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Sample records for adaptive lattice notch

  1. Numb: "Adapting" notch for endocytosis.

    PubMed

    Jafar-Nejad, Hamed; Norga, Koenraad; Bellen, Hugo

    2002-08-01

    During sensory organ precursor divisions in Drosophila, the numb gene product segregates asymmetrically into one of the two daughter cells, to which it confers a specific fate by inhibiting Notch signaling. In this issue of Developmental Cell, Berdnik et al. show that Numb recruits alpha-Adaptin and that this physical interaction plays a role in downregulating Notch, presumably by stimulating endocytosis of Notch. PMID:12194846

  2. Automatic balancing of AMB systems using plural notch filter and adaptive synchronous compensation

    NASA Astrophysics Data System (ADS)

    Xu, Xiangbo; Chen, Shao; Zhang, Yanan

    2016-07-01

    To achieve automatic balancing in active magnetic bearing (AMB) system, a control method with notch filters and synchronous compensators is widely employed. However, the control precision is significantly affected by the synchronous compensation error, which is caused by parameter errors and variations of the power amplifiers. Furthermore, the computation effort may become intolerable if a 4-degree-of-freedom (dof) AMB system is studied. To solve these problems, an adaptive automatic balancing control method in the AMB system is presented in this study. Firstly, a 4-dof radial AMB system is described and analyzed. To simplify the controller design, the 4-dof dynamic equations are transferred into two plural functions related to translation and rotation, respectively. Next, to achieve automatic balancing of the AMB system, two synchronous equations are formed. Solution of them leads to a control strategy based on notch filters and feedforward controllers with an inverse function of the power amplifier. The feedforward controllers can be simplified as synchronous phases and amplitudes. Then, a plural phase-shift notch filter which can identify the synchronous components in 2-dof motions is formulated, and an adaptive compensation method that can form two closed-loop systems to tune the synchronous amplitude of the feedforward controller and the phase of the plural notch filter is proposed. Finally, the proposed control strategy is verified by both simulations and experiments on a test rig of magnetically suspended control moment gyro. The results indicate that this method can fulfill the automatic balancing of the AMB system with a light computational load.

  3. Adaptive control of large space structures using recursive lattice filters

    NASA Technical Reports Server (NTRS)

    Sundararajan, N.; Goglia, G. L.

    1985-01-01

    The use of recursive lattice filters for identification and adaptive control of large space structures is studied. Lattice filters were used to identify the structural dynamics model of the flexible structures. This identification model is then used for adaptive control. Before the identified model and control laws are integrated, the identified model is passed through a series of validation procedures and only when the model passes these validation procedures is control engaged. This type of validation scheme prevents instability when the overall loop is closed. Another important area of research, namely that of robust controller synthesis, was investigated using frequency domain multivariable controller synthesis methods. The method uses the Linear Quadratic Guassian/Loop Transfer Recovery (LQG/LTR) approach to ensure stability against unmodeled higher frequency modes and achieves the desired performance.

  4. Two-dimensional lattice polymers: Adaptive windows simulations

    NASA Astrophysics Data System (ADS)

    Cunha-Netto, A. G.; Dickman, Ronald; Caparica, A. A.

    2009-04-01

    We report a numerical study of self-avoiding polymers on the square lattice, including an attractive potential between nonconsecutive monomers occupying neighboring lattice sites. Using Wang-Landau sampling (WLS) with adaptive windows, we obtain the density of states for chains of up to N=300 monomers and associated thermodynamic quantities. Finite size scaling analysis yields a transition temperature of Θ=1.505(18). WLS with adaptive windows enables one to simulate accurately the low-temperature regime, which is virtually inaccessible using traditional methods. Instead of defining fixed energy windows, as in usual WLS, this method uses windows with boundaries that depend on the set of energy values on which the histogram is flat at a given stage of the simulation. Shifting the windows each time the modification factor f is reduced, we eliminate border effects that arise in simulations using fixed windows.

  5. Adaptive control of large space structures using recursive lattice filters

    NASA Technical Reports Server (NTRS)

    Goglia, G. L.

    1985-01-01

    The use of recursive lattice filters for identification and adaptive control of large space structures was studied. Lattice filters are used widely in the areas of speech and signal processing. Herein, they are used to identify the structural dynamics model of the flexible structures. This identified model is then used for adaptive control. Before the identified model and control laws are integrated, the identified model is passed through a series of validation procedures and only when the model passes these validation procedures control is engaged. This type of validation scheme prevents instability when the overall loop is closed. The results obtained from simulation were compared to those obtained from experiments. In this regard, the flexible beam and grid apparatus at the Aerospace Control Research Lab (ACRL) of NASA Langley Research Center were used as the principal candidates for carrying out the above tasks. Another important area of research, namely that of robust controller synthesis, was investigated using frequency domain multivariable controller synthesis methods.

  6. Adaptive Multigrid Algorithm for the Lattice Wilson-Dirac Operator

    SciTech Connect

    Babich, R.; Brower, R. C.; Rebbi, C.; Brannick, J.; Clark, M. A.; Manteuffel, T. A.; McCormick, S. F.; Osborn, J. C.

    2010-11-12

    We present an adaptive multigrid solver for application to the non-Hermitian Wilson-Dirac system of QCD. The key components leading to the success of our proposed algorithm are the use of an adaptive projection onto coarse grids that preserves the near null space of the system matrix together with a simplified form of the correction based on the so-called {gamma}{sub 5}-Hermitian symmetry of the Dirac operator. We demonstrate that the algorithm nearly eliminates critical slowing down in the chiral limit and that it has weak dependence on the lattice volume.

  7. Adaptive multigrid algorithm for the lattice Wilson-Dirac operator.

    PubMed

    Babich, R; Brannick, J; Brower, R C; Clark, M A; Manteuffel, T A; McCormick, S F; Osborn, J C; Rebbi, C

    2010-11-12

    We present an adaptive multigrid solver for application to the non-Hermitian Wilson-Dirac system of QCD. The key components leading to the success of our proposed algorithm are the use of an adaptive projection onto coarse grids that preserves the near null space of the system matrix together with a simplified form of the correction based on the so-called γ5-Hermitian symmetry of the Dirac operator. We demonstrate that the algorithm nearly eliminates critical slowing down in the chiral limit and that it has weak dependence on the lattice volume. PMID:21231217

  8. Coordination of insulin and Notch pathway activities by microRNA miR-305 mediates adaptive homeostasis in the intestinal stem cells of the Drosophila gut

    PubMed Central

    Foronda, David; Weng, Ruifen; Verma, Pushpa; Chen, Ya-Wen

    2014-01-01

    Homeostasis of the intestine is maintained by dynamic regulation of a pool of intestinal stem cells. The balance between stem cell self-renewal and differentiation is regulated by the Notch and insulin signaling pathways. Dependence on the insulin pathway places the stem cell pool under nutritional control, allowing gut homeostasis to adapt to environmental conditions. Here we present evidence that miR-305 is required for adaptive homeostasis of the gut. miR-305 regulates the Notch and insulin pathways in the intestinal stem cells. Notably, miR-305 expression in the stem cells is itself under nutritional control via the insulin pathway. This link places regulation of Notch pathway activity under nutritional control. These findings provide a mechanism through which the insulin pathway controls the balance between stem cell self-renewal and differentiation that is required for adaptive homeostasis in the gut in response to changing environmental conditions. PMID:25367037

  9. Feedforward compensation control of rotor imbalance for high-speed magnetically suspended centrifugal compressors using a novel adaptive notch filter

    NASA Astrophysics Data System (ADS)

    Zheng, Shiqiang; Feng, Rui

    2016-03-01

    This paper introduces a feedforward control strategy combined with a novel adaptive notch filter to solve the problem of rotor imbalance in high-speed Magnetically Suspended Centrifugal Compressors (MSCCs). Unbalance vibration force of rotor in MSCC is mainly composed of current stiffness force and displacement stiffness force. In this paper, the mathematical model of the unbalance vibration with the proportional-integral-derivative (PID) control laws is presented. In order to reduce the unbalance vibration, a novel adaptive notch filter is proposed to identify the synchronous frequency displacement of the rotor as a compensation signal to eliminate the current stiffness force. In addition, a feedforward channel from position component to control output is introduced to compensate displacement stiffness force to achieve a better performance. A simplified inverse model of power amplifier is included in the feedforward channel to reject the degrade performance caused by its low-pass characteristic. Simulation and experimental results on a MSCC demonstrate a significant effect on the synchronous vibration suppression of the magnetically suspended rotor at a high speed.

  10. New Approach for IIR Adaptive Lattice Filter Structure Using Simultaneous Perturbation Algorithm

    NASA Astrophysics Data System (ADS)

    Martinez, Jorge Ivan Medina; Nakano, Kazushi; Higuchi, Kohji

    Adaptive infinite impulse response (IIR), or recursive, filters are less attractive mainly because of the stability and the difficulties associated with their adaptive algorithms. Therefore, in this paper the adaptive IIR lattice filters are studied in order to devise algorithms that preserve the stability of the corresponding direct-form schemes. We analyze the local properties of stationary points, a transformation achieving this goal is suggested, which gives algorithms that can be efficiently implemented. Application to the Steiglitz-McBride (SM) and Simple Hyperstable Adaptive Recursive Filter (SHARF) algorithms is presented. Also a modified version of Simultaneous Perturbation Stochastic Approximation (SPSA) is presented in order to get the coefficients in a lattice form more efficiently and with a lower computational cost and complexity. The results are compared with previous lattice versions of these algorithms. These previous lattice versions may fail to preserve the stability of stationary points.

  11. Adaptive identification and control of structural dynamics systems using recursive lattice filters

    NASA Technical Reports Server (NTRS)

    Sundararajan, N.; Montgomery, R. C.; Williams, J. P.

    1985-01-01

    A new approach for adaptive identification and control of structural dynamic systems by using least squares lattice filters thar are widely used in the signal processing area is presented. Testing procedures for interfacing the lattice filter identification methods and modal control method for stable closed loop adaptive control are presented. The methods are illustrated for a free-free beam and for a complex flexible grid, with the basic control objective being vibration suppression. The approach is validated by using both simulations and experimental facilities available at the Langley Research Center.

  12. Notch Antennas

    NASA Technical Reports Server (NTRS)

    Lee, Richard Q.

    2004-01-01

    Notch antennas, also known as the tapered slot antenna (TSA), have been the topics of research for decades. TSA has demonstrated multi-octave bandwidth, moderate gain (7 to 10 dB), and symmetric E- and H- plane beam patterns and can be used for many different applications. This chapter summarizes the research activities on notch antennas over the past decade with emphasis on their most recent advances and applications. This chapter begins with some discussions on the designs of single TSA; then follows with detailed discussions of issues associated with TSA designs and performance characteristics. To conclude the chapter, some recent developments in TSA arrays and their applications are highlighted.

  13. Vibration control of a flexible beam driven by a ball-screw stage with adaptive notch filters and a line enhancer

    NASA Astrophysics Data System (ADS)

    Wu, Shang-Teh; Lian, Sing-Han; Chen, Sheng-Han

    2015-07-01

    For a low-stiffness beam driven by a ball-screw stage, the lateral vibrations cannot be adequately controlled by a collocated compensator based on rotary-encoder feedback alone. Acceleration signals at the tip of the flexible beam are measured for active vibration control in addition to the collocated compensator. A second-order bandpass filter (a line enhancer) and two notch filters are included in the acceleration-feedback loop to raise modal dampings for the first and the second flexible modes without exciting higher-frequency resonances. A novel adaptation algorithm is devised to tune the center frequencies of the notch filters in real time. It consists of a second-order low-pass filter, a second-order bandpass filter and a phase detector. Improvement of the control system is elaborated progressively with the root-locus and bode-plot analyses, along with a physical interpretation. Extensive testings are conducted on an experimental device to verify the effectiveness of the control method.

  14. The Sequential Empirical Bayes Method: An Adaptive Constrained-Curve Fitting Algorithm for Lattice QCD

    SciTech Connect

    Ying Chen; Shao-Jing Dong; Terrence Draper; Ivan Horvath; Keh-Fei Liu; Nilmani Mathur; Sonali Tamhankar; Cidambi Srinivasan; Frank X. Lee; Jianbo Zhang

    2004-05-01

    We introduce the ''Sequential Empirical Bayes Method'', an adaptive constrained-curve fitting procedure for extracting reliable priors. These are then used in standard augmented-{chi}{sup 2} fits on separate data. This better stabilizes fits to lattice QCD overlap-fermion data at very low quark mass where a priori values are not otherwise known. Lessons learned (including caveats limiting the scope of the method) from studying artificial data are presented. As an illustration, from local-local two-point correlation functions, we obtain masses and spectral weights for ground and first-excited states of the pion, give preliminary fits for the a{sub 0} where ghost states (a quenched artifact) must be dealt with, and elaborate on the details of fits of the Roper resonance and S{sub 11}(N{sup 1/2-}) previously presented elsewhere. The data are from overlap fermions on a quenched 16{sup 3} x 28 lattice with spatial size La = 3.2 fm and pion mass as low as {approx}180 MeV.

  15. An adaptive lattice Boltzmann scheme for modeling two-fluid-phase flow in porous medium systems

    NASA Astrophysics Data System (ADS)

    Dye, Amanda L.; McClure, James E.; Adalsteinsson, David; Miller, Cass T.

    2016-04-01

    We formulate a multiple-relaxation-time (MRT) lattice-Boltzmann method (LBM) to simulate two-fluid-phase flow in porous medium systems. The MRT LBM is applied to simulate the displacement of a wetting fluid by a nonwetting fluid in a system corresponding to a microfluidic cell. Analysis of the simulation shows widely varying time scales for the dynamics of fluid pressures, fluid saturations, and interfacial curvatures that are typical characteristics of such systems. Displacement phenomena include Haines jumps, which are relatively short duration isolated events of rapid fluid displacement driven by capillary instability. An adaptive algorithm is advanced using a level-set method to locate interfaces and estimate their rate of advancement. Because the displacement dynamics are confined to the interfacial regions for a majority of the relaxation time, the computational effort is focused on these regions. The proposed algorithm is shown to reduce computational effort by an order of magnitude, while yielding essentially identical solutions to a conventional fully coupled approach. The challenges posed by Haines jumps are also resolved by the adaptive algorithm. Possible extensions to the advanced method are discussed.

  16. Adaptive pixel-selection using chaotic map lattices for image cryptography

    NASA Astrophysics Data System (ADS)

    Sittigorn, Jirasak; Paithoonwattanakij, Kitti; Surawatpunya, Charray

    2014-01-01

    Chaotic theory has been used in cryptography application for generating a sequence of data that is close to pseudorandom number based on an adjusted initial condition and a parameter. However, data recovery becomes a crucial problem due to the precision of the parameters. This difficulty leads to limited usage of Chaotic-based cryptography especially for error sensitive applications such as voice cryptography. In order to enhance the encryption security and overcome this limitation, an Adaptive Pixel-Selection using Chaotic Map Lattices (APCML) is proposed. In APCML, the encryption sequence has been adaptively selected based on chaos generator. Moreover, the chaotic transformation and normalization boundary have been revised to alleviate the rounding error and inappropriate normalization boundary problems. In the experiments, the measurement indices of originality preservation, visual inspection, and statistical analysis are used to evaluate the performance of the proposed APCML compared to that of the original CML. Consequently, the APCML algorithm offers greater performance with full recovery of the original message.

  17. Notch Signaling Components

    PubMed Central

    Liu, Zhi-Yan; Wu, Tao; Li, Qing; Wang, Min-Cong; Jing, Li; Ruan, Zhi-Ping; Yao, Yu; Nan, Ke-Jun; Guo, Hui

    2016-01-01

    Abstract Non-small-cell lung cancer (NSCLC) is a lethal and aggressive malignancy. Currently, the identities of prognostic and predictive makers of NSCLC have not been fully established. Dysregulated Notch signaling has been implicated in many human malignancies, including NSCLC. However, the prognostic value of measuring Notch signaling and the utility of developing Notch-targeted therapies in NSCLC remain inconclusive. The present study investigated the association of individual Notch receptor and ligand levels with lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) prognosis using the Kaplan-Meier plotte database. This online database encompasses 2437 lung cancer samples. Hazard ratios with 95% confidence intervals were calculated. The results showed that higher Notch1, Notch2, JAG1, and DLL1 mRNA expression predicted better overall survival (OS) in lung ADC, but showed no significance in SCC patients. Elevated Notch3, JAG2, and DLL3 mRNA expression was associated with poor OS of ADC patients, but not in SCC patients. There was no association between Notch4 and OS in either lung ADC or SCC patients. In conclusion, the set of Notch1, Notch2, JAG1, DLL1 and that of Notch3, JAG2, DLL3 played opposing prognostic roles in lung ADC patients. Neither set of Notch receptors and ligands was indicative of lung SCC prognosis. Notch signaling could serve as promising marker to predict outcomes in lung ADC patients. The distinct features of lung cancer subtypes and Notch components should be considered when developing future Notch-targeted therapies. PMID:27196489

  18. An adaptive lattice Boltzmann method for predicting turbulent wake fields in wind parks

    NASA Astrophysics Data System (ADS)

    Deiterding, Ralf; Wood, Stephen L.

    2014-11-01

    Wind turbines create large-scale wake structures that can affect downstream turbines considerably. Numerical simulation of the turbulent flow field is a viable approach in order to obtain a better understanding of these interactions and to optimize the turbine placement in wind parks. Yet, the development of effective computational methods for predictive wind farm simulation is challenging. As an alternative approach to presently employed vortex and actuator-based methods, we are currently developing a parallel adaptive lattice Boltzmann method for large eddy simulation of turbulent weakly compressible flows with embedded moving structures that shows good potential for effective wind turbine wake prediction. Since the method is formulated in an Eulerian frame of reference and on a dynamically changing nonuniform Cartesian grid, even moving boundaries can be considered rather easily. The presentation will describe all crucial components of the numerical method and discuss first verification computations. Among other configurations, simulations of the wake fields created by multiple Vesta V27 turbines will be shown.

  19. Predictive simulation of wind turbine wake interaction with an adaptive lattice Boltzmann method for moving boundaries

    NASA Astrophysics Data System (ADS)

    Deiterding, Ralf; Wood, Stephen L.

    2015-11-01

    Operating horizontal axis wind turbines create large-scale turbulent wake structures that affect the power output of downwind turbines considerably. The computational prediction of this phenomenon is challenging as efficient low dissipation schemes are necessary that represent the vorticity production by the moving structures accurately and are able to transport wakes without significant artificial decay over distances of several rotor diameters. We have developed the first version of a parallel adaptive lattice Boltzmann method for large eddy simulation of turbulent weakly compressible flows with embedded moving structures that considers these requirements rather naturally and enables first principle simulations of wake-turbine interaction phenomena at reasonable computational costs. The presentation will describe the employed algorithms and present relevant verification and validation computations. For instance, power and thrust coefficients of a Vestas V27 turbine are predicted within 5% of the manufacturer's specifications. Simulations of three Vestas V27-225kW turbines in triangular arrangement analyze the reduction in power production due to upstream wake generation for different inflow conditions.

  20. Massively parallel sampling of lattice proteins reveals foundations of thermal adaptation.

    PubMed

    Venev, Sergey V; Zeldovich, Konstantin B

    2015-08-01

    Evolution of proteins in bacteria and archaea living in different conditions leads to significant correlations between amino acid usage and environmental temperature. The origins of these correlations are poorly understood, and an important question of protein theory, physics-based prediction of types of amino acids overrepresented in highly thermostable proteins, remains largely unsolved. Here, we extend the random energy model of protein folding by weighting the interaction energies of amino acids by their frequencies in protein sequences and predict the energy gap of proteins designed to fold well at elevated temperatures. To test the model, we present a novel scalable algorithm for simultaneous energy calculation for many sequences in many structures, targeting massively parallel computing architectures such as graphics processing unit. The energy calculation is performed by multiplying two matrices, one representing the complete set of sequences, and the other describing the contact maps of all structural templates. An implementation of the algorithm for the CUDA platform is available at http://www.github.com/kzeldovich/galeprot and calculates protein folding energies over 250 times faster than a single central processing unit. Analysis of amino acid usage in 64-mer cubic lattice proteins designed to fold well at different temperatures demonstrates an excellent agreement between theoretical and simulated values of energy gap. The theoretical predictions of temperature trends of amino acid frequencies are significantly correlated with bioinformatics data on 191 bacteria and archaea, and highlight protein folding constraints as a fundamental selection pressure during thermal adaptation in biological evolution. PMID:26254668

  1. Notch and the Skeleton▿

    PubMed Central

    Zanotti, Stefano; Canalis, Ernesto

    2010-01-01

    Notch receptors are transmembrane receptors that regulate cell fate decisions. There are four Notch receptors in mammals. Upon binding to members of the Delta and Jagged family of transmembrane proteins, Notch is cleaved and the Notch intracellular domain (NICD) is released. NICD then translocates to the nucleus, where it associates with the CBF-1, Suppressor of Hairless, and Lag-2 (CSL) and Mastermind-Like (MAML) proteins. This complex activates the transcription of Notch target genes, such as Hairy Enhancer of Split (Hes) and Hes-related with YRPF motif (Hey). Notch signaling is critical for the regulation of mesenchymal stem cell differentiation. Misexpression of Notch in skeletal tissue indicates a role as an inhibitor of skeletal development and postnatal bone formation. Overexpression of Notch inhibits endochondral bone formation and osteoblastic differentiation, causing severe osteopenia. Conditional inactivation of Notch in the skeleton causes an increase in cancellous bone volume and enhanced osteoblastic differentiation. Notch ligands are expressed in the hematopoietic stem cell niche and are critical for the regulation of hematopoietic stem cell self-renewal. Dysregulation of Notch signaling is the underlying cause of diseases affecting the skeletal tissue, including Alagille syndrome, spondylocostal dysostosis, and possibly, osteosarcoma. PMID:19995916

  2. Massively parallel sampling of lattice proteins reveals foundations of thermal adaptation

    NASA Astrophysics Data System (ADS)

    Venev, Sergey V.; Zeldovich, Konstantin B.

    2015-08-01

    Evolution of proteins in bacteria and archaea living in different conditions leads to significant correlations between amino acid usage and environmental temperature. The origins of these correlations are poorly understood, and an important question of protein theory, physics-based prediction of types of amino acids overrepresented in highly thermostable proteins, remains largely unsolved. Here, we extend the random energy model of protein folding by weighting the interaction energies of amino acids by their frequencies in protein sequences and predict the energy gap of proteins designed to fold well at elevated temperatures. To test the model, we present a novel scalable algorithm for simultaneous energy calculation for many sequences in many structures, targeting massively parallel computing architectures such as graphics processing unit. The energy calculation is performed by multiplying two matrices, one representing the complete set of sequences, and the other describing the contact maps of all structural templates. An implementation of the algorithm for the CUDA platform is available at http://www.github.com/kzeldovich/galeprot and calculates protein folding energies over 250 times faster than a single central processing unit. Analysis of amino acid usage in 64-mer cubic lattice proteins designed to fold well at different temperatures demonstrates an excellent agreement between theoretical and simulated values of energy gap. The theoretical predictions of temperature trends of amino acid frequencies are significantly correlated with bioinformatics data on 191 bacteria and archaea, and highlight protein folding constraints as a fundamental selection pressure during thermal adaptation in biological evolution.

  3. Adaptive bimaterial lattices to mitigate thermal expansion mismatch stresses in satellite structures

    NASA Astrophysics Data System (ADS)

    Toropova, Marina M.; Steeves, Craig A.

    2015-08-01

    Earth-orbiting satellites regularly pass from sunlight to shade and back; these transitions are typically accompanied by significant temperature changes. When adjoining parts of a satellite that are made of different materials are subjected to large temperature changes, thermal mismatch stresses arise that are a function of the temperature change and the difference in coefficients of thermal expansion (CTEs) between the two materials. These thermal stresses are linked to undesirable deformation and, through long-term cycling, fatigue and failure of the structure. This paper describes a type of anisotropic lattice that can serve as a stress-free adaptor between two materials, eliminating thermal mismatch stresses and their concomitant consequences. The lattices consist of planar nonidentical anisotropic bimaterial cells, each designed based on a virtual triangle. Physically the cells consist of a triangle made of material with higher CTE surrounded by a hexagon made of material with lower CTE. Different skew angles of the hexagon make a particular cell and the whole lattice anisotropic. The cells can be designed and combined in a lattice in such a way that one edge of the lattice has CTE that coincides with the CTE of the first part of the structure (substrate 1), while the other edge of the lattice has CTE equal to the CTE of the second part of the structure (substrate 2). If all joints between the parts of each cell, neighbouring cells, and the lattice and the substrates are pinned, the whole structure will be free of thermal stresses. This paper will discuss the fundamental principles governing such lattices, their refinement for special circumstances, and opportunities for improving the structural performance of the lattices. This will be presented coupled to a rational strategy for lattice design.

  4. Notch Signaling and the Skeleton.

    PubMed

    Zanotti, Stefano; Canalis, Ernesto

    2016-06-01

    Notch 1 to 4 receptors are important determinants of cell fate and function, and Notch signaling plays an important role in skeletal development and bone remodeling. After direct interactions with ligands of the Jagged and Delta-like families, a series of cleavages release the Notch intracellular domain (NICD), which translocates to the nucleus where it induces transcription of Notch target genes. Classic gene targets of Notch are hairy and enhancer of split (Hes) and Hes-related with YRPW motif (Hey). In cells of the osteoblastic lineage, Notch activation inhibits cell differentiation and causes cancellous bone osteopenia because of impaired bone formation. In osteocytes, Notch1 has distinct effects that result in an inhibition of bone resorption secondary to an induction of osteoprotegerin and suppression of sclerostin with a consequent enhancement of Wnt signaling. Notch1 inhibits, whereas Notch2 enhances, osteoclastogenesis and bone resorption. Congenital disorders of loss- and gain-of-Notch function present with severe clinical manifestations, often affecting the skeleton. Enhanced Notch signaling is associated with osteosarcoma, and Notch can influence the invasive potential of carcinoma of the breast and prostate. Notch signaling can be controlled by the use of inhibitors of Notch activation, small peptides that interfere with the formation of a transcriptional complex, or antibodies to the extracellular domain of specific Notch receptors or to Notch ligands. In conclusion, Notch plays a critical role in skeletal development and homeostasis, and serious skeletal disorders can be attributed to alterations in Notch signaling. PMID:27074349

  5. Notch Signaling in Pancreatic Development

    PubMed Central

    Li, Xu-Yan; Zhai, Wen-Jun; Teng, Chun-Bo

    2015-01-01

    The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep involvement of Notch signaling in the development of the pancreas and the lateral inhibition of Notch signaling in pancreatic progenitor differentiation and maintenance. The targeted inactivation of the Notch pathway components promotes premature differentiation of the endocrine pancreas. However, there is still the contrary opinion that Notch signaling specifies the endocrine lineage. Here, we review the current knowledge of the Notch signaling pathway in pancreatic development and its crosstalk with the Wingless and INT-1 (Wnt) and fibroblast growth factor (FGF) pathways. PMID:26729103

  6. Amoeboid migration mode adaption in quasi-3D spatial density gradients of varying lattice geometry

    NASA Astrophysics Data System (ADS)

    Gorelashvili, Mari; Emmert, Martin; Hodeck, Kai F.; Heinrich, Doris

    2014-07-01

    Cell migration processes are controlled by sensitive interaction with external cues such as topographic structures of the cell’s environment. Here, we present systematically controlled assays to investigate the specific effects of spatial density and local geometry of topographic structure on amoeboid migration of Dictyostelium discoideum cells. This is realized by well-controlled fabrication of quasi-3D pillar fields exhibiting a systematic variation of inter-pillar distance and pillar lattice geometry. By time-resolved local mean-squared displacement analysis of amoeboid migration, we can extract motility parameters in order to elucidate the details of amoeboid migration mechanisms and consolidate them in a two-state contact-controlled motility model, distinguishing directed and random phases. Specifically, we find that directed pillar-to-pillar runs are found preferably in high pillar density regions, and cells in directed motion states sense pillars as attractive topographic stimuli. In contrast, cell motion in random probing states is inhibited by high pillar density, where pillars act as obstacles for cell motion. In a gradient spatial density, these mechanisms lead to topographic guidance of cells, with a general trend towards a regime of inter-pillar spacing close to the cell diameter. In locally anisotropic pillar environments, cell migration is often found to be damped due to competing attraction by different pillars in close proximity and due to lack of other potential stimuli in the vicinity of the cell. Further, we demonstrate topographic cell guidance reflecting the lattice geometry of the quasi-3D environment by distinct preferences in migration direction. Our findings allow to specifically control amoeboid cell migration by purely topographic effects and thus, to induce active cell guidance. These tools hold prospects for medical applications like improved wound treatment, or invasion assays for immune cells.

  7. Large eddy simulation of a high speed train geometry under cross-wind with an adaptive lattice Boltzmann method

    NASA Astrophysics Data System (ADS)

    Deiterding, Ralf; Fragner, Moritz M.

    2015-11-01

    Numerical investigations in order to determine the forces induced by side wind onto a train geometry are generally not sufficiently accurate to be used as a predictive tool for regulatory safety assessment. Especially for larger yaw angles, the turbulent cross-wind flow is characterized by highly instationary behavior, driven primarily by vortex shedding on the roof and underside geometric details, i.e., the bogie and wheel systems. While industry-typical Reynolds-averaged turbulence models are not well suited for this scenario, better results are obtained when large eddy simulation (LES) techniques are applied. Here, we employ a recently self-developed weakly compressible lattice Boltzmann method (LBM) with Smagorinsky LES model on hierarchically adaptive block-structured Cartesian meshes. Using a train front-car of 1:25 scale at yaw angle 30° and Re = 250 , 000 as main test case, we compare the LBM results with incompressible large eddy and detached eddy simulations on unstructured boundary-layer type meshes using the OpenFOAM package. It is found that time averaged force and moment predictions from our LBM code compare better to available wind tunnel data, while mesh adaptation and explicit nature of the LBM approach reduce the computational costs considerably.

  8. Total enthalpy-based lattice Boltzmann method with adaptive mesh refinement for solid-liquid phase change

    NASA Astrophysics Data System (ADS)

    Huang, Rongzong; Wu, Huiying

    2016-06-01

    A total enthalpy-based lattice Boltzmann (LB) method with adaptive mesh refinement (AMR) is developed in this paper to efficiently simulate solid-liquid phase change problem where variables vary significantly near the phase interface and thus finer grid is required. For the total enthalpy-based LB method, the velocity field is solved by an incompressible LB model with multiple-relaxation-time (MRT) collision scheme, and the temperature field is solved by a total enthalpy-based MRT LB model with the phase interface effects considered and the deviation term eliminated. With a kinetic assumption that the density distribution function for solid phase is at equilibrium state, a volumetric LB scheme is proposed to accurately realize the nonslip velocity condition on the diffusive phase interface and in the solid phase. As compared with the previous schemes, this scheme can avoid nonphysical flow in the solid phase. As for the AMR approach, it is developed based on multiblock grids. An indicator function is introduced to control the adaptive generation of multiblock grids, which can guarantee the existence of overlap area between adjacent blocks for information exchange. Since MRT collision schemes are used, the information exchange is directly carried out in the moment space. Numerical tests are firstly performed to validate the strict satisfaction of the nonslip velocity condition, and then melting problems in a square cavity with different Prandtl numbers and Rayleigh numbers are simulated, which demonstrate that the present method can handle solid-liquid phase change problem with high efficiency and accuracy.

  9. Kick it up a notch: Notch signaling and kidney fibrosis

    PubMed Central

    Sweetwyne, Mariya T; Tao, Jianling; Susztak, Katalin

    2014-01-01

    Notch is a critical regulator of kidney development, but the pathway is mostly silenced once kidney maturation is achieved. Recent reports demonstrated increased expression of Notch receptors and ligands both in acute and chronic kidney injury. In vivo studies indicated that Notch activation might contribute to regeneration after acute kidney injury; on the other hand, sustained Notch expression is causally associated with interstitial fibrosis and glomerulosclerosis. This review will summarize the current knowledge on the role of the Notch signaling with special focus on kidney fibrosis. PMID:26312157

  10. Notching on Cancer's Door: Notch Signaling in Brain Tumors.

    PubMed

    Teodorczyk, Marcin; Schmidt, Mirko H H

    2014-01-01

    Notch receptors play an essential role in the regulation of central cellular processes during embryonic and postnatal development. The mammalian genome encodes for four Notch paralogs (Notch 1-4), which are activated by three Delta-like (Dll1/3/4) and two Serrate-like (Jagged1/2) ligands. Further, non-canonical Notch ligands such as epidermal growth factor like protein 7 (EGFL7) have been identified and serve mostly as antagonists of Notch signaling. The Notch pathway prevents neuronal differentiation in the central nervous system by driving neural stem cell maintenance and commitment of neural progenitor cells into the glial lineage. Notch is therefore often implicated in the development of brain tumors, as tumor cells share various characteristics with neural stem and progenitor cells. Notch receptors are overexpressed in gliomas and their oncogenicity has been confirmed by gain- and loss-of-function studies in vitro and in vivo. To this end, special attention is paid to the impact of Notch signaling on stem-like brain tumor-propagating cells as these cells contribute to growth, survival, invasion, and recurrence of brain tumors. Based on the outcome of ongoing studies in vivo, Notch-directed therapies such as γ-secretase inhibitors and blocking antibodies have entered and completed various clinical trials. This review summarizes the current knowledge on Notch signaling in brain tumor formation and therapy. PMID:25601901

  11. Electrochemical polishing of notches

    DOEpatents

    Kephart, Alan R.; Alberts, Alfred H.

    1989-01-01

    An apparatus and method are disclosed for the selective electrochemical polishing of a lateral tip of a deep longitudinal notch in a work piece used to test crack initiation properties of materials. A DC power source is connected to the work piece and to an electrode disposed laterally along the distal end of an insulated body which is inserted in the longitudinal notch. The electrode and distal end of the body are disposed along the tip of the notch, but are spaced from the notch so as to provide a lateral passage for an electrolyte. The electrolyte is circulated through the passage so that the electrolyte only contacts the work piece adjacent the passage. Conveniently, the electrolyte is circulated by use of an inlet tube and an outlet tube provided at opposite ends of the passage. These tubes are preferably detachably located adjacent the ends of the passage and suitable seals are provided. A holding device including arms to which the tubes are attached is conveniently used to rapidly and easily locate the test specimen with the passage aligned with the tubes. The electrode is preferably a wire which is located in grooves along the distal end of the insulated body and up one side of the body or a plastic sheath insulated thin metal strip.

  12. Electrochemical polishing of notches

    DOEpatents

    Kephart, A.R.; Alberts, A.H.

    1989-02-21

    An apparatus and method are disclosed for the selective electrochemical polishing of a lateral tip of a deep longitudinal notch in a work piece used to test crack initiation properties of materials. A DC power source is connected to the work piece and to an electrode disposed laterally along the distal end of an insulated body which is inserted in the longitudinal notch. The electrode and distal end of the body are disposed along the tip of the notch, but are spaced from the notch so as to provide a lateral passage for an electrolyte. The electrolyte is circulated through the passage so that the electrolyte only contacts the work piece adjacent the passage. Conveniently, the electrolyte is circulated by use of an inlet tube and an outlet tube provided at opposite ends of the passage. These tubes are preferably detachably located adjacent the ends of the passage and suitable seals are provided. A holding device including arms to which the tubes are attached is conveniently used to rapidly and easily locate the test specimen with the passage aligned with the tubes. The electrode is preferably a wire which is located in grooves along the distal end of the insulated body and up one side of the body or a plastic sheath insulated thin metal strip. 4 figs.

  13. Notch strength of composites

    NASA Technical Reports Server (NTRS)

    Whitney, J. M.

    1983-01-01

    The notch strength of composites is discussed. The point stress and average stress criteria relate the notched strength of a laminate to the average strength of a relatively long tensile coupon. Tests of notched specimens in which microstrain gages have been placed at or near the edges of the holes have measured strains much larger that those measured in an unnotched tensile coupon. Orthotropic stress concentration analyses of failed notched laminates have also indicated that failure occurred at strains much larger than those experienced on tensile coupons with normal gage lengths. This suggests that the high strains at the edge of a hole can be related to the very short length of fiber subjected to these strains. Lockheed has attempted to correlate a series of tests of several laminates with holes ranging from 0.19 to 0.50 in. Although the average stress criterion correlated well with test results for hole sizes equal to or greater than 0.50 in., it over-estimated the laminate strength in the range of hole sizes from 0.19 to 0.38 in. It thus appears that a theory is needed that is based on the mechanics of failure and is more generally applicable to the range of hole sizes and the varieties of laminates found in aircraft construction.

  14. Notch-Mediated Cell Adhesion.

    PubMed

    Murata, Akihiko; Hayashi, Shin-Ichi

    2016-01-01

    Notch family members are generally recognized as signaling molecules that control various cellular responses in metazoan organisms. Early fly studies and our mammalian studies demonstrated that Notch family members are also cell adhesion molecules; however, information on the physiological roles of this function and its origin is limited. In this review, we discuss the potential present and ancestral roles of Notch-mediated cell adhesion in order to explore its origin and the initial roles of Notch family members dating back to metazoan evolution. We hypothesize that Notch family members may have initially emerged as cell adhesion molecules in order to mediate multicellularity in the last common ancestor of metazoan organisms. PMID:26784245

  15. Notch-Mediated Cell Adhesion

    PubMed Central

    Murata, Akihiko; Hayashi, Shin-Ichi

    2016-01-01

    Notch family members are generally recognized as signaling molecules that control various cellular responses in metazoan organisms. Early fly studies and our mammalian studies demonstrated that Notch family members are also cell adhesion molecules; however, information on the physiological roles of this function and its origin is limited. In this review, we discuss the potential present and ancestral roles of Notch-mediated cell adhesion in order to explore its origin and the initial roles of Notch family members dating back to metazoan evolution. We hypothesize that Notch family members may have initially emerged as cell adhesion molecules in order to mediate multicellularity in the last common ancestor of metazoan organisms. PMID:26784245

  16. Notch Signaling in Neuroendocrine Tumors

    PubMed Central

    Crabtree, Judy S.; Singleton, Ciera S.; Miele, Lucio

    2016-01-01

    Carcinoids and neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the neuroendocrine cells of the GI tract, endocrine pancreas, and the respiratory system. NETs remain significantly understudied with respect to molecular mechanisms of pathogenesis, particularly the role of cell fate signaling systems such as Notch. The abundance of literature on the Notch pathway is a testament to its complexity in different cellular environments. Notch receptors can function as oncogenes in some contexts and tumor suppressors in others. The genetic heterogeneity of NETs suggests that to fully understand the roles and the potential therapeutic implications of Notch signaling in NETs, a comprehensive analysis of Notch expression patterns and potential roles across all NET subtypes is required. PMID:27148486

  17. Nanoparticle optical notch filters

    NASA Astrophysics Data System (ADS)

    Kasinadhuni, Pradeep Kumar

    Developing novel light blocking products involves the design of a nanoparticle optical notch filter, working on the principle of localized surface plasmon resonance (LSPR). These light blocking products can be used in many applications. One such application is to naturally reduce migraine headaches and light sensitivity. Melanopsin ganglion cells present in the retina of the human eye, connect to the suprachiasmatic nucleus (SCN-the body's clock) in the brain, where they participate in the entrainment of the circadian rhythms. As the Melanopsin ganglion cells are involved in triggering the migraine headaches in photophobic patients, it is necessary to block the part of visible spectrum that activates these cells. It is observed from the action potential spectrum of the ganglion cells that they absorb light ranging from 450-500nm (blue-green part) of the visible spectrum with a λmax (peak sensitivity) of around 480nm (blue line). Currently prescribed for migraine patients is the FL-41 coating, which blocks a broad range of wavelengths, including wavelengths associated with melanopsin absorption. The nanoparticle optical notch filter is designed to block light only at 480nm, hence offering an effective prescription for the treatment of migraine headaches.

  18. Canonical and non-canonical Notch ligands

    PubMed Central

    D’SOUZA, BRENDAN; MELOTY-KAPELLA, LAURENCE; WEINMASTER, GERRY

    2015-01-01

    Notch signaling induced by canonical Notch ligands is critical for normal embryonic development and tissue homeostasis through the regulation of a variety of cell fate decisions and cellular processes. Activation of Notch signaling is normally tightly controlled by direct interactions with ligand-expressing cells and dysregulated Notch signaling is associated with developmental abnormalities and cancer. While canonical Notch ligands are responsible for the majority of Notch signaling, a diverse group of structurally unrelated non-canonical ligands has also been identified that activate Notch and likely contribute to the pleiotropic effects of Notch signaling. Soluble forms of both canonical and non-canonical ligands have been isolated, some of which block Notch signaling and could serve as natural inhibitors of this pathway. Ligand activity can also be indirectly regulated by other signaling pathways at the level of ligand expression, serving to spatio-temporally compartmentalize Notch signaling activity and integrate Notch signaling into a molecular network that orchestrates developmental events. Here, we review the molecular mechanisms underlying the dual role of Notch ligands as activators and inhibitors of Notch signaling. Additionally, evidence that Notch ligands function independent of Notch are presented. We also discuss how ligand post-translational modification, endocytosis, proteolysis and spatio-temporal expression regulate their signaling activity. PMID:20816393

  19. FOUR NOTCH ROADLESS AREA, TEXAS.

    USGS Publications Warehouse

    Houser, B.B.; Ryan, George S.

    1984-01-01

    A geologic and geochemical investigation of the Four Notch Roadless Area, Texas, was conducted. The area has a probable resource potential for oil and gas. There is, however, little promise for the occurrence of metallic mineral resources or other energy resources. Acquisition of seismic data and detailed comparisons with logs from wells from the vicinity of the Four Notch Roadless Area is necessary to better determine if the subsurface stratigraphy and structures are favorable for the accumulation of oil or gas.

  20. kuzbanian-mediated cleavage of Drosophila Notch

    PubMed Central

    Lieber, Toby; Kidd, Simon; Young, Michael W.

    2002-01-01

    Loss of Kuzbanian, a member of the ADAM family of metalloproteases, produces neurogenic phenotypes in Drosophila. It has been suggested that this results from a requirement for kuzbanian-mediated cleavage of the Notch ligand Delta. Using transgenic Drosophila expressing transmembrane Notch proteins, we show that kuzbanian, independent of any role in Delta processing, is required for the cleavage of Notch. We show that Kuzbanian can physically associate with Notch and that removal of kuzbanian activity by RNA-mediated interference in Drosophila tissue culture cells eliminates processing of ligand-independent transmembrane Notch molecules. Our data suggest that in Drosophila, kuzbanian can mediate S2 cleavage of Notch. PMID:11799064

  1. Cardioprotective actions of Notch1 against myocardial infarction via LKB1-dependent AMPK signaling pathway.

    PubMed

    Yang, Hui; Sun, Wanqing; Quan, Nanhu; Wang, Lin; Chu, Dongyang; Cates, Courtney; Liu, Quan; Zheng, Yang; Li, Ji

    2016-05-15

    AMP-activated protein kinase (AMPK) signaling pathway plays a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. Notch1 signaling in the adult myocardium is also activated in response to ischemic stress. However, the relationship between Notch1 and AMPK signaling pathways during ischemia remains unclear. We hypothesize that Notch1 as an adaptive signaling pathway protects the heart from ischemic injury via modulating the cardioprotective AMPK signaling pathway. C57BL/6J mice were subjected to an in vivo ligation of left anterior descending coronary artery and the hearts from C57BL/6J mice were subjected to an ex vivo globe ischemia and reperfusion in the Langendorff perfusion system. The Notch1 signaling was activated during myocardial ischemia. A Notch1 γ-secretase inhibitor, dibenzazepine (DBZ), was intraperitoneally injected into mice to inhibit Notch1 signaling pathway by ischemia. The inhibition of Notch1 signaling by DBZ significantly augmented cardiac dysfunctions caused by myocardial infarction. Intriguingly, DBZ treatment also significantly blunted the activation of AMPK signaling pathway. The immunoprecipitation experiments demonstrated that an interaction between Notch1 and liver kinase beta1 (LKB1) modulated AMPK activation during myocardial ischemia. Furthermore, a ligand of Notch1 Jagged1 can significantly reduce cardiac damage caused by ischemia via activation of AMPK signaling pathway and modulation of glucose oxidation and fatty acid oxidation during ischemia and reperfusion. But Jagged1 did not have any cardioprotections on AMPK kinase dead transgenic hearts. Taken together, the results indicate that the cardioprotective effect of Notch1 against ischemic damage is mediated by AMPK signaling via an interaction with upstream LKB1. PMID:27015742

  2. Notch signaling in skeletal health and disease.

    PubMed

    Zanotti, Stefano; Canalis, Ernesto

    2013-06-01

    Notch receptors are single-pass transmembrane proteins that determine cell fate. Upon Notch ligand interactions, proteolytic cleavages release the Notch intracellular domain, which translocates to the nucleus to regulate the transcription of target genes, including Hairy enhancer of split (Hes) and Hes related to YRPW motif (Hey). Notch is critical for skeletal development and activity of skeletal cells, and dysregulation of Notch signaling is associated with human diseases affecting the skeleton. Inherited or sporadic mutations in components of the Notch signaling pathway are associated with spondylocostal dysostosis, spondylothoracic dysostosis and recessive brachydactyly, diseases characterized by skeletal patterning defects. Inactivating mutations of the Notch ligand JAG1 or of NOTCH2 are associated with Alagille syndrome, and activating mutations in NOTCH2 are associated with Hajdu-Cheney syndrome (HCS). Individuals affected by HCS exhibit osteolysis in distal phalanges and osteoporosis. NOTCH is activated in selected tumors, such as osteosarcoma, and in breast cancer cells that form osteolytic bone metastases. In conclusion, Notch regulates skeletal development and bone remodeling, and gain- or loss-of-function mutations of Notch signaling result in important skeletal diseases. PMID:23554451

  3. Dissecting the mechanisms of Notch induced hyperplasia

    PubMed Central

    Djiane, Alexandre; Krejci, Alena; Bernard, Frédéric; Fexova, Silvie; Millen, Katherine; Bray, Sarah J

    2013-01-01

    The outcome of the Notch pathway on proliferation depends on cellular context, being growth promotion in some, including several cancers, and growth inhibition in others. Such disparate outcomes are evident in Drosophila wing discs, where Notch overactivation causes hyperplasia despite having localized inhibitory effects on proliferation. To understand the underlying mechanisms, we have used genomic strategies to identify the Notch-CSL target genes directly activated during wing disc hyperplasia. Among them were genes involved in both autonomous and non-autonomous regulation of proliferation, growth and cell death, providing molecular explanations for many characteristics of Notch induced wing disc hyperplasia previously reported. The Notch targets exhibit different response patterns, which are shaped by both positive and negative feed-forward regulation between the Notch targets themselves. We propose, therefore, that both the characteristics of the direct Notch targets and their cross-regulatory relationships are important in coordinating the pattern of hyperplasia. PMID:23232763

  4. Adaptation.

    PubMed

    Broom, Donald M

    2006-01-01

    The term adaptation is used in biology in three different ways. It may refer to changes which occur at the cell and organ level, or at the individual level, or at the level of gene action and evolutionary processes. Adaptation by cells, especially nerve cells helps in: communication within the body, the distinguishing of stimuli, the avoidance of overload and the conservation of energy. The time course and complexity of these mechanisms varies. Adaptive characters of organisms, including adaptive behaviours, increase fitness so this adaptation is evolutionary. The major part of this paper concerns adaptation by individuals and its relationships to welfare. In complex animals, feed forward control is widely used. Individuals predict problems and adapt by acting before the environmental effect is substantial. Much of adaptation involves brain control and animals have a set of needs, located in the brain and acting largely via motivational mechanisms, to regulate life. Needs may be for resources but are also for actions and stimuli which are part of the mechanism which has evolved to obtain the resources. Hence pigs do not just need food but need to be able to carry out actions like rooting in earth or manipulating materials which are part of foraging behaviour. The welfare of an individual is its state as regards its attempts to cope with its environment. This state includes various adaptive mechanisms including feelings and those which cope with disease. The part of welfare which is concerned with coping with pathology is health. Disease, which implies some significant effect of pathology, always results in poor welfare. Welfare varies over a range from very good, when adaptation is effective and there are feelings of pleasure or contentment, to very poor. A key point concerning the concept of individual adaptation in relation to welfare is that welfare may be good or poor while adaptation is occurring. Some adaptation is very easy and energetically cheap and

  5. Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension.

    PubMed

    Ragot, Hélène; Monfort, Astrid; Baudet, Mathilde; Azibani, Fériel; Fazal, Loubina; Merval, Régine; Polidano, Evelyne; Cohen-Solal, Alain; Delcayre, Claude; Vodovar, Nicolas; Chatziantoniou, Christos; Samuel, Jane-Lise

    2016-08-01

    Hypertension, which is a risk factor of heart failure, provokes adaptive changes at the vasculature and cardiac levels. Notch3 signaling plays an important role in resistance arteries by controlling the maturation of vascular smooth muscle cells. Notch3 deletion is protective in pulmonary hypertension while deleterious in arterial hypertension. Although this latter phenotype was attributed to renal and cardiac alterations, the underlying mechanisms remained unknown. To investigate the role of Notch3 signaling in the cardiac adaptation to hypertension, we used mice with either constitutive Notch3 or smooth muscle cell-specific conditional RBPJκ knockout. At baseline, both genotypes exhibited a cardiac arteriolar rarefaction associated with oxidative stress. In response to angiotensin II-induced hypertension, the heart of Notch3 knockout and SM-RBPJκ knockout mice did not adapt to pressure overload and developed heart failure, which could lead to an early and fatal acute decompensation of heart failure. This cardiac maladaptation was characterized by an absence of media hypertrophy of the media arteries, the transition of smooth muscle cells toward a synthetic phenotype, and an alteration of angiogenic pathways. A subset of mice exhibited an early fatal acute decompensated heart failure, in which the same alterations were observed, although in a more rapid timeframe. Altogether, these observations indicate that Notch3 plays a major role in coronary adaptation to pressure overload. These data also show that the hypertrophy of coronary arterial media on pressure overload is mandatory to initially maintain a normal cardiac function and is regulated by the Notch3/RBPJκ pathway. PMID:27296994

  6. Notched strength of beryllium powder and ingot sheets.

    NASA Technical Reports Server (NTRS)

    Moss, R. G.

    1972-01-01

    The effects of notches in thin beryllium sheets were studied as functions of material variables and notch severity. Double edge notched samples having stress concentration factors of 1.0 to 15.4 were prepared by milling to size, etching, and electrical discharge machining the notches. Strength was not reduced greatly by sharp notches, and duller notches were more deleterious than sharp notches. The trend was for reduced strength for dull notches, increased strength for sharper notches, and reduced strength for very sharp notches. Differences in material purity or source of the sheet had little affect on notch sensitivity. The most important factors appear to be oxide content and directionality of the sheet microstructure; high oxide content and highly directional microstructure tend to give more notch sensitivity than low oxide content, and more bidirectional microstructure. Postulated causes of the change in notched/unnotched strength are given.

  7. Simulation of reflective notching with TEMPEST

    NASA Astrophysics Data System (ADS)

    Pistor, Thomas V.; Neureuther, Andrew R.

    1997-07-01

    Reflective notching from projection printing a narrow feature over a reflective topography was simulated with the 3D electro-magnetic simulation program TEMPEST. Various topographical and optical parameters were varied to determine their effect on the reflective notching and to gain insight into the mechanism of reflective notching. It was determined that corner angles in the topography and anti-reflection coating use are important parameters while resist surface angle and polarization are not.

  8. Adapt

    NASA Astrophysics Data System (ADS)

    Bargatze, L. F.

    2015-12-01

    Active Data Archive Product Tracking (ADAPT) is a collection of software routines that permits one to generate XML metadata files to describe and register data products in support of the NASA Heliophysics Virtual Observatory VxO effort. ADAPT is also a philosophy. The ADAPT concept is to use any and all available metadata associated with scientific data to produce XML metadata descriptions in a consistent, uniform, and organized fashion to provide blanket access to the full complement of data stored on a targeted data server. In this poster, we present an application of ADAPT to describe all of the data products that are stored by using the Common Data File (CDF) format served out by the CDAWEB and SPDF data servers hosted at the NASA Goddard Space Flight Center. These data servers are the primary repositories for NASA Heliophysics data. For this purpose, the ADAPT routines have been used to generate data resource descriptions by using an XML schema named Space Physics Archive, Search, and Extract (SPASE). SPASE is the designated standard for documenting Heliophysics data products, as adopted by the Heliophysics Data and Model Consortium. The set of SPASE XML resource descriptions produced by ADAPT includes high-level descriptions of numerical data products, display data products, or catalogs and also includes low-level "Granule" descriptions. A SPASE Granule is effectively a universal access metadata resource; a Granule associates an individual data file (e.g. a CDF file) with a "parent" high-level data resource description, assigns a resource identifier to the file, and lists the corresponding assess URL(s). The CDAWEB and SPDF file systems were queried to provide the input required by the ADAPT software to create an initial set of SPASE metadata resource descriptions. Then, the CDAWEB and SPDF data repositories were queried subsequently on a nightly basis and the CDF file lists were checked for any changes such as the occurrence of new, modified, or deleted

  9. Autophagy Sustains Hematopoiesis Through Targeting Notch.

    PubMed

    Cao, Yan; Cai, Jinyang; Zhang, Suping; Yuan, Na; Fang, Yixuan; Wang, Zhijian; Li, Xin; Cao, Dan; Xu, Fei; Lin, Weiwei; Song, Lin; Wang, Zhen; Wang, Jian; Xu, Xiaoxiao; Zhang, Yi; Zhao, Wenli; Hu, Shaoyan; Zhang, Xueguang; Wang, Jianrong

    2015-11-15

    Autophagy is required for hematopoietic stem cell multilineage differentiation, but the underlying mechanism is unknown. Using a conditional mouse model and human leukemia cells, we uncovered a mechanistic link between autophagy and hematopoietic stem cell differentiation. Loss of autophagy in mouse hematopoietic stem cells diminished the bone marrow generation of functional blood cells, in particular lymphocytes, and resulted in a leukemic phenotype and elevated Notch signaling. Physiological autophagy activity in mice was inversely correlated with Notch signaling during adult hematopoietic stem cell differentiation, while pathologically low autophagy was associated with upregulated Notch signaling in dysfunctional hematopoietic stem cells of acute leukemia patients. Furthermore, we show that autophagy directly degraded intracellular Notch, the active form of Notch receptor cleaved from the full-length Notch molecule by γ-secretase. Finally, we show that hematopoietic multilineage differentiation potential was restored in autophagy defective hematopoietic stem and progenitor cells when their Notch signaling was abrogated either pharmacologically with γ-secretase inhibitor DAPT or genetically with RNA interference of Notch effector RBPJ. Hence, we propose that autophagy sustains hematopoiesis by direct targeting Notch. PMID:26178296

  10. PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

    PubMed Central

    Sjöqvist, Marika; Antfolk, Daniel; Ferraris, Saima; Rraklli, Vilma; Haga, Cecilia; Antila, Christian; Mutvei, Anders; Imanishi, Susumu Y; Holmberg, Johan; Jin, Shaobo; Eriksson, John E; Lendahl, Urban; Sahlgren, Cecilia

    2014-01-01

    Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick central nervous system and in cultured myoblasts, Notch-stimulated cells were allowed to undergo differentiation. PKCζ phosphorylates membrane-tethered forms of Notch and regulates two distinct routing steps, depending on the Notch activation state. When Notch is activated, PKCζ promotes re-localization of Notch from late endosomes to the nucleus and enhances production of the Notch intracellular domain, which leads to increased Notch activity. In the non-activated state, PKCζ instead facilitates Notch receptor internalization, accompanied with increased ubiquitylation and interaction with the endosomal sorting protein Hrs. Collectively, these data identify PKCζ as a key regulator of Notch trafficking and demonstrate that distinct steps in intracellular routing are differentially modulated depending on Notch signaling status. PMID:24662486

  11. The Different Role of Notch1 and Notch2 in Astrocytic Gliomas

    PubMed Central

    Jiang, Rongcai; Qiu, Mingzhe; Kang, Chunsheng; Jia, Zhifan; Wang, Guangxiu; Han, Lei; Fan, Xing; Pu, Peiyu

    2013-01-01

    It is well known that Notch signaling plays either oncogenic or tumor suppressive role in a variety of tumors, depending on the cellular context. However, in our previous study, we found that Notch1 was overexpressed while Notch2 downregulated in the majority of astrocytic gliomas with different grades as well as in glioblastoma cell lines U251 and A172. We had knocked down Notch1 by siRNA in glioblastoma cells, and identified that the cell growth and invasion were inhibited, whereas cell apoptosis was induced either in vitro or in vivo. For further clarification of the role of Notch2 in pathogenesis of gliomas, enforced overexpression of Notch2 was carried out with transfection of Notch2 expression plasmid in glioma cells and the cell growth, invasion and apoptosis were examined in vitro and in vivo in the present study, and siRNA targeting Notch1 was used as a positive control in vivo. The results showed that upregulating Notch2 had the effect of suppressing cell growth and invasion as well as inducing apoptosis, just the same as the results of knocking down Notch1. Meanwhile, the activity of core signaling pathway–EGFR/PI3K/AKT in astrocytic glioma cells was repressed. Thus, the present study reveals, for the first time, that Notch1 and Notch2 play different roles in the biological processes of astrocytic gliomas. Knocking down the Notch1 or enforced overexpression of Notch2 both modulate the astrocytic glioma phenotype, and the mechanism by which Notch1 and 2 play different roles in the glioma growth should be further investigated. PMID:23349727

  12. Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations

    PubMed Central

    Kofler, Natalie M.; Cuervo, Henar; Uh, Minji K.; Murtomäki, Aino; Kitajewski, Jan

    2015-01-01

    Pericytes regulate vessel stability and pericyte dysfunction contributes to retinopathies, stroke, and cancer. Here we define Notch as a key regulator of pericyte function during angiogenesis. In Notch1+/−; Notch3−/− mice, combined deficiency of Notch1 and Notch3 altered pericyte interaction with the endothelium and reduced pericyte coverage of the retinal vasculature. Notch1 and Notch3 were shown to cooperate to promote proper vascular basement membrane formation and contribute to endothelial cell quiescence. Accordingly, loss of pericyte function due to Notch deficiency exacerbates endothelial cell activation caused by Notch1 haploinsufficiency. Mice mutant for Notch1 and Notch3 develop arteriovenous malformations and display hallmarks of the ischemic stroke disease CADASIL. Thus, Notch deficiency compromises pericyte function and contributes to vascular pathologies. PMID:26563570

  13. Notching on Cancer’s Door: Notch Signaling in Brain Tumors

    PubMed Central

    Teodorczyk, Marcin; Schmidt, Mirko H. H.

