechanisms by which the membrane can directly contribute to cell tension are overlooked and poorly understood. To address this, we directly measure the stresses generated during liposome adhesion. We find that liposome spreading generates large traction stresses on compliant substrates. These stresses can be understood as the equilibration of internal, hydrostatic pressures generated by the enhanced membrane tension built up during adhesion. These results underscore the role of membranes in the generation of mechanical stresses on cellular length scales and that the modulation of hydrostatic pressure due to membrane tension and adhesion can be channelled to perform mechanical work on the environment.