    2015-01-01

    Notch receptors play an essential role in the regulation of central cellular processes during embryonic and postnatal development. The mammalian genome encodes for four Notch paralogs (Notch 1–4), which are activated by three Delta-like (Dll1/3/4) and two Serrate-like (Jagged1/2) ligands. Further, non-canonical Notch ligands such as epidermal growth factor like protein 7 (EGFL7) have been identified and serve mostly as antagonists of Notch signaling. The Notch pathway prevents neuronal differentiation in the central nervous system by driving neural stem cell maintenance and commitment of neural progenitor cells into the glial lineage. Notch is therefore often implicated in the development of brain tumors, as tumor cells share various characteristics with neural stem and progenitor cells. Notch receptors are overexpressed in gliomas and their oncogenicity has been confirmed by gain- and loss-of-function studies in vitro and in vivo. To this end, special attention is paid to the impact of Notch signaling on stem-like brain tumor-propagating cells as these cells contribute to growth, survival, invasion, and recurrence of brain tumors. Based on the outcome of ongoing studies in vivo, Notch-directed therapies such as γ-secretase inhibitors and blocking antibodies have entered and completed various clinical trials. This review summarizes the current knowledge on Notch signaling in brain tumor formation and therapy. PMID:25601901

  14. Targeting Notch to overcome radiation resistance

    PubMed Central

    Yahyanejad, Sanaz; Theys, Jan; Vooijs, Marc

    2016-01-01

    Radiotherapy represents an important therapeutic strategy in the treatment of cancer cells. However, it often fails to eliminate all tumor cells because of the intrinsic or acquired treatment resistance, which is the most common cause of tumor recurrence. Emerging evidences suggest that the Notch signaling pathway is an important pathway mediating radiation resistance in tumor cells. Successful targeting of Notch signaling requires a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to be safe and effective. Here we summarize the role of Notch in mediating resistance to radiotherapy, the different strategies to block Notch in cancer cells and how treatment scheduling can improve tumor response. Finally, we discuss a need for reliable Notch related biomarkers in specific tumors to measure pathway activity and to allow identification of a subset of patients who are likely to benefit from Notch targeted therapies. PMID:26713603

  15. Cigarette smoke induces the expression of Notch3, not Notch1, protein in lung adenocarcinoma

    PubMed Central

    CHENG, ZHENSHUN; TAN, QIUYUE; TAN, WEIJUN; ZHANG, LI

    2015-01-01

    The aim of the present study was to determine the effect of cigarette smoke on the expression of Notch proteins in lung adenocarcinoma (LAC). Protein expression levels of Notch1 and Notch3 were analyzed using immunohistochemistry in 102 human LAC specimens. Of these, 52 were obtained from smokers and 50 from non-smokers. In addition, cigarette smoke extract (CSE) at varying concentrations (1, 2.5 and 5%) was administered to A549 cells. The expression of Notch1 and Notch3 protein was then detected by western blot analysis at different time points (0, 8, 24 and 48 h). Of the 102 LAC specimens, 42 (41.2%) were positive for Notch1 and 63 (61.8%) were positive for Notch3. There was no significant difference in the level of Notch1 expression between smokers and non-smokers with LAC (P>0.05). The positive rate and staining intensity of Notch3 expression were increased in the smokers compared with the non-smokers (P<0.05). The expression of Notch3 protein in A549 cells increased in a time- and dose-dependent manner following treatment with CSE, whilst the expression of Notch1 protein appeared stable. The results suggested that cigarette smoke was able to induce the expression of Notch3, not Notch1, protein in LAC. The data revealed an upregulation of Notch3 in LAC following cigarette smoke exposure. Such findings may provide a novel therapeutic target for the treatment of LAC. PMID:26622547

  16. A novel reporter of notch signalling indicates regulated and random notch activation during vertebrate neurogenesis

    PubMed Central

    2011-01-01

    Background Building the complex vertebrate nervous system involves the regulated production of neurons and glia while maintaining a progenitor cell population. Neurogenesis starts asynchronously in different regions of the embryo and occurs over a long period of time, allowing progenitor cells to be exposed to multiple extrinsic signals that regulate the production of different cell types. Notch-mediated cell-cell signalling is one of the mechanisms that maintain the progenitor pool, however, little is known about how the timing of Notch activation is related to the cell cycle and the distinct modes of cell division that generate neurons. An essential tool with which to investigate the role of Notch signalling on cell by cell basis is the development a faithful reporter of Notch activity. Results Here we present a novel reporter for Notch activity based on the promoter of the well characterised Notch target chick Hes5-1, coupled with multiple elements that confer instability, including a destabilized nuclear Venus fluorescent protein and the 3' untranslated region (UTR) of Hes5-1. We demonstrate that this reporter faithfully recapitulates the endogenous expression of Hes5-1 and that it robustly responds to Notch activation in the chick neural tube. Analysis of the patterns of Notch activity revealed by this reporter indicates that although Notch is most frequently activated prior to mitosis it can be activated at any time within the cell cycle. Notch active progenitors undergoing mitosis generate two daughters that both continue to experience Notch signalling. However, cells lacking Notch activity before and during mitosis generate daughters with dissimilar Notch activity profiles. Conclusions A novel Notch reporter with multiple destabilisation elements provides a faithful read-out of endogenous Notch activity on a cell-by-cell basis, as neural progenitors progress through the cell cycle in the chick neural tube. Notch activity patterns in this cell population

  17. Targeting Notch Signaling in Colorectal Cancer

    PubMed Central

    Suman, Suman; Das, Trinath P.; Ankem, Murali K.; Damodaran, Chendil

    2014-01-01

    The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC), hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer. PMID:25395896

  18. Targeting Notch Signaling in Colorectal Cancer.

    PubMed

    Suman, Suman; Das, Trinath P; Ankem, Murali K; Damodaran, Chendil

    2014-12-01

    The activation of Notch signaling is implicated in tumorigenesis in the colon due to the induction of pro-survival signaling in colonic epithelial cells. Chemoresistance is a major obstacle for treatment and for the complete eradication of colorectal cancer (CRC), hence, the inhibition of Notch is an attractive target for CRC and several groups are working to identify small molecules or monoclonal antibodies that inhibit Notch or its downstream events; however, toxicity profiles in normal cells and organs often impede the clinical translation of these molecules. Dietary agents have gained momentum for targeting several pro-survival signaling cascades, and recent studies demonstrated that agents that inhibit Notch signaling result in growth inhibition in preclinical models of CRC. In this review, we focus on the importance of Notch as a preventive and therapeutic target for colon cancer and on the effect of WA on this signaling pathway in the context of colon cancer. PMID:25395896

  19. Notched Fatigue Behavior of PEEK

    PubMed Central

    Murphy, JE; Brinkman, JG; Kurtz, SM; Rimnac, CM

    2013-01-01

    Poly(ether-ether-ketone) (PEEK) has been used as a load bearing orthopaedic implant material with clinical success. All of the orthopaedic applications contain stress concentrations (notches) in their design; however, little work has been done to examine the fatigue behavior of PEEK in the presence of a notch. This work examines both stress-life (SN) fatigue behavior and the fracture behavior of unfilled PEEK under tension tension loading in circumferentially grooved round bar specimens with different elastic stress concentration factors. It was found that the majority of the loading was elastic in nature, and that there was only a small portion on the lifetime where there was a detectable change in structural behavior prior to gross fracture. Fractographic analysis via SEM further elucidated the potential fracture micromechanisms. Additional analysis was conducted to estimate the percent of the lifetime spent in crack initiation vs propagation, and it was found that the specimens spent the majority of the time in the crack initiation phase. PMID:20864160

  20. Canonical Notch activation in osteocytes causes osteopetrosis.

    PubMed

    Canalis, Ernesto; Bridgewater, David; Schilling, Lauren; Zanotti, Stefano

    2016-01-15

    Activation of Notch1 in cells of the osteoblastic lineage inhibits osteoblast differentiation/function and causes osteopenia, whereas its activation in osteocytes causes a distinct osteopetrotic phenotype. To explore mechanisms responsible, we established the contributions of canonical Notch signaling (Rbpjκ dependent) to osteocyte function. Transgenics expressing Cre recombinase under the control of the dentin matrix protein-1 (Dmp1) promoter were crossed with Rbpjκ conditional mice to generate Dmp1-Cre(+/-);Rbpjκ(Δ/Δ) mice. These mice did not have a skeletal phenotype, indicating that Rbpjκ is dispensable for osteocyte function. To study the Rbpjκ contribution to Notch activation, Rosa(Notch) mice, where a loxP-flanked STOP cassette is placed between the Rosa26 promoter and the NICD coding sequence, were crossed with Dmp1-Cre transgenic mice and studied in the context (Dmp1-Cre(+/-);Rosa(Notch);Rbpjκ(Δ/Δ)) or not (Dmp1-Cre(+/-);Rosa(Notch)) of Rbpjκ inactivation. Dmp1-Cre(+/-);Rosa(Notch) mice exhibited increased femoral trabecular bone volume and decreased osteoclasts and bone resorption. The phenotype was reversed in the context of the Rbpjκ inactivation, demonstrating that Notch canonical signaling was accountable for the phenotype. Notch activation downregulated Sost and Dkk1 and upregulated Axin2, Tnfrsf11b, and Tnfsf11 mRNA expression, and these effects were not observed in the context of the Rbpjκ inactivation. In conclusion, Notch activation in osteocytes suppresses bone resorption and increases bone volume by utilization of canonical signals that also result in the inhibition of Sost and Dkk1 and upregulation of Wnt signaling. PMID:26578715

  1. Notch3/Jagged1 circuitry reinforces notch signaling and sustains T-ALL.

    PubMed

    Pelullo, Maria; Quaranta, Roberta; Talora, Claudio; Checquolo, Saula; Cialfi, Samantha; Felli, Maria Pia; te Kronnie, Geertruy; Borga, Chiara; Besharat, Zein Mersini; Palermo, Rocco; Di Marcotullio, Lucia; Capobianco, Anthony J; Gulino, Alberto; Screpanti, Isabella; Bellavia, Diana

    2014-12-01

    Deregulated Notch signaling has been extensively linked to T-cell acute lymphoblastic leukemia (T-ALL). Here, we show a direct relationship between Notch3 receptor and Jagged1 ligand in human cell lines and in a mouse model of T-ALL. We provide evidence that Notch-specific ligand Jagged1 is a new Notch3 signaling target gene. This essential event justifies an aberrant Notch3/Jagged1 cis-expression inside the same cell. Moreover, we demonstrate in Notch3-IC-overexpressing T lymphoma cells that Jagged1 undergoes a raft-associated constitutive processing. The proteolytic cleavage allows the Jagged1 intracellular domain to empower Notch signaling activity and to increase the transcriptional activation of Jagged1 itself (autocrine effect). On the other hand, the release of the soluble Jagged1 extracellular domain has a positive impact on activating Notch signaling in adjacent cells (paracrine effect), finally giving rise to a Notch3/Jagged1 auto-sustaining loop that supports the survival, proliferation, and invasion of lymphoma cells and contributes to the development and progression of Notch-dependent T-ALL. These observations are also supported by a study conducted on a cohort of patients in which Jagged1 expression is associated to adverse prognosis. PMID:25499214

  2. Origin and Evolution of Deep Plasmaspheric Notches

    NASA Technical Reports Server (NTRS)

    Gallagher, D. L.; Adrian, M. L.; Liemohn, M. W.

    2005-01-01

    Deep plasmaspheric notches can extend over more than 2 R(sub E) in radial distance and 3 hours MLT in the magnetic equatorial plane, as observed by the extreme ultraviolet (EUV) imager on the IMAGE mission. They are among the largest evacuated features in the exterior plasmaspheric boundary. They can last for days and exhibit a variety of shapes. It appears that weak convection and limited erosion precedes notch formation at the westward, near-Earth edge of the convection plume. Eighteen clear notch events were found and analyzed in 2000. Among these events, notches were found to drift as slowly as 44% of corotation. In only one case was a notch found to drift at the corotation rate within measurement error. On average, these notches drift at about 21.5 h d(sup -1) or 90% of the corotational rate. Notches sometimes exhibit an interior structure that appears as an extended prominence of dense plasma, which forms a W- or M-like feature in IMAGE/EUV images, depending on viewing perspective. Initial modeling suggests that notches and notch prominences may be caused in part by intense small-scale potential structures that result from the localized injection of ring current plasma. Plasma filling rates during recovery are examined in three L shell ranges from L = 2 to L = 3.5 with rates ranging from 5 to 140 cm(sup -3) d(sup -1). Plasma loss during a minor substorm is found to extend to surprisingly low L shell with rates ranging from 100 to 130 cm(sup -3) d(sup -1) across the L shells examined.

  3. Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma.

    PubMed

    Gao, Juan; Xiong, Yimin; Wang, Yan; Wang, Yiming; Zheng, Guorong; Xu, Hualin

    2016-01-01

    Deregulated expression of Notch receptors and abnormal activity of Notch signaling have been observed in a growing number of malignant tumors, however, the expression and activity of Notch in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and their relationship with HBV X protein (HBx) are still not fully elucidated. To address this, we examined the overall expression of Notch receptors in HBV-associated HCC tissues, analyzed their relationship with HBx, and further investigated the role of Notch signaling in HBx stable transfected HepG2 cells (HepG2X). The results showed that Notch signaling could be activated by HBx in HepG2 cells. The expression of cytoplasmic Notch1 or nuclear Notch4 was correlated with the expression of HBx in HBV-associated HCC tissues. The expression of cytoplasmic Notch1 or nuclear Notch4 could also be upregulated by HBx in HepG2X cells. The upregulation of Notch1 by HBx was through p38 MAPK pathway. Moreover, HBx was found to directly interact with Notch1, whereas, not with Notch4 in HepG2X cells. Suppression of Notch signaling by γ-secretase inhibitor (GSI) decreased cell growth, blocked cell cycle progression and induced cell apoptosis in HepG2X cells. The present study indicates that HBx activates Notch signaling by its effects on Notch1 and Notch4, and therefore, recruits Notch signaling as a downstream pathway contributing to its carcinogenic role in HBV-associated HCC. PMID:26530164

  4. 76 FR 22745 - Three Notch Railway, LLC-Acquisition and Operation Exemption-Three Notch Railroad Co., Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-22

    ... Surface Transportation Board Three Notch Railway, LLC--Acquisition and Operation Exemption-- Three Notch Railroad Co., Inc. Three Notch Railway, LLC (TNRW), a noncarrier, has filed a verified notice of exemption under 49 CFR 1150.31 to acquire from Three Notch Railroad Co., Inc. (TNHR) and to operate...

  5. Legless locomotion in lattices

    NASA Astrophysics Data System (ADS)

    Schiebel, Perrin; Dai, Jin; Gong, Chaohui; Serrano, Miguel M.; Mendelson, Joseph R., III; Choset, Howie; Goldman, Daniel I.

    2015-03-01

    By propagating waves from head to tail, limbless organisms like snakes can traverse terrain composed of rocks, foliage, soil and sand. Previous research elucidated how rigid obstacles influence snake locomotion by studying a model terrain-symmetric lattices of pegs placed in hard ground. We want to understand how different substrate-body interaction modes affect performance in desert-adapted snakes during transit of substrates composed of both rigid obstacles and granular media (GM). We tested Chionactis occipitalis, the Mojave shovel-nosed snake, in two laboratory treatments: lattices of 0 . 64 cm diameter obstacles arrayed on both a hard, slick substrate and in a GM of ~ 0 . 3 mm diameter glass particles. For all lattice spacings, d, speed through the hard ground lattices was less than that in GM lattices. However, maximal undulation efficiencies ηu (number of body lengths advanced per undulation cycle) in both treatments were comparable when d was intermediate. For other d, ηu was lower than this maximum in hard ground lattices, while on GM, ηu was insensitive to d. To systematically explore such locomotion, we tested a physical robot model of the snake; performance depended sensitively on base substrate, d and body wave parameters.

  6. Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling

    PubMed Central

    Li, Haiying; Koo, Yeon; Mao, Xicheng; Sifuentes-Dominguez, Luis; Morris, Lindsey L.; Jia, Da; Miyata, Naoteru; Faulkner, Rebecca A.; van Deursen, Jan M.; Vooijs, Marc; Billadeau, Daniel D.; van de Sluis, Bart; Cleaver, Ondine

    2015-01-01

    Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the endolysosomal system is critical in its regulation. In this study we report that Notch recycling to the cell surface is dependent on the COMMD–CCDC22–CCDC93 (CCC) complex, a recently identified regulator of endosomal trafficking. Disruption in this system leads to intracellular accumulation of Notch2 and concomitant reduction in Notch signaling. Interestingly, among the 10 copper metabolism MURR1 domain containing (COMMD) family members that can associate with the CCC complex, only COMMD9 and its binding partner, COMMD5, have substantial effects on Notch. Furthermore, Commd9 deletion in mice leads to embryonic lethality and complex cardiovascular alterations that bear hallmarks of Notch deficiency. Altogether, these studies highlight that the CCC complex controls Notch activation by modulating its intracellular trafficking and demonstrate cargo-specific effects for members of the COMMD protein family. PMID:26553930

  7. Notch sensitivity of PEEK in monotonic tension.

    PubMed

    Sobieraj, Michael C; Kurtz, Steven M; Rimnac, Clare M

    2009-11-01

    Poly(ether-ether-ketone) (PEEK) has been used as a load bearing orthopaedic implant material with clinical success. All of the orthopaedic applications contain stress concentrations (notches) in their design; however, little work has been done to examine the stress-strain behavior of PEEK in the presence of a notch. This work examines both the stress-strain behavior and the fracture behavior of neat PEEK in a uniaxial loaded condition, and in circumferentially grooved round bar specimens with different elastic stress concentration factors. It was found that the material shows ductile necking in the smooth condition and that this is almost completely suppressed in the notched conditions. Additionally, the deformation and fracture micromechanisms changed drastically, from one of plastic deformation and void coalescence to one dominated by crazing and brittle fast fracture. This change in mechanism was explained via Neuber's theory of stresses at a notch. PMID:19733391

  8. Notch Sensitivity of PEEK in Monotonic Tension

    PubMed Central

    Sobieraj, MC; Kurtz, SM; Rimnac, CM

    2009-01-01

    Poly(ether-ether-ketone) (PEEK) has been used as a load bearing orthopaedic implant material with clinical success. All of the orthpaedic applications contain stress concentrations (notches) in their design; however, little work has been done to examine the stress-strain behavior of PEEK in the presence of a notch. This work examines both the stress-strain behavior and the fracture behavior of neat PEEK in a uniaxial loaded condition, and in circumferentially grooved round bar specimens with different elastic stress concentration factors. It was found that the material shows ductile necking in the smooth condition and that this is almost completely suppressed in the notched conditions. Additionally, the deformation and fracture micromechanisms changed drastically, from one of plastic deformation and void coalescence to one dominated by crazing and brittle fast fracture. This change in mechanism was explained via Neuber's theory of stresses at a notch. PMID:19733391

  9. Benchmark cyclic plastic notch strain measurements

    NASA Technical Reports Server (NTRS)

    Sharpe, W. N., Jr.; Ward, M.

    1983-01-01

    Plastic strains at the roots of notched specimens of Inconel 718 subjected to tension-compression cycling at 650 C are reported. These strains were measured with a laser-based technique over a gage length of 0.1 mm and are intended to serve as 'benchmark' data for further development of experimental, analytical, and computational approaches. The specimens were 250 mm by 2.5 mm in the test section with double notches of 4.9 mm radius subjected to axial loading sufficient to cause yielding at the notch root on the tensile portion of the first cycle. The tests were run for 1000 cycles at 10 cpm or until cracks initiated at the notch root. The experimental techniques are described, and then representative data for the various load spectra are presented. All the data for each cycle of every test are available on floppy disks from NASA.

  10. Xotch, the Xenopus homolog of Drosophila notch.

    PubMed

    Coffman, C; Harris, W; Kintner, C

    1990-09-21

    During the development of a vertebrate embryo, cell fate is determined by inductive signals passing between neighboring tissues. Such determinative interactions have been difficult to characterize fully without knowledge of the molecular mechanisms involved. Mutations of Drosophila and the nematode Caenorhabditis elegans have been isolated that define a family of related gene products involved in similar types of cellular inductions. One of these genes, the Notch gene from Drosophila, is involved with cell fate choices in the neurogenic region of the blastoderm, in the developing nervous system, and in the eye-antennal imaginal disc. Complementary DNA clones were isolated from Xenopus embryos with Notch DNA in order to investigate whether cell-cell interactions in vertebrate embryos also depend on Notch-like molecules. This approach identified a Xenopus molecule, Xotch, which is remarkably similar to Drosophila Notch in both structure and developmental expression. PMID:2402639

  11. Vee-notching device. [with adjustable carriage

    NASA Technical Reports Server (NTRS)

    Spier, R. A. (Inventor)

    1973-01-01

    A device is described for forming vee-notches in tensile test specimens comprising a vertically reciprocating, triangular, triple-edged cutting tool guided in a corresponding triangular slot. The specimen to be vee-notched is mounted on a carriage that is movable toward and away from the cutting tool. The specimen is precisely positioned on the carriage by tapered studs that extend into holes in the specimen and are used to expand spring collets against the wall of the holes.

  12. Lattice QCD

    SciTech Connect

    Bornyakov, V.G.

    2005-06-01

    Possibilities that are provided by a lattice regularization of QCD for studying nonperturbative properties of QCD are discussed. A review of some recent results obtained from computer calculations in lattice QCD is given. In particular, the results for the QCD vacuum structure, the hadron mass spectrum, and the strong coupling constant are considered.

  13. Benchmark notch test for life prediction

    NASA Technical Reports Server (NTRS)

    Domas, P. A.; Sharpe, W. N.; Ward, M.; Yau, J. F.

    1982-01-01

    The laser Interferometric Strain Displacement Gage (ISDG) was used to measure local strains in notched Inconel 718 test bars subjected to six different load histories at 649 C (1200 F) and including effects of tensile and compressive hold periods. The measurements were compared to simplified Neuber notch analysis predictions of notch root stress and strain. The actual strains incurred at the root of a discontinuity in cyclically loaded test samples subjected to inelastic deformation at high temperature where creep deformations readily occur were determined. The steady state cyclic, stress-strain response at the root of the discontinuity was analyzed. Flat, double notched uniaxially loaded fatigue specimens manufactured from the nickel base, superalloy Inconel 718 were used. The ISDG was used to obtain cycle by cycle recordings of notch root strain during continuous and hold time cycling at 649 C. Comparisons to Neuber and finite element model analyses were made. The results obtained provide a benchmark data set in high technology design where notch fatigue life is the predominant component service life limitation.

  14. Notch1 Autoactivation via Transcriptional Regulation of Furin, Which Sustains Notch1 Signaling by Processing Notch1-Activating Proteases ADAM10 and Membrane Type 1 Matrix Metalloproteinase

    PubMed Central

    Qiu, Hong; Tang, Xiaoying; Ma, Jun; Shaverdashvili, Khvaramze; Zhang, Keman

    2015-01-01

    Notch1 is an evolutionarily conserved transmembrane receptor involved in melanoma growth. Notch1 is first cleaved by furin in the Golgi apparatus to produce the biologically active heterodimer. Following ligand binding, Notch1 is cleaved at the cell membrane by proteases such as ADAM10 and -17 and membrane type 1 matrix metalloproteinase (MT1-MMP), the latter of which we recently identified as a novel protease involved in Notch1 processing. The final cleavage is γ-secretase dependent and releases the active Notch intracellular domain (NIC). We now demonstrate that Notch1 directly regulates furin expression. Aside from activating Notch1, furin cleaves and activates several proteases, including MT1-MMP, ADAM10, and ADAM17. By chromatin immunoprecipitation and a reporter assay, we demonstrate that Notch1 binds at position −1236 of the furin promoter and drives furin expression. The Notch1-dependent enhancement of furin expression increases the activities of MT1-MMP and ADAM10 but not that of ADAM17, as demonstrated by short hairpin RNA (shRNA) knockdown of furin, and promotes the cleavage of Notch1 itself. These data highlight a novel positive-feedback loop whereby Notch1-dependent furin expression can induce Notch1 signaling by increasing Notch1 processing and by potentiating the activity of the proteases responsible for Notch1 activation. This leads to Notch1 signal amplification, which can promote melanoma tumor growth and progression, as demonstrated by the inhibition of cell migration and invasion upon furin inhibition downstream of Notch1. Disruption of such feedback signaling might represent an avenue for the treatment of melanoma. PMID:26283728

  15. Alteration of Notch signaling in skeletal development and disease

    PubMed Central

    Tao, Jianning; Chen, Shan; Lee, Brendan

    2010-01-01

    Notch signaling is an evolutionarily conserved mechanism for specifying and regulating organogenesis and tissue renewal. Human and mouse genetic studies have demonstrated mutations in many components of the Notch signaling pathway that cause skeletal patterning defects. More recently, the in vivo effects of Notch signaling on osteoblast specification, proliferation, and differentiation have been demonstrated, in addition to its regulation of osteoclast activity. However, while our understanding of canonical Notch signaling in skeletal biology is rapidly evolving, the role of non-canonical Notch signaling is still poorly understood. In a pathological context, aberration of Notch signaling is also associated with osteosarcoma. These studies raise the question of how Notch may interact with other signaling pathways like Wnt. Finally, manipulation of Notch signaling for bone-related diseases remains complex because of the temporal and context dependent nature of Notch signaling during mesenchymal stem cell and osteoblast differentiation. PMID:20392245

  16. The Role of Notch in the Cardiovascular System: Potential Adverse Effects of Investigational Notch Inhibitors

    PubMed Central

    Rizzo, Paola; Mele, Donato; Caliceti, Cristiana; Pannella, Micaela; Fortini, Cinzia; Clementz, Anthony George; Morelli, Marco Bruno; Aquila, Giorgio; Ameri, Pietro; Ferrari, Roberto

    2015-01-01

    Targeting the Notch pathway is a new promising therapeutic approach for cancer patients. Inhibition of Notch is effective in the oncology setting because it causes a reduction of highly proliferative tumor cells and it inhibits survival of cancer stem cells, which are considered responsible for tumor recurrence and metastasis. Additionally, since Delta-like ligand 4 (Dll4)-activated Notch signaling is a major modulator of angiogenesis, anti-Dll4 agents are being investigated to reduce vascularization of the tumor. Notch plays a major role in the heart during the development and, after birth, in response to cardiac damage. Therefore, agents used to inhibit Notch in the tumors (gamma secretase inhibitors and anti-Dll4 agents) could potentially affect myocardial repair. The past experience with trastuzumab and other tyrosine kinase inhibitors used for cancer therapy demonstrates that the possible cardiotoxicity of agents targeting shared pathways between cancer and heart and the vasculature should be considered. To date, Notch inhibition in cancer patients has resulted only in mild gastrointestinal toxicity. Little is known about the potential long-term cardiotoxicity associated to Notch inhibition in cancer patients. In this review, we will focus on mechanisms through which inhibition of Notch signaling could lead to cardiomyocytes and endothelial dysfunctions. These adverse effects could contrast with the benefits of therapeutic responses in cancer cells during times of increased cardiac stress and/or in the presence of cardiovascular risk factor. PMID:25629006

  17. The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis.

    PubMed

    Liu, Zhenyi; Brunskill, Eric; Varnum-Finney, Barbara; Zhang, Chi; Zhang, Andrew; Jay, Patrick Y; Bernstein, Irv; Morimoto, Mitsuru; Kopan, Raphael

    2015-07-15

    Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half-life of NICD-RBPjk-MAML-DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlie many of the differences between Notch1 and Notch2 in all the contexts we examined, including T-cell development, skin differentiation and carcinogenesis, the inner ear, the lung and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not to intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue-specific γ-secretase complexes following the intracellular domain swap. Reinterpretation of clinical findings based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals. PMID:26062937

  18. The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis

    PubMed Central

    Liu, Zhenyi; Brunskill, Eric; Varnum-Finney, Barbara; Zhang, Chi; Zhang, Andrew; Jay, Patrick Y.; Bernstein, Irv; Morimoto, Mitsuru; Kopan, Raphael

    2015-01-01

    Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half-life of NICD-RBPjk-MAML-DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlie many of the differences between Notch1 and Notch2 in all the contexts we examined, including T-cell development, skin differentiation and carcinogenesis, the inner ear, the lung and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not to intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue-specific γ-secretase complexes following the intracellular domain swap. Reinterpretation of clinical findings based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals. PMID:26062937

  19. Clinicopathological significance of aberrant Notch receptors in intrahepatic cholangiocarcinoma

    PubMed Central

    Wu, Wen-Rui; Shi, Xiang-De; Zhang, Rui; Zhu, Man-Sheng; Xu, Lei-Bo; Yu, Xian-Huan; Zeng, Hong; Wang, Jie; Liu, Chao

    2014-01-01

    Notch signaling has been reported to be activated to promote biliary epithelial cell differentiation and tubulogenesis during bile duct development. In this study, clinicopathological significance of aberrant expression of Notch receptors in intrahepatic cholangiocarcinoma (ICC) was investigated. Thus, forty-one ICC specimens were examined by immunohistochemistry using anti-Notch1-4 antibodies, respectively. Expression of Notch receptors was scored by percentage of positive tumor cells and intensity of immunostaining. Clinicopathological parameters and survival data were compared with the expression of Notch receptors, respectively. Expression of Notch receptors was identified in cancer cells, as well as in non-neoplastic cells. Compared with adjacent non-tumor liver tissues, Notch1 and 4 were up regulated, and Notch2 and 3 were relatively weaker. Positive immunostaining of Notch1 in ICC cells was detected in 34 cases (82.9%), Notch2 in 23 (56.1%), Notch3 in 16 (39.0%) and Notch4 in 14 (34.1%). Notch1 was overexpressed in cases with tumor size > 5 cm (P = 0.036). Expression of Notch2 was correlated inversely with histological grade (P = 0.016). Overexpression of Notch4 was more common in cases with serum CA125 > 35 U/ml than cases with CA125 ≤ 35 U/ml (P = 0.048). Expression of Notch3 was not correlated with any other clinicopathological parameters. Moreover, Notch4 was related to poor survival (P < 0.001). To conclude, this study reveals that aberrant expression of Notch receptors 1 and 4 might play important roles during ICC progression. PMID:25031748

  20. Notch signaling: an emerging therapeutic target for cancer treatment.

    PubMed

    Yuan, Xun; Wu, Hua; Xu, Hanxiao; Xiong, Huihua; Chu, Qian; Yu, Shiying; Wu, Gen Sheng; Wu, Kongming

    2015-12-01

    The Notch pathway is involved in cell proliferation, differentiation and survival. The Notch signaling pathway is one of the most commonly activated signaling pathways in cancer. Alterations include activating mutations and amplification of the Notch pathway, which play key roles in the progression of cancer. Accumulating evidence suggests that the pharmacological inhibition of this pathway can overcome chemoresistance. Efforts have been taken to develop Notch inhibitors as a single agent or in combination with clinically used chemotherapeutics to treat cancer. Some Notch inhibitors have been demonstrated to have therapeutic efficacy in preclinical studies. This review summarizes the recent studies and clinical evaluations of the Notch inhibitors in cancer. PMID:26341688

  1. The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

    PubMed Central

    Kopan, Raphael; Ilagan, Ma. Xenia G.

    2009-01-01

    Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, misregulation or loss of Notch signaling underlies multiple human disorders, from developmental syndromes to adult onset diseases and cancer. Notch receptor activation is irreversible as it involves proteolysis-mediated release of the Notch intracellular domain, translocation to the nucleus, and association with a DNA-bound protein. Even though each Notch molecule signals only once without amplification by secondary messenger cascades, Notch signaling is remarkably robust in most tissues. In this review, we highlight the recent studies that reveal new molecular details involved in regulating ligand-mediated activation, receptor proteolysis and target selection. PMID:19379690

  2. Lattice Cubes

    ERIC Educational Resources Information Center

    Parris, Richard

    2011-01-01

    Given a segment that joins two lattice points in R[superscript 3], when is it possible to form a lattice cube that uses this segment as one of its twelve edges? A necessary and sufficient condition is that the length of the segment be an integer. This paper presents an algorithm for finding such a cube when the prime factors of the length are…

  3. Notch signaling in cardiovascular disease and calcification.

    PubMed

    Rusanescu, Gabriel; Weissleder, Ralph; Aikawa, Elena

    2008-08-01

    Recent increase in human lifespan has shifted the spectrum of aging-related disorders to an unprecedented upsurge in cardiovascular diseases, especially calcific aortic valve stenosis, which has an 80% risk of progression to heart failure and death. A current therapeutic option for calcified valves is surgical replacement, which provides only temporary relief. Recent progress in cardiovascular research has suggested that arterial and valve calcification are the result of an active process of osteogenic differentiation, induced by a pro-atherogenic inflammatory response. At molecular level, the calcification process is regulated by a network of signaling pathways, including Notch, Wnt and TGFbeta/BMP pathways, which control the master regulator of osteogenesis Cbfa1/Runx2. Genetic and in vitro studies have implicated Notch signaling in the regulation of macrophage activation and cardiovascular calcification. Individuals with inactivating Notch1 mutations have a high rate of cardiovascular disorders, including valve stenosis and calcification. This article reviews recent progress in the mechanism of cardiovascular calcification and discusses potential molecular mechanisms involved, focusing on Notch receptors. We propose a calcification model where extreme increases in vascular wall cell density due to inflammation-induced cell proliferation can trigger an osteogenic differentiation program mediated by Notch receptors. PMID:19936191

  4. Analysis of center-notched, unidirectional composites

    SciTech Connect

    Reedy, E.D. Jr.

    1982-01-01

    A method for calculating the stresses in a notched, unidirectional monolayer is described which permits the modeling of a finite-dimensioned monolayer containing a centered notch transverse to the fibers. Elastic-work hardening constitutive relationships may be specified for the fibers and/or matrix. Notch growth under increasing load can be analyzed. Calculations demonstrate the utility of this analysis in determining how constituent properties affect notch-tip fiber stress concentrations. Calculations for unidirectional boron/aluminum indicate that stress concentrations are reduced by a matrix with: (1) sufficiently high yield strength to prevent large-scale yielding (uniform traction loading can cause large fiber stress concentrations when global yielding occurs); and (2) a low rate of work-hardening (to reduce stress concentrations). The analysis has also been applied to Kevlar 49 plain weave fabric/epoxy monolayers. Predicted matrix and fiber stress concentrations are localized in this material with nonlinear material response limited to the notch-tip region. This is different from the widespread yielding in as-fabricated, unidirectional boron/aluminum. 6 figures.

  5. Notch Transmembrane Domain: Secondary Structure and Topology

    PubMed Central

    2016-01-01

    The Notch signaling pathway is critical in development, neuronal maintenance, and hematopoiesis. An obligate step in the activation of this pathway is cleavage of its transmembrane (TM) domain by γ-secretase. While the soluble domains have been extensively studied, little has been done to characterize its TM and flanking juxtamembrane (JM) segments. Here, we present the results of nuclear magnetic resonance (NMR) studies of the human Notch1 TM/JM domain. The TM domain is largely α-helical. While the flanking JM segments do not adopt regular secondary structure, they interact with the membrane surface, suggesting membrane interactions may play a role in modulating its cleavage by γ-secretase and subsequent NOTCH signaling function. PMID:26023825

  6. [Neural stem cells and Notch signalling].

    PubMed

    Traiffort, Elisabeth; Ferent, Julien

    2015-12-01

    Development and repair of the nervous system are based on the existence of neural stem cells (NSCs) able to generate neurons and glial cells. Among the mechanisms that are involved in the control of embryo or adult NSCs, the Notch signalling plays a major role. In embryo, the pathway participates in the maintenance of NSCs during all steps of development of the central nervous system which starts with the production of neurons also called neurogenesis and continues with gliogenesis giving rise to astrocytes and oligodendrocytes. During the postnatal and adult period, Notch signalling is still present in the major neurogenic areas, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus. In these regions, Notch maintains NSC quiescence, contributes to the heterogeneity of these cells and displays pleiotropic effects during the regeneration process occurring after a lesion. PMID:26672665

  7. Sequential Notch activation regulates ventricular chamber development

    PubMed Central

    D'Amato, Gaetano; Luxán, Guillermo; del Monte-Nieto, Gonzalo; Martínez-Poveda, Beatriz; Torroja, Carlos; Walter, Wencke; Bochter, Matthew S.; Benedito, Rui; Cole, Susan; Martinez, Fernando; Hadjantonakis, Anna-Katerina; Uemura, Akiyoshi; Jiménez-Borreguero, Luis J.; de la Pompa, José Luis

    2016-01-01

    Ventricular chambers are essential for the rhythmic contraction and relaxation occurring in every heartbeat throughout life. Congenital abnormalities in ventricular chamber formation cause severe human heart defects. How the early trabecular meshwork of myocardial fibres forms and subsequently develops into mature chambers is poorly understood. We show that Notch signalling first connects chamber endocardium and myocardium to sustain trabeculation, and later coordinates ventricular patterning and compaction with coronary vessel development to generate the mature chamber, through a temporal sequence of ligand signalling determined by the glycosyltransferase manic fringe (MFng). Early endocardial expression of MFng promotes Dll4–Notch1 signalling, which induces trabeculation in the developing ventricle. Ventricular maturation and compaction require MFng and Dll4 downregulation in the endocardium, which allows myocardial Jag1 and Jag2 signalling to Notch1 in this tissue. Perturbation of this signalling equilibrium severely disrupts heart chamber formation. Our results open a new research avenue into the pathogenesis of cardiomyopathies. PMID:26641715

  8. Laser notching ceramics for reliable fracture toughness testing

    SciTech Connect

    Barth, Holly D.; Elmer, John W.; Freeman, Dennis C.; Schaefer, Ronald D.; Derkach, Oleg; Gallegos, Gilbert F.

    2015-09-19

    A new method for notching ceramics was developed using a picosecond laser for fracture toughness testing of alumina samples. The test geometry incorporated a single-edge-V-notch that was notched using picosecond laser micromachining. This method has been used in the past for cutting ceramics, and is known to remove material with little to no thermal effect on the surrounding material matrix. This study showed that laser-assisted-machining for fracture toughness testing of ceramics was reliable, quick, and cost effective. In order to assess the laser notched single-edge-V-notch beam method, fracture toughness results were compared to results from other more traditional methods, specifically surface-crack in flexure and the chevron notch bend tests. Lastly, the results showed that picosecond laser notching produced precise notches in post-failure measurements, and that the measured fracture toughness results showed improved consistency compared to traditional fracture toughness methods.

  9. Laser notching ceramics for reliable fracture toughness testing

    DOE PAGESBeta

    Barth, Holly D.; Elmer, John W.; Freeman, Dennis C.; Schaefer, Ronald D.; Derkach, Oleg; Gallegos, Gilbert F.

    2015-09-19

    A new method for notching ceramics was developed using a picosecond laser for fracture toughness testing of alumina samples. The test geometry incorporated a single-edge-V-notch that was notched using picosecond laser micromachining. This method has been used in the past for cutting ceramics, and is known to remove material with little to no thermal effect on the surrounding material matrix. This study showed that laser-assisted-machining for fracture toughness testing of ceramics was reliable, quick, and cost effective. In order to assess the laser notched single-edge-V-notch beam method, fracture toughness results were compared to results from other more traditional methods, specificallymore » surface-crack in flexure and the chevron notch bend tests. Lastly, the results showed that picosecond laser notching produced precise notches in post-failure measurements, and that the measured fracture toughness results showed improved consistency compared to traditional fracture toughness methods.« less

  10. The Notch meeting: an odyssey from structure to function.

    PubMed

    Chitnis, Ajay; Balle-Cuif, Laure

    2016-02-15

    The Notch signaling pathway plays fundamental roles in diverse developmental processes. Studies of the basic biology of Notch function have provided insights into how its dysfunction contributes to multi-systemic diseases and cancer. In addition, our understanding of Notch signaling in maintaining stem/progenitor cell populations is revealing new avenues for rekindling regeneration. The Notch IX meeting, which was held in Athens, Greece in October 2015, brought together scientists working on different model systems and studying Notch signaling in various contexts. Here, we provide a summary of the key points that were presented at the meeting. Although we focus on the molecular mechanisms that determine Notch signaling and its role in development, we also cover talks describing roles for Notch in adulthood. Together, the talks revealed how interactions between adjacent cells mediated by Notch regulate development and physiology at multiple levels. PMID:26884393

  11. Kinase active Misshapen regulates Notch signaling in Drosophila melanogaster.

    PubMed

    Mishra, Abhinava K; Sachan, Nalani; Mutsuddi, Mousumi; Mukherjee, Ashim

    2015-11-15

    Notch signaling pathway represents a principal cellular communication system that plays a pivotal role during development of metazoans. Drosophila misshapen (msn) encodes a protein kinase, which is related to the budding yeast Ste20p (sterile 20 protein) kinase. In a genetic screen, using candidate gene approach to identify novel kinases involved in Notch signaling, we identified msn as a novel regulator of Notch signaling. Data presented here suggest that overexpression of kinase active form of Msn exhibits phenotypes similar to Notch loss-of-function condition and msn genetically interacts with components of Notch signaling pathway. Kinase active form of Msn associates with Notch receptor and regulate its signaling activity. We further show that kinase active Misshapen leads to accumulation of membrane-tethered form of Notch. Moreover, activated Msn also depletes Armadillo and DE-Cadherin from adherens junctions. Thus, this study provides a yet unknown mode of regulation of Notch signaling by Misshapen. PMID:26431585

  12. The Role of Notch Receptors in Transcriptional Regulation

    PubMed Central

    WANG, HONGFANG; ZANG, CHONGZHI; LIU, X. SHIRLEY; ASTER, JON C.

    2015-01-01

    Notch signaling has pleiotropic context-specific functions that have essential roles in many processes, including embryonic development and maintenance and homeostasis of adult tissues. Aberrant Notch signaling (both hyper- and hypoactive) is implicated in a number of human developmental disorders and many cancers. Notch receptor signaling is mediated by tightly regulated proteolytic cleavages that lead to the assembly of a nuclear Notch transcription complex, which drives the expression of downstream target genes and thereby executes Notch’s functions. Thus, understanding regulation of gene expression by Notch is central to deciphering how Notch carries out its many activities. Here, we summarize the recent findings pertaining to the complex interplay between the Notch transcriptional complex and interacting factors involved in transcriptional regulation, including co-activators, cooperating transcription factors, and chromatin regulators, and discuss emerging data pertaining to the role of Notch-regulated noncoding RNAs in transcription. PMID:25418913

  13. Solution notches, earthquakes, and sea level, Haiti

    NASA Astrophysics Data System (ADS)

    Schiffman, C. R.; Mildor, B. S.; Bilham, R. G.

    2010-12-01

    Shortly after the 12 January 2010 Haiti earthquake, we installed an array of five tide gauges to determine sea level and its variability in the region of uplifted corals on the coast SW of Leogane, Haiti, that had been uplift ≤30 cm during the earthquake. Each gauge consists of a pressure transducer bolted 50-80 cm below mean sea level, which samples the difference between atmospheric pressure and sea pressure every 10 minutes. The data are transmitted via the Iridium satellite and are publically available with a latency of 10 minutes to 2 hours. The measurements reveal a maximum tidal range of ≈50 cm with 2-4 week oscillations in mean sea level of several cm. Sea slope, revealed by differences between adjacent gauges, varies 2-5 cm per 10 km at periods of 2-5 weeks, which imposes a disappointing limit to the utility of the gauges in estimating post seismic vertical motions. A parallel study of the form and elevation of coastal notches and mushroom rocks (rocks notched on all sides, hence forming a mushroom shape), along the coast west of Petit Goave suggests that these notches may provide an uplift history of the region over the past several hundreds of years. Notch sections in two areas were contoured, digitized, and compared to mean sea level. The notches mimic the histogram of sea level, suggesting that they are formed by dissolution by acidic surface waters. Notches formed two distinct levels, one approximately 58 cm above mean sea level, and the other approximately 157 cm above mean sea level. Several landslide blocks fell into the sea during the 2010 earthquake, and we anticipate these are destined for conversion to future mushroom rocks. Surfaces have been prepared on these blocks to study the rate of notch formation in situ, and samples are being subjected to acid corrosion in laboratory conditions, with the hope that the depth of notches may provide an estimate of the time of fall of previous rocks to help constrain the earthquake history of this area

  14. Power-Tool Adapter For T-Handle Screws

    NASA Technical Reports Server (NTRS)

    Deloach, Stephen R.

    1992-01-01

    Proposed adapter enables use of pneumatic drill, electric drill, electric screwdriver, or similar power tool to tighten or loosen T-handled screws. Notched tube with perpendicular rod welded to it inserted in chuck of tool. Notched end of tube slipped over screw handle.

  15. Activation of Notch-Mediated Protective Signaling in the Myocardium

    PubMed Central

    Gude, Natalie A.; Emmanuel, Gregory; Wu, Weitao; Cottage, Christopher T.; Fischer, Kimberlee; Quijada, Pearl; Muraski, John A.; Alvarez, Roberto; Rubio, Marta; Schaefer, Eric; Sussman, Mark A.

    2013-01-01

    The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades. The impact of HGF on Notch signaling was assessed following myocardial infarction as well as in cultured cardiomyocytes. Notch1 is activated in border zone cardiomyocytes coincident with nuclear c-Met following infarction. Intramyocardial injection of HGF enhances Notch1 and Akt activation in adult mouse myocardium. Corroborating evidence in cultured cardiomyocytes shows treatment with HGF or insulin increases levels of Notch effector Hes1 in immunoblots, whereas overexpression of activated Notch intracellular domain prompts a 3-fold increase in phosphorylated Akt. Infarcted hearts injected with adenoviral vector expressing Notch intracellular domain treatment exhibit improved hemodynamic function in comparison with control mice after 4 weeks, implicating Notch signaling in a cardioprotective role following cardiac injury. These results indicate Notch activation in cardiomyocytes is mediated through c-Met and Akt survival signaling pathways, and Notch1 signaling in turn enhances Akt activity. This mutually supportive crosstalk suggests a positive survival feedback mechanism between Notch and Akt signaling in adult myocardium following injury. PMID:18369158

  16. Tidal notches in Mediterranean Sea: a comprehensive analysis

    NASA Astrophysics Data System (ADS)

    Antonioli, Fabrizio; Lo Presti, Valeria; Rovere, Alessio; Ferranti, Luigi; Anzidei, Marco; Furlani, Stefano; Mastronuzzi, Giuseppe; Orru, Paolo E.; Scicchitano, Giovanni; Sannino, Gianmaria; Spampinato, Cecilia R.; Pagliarulo, Rossella; Deiana, Giacomo; de Sabata, Eleonora; Sansò, Paolo; Vacchi, Matteo; Vecchio, Antonio

    2015-07-01

    Recent works (Evelpidou et al., 2012) suggest that the modern tidal notch is disappearing worldwide due sea level rise over the last century. In order to assess this hypothesis, we measured modern tidal notches in several of sites along the Mediterranean coasts. We report observations on tidal notches cut along carbonate coasts from 73 sites from Italy, France, Croatia, Montenegro, Greece, Malta and Spain, plus additional observations carried outside the Mediterranean. At each site, we measured notch width and depth, and we described the characteristics of the biological rim at the base of the notch. We correlated these parameters with wave energy, tide gauge datasets and rock lithology. Our results suggest that, considering 'the development of tidal notches the consequence of midlittoral bioerosion' (as done in Evelpidou et al., 2012) is a simplification that can lead to misleading results, such as stating that notches are disappearing. Important roles in notch formation can be also played by wave action, rate of karst dissolution, salt weathering and wetting and drying cycles. Of course notch formation can be augmented and favoured also by bioerosion which can, in particular cases, be the main process of notch formation and development. Our dataset shows that notches are carved by an ensemble rather than by a single process, both today and in the past, and that it is difficult, if not impossible, to disentangle them and establish which one is prevailing. We therefore show that tidal notches are still forming, challenging the hypothesis that sea level rise has drowned them.

  17. Notch as a Possible Cell Differentiation Factor in Pleomorphic Adenomas

    PubMed Central

    Takamine, Keisuke; Ueda, Yukiko; Nakano, Keisuke; Ochiai, Takanaga; Sugita, Yoshihiko; Kubo, Katsutoshi; Maeda, Hatsuhiko; Hasegawa, Hiromasa; Kawakami, Toshiyuki

    2015-01-01

    The expression of Notch in 30 cases of pleomorphic adenoma was examined by immunohistochemistry. Comparing the results of our study with previous literatures, from the partial CK7 expression and substantial Notch expression in ductal epithelial cells as well as the Notch expression in solid tumor nests, it can be inferred that Notch is involved in cell differentiation. CK13 expression was observed in cells undergoing squamous metaplasia and Notch expression was seen in the nucleus of basal and squamous cells. The intense Notch expression in basal cells and weak expression in squamous cells suggests that Notch is involved in the differentiation from basal to squamous cell. Moreover, the loss of nuclear expression on the inner layer would signify that differentiation is about to end or has been terminated. Notch was expressed in the cytoplasm of cartilage cells and in the cell membrane of mucous cells but not in the nucleus indicating that differentiation has been concluded. Notch involvement is suspected in cell differentiation in areas showing ductal structures and squamous metaplasia. In summary, Notch is involved in cell differentiation of ductal cells in PA. Nuclear expression was shown in tumor cells in solid nests and surrounding structures. Moreover, Notch is expressed by basal cells undergoing squamous metaplasia suggesting the participation of Notch in cell differentiation in PA. PMID:26516303

  18. The Notch signaling pathway as a mediator of tumor survival

    PubMed Central

    Pine, Sharon R.

    2013-01-01

    The Notch signaling pathway is evolutionarily conserved and responsible for cell fate determination in the developing embryo and mature tissue. At the molecular level, ligand binding activates Notch signaling by liberating the Notch intracellular domain, which then translocates into the nucleus and activates gene transcription. Despite the elegant simplicity of this pathway, which lacks secondary messengers or a signaling cascade, Notch regulates gene expression in a highly context- and cell-type-dependent manner. Notch signaling is frequently dysregulated, most commonly by overactivation, across many cancers and confers a survival advantage on tumors, leading to poorer outcomes for patients. Recent studies demonstrate how Notch signaling increases tumor cell proliferation and provide evidence that active Notch signaling maintains the cancer stem-cell pool, induces epithelial–mesenchymal transition and promotes chemoresistance. These studies imply that pharmacological inhibition of Notch signaling may refine control of cancer therapy and improve patient survival. Gamma secretase inhibitors (GSIs) are drugs that inhibit Notch signaling and may be successful in controlling cancer cell growth in conjunction with standard chemotherapy, but substantial side effects have hampered their widespread use. Recent efforts have been aimed at the development of antibodies against specific Notch receptors and ligands with the hope of limiting side effects while providing the same therapeutic benefit as GSIs. Together, studies characterizing Notch signaling and modulation have offered hope that refined methods targeting Notch may become powerful tools in anticancer therapeutics. PMID:23585460

  19. Notch Signaling Components: Diverging Prognostic Indicators in Lung Adenocarcinoma.

    PubMed

    Liu, Zhi-Yan; Wu, Tao; Li, Qing; Wang, Min-Cong; Jing, Li; Ruan, Zhi-Ping; Yao, Yu; Nan, Ke-Jun; Guo, Hui

    2016-05-01

    Non-small-cell lung cancer (NSCLC) is a lethal and aggressive malignancy. Currently, the identities of prognostic and predictive makers of NSCLC have not been fully established. Dysregulated Notch signaling has been implicated in many human malignancies, including NSCLC. However, the prognostic value of measuring Notch signaling and the utility of developing Notch-targeted therapies in NSCLC remain inconclusive. The present study investigated the association of individual Notch receptor and ligand levels with lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) prognosis using the Kaplan-Meier plotte database. This online database encompasses 2437 lung cancer samples. Hazard ratios with 95% confidence intervals were calculated. The results showed that higher Notch1, Notch2, JAG1, and DLL1 mRNA expression predicted better overall survival (OS) in lung ADC, but showed no significance in SCC patients. Elevated Notch3, JAG2, and DLL3 mRNA expression was associated with poor OS of ADC patients, but not in SCC patients. There was no association between Notch4 and OS in either lung ADC or SCC patients. In conclusion, the set of Notch1, Notch2, JAG1, DLL1 and that of Notch3, JAG2, DLL3 played opposing prognostic roles in lung ADC patients. Neither set of Notch receptors and ligands was indicative of lung SCC prognosis. Notch signaling could serve as promising marker to predict outcomes in lung ADC patients. The distinct features of lung cancer subtypes and Notch components should be considered when developing future Notch-targeted therapies. PMID:27196489

  20. Vee-notch tool cuts specimens

    NASA Technical Reports Server (NTRS)

    Spier, R. A.

    1970-01-01

    Triangular cutting tool uses carbide tips for notching heat-treated or abrasive materials, and alloys subjected to high structural stresses. The tool is rigidly mounted in a slot of mating contour to prevent deflection during cutting of tensile specimens. No other expensive machine equipment is required.

  1. New Insights into the Mechanism of Notch Signalling in Fibrosis

    PubMed Central

    Kavian, Niloufar; Servettaz, Amélie; Weill, Bernard; Batteux, Frédéric

    2012-01-01

    The Notch pathway is an evolutionary conserved signalling mechanism that regulates cellular fate and development in various types of cells. The full spectrum of Notch effects has been well studied over the last decade in the fields of development and embryogenesis. But only recently several studies emphasized the involvement of the Notch signalling pathway in fibrosis. This review summarizes the structure and activation of the Notch family members, and focuses on recent findings regarding the role of Notch in organ fibrogenesis, in humans and in animal models. PMID:22802907

  2. Notch regulates the angiogenic response via induction of VEGFR-1

    PubMed Central

    2010-01-01

    Notch is a critical regulator of angiogenesis and arterial specification. We show that ectopic expression of activated Notch1 induces endothelial morphogenesis in human umbilical vein endothelial cells (HUVEC) in a VEGFR-1-dependent manner. Notch1-mediated upregulation of VEGFR-1 in HUVEC increased their responsiveness to the VEGFR-1 specific ligand, Placental Growth Factor (PlGF). In mice and human endothelial cells, inhibition of Notch signaling resulted in decreased VEGFR-1 expression during VEGF-A-induced neovascularization. In summary, we show that Notch1 plays a role in endothelial cells by regulating VEGFR-1, a function that may be important for physiological and pathological angiogenesis. PMID:20298529

  3. Notch Signaling Maintains Neural Rosette Polarity

    PubMed Central

    Main, Heather; Radenkovic, Jelena; Jin, Shao-bo; Lendahl, Urban; Andersson, Emma R.

    2013-01-01

    Formation of the metazoan body plan requires a complex interplay of morphological changes and patterning, and central to these processes is the establishment of apical/basal cell polarity. In the developing nervous system, apical/basal cell polarity is essential for neural tube closure and maintenance of the neural stem cell population. In this report we explore how a signaling pathway important for nervous system development, Notch signaling, impacts on apical/basal cell polarity in neural differentiation. CSL−/− mouse embryos, which are devoid of canonical Notch signaling, demonstrated a neural tube phenotype consistent with cell polarity and convergent extension defects, including deficiencies in the restricted expression of apical polarity markers in the neuroepithelium. CSL−/− mouse embryonic stem (ES) cells, cultured at low density, behaved as wild-type in the establishment of neural progenitors and apical specification, though progression through rosette formation, an in vitro correlate of neurulation, required CSL for correct maintenance of rosette structure and regulation of neuronal differentiation. Similarly, acute pharmacological inhibition of Notch signaling led to the breakdown of neural rosettes and accelerated neuronal differentiation. In addition to functional Notch signaling, rosette integrity was found to require actin polymerization and Rho kinase (ROCK) activity. Disruption of rosettes through inhibition of actin polymerization or ROCK activity, however, had no effect on neuronal differentiation, indicating that rosette maintenance is not a prerequisite for normal neuronal differentiation. In conclusion, our data indicate that Notch signaling plays a role not only in differentiation, but also in organization and maintenance of polarity during development of the early nervous system. PMID:23675446

  4. NOTCHing the bone: Insights into multi-functionality

    PubMed Central

    Engin, Feyza; Lee, Brendan

    2010-01-01

    Evolutionarily conserved Notch signaling plays a critical role during embryonic and postnatal life. The importance of Notch signaling in the determination of cell fate, and the spatio-temporal regulation of proliferation, differentiation and apoptosis has been demonstrated in various different organ systems. However, how Notch signaling affects the bone development was unknown until now. The in vivo effects of Notch signaling in lineage commitment, bone formation and bone resorption were demonstrated in recent studies. In addition to regulation of osteoblastogenesis, osteoblast directed osteoclastogenesis by Notch signaling revealed a dimorphic effect for this signaling pathway providing another example of such in bone development. Moreover, identification of the cross-talk between the hematopoietic stem cell niche and osteoblasts through Notch signaling also suggested another important role for Notch signaling, i.e., the coupling of cellular components of the bone microenvironment. The association between the gain and loss of function of Notch activity in bone pathology highlights Notch as a potentially novel therapeutic target for the treatment of metabolic bone disease and bone cancer. In this review, we will focus primarily on the regulation of bone cells, i.e., osteoblasts and osteoclasts by Notch signaling. We will also review the importance of Notch in specifying bone-hematopoietic stem cell niche interactions within the bone microenvironment. Finally, we will discuss potential clinical implications and future directions for this field. PMID:19520195

  5. Notch Signaling in Meibomian Gland Epithelial Cell Differentiation

    PubMed Central

    Gidfar, Sanaz; Afsharkhamseh, Neda; Sanjari, Sara; Djalilian, Ali R.

    2016-01-01

    Purpose Notch1 was previously shown to play a critical role in murine meibomian gland function and maintenance. In this study, we have examined the expression and activation of Notch pathway in human meibomian gland epithelial cells in vitro. Methods An immortalized human meibomian gland epithelial cell (HMGEC) line was cultured under proliferative and differentiative conditions. Expression of Notch receptors and ligands were evaluated by quantitative PCR and Western blot. The effect of Notch inhibition and induction on oil production was also assessed. Results Human meibomian gland epithelial cell expressed Notch1, Notch2, Notch3, Jagged1, Jagged2, Delta-like 1, and Delta-like 3. The level of cleaved (activated) Notch1 strongly increased with differentiation. The expression of Notch3 was inversely correlated with proliferation. Induction and inhibition of Notch1 led to an increase and decrease in the amount of oil production, respectively. Conclusions Notch signaling appears to play an important role in human meibomian gland epithelial differentiation and oil production. This may provide a potential therapeutic pathway for treating meibomian gland dysfunction. PMID:26943148

  6. Identification of novel Notch target genes in T cell leukaemia

    PubMed Central

    Chadwick, Nicholas; Zeef, Leo; Portillo, Virginia; Fennessy, Carl; Warrander, Fiona; Hoyle, Sarah; Buckle, Anne-Marie

    2009-01-01

    Background Dysregulated Notch signalling is believed to play an important role in the development and maintenance of T cell leukaemia. At a cellular level, Notch signalling promotes proliferation and inhibits apoptosis of T cell acute lymphoblastic leukaemia (T-ALL) cells. In this study we aimed to identify novel transcriptional targets of Notch signalling in the T-ALL cell line, Jurkat. Results RNA was prepared from Jurkat cells retrovirally transduced with an empty vector (GFP-alone) or vectors containing constitutively active forms of Notch (N1ΔE or N3ΔE), and used for Affymetrix microarray analysis. A subset of genes found to be regulated by Notch was chosen for real-time PCR validation and in some cases, validation at the protein level, using several Notch-transduced T-ALL and non-T-ALL leukaemic cell lines. As expected, several known transcriptional target of Notch, such as HES1 and Deltex, were found to be overexpressed in Notch-transduced cells, however, many novel transcriptional targets of Notch signalling were identified using this approach. These included the T cell costimulatory molecule CD28, the anti-apoptotic protein GIMAP5, and inhibitor of DNA binding 1 (1D1). Conclusion The identification of such downstream Notch target genes provides insights into the mechanisms of Notch function in T cell leukaemia, and may help identify novel therapeutic targets in this disease. PMID:19508709

  7. Targeting Notch degradation system provides promise for breast cancer therapeutics.

    PubMed

    Liu, Jing; Shen, Jia-Xin; Wen, Xiao-Fen; Guo, Yu-Xian; Zhang, Guo-Jun

    2016-08-01

    Notch receptor signaling pathways play an important role, not only in normal breast development but also in breast cancer development and progression. As a group of ligand-induced proteins, different subtypes of mammalian Notch (Notch1-4) are sensitive to subtle changes in protein levels. Thus, a clear understanding of mechanisms of Notch protein turnover is essential for understanding normal and pathological mechanisms of Notch functions. It has been suggested that there is a close relationship between the carcinogenesis and the dysregulation of Notch degradation. However, this relationship remains mostly undefined in the context of breast cancer, as protein degradation is mediated by numerous signaling pathways as well as certain molecule modulators (activators/inhibitors). In this review, we summarize the published data regarding the regulation of Notch family member degradation in breast cancer, while emphasizing areas that are likely to provide new therapeutic modalities for mechanism-based anti-cancer drugs. PMID:27263934

  8. Notch -- a goldilocks signaling pathway in disease and cancer therapy.

    PubMed

    Braune, Eike-Benjamin; Lendahl, Urban

    2016-03-01

    The Notch signaling pathway is a fundamental signaling mechanism operating in most, if not all, multicellular organisms and in most cell types in the body. Like other "ivy league" pathways such as Wnt, PI3K, Sonic Hedgehog, Receptor Tyrosine Kinases (RTKs), and JAK/STAT signaling, the Notch pathway is a linear signaling mechanism, i.e., an extracellular ligand activates a receptor, which ultimately leads to transcriptional alterations in the cell nucleus, but Notch signaling is a strict cell-cell communication mechanism and lacks built-in amplification steps in the signaling pathway. Dysregulated Notch signaling, either by direct mutations in the pathway or by altered signaling output, is increasingly linked to disease, and Notch can act as an oncogene or tumor suppressor depending on the cellular context. This underscores that appropriate level of Notch signaling is important for differentiation and tissue homeostasis, a notion supported also by genetic data indicating that Notch signaling is very gene dosage-sensitive. Thus, too much or too little signaling can lead to disease and Notch can therefore be considered a Goldilocks signaling pathway. Given the emerging role of dysregulated Notch signaling in disease, there is increasing interest in developing therapeutic approaches to modulate Notch signaling. In this review we discuss recent findings on how signal transduction is tuned in the Notch pathway and how Notch signaling is dysregulated in disease. We also discuss different strategies to modulate Notch signaling for clinical use, for example by novel antibody-based tools and by taking advantage of the cross-talk between Notch and other signaling mechanisms. PMID:27115169

  9. Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation

    PubMed Central

    Aster, Jon C.; Bodnar, Nick; Xu, Lanwei; Karnell, Fredrick; Milholland, John M.; Maillard, Ivan; Histen, Gavin; Nam, Yunsun; Blacklow, Stephen C.; Pear, Warren S.

    2011-01-01

    Background The functional interchangeability of mammalian Notch receptors (Notch1-4) in normal and pathophysiologic contexts such as cancer is unsettled. We used complementary in vivo, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival. Principal Findings We find that the activated intracellular domains of Notch1-4 (ICN1-4) all support T cell development in mice and thymic organ culture. However, unlike ICN1-3, ICN4 fails to induce T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and is unable to rescue the growth of Notch1-dependent T-ALL cell lines. The ICN4 phenotype is mimicked by weak gain-of-function forms of Notch1, suggesting that it stems from a failure to transactivate one or more critical target genes above a necessary threshold. Experiments with chimeric receptors demonstrate that the Notch ankyrin repeat domains differ in their leukemogenic potential, and that this difference correlates with activation of Myc, a direct Notch target that has an important role in Notch-associated T-ALL. Conclusions/Significance We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis. PMID:22022427

  10. Phototunable reflection notches of cholesteric liquid crystals

    SciTech Connect

    Hrozhyk, Uladzimir A.; Serak, Svetlana V.; Tabiryan, Nelson V.; Bunning, Timothy J.

    2008-09-15

    The reflection notch of cholesteric liquid crystals (CLCs) formed from highly photosenstive azobenzene nematic liquid crystals doped with light-insensitive, large helical twisting power chiral dopants is shown to be widely phototunable by green laser beams. The nonlinear transmission properties of these materials were studied. We have shown that the relative shift in Bragg wavelength is independent of the chiral dopant concentration and develop a predictive theory of such behavior. The theory describes the dynamics of phototuning as well. Reflection shifts greater than 150 nm were driven with low power, cw of 532 nm in these photosensitive CLCs, previously attainable only through UV pre-exposure. A nonlinear feedback mechanism was demonstrated for CLCs of left, right, and both handedness upon laser-induced blueshifting of the reflection notch from a red wavelength using a green cw laser.

  11. The viscoelastic behavior of notched glassy polymers

    NASA Technical Reports Server (NTRS)

    Crook, R. A.; Letton, Alan

    1993-01-01

    In the bulk, glassy polymers exhibit a nonlinear viscoelastic response during deformation. Stress or strain induced damage (i.e. crazing, microshear banding) results in the production of nonrecoverable work and observed nonlinearity. Stress or strain dependent shift factors have been used to mathematically model the mechanical behavior of these polymers. Glassy polymers that have been notched, may exhibit very different load displacement response compared to the same material under bulk deformation. If a sharp notch is introduced into the body then loaded, the load displacement trace may appear to be single-valued in the absence of viscoelasticity and crack growth. This suggests the volume of damaged material is small compared to the overall dimensions of the specimen. The ability to produce a single-valued load-load-line displacement trace through the use of the Correspondence Principle may prove to be useful for fracture of viscoelastic materials.

  12. Ectopic Premolar Tooth in the Sigmoid Notch.

    PubMed

    Törenek, K; Akgül, H M; Bayrakdar, I S

    2016-01-01

    Impaction of a mandibular premolar is relatively uncommon. Ectopic placement is more unusual and there has been no discussion in the literature of an ectopic mandibular premolar in the coronoid process. In this case report, we present an impacted ectopic mandibular permanent premolar in the sigmoid notch (incisura mandibulae) region. Etiology of the tooth and treatment options are discussed and illustrated by Cone Beam Computed Tomography (CBCT) images. PMID:27547475

  13. Ectopic Premolar Tooth in the Sigmoid Notch

    PubMed Central

    Akgül, H. M.; Bayrakdar, I. S.

    2016-01-01

    Impaction of a mandibular premolar is relatively uncommon. Ectopic placement is more unusual and there has been no discussion in the literature of an ectopic mandibular premolar in the coronoid process. In this case report, we present an impacted ectopic mandibular permanent premolar in the sigmoid notch (incisura mandibulae) region. Etiology of the tooth and treatment options are discussed and illustrated by Cone Beam Computed Tomography (CBCT) images. PMID:27547475

  14. Formation of strained ring-shaped islands around square notches.

    PubMed

    Colin, Jérôme

    2012-06-01

    The location and morphology of a two-dimensional island has been studied theoretically as a function of the misfit stress in the neighbourhood of a square notch present on the free surface of an epitaxially stressed film deposited on a substrate. From a static energy calculation, it has been shown that the notches can drive the motion of the islands towards the notches. It was then found that, depending on the side length and depth of the notch, self-organized formation at constant volume of a two-dimensional ring-shaped island can be favoured along the periphery of the pre-existing notch with respect to the notch shrinking. PMID:22565196

  15. Involvement of Notch signaling in early chick ovarian follicle development.

    PubMed

    Li, Jun; Zhao, Dan; Guo, Changquan; Li, Jian; Mi, Yuling; Zhang, Caiqiao

    2016-01-01

    The formation of primordial follicles is a crucial process in the establishment of follicle pools required for the female's reproductive life span. For laying hens, ample follicles are a prerequisite for high laying performance. Notch signaling plays critical roles in germ cell cysts breakdown and in the formation of primordial follicles. Here, we investigated the role of Notch signaling in the ovarian development of post-hatch chicks. Results showed that around post-hatch day 4 (H4), the germ cell cysts broke apart, oocytes became surrounded by squamous pregranulosa cells, and the primordial follicles were then formed. Subsequently, we detected the expression of Notch signaling-related genes including Notch receptors (Notch1, 2), ligands (Jag1, 2 and Dll1, 4), and target genes (Hes1, Hey1). These genes all showed expression at H4 and some of these genes were up-regulated during primordial follicle formation. To evaluate the Notch signaling requirement for early follicular development, we adopted an in vitro ovary culture system. Suppression of Notch signaling by γ-secretase inhibitor induced a decrease of primordial follicles and an increase of germ cells in cysts. Attenuating Notch signaling also inhibited the phosphatidylinositol 3-kinase/protein kinase B pathways and suppressed cadherin expression. These results suggest that Notch signaling is endowed with an indispensable role in primordial follicle formation in post-hatch chicks. PMID:26289531

  16. Non-Canonical Notch Signaling in Cancer and Immunity

    PubMed Central

    Ayaz, Furkan; Osborne, Barbara A.

    2014-01-01

    Canonical Notch signaling is initiated by γ-secretase-mediated cleavage of the Notch receptor, leading to the release of the active intra-cellular domain of Notch that migrates to the nucleus and interacts with RBP-Jκ, resulting in the activation of downstream target genes. While canonical Notch signaling is well known to play an active role in several steps during development as well in multiple cell fate decisions, recent evidence from both invertebrate and vertebrate systems indicates that non-canonical, RBP-Jκ-independent signaling is important in several cellular processes including oncogenesis and activation of T lymphocytes. These observations raise the possibility that, through an understanding of non-canonical Notch signaling, novel strategies for inhibiting Notch signaling may prove useful in the design of therapies targeted to block aberrant Notch activity. In this mini-review, we will examine the current data demonstrating a non-canonical role for Notch signaling in both cancer and the immune system and suggest a better understanding of non-canonical signaling may reveal novel strategies to block Notch signaling in disease. PMID:25538890

  17. Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia

    PubMed Central

    Ye, Qi; Jiang, Jue; Zhan, Guanqun; Yan, Wanyao; Huang, Liang; Hu, Yufeng; Su, Hexiu; Tong, Qingyi; Yue, Ming; Li, Hua; Yao, Guangmin; Zhang, Yonghui; Liu, Hudan

    2016-01-01

    Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML therapies. N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid that we previously isolated from Zephyranthes candida, exhibiting inhibitory activities in a variety of cancer cells, particularly those from AML. Here, we report NMHC not only selectively inhibits AML cell proliferation in vitro but also hampers tumor development in a human AML xenograft model. Genome-wide gene expression profiling reveals that NMHC activates the NOTCH signaling. Combination of NMHC and recombinant human NOTCH ligand DLL4 achieves a remarkable synergistic effect on NOTCH activation. Moreover, pre-inhibition of NOTCH by overexpression of dominant negative MAML alleviates NMHC-mediated cytotoxicity in AML. Further mechanistic analysis using structure-based molecular modeling as well as biochemical assays demonstrates that NMHC docks in the hydrophobic cavity within the NOTCH1 negative regulatory region (NRR), thus promoting NOTCH1 proteolytic cleavage. Our findings thus establish NMHC as a potential NOTCH agonist that holds great promises for future development as a novel agent beneficial to patients with AML. PMID:27211848

  18. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  19. Origin of anomalous inverse notch effect in bulk metallic glasses

    NASA Astrophysics Data System (ADS)

    Pan, J.; Zhou, H. F.; Wang, Z. T.; Li, Y.; Gao, H. J.

    2015-11-01

    Understanding notch-related failure is crucial for the design of reliable engineering structures. However, substantial controversies exist in the literature on the notch effect in bulk metallic glasses (BMGs), and the underlying physical mechanism responsible for the apparent confusion is still poorly understood. Here we investigate the physical origin of an inverse notch effect in a Zr-based metallic glass, where the tensile strength of the material is dramatically enhanced, rather than decreased (as expected from the stress concentration point of view), by introduction of a notch. Our experiments and molecular dynamics simulations show that the seemingly anomalous inverse notch effect is in fact caused by a transition in failure mechanism from shear banding at the notch tip to cavitation and void coalescence. Based on our theoretical analysis, the transition occurs as the stress triaxiality in the notched sample exceeds a material-dependent threshold value. Our results fill the gap in the current understanding of BMG strength and failure mechanism by resolving the conflicts on notch effects and may inspire re-interpretation of previous reports on BMG fracture toughness where pre-existing notches were routinely adopted.

  20. The potential role of impaired Notch signalling in atopic dermatitis.

    PubMed

    Melnik, Bodo C

    2015-01-01

    This review presents recent evidence of impaired Notch signalling in atopic dermatitis (AD), which is proposed to represent the "a-topic" defect linking both epidermal and immunological barrier dysfunctions in AD. AD epidermis exhibits a marked deficiency of Notch receptors. Mouse models with genetically suppressed Notch signalling exhibit dry skin, signs of scratching, skin barrier abnormalities, increased transepidermal water loss and TH2 cell-mediated immunological changes closely resembling human AD. Notch signals are critically involved in the differentiation of regulatory T cells, in the feedback inhibition of activated innate immunity, in late epidermal differentiation associated with filaggrin- and stratum corneum barrier lipid processing. Most importantly, Notch deficiency induces keratinocyte-mediated release of thymic stromal lymphopoietin (TSLP). TSLP promotes TH2 cell-driven immune responses associated with enhanced production of interleukin (IL)-4 and IL-31. Both TSLP and IL-31 stimulate sensory cutaneous neurons involved in the induction of itch. Notably, Notch1 is a repressor of activator protein-1 (AP-1), which is upregulated in AD epidermis. Without Notch-mediated suppression of AP-1 this transcription factor promotes excess expression of TH2 cell-related cytokines. Impaired Notch signalling negatively affects the homeostasis of aquaporin 3 and of the tight junction component claudin-1, thus explains disturbed skin barrier function with increased transepidermal water loss and Staphylococcus aureus colonisation as well as increased cutaneous susceptibility for viral infections. Thus, accumulating evidence links deficient Notch signalling to key pathological features of AD. PMID:24853951

  1. Notched strength of composite laminates: Predictions and experiments - A review

    NASA Technical Reports Server (NTRS)

    Awerbuch, J.; Madhukar, M. S.

    1985-01-01

    A self-contained review of several semiempirical fracture models for predicting notched strength of composite laminates is presented, based on notched strength data on 70 different laminate configurations of graphite/epoxy, boron/aluminum, and graphite/polyimide. Emphasis is placed on experimental results concerning such failure factors as delamination, splitting, and size of damage zone. Moreover, the fracture model parameters are correlated with the notch sensitivity of composite laminates, and the applicability of the correlations in describing the material notch sensitivity is evaluated. The predictions provided by the different models were found to be identical for all practical purposes.

  2. Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia.

    PubMed

    Ye, Qi; Jiang, Jue; Zhan, Guanqun; Yan, Wanyao; Huang, Liang; Hu, Yufeng; Su, Hexiu; Tong, Qingyi; Yue, Ming; Li, Hua; Yao, Guangmin; Zhang, Yonghui; Liu, Hudan

    2016-01-01

    Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML therapies. N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid that we previously isolated from Zephyranthes candida, exhibiting inhibitory activities in a variety of cancer cells, particularly those from AML. Here, we report NMHC not only selectively inhibits AML cell proliferation in vitro but also hampers tumor development in a human AML xenograft model. Genome-wide gene expression profiling reveals that NMHC activates the NOTCH signaling. Combination of NMHC and recombinant human NOTCH ligand DLL4 achieves a remarkable synergistic effect on NOTCH activation. Moreover, pre-inhibition of NOTCH by overexpression of dominant negative MAML alleviates NMHC-mediated cytotoxicity in AML. Further mechanistic analysis using structure-based molecular modeling as well as biochemical assays demonstrates that NMHC docks in the hydrophobic cavity within the NOTCH1 negative regulatory region (NRR), thus promoting NOTCH1 proteolytic cleavage. Our findings thus establish NMHC as a potential NOTCH agonist that holds great promises for future development as a novel agent beneficial to patients with AML. PMID:27211848

  3. Lattice gas and lattice Boltzmann computational physics

    SciTech Connect

    Chen, S.

    1993-05-01

    Recent developments of the lattice gas automata method and its extension to the lattice Boltzmann method have provided new computational schemes for solving a variety of partial differential equations and modeling different physics systems. The lattice gas method, regarded as the simplest microscopic and kinetic approach which generates meaningful macroscopic dynamics, is fully parallel and can be easily programmed on parallel machines. In this talk, the author will review basic principles of the lattice gas and lattice Boltzmann method, its mathematical foundation and its numerical implementation. A detailed comparison of the lattice Boltzmann method with the lattice gas technique and other traditional numerical schemes, including the finite-difference scheme and the pseudo-spectral method, for solving the Navier-Stokes hydrodynamic fluid flows, will be discussed. Recent achievements of the lattice gas and the the lattice Boltzmann method and their applications in surface phenomena, spinodal decomposition and pattern formation in chemical reaction-diffusion systems will be presented.

  4. Area of Lattice Polygons

    ERIC Educational Resources Information Center

    Scott, Paul

    2006-01-01

    A lattice is a (rectangular) grid of points, usually pictured as occurring at the intersections of two orthogonal sets of parallel, equally spaced lines. Polygons that have lattice points as vertices are called lattice polygons. It is clear that lattice polygons come in various shapes and sizes. A very small lattice triangle may cover just 3…

  5. Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2

    PubMed Central

    Gordon, Wendy R.; Vardar-Ulu, Didem; L'Heureux, Sarah; Ashworth, Todd; Malecki, Michael J.; Sanchez-Irizarry, Cheryll; McArthur, Debbie G.; Histen, Gavin; Mitchell, Jennifer L.; Aster, Jon C.; Blacklow, Stephen C.

    2009-01-01

    Background Notch receptors are normally cleaved during maturation by a furin-like protease at an extracellular site termed S1, creating a heterodimer of non-covalently associated subunits. The S1 site lies within a key negative regulatory region (NRR) of the receptor, which contains three highly conserved Lin12/Notch repeats and a heterodimerization domain (HD) that interact to prevent premature signaling in the absence of ligands. Because the role of S1 cleavage in Notch signaling remains unresolved, we investigated the effect of S1 cleavage on the structure, surface trafficking and ligand-mediated activation of human Notch1 and Notch2, as well as on ligand-independent activation of Notch1 by mutations found in human leukemia. Principal Findings The X-ray structure of the Notch1 NRR after furin cleavage shows little change when compared with that of an engineered Notch1 NRR lacking the S1-cleavage loop. Likewise, NMR studies of the Notch2 HD domain show that the loop containing the S1 site can be removed or cleaved without causing a substantial change in its structure. However, Notch1 and Notch2 receptors engineered to resist S1 cleavage exhibit unexpected differences in surface delivery and signaling competence: S1-resistant Notch1 receptors exhibit decreased, but detectable, surface expression and ligand-mediated receptor activation, whereas S1-resistant Notch2 receptors are fully competent for cell surface delivery and for activation by ligands. Variable dependence on S1 cleavage also extends to T-ALL-associated NRR mutations, as common class 1 mutations display variable decrements in ligand-independent activation when introduced into furin-resistant receptors, whereas a class 2 mutation exhibits increased signaling activity. Conclusions/Significance S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins. These findings are consistent with

  6. Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2

    SciTech Connect

    Gordon, Wendy R.; Vardar-Ulu, Didem; L'Heureux, Sarah; Ashworth, Todd; Malecki, Michael J.; Sanchez-Irizarry, Cheryll; McArthur, Debbie G.; Histen, Gavin; Mitchell, Jennifer L.; Aster, Jon C.; Blacklow, Stephen C.

    2009-09-25

    Notch receptors are normally cleaved during maturation by a furin-like protease at an extracellular site termed S1, creating a heterodimer of non-covalently associated subunits. The S1 site lies within a key negative regulatory region (NRR) of the receptor, which contains three highly conserved Lin12/Notch repeats and a heterodimerization domain (HD) that interact to prevent premature signaling in the absence of ligands. Because the role of S1 cleavage in Notch signaling remains unresolved, we investigated the effect of S1 cleavage on the structure, surface trafficking and ligand-mediated activation of human Notch1 and Notch2, as well as on ligand-independent activation of Notch1 by mutations found in human leukemia. The X-ray structure of the Notch1 NRR after furin cleavage shows little change when compared with that of an engineered Notch1 NRR lacking the S1-cleavage loop. Likewise, NMR studies of the Notch2 HD domain show that the loop containing the S1 site can be removed or cleaved without causing a substantial change in its structure. However, Notch1 and Notch2 receptors engineered to resist S1 cleavage exhibit unexpected differences in surface delivery and signaling competence: S1-resistant Notch1 receptors exhibit decreased, but detectable, surface expression and ligand-mediated receptor activation, whereas S1-resistant Notch2 receptors are fully competent for cell surface delivery and for activation by ligands. Variable dependence on S1 cleavage also extends to T-ALL-associated NRR mutations, as common class 1 mutations display variable decrements in ligand-independent activation when introduced into furin-resistant receptors, whereas a class 2 mutation exhibits increased signaling activity. S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins. These findings are consistent with models for receptor activation in which ligand-binding or

  7. Homozygous NOTCH3 null mutation and impaired NOTCH3 signaling in recessive early-onset arteriopathy and cavitating leukoencephalopathy

    PubMed Central

    Pippucci, Tommaso; Maresca, Alessandra; Magini, Pamela; Cenacchi, Giovanna; Donadio, Vincenzo; Palombo, Flavia; Papa, Valentina; Incensi, Alex; Gasparre, Giuseppe; Valentino, Maria Lucia; Preziuso, Carmela; Pisano, Annalinda; Ragno, Michele; Liguori, Rocco; Giordano, Carla; Tonon, Caterina; Lodi, Raffaele; Parmeggiani, Antonia; Carelli, Valerio; Seri, Marco

    2015-01-01

    Notch signaling is essential for vascular physiology. Neomorphic heterozygous mutations in NOTCH3, one of the four human NOTCH receptors, cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hypomorphic heterozygous alleles have been occasionally described in association with a spectrum of cerebrovascular phenotypes overlapping CADASIL, but their pathogenic potential is unclear. We describe a patient with childhood-onset arteriopathy, cavitating leukoencephalopathy with cerebral white matter abnormalities presented as diffuse cavitations, multiple lacunar infarctions and disseminated microbleeds. We identified a novel homozygous c.C2898A (p.C966*) null mutation in NOTCH3 abolishing NOTCH3 expression and causing NOTCH3 signaling impairment. NOTCH3 targets acting in the regulation of arterial tone (KCNA5) or expressed in the vasculature (CDH6) were downregulated. Patient's vessels were characterized by smooth muscle degeneration as in CADASIL, but without deposition of granular osmiophilic material (GOM), the CADASIL hallmark. The heterozygous parents displayed similar but less dramatic trends in decrease in the expression of NOTCH3 and its targets, as well as in vessel degeneration. This study suggests a functional link between NOTCH3 deficiency and pathogenesis of vascular leukoencephalopathies. PMID:25870235

  8. Notch Signaling in Inflammation-Induced Preterm Labor

    PubMed Central

    Jaiswal, Mukesh K.; Agrawal, Varkha; Pamarthy, Sahithi; Katara, Gajendra K.; Kulshrestha, Arpita; Gilman-Sachs, Alice; Beaman, Kenneth D.; Hirsch, Emmet

    2015-01-01

    Notch signaling plays an important role in regulation of innate immune responses and trophoblast function during pregnancy. To identify the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligands (DLL (Delta-like protein)-1/3/4), Jagged 1/2) and Notch-induced transcription factor Hes1 were assessed during preterm labor. Preterm labor was initiated on gestation day 14.5 by intrauterine (IU) injection of peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C). Notch1, Notch2, Notch4, DLL-1 and nuclear localization of Hes1 were significantly elevated in uterus and placenta during PGN+poly(I:C)-induced preterm labor. Ex vivo, Gamma secretase inhibitor (GSI) (inhibitor of Notch receptor processing) significantly diminished the PGN+poly(I:C)-induced secretion of M1- and M2-associated cytokines in decidual macrophages, and of proinflammatory cytokines (IFN-γ, TNF-α and IL-6) and chemokines (MIP-1β) in decidual and placental cells. Conversely, angiogenesis factors including Notch ligands Jagged 1/2 and DLL-4 and VEGF were significantly reduced in uterus and placenta during PGN+poly(I:C)-induced preterm labor. In vivo GSI treatment prevents PGN+poly(I:C)-induced preterm delivery by 55.5% and increased the number of live fetuses in-utero significantly compared to respective controls 48 hrs after injections. In summary, Notch signaling is activated during PGN+poly(I:C)-induced preterm labor, resulting in upregulation of pro-inflammatory responses, and its inhibition improves in-utero survival of live fetuses. PMID:26472156

  9. Notch Signaling in Inflammation-Induced Preterm Labor.

    PubMed

    Jaiswal, Mukesh K; Agrawal, Varkha; Pamarthy, Sahithi; Katara, Gajendra K; Kulshrestha, Arpita; Gilman-Sachs, Alice; Beaman, Kenneth D; Hirsch, Emmet

    2015-01-01

    Notch signaling plays an important role in regulation of innate immune responses and trophoblast function during pregnancy. To identify the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligands (DLL (Delta-like protein)-1/3/4), Jagged 1/2) and Notch-induced transcription factor Hes1 were assessed during preterm labor. Preterm labor was initiated on gestation day 14.5 by intrauterine (IU) injection of peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C). Notch1, Notch2, Notch4, DLL-1 and nuclear localization of Hes1 were significantly elevated in uterus and placenta during PGN+poly(I:C)-induced preterm labor. Ex vivo, Gamma secretase inhibitor (GSI) (inhibitor of Notch receptor processing) significantly diminished the PGN+poly(I:C)-induced secretion of M1- and M2-associated cytokines in decidual macrophages, and of proinflammatory cytokines (IFN-γ, TNF-α and IL-6) and chemokines (MIP-1β) in decidual and placental cells. Conversely, angiogenesis factors including Notch ligands Jagged 1/2 and DLL-4 and VEGF were significantly reduced in uterus and placenta during PGN+poly(I:C)-induced preterm labor. In vivo GSI treatment prevents PGN+poly(I:C)-induced preterm delivery by 55.5% and increased the number of live fetuses in-utero significantly compared to respective controls 48 hrs after injections. In summary, Notch signaling is activated during PGN+poly(I:C)-induced preterm labor, resulting in upregulation of pro-inflammatory responses, and its inhibition improves in-utero survival of live fetuses. PMID:26472156

  10. Notch signaling promotes airway mucous metaplasia and inhibits alveolar development.

    PubMed

    Guseh, J Sawalla; Bores, Sam A; Stanger, Ben Z; Zhou, Qiao; Anderson, William J; Melton, Douglas A; Rajagopal, Jayaraj

    2009-05-01

    The airways are conduits that transport atmospheric oxygen to the distal alveolus. Normally, airway mucous cells are rare. However, diseases of the airway are often characterized by mucous metaplasia, in which there are dramatic increases in mucous cell numbers. As the Notch pathway is known to regulate cell fate in many contexts, we misexpressed the active intracellular domain of the mouse Notch1 receptor in lung epithelium. Notch misexpression resulted in an increase in mucous cells and a decrease in ciliated cells in the airway. Similarly, mouse embryonic tracheal explants and adult human airway epithelium treated with Notch agonists displayed increased mucous cell numbers and decreased ciliated cell numbers. Notch antagonists had the opposite effect. Notably, Notch antagonists blocked IL13-induced mucous metaplasia. IL13 has a well-established role as an inflammatory mediator of mucous metaplasia and functions through Stat6-mediated gene transcription. We found that Notch ligands, however, are able to cause mucous metaplasia in Stat6-null cultured trachea, thus identifying a novel pathway that stimulates mucous metaplasia. Notch signaling may therefore play an important role in airway disease and, by extension, Notch antagonists may have therapeutic value. Conversely, in the distal lung, Notch misexpression prevented the differentiation of alveolar cell types. Instead, the distal lung formed cysts composed of cells that were devoid of alveolar markers but that expressed some, but not all, markers of proximal airway epithelium. Occasional distal cystic cells appeared to differentiate into normal proximal airway cells, suggesting that ectopic Notch signaling arrests the normal differentiation of distal lung progenitors before they initiate an alveolar program. PMID:19369400

  11. Mechanics of dynamic fracture in notched polycarbonate

    NASA Astrophysics Data System (ADS)

    Faye, Anshul; Parmeswaran, Venkitanarayanan; Basu, Sumit

    2015-04-01

    Fracture toughness of brittle amorphous polymers (e.g. polymethyl methacrylate (PMMA)) has been reported to decrease with loading rate at moderate rates and increase abruptly thereafter to close to 5 times the static value at very high loading rates. Dynamic fracture toughness that is much higher than the static values has attractive technological possibilities. However, the reasons for the sharp increase remain unclear. Motivated by these observations, the present work focuses on the dynamic fracture behavior of polycarbonate (PC), which is also an amorphous polymer but unlike PMMA, is ductile at room temperature. Towards this end, a combined experimental and numerical approach is adopted. Dynamic fracture experiments at various loading rates are conducted on single edge notched (SEN) specimens with a notch of radius 150 μm, using a Hopkinson bar setup equipped with ultra high-speed imaging (>105 fps) for real-time observation of dynamic processes during fracture. Concurrently, 3D dynamic finite element simulations are performed using a well calibrated material model for PC. Experimentally, we were able to clearly capture the intricate details of the process, for both slowly and dynamically loaded samples, of damage nucleation and growth ahead of the notch tip followed by unstable crack propagation. These observations coupled with fractography and computer simulations led us to conclude that in PC, the fracture toughness remains invariant with loading rate at Jfrac = 12 ± 3 kN / m for the entire range of loading rates (J ˙) from static to 1 ×106 kN / m - s. However, the damage initiation toughness is significantly higher in dynamic loading compared to static situations. In dynamic situations, damage nucleation is quickly followed by initiation of radial crazes from around the void periphery that initiate and quickly bridge the ligament between the initial damaged region and the notch. Thus for PC, two criteria for two major stages in the failure process emerge

  12. Coronagraphic Notch Filter for Raman Spectroscopy

    NASA Technical Reports Server (NTRS)

    Cohen, David; Stirbl, Robert

    2004-01-01

    A modified coronagraph has been proposed as a prototype of improved notch filters in Raman spectrometers. Coronagraphic notch filters could offer alternatives to both (1) the large and expensive double or triple monochromators in older Raman spectrometers and (2) holographic notch filters, which are less expensive but are subject to environmental degradation as well as to limitations of geometry and spectral range. Measurement of a Raman spectrum is an exercise in measuring and resolving faint spectral lines close to a bright peak: In Raman spectroscopy, a monochromatic beam of light (the pump beam) excites a sample of material that one seeks to analyze. The pump beam generates a small flux of scattered light at wavelengths slightly greater than that of the pump beam. The shift in wavelength of the scattered light from the pump wavelength is known in the art as the Stokes shift. Typically, the flux of scattered light is of the order of 10 7 that of the pump beam and the Stokes shift lies in the wave-number range of 100 to 3,000 cm 1. A notch filter can be used to suppress the pump-beam spectral peak while passing the nearby faint Raman spectral lines. The basic principles of design and operation of a coronagraph offer an opportunity for engineering the spectral transmittance of the optics in a Raman spectrometer. A classical coronagraph may be understood as two imaging systems placed end to end, such that the first system forms an intermediate real image of a nominally infinitely distant object and the second system forms a final real image of the intermediate real image. If the light incident on the first telescope is collimated, then the intermediate image is a point-spread function (PSF). If an appropriately tailored occulting spot (e.g., a Gaussian-apodized spot with maximum absorption on axis) is placed on the intermediate image plane, then the instrument inhibits transmission of light from an on-axis source. However, the PSFs of off-axis light sources are

  13. The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage

    PubMed Central

    Surendran, Kameswaran; Boyle, Scott; Barak, Hila; Kim, Mijin; Stromberski, Colin; McCright, Brent; Kopan, Raphael

    2009-01-01

    We previously determined that Notch2, and not Notch1 was required for forming proximal nephron segments. The dominance of Notch2 may be conserved in humans, since Notch2 mutations occur in Alagille syndrome (ALGS) 2 patients, which includes renal complications. To test whether mutations in Notch1 could increase the severity of renal complications in ALGS, we inactivated conditional Notch1 and Notch2 alleles in mice using a Six2-GFP∷Cre. This BAC transgene is expressed mosaically in renal epithelial progenitors but uniformly in cells exiting the progenitor pool to undergo mesenchymal to epithelial transition. Although delaying Notch2 inactivation had a marginal effect on nephron numbers, it created a sensitized background in which the inactivation of Notch1 severely compromised nephron formation, function and survival. These and additional observations indicate that Notch1 in concert with Notch2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBP-J dependent manner. A significant implication is that elevating Notch1 activity could improve renal functions in ALGS2 patients. As proof of principle, we determined that conditional inactivation of Mint, an inhibitor of Notch-RBP-J interaction, resulted in a moderate rescue of Notch2 null kidneys, implying that temporal blockage of Notch signaling inhibitors downstream of receptor activation may have therapeutic benefits for ALGS patients. PMID:19914235

  14. Notch Signaling Activation in Pediatric Low-Grade Astrocytoma

    PubMed Central

    Brandt, William D.; Schreck, Karisa C.; Bar, Eli E.; Taylor, Isabella; Marchionni, Luigi; Raabe, Eric; Eberhart, Charles G.; Rodriguez, Fausto J.

    2014-01-01

    Pilocytic astrocytoma (PA) is the most common primary brain tumor in children; various signaling pathways have been implicated in its biology. The Notch signaling pathway has been found to play a role in development, stem cell biology, and the pathogenesis of several cancers but its role in PA has not been investigated. We studied alterations in Notch signaling components in tumor tissue from 18 patients with PA and 4 with other low-grade astrocytomas to identify much needed therapeutic targets. We found that Notch pathway members were overexpressed at the mRNA (NOTCH1, NOTCH2, HEY1, HEY2) and protein (HES1) levels in PAs at various anatomical sites compared to non-neoplastic brain samples. These changes were not associated with specific BRAF alterations. Inhibiting the Notch pathway in the pediatric low-grade astrocytoma cell lines Res 186 and Res 259 using either RNA interference or a γ-secretase inhibitor resulted in variable but significant reduction in cell growth and migration. This study suggests a potential role for Notch signaling in pediatric low-grade astrocytoma tumorigenesis and that Notch signaling may be a viable pathway therapeutic target. PMID:25575134

  15. Notch signaling activation in pediatric low-grade astrocytoma.

    PubMed

    Brandt, William D; Schreck, Karisa C; Bar, Eli E; Taylor, Isabella; Marchionni, Luigi; Raabe, Eric; Eberhart, Charles G; Rodriguez, Fausto J

    2015-02-01

    Pilocytic astrocytoma (PA) is the most common primary brain tumor in children; various signaling pathways have been implicated in its biology. The Notch signaling pathway has been found to play a role in the development, stem cell biology, and pathogenesis of several cancers, but its role in PA has not been investigated. We studied alterations in Notch signaling components in tumor tissue from 18 patients with PA and 4 with other low-grade astrocytomas to identify much needed therapeutic targets. We found that Notch pathway members were overexpressed at the mRNA (NOTCH1, NOTCH2, HEY1, HEY2) and protein (HES1) levels in PAs at various anatomic sites compared with non-neoplastic brain samples. These changes were not associated with specific BRAF alterations. Inhibiting the Notch pathway in the pediatric low-grade astrocytoma cell lines Res186 and Res259 using either RNA interference or a γ-secretase inhibitor resulted in variable, but significant, reduction in cell growth and migration. This study suggests a potential role for Notch signaling in pediatric low-grade astrocytoma tumorigenesis and that Notch signaling may be a viable pathway therapeutic target. PMID:25575134

  16. Notch signaling contributes to the pathogenesis of human osteosarcomas

    PubMed Central

    Engin, Feyza; Bertin, Terry; Ma, Ou; Jiang, Ming Ming; Wang, Lisa; Sutton, Richard E.; Donehower, Lawrence A.; Lee, Brendan

    2009-01-01

    Notch signaling plays an important role in developmental processes and adult tissue homeostasis. Altered Notch signaling has been associated with various diseases including cancer. While the importance of altered Notch signaling in cancers of hematopoietic and epithelial origins has been established, its role in tumors of mesenchymal origin is less clear. Here, we report that human osteosarcoma cell lines and primary human osteosarcoma tumor samples show significant up-regulation of Notch, its target genes and Osterix. Notch inhibition by γ-secretase inhibitors or by using lentiviral mediated expression of dominant negative Mastermind-like protein (DN-MAML) decreases osteosarcoma cell proliferation in vitro. In vivo, established human tumor xenografts in nude mice show decreased tumor growth after chemical or genetic inhibition of Notch signaling. Finally, transcriptional profiling of osteosarcomas from p53 mutant mice confirmed up-regulation of Notch1 target genes Hes1, Hey1 and its ligand Dll4. Our data suggest that activation of Notch signaling contributes to the pathogenesis of human osteosarcomas and its inhibition may be a therapeutic approach for the treatment of this mesenchymal tumor. PMID:19228774

  17. The Origin and Evolution of Deep Plasmaspheric Notches

    NASA Technical Reports Server (NTRS)

    Gallagher, D. L.; Adrian, M. L.; Liemohn, M.

    2004-01-01

    Deep plasmaspheric notches can extend over more than 2 RE in radial distance and 3 hours MLT in the magnetic equatorial plane. They appear to be among the largest evacuated features in the exterior plasmaspheric boundary. They can last for days and exhibit varying structure. It appears that low-density channels resulting from the entrainment of the plasmaspheric convection plume during storm-time recovery share the same origin as notches. Notches rather than channels result from differences in storm- time conditions. Strong convection tends to result in low-density channels, while weaker convection and limited erosion results in notches. Eighteen events in 2000 have been analyzed. Among these events, notches were found to drift as slowly as 72% of corotation. In only one case was a notch found to drift at the corotation rate within measurement error. On average, notches drift at about 2 1.5 hours per day or 90% of the co-rotational rate. Notches also sometimes exhibit an interior structure that appears as an extended prominence of dense plasma, which forms a W-like feature in IMAGEEUV images when viewed from Earth-center. Modeling suggests such features may be caused by small-scale potential structures that result from the localized injection of ring current plasma. Plasma filling rates during recovery and drainage during a minor storm are reported.

  18. The Notch ligand delta-1 is a hematopoietic development cofactor for plasmacytoid dendritic cells.

    PubMed

    Olivier, Aurélie; Lauret, Evelyne; Gonin, Patrick; Galy, Anne

    2006-04-01

    Plasmacytoid dendritic cells (pDCs) play an important role in innate and adaptive immunity, prompting interest in mechanisms controlling the production of this lineage of cells. Notch signaling via one of the Notch ligands, delta-like 1 (delta-1), influences the hematopoietic development of several lymphoid and myeloid lineages, but whether or not delta-1 affects the formation of pDCs is unknown and was tested here. Human CD34+ progenitor cells were cultured onto delta-1-expressing OP9 stroma in the presence of flt-3 ligand and IL-7, and this efficiently generated BDCA-2+ CD123+ CD4+ CD11c- cells with the characteristic morphology of pDCs, expressing toll-like receptor-9 (TLR9), pre-Talpha mRNAs, and secreting CpG-induced IFN-alpha. Delta-1 augmented the numbers of BDCA-2+ cells produced without affecting their proliferation, and the effect was blocked by gamma-secretase inhibition. The development of pDCs was stroma-, delta-1-, and cytokine-dependent and could be induced from committed lymphoid progenitor cells, which responded to delta-1 by opposite changes in pDC- and B-cell production. Our results identify delta-1 as a novel factor enhancing pDC hematopoiesis and delineate a new role for Notch signaling in lymphopoiesis by showing its opposite effect on pDC and B lineage determination. PMID:16357328

  19. Notch in the intestine: regulation of homeostasis and pathogenesis.

    PubMed

    Noah, Taeko K; Shroyer, Noah F

    2013-01-01

    The small and large intestines are tubular organs composed of several tissue types. The columnar epithelium that lines the inner surface of the intestines distinguishes the digestive physiology of each region of the intestine and consists of several distinct cell types that are rapidly and continually renewed by intestinal stem cells that reside near the base of the crypts of Lieberkühn. Notch signaling controls the fate of intestinal stem cells by regulating the expression of Hes genes and by repressing Atoh1. Alternate models of Notch pathway control of cell fate determination are presented. Roles for Notch signaling in development of the intestine, including mesenchymal and neural cells, are discussed. The oncogenic activities of Notch in colorectal cancer, as well as the tumor suppressive activities of Atoh1, are reviewed. Therapeutic targeting of the Notch pathway in colorectal cancers is discussed, along with potential caveats. PMID:23190077

  20. Oncogenic role of the Notch pathway in primary liver cancer

    PubMed Central

    LU, JIE; XIA, YUJING; CHEN, KAN; ZHENG, YUANYUAN; WANG, JIANRONG; LU, WENXIA; YIN, QIN; WANG, FAN; ZHOU, YINGQUN; GUO, CHUANYONG

    2016-01-01

    Primary liver cancer, which includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and fibrolamellar HCC, is one of the most common malignancies and the third leading cause of cancer-associated mortality, worldwide. Despite the development of novel therapies, the prognosis of liver cancer patients remains extremely poor. Thus, investigation of the genetic background and molecular mechanisms underlying the development and progression of this disease has gained significant attention. The Notch signaling pathway is a crucial determinant of cell fate during development and disease in several organs. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis, and is also significant in the development of HCC and ICC. These findings suggest that the modulation of Notch pathway activity may have therapeutic relevance. The present review summarizes Notch signaling during HCC and ICC development and discusses the findings of recent studies regarding Notch expression, which reveal novel insights into its function in liver cancer progression. PMID:27347091

  1. Luminance measurement to evaluate the damage of notched FRP plates in static load

    SciTech Connect

    Hyakutake, H.; Yamamoto, T.

    1995-11-01

    The validity of the damage criterion for notched FRP plates based on the concept of severity near the notch root is subjected to further experimental scrutiny. An experimental program is presented which examines the effect of notch geometry on the damage near the notch root of FRP plates. This is accomplished by obtaining experimental data on the notched specimens of a glass cloth/epoxy laminate for a wide range of notch geometries in tension and bending. The process of initiation and growth of damage near the notch root was measured by means of the luminance measurement technique with a CCD camera. The experiment shows that the growth of damage zone near the notch root was governed predominantly by both the notch-root radius and the maximum elastic stress at the notch root, while it was independent of notch depth and type of loading. On the basis of the concept of severity, the experimental results can be clearly elucidated.

  2. Role of Notch signaling during lipopolysaccharide-induced preterm labor.

    PubMed

    Agrawal, Varkha; Jaiswal, Mukesh K; Pamarthy, Sahithi; Katara, Gajendra K; Kulshrestha, Arpita; Gilman-Sachs, Alice; Hirsch, Emmet; Beaman, Kenneth D

    2016-08-01

    Notch signaling pathways exert effects throughout pregnancy and are activated in response to TLR ligands. To investigate the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligand Delta-like protein-1, transcriptional repressor hairy and enhancer of split-1, and Notch deregulator Numb were assessed. Preterm labor was initiated on gestation d 14.5 by 1 of 2 methods: 1) inflammation-induced preterm labor: intrauterine injection of LPS (a TLR4 agonist) and 2) hormonally induced preterm labor: subcutaneous injection of mifepristone. Delta-like protein-1, Notch1, and hairy and enhancer of split-1 were elevated significantly, and Numb was decreased in the uterus and placenta of inflammation-induced preterm labor mice but remained unchanged in hormonally induced preterm labor compared with their respective controls. F4/80(+) macrophage polarization was skewed in the uterus of inflammation-induced preterm labor toward M1-positive (CD11c(+)) and double-positive [CD11c(+) (M1) and CD206(+) (M2)] cells. This process is dependent on activation of Notch signaling, as shown by suppression of M1 and M2 macrophage-associated cytokines in decidual macrophages in response to γ-secretase inhibitor (an inhibitor of Notch receptor processing) treatment ex vivo. γ-Secretase inhibitor treatment also diminished the LPS-induced secretion of proinflammatory cytokines and chemokines in decidual and placental cells cultured ex vivo. Furthermore, treatment with recombinant Delta-like protein-1 ligand enhanced the LPS-induced proinflammatory response. Notch ligands (Jagged 1 and 2 and Delta-like protein-4) and vascular endothelial growth factor and its receptor involved in angiogenesis were reduced significantly in the uterus and placenta during inflammation-induced preterm labor. These results suggest that up-regulation of Notch-related inflammation and down-regulation of angiogenesis factors may be associated with inflammation-induced preterm labor but not with

  3. Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry

    PubMed Central

    Kluk, Michael J.; Ashworth, Todd; Wang, Hongfang; Knoechel, Birgit; Mason, Emily F.; Morgan, Elizabeth A.; Dorfman, David; Pinkus, Geraldine; Weigert, Oliver; Hornick, Jason L.; Chirieac, Lucian R.; Hirsch, Michelle; Oh, David J.; South, Andrew P.; Leigh, Irene M.; Pourreyron, Celine; Cassidy, Andrew J.; DeAngelo, Daniel J.; Weinstock, David M.; Krop, Ian E.; Dillon, Deborah; Brock, Jane E.; Lazar, Alexander J. F.; Peto, Myron; Cho, Raymond J.; Stoeck, Alexander; Haines, Brian B.; Sathayanrayanan, Sriram; Rodig, Scott; Aster, Jon C.

    2013-01-01

    Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical

  4. Association of transcription factor YY1 with the high molecular weight Notch complex suppresses the transactivation activity of Notch.

    PubMed

    Yeh, Tien-Shun; Lin, Yu-Min; Hsieh, Rong-Hong; Tseng, Min-Jen

    2003-10-24

    Notch receptors are evolutionarily conserved from Drosophila to human and play important roles in cell fate decisions. After ligand binding, Notch receptors are cleaved to release their intracellular domains. The intracellular domains, the activated form of Notch receptors, are then translocated into the nucleus where they interact with other transcriptional machinery to regulate the expression of cellular genes. To dissect the molecular mechanisms of Notch signaling, the cellular targets that interact with Notch1 receptor intracellular domain (N1IC) were screened. In this study, we found that endogenous transcription factor Ying Yang 1 (YY1) was associated with exogenous N1IC in human K562 erythroleukemic cells. The ankyrin (ANK) domain of N1IC and zinc finger domains of YY1 were essential for the association of N1IC and YY1 according to the pull-down assay of glutathione S-transferase fusion proteins. Furthermore, both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling. The transcription factor YY1 indirectly regulated the transcriptional activity of the wild-type CBF1-response elements via the direct interaction of N1IC and CBF1. We also demonstrated the association between endogenous N1IC and intrinsic YY1 in human acute T-cell lymphoblastic leukemia cell lines. Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex. PMID:12913000

  5. Application of equalization notch to improve synthetic aperture radar coherent data products

    NASA Astrophysics Data System (ADS)

    Musgrove, Cameron; West, James C.

    2015-05-01

    Interference and interference mitigation techniques degrade synthetic aperture radar (SAR) coherent data products. Radars utilizing stretch processing present a unique challenge for many mitigation techniques because the interference signal itself is modified through stretch processing from its original signal characteristics. Many sources of interference, including constant tones, are only present within the fast-time sample data for a limited number of samples, depending on the radar and interference bandwidth. Adaptive filtering algorithms to estimate and remove the interference signal that rely upon assuming stationary interference signal characteristics can be ineffective. An effective mitigation method, called notching, forces the value of the data samples containing interference to zero. However, as the number of data samples set to zero increases, image distortion and loss of resolution degrade both the image product and any second order image products. Techniques to repair image distortions,1 are effective for point-like targets. However, these techniques are not designed to model and repair distortions in SAR image terrain. Good terrain coherence is important for SAR second order image products because terrain occupies the majority of many scenes. For the case of coherent change detection it is the terrain coherence itself that determines the quality of the change detection image. This paper proposes an unique equalization technique that improves coherence over existing notching techniques. First, the proposed algorithm limits mitigation to only the samples containing interference, unlike adaptive filtering algorithms, so the remaining samples are not modified. Additionally, the mitigation adapts to changing interference power such that the resulting correction equalizes the power across the data samples. The result is reduced distortion and improved coherence for the terrain. SAR data demonstrates improved coherence from the proposed equalization

  6. Differential effects of targeting Notch receptors in a mouse model of liver cancer

    PubMed Central

    Huntzicker, Erik G.; Hötzel, Kathy; Choy, Lisa; Che, Li; Ross, Jed; Pau, Gregoire; Sharma, Neeraj; Siebel, Christian W.; Chen, Xin; French, Dorothy M.

    2015-01-01

    Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The Notch signaling pathway, known to be important for the proper development of liver architecture, is also a potential driver of primary liver cancer. However, with four known Notch receptors and several Notch ligands, it is not clear which Notch pathway members play the predominant role in liver cancer. To address this question we utilized antibodies to specifically target Notch1, Notch2, Notch3 or Jag1 in a mouse model of primary liver cancer driven by AKT and NRas. We show that inhibition of Notch2 reduces tumor burden by eliminating highly malignant hepatocellular carcinoma- and cholangiocarcinoma-like tumors. Inhibition of the Notch ligand Jag 1 had a similar effect, consistent with Jag1 acting in cooperation with Notch2. This effect was specific to Notch2, as Notch3 inhibition did not decrease tumor burden. Unexpectedly, Notch1 inhibition altered the relative proportion of tumor types, reducing HCC-like tumors but dramatically increasing CC-like tumors. Finally, we show that Notch2 and Jag1 are expressed in, and Notch2 signaling is activated in, a subset of human HCC samples. Conclusions: These findings underscore the distinct roles of different Notch receptors in the liver and suggest that inhibition of Notch2 signaling represents a novel therapeutic option in the treatment of liver cancer. PMID:25311838

  7. Dual Roles of O-Glucose Glycans Redundant with Monosaccharide O-Fucose on Notch in Notch Trafficking.

    PubMed

    Matsumoto, Kenjiroo; Ayukawa, Tomonori; Ishio, Akira; Sasamura, Takeshi; Yamakawa, Tomoko; Matsuno, Kenji

    2016-06-24

    Notch is a transmembrane receptor that mediates cell-cell interactions and controls various cell-fate specifications in metazoans. The extracellular domain of Notch contains multiple epidermal growth factor (EGF)-like repeats. At least five different glycans are found in distinct sites within these EGF-like repeats. The function of these individual glycans in Notch signaling has been investigated, primarily by disrupting their individual glycosyltransferases. However, we are just beginning to understand the potential functional interactions between these glycans. Monosaccharide O-fucose and O-glucose trisaccharide (O-glucose-xylose-xylose) are added to many of the Notch EGF-like repeats. In Drosophila, Shams adds a xylose specifically to the monosaccharide O-glucose. We found that loss of the terminal dixylose of O-glucose-linked saccharides had little effect on Notch signaling. However, our analyses of double mutants of shams and other genes required for glycan modifications revealed that both the monosaccharide O-glucose and the terminal dixylose of O-glucose-linked saccharides function redundantly with the monosaccharide O-fucose in Notch activation and trafficking. The terminal dixylose of O-glucose-linked saccharides and the monosaccharide O-glucose were required in distinct Notch trafficking processes: Notch transport from the apical plasma membrane to adherens junctions, and Notch export from the endoplasmic reticulum, respectively. Therefore, the monosaccharide O-glucose and terminal dixylose of O-glucose-linked saccharides have distinct activities in Notch trafficking, although a loss of these activities is compensated for by the presence of monosaccharide O-fucose. Given that various glycans attached to a protein motif may have redundant functions, our results suggest that these potential redundancies may lead to a serious underestimation of glycan functions. PMID:27129198

  8. Notch signaling promotes osteoclast maturation and resorptive activity.

    PubMed

    Ashley, Jason W; Ahn, Jaimo; Hankenson, Kurt D

    2015-11-01

    The role of Notch signaling in osteoclast differentiation is controversial with conflicting experimental evidence indicating both stimulatory and inhibitory roles. Differences in experimental protocols and in vivo versus in vitro models may explain the discrepancies between studies. In this study, we investigated cell autonomous roles of Notch signaling in osteoclast differentiation and function by altering Notch signaling during osteoclast differentiation using stimulation with immobilized ligands Jagged1 or Delta-like1 or by suppression with γ-secretase inhibitor DAPT or transcriptional inhibitor SAHM1. Stimulation of Notch signaling in committed osteoclast precursors resulted in larger osteoclasts with a greater number of nuclei and resorptive activity whereas suppression resulted in smaller osteoclasts with fewer nuclei and suppressed resorptive activity. Conversely, stimulation of Notch signaling in osteoclast precursors prior to induction of osteoclastogenesis resulted in fewer osteoclasts. Our data support a mechanism of context-specific Notch signaling effects wherein Notch stimulation inhibits commitment to osteoclast differentiation, but enhances the maturation and function of committed precursors. PMID:25914241

  9. SEPT4 is regulated by the Notch signaling pathway.

    PubMed

    Liu, Wenbin

    2012-04-01

    Notch receptor-mediated signaling is an evolutionarily conserved pathway that regulates diverse developmental processes and its dysregulation has been implicated in a variety of developmental disorders and cancers. Notch functions in these processes by activating expression of its target genes. Septin 4 (SEPT4) is a polymerizing GTP-binding protein that serves as scaffold for diverse molecules and is involved in cell proliferation and apoptosis. After activation of the Notch signal, the expression of SEPT4 is up-regulated and cell proliferation is inhibited. When the Notch signal is inhibited by the CSL (CBF1/Su(H)/Lag-1)-binding-domain-negative Mastermind-like protein 1, the expression of SEPT4 is down-regulated, proliferation and colony formation of cells are promoted, but cell adhesion ability is decreased. Nevertheless, the SEPT4 expression is not affected after knock-down of CSL. Meanwhile, if SEPT4 activity is inhibited through RNA interference, the protein level and activity of NOTCH1 remains unchanged, but cell proliferation is dysregulated. This indicates that SEPT4 is a Notch target gene. This relationship between Notch signaling pathway and SEPT4 offers a potential basis for further study of developmental control and carcinogenesis. PMID:21938432

  10. Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer

    PubMed Central

    Baker, Andrew T.; Zlobin, Andrei; Osipo, Clodia

    2014-01-01

    The Notch pathway is a well-established mediator of cell–cell communication that plays a critical role in stem cell survival, self-renewal, cell fate decisions, tumorigenesis, invasion, metastasis, and drug resistance in a variety of cancers. An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family, which consists of HER-1, -2, -3, and -4. Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease. Continued assessment of interplay between these two critical signaling networks uncovers new insight into mechanisms used by HER-driven cancer cells to exploit Notch as a compensatory pathway. The compensatory Notch pathway maintains HER-induced downstream signals transmitted to pathways such as Mitogen Activated Protein Kinase and Phosphatidylinositol 3-Kinase (PI3K), thereby allowing cancer cells to survive molecular targeted therapies, undergo epithelial to mesenchymal transitioning, and increase cellular invasion. Uncovering the critical crosstalk between the HER and Notch pathways can lead to improved screening for the expression of these oncogenes enabling patients to optimize their personal treatment options and predict potential treatment resistance. This review will focus on the current state of crosstalk between the HER and Notch receptors and the effectiveness of current therapies targeting HER-driven cancers. PMID:25566499

  11. Stability and performance of notch filter control for unbalance response

    NASA Technical Reports Server (NTRS)

    Knospe, C. R.

    1992-01-01

    Many current applications of magnetic bearings for rotating machinery employ notch filters in the feedback control loop to reduce the synchronous forces transmitted through the bearings. The capabilities and limitations of notch filter control are investigated. First, a rigid rotor is examined with some classical root locus techniques. Notch filter control is shown to result in conditional stability whenever complete synchronous attenuation is required. Next, a nondimensional parametric symmetric flexible three mass rotor model is constructed. An examination of this model for several test cases illustrates the limited attenuation possible with notch filters at and near the system critical speeds when the bearing damping is low. The notch filter's alteration of the feedback loop is shown to cause stability problems which limits performance. Poor transient response may also result. A high speed compressor is then examined as a candidate for notch filter control. A collocated 22 mass station model with lead-lag control is used. The analysis confirms the reduction in stability robustness that can occur with notch filter control. It is concluded that other methods of synchronous vibration control yield greater performance without compromising stability.

  12. Notch signaling in hematopoietic cell transplantation and T cell alloimmunity

    PubMed Central

    Ebens, Christen; Maillard, Ivan

    2013-01-01

    Notch signaling can regulate both hematopoietic progenitors and alloimmune T cells in the setting of allogeneic bone marrow or hematopoietic cell transplantation (allo-HCT). Ex vivo culture of multipotent blood progenitors with immobilized Delta-like ligands induces supraphysiological Notch signals and can markedly enhance progenitor expansion. Infusion of Notch-expanded progenitors shortened myelosuppression in preclinical and early clinical studies, while accelerating T cell reconstitution in preclinical models. Notch also plays an essential role in vivo to regulate pathogenic alloimmune T cells that mediate graft-versus-host disease (GVHD), the most severe complication of allo-HCT. In mouse allo-HCT models, Notch inhibition in donor-derived T cells or transient blockade of Delta-like ligands after transplantation profoundly decreased GVHD incidence and severity, without causing global immunosuppression. These findings identify Notch in T cells as an attractive therapeutic target to control GVHD. In this review, we discuss these contrasting functions of Notch signaling with high translational significance in allo-HCT patients. PMID:24050990

  13. Tunable high-q superconducting notch filter

    DOEpatents

    Pang, C.S.; Falco, C.M.; Kampwirth, R.T.; Schuller, I.K.

    1979-11-29

    A superconducting notch filter is made of three substrates disposed in a cryogenic environment. A superconducting material is disposed on one substrate in a pattern of a circle and an annular ring connected together. The second substrate has a corresponding pattern to form a parallel plate capacitor and the second substrate has the circle and annular ring connected by a superconducting spiral that forms an inductor. The third substrate has a superconducting spiral that is placed parallel to the first superconducting spiral to form a transformer. Relative motion of the first substrate with respect to the second is effected from outside the cryogenic environment to vary the capacitance and hence the frequency of the resonant circuit formed by the superconducting devices.

  14. Infraspinatus paralysis due to spinoglenoid notch ganglion.

    PubMed

    Skirving, A P; Kozak, T K; Davis, S J

    1994-07-01

    We describe five patients, seen since 1984, with posterior shoulder pain and isolated wasting and weakness of the infraspinatus. In four of these a ganglion in the spinoglenoid notch was demonstrated by MRI and in one recent case ultrasound scans were positive. Three patients have been treated by operation, but there was recurrence in one after five years. In each confirmed case, the ganglion straddled the base of the spine of the scapula, extending into both supraspinatus and infraspinatus fossae. The nerve was either compressed against the spine or stretched over the posterior aspect of the ganglion. Adequate surgical exposure is essential to preserve the nerve to the infraspinatus and to allow complete removal of the ganglion. This is difficult because of the location and thin-walled nature of the cysts. PMID:8027146

  15. Cyclosporin A Disrupts Notch Signaling and Vascular Lumen Maintenance

    PubMed Central

    Pandey, Raghav; Botros, Mark A.; Nacev, Benjamin A.; Albig, Allan R.

    2015-01-01

    Cyclosporin A (CSA) suppresses immune function by blocking the cyclophilin A and calcineurin/NFAT signaling pathways. In addition to immunosuppression, CSA has also been shown to have a wide range of effects in the cardiovascular system including disruption of heart valve development, smooth muscle cell proliferation, and angiogenesis inhibition. Circumstantial evidence has suggested that CSA might control Notch signaling which is also a potent regulator of cardiovascular function. Therefore, the goal of this project was to determine if CSA controls Notch and to dissect the molecular mechanism(s) by which CSA impacts cardiovascular homeostasis. We found that CSA blocked JAG1, but not Dll4 mediated Notch1 NICD cleavage in transfected 293T cells and decreased Notch signaling in zebrafish embryos. CSA suppression of Notch was linked to cyclophilin A but not calcineurin/NFAT inhibition since N-MeVal-4-CsA but not FK506 decreased Notch1 NICD cleavage. To examine the effect of CSA on vascular development and function, double transgenic Fli1-GFP/Gata1-RFP zebrafish embryos were treated with CSA and monitored for vasculogenesis, angiogenesis, and overall cardiovascular function. Vascular patterning was not obviously impacted by CSA treatment and contrary to the anti-angiogenic activity ascribed to CSA, angiogenic sprouting of ISV vessels was normal in CSA treated embryos. Most strikingly, CSA treated embryos exhibited a progressive decline in blood flow that was associated with eventual collapse of vascular luminal structures. Vascular collapse in zebrafish embryos was partially rescued by global Notch inhibition with DAPT suggesting that disruption of normal Notch signaling by CSA may be linked to vascular collapse. However, multiple signaling pathways likely cause the vascular collapse phenotype since both cyclophilin A and calcineurin/NFAT were required for normal vascular function. Collectively, these results show that CSA is a novel inhibitor of Notch signaling and

  16. Mutations in NOTCH1 cause Adams-Oliver syndrome.

    PubMed

    Stittrich, Anna-Barbara; Lehman, Anna; Bodian, Dale L; Ashworth, Justin; Zong, Zheyuan; Li, Hong; Lam, Patricia; Khromykh, Alina; Iyer, Ramaswamy K; Vockley, Joseph G; Baveja, Rajiv; Silva, Ermelinda Santos; Dixon, Joanne; Leon, Eyby L; Solomon, Benjamin D; Glusman, Gustavo; Niederhuber, John E; Roach, Jared C; Patel, Millan S

    2014-09-01

    Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway. PMID:25132448

  17. NUMB is a break of WNT-Notch signaling cycle.

    PubMed

    Katoh, Masuko; Katoh, Masaru

    2006-09-01

    Notch, FGF and WNT signaling pathways cross-talk during embryogenesis, tissue regeneration and carcinogenesis. Notch-ligand binding to Notch receptors leads to the cleavage of Notch receptors and the following nuclear translocation of Notch intracellular domain (NICD) to induce transcriptional activation of Notch target genes. Notch signaling inhibitors, NUMB and NUMB-like (NUMBL), are docking proteins with PTB domain. We searched for the TCF/LEF-binding site within the promoter region of NUMB and NUMBL genes. Because two TCF/LEF-binding sites were identified within human NUMB promoter based on bioinformatics and human intelligence (Humint), comparative integromics analyses on NUMB orthologs were further performed. Chimpanzee NUBM gene, consisting of 13 exons, was identified within NW_115880.1 genome sequence. XM_510045.1 was not the correct coding sequence for chimpanzee NUMB. Chimpanzee NUMB gene was found to encode a 651-amino-acid protein showing 99.5, 93.9 and 82.6% total-amino-acid identity with human NUMB, mouse Numb and chicken numb, respectively. Human NUMB mRNA was expressed in placenta, ES cells, neural tissues, trachea, testis, uterus, thymus, coronary artery as well as in a variety of tumors, such as cervical cancer, tong tumor, brain tumor, colorectal and breast cancer. Although distal TCF/LEF-binding site within human NUMB promoter was conserved only among primate NUMB orthologs, proximal TCF/LEF-binding site was conserved among primate and rodent NUMB orthologs. NUMB, JAG1, FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in progenitor cells. NUMB inhibits Notch signaling in progenitor cells to induce differentiation, while JAG1 activates Notch signaling in stem cells to maintain self-renewal potential. Because Notch signaling inhibitor NUMB was identified as the safe apparatus for the WNT - Notch signaling cycle, epigenetic silencing, deletion and loss-of-function mutation of NUMB gene could lead to carcinogenesis

  18. Band-notched reconfigurable CPW-fed UWB antenna

    NASA Astrophysics Data System (ADS)

    Majid, H. A.; Rahim, M. K. A.; Hamid, M. R.; Murad, N. A.; Samsuri, N. A.; Yusof, M. F. M.; Kamarudin, M. R.

    2016-04-01

    A reconfigurable band-notched CPW-fed UWB antenna using electromagnetic bandgap (EBG) structure is proposed. Two structures are positioned adjacent to the transmission line of the UWB antenna. The band-notched characteristic can be disabled by switching the state of switch place at the strip line. The EBG structure produces reconfigurable band notched at 4.0 GHz, which covers C-band satellite communication (3.625-4.2 GHz) systems. The proposed antenna is suitable for UWB systems, which requires reconfigurable band reject function.

  19. Synchronized Targeting of Notch and ERBB Signaling Suppresses Melanoma Tumor Growth through Inhibition of Notch1 and ERBB3.

    PubMed

    Zhang, Keman; Wong, Poki; Salvaggio, Christine; Salhi, Amel; Osman, Iman; Bedogni, Barbara

    2016-02-01

    Despite significant advances in melanoma therapy, melanoma remains the deadliest form of skin cancer, with a 5-year survival rate of only 15%. Thus, novel treatments are required to address this disease. Notch and ERBB are evolutionarily conserved signaling cascades required for the maintenance of melanocyte precursors. We show that active Notch1 (Notch1(NIC)) and active (phosphorylated) ERBB3 and ERBB2 correlate significantly and are similarly expressed in both mutated and wild-type BRAF melanomas, suggesting these receptors are co-reactivated in melanoma to promote survival. Whereas blocking either pathway triggers modest effects, combining a ?-secretase inhibitor to block Notch activation and a tyrosine kinase inhibitor to inhibit ERBB3/2 elicits synergistic effects, reducing cell viability by 90% and hampering melanoma tumor growth. Specific inhibition of Notch1 and ERBB3 mimics these results, suggesting these are the critical factors triggering melanoma tumor expansion. Notch and ERBB inhibition blunts AKT and NF?B signaling. Constitutive expression of NF?B partially rescues cell death. Blockade of both Notch and ERBB signaling inhibits the slow cycling JARID1B-positive cell population, which is critical for long-term maintenance of melanoma growth. We propose that blocking these pathways is an effective approach to treatment of melanoma patients regardless of whether they carry mutated or wild-type BRAF. PMID:26967479

  20. Synchronized targeting of Notch and ERBB signaling suppresses melanoma tumor growth through inhibition of Notch1 and ERBB3*

    PubMed Central

    Zhang, Keman; Wong, Poki; Salvaggio, Christine; Salhi, Amel; Osman, Iman; Bedogni, Barbara

    2015-01-01

    Despite significant advances in melanoma therapy, melanoma remains the deadliest form of skin cancer, with a five-year survival of only 15%. Novel treatments are therefore required to address this disease. Notch and ERBB are evolutionarily conserved signaling cascades required for the maintenance of melanocyte precursors. We show that active Notch1 (Notch1NIC) and active (phosphorylated) ERBB3 and ERBB2 correlate significantly and are similarly expressed in both mutated and wild type BRAF melanomas, suggesting these receptors are co-reactivated in melanoma to promote survival. Indeed, while blocking either pathway triggers modest effects, combining a γ-secretase inhibitor to block Notch activation, and a tyrosine kinase inhibitor to inhibit ERBB3/2 elicits synergistic effects, reducing cell viability by 90% and by hampering melanoma tumor growth. Specific inhibition of Notch1 and ERBB3 mimics these results, suggesting these are the critical factors triggering melanoma tumor expansion. Notch and ERBB inhibition blunts AKT and NFκB signaling; Constitutive expression of NFκB partially rescues cell death. Finally, blockade of both Notch and ERBB signaling inhibits the slow cycling JARID1B positive cell population, which is critical for long-term maintenance of melanoma growth. We propose that blocking these pathways is an effective approach to treat melanoma patients regardless of whether they carry mutated or wild type BRAF. PMID:26967479

  1. Loss of Notch1-dependent p21Waf1/Cip1 expression influences the Notch1 outcome in tumorigenesis

    PubMed Central

    Cialfi, Samantha; Palermo, Rocco; Manca, Sonia; De Blasio, Carlo; Vargas Romero, Paula; Checquolo, Saula; Bellavia, Diana; Uccelletti, Daniela; Saliola, Michele; D'Alessandro, Angelo; Zolla, Lello; Gulino, Alberto; Screpanti, Isabella; Talora, Claudio

    2014-01-01

    Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor-suppressor and oncogenic components. In this study we investigated the effects of reactive oxygen species (ROS) on Notch1 signaling outcome in keratinocyte biology. We demonstrate that Notch1 function contributes to the arsenic-induced keratinocyte transformation. We found that acute exposure to arsenite increases oxidative stress and inhibits proliferation of keratinocyte cells by upregulation of p21waf1/Cip1. The necessity of p21waf1/Cip1 for arsenite-induced cell death was demonstrated by targeted downregulation of p21waf1/Cip1 by using RNA interference. We further demonstrated that on acute exposure to arsenite, p21waf1/Cip1 is upregulated and Notch1 downmodulated, whereas on chronic exposure to arsenite, malignant progression of arsenite-treated keratinocytes cells was accompanied by regained expression and activity of Notch1. Notch1 activity in arsenite-transformed keratinocytes inhibits arsenite-induced upregulation of p21waf1/Cip1 by sustaining c-myc expression. We further demonstrated that c-myc collaborates with Nrf2, a key regulator for the maintenance of redox homeostasis, to promote metabolic activities that support cell proliferation and cytoprotection. Therefore, Notch1-mediated repression of p21waf1/Cip1 expression results in the inhibition of cell death and keratinocytes transformation. Our results not only demonstrate that sustained Notch1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect, but also may provide mechanistic insights into the molecular aspects that determine whether Notch signaling will be either oncogenic or tumor suppressive. PMID:24801890

  2. Femoral intercondylar notch shape and dimensions in ACL-injured patients.

    PubMed

    van Eck, Carola F; Martins, Cesar A Q; Vyas, Shail M; Celentano, Umberto; van Dijk, C Niek; Fu, Freddie H

    2010-09-01

    The femoral intercondylar notch has been an anatomic site of interest as it houses the anterior cruciate ligament (ACL). The objective of this study was to arthroscopically evaluate the femoral notch in patients with known ACL injury. This evaluation included establishing a classification for notch shapes, identifying the shape frequency, measuring notch dimensions, and determining correlation between notch shape, notch dimensions, and demographic patient data. In this clinical cohort study, 102 consecutive patients underwent diagnostic arthroscopic evaluation of the notch. Several intra-operative photos, videos, and measurements were taken of the notch. Demographic data for each patient were recorded including age, gender, height, weight, and BMI. Three categories of notch shape were established: 1. A-shaped; 2. U-shaped; and 3. W-shaped. Two blinded independent orthopedic surgeons were asked to categorize the recorded notches. Notch shape, dimensions, and demographic factors were correlated. Of the 102 notches evaluated, 55 notches were found to be "A-shaped," 42 "U-shaped," and 5 "W-shaped." "A-shaped" notches were narrower in all width dimensions than "U-shaped" notches. Only patient height was found to influence notch shape with a positive association between taller patients and "U-shaped" and "W-shaped" notches (P = 0.011). Women had a smaller notch width at the base and middle of the notch. With this data, surgeons who enter the knee and appreciate an "A-shaped" notch should consider placing the arthroscope in the anteromedial portal and drill the femoral tunnel through an accessory medial portal to improve visualization and accuracy in anatomic femoral tunnel creation. PMID:20390246

  3. NOTCH4 signaling controls EFNB2-induced endothelial progenitor cell dysfunction in preeclampsia.

    PubMed

    Liu, Xiaoxia; Luo, Qingqing; Zheng, Yanfang; Liu, Xiaoping; Hu, Ying; Liu, Weifang; Luo, Minglian; Zhao, Yin; Zou, Li

    2016-07-01

    Preeclampsia is a serious complication of pregnancy and is closely related to endothelial dysfunction, which can be repaired by endothelial progenitor cells (EPCs). The DLL4/NOTCH-EFNB2 (ephrinB2) cascade may be involved in the pathogenesis of preeclampsia by inhibiting the biological activity of EPCs. In addition, both NOTCH1 and NOTCH4, which are specific receptors for DLL4/NOTCH, play critical roles in the various steps of angiogenesis. However, it has not been determined which receptor (NOTCH1, NOTCH4, or both) is specific for the DLL4/NOTCH-EFNB2 cascade. Accordingly, we performed a series of investigations to evaluate it. EFNB2 expression was examined when NOTCH4 or NOTCH1 was downregulated, with or without DLL4 treatment. Then, the effects of NOTCH4 on EPC function were detected. Additionally, we analyzed NOTCH4 and EFNB2 expression in the EPCs from preeclampsia and normal pregnancies. Results showed that NOTCH4 downregulation led to decreased expression of EFNB2, which maintained the same level in the presence of DLL4/NOTCH activation. By contrast, NOTCH1 silencing resulted in a moderate increase in EFNB2 expression, which further increased in the presence of DLL4/NOTCH activation. The downregulation of NOTCH4 resulted in an increase of EPC biological activity, which was similar to EFNB2 silencing. NOTCH4 expression, consistent with the EFNB2 level, increased notably in preeclampsia EPCs compared with the controls. These findings suggest that NOTCH4, not NOTCH1, is the specific receptor for the DLL4/NOTCH-EFNB2 cascade. Blockade of this cascade may enhance the angiogenic property of EPCs, and act as a potential target to promote angiogenesis in patients with preeclampsia. PMID:27069008

  4. 8. DETAIL OF NOTCHED CONSTRUCTION ELEMENT IN GRILLAGE AT WESTERN ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    8. DETAIL OF NOTCHED CONSTRUCTION ELEMENT IN GRILLAGE AT WESTERN EDGE OF SOUTHEASTERN LEG OF SEA WALL. TIDE APPROACHING. - Fort Delaware, Sea Wall, Pea Patch Island, Delaware City, New Castle County, DE

  5. Notch signalling mediates reproductive constraint in the adult worker honeybee.

    PubMed

    Duncan, Elizabeth J; Hyink, Otto; Dearden, Peter K

    2016-01-01

    The hallmark of eusociality is the reproductive division of labour, in which one female caste reproduces, while reproduction is constrained in the subordinate caste. In adult worker honeybees (Apis mellifera) reproductive constraint is conditional: in the absence of the queen and brood, adult worker honeybees activate their ovaries and lay haploid male eggs. Here, we demonstrate that chemical inhibition of Notch signalling can overcome the repressive effect of queen pheromone and promote ovary activity in adult worker honeybees. We show that Notch signalling acts on the earliest stages of oogenesis and that the removal of the queen corresponds with a loss of Notch protein in the germarium. We conclude that the ancient and pleiotropic Notch signalling pathway has been co-opted into constraining reproduction in worker honeybees and we provide the first molecular mechanism directly linking ovary activity in adult worker bees with the presence of the queen. PMID:27485026

  6. Lock 1 View northwest of lock entrance. Notch for ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Lock 1 - View northwest of lock entrance. Notch for flash boards can be seen near center, gate pocket at left. - Savannah & Ogeechee Barge Canal, Between Ogeechee & Savannah Rivers, Savannah, Chatham County, GA

  7. A Novel UWB Antenna with Dual Band-Notched Characteristics

    NASA Astrophysics Data System (ADS)

    Lin, Yongfan; Liang, Jiangang; Wu, Goucheng; Xu, Zhiyong; Niu, Xuebin

    2015-11-01

    In this article, started from analyzing the basic principle of band-notched characteristics, a feasibly method used for band-notched antenna is demonstrated and the equivalent circuit for this method is designed. A novel UWB antenna is designed. Based on this method, two stubs which can be equivalent to shorted stubs in parallel configuration are added to realize dual band-notched characteristics. Simulated and measured results all show that the UWB antenna yields an impendence bandwidth of 2.0-10.6 GHz by defining VSWR ≦ 2, and two obvious band-notched functions (3.27-3.83 GHz, 4.60-5.90 GHz) occur at the working bandwidth of WIMAX (3.3-3.7 GHz) and HiperLAN/2 (5.15-5.35 GHz, 5.47-5.725 GHz), so the electromagnetic interference between UWB application and WIMAX, HiperLAN/2 can be suppressed.

  8. Iterative Role of Notch Signaling in Spinal Motor Neuron Diversification.

    PubMed

    Tan, G Christopher; Mazzoni, Esteban O; Wichterle, Hynek

    2016-07-26

    The motor neuron progenitor domain in the ventral spinal cord gives rise to multiple subtypes of motor neurons and glial cells. Here, we examine whether progenitors found in this domain are multipotent and which signals contribute to their cell-type-specific differentiation. Using an in vitro neural differentiation model, we demonstrate that motor neuron progenitor differentiation is iteratively controlled by Notch signaling. First, Notch controls the timing of motor neuron genesis by repressing Neurogenin 2 (Ngn2) and maintaining Olig2-positive progenitors in a proliferative state. Second, in an Ngn2-independent manner, Notch contributes to the specification of median versus hypaxial motor column identity and lateral versus medial divisional identity of limb-innervating motor neurons. Thus, motor neuron progenitors are multipotent, and their diversification is controlled by Notch signaling that iteratively increases cellular diversity arising from a single neural progenitor domain. PMID:27425621

  9. 29. RECYCLED ATTIC JOISTS SHOWING SHINGLE LATH NOTCHING ON TOP ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    29. RECYCLED ATTIC JOISTS SHOWING SHINGLE LATH NOTCHING ON TOP SURFACE (Note shadow of plaster lath on bottom surface. See also PA-1440-28.) - James McCrea Houses, 108-110 Sansom Street, Philadelphia, Philadelphia County, PA

  10. Detail section of guardrail configuration, showing notched steel post (typical) ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail section of guardrail configuration, showing notched steel post (typical) with stock steel tubing and chain link; view is to east - Mather Point Overlook, South Entrance Road, Grand Canyon Village, Coconino County, AZ

  11. Notch signalling mediates reproductive constraint in the adult worker honeybee

    PubMed Central

    Duncan, Elizabeth J.; Hyink, Otto; Dearden, Peter K.

    2016-01-01

    The hallmark of eusociality is the reproductive division of labour, in which one female caste reproduces, while reproduction is constrained in the subordinate caste. In adult worker honeybees (Apis mellifera) reproductive constraint is conditional: in the absence of the queen and brood, adult worker honeybees activate their ovaries and lay haploid male eggs. Here, we demonstrate that chemical inhibition of Notch signalling can overcome the repressive effect of queen pheromone and promote ovary activity in adult worker honeybees. We show that Notch signalling acts on the earliest stages of oogenesis and that the removal of the queen corresponds with a loss of Notch protein in the germarium. We conclude that the ancient and pleiotropic Notch signalling pathway has been co-opted into constraining reproduction in worker honeybees and we provide the first molecular mechanism directly linking ovary activity in adult worker bees with the presence of the queen. PMID:27485026

  12. 7. DETAIL, NOTCHED ROUGH HEWN JOINTS AND BEAMS PLUS WINDOW ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    7. DETAIL, NOTCHED ROUGH HEWN JOINTS AND BEAMS PLUS WINDOW UNDER 1ST FLOOR PORCH, SOUTH ELEVATION, LOOKING NORTH-NORTHWEST. - Fort Leavenworth, Building No. 17, 20-22 Sumner Place, Leavenworth, Leavenworth County, KS

  13. A Dual Role for NOTCH Signaling in Joint Cartilage Maintenance and Osteoarthritis

    PubMed Central

    Liu, Zhaoyang; Chen, Jianquan; Mirando, Anthony; Wang, Cuicui; Zuscik, Michael J.; O’Keefe, Regis J.; Hilton, Matthew J.

    2015-01-01

    Loss of NOTCH signaling in postnatal murine joints results in osteoarthritis (OA), indicating a requirement for NOTCH during joint cartilage maintenance. Unexpectedly, NOTCH components are significantly up-regulated in human and murine post-traumatic OA, suggesting either a reparative or pathological role for NOTCH activation in OA. Here we investigated the potential dual role for NOTCH in joint maintenance and OA by generating two mouse models overexpressing the NOTCH1 intracellular domain within postnatal joint cartilage; one with sustained NOTCH activation that likely resembles pathological NOTCH signaling and one with transient NOTCH activation that more closely reflects physiological NOTCH signaling. Sustained NOTCH signaling in joint cartilage leads to an early and progressive OA pathology, while on the contrary, transient NOTCH activation enhances cartilage matrix synthesis and promotes joint maintenance under normal physiological conditions. Using RNA-seq, immunohistochemical, and biochemical approaches we identified several novel targets potentially responsible for NOTCH-mediated cartilage degradation, fibrosis, and OA progression, including components of the IL6/STAT3 and ERK/p38 MAPK pathways; factors that may also contribute to post-traumatic OA development. Collectively, these data demonstrate a dual role for the NOTCH pathway in joint cartilage and identify important downstream NOTCH effectors as potential targets for disease modifying osteoarthritis drugs (DMOADs). PMID:26198357

  14. Decidual vascular endothelial cells promote maternal-fetal immune tolerance by inducing regulatory T cells through canonical Notch1 signaling.

    PubMed

    Yao, Yanyi; Song, Jieping; Wang, Weipeng; Liu, Nian

    2016-05-01

    Adaptation of the maternal immune response to accommodate the semiallogeneic fetus is necessary for pregnancy success. However, the mechanisms by which the fetus avoids rejection despite expression of paternal alloantigens remain incompletely understood. Regulatory T cells (Treg cells) are pivotal for maintaining immune homeostasis, preventing autoimmune disease and fetus rejection. In this study, we found that maternal decidual vascular endothelial cells (DVECs) sustained Foxp3 expression in resting Treg cells in vitro. Moreover, under in vitro Treg cell induction condition with agonistic antibodies and transforming growth factor (TGF)-β, DVECs promoted Treg cell differentiation from non-Treg conventional T cells. Consistent with the promotion of Treg cell maintenance and differentiation, Treg cell-associated gene expression such as TGF-β, Epstein-Barr-induced gene-3, CD39 and glucocorticoid-induced tumor necrosis factor receptor was also increased in the presence of DVECs. Further study revealed that DVECs expressed Notch ligands such as Jagged-1, Delta-like protein 1 (DLL-1) and DLL-4, while Treg cells expressed Notch1 on their surface. The effects of DVECs on Treg cells was inhibited by siRNA-induced knockdown of expression of Jagged-1 and DLL-1 in DVECs. Downregulation of Notch1 in Treg cells using lentiviral shRNA transduction decreased Foxp3 expression in Treg cells. Adoptive transfer of Notch1-deficient Treg cells increased abortion rate in a murine semiallogeneic pregnancy model. Taken together, our study suggests that maternal DVECs are able to maintain decidual Treg cell identity and promote Treg cell differentiation through activation of Notch1 signal pathway in Treg cells and subsequently inhibit the immune response against semiallogeneic fetuses and preventing spontaneous abortion. PMID:26714886

  15. 42. GARRET, SOUTHWEST CORNER. The roof rafters have been notched ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    42. GARRET, SOUTHWEST CORNER. The roof rafters have been notched for shingle lath. In some places the notches and lath do not align. Attached to each joist are furring strips for the 1812 ceiling, allowing it to be lowered about one inch below the under surfaces of the joists. Note that the 1851 shingles were left in place when the 1873-74 tin roof was added. - Twelfth Street Meeting House, 20 South Twelfth Street, Philadelphia, Philadelphia County, PA

  16. Uncommon Cause of Trigeminal Neuralgia: Tentorial Ossification over Trigeminal Notch

    PubMed Central

    Bang, Sun Woo; Han, Kyung Ream; Kim, Seung Ho; Jeong, Won Ho; Kim, Eun Jin; Choi, Jin Wook; Kim, Chan

    2015-01-01

    Ossification of the tentorium cerebelli over the trigeminal notch is rare, but it may cause compression of the trigeminal nerve, leading to trigeminal neuralgia (TN). We were unable to find any previously reported cases with radiological evaluation, although we did find one case with surgically proven ossification of the tentorium cerebelli. Here, we present a case of TN caused by tentorial ossification over the trigeminal notch depicted on magnetic resonance imaging (MRI) and computed tomography (CT). PMID:26380124

  17. SAR imaging in the presence of spectrum notches via fast missing data IAA

    NASA Astrophysics Data System (ADS)

    Rowe, William; Karlsson, Johan; Xu, Luzhou; Glentis, George-Othon; Li, Jian

    2013-05-01

    A synthetic aperture radar system operating in congested frequency bands suffers from radio frequency inter­ ference (RFI) from narrowband sources. When RFI interference is suppressed by frequency notching, gaps are introduced into the fast time phase history. This results in a missing data spectral estimation problem, where the missing data increases sidelobe energy and degrades image quality. The adaptive spectral estimation method Iterative Adaptive Approach (IAA) has been shown to provide higher resolution and lower sidelobes than comparable methods, but at the cost of higher computationally complexity. Current fast IAA algorithms reduce the computational complexity using Toeplitz /Vandermonde structures, but are not applicable for missing data cases because these structures are lost. When the number of missing data samples is small, which often is the case in SAR with RFI, we use a low rank completion to restore the Toeplitz/ Vandermonde structures. We show that the computational complexity of the proposed algorithm is considerably lower than the state-of-the-art and demonstrate the utility on a simulated frequency notched SAR imaging problem.

  18. Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

    SciTech Connect

    Lagadec, Chann; Vlashi, Erina; Alhiyari, Yazeed; Phillips, Tiffany M.; Bochkur Dratver, Milana; Pajonk, Frank

    2013-11-01

    Purpose: To explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for γ-secretase inhibitors if combined with radiation. Methods and Materials: Using MCF-7 and T47D breast cancer cell lines, we used real-time reverse transcription–polymerase chain reaction to study the Notch pathway in response to radiation. Results: We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dose–dependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a γ-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool. Conclusions: Our results indicate that, if combined with radiation, γ-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells.

  19. Notch signal strength controls cell fate in the haemogenic endothelium.

    PubMed

    Gama-Norton, Leonor; Ferrando, Eva; Ruiz-Herguido, Cristina; Liu, Zhenyi; Liu, Zenhy; Guiu, Jordi; Islam, Abul B M M K; Lee, Sung-Uk; Yan, Minhong; Guidos, Cynthia J; López-Bigas, Nuria; Maeda, Takahiro; Espinosa, Lluis; Kopan, Raphael; Bigas, Anna

    2015-01-01

    Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta-gonad-mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage. PMID:26465397

  20. Why does necking ignore notches in dynamic tension?

    NASA Astrophysics Data System (ADS)

    Rotbaum, Y.; Osovski, S.; Rittel, D.

    2015-05-01

    Recent experimental work has revealed that notched tensile specimens, subjected to dynamic loading, may fail by growing a neck outside of the notched region. This apparent lack of sensitivity to a classical stress concentration case was reported but not explained or modeled. The present paper combines experimental and numerical work to address this issue. Specifically, it is shown that the dynamic tensile failure locus is dictated by both the applied velocity boundary condition and the material mechanical properties, specifically strain-rate sensitivity and strain-rate hardening. It is shown that at sufficiently high impact velocities, the flows stress in the notch vicinity becomes quite higher than in the rest of the specimen, so that while the former resists deformation, it transfers the load to the latter. The result will be the formation of a local neck and failure away from the notch. This effect is shown to be active when the material properties are perturbed only at the local level, as in the case of machining of the notch, which in itself may again be sufficient to stabilize the structure under local failure until a neck forms elsewhere. While the physical observations are quite counterintuitive with respect to the engineering views of stress concentrator's effect, the present work rationalizes those observations and also provides information for the designers of dynamically tensioned structures that may contain notches or similar flaws.

  1. LKB1 and Notch Pathways Interact and Control Biliary Morphogenesis

    PubMed Central

    Just, Pierre-Alexandre; Poncy, Alexis; Charawi, Sara; Dahmani, Rajae; Traore, Massiré; Dumontet, Typhanie; Drouet, Valérie; Dumont, Florent; Gilgenkrantz, Hélène; Colnot, Sabine; Terris, Benoit; Coulouarn, Cédric; Lemaigre, Frédéric; Perret, Christine

    2015-01-01

    Background LKB1 is an evolutionary conserved kinase implicated in a wide range of cellular functions including inhibition of cell proliferation, regulation of cell polarity and metabolism. When Lkb1 is inactivated in the liver, glucose homeostasis is perturbed, cellular polarity is affected and cholestasis develops. Cholestasis occurs as a result from deficient bile duct development, yet how LKB1 impacts on biliary morphogenesis is unknown. Methodology/Principal Findings We characterized the phenotype of mice in which deletion of the Lkb1 gene has been specifically targeted to the hepatoblasts. Our results confirmed that lack of LKB1 in the liver results in bile duct paucity leading to cholestasis. Immunostaining analysis at a prenatal stage showed that LKB1 is not required for differentiation of hepatoblasts to cholangiocyte precursors but promotes maturation of the primitive ductal structures to mature bile ducts. This phenotype is similar to that obtained upon inactivation of Notch signaling in the liver. We tested the hypothesis of a functional overlap between the LKB1 and Notch pathways by gene expression profiling of livers deficient in Lkb1 or in the Notch mediator RbpJκ and identified a mutual cross-talk between LKB1 and Notch signaling. In vitro experiments confirmed that Notch activity was deficient upon LKB1 loss. Conclusion LKB1 and Notch share a common genetic program in the liver, and regulate bile duct morphogenesis. PMID:26689699

  2. Mechanical Behavior of Notched SiC/SiC Composites

    NASA Technical Reports Server (NTRS)

    Morscher, Gregory N.; Gyekenyesi, John Z.; Gyekenyesi, Andrew L.; Levine, Stanley (Technical Monitor)

    2001-01-01

    Gas turbine components such as combustor liners or turbine vanes are subject to regions of high stress-concentration, e.g., attachment to the frame or at cooling holes. Ceramic matrix composites (CMCs) are potential materials for high temperature applications in gas turbines. They offer some capability to relieve stress at regions of high stress-concentration via matrix damage accumulation. In this study notch sensitivity was examined for woven SiC fiber reinforced, melt-infiltrated SiC matrix composites with a BN interphase, utilizing either Hi-Nicalo(TM) fibers or the stiffer Sylramic fibers. The double-edge notched tensile test approach was used for a wide range of notch sizes and specimen widths. Both composite systems exhibited mild notch sensitivity similar to other CMC systems. Acoustic emission, detected during the tensile tests, indicated that matrix cracking occurred around notches at net-section stresses below the stress where matrix cracking first occurs in unnotched specimens. However, thermoelastic stress analysis did not show any measurable stress relief around notches after the specimens were preloaded.

  3. Notch Fatigue Strength of a PM Disk Superalloy

    NASA Technical Reports Server (NTRS)

    Gayda, John; Gabb, Timothy P.; Telesman, Jack

    2007-01-01

    New powder metallurgy (PM) disk superalloys, such as ME3, LSHR, and Alloy 10, have been developed in recent years which enable rim temperatures in turbine disk applications to approach 1300 F. Before these alloys can be utilized at 1300 F their long term durability must be ensured. One of the key requirements for disk rims is notch fatigue strength. This issue is extremely important and is a direct result of the blade attachment geometry employed at the disk rim. Further, the imposition of a dwell at maximum load, associated with take off and landing, can also affect notch fatigue strength. For these reasons a study has been undertaken to assess the notch dwell fatigue strength of a modern PM disk alloy through spin pit evaluation of a prototypical disk. The first element of this program involves screening potential heat treatments with respect to notch fatigue strength at 1300 F utilizing a conventional notch fatigue specimen with a stress concentration factor (K(sub t)) of 2 and a 90 sec dwell at peak load. The results of this effort are reported in this paper including the downselect of an optimal heat treatment, from a notch fatigue standpoint.

  4. NOTCH signaling in skeletal progenitors is critical for fracture repair.

    PubMed

    Wang, Cuicui; Inzana, Jason A; Mirando, Anthony J; Ren, Yinshi; Liu, Zhaoyang; Shen, Jie; O'Keefe, Regis J; Awad, Hani A; Hilton, Matthew J

    2016-04-01

    Fracture nonunions develop in 10%-20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH-deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity. PMID:26950423

  5. Notch signaling: switching an oncogene to a tumor suppressor

    PubMed Central

    Lobry, Camille; Oh, Philmo; Mansour, Marc R.; Look, A. Thomas

    2014-01-01

    The Notch signaling pathway is a regulator of self-renewal and differentiation in several tissues and cell types. Notch is a binary cell-fate determinant, and its hyperactivation has been implicated as oncogenic in several cancers including breast cancer and T-cell acute lymphoblastic leukemia (T-ALL). Recently, several studies also unraveled tumor-suppressor roles for Notch signaling in different tissues, including tissues where it was before recognized as an oncogene in specific lineages. Whereas involvement of Notch as an oncogene in several lymphoid malignancies (T-ALL, B-chronic lymphocytic leukemia, splenic marginal zone lymphoma) is well characterized, there is growing evidence involving Notch signaling as a tumor suppressor in myeloid malignancies. It therefore appears that Notch signaling pathway’s oncogenic or tumor-suppressor abilities are highly context dependent. In this review, we summarize and discuss latest advances in the understanding of this dual role in hematopoiesis and the possible consequences for the treatment of hematologic malignancies. PMID:24608975

  6. NOTCH signaling in skeletal progenitors is critical for fracture repair

    PubMed Central

    Wang, Cuicui; Inzana, Jason A.; Mirando, Anthony J.; Liu, Zhaoyang; Shen, Jie; O’Keefe, Regis J.; Awad, Hani A.; Hilton, Matthew J.

    2016-01-01

    Fracture nonunions develop in 10%–20% of patients with fractures, resulting in prolonged disability. Current data suggest that bone union during fracture repair is achieved via proliferation and differentiation of skeletal progenitors within periosteal and soft tissues surrounding bone, while bone marrow stromal/stem cells (BMSCs) and other skeletal progenitors may also contribute. The NOTCH signaling pathway is a critical maintenance factor for BMSCs during skeletal development, although the precise role for NOTCH and the requisite nature of BMSCs following fracture is unknown. Here, we evaluated whether NOTCH and/or BMSCs are required for fracture repair by performing nonstabilized and stabilized fractures on NOTCH-deficient mice with targeted deletion of RBPjk in skeletal progenitors, maturing osteoblasts, and committed chondrocytes. We determined that removal of NOTCH signaling in BMSCs and subsequent depletion of this population result in fracture nonunion, as the fracture repair process was normal in animals harboring either osteoblast- or chondrocyte-specific deletion of RBPjk. Together, this work provides a genetic model of a fracture nonunion and demonstrates the requirement for NOTCH and BMSCs in fracture repair, irrespective of fracture stability and vascularity. PMID:26950423

  7. Notch3 Activation Promotes Invasive Glioma Formation in a Tissue Site-Specific Manner

    PubMed Central

    Pierfelice, Tarran J.; Schreck, Karisa C.; Dang, Louis; Asnaghi, Laura; Gaiano, Nicholas; Eberhart, Charles G.

    2010-01-01

    While Notch signaling has been widely implicated in neoplastic growth, direct evidence for in vivo initiation of neoplasia by the pathway in murine models has been limited to tumors of lymphoid, breast, and choroid plexus cells. To examine tumorigenic potential in the eye and brain, we injected retroviruses encoding activated forms of Notch1, Notch2, or Notch3 into embryonic mice. Interestingly, the majority of animals infected with active Notch3 developed proliferative lesions comprised of pigmented ocular choroid cells, retinal and optic nerve glia, and lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. While Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, while Notch3 was ten-fold more efficient at generating growths, many of which were large invasive gliomas. Expression of active Notch1/Notch3 chimeric receptors implicated the RAM (RBPjk-association molecule) and transactivation domains (TAD) of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors. Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve, but not the brain, are susceptible to transformation by Notch3. PMID:21245095

  8. Exotic damping ring lattices

    SciTech Connect

    Palmer, R.B.

    1987-05-01

    This paper looks at, and compares three types of damping ring lattices: conventional, wiggler lattice with finite ..cap alpha.., wiggler lattice with ..cap alpha.. = 0, and observes the attainable equilibrium emittances for the three cases assuming a constraint on the attainable longitudinal impedance of 0.2 ohms. The emittance obtained are roughly in the ratio 4:2:1 for these cases.

  9. The History of the Kernohan Notch Revisited.

    PubMed

    Dammers, Ruben; Volovici, Victor; Kompanje, Erwin J O

    2016-04-01

    The history of false localizing signs is intimately linked to the birth of modern neurology and the unraveling of the mysteries of localization through neurological examination at the end of the 19th century. This phenomenon has attracted much attention but has not been properly explained, even in the authoritative handbooks such as that by Oppenheim. A scholarly article written by Kernohan and Woltman in 1929 is considered to be a landmark in the history of neurology and neurosurgery in that it provided the definitive answer and an exhaustive explanation of the problem, leading some neurologists to conclude that the localization of a lesion is not an exact science. However, despite the professional manner in which Kernohan and Woltman presented their case, they did not offer an explanation. In another article published 2 years earlier in 1927, Groeneveld and Schaltenbrand provided a pathophysiological and anatomical explanation of the phenomenon, described in detail. Although Kernohan and Woltman themselves refer to that previous article, it was this article that provided the first logical, clear, indubitable explanation of the phenomenon that we today refer to as the Kernohan notch. PMID:26528671

  10. Botch is a γ-glutamyl Cyclotransferase that Deglycinates and Antagonizes Notch

    PubMed Central

    Chi, Zhikai; Byrne, Sean T.; Dolinko, Andrew; Harraz, Maged M.; Kim, Min-Sik; Umanah, George; Zhong, Jun; Chen, Rong; Zhang, Jianmin; Xu, Jinchong; Chen, Li; Pandey, Akhilesh; Dawson, Ted M.; Dawson, Valina L.

    2014-01-01

    SUMMARY Botch promotes embryonic neurogenesis through inhibition of Notch-1 signaling through inhibition of the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here we show that Botch has γ-glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is mono-glycinated on the γ-glutamyl carbon of glutamate 1669. The deglycinase activity of Botch is required for inhibition of Notch signaling, both in vitro and in vivo. When the γ-glutamyl-glycine at position 1669 of Notch is degylcinated it is replaced by 5-oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a novel posttranslational modification of Notch that plays an important role in neurogenesis. PMID:24767995

  11. Notched Audiograms and Noise Exposure History in Older Adults

    PubMed Central

    Nondahl, DM; Shi, X; Cruickshanks, KJ; Dalton, DS; Tweed, TS; Wiley, TL; Carmichael, LL

    2009-01-01

    OBJECTIVE Using data from a population-based cohort study, we compared four published algorithms for identifying notched audiograms, along with how their resulting classifications compare with noise exposure history. DESIGN Four algorithms: 1) Coles, Lutman & Buffin (2000), 2) McBride & Williams (2001), 3) Dobie & Rabinowitz (2002), and 4) Hoffman et al. (2006) were used to identify notched audiograms. Audiometric evaluations were collected as part of the Epidemiology of Hearing Loss Study 10-year follow-up examinations, in Beaver Dam, WI (2003–2005, n=2395). Detailed noise exposure histories were collected by interview at the baseline examination (1993–95) and updated at subsequent visits. An extensive history of occupational noise exposure, participation in noisy hobbies, and firearm usage were used to evaluate consistency of the notch classifications with history of noise exposure. RESULTS The prevalence of notched audiograms varied greatly by definition (31.7%, 25.9%, 47.2%, and 11.7% for methods 1, 2, 3, and 4, respectively). In this cohort, a history of noise exposure was common (56.2% for occupational noise, 71.7% for noisy hobbies, 13.4% for firearms, 81.2% for any of these three sources). Among participants with a notched audiogram, almost one third did not have a history of occupational noise exposure (31.4%, 33.0%, 32.5%, and 28.1% for methods 1, 2, 3, and 4, respectively) and approximately 11% did not have a history of exposure to any of the three sources of noise (11.5%, 13.6%, 10.3%, and 7.6%). Discordance was greater among women than men. CONCLUSIONS These results suggest that there is poor agreement across existing algorithms for audiometric notches. In addition, notches can occur in the absence of a positive noise history. In the absence of an objective consensus definition of a notched audiogram, and in light of the degree of discordance in women between noise history and notches by each of these algorithms, researchers should be cautious

  12. Notch regulation of bone development and remodeling and related skeletal disorders.

    PubMed

    Zanotti, Stefano; Canalis, Ernesto

    2012-02-01

    Notch signaling mediates cell-to-cell interactions that are critical for embryonic development and tissue renewal. In the canonical signaling pathway, the Notch receptor is cleaved following ligand binding, resulting in the release and nuclear translocation of the Notch intracellular domain (NICD). NICD induces gene expression by forming a ternary complex with the DNA binding protein CBF1/Rbp-Jk, Suppressor of Hairless, Lag1, and Mastermind-Like (Maml). Hairy Enhancer of Split (Hes) and Hes related with YRPW motif (Hey) are classic Notch targets. Notch canonical signaling plays a central role in skeletal development and bone remodeling by suppressing the differentiation of skeletal cells. The skeletal phenotype of mice misexpressing Hes1 phenocopies partially the effects of Notch misexpression, suggesting that Hey proteins mediate most of the skeletal effects of Notch. Dysregulation of Notch signaling is associated with diseases affecting human skeletal development, such as Alagille syndrome, brachydactyly and spondylocostal dysostosis. Somatic mutations in Notch receptors and ligands are found in tumors of the skeletal system. Overexpression of NOTCH1 is associated with osteosarcoma, and overexpression of NOTCH3 or JAGGED1 in breast cancer cells favors the formation of osteolytic bone metastasis. Activating mutations in NOTCH2 cause Hajdu-Cheney syndrome, which is characterized by skeletal defects and fractures, and JAG1 polymorphisms, are associated with variations in bone mineral density. In conclusion, Notch is a regulator of skeletal development and bone remodeling, and abnormal Notch signaling is associated with developmental and postnatal skeletal disorders. PMID:22002679

  13. Hepatitis B Virus HBx Activates Notch Signaling via Delta-Like 4/Notch1 in Hepatocellular Carcinoma

    PubMed Central

    Kongkavitoon, Pornrat; Tangkijvanich, Pisit; Hirankarn, Nattiya; Palaga, Tanapat

    2016-01-01

    Hepatitis virus B (HBV) infection is one of the major causes of hepatocellular carcinomas (HCC). HBx protein encoded in HBV genome is one of the key viral factors leading to malignant transformation of infected cells. HBx functions by interfering with cellular functions, causing aberration in cellular behaviour and transformation. Notch signalling is a well-conserved pathway involved in cellular differentiation, cell survival and cell death operating in various types of cells. Aberration in the Notch signalling pathways is linked to various tumors, including HCC. The role of HBx on the Notch signalling in HCC, however, is still controversial. In this study, we reported that HBV genome-containing HCC cell line HepG2 (HepG2.2.15) expressed higher Notch1 and Delta-like 4 (Dll4), compared to the control HepG2 without HBV genome. This upregulation coincided with increased appearance of the cleavage of Notch1, indicating constitutively activated Notch signalling. Silencing of HBx specifically reduced the level of Dll4 and cleaved Notch1. The increase in Dll4 level was confirmed in clinical specimens of HCC lesion, in comparison with non-tumor lesions. Using specific signalling pathway inhibitors, we found that MEK1/2, PI3K/AKT and NF-κB pathways are critical for HBx-mediated Dll4 upregulation. Silencing of HBx clearly decreased the level of phosphorylation of Akt and Erk1/2. Upon silencing of Dll4 in HepG2.2.15, decreased cleaved Notch1, increased apoptosis and cell cycle arrest were observed, suggesting a critical role of HBx-Dll4-Notch1 axis in regulating cell survival in HCC. Furthermore, clonogenic assay confirmed the important role of Dll4 in regulating cell survival of HBV-genome containing HCC cell line. Taken together, we reported a link between HBx and the Notch signalling in HCC that affects cell survival of HCC, which can be a potential target for therapy. PMID:26766040

  14. A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer

    PubMed Central

    Arcaroli, John J.; Tai, W.M.; McWilliams, Ryan; Bagby, Stacey; Blatchford, Patrick J.; Varella-Garcia, Marileila; Purkey, Alicia; Quackenbush, Kevin S.; Song, Eun-Kee; Pitts, Todd M.; Gao, Dexiang; Lieu, Chris; McManus, Martine; Tan, Aik Choon; Zheng, Xianxian; Zhang, Qin; Ozeck, Mark; Olson, Peter; Jiang, Zhi-Qin; Kopetz, Scott; Jimeno, Antonio; Keysar, Stephen; Eckhardt, Gail; Messersmith, Wells A.

    2015-01-01

    Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes. PMID:26152787

  15. A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer.

    PubMed

    Arcaroli, John J; Tai, W M; McWilliams, Ryan; Bagby, Stacey; Blatchford, Patrick J; Varella-Garcia, Marileila; Purkey, Alicia; Quackenbush, Kevin S; Song, Eun-Kee; Pitts, Todd M; Gao, Dexiang; Lieu, Chris; McManus, Martine; Tan, Aik Choon; Zheng, Xianxian; Zhang, Qin; Ozeck, Mark; Olson, Peter; Jiang, Zhi-Qin; Kopetz, Scott; Jimeno, Antonio; Keysar, Stephen; Eckhardt, Gail; Messersmith, Wells A

    2016-01-01

    Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes. PMID:26152787

  16. Risk of Anterior Femoral Notching in Navigated Total Knee Arthroplasty

    PubMed Central

    Lee, Ju Hong

    2015-01-01

    Background We retrospectively investigated the prevalence of femoral anterior notching and risk factors after total knee arthroplasty (TKA) using an image-free navigation system. Methods We retrospectively reviewed 148 consecutive TKAs in 130 patients beginning in July 2005. Seventy knees (62 patients) underwent conventional TKA, and 78 knees (68 patients) received navigated TKA. We investigated the prevalence of femoral anterior notching and measured notching depth by conventional and navigated TKA. Additionally, the navigated TKA group was categorized into two subgroups according to whether anterior femoral notching had occurred. The degree of preoperative varus deformity, femoral bowing, and mediolateral suitability of the size of the femoral component were determined by reviewing preoperative and postoperative radiographs. The resection angle on the sagittal plane and the angle of external rotation that was set by the navigation system were checked when resecting the distal femur. Clinical outcomes were compared using range of motion (ROM) and the Hospital for Special Surgery (HSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAX) scores between the two groups. Results The prevalence of anterior femoral notching by conventional TKA was 5.7%, and that for navigated TKA was 16.7% (p = 0.037). Mean notching depth by conventional TKA was 2.92 ± 1.18 mm (range, 1.8 to 4.5 mm) and 3.32 ± 1.54 mm (range, 1.55 to 6.93 mm) by navigated TKA. Preoperative anterior femoral bowing was observed in 61.5% (p = 0.047) and both anterior and lateral femoral bowing in five cases in notching group during navigated TKA (p = 0.021). Oversized femoral components were inserted in 53.8% of cases (p = 0.035). No differences in clinical outcomes for ROM or the HSS and WOMAX scores were observed between the groups. A periprosthetic fracture, which was considered a notching-related side effect, occurred in one case each in the conventional and navigated TKA groups

  17. Suprascapular Notch Asymmetry: A Study on 311 Patients

    PubMed Central

    Polguj, Michał; Sibiński, Marcin; Grzegorzewski, Andrzej; Grzelak, Piotr; Stefańczyk, Ludomir; Topol, Mirosław

    2014-01-01

    The most important risk factor of suprascapular nerve entrapment is probably the shape of the suprascapular notch (SSN). The aim of the study was to perform a radiological study of the symmetry of SSN. Included in the study were 311 patients (137 women and 174 men) who underwent standard computed tomography investigation of the chest. A total of 622 computed tomography scans of scapulae were retrospectively analyzed to classify suprascapular notches into five types. Suprascapular notch was recognized as a symmetrical feature in 53.45% of the patients. Symmetry was more frequently seen in females (54.0% versus 52.9%), but not to any significant degree (P = 0.8413). Type III was the most commonly noted symmetrical feature (66.9%) and type II was less common (0.6%). Type III was the most symmetrical type of suprascapular notch, occurring significantly more often as a symmetrical feature in comparison with type I (P < 0.0001), type II (P = 0.00137), or type IV (P = 0.001). Our investigation did not show that the suprascapular notch is a symmetrical feature. However, symmetry was recognized more frequently in the case of type III SSN. No significant differences in symmetry were found with regard to sex. PMID:24949427

  18. Does therapeutic intervention in atopic dermatitis normalize epidermal Notch deficiency?

    PubMed

    Melnik, Bodo C

    2014-10-01

    This viewpoint presents a unifying concept for the treatment of atopic dermatitis (AD) that is based on the improvement of deficient Notch signalling, which appears to represent the fundamental epithelial defect of AD resulting in epidermal and immunological barrier dysfunction. One study of AD patients demonstrated a marked epidermal deficiency of Notch receptors and several mouse models with genetically suppressed Notch signalling exhibit dry skin, signs of scratching, skin barrier abnormalities, increased transepidermal water loss and Th2 cell-mediated immunological changes closely resembling human AD. Notch signalling is critically involved in the differentiation of regulatory T cells, in the feedback inhibition of activated innate immunity, in the repression of activating protein-1 (AP-1), the regulation of late epidermal differentiation associated with filaggrin- and stratum corneum barrier lipid processing, in aquaporin 3- and claudin-1 expression and in keratinocyte-mediated release of thymic stromal lymphopoietin (TSLP), which promotes Th2-driven immune responses with TSLP- and IL-31-mediated stimulation of cutaneous sensory neurons involved in the induction of itch. Translational evidence will be provided that all major therapeutic regimens employed for the treatment of AD such as glucocorticoids, calcineurin inhibitors and UV radiation may converge in the upregulation of impaired Notch signalling, the proposed pathogenic defect of AD. PMID:24889007

  19. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

    NASA Astrophysics Data System (ADS)

    Ramasamy, Saravana K.; Kusumbe, Anjali P.; Wang, Lin; Adams, Ralf H.

    2014-03-01

    Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.

  20. Why does necking ignore notches in dynamic tension?

    NASA Astrophysics Data System (ADS)

    Rotbaum, Y.; Osovski, S.; Rittel, D.

    2015-09-01

    Recent experimental work has revealed that necking of tensile specimens, subjected to dynamic loading, is a deterministic phenomenon, governed by the applied boundary conditions. Furthermore it was shown that the potential sited, dictated by the boundary conditions, may prevail even in the presence of a notch, thus necking may occur away of the notched region. The present paper combines experimental and numerical work to address this issue. Specifically, it is shown that the dynamic tensile failure locus is dictated by both the applied velocity boundary condition and the material mechanical properties, specifically strain-rate sensitivity and strain-rate hardening. It is shown that at sufficiently high impact velocities, the flows stress in the notch vicinity becomes quite higher than in the rest of the specimen, so that while the former resists deformation, it transfers the load to the latter, resulting in the formation of a local neck and failure away from the notch. Small local perturbations in the material properties are shown to be sufficient to stabilize the structure under local failure until a neck forms elsewhere. While the physical observations are quite counterintuitive with respect to the engineering views of stress concentrator's effect, the present work rationalizes those observations and also provides information for the designers of dynamically tensioned structures that may contain notches or similar flaws.

  1. Parallel Helmholtz resonators for a planar acoustic notch filter

    NASA Astrophysics Data System (ADS)

    Isozaki, Akihiro; Takahashi, Hidetoshi; Tamura, Hiroto; Takahata, Tomoyuki; Matsumoto, Kiyoshi; Shimoyama, Isao

    2014-12-01

    This paper reports on an acoustic planar notch filter with a sub-wavelength thickness at the notch frequency. The developed notch filter consists of a number of spherical Helmholtz resonators (HRs) connected to a hole created in a plate. The HRs were placed at the in-plane vertices of a regular polygon. A simulated pressure distribution revealed that this uniform arrangement of HRs improves the silencing effect because the uniform applied waves emitted from the HRs act as canceling waves to the cross-section of the short hole (in this case, the length of the hole is sub-wavelength). The total pressure emitted from the HRs is equal regardless of the number of HRs connected to the hole. Therefore, the arrangement of HRs is essential for realizing a planar notch filter. Simulated transmittance spectra showed that the depth of the dip in the transmittance increased with the number of uniformly arranged HRs. We confirmed that the experimental transmittance spectra of fabricated notch filters, which consisted of between one and six HRs, agreed with the simulated transmittance spectra. The design of the acoustic filter presented in this study and the corresponding analysis should motivate further development of thin acoustic filters.

  2. The dicrotic notch analyzed by a numerical model.

    PubMed

    Politi, María Teresa; Ghigo, Arthur; Fernández, Juan Manuel; Khelifa, Ismaïl; Gaudric, Julien; Fullana, José María; Lagrée, Pierre-Yves

    2016-05-01

    Divergent concepts on the origin of the dicrotic notch are widespread in medical literature and education. Since most medical textbooks explain the origin of the dicrotic notch as caused by the aortic valve closure itself, this is commonly transmitted in medical physiology courses. We present clinical data and numerical simulations to demonstrate that reflected pressure waves could participate as one of the causes of the dicrotic notch. Our experimental data from continuous arterial pressure measurements from adult patients undergoing vascular surgery suggest that isolated changes in peripheral vascular resistance using an intravenous bolus of phenylephrine (a selective alpha 1-receptor agonist and thus a potent vasoconstrictor) modify the dicrotic notch. We then explore the mechanisms behind this phenomenon by using a numerical model based on integrated axisymmetric Navier-Stokes equations to compute the hemodynamic flow. Our model illustrates clearly how modifications in peripheral artery resistance may result in changes in the amplitude of the dicrotic notch by modifying reflected pressure waves. We believe that this could be a useful tool in teaching medical physiology courses. PMID:27016670

  3. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

    PubMed Central

    Wang, Lin; Adams, Ralf H.

    2016-01-01

    Blood vessel growth in the skeletal system and osteogenesis appear coupled suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells1,2. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here, we show that vascular growth in bone involves a specialised, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours3,4. Endothelial cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae, and decreased bone mass. Based on a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralisation, chondrocyte maturation, the formation of trabeculae, and osteoprogenitor numbers in endothelial cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications. PMID:24647000

  4. Loss of the Notch effector RBPJ promotes tumorigenesis

    PubMed Central

    Kulic, Iva; Robertson, Gordon; Chang, Linda; Baker, Jennifer H.E.; Lockwood, William W.; Mok, Winnie; Fuller, Megan; Fournier, Michèle; Wong, Nelson; Chou, Vennie; Robinson, Mark D.; Chun, Hye-Jung; Gilks, Blake; Kempkes, Bettina; Thomson, Thomas A.; Hirst, Martin; Minchinton, Andrew I.; Lam, Wan L.; Jones, Steven; Marra, Marco

    2015-01-01

    Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumorigenesis. PMID:25512468

  5. Oncogenic programmes and Notch activity: an 'organized crime'?

    PubMed

    Dominguez, Maria

    2014-04-01

    The inappropriate Notch signalling can influence virtually all aspect of cancer, including tumour-cell growth, survival, apoptosis, angiogenesis, invasion and metastasis, although it does not do this alone. Hence, elucidating the partners of Notch that are active in cancer is now the focus of much intense research activity. The genetic toolkits available, coupled to the small size and short life of the fruit fly Drosophila melanogaster, makes this an inexpensive and effective animal model, suited to large-scale cancer gene discovery studies. The fly eye is not only a non-vital organ but its stereotyped size and disposition also means it is easy to screen for mutations that cause tumours and metastases and provides ample opportunities to test cancer theories and to unravel unanticipated nexus between Notch and other cancer genes, or to discover unforeseen Notch's partners in cancer. These studies suggest that Notch's oncogenic capacity is brought about not simply by increasing signal strength but through partnerships, whereby oncogenes gain more by cooperating than acting individually, as in a ring 'organized crime'. PMID:24780858

  6. Characterization of Notch Signaling During Osteogenic Differentiation in Human Osteosarcoma Cell Line MG63.

    PubMed

    Ongaro, Alessia; Pellati, Agnese; Bagheri, Leila; Rizzo, Paola; Caliceti, Cristiana; Massari, Leo; De Mattei, Monica

    2016-12-01

    Osteogenic differentiation is a multi-step process controlled by a complex molecular framework. Notch is an evolutionarily conserved intercellular signaling pathway playing a prominent role in cell fate and differentiation, although the mechanisms by which this pathway regulates osteogenesis remain controversial. This study aimed to investigate, in vitro, the involvement of Notch pathway during all the developmental stages of osteogenic differentiation in human osteosarcoma cell line MG63. Cells were cultured in basal condition (control) and in osteoinductive medium (OM). Notch inhibitors were also added in OM to block Notch pathway. During osteogenic differentiation, early (alkaline phosphatase activity and collagen type I) and late osteogenic markers (osteocalcin levels and matrix mineralization), as well as the gene expression of the main osteogenic transcription factors (Runx2, Osterix, and Dlx5) increased. Time dependent changes in the expression of specific Notch receptors were identified in OM versus control with a significant reduction in the expression of Notch1 and Notch3 receptors in the early phase of differentiation, and an increase of Notch2 and Notch4 receptors in the late phase. Among Notch nuclear target genes, Hey1 expression was significantly higher in OM than control, while Hes5 expression decreased. Osteogenic markers were reduced and Hey1 was significantly inhibited by Notch inhibitors, suggesting a role for Notch through the canonical pathway. In conclusion, Notch pathway might be involved with a dual role in osteogenesis of MG63, through the activation of Notch2, Notch4, and Hey1, inducing osteoblast differentiation and the depression of Notch1, Notch3, and Hes5, maintaining an undifferentiated status. J. Cell. Physiol. 231: 2652-2663, 2016. © 2016 Wiley Periodicals, Inc. PMID:26946465

  7. Discrete Notch signaling requirements in the specification of hematopoietic stem cells

    PubMed Central

    Kim, Albert D; Melick, Chase H; Clements, Wilson K; Stachura, David L; Distel, Martin; Panáková, Daniela; MacRae, Calum; Mork, Lindsey A; Crump, J Gage; Traver, David

    2014-01-01

    Hematopoietic stem cells (HSCs) require multiple molecular inputs for proper specification, including activity of the Notch signaling pathway. A requirement for the Notch1 and dispensability of the Notch2 receptor has been demonstrated in mice, but the role of the remaining Notch receptors has not been investigated. Here, we demonstrate that three of the four Notch receptors are independently required for the specification of HSCs in the zebrafish. The orthologues of the murine Notch1 receptor, Notch1a and Notch1b, are each required intrinsically to fate HSCs, just prior to their emergence from aortic hemogenic endothelium. By contrast, the Notch3 receptor is required earlier within the developing somite to regulate HSC emergence in a non-cell-autonomous manner. Epistatic analyses demonstrate that Notch3 function lies downstream of Wnt16, which is required for HSC specification through its regulation of two Notch ligands, dlc and dld. Collectively, these findings demonstrate for the first time that multiple Notch signaling inputs are required to specify HSCs and that Notch3 performs a novel role within the somite to regulate the neighboring precursors of hemogenic endothelium. PMID:25230933

  8. Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model.

    PubMed

    Baumgart, A; Mazur, P K; Anton, M; Rudelius, M; Schwamborn, K; Feuchtinger, A; Behnke, K; Walch, A; Braren, R; Peschel, C; Duyster, J; Siveke, J T; Dechow, T

    2015-01-29

    Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in β-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for β-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of

  9. Characterization and developmental expression of the amphioxus homolog of Notch (AmphiNotch): evolutionary conservation of multiple expression domains in amphioxus and vertebrates.

    PubMed

    Holland, L Z; Rached, L A; Tamme, R; Holland, N D; Kortschak, D; Inoko, H; Shiina, T; Burgtorf, C; Lardelli, M

    2001-04-15

    Notch encodes a transmembrane protein that functions in intercellular signaling. Although there is one Notch gene in Drosophila, vertebrates have three or more with overlapping patterns of embryonic expression. We cloned the entire 7575-bp coding region of an amphioxus Notch gene (AmphiNotch), encoding 2524 amino acids, and obtained the exon/intron organization from a genomic cosmid clone. Southern blot and PCR data indicate that AmphiNotch is the only Notch gene in amphioxus. AmphiNotch, like Drosophila Notch and vertebrate Notch1 and Notch2, has 36 EGF repeats, 3 Notch/lin-12 repeats, a transmembrane region, and 6 ankyrin repeats. Phylogenetic analysis places it at the base of all the vertebrate genes, suggesting it is similar to the ancestral gene from which the vertebrate Notch family genes evolved. AmphiNotch is expressed in all three embryonic germ layers in spatiotemporal patterns strikingly similar to those of all the vertebrate homologs combined. In the developing nerve cord, AmphiNotch is first expressed in the posteriormost part of the neural plate, then it becomes more broadly expressed and later is localized dorsally in the anteriormost part of the nerve cord corresponding to the diencephalon. In late embryos and larvae, AmphiNotch is also expressed in parts of the pharyngeal endoderm, in the anterior gut diverticulum, and, like AmphiPax2/5/8, in the rudiment of Hatschek's kidney. A comparison with Notch1 and Pax5 and Pax8 expression in the embryonic mouse kidney helps support homology of the amphioxus and vertebrate kidneys. AmphiNotch is also an early marker for presumptive mesoderm, transcripts first being detectable at the gastrula stage in a ring of mesendoderm just inside the blastopore and subsequently in the posterior mesoderm, notochord, and somites. As in sea urchins and vertebrates, these domains of AmphiNotch expression overlap with those of several Wnt genes and brachyury. These relationships suggest that amphioxus shares with other

  10. Notch Activation as a Driver of Osteogenic Sarcoma

    PubMed Central

    Tao, Jianning; Jiang, Ming-Ming; Jiang, Lichun; Salvo, Jason S.; Zeng, Huan-Chang; Dawson, Brian; Bertin, Terry K.; Rao, Pulivarthi H.; Chen, Rui; Donehower, Lawrence A.; Gannon, Francis; Lee, Brendan H.

    2014-01-01

    Summary Osteogenic sarcoma (OS) is a deadly skeletal malignancy whose cause is unknown. We report here a mouse model of OS based on conditional expression of the intracellular domain of Notch1 (NICD). Expression of the NICD in immature osteoblasts was sufficient to drive the formation of bone tumors, including OS, with complete penetrance. These tumors display features of human OS, namely histopathology, cytogenetic complexity, and metastatic potential. We show that Notch activation combined with loss of p53 synergistically accelerates OS development in mice although p53-driven OS is not Rbpj-dependent, which demonstrates a dual dominance of the Notch oncogene and p53 mutation in the development of OS. Using this model, we also reveal the osteoblasts as the potential sources of OS. PMID:25203324

  11. Failure mechanics of fiber composite notched charpy specimens. [stress analysis

    NASA Technical Reports Server (NTRS)

    Chamis, C. C.

    1976-01-01

    A finite element stress analysis was performed to determine the stress variation in the vicinity of the notch and far field of fiber composites Charpy specimens (ASTM Standard). NASTRAN was used for the finite element analysis assuming linear behavior and equivalent static load. The unidirectional composites investigated ranged from Thornel 75 Epoxy to S-Glass/Epoxy with the fiber direction parallel to the long dimension of the specimen. The results indicate a biaxial stress state exists in (1) the notch vicinity which is dominated by transverse tensile and interlaminar shear and (2) near the load application point which is dominated by transverse compression and interlaminar shear. The results also lead to the postulation of hypotheses for the predominant failure modes, the fracture initiation, and the fracture process. Finally, the results indicate that the notched Charpy test specimen is not suitable for assessing the impact resistance of nonmetallic fiber composites directly.

  12. Broadband notch filter design for millimeter-wave plasma diagnosticsa)

    NASA Astrophysics Data System (ADS)

    Furtula, V.; Michelsen, P. K.; Leipold, F.; Salewski, M.; Korsholm, S. B.; Meo, F.; Nielsen, S. K.; Stejner, M.; Moseev, D.; Johansen, T.

    2010-10-01

    Notch filters are integrated in plasma diagnostic systems to protect millimeter-wave receivers from intensive stray radiation. Here we present a design of a notch filter with a center frequency of 140 GHz, a rejection bandwidth of ˜900 MHz, and a typical insertion loss below 2 dB in the passband of ±9 GHz. The design is based on a fundamental rectangular waveguide with eight cylindrical cavities coupled by T-junction apertures formed as thin slits. Parameters that affect the notch performance such as physical lengths and conductor materials are discussed. The excited resonance mode in the cylindrical cavities is the fundamental TE11. The performance of the constructed filter is measured using a vector network analyzer monitoring a total bandwidth of 30 GHz. We compare the measurements with numerical simulations.

  13. Notch activation as a driver of osteogenic sarcoma.

    PubMed

    Tao, Jianning; Jiang, Ming-Ming; Jiang, Lichun; Salvo, Jason S; Zeng, Huan-Chang; Dawson, Brian; Bertin, Terry K; Rao, Pulivarthi H; Chen, Rui; Donehower, Lawrence A; Gannon, Francis; Lee, Brendan H

    2014-09-01

    Osteogenic sarcoma (OS) is a deadly skeletal malignancy whose cause is unknown. We report here a mouse model of OS based on conditional expression of the intracellular domain of Notch1 (NICD). Expression of the NICD in immature osteoblasts was sufficient to drive the formation of bone tumors, including OS, with complete penetrance. These tumors display features of human OS; namely, histopathology, cytogenetic complexity, and metastatic potential. We show that Notch activation combined with loss of p53 synergistically accelerates OS development in mice, although p53-driven OS is not Rbpj dependent, which demonstrates a dual dominance of the Notch oncogene and p53 mutation in the development of OS. Using this model, we also reveal the osteoblasts as the potential sources of OS. PMID:25203324

  14. Structural basis for Notch1 engagement of Delta-like 4

    SciTech Connect

    Luca, Vincent C.; Jude, Kevin M.; Pierce, Nathan W.; Nachury, Maxence V.; Fischer, Suzanne; Garcia, K. Christopher

    2015-02-20

    Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor–like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. Lastly, the elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.

  15. In Vivo Notch Signaling Blockade Induces Abnormal Spermatogenesis in the Mouse

    PubMed Central

    Murta, Daniel; Batista, Marta; Trindade, Alexandre; Silva, Elisabete; Henrique, Domingos; Duarte, António; Lopes-da-Costa, Luís

    2014-01-01

    In a previous study we identified active Notch signaling in key cellular events occurring at adult spermatogenesis. In this study, we evaluated the function of Notch signaling in spermatogenesis through the effects of in vivo Notch blockade. Adult CD1 male mice were either submitted to a long term DAPT (?-secretase inhibitor) or vehicle treatment. Treatment duration was designed to attain one half the time (25 days) or the time (43 days) required to accomplish a complete cycle of spermatogenesis. Blockade of Notch signaling was depicted from decreased transcription of Notch effector genes. Notch signaling blockade disrupted the expression patterns of Notch components in the testis, induced male germ cell fate aberrations, and significantly increased germ cell apoptosis, mainly in the last stages of the spermatogenic cycle, and epididymis spermatozoa morphological defects. These effects were more pronounced following the 43 day than the 25 day DAPT treatment schedule. These results indicate a relevant regulatory role of Notch signaling in mammalian spermatogenesis. PMID:25412258

  16. Endothelial-to-hematopoietic transition: Notch-ing vessels into blood.

    PubMed

    Kanz, Dirk; Konantz, Martina; Alghisi, Elisa; North, Trista E; Lengerke, Claudia

    2016-04-01

    During development, hematopoietic stem cells (HSCs) are formed in a temporally and spatially restricted manner, arising from specialized endothelial cells (ECs) in the ventral wall of the dorsal aorta within the evolutionary conserved aorta-gonad-mesonephros region. Our understanding of the processes regulating the birth of HSCs from ECs has been recently advanced by comprehensive molecular analyses of developing murine hematopoietic cell populations complemented by studies in the zebrafish model, with the latter offering unique advantages for genetic studies and direct in vivo visualization of HSC emergence. Here, we provide a concise review of the current knowledge and recent advances regarding the cellular origin and molecular regulation of HSC development, with particular focus on the process of endothelial-to-hematopoietic transition and its primary regulator, the Notch signaling pathway. PMID:27015586

  17. Lattice invariants for knots

    SciTech Connect

    Janse Van Rensburg, E.J.

    1996-12-31

    The geometry of polygonal knots in the cubic lattice may be used to define some knot invariants. One such invariant is the minimal edge number, which is the minimum number of edges necessary (and sufficient) to construct a lattice knot of given type. In addition, one may also define the minimal (unfolded) surface number, and the minimal (unfolded) boundary number; these are the minimum number of 2-cells necessary to construct an unfolded lattice Seifert surface of a given knot type in the lattice, and the minimum number of edges necessary in a lattice knot to guarantee the existence of an unfolded lattice Seifert surface. In addition, I derive some relations amongst these invariants. 8 refs., 5 figs., 2 tabs.

  18. Honokiol inhibits melanoma stem cells by targeting notch signaling.

    PubMed

    Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu; Standing, David; Subramaniam, Dharmalingam; Umar, Shahid; Jensen, Roy A; Anant, Shrikant; Mammen, Joshua M V

    2015-12-01

    Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling. PMID:25491779

  19. Molecular Characterization of Notch1 Positive Progenitor Cells in the Developing Retina

    PubMed Central

    Dvoriantchikova, Galina; Perea-Martinez, Isabel; Pappas, Steve; Barry, Ariel Faye; Danek, Dagmara; Dvoriantchikova, Xenia; Pelaez, Daniel; Ivanov, Dmitry

    2015-01-01

    The oscillatory expression of Notch signaling in neural progenitors suggests that both repressors and activators of neural fate specification are expressed in the same progenitors. Since Notch1 regulates photoreceptor differentiation and contributes (together with Notch3) to ganglion cell fate specification, we hypothesized that genes encoding photoreceptor and ganglion cell fate activators would be highly expressed in Notch1 receptor-bearing (Notch1+) progenitors, directing these cells to differentiate into photoreceptors or into ganglion cells when Notch1 activity is diminished. To identify these genes, we used microarray analysis to study expression profiles of whole retinas and isolated from them Notch1+ cells at embryonic day 14 (E14) and postnatal day 0 (P0). To isolate Notch1+ cells, we utilized immunomagnetic cell separation. We also used Notch3 knockout (Notch3KO) animals to evaluate the contribution of Notch3 signaling in ganglion cell differentiation. Hierarchical clustering of 6,301 differentially expressed genes showed that Notch1+ cells grouped near the same developmental stage retina cluster. At E14, we found higher expression of repressors (Notch1, Hes5) and activators (Dll3, Atoh7, Otx2) of neuronal differentiation in Notch1+ cells compared to whole retinal cell populations. At P0, Notch1, Hes5, and Dll1 expression was significantly higher in Notch1+ cells than in whole retinas. Otx2 expression was more than thirty times higher than Atoh7 expression in Notch1+ cells at P0. We also observed that retinas of wild type animals had only 14% (P < 0.05) more ganglion cells compared to Notch3KO mice. Since this number is relatively small and Notch1 has been shown to contribute to ganglion cell fate specification, we suggested that Notch1 signaling may play a more significant role in RGC development than the Notch3 signaling cascade. Finally, our findings suggest that Notch1+ progenitors—since they heavily express both pro-ganglion cell (Atoh7) and pro

  20. Notch Receptor Expression in Neurogenic Regions of the Adult Zebrafish Brain

    PubMed Central

    de Oliveira-Carlos, Vanessa; Ganz, Julia; Hans, Stefan; Kaslin, Jan; Brand, Michael

    2013-01-01

    The adult zebrash brain has a remarkable constitutive neurogenic capacity. The regulation and maintenance of its adult neurogenic niches are poorly understood. In mammals, Notch signaling is involved in stem cell maintenance both in embryonic and adult CNS. To better understand how Notch signaling is involved in stem cell maintenance during adult neurogenesis in zebrafish we analysed Notch receptor expression in five neurogenic zones of the adult zebrafish brain. Combining proliferation and glial markers we identified several subsets of Notch receptor expressing cells. We found that 90 of proliferating radial glia express notch1a, notch1b and notch3. In contrast, the proliferating non-glial populations of the dorsal telencephalon and hypothalamus rarely express notch3 and about half express notch1a/1b. In the non-proliferating radial glia notch3 is the predominant receptor throughout the brain. In the ventral telencephalon and in the mitotic area of the optic tectum, where cells have neuroepithelial properties, notch1a/1b/3 are expressed in most proliferating cells. However, in the cerebellar niche, although progenitors also have neuroepithelial properties, only notch1a/1b are expressed in a high number of PCNA cells. In this region notch3 expression is mostly in Bergmann glia and at low levels in few PCNA cells. Additionally, we found that in the proliferation zone of the ventral telencephalon, Notch receptors display an apical high to basal low gradient of expression. Notch receptors are also expressed in subpopulations of oligodendrocytes, neurons and endothelial cells. We suggest that the partial regional heterogeneity observed for Notch expression in progenitor cells might be related to the cellular diversity present in each of these neurogenic niches. PMID:24039926

  1. Deformation characteristics and time-dependent notch sensitivity of Udimet 700 at intermediate temperatures

    NASA Technical Reports Server (NTRS)

    Wilson, D. J.

    1974-01-01

    Time dependent notch sensitivity was observed in Udimet 700 sheet, bar, and investment castings between 1000 and 1400 F (538 -760 C), but not at 1600 F (871 C). As was the case for modified Waspaloy, Waspaloy and Inconel 718, it occurred in notched specimens loaded below the yield strength when the creep deformation was localized. For each alloy and notched specimen geometry, a stress-average particle size zone can be defined that characterizes the notch sensitive behavior.

  2. Use of notched beams to establish fracture criteria for beryllium

    SciTech Connect

    Mayville, R.A.

    1980-01-04

    The fracture of an improved form of pure beryllium was studied under triaxial tensile stresses. This state of stress was produced by testing notched beams, which were thick enough to be in a state of plane strain at the center. A plane strain, elastic-incremental plasticity finite element program was then used to determine the stress and strain distributions at fracture. A four-point bend fixture was used to load the specimens. It was carefully designed and manufactured to eliminate virtually all of the shear stresses at the reduced section of the notched beams. The unixial properties were obtained.

  3. Audiometric notch as a sign of noise induced hearing loss

    PubMed Central

    McBride, D; Williams, S

    2001-01-01

    OBJECTIVES—To investigate the relation between different types of exposure to noise and a classic sign of noise induced hearing loss (NIHL), the audiometric notch.
METHODS—The study sample had exposure to both continuous and impulse noise and was drawn from a population of electrical transmission workers. Audiograms, taken as part of a hearing conservation programme, were read by three clinicians experienced in the assessment of NIHL. Working independently and using their clinical judgment, they were asked to identify localised increases in the threshold of hearing (audiometric notches) which they would attribute to noise, had a suitable history of exposure been elicited. Prevalent cases of NIHL were identified by the presence of a notch in either ear. Risk factors for NIHL were assessed by a questionnaire which sought information about exposure to air blast circuit breaker noise; firearms; explosions, and continuous noise. The odds of exposure to these factors in those with and without hearing loss were calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated by logistic regression.
RESULTS—Of the 648 questionnaires sent out 357 were returned, a response rate of 55%. Of these, at least two out of the three assessors identified 175 (49%) people with a notch at any audiometric frequency. There was no association between these cases and the NIHL risk factors identified by the questionnaire, but a further frequency specific analysis showed a small proportion of people (15 (4%)) with notches at 4 kHz who had the expected associations with exposure to noise and a significant OR for firearms of 4.25 (95% CI 1.28 to 14.1). The much larger proportion of people with 6 kHz notches (110 (31%)) did not show these associations.
CONCLUSIONS—To diagnose NIHL it is important to elicit a detailed and accurate history of exposure to noise: although the notch at 4 kHz is a well established clinical sign and may be valuable in

  4. Nonlinear acoustic measurements ahead of a notch during fatigue

    NASA Astrophysics Data System (ADS)

    Martin, R. W.; Mooers, R. D.; Hutson, A. L.; Sathish, S.; Blodgett, M. P.

    2013-01-01

    This paper presents measurements of relative nonlinear acoustic parameter (βrel), ahead of a notch in Al 7075-T651 dog bone samples, subjected to fatigue. It is compared with crack growth measurements on the same samples. Measurements performed on two samples subjected to identical fatigue conditions that failed at vastly different number of fatigue cycles are described. The βrel measurement for both samples as a function of fatigue cycles was fit a Boltzmann curve. The role of changing βrel ahead of a notch is explored as a possible approach for remain life evaluation.

  5. Kicking it up a Notch for the best in show: Scalloped leads Yorkie into the haematopoietic arena

    PubMed Central

    Ferguson, Gabriel B; Martinez-Agosto, Julian A

    2014-01-01

    Maintenance and differentiation of progenitor cells is essential for proper organ development and adaptation to environmental stress and injury. In Drosophila melanogaster, the haematopietic system serves as an ideal model for interrogating the function of signaling pathways required for progenitor maintenance and cell fate determination. Here we focus on the role of the Hippo pathway effectors Yorkie and Scalloped in mediating and facilitating Notch signaling-mediated lineage specification in the lymph gland, the primary center for haematopoiesis within the developing larva. We discuss the regulatory mechanisms which promote Notch activity during normal haematopoiesis and its modulation during immune challenge conditions. We provide additional evidence establishing the hierarchy of signaling events during crystal cell formation, highlighting the relationship between Yorkie, Scalloped and Lozenge, while expanding on the role of Yorkie in promoting hemocyte survival and the developmental regulation of Notch and its ligand, Serrate, within the lymph gland. Finally, we propose additional areas of exploration that may provide mechanistic insight into the environmental and non-cell autonomous regulation of cell fate in the blood system. PMID:26151599

  6. High NOTCH activity induces radiation resistance in non small cell lung cancer

    PubMed Central

    Habets, Roger; Span, Paul; Dubois, Ludwig; Paesmans, Kim; Kattenbeld, Bo; Cleutjens, Jack; Groot, Arjan J.; Schuurbiers, Olga C.J.; Lambin, Philippe; Bussink, Jan; Vooijs, Marc

    2016-01-01

    Background and purpose Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesized that high NOTCH activity contributes to radiation resistance. Materials and methods NOTCH signaling in NSCLC patient samples was investigated using quantitative RT-PCR. H460 NSCLC cells with either high or blocked NOTCH activity were generated and their radiation sensitivity monitored using clonogenic assays. In vivo, xenograft tumors were irradiated and response assessed using growth delay. Microenvironmental parameters were analyzed by immunohistochemistry. Results Patients with high NOTCH activity in tumors showed significantly worse disease-free survival. In vitro, NOTCH activity did not affect the proliferation or intrinsic radiosensitivity of NSCLC cells. In contrast, xenografts with blocked NOTCH activity grew slower than wild type tumors. Tumors with high NOTCH activity grew significantly faster, were more hypoxic and showed a radioresistant phenotype. Conclusions We demonstrate an important role for NOTCH in tumor growth and correlate high NOTCH activity with poor prognosis and radioresistance. Blocking NOTCH activity in NSCLC might be a promising intervention to improve outcome after radiotherapy. PMID:23891097

  7. Tension Strength, Failure Prediction and Damage Mechanisms in 2D Triaxial Braided Composites with Notch

    NASA Technical Reports Server (NTRS)

    Norman, Timothy L.; Anglin, Colin

    1995-01-01

    The unnotched and notched (open hole) tensile strength and failure mechanisms of two-dimensional (2D) triaxial braided composites were examined. The effect of notch size and notch position were investigated. Damage initiation and propagation in notched and unnotched coupons were also examined. Theory developed to predict the normal stress distribution near an open hole and failure for tape laminated composites was evaluated for its applicability to 2D triaxial braided textile composite materials. Four different fiber architectures were considered; braid angle, yarn and braider size, percentage of longitudinal yarns and braider angle varied. Tape laminates equivalent to textile composites were also constructed for comparison. Unnotched tape equivalents were stronger than braided textiles but exhibited greater notch sensitivity. Notched textiles and tape equivalents have roughly the same strength at large notch sizes. Two common damage mechanisms were found: braider yarn cracking and near notch longitudinal yarn splitting. Cracking was found to initiate in braider yarns in unnotched and notched coupons, and propagate in the direction of the braider yarns until failure. Damage initiation stress decreased with increasing braid angle. No significant differences in prediction of near notch strain between textile and tape equivalents could be detected for small braid angle, but the correlations were weak for textiles with large braid angle. Notch strength could not be predicted using existing anisotropic theory for braided textiles due to their insensitivity to notch.

  8. Notch1 endocytosis is induced by ligand and is required for signal transduction.

    PubMed

    Chapman, G; Major, J A; Iyer, K; James, A C; Pursglove, S E; Moreau, J L M; Dunwoodie, S L

    2016-01-01

    The Notch signalling pathway is widely utilised during embryogenesis in situations where cell-cell interactions are important for cell fate specification and differentiation. DSL ligand endocytosis into the ligand-expressing cell is an important aspect of Notch signalling because it is thought to supply the force needed to separate the Notch heterodimer to initiate signal transduction. A functional role for receptor endocytosis during Notch signal transduction is more controversial. Here we have used live-cell imaging to examine trafficking of the Notch1 receptor in response to ligand binding. Contact with cells expressing ligands induced internalisation and intracellular trafficking of Notch1. Notch1 endocytosis was accompanied by transendocytosis of ligand into the Notch1-expressing signal-receiving cell. Ligand caused Notch1 endocytosis into SARA-positive endosomes in a manner dependent on clathrin and dynamin function. Moreover, inhibition of endocytosis in the receptor-expressing cell impaired ligand-induced Notch1 signalling. Our findings resolve conflicting observations from mammalian and Drosophila studies by demonstrating that ligand-dependent activation of Notch1 signalling requires receptor endocytosis. Endocytosis of Notch1 may provide a force on the ligand:receptor complex that is important for potent signal transduction. PMID:26522918

  9. Tumor suppressor role of Notch3 in Medullary Thyroid Carcinoma revealed by genetic and pharmacological induction

    PubMed Central

    Jaskula-Sztul, Renata; Eide, Jacob; Tesfazghi, Sara; Dammalapati, Ajitha; Harrison, April D.; Yu, Xiao-Min; Scheinebeck, Casi; Winston-McPherson, Gabrielle; Kupcho, Kevin R.; Robers, Matthew B.; Hundal, Amrit K.; Tang, Weiping; Chen, Herbert

    2014-01-01

    Notch1-3 are transmembrane receptors that appear to be absent in Medullary Thyroid Cancer (MTC). Previous research has shown that induction of Notch1 has a tumor suppressor effect in MTC cell lines, but little is known about the biological consequences of Notch3 activation for the progression of the disease. We elucidate the role of Notch3 in MTC by genetic (doxycycline inducible Notch3 intracellular domain) and pharmacological (AB3, novel HDAC inhibitor) approaches. We find that overexpression of Notch3 leads to the dose dependent reduction of neuroendocrine tumor markers. In addition, Notch3 activity is required to suppress MTC cell proliferation, and the extent of growth repression depends on the amount of Notch3 protein expressed. Moreover, activation of Notch3 induces apoptosis. The translational significance of this finding is highlighted by our observation that MTC tumors lack active Notch3 protein and reinstitution of this isoform could be a therapeutic strategy to treat patients with MTC. We demonstrate, for the first time, that overexpression of Notch3 in MTC cells can alter malignant neuroendocrine phenotype in both in vitro and in vivo models. In addition, our study provides a strong rationale for using Notch3 as a therapeutic target to provide novel pharmacological treatment options for MTC. PMID:25512616

  10. Impact of Spectral Notch Width on Neurophysiological Plasticity and Clinical Effectiveness of the Tailor-Made Notched Music Training.

    PubMed

    Wunderlich, Robert; Lau, Pia; Stein, Alwina; Engell, Alva; Wollbrink, Andreas; Rudack, Claudia; Pantev, Christo

    2015-01-01

    Tinnitus, the ringing in the ears that is unrelated to any external source, causes a significant loss in quality of life, involving sleep disturbance and depression for 1 to 3% of the general population. While in the first place tinnitus may be triggered by damage to the inner ear cells, the neural generators of subjective tinnitus are located in central regions of the nervous system. A loss of lateral inhibition, tonotopical reorganization and a gain-increase in response to the sensory deprivation result in hypersensitivity and hyperactivity in certain regions of the auditory cortex. In the tailor-made notched music training (TMNMT) patients listen to music from which the frequency spectrum of the tinnitus has been removed. This evokes strong lateral inhibition from neurons tuned to adjacent frequencies onto the neurons involved in the tinnitus percept. A reduction of tinnitus loudness and tinnitus-related neural activity was achieved with TMNMT in previous studies. As the effect of lateral inhibition depends on the bandwidth of the notch, in the current study we altered the notch width to find the most effective notch width for TMNMT. We compared 1-octave notch width with ½-octave and ¼-octave. Participants chose their favorite music for the training that included three month of two hours daily listening. The outcome was measured by means of standardized questionnaires and magnetoencephalography. We found a general reduction of tinnitus distress in all administered tinnitus questionnaires after the training. Additionally, tinnitus-related neural activity was reduced after the training. Nevertheless, notch width did not have an influence on the behavioral or neural effects of TMNMT. This could be due to a non-linear resolution of lateral inhibition in high frequencies. PMID:26406446

  11. Impact of Spectral Notch Width on Neurophysiological Plasticity and Clinical Effectiveness of the Tailor-Made Notched Music Training

    PubMed Central

    Wunderlich, Robert; Lau, Pia; Stein, Alwina; Engell, Alva; Wollbrink, Andreas; Rudack, Claudia; Pantev, Christo

    2015-01-01

    Tinnitus, the ringing in the ears that is unrelated to any external source, causes a significant loss in quality of life, involving sleep disturbance and depression for 1 to 3% of the general population. While in the first place tinnitus may be triggered by damage to the inner ear cells, the neural generators of subjective tinnitus are located in central regions of the nervous system. A loss of lateral inhibition, tonotopical reorganization and a gain-increase in response to the sensory deprivation result in hypersensitivity and hyperactivity in certain regions of the auditory cortex. In the tailor-made notched music training (TMNMT) patients listen to music from which the frequency spectrum of the tinnitus has been removed. This evokes strong lateral inhibition from neurons tuned to adjacent frequencies onto the neurons involved in the tinnitus percept. A reduction of tinnitus loudness and tinnitus-related neural activity was achieved with TMNMT in previous studies. As the effect of lateral inhibition depends on the bandwidth of the notch, in the current study we altered the notch width to find the most effective notch width for TMNMT. We compared 1-octave notch width with ½-octave and ¼-octave. Participants chose their favorite music for the training that included three month of two hours daily listening. The outcome was measured by means of standardized questionnaires and magnetoencephalography. We found a general reduction of tinnitus distress in all administered tinnitus questionnaires after the training. Additionally, tinnitus-related neural activity was reduced after the training. Nevertheless, notch width did not have an influence on the behavioral or neural effects of TMNMT. This could be due to a non-linear resolution of lateral inhibition in high frequencies. PMID:26406446

  12. Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL

    PubMed Central

    Jeannet, Robin; Mastio, Jérôme; Macias-Garcia, Alejandra; Oravecz, Attila; Ashworth, Todd; Geimer Le Lay, Anne-Solen; Jost, Bernard; Le Gras, Stéphanie; Ghysdael, Jacques; Gridley, Thomas; Honjo, Tasuku; Radtke, Freddy; Aster, Jon C.; Kastner, Philippe

    2010-01-01

    The Notch pathway is frequently activated in T-cell acute lymphoblastic leukemias (T-ALLs). Of the Notch receptors, Notch1 is a recurrent target of gain-of-function mutations and Notch3 is expressed in all T-ALLs, but it is currently unclear how these receptors contribute to T-cell transformation in vivo. We investigated the role of Notch1 and Notch3 in T-ALL progression by a genetic approach, in mice bearing a knockdown mutation in the Ikaros gene that spontaneously develop Notch-dependent T-ALL. While deletion of Notch3 has little effect, T cell–specific deletion of floxed Notch1 promoter/exon 1 sequences significantly accelerates leukemogenesis. Notch1-deleted tumors lack surface Notch1 but express γ-secretase–cleaved intracellular Notch1 proteins. In addition, these tumors accumulate high levels of truncated Notch1 transcripts that are caused by aberrant transcription from cryptic initiation sites in the 3′ part of the gene. Deletion of the floxed sequences directly reprograms the Notch1 locus to begin transcription from these 3′ promoters and is accompanied by an epigenetic reorganization of the Notch1 locus that is consistent with transcriptional activation. Further, spontaneous deletion of 5′ Notch1 sequences occurs in approximately 75% of Ikaros-deficient T-ALLs. These results reveal a novel mechanism for the oncogenic activation of the Notch1 gene after deletion of its main promoter. PMID:20829372

  13. Supersymmetry on the lattice

    NASA Astrophysics Data System (ADS)

    Bergner, Georg; Catterall, Simon

    2016-08-01

    We discuss the motivations, difficulties and progress in the study of supersymmetric lattice gauge theories focusing in particular on 𝒩 = 1 and 𝒩 = 4 super-Yang-Mills in four dimensions. Brief reviews of the corresponding lattice formalisms are given and current results are presented and discussed. We conclude with a summary of the main aspects of current work and prospects for the future.

  14. Flat Band Quastiperiodic Lattices

    NASA Astrophysics Data System (ADS)

    Bodyfelt, Joshua; Flach, Sergej; Danieli, Carlo

    2014-03-01

    Translationally invariant lattices with flat bands (FB) in their band structure possess irreducible compact localized flat band states, which can be understood through local rotation to a Fano structure. We present extension of these quasi-1D FB structures under incommensurate lattices, reporting on the FB effects to the Metal-Insulator Transition.

  15. Laterally closed lattice homomorphisms

    NASA Astrophysics Data System (ADS)

    Toumi, Mohamed Ali; Toumi, Nedra

    2006-12-01

    Let A and B be two Archimedean vector lattices and let be a lattice homomorphism. We call that T is laterally closed if T(D) is a maximal orthogonal system in the band generated by T(A) in B, for each maximal orthogonal system D of A. In this paper we prove that any laterally closed lattice homomorphism T of an Archimedean vector lattice A with universal completion Au into a universally complete vector lattice B can be extended to a lattice homomorphism of Au into B, which is an improvement of a result of M. Duhoux and M. Meyer [M. Duhoux and M. Meyer, Extended orthomorphisms and lateral completion of Archimedean Riesz spaces, Ann. Soc. Sci. Bruxelles 98 (1984) 3-18], who established it for the order continuous lattice homomorphism case. Moreover, if in addition Au and B are with point separating order duals (Au)' and B' respectively, then the laterally closedness property becomes a necessary and sufficient condition for any lattice homomorphism to have a similar extension to the whole Au. As an application, we give a new representation theorem for laterally closed d-algebras from which we infer the existence of d-algebra multiplications on the universal completions of d-algebras.

  16. Continuous partition lattice

    PubMed Central

    Björner, Anders

    1987-01-01

    A continuous analogue to the partition lattices is presented. This is the metric completion of the direct limit of a system of embeddings of the finite partition lattices. The construction is analogous to von Neumann's construction of a continuous geometry over a field F from the finite-dimensional projective geometries over F. PMID:16593874

  17. TSG attenuates LPC-induced endothelial cells inflammatory damage through notch signaling inhibition.

    PubMed

    Zhao, Jing; Liang, Yuan; Song, Fan; Xu, Shouzhu; Nian, Lun; Zhou, Xuanxuan; Wang, Siwang

    2016-01-01

    Lysophosphatidylcholine (LPC) induces inflammation in endothelial cells (ECs) but the mechanism is not fully understood. The Notch signaling pathway is involved in chronic EC inflammation, but its functions in LPC-induced endothelial inflammatory damage and 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside's (TSG) protective effect during LPC-induced inflammatory damage in human umbilical vein endothelial cells (HUVECs) is largely unknown. We report that Notch signaling activation contributed to LPC-induced injury in HUVECs, and that TSG protected HUVECs from LPC-induced injury by antagonizing Notch signaling activation by LPC. γ-secretase inhibitor (DAPT), a specific inhibitor of the Notch signaling pathway, and Notch1 siRNA were used to inhibit Notch activity. HUVECs were exposed to LPC in the presence or absence of TSG, DAPT, and Notch1 siRNA. LPC treatment of HUVECs resulted in reduced cell viability, and Notch1 and Hes1 upregulation. Either silencing of Notch1 by siRNA or pharmacological inhibition of Notch signaling by DAPT prevented the loss of cell viability, and induction of apoptosis, and enhanced expression Notch1, Hes1 and MCP-1 by LPC in HUVECs. Similarly, TSG reduced LPC stimulation of Notch1, Hes1, and MCP-1 expression, prevented the release of IL-6 and CRP and rescued HUVECs from LPC-induced cell damage. Our data indicate that the Notch signaling pathway is a crucial mediator of endothelial inflammatory damage and that TSG protects against endothelial inflammatory damage by inhibiting the Notch signaling pathway. Our findings suggest that targeting Notch signaling by natural products such as TSG is a promising strategy for the prevention and treatment of chronic inflammation associated diseases, including atherosclerosis. © 2015 IUBMB Life, 68(1):37-50, 2016. PMID:26662286

  18. Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9.

    PubMed

    Chen, Shan; Tao, Jianning; Bae, Yangjin; Jiang, Ming-Ming; Bertin, Terry; Chen, Yuqing; Yang, Tao; Lee, Brendan

    2013-03-01

    Notch signaling plays a critical role during development by directing the binary cell fate decision between progenitors and differentiated cells. Previous studies have shown sustained Notch activation in cartilage leads to chondrodysplasia. Genetic evidence indicates that Notch regulates limb bud mesenchymal stem cell differentiation into chondrocytes via an Rbpj-dependent Notch pathway. However, it is still unknown how Notch governs chondrogenesis in the axial skeleton where Notch serves a primary patterning function. We hypothesized that both Rbpj-dependent and Rbpj-independent Notch signaling mechanisms might be involved. Cartilage-specific Notch gain-of-function (GOF) mutant mice display chondrodysplasia accompanied by loss of Sox9 expression in vertebrae. To evaluate the contribution of an Rbpj-dependent Notch signaling to this phenotype, we deleted Rbpj on the Notch GOF background. These mice showed persistent spine abnormalities characterized by "butterfly" vertebrae suggesting that removal of Rbpj does not fully rescue the axial skeleton deformities caused by Notch GOF. However, Sox9 protein level was restored in Rbpj-deficient Notch GOF mice compared with Notch GOF mutants, demonstrating that regulation of Sox9 expression is canonical or Rbpj-dependent. To further understand the molecular basis of this regulation, we performed chromatin immunoprecipitation (ChIP) assays and detected the recruitment of the Rbpj/NICD transcription complex to Rbpj-binding sites upstream of the Sox9 promoter. The association of the Rbpj/NICD complex with the Sox9 promoter is associated with transcriptional repression of Sox9 in a cellular model of chondrocyte differentiation. Hence, Notch negatively regulates chondrocyte differentiation in the axial skeleton by suppressing Sox9 transcription, and Rbpj-independent Notch signaling mechanisms may also contribute to axial skeletogenesis. PMID:22991339

  19. Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9

    PubMed Central

    Chen, Shan; Tao, Jianning; Bae, Yangjin; Jiang, Ming-Ming; Bertin, Terry; Chen, Yuqing; Yang, Tao; Lee, Brendan

    2013-01-01

    Abstract Notch signaling plays a critical role during development by directing the binary cell fate decision between progenitors and differentiated cells. Previous studies have shown sustained Notch activation in cartilage leads to chondrodysplasia. Genetic evidence indicates that Notch regulates limb bud mesenchymal stem cell differentiation into chondrocytes via an Rbpj-dependent Notch pathway. However, it is still unknown how Notch governs chondrogenesis in the axial skeleton where Notch serves a primary patterning function. We hypothesized that both Rbpj-dependent and Rbpj-independent Notch signaling mechanisms might be involved. Cartilage-specific Notch gain-of-function (GOF) mutant mice display chondrodysplasia accompanied by loss of Sox9 expression in vertebrae. To evaluate the contribution of an Rbpj-dependent Notch signaling to this phenotype, we deleted Rbpj on the Notch GOF background. These mice showed persistent spine abnormalities characterized by “butterfly” vertebrae suggesting that removal of Rbpj does not fully rescue the axial skeleton deformities caused by Notch GOF. However, Sox9 protein level was restored in Rbpj-deficient Notch GOF mice compared with Notch GOF mutants, demonstrating that regulation of Sox9 expression is canonical or Rbpj-dependent. To further understand the molecular basis of this regulation, we performed chromatin immunoprecipitation (ChIP) assays and detected the recruitment of the Rbpj/NICD transcription complex to Rbpj-binding sites upstream of the Sox9 promoter. The association of the Rbpj/NICD complex with the Sox9 promoter is associated with transcriptional repression of Sox9 in a cellular model of chondrocyte differentiation. Hence, Notch negatively regulates chondrocyte differentiation in the axial skeleton by suppressing Sox9 transcription, and Rbpj-independent Notch signaling mechanisms may also contribute to axial skeletogenesis. PMID:22991339

  20. Honeycomb lattices with defects

    NASA Astrophysics Data System (ADS)

    Spencer, Meryl A.; Ziff, Robert M.

    2016-04-01

    In this paper, we introduce a variant of the honeycomb lattice in which we create defects by randomly exchanging adjacent bonds, producing a random tiling with a distribution of polygon edges. We study the percolation properties on these lattices as a function of the number of exchanged bonds using an alternative computational method. We find the site and bond percolation thresholds are consistent with other three-coordinated lattices with the same standard deviation in the degree distribution of the dual; here we can produce a continuum of lattices with a range of standard deviations in the distribution. These lattices should be useful for modeling other properties of random systems as well as percolation.

  1. Experimental and Numerical Analysis of Notched Composites Under Tension Loading

    NASA Astrophysics Data System (ADS)

    Aidi, Bilel; Case, Scott W.

    2015-12-01

    Experimental quasi-static tests were performed on center notched carbon fiber reinforced polymer (CFRP) composites having different stacking sequences made of G40-600/5245C prepreg. The three-dimensional Digital Image Correlation (DIC) technique was used during quasi-static tests conducted on quasi-isotropic notched samples to obtain the distribution of strains as a function of applied stress. A finite element model was built within Abaqus to predict the notched strength and the strain profiles for comparison with measured results. A user-material subroutine using the multi-continuum theory (MCT) as a failure initiation criterion and an energy-based damage evolution law as implemented by Autodesk Simulation Composite Analysis (ASCA) was used to conduct a quantitative comparison of strain components predicted by the analysis and obtained in the experiments. Good agreement between experimental data and numerical analyses results are observed. Modal analysis was carried out to investigate the effect of static damage on the dominant frequencies of the notched structure using the resulted degraded material elements. The first in-plane mode was found to be a good candidate for tracking the level of damage.

  2. Depinning of domain walls in permalloy nanowires with asymmetric notches.

    PubMed

    Gao, Y; You, B; Ruan, X Z; Liu, M Y; Yang, H L; Zhan, Q F; Li, Z; Lei, N; Zhao, W S; Pan, D F; Wan, J G; Wu, J; Tu, H Q; Wang, J; Zhang, W; Xu, Y B; Du, J

    2016-01-01

    Effective control of the domain wall (DW) motion along the magnetic nanowires is of great importance for fundamental research and potential application in spintronic devices. In this work, a series of permalloy nanowires with an asymmetric notch in the middle were fabricated with only varying the width (d) of the right arm from 200 nm to 1000 nm. The detailed pinning and depinning processes of DWs in these nanowires have been studied by using focused magneto-optic Kerr effect (FMOKE) magnetometer, magnetic force microscopy (MFM) and micromagnetic simulation. The experimental results unambiguously exhibit the presence of a DW pinned at the notch in a typical sample with d equal to 500 nm. At a certain range of 200 nm < d < 500 nm, both the experimental and simulated results show that the DW can maintain or change its chirality randomly during passing through the notch, resulting in two DW depinning fields. Those two depinning fields have opposite d dependences, which may be originated from different potential well/barrier generated by the asymmetric notch with varying d. PMID:27600627

  3. Surface Fatigue Crack Growth Behavior from Small Notch in Waspaloy

    NASA Astrophysics Data System (ADS)

    Suh, Chang-Min; Kim, Seon-Gab

    We investigated the surface fatigue crack behaviors including initial surface crack appearances depend on three artificial notch lengths applied with the axle load level of the maximum load, 1,103 MPa and minimum load 55.3 MPa at the stress ratio of 0.05. This load level is the F100 engine's maximum operation condition of Waspaloy. The initial cracking site in depth is started from multi-origin. The effectiveness of crack growth rate by ductile striation space measurement on the fractured surface is confirmed by the working load and the stress intensity factor range. The surface cracks of Waspaloy at room temperature in air follow the ΔK vs da/dN and db/dN relation, even though the crack length initiated early in notch size 1 mm and initiated very late in notch size 4 mm. And the ΔK vs da/dN and db/dN relation have similar slope at 3 kinds of notches.

  4. Syndecan-3 and Notch cooperate in regulating adult myogenesis

    PubMed Central

    Pisconti, Addolorata; Cornelison, D.D.W.; Olguín, Hugo C.; Antwine, Tiffany L.

    2010-01-01

    Skeletal muscle postnatal growth and repair depend on satellite cells and are regulated by molecular signals within the satellite cell niche. We investigated the molecular and cellular events that lead to altered myogenesis upon genetic ablation of Syndecan-3, a component of the satellite cell niche. In the absence of Syndecan-3, satellite cells stall in S phase, leading to reduced proliferation, increased cell death, delayed onset of differentiation, and markedly reduced numbers of Pax7+ satellite cells accompanied by myofiber hypertrophy and an increased number of centrally nucleated myofibers. We show that the aberrant cell cycle and impaired self-renewal of explanted Syndecan-3–null satellite cells are rescued by ectopic expression of the constitutively active Notch intracellular domain. Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-α–converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. PMID:20696709

  5. Syndecan-3 and Notch cooperate in regulating adult myogenesis.

    PubMed

    Pisconti, Addolorata; Cornelison, D D W; Olguín, Hugo C; Antwine, Tiffany L; Olwin, Bradley B

    2010-08-01

    Skeletal muscle postnatal growth and repair depend on satellite cells and are regulated by molecular signals within the satellite cell niche. We investigated the molecular and cellular events that lead to altered myogenesis upon genetic ablation of Syndecan-3, a component of the satellite cell niche. In the absence of Syndecan-3, satellite cells stall in S phase, leading to reduced proliferation, increased cell death, delayed onset of differentiation, and markedly reduced numbers of Pax7(+) satellite cells accompanied by myofiber hypertrophy and an increased number of centrally nucleated myofibers. We show that the aberrant cell cycle and impaired self-renewal of explanted Syndecan-3-null satellite cells are rescued by ectopic expression of the constitutively active Notch intracellular domain. Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. PMID:20696709

  6. Galectin-3 Inhibits Osteoblast Differentiation through Notch Signaling12

    PubMed Central

    Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi; Harazono, Yosuke; Gao, Xiaoge; Hogan, Victor; Raz, Avraham

    2014-01-01

    Patients with bone cancer metastasis suffer from unbearable pain and bone fractures due to bone remodeling. This is caused by tumor cells that disturb the bone microenvironment. Here, we have investigated the role of tumor-secreted sugar-binding protein, i.e., galectin-3, on osteoblast differentiation and report that it downregulates the expression of osteoblast differentiation markers, e.g., RUNX2, SP7, ALPL, COL1A1, IBSP, and BGLAP, of treated human fetal osteoblast (hFOB) cells. Co-culturing of hFOB cells with human breast cancer BT-549 and prostate cancer LNCaP cells harboring galectin-3 has resulted in inhibition of osteoblast differentiation by the secreted galectin-3 into culture medium. The inhibitory effect of galectin-3 was found to be through its binding to Notch1 in a sugar-dependent manner that has led to accelerated Notch1 cleavage and activation of Notch signaling. Taken together, our findings show that soluble galectin-3 in the bone microenvironment niche regulates bone remodeling through Notch signaling, suggesting a novel bone metastasis therapeutic target. PMID:25425968

  7. Depinning of domain walls in permalloy nanowires with asymmetric notches

    PubMed Central

    Gao, Y.; You, B.; Ruan, X. Z.; Liu, M. Y.; Yang, H. L.; Zhan, Q. F.; Li, Z.; Lei, N.; Zhao, W. S.; Pan, D. F.; Wan, J. G.; Wu, J.; Tu, H. Q.; Wang, J.; Zhang, W.; Xu, Y. B.; Du, J.

    2016-01-01

    Effective control of the domain wall (DW) motion along the magnetic nanowires is of great importance for fundamental research and potential application in spintronic devices. In this work, a series of permalloy nanowires with an asymmetric notch in the middle were fabricated with only varying the width (d) of the right arm from 200 nm to 1000 nm. The detailed pinning and depinning processes of DWs in these nanowires have been studied by using focused magneto-optic Kerr effect (FMOKE) magnetometer, magnetic force microscopy (MFM) and micromagnetic simulation. The experimental results unambiguously exhibit the presence of a DW pinned at the notch in a typical sample with d equal to 500 nm. At a certain range of 200 nm < d < 500 nm, both the experimental and simulated results show that the DW can maintain or change its chirality randomly during passing through the notch, resulting in two DW depinning fields. Those two depinning fields have opposite d dependences, which may be originated from different potential well/barrier generated by the asymmetric notch with varying d. PMID:27600627

  8. Rnd3 regulates lung cancer cell proliferation through notch signaling.

    PubMed

    Tang, Yongjun; Hu, Chengping; Yang, Huaping; Cao, Liming; Li, Yuanyuan; Deng, Pengbo; Huang, Li

    2014-01-01

    Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC) remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD) protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase. PMID:25372032

  9. Rnd3 Regulates Lung Cancer Cell Proliferation through Notch Signaling

    PubMed Central

    Tang, Yongjun; Hu, Chengping; Yang, Huaping; Cao, Liming; Li, Yuanyuan; Deng, Pengbo; Huang, Li

    2014-01-01

    Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC) remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD) protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase. PMID:25372032

  10. Fracture toughness of brittle materials determined with chevron notch specimens

    NASA Technical Reports Server (NTRS)

    Shannon, J. L., Jr.; Bursey, R. T.; Munz, D.; Pierce, W. S.

    1980-01-01

    The use of chevron-notch specimens for determining the plane strain fracture toughness (K sub Ic) of brittle materials is discussed. Three chevron-notch specimens were investigated: short bar, short rod, and four-point-bend. The dimensionless stress intensity coefficient used in computing K sub Ic is derived for the short bar specimen from the superposition of ligament-dependent and ligament-independent solutions for the straight through crack, and also from experimental compliance calibrations. Coefficients for the four-point-bend specimen were developed by the same superposition procedure, and with additional refinement using the slice model of Bluhm. Short rod specimen stress intensity coefficients were determined only by experimental compliance calibration. Performance of the three chevron-notch specimens and their stress intensity factor relations were evaluated by tests on hot-pressed silicon nitride and sintered aluminum oxide. Results obtained with the short bar and the four-point-bend specimens on silicon nitride are in good agreement and relatively free of specimen geometry and size effects within the range investigated. Results on aluminum oxide were affected by specimen size and chevron-notch geometry, believed due to a rising crack growth resistance curve for the material. Only the results for the short bar specimen are presented in detail.

  11. Notch-Boosted Domain Wall Propagation in Magnetic Nanowires

    NASA Astrophysics Data System (ADS)

    Wang, Xiang Rong; Yuan, Hauiyang

    Magnetic domain wall (DW) motion along a nanowire underpins many proposals of spintronic devices. High DW propagation velocity is obviously important because it determines the device speed. Thus it is interesting to search for effective control knobs of DW dynamics. We report a counter-intuitive finding that notches in an otherwise homogeneous magnetic nanowire can boost current-induced domain wall (DW) propagation. DW motion in notch-modulated wires can be classified into three phases: 1) A DW is pinned around a notch when the current density is below the depinning current density. 2) DW propagation velocity above the depinning current density is boosted by notches when non-adiabatic spin-transfer torque strength is smaller than the Gilbert damping constant. The boost can be many-fold. 3) DW propagation velocity is hindered when non-adiabatic spin-transfer torque strength is larger than the Gilbert damping constant. This work was supported by Hong Kong GRF Grants (Nos. 163011151 and 605413) and the Grant from NNSF of China (No. 11374249).

  12. Formation of fast ``notched'' current waveforms through a high inductance

    NASA Astrophysics Data System (ADS)

    Spanjers, G.; Nelson, B. A.; Ribe, F. L.

    1991-10-01

    A fast ``notch'' current has been produced on the (4 μH) hardcore central conductor [C. M. Greenfield, M. E. Koepke, and F. L. Ribe, Phys. Fluids B 2, 133 (1990)] of the high beta Q machine, a 2.6 m theta pinch [S. O. Knox, H. Meuth, E. Sevillano, and F. L. Ribe, 3rd IEEE International Pulsed Power Conf., 1981, IEEE Publ. 81 CH1662/6, paper 3.1]. With the notch circuitry, the current can be slowly (τ1/4 = 14 μs) brought to a crowbarred dc value (20 kA) and then quickly (τ1/4 = 1.3 μs) ``notched'' to a different value (typically either 0 kA or twice the dc value) and then quickly returned to the dc value. The use of a new inductively loaded spark gap switch eliminates extraneous ringing in the final crowbarred current waveform. As described here, by driving the hardcore circuit with two isolated capacitor banks, and a voltage stepup transformer, the notch current is created using spark gaps and ignitrons for switching, resulting in an inexpensive and technically simple circuit.

  13. Planar Microstrip Yagi Array with Notched Parasitic Elements

    NASA Technical Reports Server (NTRS)

    Lee, Richard Q.; Zaman, Afoz J.

    2001-01-01

    The design and radiation characteristics of a planar microstrip Yagi array with notched parasitic elements are presented. Results indicate that a directional beam 45 deg from the broadside direction with a gain over 7 dB can be achieved. Good agreements were observed between experimental and analytical results.

  14. Notch intracellular domain overexpression in adipocytes confers lipodystrophy in mice

    PubMed Central

    Chartoumpekis, Dionysios V.; Palliyaguru, Dushani L.; Wakabayashi, Nobunao; Khoo, Nicholas K.H.; Schoiswohl, Gabriele; O'Doherty, Robert M.; Kensler, Thomas W.

    2015-01-01

    Objective The Notch family of intermembrane receptors is highly conserved across species and is involved in cell fate and lineage control. Previous in vitro studies have shown that Notch may inhibit adipogenesis. Here we describe the role of Notch in adipose tissue by employing an in vivo murine model which overexpresses Notch in adipose tissue. Methods Albino C57BL/6J RosaNICD/NICD::Adipoq-Cre (Ad-NICD) male mice were generated to overexpress the Notch intracellular domain (NICD) specifically in adipocytes. Male RosaNICD/NICD mice were used as controls. Mice were evaluated metabolically at the ages of 1 and 3 months by assessing body weights, serum metabolites, body composition (EchoMRI), glucose tolerance and insulin tolerance. Histological sections of adipose tissue depots as well as of liver were examined. The mRNA expression profile of genes involved in adipogenesis was analyzed by quantitative real-time PCR. Results The Ad-NICD mice were heavier with significantly lower body fat mass compared to the controls. Small amounts of white adipose tissue could be seen in the 1-month old Ad-NICD mice, but was almost absent in the 3-months old mice. The Ad-NICD mice also had higher serum levels of glucose, insulin, triglyceride and non-esterified fatty acids. These differences were more prominent in the older (3-months) than in the younger (1-month) mice. The Ad-NICD mice also showed severe insulin resistance along with a steatotic liver. Gene expression analysis in the adipose tissue depots showed a significant repression of lipogenic (Fasn, Acacb) and adipogenic pathways (C/ebpα, C/ebpβ, Pparγ2, Srebf1). Conclusions Increased Notch signaling in adipocytes in mice results in blocked expansion of white adipose tissue which leads to ectopic accumulation of lipids and insulin resistance, thus to a lipodystrophic phenotype. These results suggest that further investigation of the role of Notch signaling in adipocytes could lead to the manipulation of this pathway for

  15. Vortex-assisted domain wall depinning and propagation in notched nanowires

    NASA Astrophysics Data System (ADS)

    Yuan, Huaiyang; Wang, Xiangrong

    2015-09-01

    Various notches are often introduced in spintronics to trap a domain wall (DW). Common wisdom would expect notches to strengthen DW pinning and to hinder DW motion. Interestingly, our simulations show that notches help electric current to depin a DW with the assistance of vortex generation. The DW displacement is insensitive to notch geometry and current density. This phenomenon is explained by the Thiele equation. Moreover, a current density below the intrinsic threshold value, which is the minimum current to sustain continuous DW motion in a uniform nanowire, can induce a continuous DW propagation along a wire with a series of notches.

  16. From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling

    PubMed Central

    Ntziachristos, Panagiotis; Lim, Jing Shan; Sage, Julien; Aifantis, Iannis

    2014-01-01

    Since Notch phenotypes in Drosophila melanogaster were identified 100 years, Notch signaling has been extensively characterized as a regulator of cell fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this Perspective, we discuss the pro-tumorigenic and tumor suppressive functions of Notch signaling and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. PMID:24651013

  17. Resveratrol can prevent CCl₄-induced liver injury by inhibiting Notch signaling pathway.

    PubMed

    Tanriverdi, Gamze; Kaya-Dagistanli, Fatma; Ayla, Sule; Demirci, Sibel; Eser, Mediha; Unal, Z Seda; Cengiz, Mujgan; Oktar, Huseyin

    2016-07-01

    We investigated whether Notch signaling was increased in an experimental liver fibrosis model and examined the effects of resveratrol on Notch expression. Rats were divided into four groups: the control group, injected with physiological saline; the CCl₄ group; the CCl₄ plus resveratrol group; and the resveratrol group. After treatment, immunostaining was performed to detect Notch1, Notch3, Notch4, transforming growth factor (TGF)-beta, alpha-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and proliferating cell nuclear antigen (PCNA), and TUNEL assays were performed to evaluate apoptosis. Sirius red staining was used to detect fibrosis. Samples were also biochemically evaluated for glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), lipid peroxidation, and protein oxidation. GSH, GPx, and catalase activities were significantly decreased (p⟨0.001) in the CCl₄ group. Distinct collagen accumulation was detected around the central vein and portal areas, and numbers of Notch1-, Notch3-, and Notch4-positive cells were significantly increased (p⟨0.001) in fibrotic areas in the CCl₄ group. Increased expression of Notch proteins in fibrotic areas may support the role of Notch in mediating signaling associated with liver fibrosis through activation of hepatic stellate and progenitor cells. In contrast, resveratrol prevented liver fibrosis by decreasing lipid peroxidation and may be effective for inhibiting Notch signaling. PMID:26742567

  18. Notch strengthening or weakening governed by transition of shear failure to normal mode fracture

    PubMed Central

    Lei, Xianqi; Li, Congling; Shi, Xinghua; Xu, Xianghong; Wei, Yujie

    2015-01-01

    It is generally observed that the existence of geometrical discontinuity like notches in materials will lead to strength weakening, as a resultant of local stress concentration. By comparing the influence of notches to the strength of three typical materials, aluminum alloys with intermediate tensile ductility, metallic glasses with no tensile ductility, and brittle ceramics, we observed strengthening in aluminum alloys and metallic glasses: Tensile strength of the net section in circumferentially notched cylinders increases with the constraint quantified by the ratio of notch depth over notch root radius; in contrast, the ceramic exhibit notch weakening. The strengthening in the former two is due to resultant deformation transition: Shear failure occurs in intact samples while samples with deep notches break in normal mode fracture. No such deformation transition was observed in the ceramic, and stress concentration leads to its notch weakening. The experimental results are confirmed by theoretical analyses and numerical simulation. The results reported here suggest that the conventional criterion to use brittleness and/or ductility to differentiate notch strengthening or weakening is not physically sound. Notch strengthening or weakening relies on the existence of failure mode transition and materials exhibiting shear failure while subjected to tension will notch strengthen. PMID:26022892

  19. Human NOTCH2 Is Resistant to Ligand-independent Activation by Metalloprotease Adam17*

    PubMed Central

    Habets, Roger A. J.; Groot, Arjan J.; Yahyanejad, Sanaz; Tiyanont, Kittichoat; Blacklow, Stephen C.; Vooijs, Marc

    2015-01-01

    Cell surface receptors of the NOTCH family of proteins are activated by ligand induced intramembrane proteolysis. Unfolding of the extracellular negative regulatory region (NRR), enabling successive proteolysis by the enzymes Adam10 and γ-secretase, is rate-limiting in NOTCH activation. Mutations in the NOTCH1 NRR are associated with ligand-independent activation and frequently found in human T-cell malignancies. In mammals four NOTCH receptors and five Delta/Jagged ligands exist, but mutations in the NRR are only rarely reported for receptors other than NOTCH1. Using biochemical and functional assays, we compared the molecular mechanisms of ligand-independent signaling in NOTCH1 and the highly related NOTCH2 receptor. Both murine Notch1 and Notch2 require the metalloprotease protease Adam17, but not Adam10 during ligand-independent activation. Interestingly, the human NOTCH2 receptor is resistant to ligand-independent activation compared with its human homologs or murine orthologs. Taken together, our data reveal subtle but functionally important differences for the NRR among NOTCH paralogs and homologs. PMID:25918160

  20. Notch2 is required for maintaining sustentacular cell function in the adult mouse main olfactory epithelium

    PubMed Central

    Rodriguez, Steve; Sickles, Heather M.; DeLeonardis, Chris; Alcaraz, Ana; Gridley, Thomas; Lin, David M.

    2008-01-01

    Notch receptors are expressed in neurons and glia in the adult nervous system, but why this expression persists is not well-understood. Here we examine the role of the Notch pathway in the postnatal mouse main olfactory system, and show evidence consistent with a model where Notch2 is required for maintaining sustentacular cell function. In the absence of Notch2, the laminar nature of these glial-like cells is disrupted. Hes1, Hey1, and Six1, which are downstream effectors of the Notch pathway, are down-regulated, and cytochrome P450 and Glutathione S-transferase (GST) expression by sustentacular cells is reduced. Functional levels of GST activity are also reduced. These disruptions are associated with increased olfactory sensory neuron degeneration. Surprisingly, expression of Notch3 is also down-regulated. This suggests the existence of a feedback loop where expression of Notch3 is initially independent of Notch2, but requires Notch2 for maintained expression. While the Notch pathway has previously been shown to be important for promoting gliogenesis during development, this is the first demonstration that the persistent expression of Notch receptors is required for maintaining glial function in adult. PMID:18155189

  1. Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells.

    PubMed

    Zhou, Jiesi; Jain, Saket; Azad, Abul K; Xu, Xia; Yu, Hai Chuan; Xu, Zhihua; Godbout, Roseline; Fu, YangXin

    2016-08-01

    Epithelial-mesenchymal transition (EMT) plays a critical role in the progression of epithelial ovarian cancer (EOC). However, the mechanisms that regulate EMT in EOC are not fully understood. Here, we report that activation of Notch1 induces EMT in EOC cells as evidenced by downregulation of E-cadherin and cytokeratins, upregulation of Slug and Snail, as well as morphological changes. Interestingly, activation of Notch1 increases TGFβ/Smad signaling by upregulating the expression of TGFβ and TGFβ type 1 receptor. Time course experiments demonstrate that inhibition of Notch by DAPT (a γ-secretase inhibitor) decreases TGFβ-induced phosphorylation of receptor Smads at late, but not at early, timepoints. These results suggest that Notch activation plays a role in sustaining TGFβ/Smad signaling in EOC cells. Furthermore, inhibition of Notch by DAPT decreases TGFβ induction of Slug and repression of E-cadherin and knockdown of Notch1 decreases TGFβ-induced repression of E-cadherin, indicating that Notch is required, at least in part, for TGFβ-induced EMT in EOC cells. On the other hand, TGFβ treatment increases the expression of Notch ligand Jagged1 and Notch target gene HES1 in EOC cells. Functionally, the combination of Notch1 activation and TGFβ treatment is more potent in promoting motility and migration of EOC cells than either stimulation alone. Taken together, our results indicate that Notch and TGFβ form a reciprocal positive regulatory loop and cooperatively regulate EMT and promote EOC cell motility and migration. PMID:27075926

  2. Notch strengthening or weakening governed by transition of shear failure to normal mode fracture.

    PubMed

    Lei, Xianqi; Li, Congling; Shi, Xinghua; Xu, Xianghong; Wei, Yujie

    2015-01-01

    It is generally observed that the existence of geometrical discontinuity like notches in materials will lead to strength weakening, as a resultant of local stress concentration. By comparing the influence of notches to the strength of three typical materials, aluminum alloys with intermediate tensile ductility, metallic glasses with no tensile ductility, and brittle ceramics, we observed strengthening in aluminum alloys and metallic glasses: Tensile strength of the net section in circumferentially notched cylinders increases with the constraint quantified by the ratio of notch depth over notch root radius; in contrast, the ceramic exhibit notch weakening. The strengthening in the former two is due to resultant deformation transition: Shear failure occurs in intact samples while samples with deep notches break in normal mode fracture. No such deformation transition was observed in the ceramic, and stress concentration leads to its notch weakening. The experimental results are confirmed by theoretical analyses and numerical simulation. The results reported here suggest that the conventional criterion to use brittleness and/or ductility to differentiate notch strengthening or weakening is not physically sound. Notch strengthening or weakening relies on the existence of failure mode transition and materials exhibiting shear failure while subjected to tension will notch strengthen. PMID:26022892

  3. Nandrolone reduces activation of Notch signaling in denervated muscle associated with increased Numb expression

    SciTech Connect

    Liu, Xin-Hua; Yao, Shen; Qiao, Rui-Fang; Levine, Alice C.; Kirschenbaum, Alexander; Pan, Jiangping; Wu, Yong; Qin, Weiping; Bauman, William A.; Cardozo, Christopher P.

    2011-10-14

    Highlights: {yields} Nerve transection increased Notch signaling in paralyzed muscle. {yields} Nandrolone prevented denervation-induced Notch signaling. {yields} Nandrolone induced the expression of an inhibitor of the Notch signaling, Numb. {yields} Reduction of denervation-induced Notch signaling by nandrolone is likely through upregulation of Numb. -- Abstract: Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy.

  4. Notch2 signaling contributes to cell growth, invasion, and migration in salivary adenoid cystic carcinoma.

    PubMed

    Qu, Jing; Song, Min; Xie, Jian; Huang, Xiao-Yu; Hu, Xiao-Meng; Gan, Rui-Huan; Zhao, Yong; Lin, Li-Song; Chen, Jiang; Lin, Xu; Zheng, Da-Li; Lu, You-Guang

    2016-01-01

    Many studies have explored whether the Notch signaling pathway has a tumor-suppressive or an oncogenic role in various tumors; however, the role of the Notch signaling pathway in salivary adenoid cystic carcinoma (SACC) is still unknown. In this study, we attempt to define the role of Notch2 signaling in cell growth, invasion, and migration in SACC. We compared Notch2 expression in clinical SACC samples with that of normal samples by using immunohistochemical staining. Then, we down-regulated Notch2 expression to observe the effect of Notch2 on proliferation, invasion, migration, and the expression of known target genes of Notch signal pathway. According to our results, Notch2 expression was higher in SACC tissues compared with normal tissues. Knockdown of Notch2 inhibited cell proliferation, invasion, and migration in vitro and down-regulated the expression of HEY2 and CCND1. The results of this study suggest that Notch2 has an essential role in the cell growth, invasion, and migration of SACC. Notch2 may therefore be a potential target gene for the treatment of SACC by interfering with cell growth and metastasis. PMID:26427670

  5. Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1

    PubMed Central

    Nagaoka, Tadahiro; Lee, Joseph M.; Bianco, Caterina; Gonzales, Monica; Castro, Nadia P.; Rangel, Maria Cristina; Sakamoto, Kei; Sun, Youping; Callahan, Robert

    2009-01-01

    Nodal and Notch signaling pathways play essential roles in vertebrate development. Through a yeast two-hybrid screening, we identified Notch3 as a candidate binding partner of the Nodal coreceptor Cripto-1. Coimmunoprecipitation analysis confirmed the binding of Cripto-1 with all four mammalian Notch receptors. Deletion analyses revealed that the binding of Cripto-1 and Notch1 is mediated by the Cripto-1/FRL-1/Cryptic domain of Cripto-1 and the C-terminal region of epidermal growth factor–like repeats of Notch1. Binding of Cripto-1 to Notch1 occurred mainly in the endoplasmic reticulum–Golgi network. Cripto-1 expression resulted in the recruitment of Notch1 protein into lipid raft microdomains and enhancement of the furin-like protein convertase-mediated proteolytic maturation of Notch1 (S1 cleavage). Enhanced S1 cleavage resulted in the sensitization to ligand-induced activation of Notch signaling. In addition, knockdown of Cripto-1 expression in human and mouse embryonal carcinoma cells desensitized the ligand-induced Notch signaling activation. These results suggest a novel role of Cripto-1 in facilitating the posttranslational maturation of Notch receptors. PMID:19948478

  6. Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer

    PubMed Central

    Roti, Giovanni; Carlton, Anne; Ross, Kenneth N.; Markstein, Michele; Pajcini, Kostandin; Su, Angela H.; Perrimon, Norbert; Pear, Warren S.; Kung, Andrew L.; Blacklow, Stephen C.; Aster, Jon C.; Stegmaier, Kimberly

    2013-01-01

    SUMMARY Notch1 is a rational therapeutic target in several human cancers, but as a transcriptional regulator, it poses a drug discovery challenge. To identify Notch1 modulators, we performed two cell-based, high-throughput screens for small-molecule inhibitors and cDNA enhancers of a NOTCH1 allele bearing a leukemia-associated mutation. SERCA calcium channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G0/G1 arrest in NOTCH1-mutated human leukemia cells. A small-molecule SERCA inhibitor has on-target activity in two mouse models of human leukemia and interferes with Notch signaling in Drosophila. These studies “credential” SERCA as a therapeutic target in cancers associated with NOTCH1 mutations. PMID:23434461

  7. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in acute lymphoblastic leukemia

    PubMed Central

    Herranz, Daniel; Ambesi-Impiombato, Alberto; Sudderth, Jessica; Sánchez-Martín, Marta; Belver, Laura; Tosello, Valeria; Xu, Luyao; Wendorff, Agnieszka A.; Castillo, Mireia; Haydu, J. Erika; Márquez, Javier; Matés, José M.; Kung, Andrew L.; Rayport, Stephen; Cordon-Cardo, Carlos; DeBerardinis, Ralph J.; Ferrando, Adolfo A.

    2015-01-01

    Activating mutations in NOTCH1 are common in T-cell acute lymphoblastic leukemia (TALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of clinical response to anti-NOTCH1 therapies. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, both inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapies. Moreover, we demonstrate that Pten loss induces increased glycolysis and consequently rescues leukemic cell metabolism abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL. PMID:26390244

  8. Notch signalling in T cell lymphoblastic leukaemia/lymphoma and other haematological malignancies

    PubMed Central

    Aster, Jon C.; Blacklow, Stephen C.; Pear, Warren S.

    2010-01-01

    Notch receptors participate in a highly conserved signalling pathway that regulates normal development and tissue homeostasis in a context- and dose-dependent manner. Deregulated Notch signalling has been implicated in many diseases, but the clearest example of a pathogenic role is found in T cell lymphoblastic leukaemia/lymphoma (T-LL), in which the majority of human and murine tumours have acquired mutations that lead to aberrant increases in Notch1 signalling. Remarkably, it appears that the selective pressure for Notch mutations is virtually unique among cancers to T-LL, presumably reflecting a special context-dependent role for Notch in normal T cell progenitors. Nevertheless, there are some recent reports suggesting that Notch signalling has subtle yet important roles in other forms of hematologic malignancy as well. Here, we review the role of Notch signalling in various blood cancers, focusing on T-LL with an eye toward targeted therapeutics. PMID:20967796

  9. Fas-Associated Protein with Death Domain Regulates Notch Signaling during Muscle Regeneration.

    PubMed

    Zhang, Rong; Wang, Lu; He, Liangqiang; Yang, Bingya; Yao, Chun; Du, Pan; Xu, Qiang; Cheng, Wei; Hua, Zi-Chun

    2014-01-01

    Notch signaling plays critical roles during myogenesis by promoting the proliferation and inhibiting the differentiation of myogenic progenitors. However, the mechanism of the temporal regulation of Notch signaling during the myogenic lineage progression remains elusive. In the present study, we show that a constitutively phosphoryl-mimicking mutation of Fas-associated death domain (FADD-D) enhances Notch-1 signaling and compromises Wnt signaling in both cultured myoblasts and regenerating muscles, which results in inhibited myogenic differentiation and muscle regeneration. Inhibition of Notch signaling recovers the regeneration ability in injured FADD-D muscles through rescuing Wnt signaling. Furthermore, we found that protein kinase Cα mediates FADD-D-induced Notch-1 signaling by stabilizing Notch-1. Collectively, these data identify a novel mechanism for the temporal regulation of Notch signaling during myogenic lineage progression and muscle regeneration. PMID:26303234

  10. Nandrolone reduces activation of Notch signaling in denervated muscle associated with increased Numb expression.

    PubMed

    Liu, Xin-Hua; Yao, Shen; Qiao, Rui-Fang; Levine, Alice C; Kirschenbaum, Alexander; Pan, Jiangping; Wu, Yong; Qin, Weiping; Bauman, William A; Cardozo, Christopher P

    2011-10-14

    Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy. PMID:21945932

  11. A realistic lattice example

    SciTech Connect

    Courant, E.D.; Garren, A.A.

    1985-10-01

    A realistic, distributed interaction region (IR) lattice has been designed that includes new components discussed in the June 1985 lattice workshop. Unlike the test lattices, the lattice presented here includes utility straights and the mechanism for crossing the beams in the experimental straights. Moreover, both the phase trombones and the dispersion suppressors contain the same bending as the normal cells. Vertically separated beams and 6 Tesla, 1-in-1 magnets are assumed. Since the cells are 200 meters long, and have 60 degree phase advance, this lattice has been named RLD1, in analogy with the corresponding test lattice, TLD1. The quadrupole gradient is 136 tesla/meter in the cells, and has similar values in other quadrupoles except in those in the IR`s, where the maximum gradient is 245 tesla/meter. RLD1 has distributed IR`s; however, clustered realistic lattices can easily be assembled from the same components, as was recently done in a version that utilizes the same type of experimental and utility straights as those of RLD1.

  12. notch3 is essential for oligodendrocyte development and vascular integrity in zebrafish

    PubMed Central

    Zaucker, Andreas; Mercurio, Sara; Sternheim, Nitzan; Talbot, William S.; Marlow, Florence L.

    2013-01-01

    SUMMARY Mutations in the human NOTCH3 gene cause CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL is an inherited small vessel disease characterized by diverse clinical manifestations including vasculopathy, neurodegeneration and dementia. Here we report two mutations in the zebrafish notch3 gene, one identified in a previous screen for mutations with reduced expression of myelin basic protein (mbp) and another caused by a retroviral insertion. Reduced mbp expression in notch3 mutant embryos is associated with fewer oligodendrocyte precursor cells (OPCs). Despite an early neurogenic phenotype, mbp expression recovered at later developmental stages and some notch3 homozygous mutants survived to adulthood. These mutants, as well as adult zebrafish carrying both mutant alleles together, displayed a striking stress-associated accumulation of blood in the head and fins. Histological analysis of mutant vessels revealed vasculopathy, including: an enlargement (dilation) of vessels in the telencephalon and fin, disorganization of the normal stereotyped arrangement of vessels in the fin, and an apparent loss of arterial morphological structure. Expression of hey1, a well-known transcriptional target of Notch signaling, was greatly reduced in notch3 mutant fins, suggesting that Notch3 acts via a canonical Notch signaling pathway to promote normal vessel structure. Ultrastructural analysis confirmed the presence of dilated vessels in notch3 mutant fins and revealed that the vessel walls of presumed arteries showed signs of deterioration. Gaps in the arterial wall and the presence of blood cells outside of vessels in mutants indicated that compromised vessel structure led to hemorrhage. In notch3 heterozygotes, we found elevated expression of both notch3 itself and target genes, indicating that specific alterations in gene expression due to partial loss of Notch3 function might contribute to the

  13. The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy

    PubMed Central

    Tosello, Valeria

    2013-01-01

    T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights the critical role of NOTCH signaling in the pathogenesis of this disease and has prompted the development of therapeutic approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are strongly synergistic and may overcome the gastrointestinal toxicity associated with systemic inhibition of the NOTCH pathway. In addition, emerging new anti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 antibodies and stapled peptides targeting the NOTCH transcriptional complex in the nucleus. PMID:23730497

  14. Lattice Boltzmann model for simulation of magnetohydrodynamics

    NASA Technical Reports Server (NTRS)

    Chen, Shiyi; Chen, Hudong; Martinez, Daniel; Matthaeus, William

    1991-01-01

    A numerical method, based on a discrete Boltzmann equation, is presented for solving the equations of magnetohydrodynamics (MHD). The algorithm provides advantages similar to the cellular automaton method in that it is local and easily adapted to parallel computing environments. Because of much lower noise levels and less stringent requirements on lattice size, the method appears to be more competitive with traditional solution methods. Examples show that the model accurately reproduces both linear and nonlinear MHD phenomena.

  15. Shaken lattice interferometry

    NASA Astrophysics Data System (ADS)

    Weidner, Carrie; Yu, Hoon; Anderson, Dana

    2016-05-01

    In this work, we report on progress towards performing interferometry using atoms trapped in an optical lattice. That is, we start with atoms in the ground state of an optical lattice potential V(x) =V0cos [ 2 kx + ϕ(t) ] , and by a prescribed phase function ϕ(t) , transform from one atomic wavefunction to another. In this way, we implement the standard interferometric sequence of beam splitting, propagation, reflection, reverse propagation, and recombination. Through the use of optimal control techniques, we have computationally demonstrated a scalable accelerometer that provides information on the sign of the applied acceleration. Extension of this idea to a two-dimensional shaken-lattice-based gyroscope is discussed. In addition, we report on the experimental implementation of the shaken lattice system.

  16. SPIN ON THE LATTICE.

    SciTech Connect

    ORGINOS,K.

    2003-01-07

    I review the current status of hadronic structure computations on the lattice. I describe the basic lattice techniques and difficulties and present some of the latest lattice results; in particular recent results of the RBC group using domain wall fermions are also discussed. In conclusion, lattice computations can play an important role in understanding the hadronic structure and the fundamental properties of Quantum Chromodynamics (QCD). Although some difficulties still exist, several significant steps have been made. Advances in computer technology are expected to play a significant role in pushing these computations closer to the chiral limit and in including dynamical fermions. RBC has already begun preliminary dynamical domain wall fermion computations [49] which we expect to be pushed forward with the arrival of QCD0C. In the near future, we also expect to complete the non-perturbative renormalization of the relevant derivative operators in quenched QCD.

  17. Superalloy Lattice Block Structures

    NASA Technical Reports Server (NTRS)

    Nathal, M. V.; Whittenberger, J. D.; Hebsur, M. G.; Kantzos, P. T.; Krause, D. L.

    2004-01-01

    Initial investigations of investment cast superalloy lattice block suggest that this technology will yield a low cost approach to utilize the high temperature strength and environmental resistance of superalloys in lightweight, damage tolerant structural configurations. Work to date has demonstrated that relatively large superalloy lattice block panels can be successfully investment cast from both IN-718 and Mar-M247. These castings exhibited mechanical properties consistent with the strength of the same superalloys measured from more conventional castings. The lattice block structure also accommodates significant deformation without failure, and is defect tolerant in fatigue. The potential of lattice block structures opens new opportunities for the use of superalloys in future generations of aircraft applications that demand strength and environmental resistance at elevated temperatures along with low weight.

  18. Automated Lattice Perturbation Theory

    SciTech Connect

    Monahan, Christopher

    2014-11-01

    I review recent developments in automated lattice perturbation theory. Starting with an overview of lattice perturbation theory, I focus on the three automation packages currently "on the market": HiPPy/HPsrc, Pastor and PhySyCAl. I highlight some recent applications of these methods, particularly in B physics. In the final section I briefly discuss the related, but distinct, approach of numerical stochastic perturbation theory.

  19. NOTCH1 Regulates Matrix Gla Protein and Calcification Gene Networks in Human Valve Endothelium

    PubMed Central

    White, Mark P.; Theodoris, Christina V.; Liu, Lei; Collins, William J.; Blue, Kathleen W.; Lee, Joon Ho; Meng, Xianzhong; Robbins, Robert C.; Ivey, Kathryn N.; Srivastava, Deepak

    2015-01-01

    Valvular and vascular calcification are common causes of cardiovascular morbidity and mortality. Developing effective treatments requires understanding the molecular underpinnings of these processes. Shear stress is thought to play a role in inhibiting calcification. Furthermore, NOTCH1 regulates vascular and valvular endothelium, and human mutations in NOTCH1 can cause calcific aortic valve disease. Here, we determined the genome-wide impact of altering shear stress and NOTCH signaling on aortic valve endothelium. mRNA-sequencing of human aortic valve endothelial cells (HAVECs) with or without knockdown of NOTCH1, in the presence or absence of shear stress, revealed NOTCH1-dependency of the atherosclerosis-related gene connexin 40 (GJA5), and numerous repressors of endochondral ossification. Among these, Matrix GLA Protein (MGP) is highly expressed in aortic valve and vasculature, and inhibits soft tissue calcification by sequestering bone morphogenetic proteins (BMPs). Altering NOTCH1 levels affected MGP mRNA and protein in HAVECs. Furthermore, shear stress activated NOTCH signaling and MGP in a NOTCH1-dependent manner. NOTCH1 positively regulated endothelial MGP in vivo through specific binding motifs upstream of MGP. Our studies suggest that shear stress activates NOTCH1 in primary human aortic valve endothelial cells leading to downregulation of osteoblast-like gene networks that play a role in tissue calcification. PMID:25871831

  20. Notch signaling represses GATA4-induced expression of genes involved in steroid biosynthesis.

    PubMed

    George, Rajani M; Hahn, Katherine L; Rawls, Alan; Viger, Robert S; Wilson-Rawls, Jeanne

    2015-10-01

    Notch2 and Notch3 and genes of the Notch signaling network are dynamically expressed in developing follicles, where they are essential for granulosa cell proliferation and meiotic maturation. Notch receptors, ligands, and downstream effector genes are also expressed in testicular Leydig cells, predicting a potential role in regulating steroidogenesis. In this study, we sought to determine if Notch signaling in small follicles regulates the proliferation response of granulosa cells to FSH and represses the up-regulation steroidogenic gene expression that occurs in response to FSH as the follicle grows. Inhibition of Notch signaling in small preantral follicles led to the up-regulation of the expression of genes in the steroid biosynthetic pathway. Similarly, progesterone secretion by MA-10 Leydig cells was significantly inhibited by constitutively active Notch. Together, these data indicated that Notch signaling inhibits steroidogenesis. GATA4 has been shown to be a positive regulator of steroidogenic genes, including STAR protein, P450 aromatase, and 3B-hydroxysteroid dehydrogenase. We observed that Notch downstream effectors HEY1, HEY2, and HEYL are able to differentially regulate these GATA4-dependent promoters. These data are supported by the presence of HEY/HES binding sites in these promoters. These studies indicate that Notch signaling has a role in the complex regulation of the steroidogenic pathway. PMID:26183893

  1. Regulation of Notch 1 signaling in THP-1 cells enhances M2 macrophage differentiation.

    PubMed

    Singla, Reetu D; Wang, Jing; Singla, Dinender K

    2014-12-01

    Macrophage polarization is emerging as an important area of research for the development of novel therapeutics to treat inflammatory diseases. Within the current study, the role of Notch1R in macrophage differentiation was investigated as well as downstream effects in THP-1 monocytes cultured in "inflammation mimicry" media. Interference of Notch signaling was achieved using either the pharmaceutical inhibitor DAPT or Notch1R small interfering RNA (siRNA), and Notch1R expression, macrophage phenotypes, and anti- and proinflammatory cytokine expression were evaluated. Data presented show that Notch1R expression on M1 macrophages as well as M1 macrophage differentiation is significantly elevated during cellular stress (P < 0.05). However, under identical culture conditions, interference to Notch signaling via Notch1R inhibition mitigated these results as well as promoted M2 macrophage differentiation. Moreover, when subjected to cellular stress, macrophage secretion of proinflammatory cytokines was significantly heightened (P < 0.05). Importantly, Notch1R inhibition not only diminished proinflammatory cytokine secretion but also enhanced anti-inflammatory protein release (P < 0.05). Our data suggest that Notch1R plays a pivotal role in M1 macrophage differentiation and heightened inflammatory responses. Therefore, we conclude that inhibition of Notch1R and subsequent downstream signaling enhances monocyte to M2 polarized macrophage outcomes and promotes anti-inflammatory mediation during cellular stress. PMID:25260616

  2. Drosophila Cyclin G Is a Regulator of the Notch Signalling Pathway during Wing Development

    PubMed Central

    Nagel, Anja C.; Szawinski, Jutta; Zimmermann, Mirjam; Preiss, Anette

    2016-01-01

    Notch signalling regulates a multitude of differentiation processes during Drosophila development. For example, Notch activity is required for proper wing vein differentiation which is hampered in mutants of either the receptor Notch, the ligand Delta or the antagonist Hairless. Moreover, the Notch pathway is involved in several aspects of Drosophila oogenesis as well. We have identified Drosophila Cyclin G (CycG) as a molecular interaction partner of Hairless, the major antagonist in the Notch signalling pathway, in vitro and in vivo. Loss of CycG was shown before to cause female sterility and to disturb the architecture of the egg shell. Nevertheless, Notch dependent processes during oogenesis appeared largely unaffected in cycG mutant egg chambers. Loss of CycG modified the dominant wing phenotypes of Notch, Delta and Hairless mutants. Whereas the Notch loss of function phenotype was ameliorated by a loss of CycG, the phenotypes of either Notch gain of function or of Delta or Hairless loss of function were enhanced. In contrast, loss of CycG had only a minor effect on the wing vein phenotype of mutants affecting the EGFR signalling pathway emphasizing the specificity of the interaction of CycG and Notch pathway members. PMID:26963612

  3. The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis.

    PubMed

    Astudillo, Luisana; Da Silva, Thiago G; Wang, Zhiqiang; Han, Xiaoqing; Jin, Ke; VanWye, Jeffrey; Zhu, Xiaoxia; Weaver, Kelly; Oashi, Taiji; Lopes, Pedro E M; Orton, Darren; Neitzel, Leif R; Lee, Ethan; Landgraf, Ralf; Robbins, David J; MacKerell, Alexander D; Capobianco, Anthony J

    2016-06-15

    In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593-603. ©2016 AACR. PMID:27197169

  4. Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention

    PubMed Central

    Wang, Weihuan; Yu, Shuiliang; Zimmerman, Grant; Wang, Yiwei; Myers, Jay; Yu, Vionnie W.C.; Huang, Dan; Huang, Xiaoran; Shim, Jeongsup; Huang, Yuanshuai; Xin, William; Qiao, Peter; Yan, Minhong; Xin, Wei; Scadden, David T.; Stanley, Pamela; Lowe, John B.; Huang, Alex Y.; Siebel, Christian W.; Zhou, Lan

    2015-01-01

    Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here we reveal a novel adhesive role of Notch-ligand engagement in hematopoietic stem and progenitor cells (HSPCs). Using mice with conditional loss of O-fucosylglycans on Notch EGF-like repeats important for the binding of Notch ligands, we report that HSPCs with faulty ligand binding ability display enhanced cycling accompanied by increased egress from the marrow, a phenotype mainly attributed to their reduced adhesion to Notch ligand-expressing stromal cells and osteoblastic cells and their altered occupation in osteoblastic niches. Adhesion to Notch ligand-bearing osteoblastic or stromal cells inhibits wild type but not O-fucosylglycan-deficient HSPC cycling, independent of RBP-JK-mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-JK-independent HSPC egress and enhanced HSPC mobilization. We therefore conclude that Notch receptor-ligand engagement controls HSPC quiescence and retention in the marrow niche that is dependent on O-fucosylglycans on Notch. PMID:25851125

  5. Notch Signaling Regulates the Homeostasis of Tissue-Restricted Innate-like T Cells.

    PubMed

    Chennupati, Vijaykumar; Koch, Ute; Coutaz, Manuel; Scarpellino, Leonardo; Tacchini-Cottier, Fabienne; Luther, Sanjiv A; Radtke, Freddy; Zehn, Dietmar; MacDonald, H Robson

    2016-08-01

    Although Notch signaling plays important roles in lineage commitment and differentiation of multiple cell types including conventional T cells, nothing is currently known concerning Notch function in innate-like T cells. We have found that the homeostasis of several well-characterized populations of innate-like T cells including invariant NKT cells (iNKT), CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells is controlled by Notch. Notch selectively regulates hepatic iNKT cell survival via tissue-restricted control of B cell lymphoma 2 and IL-7Rα expression. More generally, Notch regulation of innate-like T cell homeostasis involves both cell-intrinsic and -extrinsic mechanisms and relies upon context-dependent interactions with Notch ligand-expressing fibroblastic stromal cells. Collectively, using conditional ablation of Notch receptors on peripheral T cells or Notch ligands on putative fibroblastic stromal cells, we show that Notch signaling is indispensable for the homeostasis of three tissue-restricted populations of innate-like T cells: hepatic iNKT, CD8ααTCRαβ small intestinal intraepithelial lymphocytes, and innate memory phenotype CD8 T cells, thus supporting a generalized role for Notch in innate T cell homeostasis. PMID:27324132

  6. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia.

    PubMed

    Rossi, Davide; Rasi, Silvia; Fabbri, Giulia; Spina, Valeria; Fangazio, Marco; Forconi, Francesco; Marasca, Roberto; Laurenti, Luca; Bruscaggin, Alessio; Cerri, Michaela; Monti, Sara; Cresta, Stefania; Famà, Rosella; De Paoli, Lorenzo; Bulian, Pietro; Gattei, Valter; Guarini, Anna; Deaglio, Silvia; Capello, Daniela; Rabadan, Raul; Pasqualucci, Laura; Dalla-Favera, Riccardo; Foà, Robin; Gaidano, Gianluca

    2012-01-12

    Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P < .001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis. PMID:22077063

  7. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia

    PubMed Central

    Rasi, Silvia; Fabbri, Giulia; Spina, Valeria; Fangazio, Marco; Forconi, Francesco; Marasca, Roberto; Laurenti, Luca; Bruscaggin, Alessio; Cerri, Michaela; Monti, Sara; Cresta, Stefania; Famà, Rosella; De Paoli, Lorenzo; Bulian, Pietro; Gattei, Valter; Guarini, Anna; Deaglio, Silvia; Capello, Daniela; Rabadan, Raul; Pasqualucci, Laura; Dalla-Favera, Riccardo; Foà, Robin; Gaidano, Gianluca

    2012-01-01

    Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P < .001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis. PMID:22077063

  8. Heterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency.

    PubMed

    Lebkuechner, Isabell; Wilhelmsson, Ulrika; Möllerström, Elin; Pekna, Marcela; Pekny, Milos

    2015-10-01

    Astrocytes have multiple roles in the CNS including control of adult neurogenesis. We recently showed that astrocyte inhibition of neurogenesis through Notch signaling depends on the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. Here, we used real-time quantitative PCR to analyze gene expression in individual mouse astrocytes in primary cultures and in GFAP(POS) or Aldh1L1(POS) astrocytes freshly isolated from uninjured, contralesional and lesioned hippocampus 4 days after entorhinal cortex lesion. To determine the Notch signaling competence of individual astrocytes, we measured the mRNA levels of Notch ligands and Notch1 receptor. We found that whereas most cultured and freshly isolated astrocytes were competent to receive Notch signals, only a minority of astrocytes were competent to send Notch signals. Injury increased the fraction of astrocyte subpopulation unable to send and receive Notch signals, thus resembling primary astrocytes in vitro. Astrocytes deficient of GFAP and vimentin showed decreased Notch signal sending competence and altered expression of Notch signaling pathway-related genes Dlk2, Notch1, and Sox2. Furthermore, we identified astrocyte subpopulations based on their mRNA and protein expression of nestin and HB-EGF. This study improves our understanding of astrocyte heterogeneity, and points to astrocyte cytoplasmic intermediate filaments as targets for neural cell replacement strategies. PMID:26118771

  9. Study of the Effects of Edm Notch Width on Eddy Current Signal Response

    NASA Astrophysics Data System (ADS)

    Nakagawa, N.; Yang, M.; Larson, B. F.; Madison, E. M.; Raulerson, D.

    2009-03-01

    A sometimes stated rule of thumb is that the eddy current signal from a fatigue crack can be 60% of the strength produced by a similarly sized, rectangular EDM notch. A study was conducted to explore the effect that the width of a discontinuity has on signal strength when inspecting low conductivity materials for small cracks with eddy current surface probes. EDM notches of different sizes and shapes were planted in Ti-6246 and IN-100 specimens. Each of the two materials received six 0.020 inch long by 0.010 inch deep notches and six 0.030 inch and 0.015 inch deep notches. Three of the notches of each size were rectangular shaped and three were semicircular shaped. One of the notches in each material size group was 0.005 inch wide, one was 0.003 inch wide and one was 0.001 inch wide. Each of the notches was scanned using absolute and differential pencil probes driven at several different frequencies. The experimental results were compared with numerically generated results, which allowed for a zero width notch to be considered. The results indicated that the signal reduction factor from a 0.005 inch wide, rectangular notch to a theoretical zero-width notch of the same size ranged from 25 to 42%.

  10. Activation Dynamics and Signaling Properties of Notch3 Receptor in the Developing Pulmonary Artery*

    PubMed Central

    Ghosh, Shamik; Paez-Cortez, Jesus R.; Boppidi, Karthik; Vasconcelos, Michelle; Roy, Monideepa; Cardoso, Wellington; Ai, Xingbin; Fine, Alan

    2011-01-01

    Notch3 signaling is fundamental for arterial specification of systemic vascular smooth muscle cells (VSMCs). However, the developmental role and signaling properties of the Notch3 receptor in the mouse pulmonary artery remain unknown. Here, we demonstrate that Notch3 is expressed selectively in pulmonary artery VSMCs, is activated from late fetal to early postnatal life, and is required to maintain the morphological characteristics and smooth muscle gene expression profile of the pulmonary artery after birth. Using a conditional knock-out mouse model, we show that Notch3 receptor activation in VSMCs is Jagged1-dependent. In vitro VSMC lentivirus-mediated Jagged1 knockdown, confocal localization analysis, and co-culture experiments revealed that Notch3 activation is cell-autonomous and occurs through the physical engagement of Notch3 and VSMC-derived Jagged1 in the interior of the same cell. Although the current models of mammalian Notch signaling involve a two-cell system composed of a signal-receiving cell that expresses a Notch receptor on its surface and a neighboring signal-sending cell that provides membrane-bound activating ligand, our data suggest that pulmonary artery VSMC Notch3 activation is cell-autonomous. This unique mechanism of Notch activation may play an important role in the maturation of the pulmonary artery during the transition to air breathing. PMID:21536678

  11. Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia

    PubMed Central

    Yashiro-Ohtani, Yumi; Wang, Hongfang; Zang, Chongzhi; Arnett, Kelly L.; Bailis, Will; Ho, Yugong; Knoechel, Birgit; Lanauze, Claudia; Louis, Lumena; Forsyth, Katherine S.; Chen, Sujun; Chung, Yoonjie; Schug, Jonathan; Blobel, Gerd A.; Liebhaber, Stephen A.; Bernstein, Bradley E.; Blacklow, Stephen C.; Liu, Xiaole Shirley; Aster, Jon C.; Pear, Warren S.

    2014-01-01

    Notch is needed for T-cell development and is a common oncogenic driver in T-cell acute lymphoblastic leukemia. The protooncogene c-Myc (Myc) is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3′ of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell-context–specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region comprises an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of bromodomain containing 4 (Brd4), a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3′ enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia. PMID:25369933

  12. Faster embryonic segmentation through elevated Delta-Notch signalling

    PubMed Central

    Liao, Bo-Kai; Jörg, David J.; Oates, Andrew C.

    2016-01-01

    An important step in understanding biological rhythms is the control of period. A multicellular, rhythmic patterning system termed the segmentation clock is thought to govern the sequential production of the vertebrate embryo's body segments, the somites. Several genetic loss-of-function conditions, including the Delta-Notch intercellular signalling mutants, result in slower segmentation. Here, we generate DeltaD transgenic zebrafish lines with a range of copy numbers and correspondingly increased signalling levels, and observe faster segmentation. The highest-expressing line shows an altered oscillating gene expression wave pattern and shortened segmentation period, producing embryos with more, shorter body segments. Our results reveal surprising differences in how Notch signalling strength is quantitatively interpreted in different organ systems, and suggest a role for intercellular communication in regulating the output period of the segmentation clock by altering its spatial pattern. PMID:27302627

  13. Analysis of notched metal matrix composites under tension loading

    NASA Technical Reports Server (NTRS)

    Bigelow, C. A.

    1988-01-01

    Presented are techniques based on 3-D finite-element analysis for the examination of continuous fiber reinforced metal matrix composites. Examples are shown for specific metal matrix composites such as boron/aluminum and silicon-carbide/aluminum. Specimen stress-strain behavior and stress at first fiber failure were predicted for boron/aluminum laminates containing circular holes and crack-like slits. The predictions compared very well for (+ or - 45) sub 2s laminates. Mesh configuration was shown to have an effect on the calculation of stresses local to the notch. The presence of thin interface layers of matrix material had a significant influence on the slit-tip stress state, causing sharper stress gradients near the notch. Interface layers reduced the slit-tip fibers stresses in a (+ or - 45) sub s silicon-carbide/aluminum laminate but increased them in a (0/90) sub s laminate.

  14. Faster embryonic segmentation through elevated Delta-Notch signalling.

    PubMed

    Liao, Bo-Kai; Jörg, David J; Oates, Andrew C

    2016-01-01

    An important step in understanding biological rhythms is the control of period. A multicellular, rhythmic patterning system termed the segmentation clock is thought to govern the sequential production of the vertebrate embryo's body segments, the somites. Several genetic loss-of-function conditions, including the Delta-Notch intercellular signalling mutants, result in slower segmentation. Here, we generate DeltaD transgenic zebrafish lines with a range of copy numbers and correspondingly increased signalling levels, and observe faster segmentation. The highest-expressing line shows an altered oscillating gene expression wave pattern and shortened segmentation period, producing embryos with more, shorter body segments. Our results reveal surprising differences in how Notch signalling strength is quantitatively interpreted in different organ systems, and suggest a role for intercellular communication in regulating the output period of the segmentation clock by altering its spatial pattern. PMID:27302627

  15. Fatigue of notched fiber composite laminates. Part 1: Analytical model

    NASA Technical Reports Server (NTRS)

    Mclaughlin, P. V., Jr.; Kulkarni, S. V.; Huang, S. N.; Rosen, B. W.

    1975-01-01

    A description is given of a semi-empirical, deterministic analysis for prediction and correlation of fatigue crack growth, residual strength, and fatigue lifetime for fiber composite laminates containing notches (holes). The failure model used for the analysis is based upon composite heterogeneous behavior and experimentally observed failure modes under both static and fatigue loading. The analysis is consistent with the wearout philosophy. Axial cracking and transverse cracking failure modes are treated together in the analysis. Cracking off-axis is handled by making a modification to the axial cracking analysis. The analysis predicts notched laminate failure from unidirectional material fatique properties using constant strain laminate analysis techniques. For multidirectional laminates, it is necessary to know lamina fatique behavior under axial normal stress, transverse normal stress and axial shear stress. Examples of the analysis method are given.

  16. Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features.

    PubMed

    Rettig, Eleni M; Chung, Christine H; Bishop, Justin A; Howard, Jason D; Sharma, Rajni; Li, Ryan J; Douville, Christopher; Karchin, Rachel; Izumchenko, Evgeny; Sidransky, David; Koch, Wayne; Califano, Joseph; Agrawal, Nishant; Fakhry, Carole

    2015-04-01

    The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P < 0.001). Most NOTCH1-wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31-276.15; P = 0.031). TP53 disruptive mutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein. PMID:25633867

  17. Sexual dimorphism of the suprascapular notch – morphometric study

    PubMed Central

    Jędrzejewski, Kazimierz S.; Topol, Mirosław

    2013-01-01

    Introduction The concept of the study was to compare the morphometry of the suprascapular notch (SSN) in females and males because its size and shape may be a factor in suprascapular nerve entrapment. Material and methods The measurements of 81 scapulae included morphological length and width, maximal width and length projection of the scapular spine, and width and length of the glenoid cavity. The width-length scapular and glenoid cavity indices were calculated. In addition to standard anthropometric measurements three other dimensions were defined and collected for every SSN: maximal depth (MD), superior (STD) and middle (MTD) transverse diameters. Results The analysis of the measurements allowed us to distinguish five types of SSN. Type I (26%) had longer maximal depth than superior transverse diameter. Type II (3%) had equal MD, STD and MTD. In type III (57.6%) superior transverse diameter was longer than maximal depth. In type IV (7.4%) a bony foramen was present. Type V (6%) was without a discrete notch. Types I and III were divided into two subtypes: A (MTD was longer than STD) and B (MTD < STD). Distribution of the suprascapular notch types in both sexes was similar. However, MD, STD and MTD were significantly higher in males. The superior transverse suprascapular ligament was completely and partially ossified in 7.4% and 24.7% respectively. Conclusions The presented classification of the suprascapular notch is simple, easy to use, and based on specific geometric parameters which allow one to clearly distinguish five types of these structures. All dimensions of SSN were significantly higher in males than in females. PMID:23515320

  18. Compliance measurements of chevron notched four point bend specimen

    NASA Technical Reports Server (NTRS)

    Calomino, Anthony; Bubsey, Raymond; Ghosn, Louis J.

    1994-01-01

    The experimental stress intensity factors for various chevron notched four point bend specimens are presented. The experimental compliance is verified using the analytical solution for a straight through crack four point bend specimen and the boundary integral equation method for one chevron geometry. Excellent agreement is obtained between the experimental and analytical results. In this report, stress intensity factors, loading displacements and crack mouth opening displacements are reported for different crack lengths and different chevron geometries, under four point bend loading condition.

  19. Xanthohumol Inhibits Notch Signaling and Induces Apoptosis in Hepatocellular Carcinoma

    PubMed Central

    Kunnimalaiyaan, Selvi; Gamblin, T. Clark; Kunnimalaiyaan, Muthusamy

    2015-01-01

    Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC) remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN), a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro. XN treatment in healthy mice and humans yielded favorable pharmacokinetics and bioavailability. Therefore, we determined to study the effects of XN and understand the mechanism of its action in HCC. The effects of XN on a panel of HCC cell lines were assessed for cell viability, colony forming ability, and cellular proliferation. Cell lysates were analyzed for pro-apoptotic (c-PARP and cleaved caspase-3) and anti-apoptotic markers (survivin, cyclin D1, and Mcl-1). XN concentrations of 5μM and above significantly reduced the cell viability, colony forming ability and also confluency of all four HCC cell lines studied. Furthermore, growth suppression due to apoptosis was evidenced by increased expression of pro-apoptotic and reduced expression of anti-apoptotic proteins. Importantly, XN treatment inhibited the Notch signaling pathway as evidenced by the decrease in the expression of Notch1 and HES-1 proteins. Ectopic expression of Notch1 in HCC cells reverses the anti-proliferative effect of XN as evidenced by reduced growth suppression compared to control. Taken together these results suggested that XN mediated growth suppression is appeared to be mediated by the inhibition of the Notch signaling pathway. Therefore, our findings warrants further studies on XN as a potential agent for the treatment for HCC. PMID:26011160

  20. Delta-Notch Lateral Inhibition within the Organ of Corti

    NASA Astrophysics Data System (ADS)

    Summers, R.; Abdulla, T.; Luff, R.

    2013-09-01

    Lateral inhibition is described as an emergent property of the Delta-Notch signalling network. Two separate model representations of lateral inhibition are proposed for different purposes. One provides information about bioenergetics while the other has the capability to produce a physical representation. It is proposed that both can be used in further studies of the sensory pathways in the human connectome model of brain function.

  1. Promoting Angiogenesis via Manipulation of VEGF Responsiveness with Notch Signaling

    PubMed Central

    Cao, Lan; Arany, Praveen R.; Wang, Yuan-Shuo; Mooney, David J.

    2009-01-01

    Promoting angiogenesis via delivery of vascular endothelial growth factor (VEGF) and other angiogenic factors is both a potential therapy for cardiovascular diseases and a critical aspect for tissue regeneration. The recent demonstration that VEGF signaling is modulated by the Notch signaling pathway, however, suggests that inhibiting Notch signaling may enhance regional neovascularization, by altering the responsiveness of local endothelial cells to angiogenic stimuli. We tested this possibility with in vitro assays using human endothelial cells, as well as in a rodent hindlimb ischemia model. Treatment of cultured human endothelial cells with DAPT, a gamma secretase inhibitor, increased cell migration and sprout formation in response to VEGF stimulation with a biphasic dependence on DAPT concentration. Further, delivery of an appropriate combination of DAPT and VEGF from an injectable alginate hydrogel system into ischemic hindlimbs led to a faster recovery of blood flow than VEGF or DAPT alone; perfusion levels reached 80% of the normal level by week 4 with combined DAPT and VEGF delivery. Direct intramuscular or intraperitoneal injection of DAPT did not result in the same level of improvement, suggesting that appropriate presentation of DAPT (gel delivery) is important for its activity. DAPT delivery from the hydrogels also did not lead to any adverse side effects, in contrast to systemic introduction of DAPT. Altogether, these results suggest a new approach to promote angiogenesis by controlling Notch signaling, and may provide new options to treat patients with diseases that diminish angiogenic responsiveness. PMID:19481797

  2. The Notch intracellular domain represses CRE-dependent transcription.

    PubMed

    Hallaq, Rania; Volpicelli, Floriana; Cuchillo-Ibanez, Inmaculada; Hooper, Claudie; Mizuno, Keiko; Uwanogho, Dafe; Causevic, Mirsada; Asuni, Ayodeji; To, Alvina; Soriano, Salvador; Giese, K Peter; Lovestone, Simon; Killick, Richard

    2015-03-01

    Members of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate the expression of genes needed for long-term memory formation. Loss of Notch impairs long-term, but not short-term, memory in flies and mammals. We investigated if the Notch-1 (N1) exerts an effect on CREB-dependent gene transcription. We observed that N1 inhibits CREB mediated activation of cyclic-AMP response element (CRE) containing promoters in a γ-secretase-dependent manner. We went on to find that the γ-cleaved N1 intracellular domain (N1ICD) sequesters nuclear CREB1α, inhibits cAMP/PKA-mediated neurite outgrowth and represses the expression of specific CREB regulated genes associated with learning and memory in primary cortical neurons. Similar transcriptional effects were observed with the N2ICD, N3ICD and N4ICDs. Together, these observations indicate that the effects of Notch on learning and memory are, at least in part, via an effect on CREB-regulated gene expression. PMID:25479589

  3. Notch signaling regulates venous arterialization during zebrafish fin regeneration

    PubMed Central

    Kametani, Yoshiko; Chi, Neil C.; Stainier, Didier Y.R.; Takada, Shinji

    2015-01-01

    In order to protect against blood pressure, a mature artery is supported by mural cells which include vascular smooth muscle cells and pericytes. To regenerate a functional vascular system, arteries should be properly reconstructed with mural cells although the mechanisms underlying artery reconstruction remain unclear. In this study, we examined the process of artery reconstruction during regeneration of the zebrafish caudal fin as a model to study arterial formation in an adult setting. During fin regeneration, the arteries and veins form a net-like vasculature called the vascular plexus, and this plexus undergoes remodeling to form a new artery and 2 flanking veins. We found that the new vascular plexus originates mainly from venous cells in the stump but very rarely from the arterial cells. Interestingly, these vein-derived cells contributed to the reconstructed arteries. This arterialization was dependent on Notch signaling, and further analysis revealed that Notch signaling was required for the initiation of arterial gene expression. In contrast, venous remodeling did not require Notch signaling. These results provide new insights towards understanding mechanisms of vascular regeneration and illustrate the utility of the adult zebrafish fin to study this process. PMID:25810153

  4. Conformational locking upon cooperative assembly of Notch transcription complexes

    PubMed Central

    Choi, Sung Hee; Wales, Thomas E.; Nam, Yunsun; O’Donovan, Daniel; Sliz, Piotr; Engen, John R.; Blacklow, Stephen C.

    2012-01-01

    The Notch intracellular domain (NICD) forms a transcriptional activation complex with the DNA-binding factor CSL and a transcriptional co-activator of the Mastermind family (MAML). The "RAM" region of NICD recruits Notch to CSL, facilitating the binding of MAML at the interface between the ankyrin (ANK) repeat domain of NICD and CSL. Here, we report the X-ray structure of a human MAML1/RAM/ANK/CSL/DNA complex, and probe changes in component dynamics upon stepwise assembly of a MAML1/NICD/CSL complex using HX-MS. Association of CSL with NICD exerts remarkably little effect on the exchange kinetics of the ANK domain, whereas MAML1 binding greatly retards the exchange kinetics of ANK repeats 2–3. These exchange patterns identify critical features contributing to the cooperative assembly of Notch transcription complexes (NTCs), highlight the importance of MAML recruitment in rigidifying the ANK domain and stabilizing its interface with CSL, and rationalize the requirement for MAML1 in driving cooperative dimerization of NTCs on paired site DNA. PMID:22325781

  5. Sub-microsecond beam notching at low energy

    SciTech Connect

    Moehs, D.P.; /Fermilab

    2005-09-01

    A technique for creating a burst of 100 ns notches (beam extinctions) in an H{sup -} beam at 454 kHz has been developed at {le} 20 keV utilizing a Magnetron ion source with a slit extraction system and a split extractor. Each half of the extractor is treated as part of a 50 ohm transmission line which can be pulsed at {+-} 700 volts creating a 1400 volt gradient across the extractor. A beam current reduction of better than 95% has been observed at the end of the Fermilab 400 MeV Linac. Notched multi-turn charge-exchange injection into the Booster, a 400 MeV to 8 GeV synchrotron, has been demonstrated with a charge reduction in the resulting beam gap of 83%. Presently, the trailing edge of the notch may be adversely affected by space charge resulting in a beam recovery with two different time constants. Efforts to minimize this effect are discussed.

  6. Notched graphite polymimide composites at room and notched graphite polymide composites at room and elevated temperatures. [nondestructive test techniques

    NASA Technical Reports Server (NTRS)

    Awerbuch, J.; Perkinson, H. E.; Kamel, I. L.

    1980-01-01

    The fracture behavior in graphite/polyimide (Gr/PI) Celion 6000/PMR-15 composites was characterized. Emphasis was placed on the correlation between the observed failure modes and the deformation characteristics of center-notched Gr/Pl laminates. Crack tip damage growth, fracture strength and notch sensitivity, and the associated characterization methods were also examined. Special attention was given to nondestructive evaluation of internal damage and damage growth, techniques such as acoustic emission, X-ray radiography, and ultrasonic C-scan. Microstructural studies using scanning electron microscopy, photomicrography, and the pulsed nuclear magnetic resonance technique were employed as well. All experimental procedures and techniques are described and a summary of representative results for Gr/Pl laminates is given.

  7. Measuring on Lattices

    NASA Astrophysics Data System (ADS)

    Knuth, Kevin H.

    2009-12-01

    Previous derivations of the sum and product rules of probability theory relied on the algebraic properties of Boolean logic. Here they are derived within a more general framework based on lattice theory. The result is a new foundation of probability theory that encompasses and generalizes both the Cox and Kolmogorov formulations. In this picture probability is a bi-valuation defined on a lattice of statements that quantifies the degree to which one statement implies another. The sum rule is a constraint equation that ensures that valuations are assigned so as to not violate associativity of the lattice join and meet. The product rule is much more interesting in that there are actually two product rules: one is a constraint equation arises from associativity of the direct products of lattices, and the other a constraint equation derived from associativity of changes of context. The generality of this formalism enables one to derive the traditionally assumed condition of additivity in measure theory, as well introduce a general notion of product. To illustrate the generic utility of this novel lattice-theoretic foundation of measure, the sum and product rules are applied to number theory. Further application of these concepts to understand the foundation of quantum mechanics is described in a joint paper in this proceedings.

  8. Resonant translational, breathing, and twisting modes of transverse magnetic domain walls pinned at notches

    NASA Astrophysics Data System (ADS)

    Metaxas, Peter J.; Albert, Maximilian; Lequeux, Steven; Cros, Vincent; Grollier, Julie; Bortolotti, Paolo; Anane, Abdelmadjid; Fangohr, Hans

    2016-02-01

    We study resonant translational, breathing, and twisting modes of transverse magnetic domain walls pinned at notches in ferromagnetic nanostrips. We demonstrate that a mode's sensitivity to notches depends strongly on the mode's characteristics. For example, the frequencies of modes that involve lateral motion of the wall are the most sensitive to changes in the notch intrusion depth, especially at the narrow, more strongly confined end of the domain wall. In contrast, the breathing mode, whose dynamics are concentrated away from the notches is relatively insensitive to changes in the notches' sizes. We also demonstrate a sharp drop in the translational mode's frequency towards zero when approaching depinning which is confirmed, using a harmonic oscillator model, to be consistent with a reduction in the local slope of the notch-induced confining potential at its edge.

  9. Notch-tip deformation of Ni{sub 3}Al single crystals

    SciTech Connect

    Schulson, E.M.; Xu, Y.

    1997-12-31

    In a recent paper on the deformation of notched polycrystals of Ni-rich Ni{sub 3}Al doped with boron, the authors showed that the notch sensitivity of this material is related to the suppression of plastic flow by the triaxial state of tensile stress induced by the notch. Cracks initiate on crystallographic slip planes at the tip of the notch, where the stress and inelastic strain are concentrated, and then propagate once the degree of triaxialty exceeds a critical level. The tensile strength appears to be controlled by crack initiation. To explore further the notch sensitivity of boron-doped Ni{sub 3}Al the authors performed new experiments using notched single crystals. This paper summarizes their observations.

  10. Compensatory Flux Changes within an Endocytic Trafficking Network Maintain Thermal Robustness of Notch Signaling

    PubMed Central

    Shimizu, Hideyuki; Woodcock, Simon A.; Wilkin, Marian B.; Trubenová, Barbora; Monk, Nicholas A.M.; Baron, Martin

    2014-01-01

    Summary Developmental signaling is remarkably robust to environmental variation, including temperature. For example, in ectothermic animals such as Drosophila, Notch signaling is maintained within functional limits across a wide temperature range. We combine experimental and computational approaches to show that temperature compensation of Notch signaling is achieved by an unexpected variety of endocytic-dependent routes to Notch activation which, when superimposed on ligand-induced activation, act as a robustness module. Thermal compensation arises through an altered balance of fluxes within competing trafficking routes, coupled with temperature-dependent ubiquitination of Notch. This flexible ensemble of trafficking routes supports Notch signaling at low temperature but can be switched to restrain Notch signaling at high temperature and thus compensates for the inherent temperature sensitivity of ligand-induced activation. The outcome is to extend the physiological range over which normal development can occur. Similar mechanisms may provide thermal robustness for other developmental signals. PMID:24855951

  11. Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis.

    PubMed

    Tian, Hua; Biehs, Brian; Chiu, Cecilia; Siebel, Christian W; Wu, Yan; Costa, Mike; de Sauvage, Frederic J; Klein, Ophir D

    2015-04-01

    Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration of multiple inputs. In the mouse small intestine, Notch and Wnt signaling are required both for stem cell maintenance and for a proper balance of differentiation between secretory and absorptive cell lineages. In the absence of Notch signaling, stem cells preferentially generate secretory cells at the expense of absorptive cells. Here, we use function-blocking antibodies against Notch receptors to demonstrate that Notch blockade perturbs intestinal stem cell function by causing a derepression of the Wnt signaling pathway, leading to misexpression of prosecretory genes. Importantly, attenuation of the Wnt pathway rescued the phenotype associated with Notch blockade. These studies bring to light a negative regulatory mechanism that maintains stem cell activity and balanced differentiation, and we propose that the interaction between Wnt and Notch signaling described here represents a common theme in adult stem cell biology. PMID:25818302

  12. Notch Lineages and Activity in Intestinal Stem Cells Determined by a New Set of Knock-In Mice

    PubMed Central

    Fre, Silvia; Hannezo, Edouard; Sale, Sanja; Huyghe, Mathilde; Lafkas, Daniel; Kissel, Holger; Louvi, Angeliki; Greve, Jeffrey; Louvard, Daniel; Artavanis-Tsakonas, Spyros

    2011-01-01

    The conserved role of Notch signaling in controlling intestinal cell fate specification and homeostasis has been extensively studied. Nevertheless, the precise identity of the cells in which Notch signaling is active and the role of different Notch receptor paralogues in the intestine remain ambiguous, due to the lack of reliable tools to investigate Notch expression and function in vivo. We generated a new series of transgenic mice that allowed us, by lineage analysis, to formally prove that Notch1 and Notch2 are specifically expressed in crypt stem cells. In addition, a novel Notch reporter mouse, Hes1-EmGFPSAT, demonstrated exclusive Notch activity in crypt stem cells and absorptive progenitors. This roster of knock-in and reporter mice represents a valuable resource to functionally explore the Notch pathway in vivo in virtually all tissues. PMID:21991352

  13. V-Notched Bar Creep Life Prediction: GH3536 Ni-Based Superalloy Under Multiaxial Stress State

    NASA Astrophysics Data System (ADS)

    Zhang, D. X.; Wang, J. P.; Wen, Z. X.; Liu, D. S.; Yue, Z. F.

    2016-07-01

    In this study, creep experiments on smooth and circumferential V-type notched round bars were conducted in GH3536 Ni-based superalloy at 750 °C to identify notch strengthening effect in notched specimens. FE analysis was carried out, coupled with continuum damage mechanics (CDM), to analyze stress distribution and damage evolution under multiaxial stress state. The creep deformation of smooth specimens and the rupture life of both smooth and notched specimens showed good agreement between experimental results and FE analysis predictions; the creep rupture life for the notched specimen was successfully predicted via the "skeletal point" concept. Both creep damage analysis and the observed fracture morphology suggest that creep rupture started first at the root in the V-type notched specimens, and shifted to the region close to the notch root when the notch was relatively shallow compared to U-type notched specimens.

  14. V-Notched Bar Creep Life Prediction: GH3536 Ni-Based Superalloy Under Multiaxial Stress State

    NASA Astrophysics Data System (ADS)

    Zhang, D. X.; Wang, J. P.; Wen, Z. X.; Liu, D. S.; Yue, Z. F.

    2016-05-01

    In this study, creep experiments on smooth and circumferential V-type notched round bars were conducted in GH3536 Ni-based superalloy at 750 °C to identify notch strengthening effect in notched specimens. FE analysis was carried out, coupled with continuum damage mechanics (CDM), to analyze stress distribution and damage evolution under multiaxial stress state. The creep deformation of smooth specimens and the rupture life of both smooth and notched specimens showed good agreement between experimental results and FE analysis predictions; the creep rupture life for the notched specimen was successfully predicted via the "skeletal point" concept. Both creep damage analysis and the observed fracture morphology suggest that creep rupture started first at the root in the V-type notched specimens, and shifted to the region close to the notch root when the notch was relatively shallow compared to U-type notched specimens.

  15. Evaluation and expansion of an analytical model for fatigue of notched composite laminates

    NASA Technical Reports Server (NTRS)

    Ramkumar, R. L.; Kulkarni, S. V.; Pipes, R. B.

    1978-01-01

    The analytical and experimental study performed to expand the existing static and fatigue failure analysis is described. The analytical effort extended the analysis to include interlaminar effects, while the experimental effort developed methods to obtain basic experimental data required as input to the analysis. The static failure analysis for notched laminates was modified to include interlaminar effects near the notch. Three dimensional elastic and two dimensional elasticplastic finite element analysis were performed for some notched laminates.

  16. Determination of the crack resistance of a ceramic in bending of beams with a notch

    SciTech Connect

    Gogotsi, G.A.; Petrenko, V.P.; Zavada, V.P.

    1985-06-01

    These authors investigate crack resistance in new ceramic materials with particular regard to temperature and to the features of notches. Charts present data on the relationship of experimental values of crack resistance to crack depth for silicon carbide; on the influence of notch depth on crack resistance; on the relationship of stress intensity to notch tip radius; on characteristic load-time curves for various materials; and on the relationship of temperature to crack resistance.

  17. Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma.

    PubMed

    Wang, Xiao Qi; Zhang, Wu; Lui, Eric L H; Zhu, Yongqiang; Lu, Ping; Yu, Xiaoming; Sun, Jisan; Yang, Sitian; Poon, Ronnie T P; Fan, Sheung Tat

    2012-08-01

    Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid-based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor-node-metastasis Stages III-IV and tumor venous invasion. Knocking-down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E-cadherin; the Notch1-Snail1-E-cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the re-establishment of repressed E-cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1-Snail1-E-cadherin pathway. Knock-down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis. PMID:22052196

  18. Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling

    PubMed Central

    Brai, Emanuele; Marathe, Swananda; Astori, Simone; Fredj, Naila Ben; Perry, Elisabeth; Lamy, Christophe; Scotti, Alessandra; Alberi, Lavinia

    2015-01-01

    Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia. Highlights In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: Notch1 interacts with another important developmental pathway, the Reelin cascade. Notch1 regulates both NMDAR expression and composition. Notch1 influences a cascade of cellular events culminating in CREB activation. PMID:26635527

  19. Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes

    SciTech Connect

    Lai, Peng-Yeh; Tsai, Chong-Bin; Department of Ophthalmology, Chiayi Christian Hospital, Chiayi 600, Taiwan, ROC ; Tseng, Min-Jen

    2013-01-18

    Highlights: ► Notch4IC modulates the ERK pathway and cell cycle to promote 3T3-L1 proliferation. ► Notch4IC facilitates 3T3-L1 differentiation by up-regulating proadipogenic genes. ► Notch4IC promotes proliferation during the early stage of 3T3-L1 adipogenesis. ► Notch4IC enhances differentiation during subsequent stages of 3T3-L1 adipogenesis. -- Abstract: Adipose tissue is composed of adipocytes, which differentiate from precursor cells in a process called adipogenesis. Many signal molecules are involved in the transcriptional control of adipogenesis, including the Notch pathway. Previous adipogenic studies of Notch have focused on Notch1 and HES1; however, the role of other Notch receptors in adipogenesis remains unclear. Q-RT-PCR analyses showed that the augmentation of Notch4 expression during the differentiation of 3T3-L1 preadipocytes was comparable to that of Notch1. To elucidate the role of Notch4 in adipogenesis, the human active form Notch4 (N4IC) was transiently transfected into 3T3-L1 cells. The expression of HES1, Hey1, C/EBPδ and PPARγ was up-regulated, and the expression of Pref-1, an adipogenic inhibitor, was down-regulated. To further characterize the effect of N4IC in adipogenesis, stable cells expressing human N4IC were established. The expression of N4IC promoted proliferation and enhanced differentiation of 3T3-L1 cells compared with those of control cells. These data suggest that N4IC promoted proliferation through modulating the ERK pathway and the cell cycle during the early stage of 3T3-L1 adipogenesis and facilitated differentiation through up-regulating adipogenic genes such as C/EBPα, PPARγ, aP2, LPL and HSL during the middle and late stages of 3T3-L1 adipogenesis.

  20. Lattice Boltzmann Stokesian dynamics.

    PubMed

    Ding, E J

    2015-11-01

    Lattice Boltzmann Stokesian dynamics (LBSD) is presented for simulation of particle suspension in Stokes flows. This method is developed from Stokesian dynamics (SD) with resistance and mobility matrices calculated using the time-independent lattice Boltzmann algorithm (TILBA). TILBA is distinguished from the traditional lattice Boltzmann method (LBM) in that a background matrix is generated prior to the calculation. The background matrix, once generated, can be reused for calculations for different scenarios, thus the computational cost for each such subsequent calculation is significantly reduced. The LBSD inherits the merits of the SD where both near- and far-field interactions are considered. It also inherits the merits of the LBM that the computational cost is almost independent of the particle shape. PMID:26651812

  1. Latticed pentamode acoustic cloak

    PubMed Central

    Chen, Yi; Liu, Xiaoning; Hu, Gengkai

    2015-01-01

    We report in this work a practical design of pentamode acoustic cloak with microstructure. The proposed cloak is assembled by pentamode lattice made of a single-phase solid material. The function of rerouting acoustic wave round an obstacle has been demonstrated numerically. It is also revealed that shear related resonance due to weak shear resistance in practical pentamode lattices punctures broadband feature predicted based on ideal pentamode cloak. As a consequence, the latticed pentamode cloak can only conceal the obstacle in segmented frequency ranges. We have also shown that the shear resonance can be largely reduced by introducing material damping, and an improved broadband performance can be achieved. These works pave the way for experimental demonstration of pentamode acoustic cloak. PMID:26503821

  2. Lattice Boltzmann Stokesian dynamics

    NASA Astrophysics Data System (ADS)

    Ding, E. J.

    2015-11-01

    Lattice Boltzmann Stokesian dynamics (LBSD) is presented for simulation of particle suspension in Stokes flows. This method is developed from Stokesian dynamics (SD) with resistance and mobility matrices calculated using the time-independent lattice Boltzmann algorithm (TILBA). TILBA is distinguished from the traditional lattice Boltzmann method (LBM) in that a background matrix is generated prior to the calculation. The background matrix, once generated, can be reused for calculations for different scenarios, thus the computational cost for each such subsequent calculation is significantly reduced. The LBSD inherits the merits of the SD where both near- and far-field interactions are considered. It also inherits the merits of the LBM that the computational cost is almost independent of the particle shape.

  3. Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

    PubMed

    Zhang, Min; Biswas, Sangita; Qin, Xin; Gong, Wenrong; Deng, Wenbing; Yu, Hongjun

    2016-08-01

    The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro-oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers. PMID:27228302

  4. Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals

    PubMed Central

    Mckenzie, Grahame; Ward, George; Stallwood, Yvette; Briend, Emmanuel; Papadia, Sofia; Lennard, Andrew; Turner, Martin; Champion, Brian; Hardingham, Giles E

    2006-01-01

    Background Notch plays a wide-ranging role in controlling cell fate, differentiation and development. The PI3K-Akt pathway is a similarly conserved signalling pathway which regulates processes such as differentiation, proliferation and survival. Mice with disrupted Notch and PI3K signalling show phenotypic similarities during haematopoietic cell development, suggesting functional interaction between these pathways. Results We show that cellular responsiveness to Notch signals depends on the activity of the PI3K-Akt pathway in cells as diverse as CHO cells, primary T-cells and hippocampal neurons. Induction of the endogenous PI3K-Akt pathway in CHO cells (by the insulin pathway), in T-cells (via TCR activation) or in neurons (via TrKB activation) potentiates Notch-dependent responses. We propose that the PI3K-Akt pathway exerts its influence on Notch primarily via inhibition of GSK3-beta, a kinase known to phosphorylate and regulate Notch signals. Conclusion The PI3K-Akt pathway acts as a "gain control" for Notch signal responses. Since physiological levels of intracellular Notch are often low, coincidence with PI3K-activation may be crucial for induction of Notch-dependent responses. PMID:16507111

  5. Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma.

    PubMed

    Mu, Xiaodong; Agarwal, Rashmi; March, Daniel; Rothenberg, Adam; Voigt, Clifford; Tebbets, Jessica; Huard, Johnny; Weiss, Kurt

    2016-01-01

    Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia. PMID:27378829

  6. A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons.

    PubMed

    Hayashi, Yukari; Nishimune, Hiroshi; Hozumi, Katsuto; Saga, Yumiko; Harada, Akihiro; Yuzaki, Michisuke; Iwatsubo, Takeshi; Kopan, Raphael; Tomita, Taisuke

    2016-01-01

    Notch signaling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Although recent studies implicate that Notch regulates synaptic plasticity or cognitive performance, the molecular mechanism how Notch works in mature neurons remains uncertain. Here we demonstrate that a novel Notch signaling is involved in expression of synaptic proteins in postmitotic neurons. Levels of several synaptic vesicle proteins including synaptophysin 1 and VGLUT1 were increased when neurons were cocultured with Notch ligands-expressing NIH3T3 cells. Neuron-specific deletion of Notch genes decreased these proteins, suggesting that Notch signaling maintains the expression of synaptic vesicle proteins in a cell-autonomous manner. Unexpectedly, cGMP-dependent protein kinase (PKG) inhibitor, but not γ-secretase inhibitor, abolished the elevation of synaptic vesicle proteins, suggesting that generation of Notch intracellular domain is dispensable for this function. These data uncover a ligand-dependent, but γ-secretase-independent, non-canonical Notch signaling involved in presynaptic protein expression in postmitotic neurons. PMID:27040987

  7. Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling.

    PubMed

    Hu, Bin; Nandhu, Mohan S; Sim, Hosung; Agudelo-Garcia, Paula A; Saldivar, Joshua C; Dolan, Claire E; Mora, Maria E; Nuovo, Gerard J; Cole, Susan E; Viapiano, Mariano S

    2012-08-01

    Malignant gliomas are highly invasive and chemoresistant brain tumors with extremely poor prognosis. Targeting of the soluble factors that trigger invasion and resistance, therefore, could have a significant impact against the infiltrative glioma cells that are a major source of recurrence. Fibulin-3 is a matrix protein that is absent in normal brain but upregulated in gliomas and promotes tumor invasion by unknown mechanisms. Here, we show that fibulin-3 is a novel soluble activator of Notch signaling that antagonizes DLL3, an autocrine inhibitor or Notch, and promotes tumor cell survival and invasion in a Notch-dependent manner. Using a strategy for inducible knockdown, we found that controlled downregulation of fibulin-3 reduced Notch signaling and led to increased apoptosis, reduced self-renewal of glioblastoma-initiating cells, and impaired growth and dispersion of intracranial tumors. In addition, fibulin-3 expression correlated with expression levels of Notch-dependent genes and was a marker of Notch activation in patient-derived glioma samples. These findings underscore a major role for the tumor extracellular matrix in regulating glioma invasion and resistance to apoptosis via activation of the key Notch pathway. More importantly, this work describes a noncanonical, soluble activator of Notch in a cancer model and shows how Notch signaling can be reduced by targeting tumor-specific accessible molecules in the tumor microenvironment. PMID:22665268

  8. Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis

    PubMed Central

    Briot, Anaïs; Civelek, Mete; Seki, Atsuko; Hoi, Karen; Mack, Julia J.; Lee, Stephen D.; Kim, Jason; Hong, Cynthia; Yu, Jingjing; Fishbein, Gregory A.; Vakili, Ladan; Fogelman, Alan M.; Fishbein, Michael C.; Lusis, Aldons J.; Tontonoz, Peter; Navab, Mohamad; Berliner, Judith A.

    2015-01-01

    Although much progress has been made in identifying the mechanisms that trigger endothelial activation and inflammatory cell recruitment during atherosclerosis, less is known about the intrinsic pathways that counteract these events. Here we identified NOTCH1 as an antagonist of endothelial cell (EC) activation. NOTCH1 was constitutively expressed by adult arterial endothelium, but levels were significantly reduced by high-fat diet. Furthermore, treatment of human aortic ECs (HAECs) with inflammatory lipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [Ox-PAPC]) and proinflammatory cytokines (TNF and IL1β) decreased Notch1 expression and signaling in vitro through a mechanism that requires STAT3 activation. Reduction of NOTCH1 in HAECs by siRNA, in the absence of inflammatory lipids or cytokines, increased inflammatory molecules and binding of monocytes. Conversely, some of the effects mediated by Ox-PAPC were reversed by increased NOTCH1 signaling, suggesting a link between lipid-mediated inflammation and Notch1. Interestingly, reduction of NOTCH1 by Ox-PAPC in HAECs was associated with a genetic variant previously correlated to high-density lipoprotein in a human genome-wide association study. Finally, endothelial Notch1 heterozygous mice showed higher diet-induced atherosclerosis. Based on these findings, we propose that reduction of endothelial NOTCH1 is a predisposing factor in the onset of vascular inflammation and initiation of atherosclerosis. PMID:26552708

  9. A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons

    PubMed Central

    Hayashi, Yukari; Nishimune, Hiroshi; Hozumi, Katsuto; Saga, Yumiko; Harada, Akihiro; Yuzaki, Michisuke; Iwatsubo, Takeshi; Kopan, Raphael; Tomita, Taisuke

    2016-01-01

    Notch signaling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Although recent studies implicate that Notch regulates synaptic plasticity or cognitive performance, the molecular mechanism how Notch works in mature neurons remains uncertain. Here we demonstrate that a novel Notch signaling is involved in expression of synaptic proteins in postmitotic neurons. Levels of several synaptic vesicle proteins including synaptophysin 1 and VGLUT1 were increased when neurons were cocultured with Notch ligands-expressing NIH3T3 cells. Neuron-specific deletion of Notch genes decreased these proteins, suggesting that Notch signaling maintains the expression of synaptic vesicle proteins in a cell-autonomous manner. Unexpectedly, cGMP-dependent protein kinase (PKG) inhibitor, but not γ-secretase inhibitor, abolished the elevation of synaptic vesicle proteins, suggesting that generation of Notch intracellular domain is dispensable for this function. These data uncover a ligand-dependent, but γ-secretase-independent, non-canonical Notch signaling involved in presynaptic protein expression in postmitotic neurons. PMID:27040987

  10. Notch fatigue of ultrahigh molecular weight polyethylene (UHMWPE) used in total joint replacements.

    PubMed

    Ansari, Farzana; Gludovatz, Bernd; Kozak, Adam; Ritchie, Robert O; Pruitt, Lisa A

    2016-07-01

    Ultrahigh molecular weight polyethylene (UHMWPE) has remained the primary polymer used in hip, knee and shoulder replacements for over 50 years. Recent case studies have demonstrated that catastrophic fatigue fracture of the polymer can severely limit device lifetime and are often associated with stress concentration (notches) integrated into the design. This study evaluates the influence of notch geometry on the fatigue of three formulations of UHMWPE that are in use today. A linear-elastic fracture mechanics approach is adopted to evaluate crack propagation as a function of notch root radius, heat treatment and Vitamin E additions. Specifically, a modified stress-intensity factor that accounts for notch geometry was utilized to model the crack driving force. The degree of notch plasticity for each material/notch combination was further evaluated using finite element methods. Experimental evaluation of crack speed as a function of stress intensity was conducted under cyclic tensile loading, taking crack length and notch plasticity into consideration. Results demonstrated that crack propagation in UHMWPE emanating from a notch was primarily affected by microstructural influences (cross-linking) rather than differences in notch geometry. PMID:26919563

  11. Notch inhibits chondrogenic differentiation of mesenchymal progenitor cells by targeting Twist1.

    PubMed

    Tian, Ye; Xu, Ying; Fu, Qin; Chang, Martin; Wang, Yongjun; Shang, Xifu; Wan, Chao; Marymont, John V; Dong, Yufeng

    2015-03-01

    While Notch signaling plays a critical role in the regulation of cartilage formation, its downstream targets are unknown. To address this we performed gain and losses of function experiments and demonstrate that Notch inhibition of chondrogenesis acts via up-regulation of the transcription factor Twist1. Upon Notch activation, murine limb bud mesenchymal progenitor cells in micromass culture displayed an inhibition of chondrogenesis. Twist1 was found to be exclusively expressed in mesenchymal progenitor cells at the onset stage of chondrogenesis during Notch activation. Inhibition of Notch signaling in these cells significantly reduced protein expression of Twist1. Furthermore, the inhibition effect of NICD1 on MPC chondrogenesis was markedly reduced by knocking down of Twist1. Constitutively active Notch signaling significantly enhanced Twist1 promoter activity; whereas mutation studies indicated that a putative NICD/RBPjK binding element in the promoter region is required for the Notch-responsiveness of the Twist1 promoter. Finally, chromatin immunoprecipitation assays further confirmed that the Notch intracellular domain influences Twist1 by directly binding to the Twist1 promoter. These data provide a novel insight into understanding the molecular mechanisms behind Notch inhibition of the onset of chondrogenesis. PMID:25596548

  12. Deformation characteristics and time-dependent notch sensitivity of Udimet 700 at intermediate temperatures

    NASA Technical Reports Server (NTRS)

    Wilson, D. J.

    1975-01-01

    Time-dependent notch sensitivity of Udimet 700 sheet, bar, and investment castings was observed between 1000 and 1400 F (538-760 C) but not at 1600 F (871 C). As was the case for Modified Waspaloy, Waspaloy, Rene 41, Inconel 718, and TD-NiCr, it occurred when notched specimens were loaded below the yield strength and when creep deformation was localized. For each gamma-prime strengthened alloy and notched specimen geometry, a stress-average particle size zone can be defined to characterize the notch-sensitive behavior.

  13. hCLP46 regulates U937 cell proliferation via Notch signaling pathway

    SciTech Connect

    Ma, Wenzhan; Du, Jie; Chu, Qiaoyun; Wang, Youxin; Liu, Lixin; Song, Manshu; Wang, Wei

    2011-04-29

    Highlights: {yields} Knock down of hCLP46 by RNAi impairs mammalian Notch signaling. {yields} hCLP46 affects neither cell surface Notch1 expression nor ligand-receptor binding. {yields} Knock down of hCLP46 inhibits U937 cell-growth by up-regulation of CDKN1B. -- Abstract: Human CAP10-like protein 46 kDa (hCLP46) is the homolog of Rumi, which is the first identified protein O-glucosyltransferase that modifies Notch receptor in Drosophila. Dysregulation of hCLP46 occurs in many hematologic diseases, but the role of hCLP46 remains unclear. Knockdown of hCLP46 by RNA interference resulted in decreased protein levels of endogenous Notch1, Notch intracellular domain (NICD) and Notch target gene Hes-1, suggesting the impairment of the Notch signaling. However, neither cell surface Notch expression nor ligand binding activities were affected. In addition, down-regulated expression of hCLP46 inhibited the proliferation of U937 cells, which was correlated with increased cyclin-dependent kinase inhibitor (CDKI) CDKN1B (p27) and decreased phosphorylation of retinoblastoma (RB) protein. We showed that lack of hCLP46 results in impaired ligand induced Notch activation in mammalian cell, and hCLP46 regulates the proliferation of U937 cell through CDKI-RB signaling pathway, which may be important for the pathogenesis of leukemia.

  14. A Role for Notch Signalling in Breast Cancer and Endocrine Resistance

    PubMed Central

    Acar, Ahmet; Simões, Bruno M.; Clarke, Robert B.; Brennan, Keith

    2016-01-01

    Over the past decade, there has been growing interest in the Notch signalling pathway within the breast cancer field. This interest stemmed initially from the observation that Notch signalling is aberrantly activated in breast cancer and its effects on various cellular processes including proliferation, apoptosis, and cancer stem cell activity. However more recently, elevated Notch signalling has been correlated with therapy resistance in oestrogen receptor-positive breast cancer. As a result, inhibiting Notch signalling with therapeutic agents is being explored as a promising treatment option for breast cancer patients. PMID:26880941

  15. Microwave photonic notch filter based on a dual-Sagnac-loop structure.

    PubMed

    Wang, Xudong; Chan, Erwin H W; Minasian, Robert A

    2010-11-20

    A new single-wavelength, coherence-free microwave photonic notch filter is presented. The concept is based on a dual-Sagnac-loop structure that functions with a new principle in which the two loops operate with different free spectral ranges, and which generate noncommensurate taps. It has the ability to generate a narrow notch response and can operate to high frequencies. Experimental results demonstrate a notch filter with a narrow notch width, a flat passband, and high stop-band attenuation of over 40dB. PMID:21102681

  16. Interactions of Vestigial and Scabrous with the Notch Locus of Drosophila Melanogaster

    PubMed Central

    Rabinow, L.; Birchler, J. A.

    1990-01-01

    Interactions are described between the Notch locus of Drosophila melanogaster, and two other loci, scabrous and vestigial, which respectively affect the eyes and wings. The Notch locus is responsible for mediating decisions of cell fate throughout development in many different tissues. Mutations and duplications of vestigial and scabrous alter the severity of phenotypes associated with Notch mutations and duplications in a manner that is essentially tissue- and allele-specific. These interactions indicate that the products of vestigial and scabrous act in conjunction with Notch to stimulate the differentiation of specific cell types. PMID:2160402

  17. Characterization and analysis of surface notches on Ti-alloy plates fabricated by additive manufacturing techniques

    NASA Astrophysics Data System (ADS)

    Chan, Kwai S.

    2015-12-01

    Rectangular plates of Ti-6Al-4V with extra low interstitial (ELI) were fabricated by layer-by-layer deposition techniques that included electron beam melting (EBM) and laser beam melting (LBM). The surface conditions of these plates were characterized using x-ray micro-computed tomography. The depth and radius of surface notch-like features on the LBM and EBM plates were measured from sectional images of individual virtual slices of the rectangular plates. The stress concentration factors of individual surface notches were computed and analyzed statistically to determine the appropriate distributions for the notch depth, notch radius, and stress concentration factor. These results were correlated with the fatigue life of the Ti-6Al-4V ELI alloys from an earlier investigation. A surface notch analysis was performed to assess the debit in the fatigue strength due to the surface notches. The assessment revealed that the fatigue lives of the additively manufactured plates with rough surface topographies and notch-like features are dominated by the fatigue crack growth of large cracks for both the LBM and EBM materials. The fatigue strength reduction due to the surface notches can be as large as 60%-75%. It is concluded that for better fatigue performance, the surface notches on EBM and LBM materials need to be removed by machining and the surface roughness be improved to a surface finish of about 1 μm.

  18. Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9

    PubMed Central

    Kohn, Anat; Rutkowski, Timothy P; Liu, Zhaoyang; Mirando, Anthony J; Zuscik, Michael J; O’Keefe, Regis J; Hilton, Matthew J

    2015-01-01

    RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissue-specific Rbpjk mutant (Prx1Cre;Rbpjkf/f), Rbpjk mutant/Sox9 haploinsufficient (Prx1Cre;Rbpjkf/f;Sox9f/+), and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors. PMID:26558140

  19. Epithelial Notch signaling regulates lung alveolar morphogenesis and airway epithelial integrity.

    PubMed

    Tsao, Po-Nien; Matsuoka, Chisa; Wei, Shu-Chen; Sato, Atsuyasu; Sato, Susumu; Hasegawa, Koichi; Chen, Hung-Kuan; Ling, Thai-Yen; Mori, Munemasa; Cardoso, Wellington V; Morimoto, Mitsuru

    2016-07-19

    Abnormal enlargement of the alveolar spaces is a hallmark of conditions such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. Notch signaling is crucial for differentiation and regeneration and repair of the airway epithelium. However, how Notch influences the alveolar compartment and integrates this process with airway development remains little understood. Here we report a prominent role of Notch signaling in the epithelial-mesenchymal interactions that lead to alveolar formation in the developing lung. We found that alveolar type II cells are major sites of Notch2 activation and show by Notch2-specific epithelial deletion (Notch2(cNull)) a unique contribution of this receptor to alveologenesis. Epithelial Notch2 was required for type II cell induction of the PDGF-A ligand and subsequent paracrine activation of PDGF receptor-α signaling in alveolar myofibroblast progenitors. Moreover, Notch2 was crucial in maintaining the integrity of the epithelial and smooth muscle layers of the distal conducting airways. Our data suggest that epithelial Notch signaling regulates multiple aspects of postnatal development in the distal lung and may represent a potential target for intervention in pulmonary diseases. PMID:27364009

  20. Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer

    PubMed Central

    Brooks, Yang Sui; Ostano, Paola; Jo, Seung-Hee; Dai, Jun; Getsios, Spiro; Dziunycz, Piotr; Hofbauer, Günther F.L.; Cerveny, Kara; Chiorino, Giovanna; Lefort, Karine; Dotto, G. Paolo

    2014-01-01

    Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ–dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer. PMID:24743148

  1. The effect of electric discharge machined notches on the fracture toughness of several structural alloys

    SciTech Connect

    Joyce, J.A.; Link, R.E.

    1993-09-01

    Recent computational studies of the stress and strain fields at the tip of very sharp notches have shown that the stress and strain fields are very weakly dependent on the initial geometry of the notch once the notch has been blunted to a radius that is 6 to 10 times the initial root radius. It follows that if the fracture toughness of a material is sufficiently high so that fracture initiation does not occur in a specimen until the crack-tip opening displacement (CTOD) reaches a value from 6 to 10 times the size of the initial notch tip diameter, then the fracture toughness will be independent of whether a fatigue crack or a machined notch served as the initial crack. In this experimental program the fracture toughness (J{sub Ic} and J resistance (J-R) curve, and CTOD) for several structure alloys was measured using specimens with conventional fatigue cracks and with EDM machined notches. The results of this program have shown, in fact, that most structural materials do not achieve initiation CTOD values on the order of 6 to 10 times the radius of even the smallest EDM notch tip presently achievable. It is found furthermore that tougher materials do not seem to be less dependent on the type of notch tip present. Some materials are shown to be much more dependent on the type of notch tip used, but no simple pattern is found that relates this observed dependence to the material strength toughness, or strain hardening rate.

  2. Si₃N₄ ring resonator-based microwave photonic notch filter with an ultrahigh peak rejection.

    PubMed

    Marpaung, David; Morrison, Blair; Pant, Ravi; Roeloffzen, Chris; Leinse, Arne; Hoekman, Marcel; Heideman, Rene; Eggleton, Benjamin J

    2013-10-01

    We report a simple technique in microwave photonic (MWP) signal processing that allows the use of an optical filter with a shallow notch to exhibit a microwave notch filter with anomalously high rejection level. We implement this technique using a low-loss, tunable Si₃N₄ optical ring resonator as the optical filter, and achieved an MWP notch filter with an ultra-high peak rejection > 60 dB, a tunable high resolution bandwidth of 247-840 MHz, and notch frequency tuning of 2-8 GHz. To our knowledge, this is a record combined peak rejection and resolution for an integrated MWP filter. PMID:24104242

  3. The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis

    PubMed Central

    Ho, Diana M; Pallavi, SK; Artavanis-Tsakonas, Spyros

    2015-01-01

    Notch signaling controls a wide range of cell fate decisions during development and disease via synergistic interactions with other signaling pathways. Here, through a genome-wide genetic screen in Drosophila, we uncover a highly complex Notch-dependent genetic circuitry that profoundly affects proliferation and consequently hyperplasia. We report a novel synergistic relationship between Notch and either of the non-receptor tyrosine kinases Src42A and Src64B to promote hyperplasia and tissue disorganization, which results in cell cycle perturbation, JAK/STAT signal activation, and differential regulation of Notch targets. Significantly, the JNK pathway is responsible for the majority of the phenotypes and transcriptional changes downstream of Notch-Src synergy. We previously reported that Notch-Mef2 also activates JNK, indicating that there are commonalities within the Notch-dependent proliferation circuitry; however, the current data indicate that Notch-Src accesses JNK in a significantly different fashion than Notch-Mef2. DOI: http://dx.doi.org/10.7554/eLife.05996.001 PMID:26222204

  4. Epithelial Notch signaling regulates lung alveolar morphogenesis and airway epithelial integrity

    PubMed Central

    Tsao, Po-Nien; Matsuoka, Chisa; Wei, Shu-Chen; Sato, Atsuyasu; Sato, Susumu; Hasegawa, Koichi; Chen, Hung-kuan; Ling, Thai-Yen; Mori, Munemasa; Cardoso, Wellington V.; Morimoto, Mitsuru

    2016-01-01

    Abnormal enlargement of the alveolar spaces is a hallmark of conditions such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. Notch signaling is crucial for differentiation and regeneration and repair of the airway epithelium. However, how Notch influences the alveolar compartment and integrates this process with airway development remains little understood. Here we report a prominent role of Notch signaling in the epithelial–mesenchymal interactions that lead to alveolar formation in the developing lung. We found that alveolar type II cells are major sites of Notch2 activation and show by Notch2-specific epithelial deletion (Notch2cNull) a unique contribution of this receptor to alveologenesis. Epithelial Notch2 was required for type II cell induction of the PDGF-A ligand and subsequent paracrine activation of PDGF receptor-α signaling in alveolar myofibroblast progenitors. Moreover, Notch2 was crucial in maintaining the integrity of the epithelial and smooth muscle layers of the distal conducting airways. Our data suggest that epithelial Notch signaling regulates multiple aspects of postnatal development in the distal lung and may represent a potential target for intervention in pulmonary diseases. PMID:27364009

  5. 3D numerical analysis of crack propagation of heterogeneous notched rock under uniaxial tension

    NASA Astrophysics Data System (ADS)

    Wang, S. Y.; Sloan, S. W.; Sheng, D. C.; Tang, C. A.

    2016-05-01

    Macroscopic notches play an important role in evaluating the fracture process zone (FPZ) and the strengths of a heterogeneous rock mass. Crack initiation, propagation and coalescence for unnotched, single-notched and double-notched rock specimens are numerically simulated in a 3-D numerical model (RFPA3D). A feature of the code RFPA3D is that it can numerically simulate the evolution of cracks in three-dimensional space, as well as the heterogeneity of the rock mass. For the unnotched case, special attention is given to the complete stress-strain curve and the corresponding AE events for the failure process of rock specimen. By comparing with published experimental results, the simulation results from RFPA3D are found to be satisfactory. For the single-notched case, the effect of the length and the depth of the single notch and the thickness of the specimen on the failure mode and peak stress are evaluated. The 3D FPZ is very different from that in two dimensions. For the double-notched case, the effects of the separation distance and overlap distance of the double notches, as well as influence of the homogeneity index (m) are also investigated. As the overlap distance increases, the direction of the principal tensile stress at each notch-end changes from a perpendicular direction (tensile stress field) to a nearly parallel direction (compressive stress field), which affects the evolution of the cracks from the two notches.

  6. Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma

    PubMed Central

    Agarwal, Rashmi; March, Daniel; Voigt, Clifford

    2016-01-01

    Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia. PMID:27378829

  7. Fatigue life estimation for different notched specimens based on the volumetric approach

    NASA Astrophysics Data System (ADS)

    Zehsaz, M.; Hassanifard, S.; Esmaeili, F.

    2010-06-01

    In this paper, the effects of notch radius for different notched specimens has been studied on the values of stress concentration factor, notch strength reduction factor, and fatigue life duration of the specimens. The material which has been selected for this investigation is Al 2024T3 . Volumetric approach has been applied to obtain the values of notch strength reduction factor and results have been compared with those obtained from the Neuber and Peterson methods. Load controlled fatigue tests of mentioned specimens have been conducted on the 250kN servo-hydraulic Zwick/Amsler fatigue testing machine with the frequency of 10Hz. The fatigue lives of the specimens have also been predicted based on the available smooth S-N curve of Al2024-T3 and also the amounts of notch strength reduction factor which have been obtained from volumetric, Neuber and Peterson methods. The values of stress and strain around the notch roots are required to predict the fatigue life of notched specimens, so Ansys finite element code has been used and non-linear analyses have been performed to obtain the stress and strain distributions around the notches. The plastic deformations of the material have been simulated using multi-linear kinematic hardening and cyclic stress-strain relation. The work here shows that the volumetric approach does a very good job for predicting the fatigue life of the notched specimens.

  8. Exact Lattice Supersymmetry

    SciTech Connect

    Catterall, Simon; Kaplan, David B.; Unsal, Mithat

    2009-03-31

    We provide an introduction to recent lattice formulations of supersymmetric theories which are invariant under one or more real supersymmetries at nonzero lattice spacing. These include the especially interesting case of N = 4 SYM in four dimensions. We discuss approaches based both on twisted supersymmetry and orbifold-deconstruction techniques and show their equivalence in the case of gauge theories. The presence of an exact supersymmetry reduces and in some cases eliminates the need for fine tuning to achieve a continuum limit invariant under the full supersymmetry of the target theory. We discuss open problems.

  9. Contrasting Roles for C/EBPα and Notch in Irradiation-Induced Multipotent Hematopoietic Progenitor Cell Defects

    PubMed Central

    Fleenor, Courtney Jo; Rozhok, Andrii Ivan; Zaberezhnyy, Vadym; Mathew, Divij; Kim, Jihye; Tan, Aik-Choon; Bernstein, Irwin David; DeGregori, James

    2014-01-01

    Ionizing radiation (IR) is associated with reduced hematopoietic function and increased risk of hematopoietic malignancies, although the mechanisms behind these relationships remain poorly understood. Both effects of IR have been commonly attributed to the direct induction of DNA mutations, but evidence supporting these hypotheses is largely lacking. Here we demonstrate that IR causes long-term, somatically heritable, cell-intrinsic reductions in hematopoietic stem cell (HSC) and multipotent hematopoietic progenitor cell (mHPC) self-renewal that are mediated by C/EBPα and reversed by Notch. mHPC from previously irradiated (>9 weeks prior), homeostatically restored mice exhibit gene expression profiles consistent with their precocious differentiation phenotype, including decreased expression of HSC-specific genes and increased expression of myeloid program genes (including C/EBPα). These gene expression changes are reversed by ligand-mediated activation of Notch. Loss of C/EBPα expression is selected for within previously irradiated HSC and mHPC pools, and is associated with reversal of IR-dependent precocious differentiation and restoration of self-renewal. Remarkably, restoration of mHPC self-renewal by ligand-mediated activation of Notch prevents selection for C/EBPα loss of function in previously irradiated mHPC pools. We propose that environmental insults prompt HSC to initiate a program limiting their self-renewal, leading to loss of the damaged HSC from the pool while allowing this HSC to temporarily contribute to differentiated cell pools. This “programmed mediocrity” is advantageous for the sporadic genotoxic insults animals have evolved to deal with, but becomes tumor promoting when the entire HSC compartment is damaged, such as during total body irradiation, by increasing selective pressure for adaptive oncogenic mutations. PMID:25546133

  10. Contrasting roles for C/EBPα and Notch in irradiation-induced multipotent hematopoietic progenitor cell defects.

    PubMed

    Fleenor, Courtney Jo; Rozhok, Andrii Ivan; Zaberezhnyy, Vadym; Mathew, Divij; Kim, Jihye; Tan, Aik-Choon; Bernstein, Irwin David; DeGregori, James

    2015-04-01

    Ionizing radiation (IR) is associated with reduced hematopoietic function and increased risk of hematopoietic malignancies, although the mechanisms behind these relationships remain poorly understood. Both effects of IR have been commonly attributed to the direct induction of DNA mutations, but evidence supporting these hypotheses is largely lacking. Here we demonstrate that IR causes long-term, somatically heritable, cell-intrinsic reductions in hematopoietic stem cell (HSC) and multipotent hematopoietic progenitor cell (mHPC) self-renewal that are mediated by C/EBPα and reversed by Notch. mHPC from previously irradiated (>9 weeks prior), homeostatically restored mice exhibit gene expression profiles consistent with their precocious differentiation phenotype, including decreased expression of HSC-specific genes and increased expression of myeloid program genes (including C/EBPα). These gene expression changes are reversed by ligand-mediated activation of Notch. Loss of C/EBPα expression is selected for within previously irradiated HSC and mHPC pools and is associated with reversal of IR-dependent precocious differentiation and restoration of self-renewal. Remarkably, restoration of mHPC self-renewal by ligand-mediated activation of Notch prevents selection for C/EBPα loss of function in previously irradiated mHPC pools. We propose that environmental insults prompt HSC to initiate a program limiting their self-renewal, leading to loss of the damaged HSC from the pool while allowing this HSC to temporarily contribute to differentiated cell pools. This "programmed mediocrity" is advantageous for the sporadic genotoxic insults animals have evolved to deal with but becomes tumor promoting when the entire HSC compartment is damaged, such as during total body irradiation, by increasing selective pressure for adaptive oncogenic mutations. PMID:25546133

  11. A Lattice Model for Influenza Spreading

    PubMed Central

    Liccardo, Antonella; Fierro, Annalisa

    2013-01-01

    We construct a stochastic SIR model for influenza spreading on a D-dimensional lattice, which represents the dynamic contact network of individuals. An age distributed population is placed on the lattice and moves on it. The displacement from a site to a nearest neighbor empty site, allows individuals to change the number and identities of their contacts. The dynamics on the lattice is governed by an attractive interaction between individuals belonging to the same age-class. The parameters, which regulate the pattern dynamics, are fixed fitting the data on the age-dependent daily contact numbers, furnished by the Polymod survey. A simple SIR transmission model with a nearest neighbors interaction and some very basic adaptive mobility restrictions complete the model. The model is validated against the age-distributed Italian epidemiological data for the influenza A(H1N1) during the season, with sensible predictions for the epidemiological parameters. For an appropriate topology of the lattice, we find that, whenever the accordance between the contact patterns of the model and the Polymod data is satisfactory, there is a good agreement between the numerical and the experimental epidemiological data. This result shows how rich is the information encoded in the average contact patterns of individuals, with respect to the analysis of the epidemic spreading of an infectious disease. PMID:23717512

  12. On lattice protein structure prediction revisited.

    PubMed

    Dotu, Ivan; Cebrián, Manuel; Van Hentenryck, Pascal; Clote, Peter

    2011-01-01

    Protein structure prediction is regarded as a highly challenging problem both for the biology and for the computational communities. In recent years, many approaches have been developed, moving to increasingly complex lattice models and off-lattice models. This paper presents a Large Neighborhood Search (LNS) to find the native state for the Hydrophobic-Polar (HP) model on the Face-Centered Cubic (FCC) lattice or, in other words, a self-avoiding walk on the FCC lattice having a maximum number of H-H contacts. The algorithm starts with a tabu-search algorithm, whose solution is then improved by a combination of constraint programming and LNS. The flexible framework of this hybrid algorithm allows an adaptation to the Miyazawa-Jernigan contact potential, in place of the HP model, thus suggesting its potential for tertiary structure prediction. Benchmarking statistics are given for our method against the hydrophobic core threading program HPstruct, an exact method which can be viewed as complementary to our method. PMID:21358007

  13. Fibonacci Optical Lattices

    NASA Astrophysics Data System (ADS)

    Singh, Kevin; Geiger, Zachary; Senaratne, Ruwan; Rajagopal, Shankari; Fujiwara, Kurt; Weld, David; Weld Group Team

    2015-05-01

    Quasiperiodicity is intimately involved in quantum phenomena from localization to the quantum Hall effect. Recent experimental investigation of quasiperiodic quantum effects in photonic and electronic systems have revealed intriguing connections to topological phenomena. However, such experiments have been limited by the absence of techniques for creating tunable quasiperiodic structures. We propose a new type of quasiperiodic optical lattice, constructed by intersecting a Gaussian beam with a 2D square lattice at an angle with an irrational tangent. The resulting potential, a generalization of the Fibonacci lattice, is a physical realization of the mathematical ``cut-and-project'' construction which underlies all quasiperiodic structures. Calculation of the energies and wavefunctions of atoms loaded into the proposed quasiperiodic lattice demonstrate a fractal energy spectrum and the existence of edge states. We acknowledge support from the ONR (award N00014-14-1-0805), the ARO and the PECASE program (award W911NF-14-1-0154), the AFOSR (award FA9550-12-1-0305), and the Alfred P. Sloan foundation (grant BR2013-110).

  14. Progress in lattice QCD

    SciTech Connect

    Andreas S. Kronfeld

    2002-09-30

    After reviewing some of the mathematical foundations and numerical difficulties facing lattice QCD, I review the status of several calculations relevant to experimental high-energy physics. The topics considered are moments of structure functions, which may prove relevant to search for new phenomena at the LHC, and several aspects of flavor physics, which are relevant to understanding CP and flavor violation.

  15. Random lattice superstrings

    SciTech Connect

    Feng Haidong; Siegel, Warren

    2006-08-15

    We propose some new simplifying ingredients for Feynman diagrams that seem necessary for random lattice formulations of superstrings. In particular, half the fermionic variables appear only in particle loops (similarly to loop momenta), reducing the supersymmetry of the constituents of the type IIB superstring to N=1, as expected from their interpretation in the 1/N expansion as super Yang-Mills.

  16. Convex Lattice Polygons

    ERIC Educational Resources Information Center

    Scott, Paul

    2006-01-01

    A "convex" polygon is one with no re-entrant angles. Alternatively one can use the standard convexity definition, asserting that for any two points of the convex polygon, the line segment joining them is contained completely within the polygon. In this article, the author provides a solution to a problem involving convex lattice polygons.

  17. Supersymmetry on the Lattice

    NASA Astrophysics Data System (ADS)

    Schaich, David

    2016-03-01

    Lattice field theory provides a non-perturbative regularization of strongly interacting systems, which has proven crucial to the study of quantum chromodynamics among many other theories. Supersymmetry plays prominent roles in the study of physics beyond the standard model, both as an ingredient in model building and as a tool to improve our understanding of quantum field theory. Attempts to apply lattice techniques to supersymmetric field theories have a long history, but until recently these efforts have generally encountered insurmountable difficulties related to the interplay of supersymmetry with the lattice discretization of spacetime. In recent years these difficulties have been overcome for a class of theories that includes the particularly interesting case of maximally supersymmetric Yang-Mills (N = 4 SYM) in four dimensions, which is a cornerstone of AdS/CFT duality. In combination with computational advances this progress enables practical numerical investigations of N = 4 SYM on the lattice, which can address questions that are difficult or impossible to handle through perturbation theory, AdS/CFT duality, or the conformal bootstrap program. I will briefly review some of the new ideas underlying this recent progress, and present some results from ongoing large-scale numerical calculations, including comparisons with analytic predictions.

  18. Shaken Lattice Interferometry

    NASA Astrophysics Data System (ADS)

    Weidner, Carrie; Yu, Hoon; Anderson, Dana

    2015-05-01

    This work introduces a method to perform interferometry using atoms trapped in an optical lattice. Starting at t = 0 with atoms in the ground state of a lattice potential V(x) =V0cos [ 2 kx + ϕ(t) ] , we show that it is possible to transform from one atomic wavefunction to another by a prescribed shaking of the lattice, i.e., by an appropriately tailored time-dependent phase shift ϕ(t) . In particular, the standard interferometer sequence of beam splitting, propagation, reflection, reverse propagation, and recombination can be achieved via a set of phase modulation operations {ϕj(t) } . Each ϕj(t) is determined using a learning algorithm, and the split-step method calculates the wavefunction dynamics. We have numerically demonstrated an interferometer in which the shaken wavefunctions match the target states to better than 1 % . We carried out learning using a genetic algorithm and optimal control techniques. The atoms remain trapped in the lattice throughout the full interferometer sequence. Thus, the approach may be suitable for use in an dynamic environment. In addition to the general principles, we discuss aspects of the experimental implementation. Supported by the Office of Naval Research (ONR) and Northrop Grumman.

  19. Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1β

    PubMed Central

    Verginelli, Federica; Adesso, Laura; Limon, Isabelle; Alisi, Anna; Gueguen, Marie; Panera, Nadia; Giorda, Ezio; Raimondi, Lavinia; Ciarapica, Roberta; Campese, Antonio F.; Screpanti, Isabella; Stifani, Stefano; Kitajewski, Jan; Miele, Lucio

    2015-01-01

    The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced. Conversely, the forced expression of Notch1ICD in naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation. In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium. PMID:26646450

  20. Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1β.

    PubMed

    Verginelli, Federica; Adesso, Laura; Limon, Isabelle; Alisi, Anna; Gueguen, Marie; Panera, Nadia; Giorda, Ezio; Raimondi, Lavinia; Ciarapica, Roberta; Campese, Antonio F; Screpanti, Isabella; Stifani, Stefano; Kitajewski, Jan; Miele, Lucio; Rota, Rossella; Locatelli, Franco

    2015-12-22

    The Notch1 and Notch4 signaling pathways regulate endothelial cell homeostasis. Inflammatory cytokines induce the expression of endothelial adhesion molecules, including VCAM1, partly by downregulating Notch4 signaling. We investigated the role of endothelial Notch1 in this IL-1β-mediated process. Brief treatment with IL-1β upregulated endothelial VCAM1 and Notch ligand Jagged1. IL-1β decreased Notch1 mRNA levels, but levels of the active Notch1ICD protein remained constant. IL-1β-mediated VCAM1 induction was downregulated in endothelial cells subjected to pretreatment with a pharmacological inhibitor of the γ-secretase, which activates Notch receptors, producing NotchICD. It was also downregulated in cells in which Notch1 and/or Jagged1 were silenced.Conversely, the forced expression of Notch1ICD in naïve endothelial cells upregulated VCAM1 per se and amplified IL-1β-mediated VCAM1 induction. Jagged1 levels increased and Notch4 signaling was downregulated in parallel. Finally, Notch1ICD and Jagged1 expression was upregulated in the endothelium of the liver in a model of chronic liver inflammation.In conclusion, we describe here a cell-autonomous, pro-inflammatory endothelial Notch1-Jagged1 circuit (i) triggering the expression of VCAM1 even in the absence of inflammatory cytokines and (ii) enhancing the effects of IL-1β. Thus, IL-1β regulates Notch1 and Notch4 activity in opposite directions, consistent with a selective targeting of Notch1 in inflamed endothelium. PMID:26646450

  1. Downregulation of Notch Signaling Pathway in Late Preterm and Term Placentas from Pregnancies Complicated by Preeclampsia

    PubMed Central

    Fragkiadaki, Persefoni; Soulitzis, Nikolaos; Sifakis, Stavros; Koutroulakis, Demetrios; Gourvas, Victor; Vrachnis, Nikolaos; Spandidos, Demetrios A.

    2015-01-01

    Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3–5% of all pregnancies. The Notch signaling pathway plays an important role during placental development, activating several target genes. Defects in the Notch pathway have adverse effect on placentation. The aim of this study was to investigate the expression of receptors NOTCH1,-2,-3,-4, ligands DLL1,-3,-4, JAG1,-2 and target genes HEY1,-2 in placental tissue samples from 20 late preterm or term pregnancies complicated by PE versus 20 normal pregnancies. mRNA levels of the studied molecules were measured by quantitative Real-Time PCR (qRT-PCR), while the protein expression of the intracellular domain of NOTCH2 (NICD2) and NOTCH3 (NICD3) was measured by Western Blot (WB). qRT-PCR analysis revealed that NOTCH1, NOTCH4 and DLL1 were not expressed in the placenta. On the contrary, NOTCH2, NOTCH3, DLL3, DLL4, JAG1, JAG2, HEY1 and HEY2 mRNA levels were downregulated in PE samples vs. controls (p<0.01). WB confirmed that NICD2 (p = 0.014) and NICD3 (p<0.001) protein levels were also lower in PE specimens. Statistical analysis revealed several significant associations: of NOTCH3 mRNA expression with smoking during pregnancy (p = 0.029), of NICD3 protein levels (p = 0.028) and DLL3 mRNA levels (p = 0.041) with birth weight centile, and of HEY2 transcript levels with parity (p = 0.034) and mode of delivery (p = 0.028). Our results suggest that Notch pathway downregulation is associated with PE. Further studies are required in order to determine the role of these molecules in PE pathogenesis and to evaluate their potential use for the early detection and treatment of PE. PMID:25962154

  2. Effect of verteporfin-PDT on the Notch signaling pathway in cholangiocarcinoma (CCA) cell lines

    NASA Astrophysics Data System (ADS)

    Cerec, Virginie; Andreola, Fausto; Pereira, Stephen P.

    2009-06-01

    Accumulating preclinical and clinical evidence supports a pro-oncogenic function for Notch signaling in several solid tumors. Therefore, Notch inhibitory agents, such as gamma-secretase inhibitors (GSI), are being investigated as cancer therapeutic agents and a potential adjuvant to conventional chemo/radiotherapy. To date, no in vitro data are available on the cellular response and effect of either photodynamic therapy (PDT) or GSI on human cholangiocarcinoma (CCA). Consequently, we aimed to study the: (i) constitutive expression of Notch signaling pathway in CCA cell lines; (ii) response to Verteporfin-PDT and to GSI, as single agents on CCA cell lines; (iii) effect of Verteporfin-PDT on Notch signaling pathway expression. Expression of Notch signaling components was studied in two cholangiocarcinoma cell lines, HuCCT1 and TFK-1 (intra- and extrahepatic, respectively). No difference in basal expression of Notch1, 2 and Jagged1 was observed in either cell line. In contrast, Notch3 was found to be weakly and highly expressed in HuCCT1 and TFK-1 cells, respectively - supporting our recent microarray data which showed Notch3 overexpression in biliary brushings from patients with extrahepatic CCA. HuCCT1 and TFK-1 differentially responded to Verteporfin-PDT treatment; preliminary data showed no clear effect of GSI on proliferation/apoptosis in either cell line following short exposure (6 and 24h). Following Verteporfin-PDT, Notch1, 2 and Jagged-1 expression was down-regulated in both cell lines, while Notch3 expression was unaffected in HuCCT1 cells and down-regulated in TFK-1 cells. The Notch signaling pathway could represent a potential target for combination therapy in CCA treatment.

  3. Notch2 activation is protective against anticancer effects of zerumbone in human breast cancer cells.

    PubMed

    Sehrawat, Anuradha; Sakao, Kozue; Singh, Shivendra V

    2014-08-01

    We showed previously that zerumbone (ZER), a sesquiterpene isolated from subtropical ginger, inhibited in vitro (MCF-7 and MDA-MB-231cells) and in vivo (MDA-MB-231 cells) growth of human breast cancer cells in association with apoptosis induction. Here, we investigated the role of Notch receptors in anticancer effects of ZER (cell migration inhibition and apoptosis induction) using breast cancer cells. Western blotting was performed to determine protein expression changes. Effect of ZER on transcriptional activity of Notch was assessed by luciferase reporter assays. Transfection with small hairpin RNA or small interfering RNA was performed for knockdown of Notch2 or Presenilin-1 protein. Cell migration and apoptosis were quantitated by Boyden chamber assay and flow cytometry, respectively. Exposure of MDA-MB-231, MCF-7, and SUM159 cells to ZER resulted in increased cleavage of Notch2 in each cell line. On the other hand, levels of cleaved Notch1 and Notch4 proteins were decreased following ZER treatment. Increased cleavage of Notch2 in ZER-treated cells was accompanied by induction of Presenilin-1 protein and transcriptional activation of Notch. Inhibition of cell migration as well as apoptosis induction resulting from ZER exposure was significantly augmented by knockdown of Notch2 protein. ZER-mediated cleavage of Notch2 protein in MDA-MB-231 cells was markedly attenuated upon RNA interference of Presenilin-1. Knockdown of Presenilin-1 protein also resulted in escalation of ZER-induced apoptosis. The present study indicates that Notch2 activation by ZER inhibits its proapoptotic and anti-migratory response at least in breast cancer cells. PMID:25038880

  4. Constructing notches in foredunes: Effect on sediment dynamics in the dune hinterland

    NASA Astrophysics Data System (ADS)

    Riksen, Michel J. P. M.; Goossens, Dirk; Huiskes, Hendrik P. J.; Krol, Johan; Slim, Pieter A.

    2016-01-01

    Measurements were carried out on the island of Ameland (The Netherlands) to determine whether notches cut into foredunes stimulated the supply of fresh calcareous beach and dune sand into the white and grey dune habitats behind the dunes, increasing these habitats' biological quality. Sediment characteristics and dynamics (deposition flux and grain size properties) as well as aspects of the vegetation (occurrence, composition and cover density) were studied along six transects, three behind an intact foredune and three behind a foredune with a notch cut into it. Compared to an intact foredune, the notched foredune exhibited higher deposition and accumulation behind the dune. The extra supply of sand was small, however, and for the notches studied, limited to the zone within approximately 50-60 m of the foredune's crest. Farther away from the dune, the effect of the notches became negligible. The presence of a notch did affect the grain size composition of sediment deposited behind the foredune. For intact foredunes, the grain size composition behind the dune was similar to that on the dune itself. When a notch had been cut, the sediment was finer behind the foredune, gradually coarsening away from the dune. Sand spray (deposition of sand eroded from the dune and transported in modified saltation during heavy winds) explains these granulometric results. The effect of the notches on the vegetation in the grey dune habitat behind the foredune was small and, for the notches studied, limited to the first approximately 35 m of the grey dune area, between 30 and 65 m from the foredune's crest. The notches had a greater effect on the white dune habitat but - in the opinion of the authors - this remained disproportionately small relative to the effort required for notch excavation and maintenance.

  5. Regulation of Notch Signaling by an Evolutionary Conserved DEAD Box RNA Helicase, Maheshvara in Drosophila melanogaster.

    PubMed

    Surabhi, Satya; Tripathi, Bipin K; Maurya, Bhawana; Bhaskar, Pradeep K; Mukherjee, Ashim; Mutsuddi, Mousumi

    2015-11-01

    Notch signaling is an evolutionary conserved process that influences cell fate determination, cell proliferation, and cell death in a context-dependent manner. Notch signaling is fine-tuned at multiple levels and misregulation of Notch has been implicated in a variety of human diseases. We have characterized maheshvara (mahe), a novel gene in Drosophila melanogaster that encodes a putative DEAD box protein that is highly conserved across taxa and belongs to the largest group of RNA helicase. A dynamic pattern of mahe expression along with the maternal accumulation of its transcripts is seen during early stages of embryogenesis. In addition, a strong expression is also seen in the developing nervous system. Ectopic expression of mahe in a wide range of tissues during development results in a variety of defects, many of which resemble a typical Notch loss-of-function phenotype. We illustrate that ectopic expression of mahe in the wing imaginal discs leads to loss of Notch targets, Cut and Wingless. Interestingly, Notch protein levels are also lowered, whereas no obvious change is seen in the levels of Notch transcripts. In addition, mahe overexpression can significantly rescue ectopic Notch-mediated proliferation of eye tissue. Further, we illustrate that mahe genetically interacts with Notch and its cytoplasmic regulator deltex in trans-heterozygous combination. Coexpression of Deltex and Mahe at the dorso-ventral boundary results in a wing-nicking phenotype and a more pronounced loss of Notch target Cut. Taken together we report identification of a novel evolutionary conserved RNA helicase mahe, which plays a vital role in regulation of Notch signaling. PMID:26400611

  6. A Novel High-Throughput 1536-well Notch1 γ-Secretase AlphaLISA Assay

    PubMed Central

    Chau, De-ming; Shum, David; Radu, Constantin; Bhinder, Bhavneet; Gin, David; Gilchrist, M. Lane; Djaballah, Hakim; Li, Yue-Ming

    2013-01-01

    The Notch pathway plays a crucial role in cell fate decisions through controlling various cellular processes. Overactive Notch signal contributes to cancer development from leukemias to solid tumors. γ-Secretase is an intramembrane protease responsible for the final proteolytic step of Notch that releases the membrane-tethered Notch fragment for signaling. Therefore, γ-secretase is an attractive drug target in treating Notch-mediated cancers. However, the absence of high-throughput γ-secretase assay using Notch substrate has limited the identification and development of γ-secretase inhibitors that specifically target the Notch signaling pathway. Here, we report on the development of a 1536-well γ-secretase assay using a biotinylated recombinant Notch1 substrate. We effectively assimilated and miniaturized this newly developed Notch1 substrate with the AlphaLISA detection technology and demonstrated its robustness with a calculated Z’ score of 0.66. We further validated this optimized assay by performing a pilot screening against a chemical library consisting of ~5,600 chemicals and identified known γ-secretase inhibitors e.g. DAPT, and Calpeptin; as well as a novel γ-secretase inhibitor referred to as KD-I-085. This assay is the first reported 1536-well AlphaLISA format and represents a novel high-throughput Notch1-γ-secretase assay, which provides an unprecedented opportunity to discover Notch-selective γ-secretase inhibitors that can be potentially used for the treatment of cancer and other human disorders. PMID:23448293

  7. Blocking Notch in endothelial cells prevents arteriovenous fistula failure despite CKD.

    PubMed

    Wang, Yun; Liang, Anlin; Luo, Jinlong; Liang, Ming; Han, Guofeng; Mitch, William E; Cheng, Jizhong

    2014-04-01

    Neointima formation causes the failure of 60% of arteriovenous fistulas (AVFs) within 2 years. Neointima-forming mechanisms are controversial but possibly linked to excess proinflammatory responses and dysregulated Notch signaling. To identify how AVFs fail, we anastomosed the carotid artery to the internal jugular vein in normal and uremic mice and compared these findings with those in failed AVFs from patients with ESRD. Endothelial cells (ECs) of AVFs in uremic mice or patients expressed mesenchymal markers (FSP-1 and/or α-SMA) and exhibited increased expression and nuclear localization of Notch intracellular domain compared with ECs of AVFs in pair-fed control mice. Furthermore, expression of VE-Cadherin decreased, whereas expression of Notch1 and -4, Notch ligands, the downstream transcription factor of Notch, RBP-Jκ, and Notch target genes increased in ECs of AVFs in uremic mice. In cultured ECs, ectopic expression of Notch ligand or treatment with TGF-β1 triggered the expression of mesenchymal markers and induced endothelial cell barrier dysfunction, both of which were blocked by Notch inhibition or RBP-Jκ knockout. Furthermore, Notch-induced defects in barrier function, invasion of inflammatory cells, and neointima formation were suppressed in mice with heterozygous knockdown of endothelial-specific RBP-Jκ. These results suggest that increased TGF-β1, a complication of uremia, activates Notch in endothelial cells of AVFs, leading to accelerated neointima formation and AVF failure. Suppression of Notch activation could be a strategy for improving AFV function in uremia. PMID:24480830

  8. A new NOTCH3 mutation presenting as primary intracerebral haemorrhage.

    PubMed

    Pradotto, Luca; Orsi, Laura; Daniele, Dino; Caroppo, Paola; Lauro, Danilo; Milesi, Alessandra; Sellitti, Luigi; Mauro, Alessandro

    2012-04-15

    Primary intracerebral haemorrhages (PICH) are defined as haemorrhages within the brain parenchyma in the absence of readily identifiable causes. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary vascular disease and its mainly clinical manifestations are early-onset infarcts. Spontaneous lobar haematomas are a rare occurrence. We report a very unusual presentation of CADASIL in a 65 year-old man carrying a new NOTCH3 mutation. The clinical onset of the disease was related to an intracerebral haematoma following colon surgery and causing a delirium. In brief, our report suggests that CADASIL must be considered in patient with PICH. PMID:22206696

  9. The strength and notch-sensitivity of ceramic matrix composites

    NASA Astrophysics Data System (ADS)

    McNulty, John Clark

    The mechanisms that govern the strength of three Nicalon fiber-reinforced ceramic matrix composites (CMCs) have been elucidated. Specific regard was given to the volume-dependence of tensile strength, the fatigue resistance at ambient and elevated temperatures, and the notch-sensitivity of strength. Mechanism-based materials models were employed to describe these properties. The utility of the models was assessed through comparison with experiments. The CMCs investigated in this study exhibit stochastic behavior, manifested as volume-dependent strength. The volume-dependence was demonstrated through a technique relating the strengths obtained in flexure and tension, coupled with the application of weakest-link statistics. The results indicate that the CMCs exhibit a high reliability, with Weibull moduli being in the range of ˜20 to 40. The reduction in strength under cyclic loading is due to degradation of the interface sliding stress, via a frictional wear process, and the associated reduction in the fiber bundle strength. This degradation was evaluated using hysteresis loop measurements, as well as fiber pullout and push-in techniques. The fatigue thresholds predicted using a model based on the degradation of the sliding stress showed reasonable agreement with the experimental measurements. The moderately notch-insensitive behavior of the CMCs is due to a combination of stress redistribution, arising from inelastic straining, and volume-dependent strength. The variation in notch-sensitivity with notch size and shape was modeled using a non-linear constitutive law to describe the stress-strain response coupled with a fracture criterion that accounts for the size-dependence of the strength. Excellent correlations are obtained between experiment and theory. Due to the poor chemical stability of Nicalon fibers, the strength-limiting mechanism at elevated temperatures is oxidation of the fibers, rather than degradation of the sliding stress. The oxidation mechanism

  10. Mib1 modulates dynamin 2 recruitment via Snx18 to promote Dll1 endocytosis for efficient Notch signaling.

    PubMed

    Okano, Makoto; Matsuo, Hiromi; Nishimura, Yuya; Hozumi, Katsuto; Yoshioka, Saho; Tonoki, Ayako; Itoh, Motoyuki

    2016-05-01

    Notch signaling regulates normal development and tissue homeostasis. Ligand endocytosis plays critical roles in Notch signaling activation. Endocytic proteins such as epsin and dynamin participate in Notch ligand activity by mediating Notch ligand endocytosis. The ubiquitin ligase Mib1 also plays essential roles in Notch signaling via Notch ligand ubiquitination. However, the molecular links between Mib1 and endocytic proteins have not been fully defined. Here, we show that Mib1 is involved in dynamin 2 recruitment to Dll1 and that Snx18, which interacts with dynamin 2, modestly regulates Dll1 endocytosis. Furthermore, the ubiquitin ligase activity of Mib1 is induced by Notch ligand-receptor interactions. Mib1 promotes the interaction between dynamin 2 and Snx18 in an ubiquitin ligase activity-dependent manner. These results suggest that Mib1 modulates dynamin recruitment by regulating the interaction between Snx18 and dynamin 2, thereby helping to ensure the efficient signaling activity of Notch ligands. PMID:26923255

  11. Notch1 regulated autophagy controls survival and suppressor activity of activated murine T-regulatory cells

    PubMed Central

    Marcel, Nimi; Sarin, Apurva

    2016-01-01

    Cell survival is one of several processes regulated by the Notch pathway in mammalian cells. Here we report functional outcomes of non-nuclear Notch signaling to activate autophagy, a conserved cellular response to nutrient stress, regulating survival in murine natural T-regulatory cells (Tregs), an immune subset controlling tolerance and inflammation. Induction of autophagy required ligand-dependent, Notch intracellular domain (NIC) activity, which controlled mitochondrial organization and survival of activated Tregs. Consistently, NIC immune-precipitated Beclin and Atg14, constituents of the autophagy initiation complex. Further, ectopic expression of an effector of autophagy (Atg3) or recombinant NIC tagged to a nuclear export signal (NIC-NES), restored autophagy and suppressor function in Notch1-/- Tregs. Furthermore, Notch1 deficiency in the Treg lineage resulted in immune hyperactivity, implicating Notch activity in Treg homeostasis. Notch1 integration with autophagy, revealed in these experiments, holds implications for Notch regulated cell-fate decisions governing differentiation. DOI: http://dx.doi.org/10.7554/eLife.14023.001 PMID:27267497

  12. Notch Cooperates with Survivin to Maintain Stemness and to Stimulate Proliferation in Human Keratinocytes during Ageing

    PubMed Central

    Palazzo, Elisabetta; Morandi, Paolo; Lotti, Roberta; Saltari, Annalisa; Truzzi, Francesca; Schnebert, Sylvianne; Dumas, Marc; Marconi, Alessandra; Pincelli, Carlo

    2015-01-01

    The Notch signaling pathway orchestrates cell fate by either inducing cell differentiation or maintaining cells in an undifferentiated state. This study aims to evaluate Notch expression and function in normal human keratinocytes. Notch1 is expressed in all epidermal layers, though to a different degree of intensity, with a dramatic decrease during ageing. Notch1 intracellular domain (N1ICD) levels are decreased during transit from keratinocyte stem cells (KSC) to transit amplifying (TA) cells, mimicking survivin expression in samples from donors of all ages. Calcium markedly reduces N1ICD levels in keratinocytes. N1ICD overexpression induces the up-regulation of survivin and the down-regulation of keratin 10 and involucrin, while increasing the S phase of the cell cycle. On the other hand, Notch1 inhibition (DAPT) dose-dependently decreases survivin, stimulates differentiation, and reduces keratinocyte proliferation in samples from donors of all ages. Silencing Notch downgrades survivin and increases keratin 10. In addition, Notch1 inhibition decreases survivin levels and proliferation both in KSC and TA cells. Finally, while survivin overexpression decreases keratinocyte differentiation and increases N1ICD expression both in KSC and TA cells, silencing survivin results in N1ICD down-regulation and an increase in differentiation markers. These results suggest that the Notch1/survivin crosstalk contributes to the maintenance of stemness in human keratinocytes. PMID:26540052

  13. Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer

    PubMed Central

    Kim, Hyun-A; Koo, Bon-Kyoung; Cho, Ji-Hoon; Kim, Yoon-Young; Seong, Jinwoo; Chang, Hee Jin; Oh, Young Min; Stange, Daniel E.; Park, Jae-Gahb; Hwang, Daehee; Kong, Young-Yun

    2012-01-01

    Crosstalk between the Notch and wingless-type MMTV integration site (WNT) signaling pathways has been investigated for many developmental processes. However, this negative correlation between Notch and WNT/β-catenin signaling activity has been studied primarily in normal developmental and physiological processes in which negative feedback loops for both signaling pathways are intact. We found that Notch1 signaling retained the capability of suppressing the expression of WNT target genes in colorectal cancers even when β-catenin destruction by the adenomatous polyposis coli (APC) complex was disabled. Activation of Notch1 converted high-grade adenoma into low-grade adenoma in an Apcmin mouse colon cancer model and suppressed the expression of WNT target genes in human colorectal cancer cells through epigenetic modification recruiting histone methyltransferase SET domain bifurcated 1 (SETDB1). Extensive microarray analysis of human colorectal cancers also showed a negative correlation between the Notch1 target gene, Notch-regulated ankyrin repeat protein 1 (NRARP), and WNT target genes. Notch is known to be a strong promoter of tumor initiation, but here we uncovered an unexpected suppressive role of Notch1 on WNT/β-catenin target genes involved in colorectal cancer. PMID:22863622

  14. Notch1 targeting siRNA delivery nanoparticles for rheumatoid arthritis therapy.

    PubMed

    Kim, Min Ju; Park, Jong-Sung; Lee, So Jin; Jang, Jiyeon; Park, Jin Su; Back, Seung Hyun; Bahn, Gahee; Park, Jae Hyung; Kang, Young Mo; Kim, Sun Hwa; Kwon, Ick Chan; Jo, Dong-Gyu; Kim, Kwangmeyung

    2015-10-28

    Notch pathway plays a pivotal role in synoviocytes involved in progression of rheumatoid arthritis (RA). Herein, we designed the Notch1 targeting siRNA delivery nanoparticles (siRNA-NPs) in order to confirm the anti-inflammatory effect in collagen-induced arthritis (CIA) model. The siRNA-NPs were successfully produced by encapsulating polymerized siRNA (poly-siRNA) into thiolated glycol chitosan (tGC) nanoparticles in aqueous condition. The in vitro Notch1 inhibition of siRNA-NPs in murine macrophage cell (RAW 264.7) was confirmed using confocal microscopy and real time PCR. Fluorescently labeled siRNA-NPs were successfully transfected in RAW 264.7 and modulated the expression of Notch1 in mRNA level. For in vivo study, siRNA-NPs exhibited the higher targeting efficiency in the arthritic joins of CIA mice, confirmed by the near-infrared fluorescence (NIRF) imaging. Furthermore, inhibition of Notch1 with siRNA-NPs resulted in retarded progression of inflammation, bone erosion, and cartilage damage in CIA mice. Novel Notch1 targeting siRNA delivery system of siRNA-NPs showed effective RA treatment by suppressing Notch1 signaling pathway without undesirable severe toxicity. Thus, Notch1 inhibiting siRNA-NPs demonstrated the great potential in RA therapeutics that was hard to be achieved using conventional drugs. PMID:26282098

  15. Canonical Notch Signaling Is Dispensable for Early Cell Fate Specifications in Mammals

    PubMed Central

    Shi, Shaolin; Stahl, Mark; Lu, Linchao; Stanley, Pamela

    2005-01-01

    The canonical Notch signaling pathway mediated by Delta- and Jagged-like Notch ligands determines a variety of cell fates in metazoa. In Caenorhabditis elegans and sea urchins, canonical Notch signaling is essential for different cell fate specifications during early embryogenesis or the formation of endoderm, mesoderm, or ectoderm germ layers. Transcripts of Notch signaling pathway genes are present during mouse blastogenesis, suggesting that the canonical Notch signaling pathway may also function in early mammalian development. To test this directly, we used conditional deletion in oocytes carrying a ZP3Cre recombinase transgene to generate mouse embryos lacking both maternal and zygotic protein O-fucosyltransferase 1, a cell-autonomous and essential component of canonical Notch receptor signaling. Homozygous mutant embryos derived from eggs lacking Pofut1 gene transcripts developed indistinguishably from the wild type until approximately embryonic day 8.0, a postgastrulation stage after the formation of the three germ layers. Thus, in contrast to the case with C. elegans and sea urchins, canonical Notch signaling is not required in mammals for earliest cell fate specifications or for formation of the three germ layers. The use of canonical Notch signaling for early cell fate specifications by lower organisms may represent co-option of a regulatory pathway originally used later in development by all metazoa. PMID:16227600

  16. Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway.

    PubMed

    Ma, Lijie; Dong, Pingping; Liu, Longzi; Gao, Qiang; Duan, Meng; Zhang, Si; Chen, She; Xue, Ruyi; Wang, Xiaoying

    2016-04-29

    Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. PMID:27003260

  17. Prognostic values of four Notch receptor mRNA expression in gastric cancer

    PubMed Central

    Wu, Xiaoyu; Liu, Wentao; Tang, Ding; Xiao, Haijuan; Wu, Zhenfeng; Chen, Che; Yao, Xuequan; Liu, Fukun; Li, Gang

    2016-01-01

    Notch ligands and receptors are frequently deregulated in several human malignancies including gastric cancer. The activation of Notch signaling has been reported to contribute to gastric carcinogenesis and progression. However, the prognostic roles of individual Notch receptors in gastric cancer patients remain elusive. In the current study, we accessed the prognostic roles of four Notch receptors, Notch 1–4, in gastric cancer patients through “The Kaplan-Meier plotter” (KM plotter) database, in which updated gene expression data and survival information include a total of 876 gastric cancer patients. All four Notch receptors’ high mRNA expression was found to be correlated to worsen overall survival (OS) for all gastric cancer patients followed for 20 years. We further accessed the prognostic roles of individual Notch receptors in different clinicopathological features using Lauren classification, pathological grades, clinical grades, HER2 status and different choices of treatments of gastric cancer patients. These results indicate that there are critical prognostic values of the four Notch receptors in gastric cancer. This information will be useful for better understanding of the heterogeneity and complexity in the molecular biology of gastric cancer and to develop tools to more accurately predict their prognosis. PMID:27363496

  18. Inhibition of CK2α down-regulates Notch1 signalling in lung cancer cells

    PubMed Central

    Zhang, Shulin; Long, Hao; Yang, Yi-Lin; Wang, Yucheng; Hsieh, David; Li, Weiming; Au, Alfred; Stoppler, Hubert J; Xu, Zhidong; Jablons, David M; You, Liang

    2013-01-01

    Protein kinase CK2 is frequently elevated in a variety of human cancers. The Notch1 signalling pathway has been implicated in stem cell maintenance and its aberrant activation has been shown in several types of cancer including lung cancer. Here, we show, for the first time, that CK2α is a positive regulator of Notch1 signalling in lung cancer cell lines A549 and H1299. We found that Notch1 protein level was reduced after CK2α silencing. Down-regulation of Notch1 transcriptional activity was demonstrated after the silencing of CK2α in lung cancer cells. Furthermore, small-molecule CK2α inhibitor CX-4945 led to a dose-dependent inhibition of Notch1 transcriptional activity. Conversely, forced overexpression of CK2α resulted in an increase in Notch1 transcriptional activity. Finally, the inhibition of CK2α led to a reduced proportion of stem-like CD44 + /CD24− cell population. Thus, we report that the inhibition of CK2α down-regulates Notch1 signalling and subsequently reduces a cancer stem-like cell population in human lung cancer cells. Our data suggest that CK2α inhibitors may be beneficial to the lung cancer patients with activated Notch1 signalling. PMID:23651443

  19. Structural basis for Notch1 engagement of Delta-like 4

    DOE PAGESBeta

    Luca, Vincent C.; Jude, Kevin M.; Pierce, Nathan W.; Nachury, Maxence V.; Fischer, Suzanne; Garcia, K. Christopher

    2015-02-20

    Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor–like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. Lastly, the elucidation of a directmore » chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.« less

  20. Marking small hive beetles with thoracic notching: Effects on longevity, flight ability and fecundity.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We tested two marking techniques for adult small hive beetles (SHB): dusting and thoracic notching. The use of blue and red chalk dusts to mark beetles was not persistent and caused early death of SHB with an average survival of 52.6 ± 23.8 and 13.9 ± 7.3 days, respectively. In contrast, notched bee...

  1. Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis

    PubMed Central

    Koduru, Srinivas; Kumar, Raj; Srinivasan, Sowmyalakshmi; Evers, Mark B; Damodaran, Chendil

    2011-01-01

    Notch signaling plays a crucial role in the development of colon cancer; targeting the Notch pathway may sensitize colon cancers to various adjuvant agents. The focus of our current study is to identify natural compounds that target Notch signaling and that might be beneficial for the prevention and treatment of colon cancer. Withaferin-A (WA) is a bioactive compound derived from Withania somnifera, which inhibits Notch-1 signaling and downregulates pro-survival pathways, such as Akt/NF-κB/Bcl-2, in three colon cancer cell lines (HCT-116, SW-480 and SW-620). In addition, WA downregulated expression of mTOR signaling components, pS6K and p4E-BP1 and activated JNK-mediated apoptosis in colon cancer cells. We also established the molecular link between Notch/Akt/mTOR signaling by complementary approaches (i.e., overexpression of Notch-1 or inhibition of Notch-1 by siRNA). Our results suggest that WA inhibits Notch-mediated pro-survival signaling, which facilitates JNK mediated apoptosis in colon cancer cell lines. These results underscore the anti-cancer activity of WA, which exhibits potential for further development for targeted chemotherapy and/or chemoprevention strategies in the context of colon cancer. PMID:20053782

  2. Notch-1 activates estrogen receptor-α-dependent transcription via IKKα in breast cancer cells

    PubMed Central

    Hao, L; Rizzo, P; Osipo, C; Pannuti, A; Wyatt, D; Cheung, LW-K; Sonenshein, G; Osborne, BA; Miele, L

    2016-01-01

    Approximately 80% of breast cancers express the estrogen receptor-α (ERα) and are treated with anti-estrogens. Resistance to these agents is a major cause of mortality. We have shown that estrogen inhibits Notch, whereas anti-estrogens or estrogen withdrawal activate Notch signaling. Combined inhibition of Notch and estrogen signaling has synergistic effects in ERα-positive breast cancer models. However, the mechanisms whereby Notch-1 promotes the growth of ERα-positive breast cancer cells are unknown. Here, we demonstrate that Notch-1 increases the transcription of ERα-responsive genes in the presence or absence of estrogen via a novel chromatin crosstalk mechanism. Our data support a model in which Notch-1 can activate the transcription of ERα-target genes via IKKα-dependent cooperative chromatin recruitment of Notch–CSL–MAML1 transcriptional complexes (NTC) and ERα, which promotes the recruitment of p300. CSL binding elements frequently occur in close proximity to estrogen-responsive elements (EREs) in the human and mouse genomes. Our observations suggest that a hitherto unknown Notch-1/ERα chromatin crosstalk mediates Notch signaling effects in ERα-positive breast cancer cells and contributes to regulate the transcriptional functions of ERα itself. PMID:19838210

  3. Structural basis for Notch1 engagement of Delta-like 4

    PubMed Central

    Luca, Vincent C.; Jude, Kevin M.; Pierce, Nathan W.; Nachury, Maxence V.; Fischer, Suzanne; Garcia, K. Christopher

    2015-01-01

    Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor–like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways. PMID:25700513

  4. Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels.

    PubMed

    Murphy, Patrick A; Kim, Tyson N; Huang, Lawrence; Nielsen, Corinne M; Lawton, Michael T; Adams, Ralf H; Schaffer, Chris B; Wang, Rong A

    2014-12-16

    Arteriovenous (AV) malformation (AVM) is a devastating condition characterized by focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. AVMs can form anywhere in the body and can cause debilitating ischemia and life-threatening hemorrhagic stroke. The mechanisms that underlie AVM formation remain poorly understood. Here, we examined the cellular and hemodynamic changes at the earliest stages of brain AVM formation by time-lapse two-photon imaging through cranial windows of mice expressing constitutively active Notch4 (Notch4*). AVMs arose from enlargement of preexisting microvessels with capillary diameter and blood flow and no smooth muscle cell coverage. AV shunting began promptly after Notch4* expression in endothelial cells (ECs), accompanied by increased individual EC areas, rather than increased EC number or proliferation. Alterations in Notch signaling in ECs of all vessels, but not arteries alone, affected AVM formation, suggesting that Notch functions in the microvasculature and/or veins to induce AVM. Increased Notch signaling interfered with the normal biological control of hemodynamics, permitting a positive feedback loop of increasing blood flow and vessel diameter and driving focal AVM growth from AV connections with higher blood velocity at the expense of adjacent AV connections with lower velocity. Endothelial expression of constitutively active Notch1 also led to brain AVMs in mice. Our data shed light on cellular and hemodynamic mechanisms underlying AVM pathogenesis elicited by increased Notch signaling in the endothelium. PMID:25468970

  5. Border of Notch activity establishes a boundary between the two dorsal appendage tube cell types.

    PubMed

    Ward, Ellen J; Zhou, Xiaofeng; Riddiford, Lynn M; Berg, Celeste A; Ruohola-Baker, Hannele

    2006-09-15

    Boundaries establish and maintain separate populations of cells critical for organ formation. We show that Notch signaling establishes the boundary between two types of post-mitotic epithelial cells, the Rhomboid- and the Broad-positive cells. These cells will undergo morphogenetic movements to generate the two sides of a simple organ, the dorsal appendage tube of the Drosophila egg chamber. The boundary forms due to a difference in Notch levels in adjacent cells. The Notch expression pattern mimics the boundary; Notch levels are high in Rhomboid cells and low in Broad cells. Notch(-) mutant clones generate an ectopic boundary: ectopic Rhomboid cells arise in Notch(+) cells adjacent to the Notch(-) mutant cells but not further away from the clonal border. Pangolin, a component of the Wingless pathway, is required for Broad expression and for rhomboid repression. We further show that Broad represses rhomboid cell autonomously. Our data provide a foundation for understanding how a single row of Rhomboid cells arises adjacent to the Broad cells in the dorsal appendage primordia. Generating a boundary by the Notch pathway might constitute an evolutionarily conserved first step during organ formation in many tissues. PMID:16828735

  6. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice

    PubMed Central

    Sparks, Erin E.; Huppert, Kari A.; Brown, Melanie A.; Washington, M. Kay; Huppert, Stacey S.

    2010-01-01

    Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bi-potential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. While Notch2 has a dominant role in IHBD formation there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Since changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs. Conclusion There is a threshold requirement for Notch signaling at multiple steps, IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture. PMID:20069650

  7. Notch-1 Signalling Is Activated in Brain Arteriovenous Malformations in Humans

    ERIC Educational Resources Information Center

    ZhuGe, Qichuan; Zhong, Ming; Zheng, WeiMing; Yang, Guo-Yuan; Mao, XiaoOu; Xie, Lin; Chen, Gourong; Chen, Yongmei; Lawton, Michael T.; Young, William L.; Greenberg, David A.; Jin, Kunlin

    2009-01-01

    A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that,…

  8. Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone.

    PubMed

    Andreu-Agulló, Celia; Morante-Redolat, José Manuel; Delgado, Ana C; Fariñas, Isabel

    2009-12-01

    We sought to address the fundamental question of how stem cell microenvironments can regulate self-renewal. We found that Notch was active in astroglia-like neural stem cells (NSCs), but not in transit-amplifying progenitors of the murine subependymal zone, and that the level of Notch transcriptional activity correlated with self-renewal and multipotency. Moreover, dividing NSCs appeared to balance renewal with commitment via controlled segregation of Notch activity, leading to biased expression of known (Hes1) and previously unknown (Egfr) Notch target genes in daughter cells. Pigment epithelium-derived factor (PEDF) enhanced Notch-dependent transcription in cells with low Notch signaling, thereby subverting the output of an asymmetrical division to the production of two highly self-renewing cells. Mechanistically, PEDF induced a non-canonical activation of the NF-kappaB pathway, leading to the dismissal of the transcriptional co-repressor N-CoR from specific Notch-responsive promoters. Our data provide a basis for stemness regulation in vascular niches and indicate that Notch and PEDF cooperate to regulate self-renewal. PMID:19898467

  9. Notch1 deficiency decreases hepatic lipid accumulation by induction of fatty acid oxidation.

    PubMed

    Song, No-Joon; Yun, Ui Jeong; Yang, Sunghee; Wu, Chunyan; Seo, Cho-Rong; Gwon, A-Ryeong; Baik, Sang-Ha; Choi, Yuri; Choi, Bo Youn; Bahn, Gahee; Kim, Suji; Kwon, So-Mi; Park, Jin Su; Baek, Seung Hyun; Park, Tae Joo; Yoon, Keejung; Kim, Byung-Joon; Mattson, Mark P; Lee, Sung-Joon; Jo, Dong-Gyu; Park, Kye Won

    2016-01-01

    Notch signaling pathways modulate various cellular processes, including cell proliferation, differentiation, adhesion, and communication. Recent studies have demonstrated that Notch1 signaling also regulates hepatic glucose production and lipid synthesis. However, the effect of Notch1 signaling on hepatic lipid oxidation has not yet been directly investigated. To define the function of Notch1 signaling in hepatic lipid metabolism, wild type mice and Notch1 deficient antisense transgenic (NAS) mice were fed a high-fat diet. High-fat diet -fed NAS mice exhibited a marked reduction in hepatic triacylglycerol accumulation compared with wild type obese mice. The improved fatty liver was associated with an increased expression of hepatic genes involved in fatty acid oxidation. However, lipogenic genes were not differentially expressed in the NAS liver, suggesting lipolytic-specific regulatory effects by Notch1 signaling. Expression of fatty acid oxidative genes and the rate of fatty acid oxidation were also increased by inhibition of Notch1 signaling in HepG2 cells. In addition, similar regulatory effects on lipid accumulation were observed in adipocytes. Taken together, these data show that inhibition of Notch1 signaling can regulate the expression of fatty acid oxidation genes and may provide therapeutic strategies in obesity-induced hepatic steatosis. PMID:26786165

  10. Notch1 deficiency decreases hepatic lipid accumulation by induction of fatty acid oxidation

    PubMed Central

    Song, No-Joon; Yun, Ui Jeong; Yang, Sunghee; Wu, Chunyan; Seo, Cho-Rong; Gwon, A-Ryeong; Baik, Sang-Ha; Choi, Yuri; Choi, Bo Youn; Bahn, Gahee; Kim, Suji; Kwon, So-Mi; Park, Jin Su; Baek, Seung Hyun; Park, Tae Joo; Yoon, Keejung; Kim, Byung-Joon; Mattson, Mark P.; Lee, Sung-Joon; Jo, Dong-Gyu; Park, Kye Won

    2016-01-01

    Notch signaling pathways modulate various cellular processes, including cell proliferation, differentiation, adhesion, and communication. Recent studies have demonstrated that Notch1 signaling also regulates hepatic glucose production and lipid synthesis. However, the effect of Notch1 signaling on hepatic lipid oxidation has not yet been directly investigated. To define the function of Notch1 signaling in hepatic lipid metabolism, wild type mice and Notch1 deficient antisense transgenic (NAS) mice were fed a high-fat diet. High-fat diet -fed NAS mice exhibited a marked reduction in hepatic triacylglycerol accumulation compared with wild type obese mice. The improved fatty liver was associated with an increased expression of hepatic genes involved in fatty acid oxidation. However, lipogenic genes were not differentially expressed in the NAS liver, suggesting lipolytic-specific regulatory effects by Notch1 signaling. Expression of fatty acid oxidative genes and the rate of fatty acid oxidation were also increased by inhibition of Notch1 signaling in HepG2 cells. In addition, similar regulatory effects on lipid accumulation were observed in adipocytes. Taken together, these data show that inhibition of Notch1 signaling can regulate the expression of fatty acid oxidation genes and may provide therapeutic strategies in obesity-induced hepatic steatosis. PMID:26786165

  11. The Notch pathway mediates the angiotensin II-induced synthesis of extracellular matrix components in podocytes.

    PubMed

    Yao, Min; Wang, Xiaomei; Wang, Xiaomeng; Zhang, Tao; Chi, Yanqing; Gao, Feng

    2015-07-01

    The Notch pathway is known to contribute to the development of glomerular disease. Angiotensin II (Ang II), an important member of the renin-angiotensin system, stimulates the accumulation of extracellular matrix components in glomerular disease; however, the exact mechanisms involved remain to be elucidated. In the present study, we aimed to investigate the effects of the Notch pathway on the synthesis of extracellular matrix components in Ang II-stimulated podocytes. Mouse podocytes were stimulated with Ang II (10-6 mol/l). The activation of the Notch pathway was inhibited by a vector carrying short hairpin RNA (shRNA) targeting Notch1 (sh-Notch1) or by γ-secretase inhibitor (GSI). The protein levels of Notch1, Notch intracellular domain 1 (NICD1), hairy and enhancer of split-1 (Hes1), matrix metalloproteinase (MMP)-2, MMP-9, transforming growth factor-β1 (TGF-β1), type IV collagen and laminin were determined by western blot analysis. The Notch1, Hes1, MMP-2, MMP-9, TGF-β1, type IV collagen and laminin mRNA levels were detected by RT-PCR. The MMP-2 and MMP-9 activity was measured using a cell active fluorescence assay kit. The levels of TGF-β1, type IV collagen and laminin were determined in the culture medium of the podocytes by enzyme-linked immunosorbent assay (ELISA). Our results revealed that Ang II upregulated Notch1, NICD1, Hes1, TGF-β1, type IV collagen and laminin expression and downregulated MMP-2 and MMP-9 expression in the cultured podocytes. The inhibition of the Notch pathway by sh-Notch1 or GSI increased MMP-2 and MMP-9 expression, decreased the TGF-β1 level and suppressed type IV collagen and laminin expression. The inhibition of the Notch pathway by sh-Notch1 or GSI also increased MMP-2 and MMP-9 activity, and decreased TGF-β1 levels, type IV collagen levels and laminin secretion. These findings indicate that the Notch pathway potentially mediates the Ang II-induced synthesis of extracellular matrix components in podocytes through the

  12. Statistics of lattice animals

    NASA Astrophysics Data System (ADS)

    Hsu, Hsiao-Ping; Nadler, Walder; Grassberger, Peter

    2005-07-01

    The scaling behavior of randomly branched polymers in a good solvent is studied in two to nine dimensions, modeled by lattice animals on simple hypercubic lattices. For the simulations, we use a biased sequential sampling algorithm with re-sampling, similar to the pruned-enriched Rosenbluth method (PERM) used extensively for linear polymers. We obtain high statistics of animals with up to several thousand sites in all dimension 2⩽d⩽9. The partition sum (number of different animals) and gyration radii are estimated. In all dimensions we verify the Parisi-Sourlas prediction, and we verify all exactly known critical exponents in dimensions 2, 3, 4, and ⩾8. In addition, we present the hitherto most precise estimates for growth constants in d⩾3. For clusters with one site attached to an attractive surface, we verify the superuniversality of the cross-over exponent at the adsorption transition predicted by Janssen and Lyssy.

  13. Lattice Boltzmann morphodynamic model

    NASA Astrophysics Data System (ADS)

    Zhou, Jian Guo

    2014-08-01

    Morphological change due to sediment transport is a common natural phenomenon in real flows. It involves complex processes of erosion and deposition such as those along beaches and in river beds, imposing a strong strain on human beings. Studying and understanding morphodynamic evolution are essential to protect living environment. Although there are conventional numerical methods like finite difference method and finite volume method for forecast of morphological change by solving flow and morphodynamic equations, the methods are too complex/inefficient to be applied to a real large scale problem. To overcome this, a lattice Boltzmann method is developed to simulate morphological evolution under flows. It provides an alternative way of studying morphodynamics at the full advantages of the lattice Boltzmann methodology. The model is verified by applications to the evolution of one and two dimensional sand dunes under shallow water flows.

  14. Introduction to lattice QCD

    SciTech Connect

    Gupta, R.

    1998-12-31

    The goal of the lectures on lattice QCD (LQCD) is to provide an overview of both the technical issues and the progress made so far in obtaining phenomenologically useful numbers. The lectures consist of three parts. The author`s charter is to provide an introduction to LQCD and outline the scope of LQCD calculations. In the second set of lectures, Guido Martinelli will discuss the progress they have made so far in obtaining results, and their impact on Standard Model phenomenology. Finally, Martin Luescher will discuss the topical subjects of chiral symmetry, improved formulation of lattice QCD, and the impact these improvements will have on the quality of results expected from the next generation of simulations.

  15. A simple nonlocal damage model for predicting failure of notched laminates

    NASA Technical Reports Server (NTRS)

    Kennedy, T. C.; Nahan, M. F.

    1995-01-01

    The ability to predict failure loads in notched composite laminates is a requirement in a variety of structural design circumstances. A complicating factor is the development of a zone of damaged material around the notch tip. The objective of this study was to develop a computational technique that simulates progressive damage growth around a notch in a manner that allows the prediction of failure over a wide range of notch sizes. This was accomplished through the use of a relatively simple, nonlocal damage model that incorporates strain-softening. This model was implemented in a two-dimensional finite element program. Calculations were performed for two different laminates with various notch sizes under tensile loading, and the calculations were found to correlate well with experimental results.

  16. Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells.

    PubMed

    Li, Li; Grausam, Katie B; Wang, Jun; Lun, Melody P; Ohli, Jasmin; Lidov, Hart G W; Calicchio, Monica L; Zeng, Erliang; Salisbury, Jeffrey L; Wechsler-Reya, Robert J; Lehtinen, Maria K; Schüller, Ulrich; Zhao, Haotian

    2016-04-01

    Aberrant Notch signalling has been linked to many cancers including choroid plexus (CP) tumours, a group of rare and predominantly paediatric brain neoplasms. We developed animal models of CP tumours, by inducing sustained expression of Notch1, that recapitulate properties of human CP tumours with aberrant NOTCH signalling. Whole-transcriptome and functional analyses showed that tumour cell proliferation is associated with Sonic Hedgehog (Shh) in the tumour microenvironment. Unlike CP epithelial cells, which have multiple primary cilia, tumour cells possess a solitary primary cilium as a result of Notch-mediated suppression of multiciliate differentiation. A Shh-driven signalling cascade in the primary cilium occurs in tumour cells but not in epithelial cells. Lineage studies show that CP tumours arise from monociliated progenitors in the roof plate characterized by elevated Notch signalling. Abnormal SHH signalling and distinct ciliogenesis are detected in human CP tumours, suggesting the SHH pathway and cilia differentiation as potential therapeutic avenues. PMID:26999738

  17. Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch

    PubMed Central

    Gordon, Wendy R.; Zimmerman, Brandon; He, Li; Miles, Laura J.; Huang, Jiuhong; Tiyanont, Kittichoat; McArthur, Debbie G.; Aster, Jon C.; Perrimon, Norbert; Loparo, Joseph J.; Blacklow, Stephen C.

    2015-01-01

    Summary Ligands stimulate Notch receptors by inducing regulated intramembrane proteolysis (RIP) to produce a transcriptional effector. Notch activation requires unmasking of a metalloprotease cleavage site remote from the site of ligand binding, raising the question of how proteolytic sensitivity is achieved. Here, we show that application of physiologically relevant forces to the regulatory switch results in sensitivity to metalloprotease cleavage, and that bound ligands induce Notch signal transduction in cells only in the presence of applied mechanical force. Synthetic receptor-ligand systems that remove the native ligand-receptor interaction also activate Notch by inducing proteolysis of the regulatory switch. Together, these studies show that mechanical force exerted by signal-sending cells is required for ligand-induced Notch activation, and establish that force-induced proteolysis can act as a mechanism of cellular mechanotransduction. PMID:26051539

  18. A Smile Face Monopole Antenna with Quadruple Band-Notched Characteristics

    NASA Astrophysics Data System (ADS)

    Yang, Xiao-Lin; Kong, Fang-Ling; Wang, Yan

    2015-05-01

    A compact planar ultra-wideband (UWB) monopole antenna with quadruple band-notched characteristics is presented. The notched band at 3.3-4.2 GHz (C-band) is obtained by embedding a pair of Z-shaped slots on the elliptical radiation patch. Meanwhile, a modified U-shaped slot is etched in the radiation patch to create the notched band at 4.9-5.4 GHz for WLAN. In addition, by introducing E-shaped stubs on the back layer, the notched bands at 5.5-6.1 GHz for WLAN and 7-8.15 GHz for downlink of X-band satellite communication system are obtained. The antenna is fabricated and measured, showing broadband matched impedance and good Omni-directional patterns with high fidelity and phase linearity (outside the notched bands).

  19. Cyclic-inelastic deformation and fatigue resistance of notched-thin aluminum plates

    NASA Technical Reports Server (NTRS)

    Leis, B. N.; Frey, N. D.

    1982-01-01

    The results of experiments designed to develop data to assess the accuracy and utility of the critical location concept in applications of fatigue-crack nucleation analysis at notch roots are presented and discussed. Fully reversed and nonzero mean-stress data are presented over a range of lives which encompass both elastic and inelastic deformations for thin-notched specimens and smooth specimens made of 2024 T351 aluminum-alloy sheet. Notch-root strains were measured via an extensometer, whereas the formation of small cracks was detected via an eddy-current transducer. Data reported indicated the validity of the assumption that smooth and notched specimens form cracks at the same cycle number when identical deformation histories are imposed at their respective critical locations. They also serve to demonstrate the accuracy and utility of the critical-location approach in analysis to predict the formation of small cracks at notches in coupons and components.

  20. Effects of loading sequence for notched specimens under high-low two-step fatigue loading

    NASA Technical Reports Server (NTRS)

    Crews, J. H., Jr.

    1971-01-01

    The effects of loading sequence on crack-initiation period were investigated for notched aluminum-alloy specimens under high-low two-step loading with special emphasis on local cyclic stresses and strains at the notch root. Local stress and strain were determined by a procedure based on an equation proposed by Neuber which relates elastoplastic stress and strain at a notch. Local stress and strain were also measured experimentally to verify the Neuber equation. The effects of initial high load on the crack-initiation periods were demonstrated with notched specimens and were simulated in unnotched specimens fatigue tested with local stress sequences. An analysis of the results indicated that sequence effects were not caused solely by local residual stresses, as is usually assumed; the existence of a damaging effect, resulting from the high local strain cycles, was demonstrated. The sequence effects observed with notched specimens were interpreted as the combined result of residual stresses and high local strain cycles.

  1. Effect of clathrin light chains on the stiffness of clathrin lattices and membrane budding.

    PubMed

    Dannhauser, Philip N; Platen, Mitja; Böning, Heike; Ungewickell, Huberta; Schaap, Iwan A T; Ungewickell, Ernst J

    2015-05-01

    Clathrin-dependent transport processes require the polymerization of clathrin triskelia into polygonal scaffolds. Together with adapter proteins, clathrin collects cargo and induces membrane bud formation. It is not known to what extent clathrin light chains affect the structural and functional properties of clathrin lattices and the ability of clathrin to deform membranes. To address these issues, we have developed a novel procedure for analyzing clathrin lattice formation on rigid surfaces. We found that lattices can form on adaptor-coated convex-, planar- and even shallow concave surfaces, but the rate of formation and resistance to thermal dissociation of the lattice are greatly enhanced on convex surfaces. Atomic force microscopy on planar clathrin lattices demonstrates that the stiffness of the clathrin lattice is strictly dependent on light chains. The reduced stiffness of the lattice also compromised the ability of clathrin to generate coated buds on the surface of rigid liposomal membranes. PMID:25652138

  2. On plastic flow in notched hexagonal close packed single crystals

    NASA Astrophysics Data System (ADS)

    Selvarajou, Balaji; Kondori, Babak; Benzerga, A. Amine; Joshi, Shailendra P.

    2016-09-01

    The micromechanics of anisotropic plastic flow by combined slip and twinning is investigated computationally in single crystal notched specimens. Constitutive relations for hexagonal close packed materials are used which take into account elastic anisotropy, thirty potential deformation systems, various hardening mechanisms and rate-sensitivity. The specimens are loaded perpendicular to the c-axis but the presence of a notch generates three-dimensional triaxial stress states. The study is motivated by recent experiments on a polycrystalline magnesium alloy. To enable comparisons with these where appropriate, three sets of activation thresholds for the various deformation systems are used. For the conditions that most closely mimic the alloy material, attention is focused on the relative roles of pyramidal < c + a > and prismatic < a > slip, as well as on the emergence of {1012bar}[101bar1] extension twinning at sufficiently high triaxiality. In all cases, the spatial variations of stress triaxiality and plastic strain, inclusive of various system activities, are quantified along with their evolution upon straining. The implications of these findings in fundamental understanding of ductile failure of HCP alloys in general and Mg alloys in particular are discussed.

  3. Investigation of reflective notching with massively parallel simulation

    NASA Astrophysics Data System (ADS)

    Tadros, Karim H.; Neureuther, Andrew R.; Gamelin, John K.; Guerrieri, Roberto

    1990-06-01

    A massively parallel simulation program TEMPEST is used to investigate the role of topography in generating reflective notching and to study the possibility of reducing effects through the introduction of special properties of resists and antireflection coating materials. The emphasis is on examining physical scattering mechanisms such as focused specular reflections resist thickness interference effects reflections from substrate grains and focusing of incident light by the resist curvature. Specular reflection from topography can focus incident radiation causing a 10-fold increase in effective exposure. Further complications such as dimples in the surface of positive resist features can result from a second reflection of focused energy by the resist/air interface. Variations in line-edge exposure due to substrate grain structure are primarily specular in nature and can become significant for grains larger than )tresi Local exposure variations due to vertical standing waves and changes in energy coupling due to changes in resist thickness are displaced laterally and are significant effects even though they are slightly less severe than vertical wave propagation theory suggests. Focusing effects due to refraction by the curved surface of the resist produce only minor changes in exposure. Increased resist contrast and resist absorption offer some improvement in reducing notching effects though minimizing substrate reflectivity is more effective. CPU time using 32 virtual nodes to simulate a 4 pm by 2 pm isolated domain with 13 bleaching steps was 30 minutes

  4. Analysis of notched metal matrix composites under tensile loading

    NASA Technical Reports Server (NTRS)

    Bigelow, C. A.

    1989-01-01

    This paper presents techniques based on a three-dimensional finite-element analysis for the analysis of continuous fiber reinforced metal matrix composite. Examples are shown for specific metal matrix composites such as boron/aluminum and silicon-carbide/aluminum. Specimen stress-strain behavior and stress at first fiber failure were predicted for boron/aluminum laminates containing circular holes and crack-like slits. The predictions compared very well with test data for laminates containing 0 deg fibers and reasonably well for (+/-45)2s laminates. Mesh configuration was shown to have an effect on the calculation of stresses local to the notch. The presence of thin interface layers of matrix material had a significant influence on the slit tip stress state, causing sharper stress gradients near the notch. Interface layers reduced the slit-tip fibers stress in a (+/-45)2s silicon-carbide/aluminum laminate but increased them in a (0/90)2s laminate.

  5. Structural Efficiency and Behavior of Pristine and Notched Stitched Structure

    NASA Technical Reports Server (NTRS)

    Jegley, Dawn C.

    2011-01-01

    Two driving factors in aircraft panel design are structural efficiency and response to in-service damage. Stitching through the thickness can improve both of these considerations. Combining stitching with a post-buckling design approach can provide additional improvements. The buckling behavior of stitched structure is considered since lighter structures can be achieved if local skin buckling is allowed to occur at less than design ultimate load. Through-the-thickness stitching can suppress delamination between skin and flange, thereby allowing the structure to reliably carry load into the postbuckling range. Hat-stiffened and rod-stiffened panels in which the skin and flanges were stitched together through-the-thickness prior to curing are considered through experiment and analysis. In both types of panels no mechanical fasteners were used for the assembly. Specimens were loaded to failure in axial compression. In this study all specimens buckled in the skin between the stiffeners and continued to carry load. In addition, the behavior of panels with a severed stringer or notch are considered. Failure loads and strain distributions in the notched panel are compared to those in the unnotched panel.

  6. Predictions from lattice QCD

    SciTech Connect

    Kronfeld, A.S.; Allison, I.F.; Aubin, C.; Bernard, C.; Davies, C.T.H.; DeTar, C.; Di Pierro, M.; Freeland, E.D.; Gottlieb, Steven; Gray, A.; Gregor, E.; Heller, U.M.; Hetrick, J.E.; El-Khadra, Aida X.; Levkova, L.; Mackenzie, P.B.; Maresca, F.; Menscher, D.; Nobes, M.; Okamoto, M.; Oktay, M.B.; /Fermilab /Glasgow U. /Columbia U. /Washington U., St. Louis /Utah U. /DePaul U. /Art Inst. of Chicago /Indiana U. /Ohio State U. /Arizona U. /APS, New York /U. Pacific, Stockton /Illinois U., Urbana /Cornell U., LEPP /Simon Fraser U. /UC, Santa Barbara

    2005-09-01

    In the past year, we calculated with lattice QCD three quantities that were unknown or poorly known. They are the q{sup 2} dependence of the form factor in semileptonic D {yields} K/{nu} decay, the decay constant of the D meson, and the mass of the B{sub c} meson. In this talk, we summarize these calculations, with emphasis on their (subsequent) confirmation by experiments.

  7. Multipole plasmonic lattice solitons

    SciTech Connect

    Kou Yao; Ye Fangwei; Chen Xianfeng

    2011-09-15

    We theoretically demonstrate a variety of multipole plasmonic lattice solitons, including dipoles, quadrupoles, and necklaces, in two-dimensional metallic nanowire arrays with Kerr-type nonlinearities. Such solitons feature complex internal structures with an ultracompact mode size approaching or smaller than one wavelength. Their mode sizes and the stability characteristics are studied in detail within the framework of coupled mode theory. The conditions to form and stabilize these highly confined solitons are within the experimentally achievable range.

  8. Second-generation Notch1 activity-trap mouse line (N1IP::CreHI) provides a more comprehensive map of cells experiencing Notch1 activity

    PubMed Central

    Liu, Zhenyi; Brunskill, Eric; Boyle, Scott; Chen, Shuang; Turkoz, Mustafa; Guo, Yuxuan; Grant, Rachel; Kopan, Raphael

    2015-01-01

    We have previously described the creation and analysis of a Notch1 activity-trap mouse line, Notch1 intramembrane proteolysis-Cre6MT or N1IP::CreLO, that marked cells experiencing relatively high levels of Notch1 activation. Here, we report and characterize a second line with improved sensitivity (N1IP::CreHI) to mark cells experiencing lower levels of Notch1 activation. This improvement was achieved by increasing transcript stability and by restoring the native carboxy terminus of Cre, resulting in a five- to tenfold increase in Cre activity. The magnitude of this effect probably impacts Cre activity in strains with carboxy-terminal Ert2 fusion. These two trap lines and the related line N1IP::CreERT2 form a complementary mapping tool kit to identify changes in Notch1 activation patterns in vivo as the consequence of genetic or pharmaceutical intervention, and illustrate the variation in Notch1 signal strength from one tissue to the next and across developmental time. PMID:25725069

  9. Second-generation Notch1 activity-trap mouse line (N1IP::CreHI) provides a more comprehensive map of cells experiencing Notch1 activity.

    PubMed

    Liu, Zhenyi; Brunskill, Eric; Boyle, Scott; Chen, Shuang; Turkoz, Mustafa; Guo, Yuxuan; Grant, Rachel; Kopan, Raphael

    2015-03-15

    We have previously described the creation and analysis of a Notch1 activity-trap mouse line, Notch1 intramembrane proteolysis-Cre6MT or N1IP::Cre(LO), that marked cells experiencing relatively high levels of Notch1 activation. Here, we report and characterize a second line with improved sensitivity (N1IP::Cre(HI)) to mark cells experiencing lower levels of Notch1 activation. This improvement was achieved by increasing transcript stability and by restoring the native carboxy terminus of Cre, resulting in a five- to tenfold increase in Cre activity. The magnitude of this effect probably impacts Cre activity in strains with carboxy-terminal Ert2 fusion. These two trap lines and the related line N1IP::Cre(ERT2) form a complementary mapping tool kit to identify changes in Notch1 activation patterns in vivo as the consequence of genetic or pharmaceutical intervention, and illustrate the variation in Notch1 signal strength from one tissue to the next and across developmental time. PMID:25725069

  10. NOTCH1 mutations associate with low CD20 level in chronic lymphocytic leukemia: evidence for a NOTCH1 mutation-driven epigenetic dysregulation.

    PubMed

    Pozzo, F; Bittolo, T; Arruga, F; Bulian, P; Macor, P; Tissino, E; Gizdic, B; Rossi, F M; Bomben, R; Zucchetto, A; Benedetti, D; Degan, M; D'Arena, G; Chiarenza, A; Zaja, F; Pozzato, G; Rossi, D; Gaidano, G; Del Poeta, G; Deaglio, S; Gattei, V; Dal Bo, M

    2016-01-01

    In chronic lymphocytic leukemia (CLL), NOTCH1 mutations have been associated with clinical resistance to the anti-CD20 rituximab, although the mechanisms behind this peculiar behavior remain to be clarified. In a wide CLL series (n=692), we demonstrated that CLL cells from NOTCH1-mutated cases (87/692) were characterized by lower CD20 expression and lower relative lysis induced by anti-CD20 exposure in vitro. Consistently, CD20 expression by CLL cells was upregulated in vitro by γ-secretase inhibitors or NOTCH1-specific small interfering RNA and the stable transfection of a mutated (c.7541-7542delCT) NOTCH1 intracellular domain (NICD-mut) into CLL-like cells resulted in a strong downregulation of both CD20 protein and transcript. By using these NICD-mut transfectants, we investigated protein interactions of RBPJ, a transcription factor acting either as activator or repressor of NOTCH1 pathway when respectively bound to NICD or histone deacetylases (HDACs). Compared with controls, NICD-mut transfectants had RBPJ preferentially complexed to NICD and showed higher levels of HDACs interacting with the promoter of the CD20 gene. Finally, treatment with the HDAC inhibitor valproic acid upregulated CD20 in both NICD-mut transfectants and primary CLL cells. In conclusion, NOTCH1 mutations are associated with low CD20 levels in CLL and are responsible for a dysregulation of HDAC-mediated epigenetic repression of CD20 expression. PMID:26165233

  11. Nucleon Structure from Lattice QCD

    SciTech Connect

    David Richards

    2007-09-05

    Recent advances in lattice field theory, in computer technology and in chiral perturbation theory have enabled lattice QCD to emerge as a powerful quantitative tool in understanding hadron structure. I describe recent progress in the computation of the nucleon form factors and moments of parton distribution functions, before proceeding to describe lattice studies of the Generalized Parton Distributions (GPDs). In particular, I show how lattice studies of GPDs contribute to building a three-dimensional picture of the proton, I conclude by describing the prospects for studying the structure of resonances from lattice QCD.

  12. Crystallographic Lattice Boltzmann Method.

    PubMed

    Namburi, Manjusha; Krithivasan, Siddharth; Ansumali, Santosh

    2016-01-01

    Current approaches to Direct Numerical Simulation (DNS) are computationally quite expensive for most realistic scientific and engineering applications of Fluid Dynamics such as automobiles or atmospheric flows. The Lattice Boltzmann Method (LBM), with its simplified kinetic descriptions, has emerged as an important tool for simulating hydrodynamics. In a heterogeneous computing environment, it is often preferred due to its flexibility and better parallel scaling. However, direct simulation of realistic applications, without the use of turbulence models, remains a distant dream even with highly efficient methods such as LBM. In LBM, a fictitious lattice with suitable isotropy in the velocity space is considered to recover Navier-Stokes hydrodynamics in macroscopic limit. The same lattice is mapped onto a cartesian grid for spatial discretization of the kinetic equation. In this paper, we present an inverted argument of the LBM, by making spatial discretization as the central theme. We argue that the optimal spatial discretization for LBM is a Body Centered Cubic (BCC) arrangement of grid points. We illustrate an order-of-magnitude gain in efficiency for LBM and thus a significant progress towards feasibility of DNS for realistic flows. PMID:27251098

  13. Crystallographic Lattice Boltzmann Method

    PubMed Central

    Namburi, Manjusha; Krithivasan, Siddharth; Ansumali, Santosh

    2016-01-01

    Current approaches to Direct Numerical Simulation (DNS) are computationally quite expensive for most realistic scientific and engineering applications of Fluid Dynamics such as automobiles or atmospheric flows. The Lattice Boltzmann Method (LBM), with its simplified kinetic descriptions, has emerged as an important tool for simulating hydrodynamics. In a heterogeneous computing environment, it is often preferred due to its flexibility and better parallel scaling. However, direct simulation of realistic applications, without the use of turbulence models, remains a distant dream even with highly efficient methods such as LBM. In LBM, a fictitious lattice with suitable isotropy in the velocity space is considered to recover Navier-Stokes hydrodynamics in macroscopic limit. The same lattice is mapped onto a cartesian grid for spatial discretization of the kinetic equation. In this paper, we present an inverted argument of the LBM, by making spatial discretization as the central theme. We argue that the optimal spatial discretization for LBM is a Body Centered Cubic (BCC) arrangement of grid points. We illustrate an order-of-magnitude gain in efficiency for LBM and thus a significant progress towards feasibility of DNS for realistic flows. PMID:27251098

  14. Crystallographic Lattice Boltzmann Method

    NASA Astrophysics Data System (ADS)

    Namburi, Manjusha; Krithivasan, Siddharth; Ansumali, Santosh

    2016-06-01

    Current approaches to Direct Numerical Simulation (DNS) are computationally quite expensive for most realistic scientific and engineering applications of Fluid Dynamics such as automobiles or atmospheric flows. The Lattice Boltzmann Method (LBM), with its simplified kinetic descriptions, has emerged as an important tool for simulating hydrodynamics. In a heterogeneous computing environment, it is often preferred due to its flexibility and better parallel scaling. However, direct simulation of realistic applications, without the use of turbulence models, remains a distant dream even with highly efficient methods such as LBM. In LBM, a fictitious lattice with suitable isotropy in the velocity space is considered to recover Navier-Stokes hydrodynamics in macroscopic limit. The same lattice is mapped onto a cartesian grid for spatial discretization of the kinetic equation. In this paper, we present an inverted argument of the LBM, by making spatial discretization as the central theme. We argue that the optimal spatial discretization for LBM is a Body Centered Cubic (BCC) arrangement of grid points. We illustrate an order-of-magnitude gain in efficiency for LBM and thus a significant progress towards feasibility of DNS for realistic flows.

  15. Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis

    PubMed Central

    Yuan, Xun; Wu, Hua; Xu, Hanxiao; Han, Na; Chu, Qian; Yu, Shiying; Chen, Yuan; Wu, Kongming

    2015-01-01

    Various studies have assessed the clinicopathological and prognostic value of Notch1 and Notch3 expression in Non-small cell lung cancer (NSCLC), but their results remain controversial. This meta-analysis was conducted to address the above issues by using a total of 19 studies involving 3663 patients. The correlations between Notch1 and Notch3 expression and clinicopathological features and NSCLC prognosis were analyzed. The meta-analysis indicated that higher expression of Notch1 was associated with greater possibility of lymph node metastasis and higher TNM stages. Moreover, patients with Notch1 overexpression and Notch3 overexpression showed significantly poor overall survival (Notch1: HR, 1.29; 95% CI, 1.06–1.57, p = 0.468 and I2 = 0.0%; Notch3: HR, 1.57; 95%CI, 1.04-2.36, p = 0.445 and I2 = 0.0%). Furthermore, there are statistically significant association between overall survival of NSCLC patients and the expression of Notch signaling ligand DLL3 and target gene HES1. Our meta-analysis supports that Notch signaling is a valuable bio-marker to predict progression and targeting Notch signaling could benefit subpopulation of NSCLC patients. PMID:25996086

  16. Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness.

    PubMed

    Zhang, P; Yang, Y; Nolo, R; Zweidler-McKay, P A; Hughes, D P M

    2010-05-20

    The highly conserved NOTCH signaling pathway has many essential functions in the development of diverse cells, tissues and organs from Drosophila to humans, and dysregulated NOTCH signaling contributes to several disorders, including vascular and bone defects, as well as several cancers. Here we describe a novel mechanism of NOTCH regulation by reciprocal inhibition of two NOTCH downstream effectors: Deltex1 and HES1. This mechanism appears to regulate invasion of osteosarcoma cells, as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH/HES1 signaling. The inhibitory effect of endogenous Deltex1 on NOTCH signaling is mediated through binding with the intracellular domain of NOTCH and ubiquitination and degradation of NOTCH receptors. Conversely, we show that the NOTCH target gene HES1 causes transcriptional inhibition of Deltex1 by directly binding to the promoter of Deltex1. An HES1 binding site is identified 400 bp upstream of the transcription start site of Deltex1. HES1-mediated repression of Deltex1 requires the C-terminal H3/H4 and WRPW domains of HES1, which associate with the TLE/Groucho corepressors. Taken together, we define a molecular mechanism regulating NOTCH signaling by reciprocal inhibition of the NOTCH target genes HES1 and Deltex1 in mammalian cells. This mechanism may have important clinical implications for targeting NOTCH signaling in osteosarcoma and other cancers. PMID:20208568

  17. Notch3 and Hey-1 as Prognostic Biomarkers in Pancreatic Adenocarcinoma

    PubMed Central

    Mann, Christopher D.; Bastianpillai, Christopher; Neal, Christopher P.; Masood, Muhammad M.; Jones, Donald J. L.; Teichert, Friederike; Singh, Rajinder; Karpova, Elena; Berry, David P.; Manson, Margaret M.

    2012-01-01

    In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p≤0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls. PMID:23226563

  18. Notch signaling is active in normal mouse middle ear epithelial cells

    PubMed Central

    LIU, XIANG; SHENG, HAI-BIN; MA, RUI; YANG, JUAN-MEI; LUO, WEN-WEI; YANG, XIAO-YU; REN, DONG-DONG; CHI, FANG-LU

    2016-01-01

    Mucous cell metaplasia/hyperplasia in the middle ear epithelium is associated with the occurrence of otitis media with effusion during infections. However, the mechanism by which Notch signaling regulates cell fate in the middle ear epithelium is unclear. The aim of the present study was to elucidate this mechanism by investigating the localization of Notch receptors, such as Notch1 and Notch2, and Notch ligands, such as Jagged1, in the normal mouse middle ear epithelium (NMMEE) using immunofluorescence. Furthermore, the mRNA expression levels of Notch receptors and ligands were evaluated using reverse transcription polymerase chain reaction (PCR). The effects of the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT) on epithelial cell proliferation were determined using 5-ethynyl-2′-deoxyuridine (EdU) staining and immunofluorescence staining of the apoptosis marker caspase-3 and the epithelial proliferation marker pan-cytokeratine. In addition, the differentiation of the NMMEE cells was characterized by evaluating the mRNA expression levels of the mucous cell-associated genes Arg2, Muc2, Spdef, Spink4 and Tff1 using quantitative PCR. Notch1, Notch2 and Jagged1 were observed to be co-localized throughout the mouse middle ear epithelium. Furthermore, Notch1-4, Jagged1, Jagged2, Dll1 and Dll4 mRNAs were expressed in the NMMEE cells. The inhibition of Notch by DAPT resulted in fewer EdU-positive cells and the upregulation of the expression levels of various mucous cell-associated genes. The results indicate that DAPT suppresses the proliferation of NMMEE cells while promoting their differentiation into mucous cells. Therefore, DAPT may provide a specific therapeutic strategy for the reversal of multiple pathological processes that are associated with epithelium thickening in the middle ear. PMID:27168786

  19. Direct regulation of interleukin-6 expression by Notch signaling in macrophages

    PubMed Central

    Wongchana, Wipawee; Palaga, Tanapat

    2012-01-01

    Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine produced by various types of cells, including macrophages. Within the IL-6 gene promoter region, the signature binding motif of CBF1/Su(H)/Lag-1 (CSL), a key DNA-binding protein in the Notch signaling pathway, was identified and found to overlap with a consensus nuclear factor (NF)-κB-binding site. Notch signaling is highly conserved and is involved in the regulation of biological functions in immune cells. In this study, we investigated the role of Notch signaling in the regulation of the IL-6 transcript in murine macrophages. The upregulation of Notch1 protein levels and the appearance of cleaved Notch1 (Val1744) correlated well with the increased IL-6 mRNA expression levels in murine primary bone marrow-derived macrophages (BMMφ) after activation by lipopolysaccharide (LPS) together with interferon-gamma (IFN-γ). Treatment of BMMφ with the γ-secretase inhibitor IL-CHO to suppress the transduction of Notch signaling resulted in a partial decrease in the level of IL-6 mRNA and the amount of IL-6 protein produced. In contrast, the overexpression of a constitutively activated intracellular Notch1 protein (NIC) in the RAW264.7 macrophage-like cell line resulted in significantly higher IL-6 transcript expression levels than in cells transfected with the empty vector control. The NF-κB inhibitor completely abrogated IL-6 mRNA expression induced by the overexpression of NIC. Chromatin immunoprecipitation (ChIP) using an anti-Notch1 antibody demonstrated that Notch1 is associated with the IL-6 promoter in RAW264.7 cells activated by LPS/IFN-γ but not in unstimulated cells. Taken together, these results strongly suggest that Notch1 positively regulates IL-6 expression via NF-κB in activated macrophages. PMID:21983868

  20. EWS-FLI1 Suppresses NOTCH-Activated p53 in Ewing’s Sarcoma

    PubMed Central

    Ban, Jozef; Bennani-Baiti, Idriss M.; Kauer, Max; Schaefer, Karl-Ludwig; Poremba, Christopher; Jug, Gunhild; Schwentner, Raphaela; Smrzka, Oskar; Muehlbacher, Karin; Aryee, Dave N.T.; Kovar, Heinrich

    2016-01-01

    Although p53 is the most frequently mutated gene in cancer, half of human tumors retain wild-type p53, whereby it is unknown whether normal p53 function is compromised by other cancer-associated alterations. One example is Ewing’s sarcoma family tumors (ESFT), where 90% express wild-type p53. ESFT are characterized by EWS-FLI1 oncogene fusions. Studying 6 ESFT cell lines, silencing of EWS-FLI1 in a wild-type p53 context resulted in increased p53 and p21WAF1/CIP1 levels, causing cell cycle arrest. Using a candidate gene approach, HEY1 was linked to p53 induction. HEY1 was rarely expressed in 59 primary tumors, but consistently induced upon EWS-FLI1 knockdown in ESFT cell lines. The NOTCH signaling pathway targets HEY1, and we show NOTCH2 and NOTCH3 to be expressed in ESFT primary tumors and cell lines. Upon EWS-FLI1 silencing, NOTCH3 processing accompanied by nuclear translocation of the activated intracellular domain was observed in all but one p53-mutant cell line. In cell lines with the highest HEY1 induction, NOTCH3 activation was the consequence of JAG1 transcriptional induction. JAG1 modulation by specific siRNA, NOTCH-processing inhibition by either GSI or ectopic NUMB1, and siRNA-mediated HEY1 knockdown all inhibited p53 and p21WAF1/CIP1 induction. Conversely, forced expression of JAG1, activated NOTCH3, or HEY1 induced p53 and p21WAF1/CIP1. These results indicate that suppression of EWS-FLI1 reactivates NOTCH signaling in ESFT cells, resulting in p53-dependent cell cycle arrest. Our data link EWS-FLI1 to the NOTCH and p53 pathways and provide a plausible basis both for NOTCH tumor suppressor effects and oncogenesis of cancers that retain wild-type p53. PMID:18757425

  1. A Potential Role for Notch Signaling in the Pathogenesis and Regulation of Hemangiomas

    PubMed Central

    Wu, June K.; Kitajewski, Jan K.

    2013-01-01

    Hemangiomas are the most common benign tumor of infancy, yet its pathogenesis and the mechanisms governing proliferation and involution are not well understood. It is believed that hemangiomas arise out of clonal, abnormal hemangioma endothelial cells (HemECs). The underlying anomaly of the HemEC is not known, although studies have shown that vascular endothelial growth factor (VEGF) and VEGF signaling may influence HemECs. Moreover, there are numerous subtypes of hemangiomas, with differences in natural history, potential for morbidity, and prognosis, and little is known how this relates to HemEC. The Notch signaling pathway is a highly conserved pathway across species from worms to mammals. Notch signaling has been shown to play a role during embryogenesis in directing vascular patterning and development and arterial and venous cell fate determination. Postnatally, it has been implicated in tumor angiogenesis in multiple malignancies. Notch signaling triggers tumor angiogenesis at least in part to stimulation by VEGF, thus establishing that there is a cross talk between the VEGF and Notch pathways. Given the presence of VEGF and its receptors in hemangiomas and known VEGF-Notch cross talk in tumor angiogenesis, the authors hypothesize that Notch signaling may contribute to hemangioma proliferation and involution. Preliminary studies of resected hemangioma specimens by reverse transcription polymerase chain reaction (RT-PCR) show that all 4 Notch receptors and 2 Notch ligands, Jagged1 and Delta-like ligand 4, are expressed by hemangiomas. These findings support a role for Notch in hemangiomas, meriting further analysis of the functional relevance of Notch signaling in hemangiomas. PMID:19169152

  2. Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia.

    PubMed

    Takam Kamga, Paul; Bassi, Giulio; Cassaro, Adriana; Midolo, Martina; Di Trapani, Mariano; Gatti, Alessandro; Carusone, Roberta; Resci, Federica; Perbellini, Omar; Gottardi, Michele; Bonifacio, Massimiliano; Nwabo Kamdje, Armel Hervé; Ambrosetti, Achille; Krampera, Mauro

    2016-04-19

    Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB.These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML. PMID:26967055

  3. Activated Notch1 expression is associated with angiogenesis in cutaneous melanoma.

    PubMed

    Murtas, Daniela; Piras, Franca; Minerba, Luigi; Maxia, Cristina; Ferreli, Caterina; Demurtas, Paolo; Lai, Simone; Mura, Ester; Corrias, Michela; Sirigu, Paola; Perra, Maria Teresa

    2015-08-01

    An early event in melanocytic tumor growth is the upregulation of Notch signaling. When an active form of Notch1 is overexpressed in primary human melanocytes, it increases cell growth, survival and invasive properties, promoting melanoma progression. Recent evidence suggested that tumor initiation and growth are driven by a subset of tumor-initiating cells termed cancer stem cells. Notch1 plays a predominant role in the maintenance of melanoblasts, including melanocyte stem cells, by preventing initiation of apoptosis. Moreover, the importance of Notch1 in the regulation of tumor angiogenesis is supported by growing evidence in various cancers. Nestin has been widely used as a marker for melanocyte stem cells as well as an angiogenic marker to evaluate neovascularity of endothelial cells in tumors. To gain an insight into the impact of Notch1 activation on the maintenance of melanocyte stem cells and angiogenesis in melanoma, the expression levels of activated Notch1 and nestin were analyzed by immunohistochemistry in 114 primary cutaneous melanomas and 35 lymph node metastases. Activated Notch1 and nestin expression was also evaluated in four dysplastic melanocytic nevi. This study provides evidence that activated Notch1 is overexpressed in cutaneous melanoma, in tumor cells as well as in microvessel endothelium, and that it can promote tumor angiogenesis. Indeed, the overexpression of activated Notch1 in both tumor and vascular endothelial cells was significantly associated with microvascular density in melanoma samples. Thus, activated Notch1 inhibitors may provide a therapeutic strategy in the treatment of melanoma by blocking tumor-associated vascularization. PMID:25034654

  4. Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

    PubMed Central

    Kamga, Paul Takam; Bassi, Giulio; Cassaro, Adriana; Midolo, Martina; Di Trapani, Mariano; Gatti, Alessandro; Carusone, Roberta; Resci, Federica; Perbellini, Omar; Gottardi, Michele; Bonifacio, Massimiliano; Kamdje, Armel Hervé Nwabo; Ambrosetti, Achille; Krampera, Mauro

    2016-01-01

    Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB. These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML. PMID:26967055

  5. Lattice QCD for parallel computers

    NASA Astrophysics Data System (ADS)

    Quadling, Henley Sean

    Lattice QCD is an important tool in the investigation of Quantum Chromodynamics (QCD). This is particularly true at lower energies where traditional perturbative techniques fail, and where other non-perturbative theoretical efforts are not entirely satisfactory. Important features of QCD such as confinement and the masses of the low lying hadronic states have been demonstrated and calculated in lattice QCD simulations. In calculations such as these, non-lattice techniques in QCD have failed. However, despite the incredible advances in computer technology, a full solution of lattice QCD may still be in the too-distant future. Much effort is being expended in the search for ways to reduce the computational burden so that an adequate solution of lattice QCD is possible in the near future. There has been considerable progress in recent years, especially in the research of improved lattice actions. In this thesis, a new approach to lattice QCD algorithms is introduced, which results in very significant efficiency improvements. The new approach is explained in detail, evaluated and verified by comparing physics results with current lattice QCD simulations. The new sub-lattice layout methodology has been specifically designed for current and future hardware. Together with concurrent research into improved lattice actions and more efficient numerical algorithms, the very significant efficiency improvements demonstrated in this thesis can play an important role in allowing lattice QCD researchers access to much more realistic simulations. The techniques presented in this thesis also allow ambitious QCD simulations to be performed on cheap clusters of commodity computers.

  6. Toward lattice fractional vector calculus

    NASA Astrophysics Data System (ADS)

    Tarasov, Vasily E.

    2014-09-01

    An analog of fractional vector calculus for physical lattice models is suggested. We use an approach based on the models of three-dimensional lattices with long-range inter-particle interactions. The lattice analogs of fractional partial derivatives are represented by kernels of lattice long-range interactions, where the Fourier series transformations of these kernels have a power-law form with respect to wave vector components. In the continuum limit, these lattice partial derivatives give derivatives of non-integer order with respect to coordinates. In the three-dimensional description of the non-local continuum, the fractional differential operators have the form of fractional partial derivatives of the Riesz type. As examples of the applications of the suggested lattice fractional vector calculus, we give lattice models with long-range interactions for the fractional Maxwell equations of non-local continuous media and for the fractional generalization of the Mindlin and Aifantis continuum models of gradient elasticity.

  7. A Mechanical Lattice Aid for Crystallography Teaching.

    ERIC Educational Resources Information Center

    Amezcua-Lopez, J.; Cordero-Borboa, A. E.

    1988-01-01

    Introduces a 3-dimensional mechanical lattice with adjustable telescoping mechanisms. Discusses the crystalline state, the 14 Bravais lattices, operational principles of the mechanical lattice, construction methods, and demonstrations in classroom. Provides lattice diagrams, schemes of the lattice, and various pictures of the lattice. (YP)

  8. Anyonic braiding in optical lattices

    PubMed Central

    Zhang, Chuanwei; Scarola, V. W.; Tewari, Sumanta; Das Sarma, S.

    2007-01-01

    Topological quantum states of matter, both Abelian and non-Abelian, are characterized by excitations whose wavefunctions undergo nontrivial statistical transformations as one excitation is moved (braided) around another. Topological quantum computation proposes to use the topological protection and the braiding statistics of a non-Abelian topological state to perform quantum computation. The enormous technological prospect of topological quantum computation provides new motivation for experimentally observing a topological state. Here, we explicitly work out a realistic experimental scheme to create and braid the Abelian topological excitations in the Kitaev model built on a tunable robust system, a cold atom optical lattice. We also demonstrate how to detect the key feature of these excitations: their braiding statistics. Observation of this statistics would directly establish the existence of anyons, quantum particles that are neither fermions nor bosons. In addition to establishing topological matter, the experimental scheme we develop here can also be adapted to a non-Abelian topological state, supported by the same Kitaev model but in a different parameter regime, to eventually build topologically protected quantum gates. PMID:18000038

  9. Sharply notch cylindrical tension specimen for screening plane-strain fracture toughness. I - Influence of fundamental testing variables on notch strength. II Applications in aluminum alloy quality assurance of fracture toughness

    NASA Technical Reports Server (NTRS)

    Jones, M. H.; Bubsey, R. T.; Brown, W. F., Jr.; Bucci, R. J.; Collis, S. F.; Kohm, R. F.; Kaufman, J. G.

    1977-01-01

    A description is presented of studies which have been conducted to establish an improved technology base for a use of the sharply notched cylindrical specimen in quality assurance tests of aluminum alloy products. The results are presented of an investigation of fundamental variables associated with specimen preparation and testing, taking into account the influence of the notch root radius, the eccentricity of loading, the specimen diameter, and the notch depth on the sharp notch strength. Attention is given to the statistical procedures which are necessary to establish correlations between the sharp notch strength and the plane-strain fracture toughness for high-strength aluminum alloys.

  10. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept.

    PubMed

    Rutten, Julie W; Dauwerse, Hans G; Peters, Dorien J M; Goldfarb, Andrew; Venselaar, Hanka; Haffner, Christof; van Ommen, Gert-Jan B; Aartsma-Rus, Annemieke M; Lesnik Oberstein, Saskia A J

    2016-04-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, is a hereditary cerebral small vessel disease caused by characteristic cysteine altering missense mutations in theNOTCH3gene.NOTCH3mutations in CADASIL result in an uneven number of cysteine residues in one of the 34 epidermal growth factor like-repeat (EGFr) domains of the NOTCH3 protein. The consequence of an unpaired cysteine residue in an EGFr domain is an increased multimerization tendency of mutant NOTCH3, leading to toxic accumulation of the protein in the (cerebro)vasculature, and ultimately reduced cerebral blood flow, recurrent stroke and vascular dementia. There is no therapy to delay or alleviate symptoms in CADASIL. We hypothesized that exclusion of the mutant EGFr domain from NOTCH3 would abolish the detrimental effect of the unpaired cysteine and thus prevent toxic NOTCH3 accumulation and the negative cascade of events leading to CADASIL. To accomplish this NOTCH3 cysteine correction by EGFr domain exclusion, we used pre-mRNA antisense-mediated skipping of specificNOTCH3exons. Selection of these exons was achieved usingin silicostudies and based on the criterion that skipping of a particular exon or exon pair would modulate the protein in such a way that the mutant EGFr domain is eliminated, without otherwise corrupting NOTCH3 structure and function. Remarkably, we found that this strategy closely mimics evolutionary events, where the elimination and fusion of NOTCH EGFr domains led to the generation of four functional NOTCH homologues. We modelled a selection of exon skip strategies using cDNA constructs and show that the skip proteins retain normal protein processing, can bind ligand and be activated by ligand. We then determined the technical feasibility of targetedNOTCH3exon skipping, by designing antisense oligonucleotides targeting exons 2-3, 4-5 and 6, which together harbour the majority of distinct CADASIL-causing mutations. Transfection of

  11. Bruton's Tyrosine Kinase Synergizes with Notch2 to Govern Marginal Zone B Cells in Nonobese Diabetic Mice1,2

    PubMed Central

    Nyhoff, Lindsay E.; Steinberg, Hannah E.; Sullivan, Allison M.; Kendall, Peggy L.

    2015-01-01

    Expansion of autoimmune-prone marginal zone (MZ) B cells has been implicated in type 1 diabetes (T1D). To test disease contributions of MZ B cells in NOD mice, Notch2 haploinsufficiency (Notch2+/−) was introduced, but failed to eliminate the MZ, as it does in C57BL/6 mice. Notch2+/−/NOD have MZ B cell numbers similar to WT C57BL/6, yet still develop diabetes. To test whether BCR-signaling supports Notch2+/−/NOD MZ B cells, Bruton's tyrosine kinase (Btk)-deficiency was introduced. Surprisingly, MZ B cells failed to develop in Btk-deficient Notch2+/−/NOD mice. Expression of Notch2 and its transcriptional target, Hes5, were increased in NOD MZ B cells compared with C57BL/6 MZ B cells. Btk-deficiency reduced Notch2+/− signaling exclusively in NOD B cells, suggesting that BCR-signaling enhances Notch2 signaling in this autoimmune model. The role of BCR-signaling was further investigated using an anti-insulin transgenic BCR (125Tg). Anti-insulin B cells in 125Tg/Notch2+/−/NOD mice populate an enlarged MZ, suggesting that low level BCR signaling overcomes reliance on Notch2. Tracking clonotypes of anti-insulin B cells in H chain only VH125Tg/NOD mice showed that BTK-dependent selection into the MZ depends on strength of antigenic binding, while Notch2-mediated selection does not. Importantly, anti-insulin B cell numbers were reduced by Btk-deficiency, but not Notch2-haploinsufficiency. These studies show that: 1) Notch2-haploinsufficiency limits NOD MZ B cell expansion without preventing T1D, 2) BTK supports the Notch2 pathway in NOD MZ B cells, and 3) autoreactive NOD B cell survival relies on BTK more than Notch2, regardless of MZ location, which may have important implications for disease-intervention strategies. PMID:26034172

  12. Notch signaling enhances FcεRI-mediated cytokine production by mast cells through direct and indirect mechanisms.

    PubMed

    Nakano, Nobuhiro; Nishiyama, Chiharu; Yagita, Hideo; Hara, Mutsuko; Motomura, Yasutaka; Kubo, Masato; Okumura, Ko; Ogawa, Hideoki

    2015-05-01

    Th2-type cytokines and TNF-α secreted by activated mast cells upon cross-linking of FcεRI contribute to the development and maintenance of Th2 immunity to parasites and allergens. We have previously shown that cytokine secretion by mouse mast cells is enhanced by signaling through Notch receptors. In this study, we investigated the molecular mechanisms by which Notch signaling enhances mast cell cytokine production induced by FcεRI cross-linking. FcεRI-mediated production of cytokines, particularly IL-4, was significantly enhanced in mouse bone marrow-derived mast cells by priming with Notch ligands. Western blot analysis showed that Notch signaling augmented and prolonged FcεRI-mediated phosphorylation of MAPKs, mainly JNK and p38 MAPK, through suppression of the expression of SHIP-1, a master negative regulator of FcεRI signaling, resulting in the enhanced production of multiple cytokines. The enhancing effect of Notch ligand priming on multiple cytokine production was abolished by knockdown of Notch2, but not Notch1, and FcεRI-mediated production of multiple cytokines was enhanced by retroviral transduction with the intracellular domain of Notch2. However, only IL-4 production was enhanced by both Notch1 and Notch2. The enhancing effect of Notch signaling on IL-4 production was lost in bone marrow-derived mast cells from mice lacking conserved noncoding sequence 2, which is located at the distal 3' element of the Il4 gene locus and contains Notch effector RBP-J binding sites. These results indicate that Notch2 signaling indirectly enhances the FcεRI-mediated production of multiple cytokines, and both Notch1 and Notch2 signaling directly enhances IL-4 production through the noncoding sequence 2 enhancer of the Il4 gene. PMID:25821223

  13. The Prevalence of Notched Audiograms in a Cross-Sectional Study of 12,055 Railway Workers

    PubMed Central

    Skogstad, Marit; Johnsen, Torstein Seip; Engdahl, Bo; Tambs, Kristian

    2015-01-01

    Objective: Noise-induced hearing loss (NIHL) is one of the most reported occupational diseases internationally. The occurrence of audiometric notches is emphasized in both American and European guidelines for the diagnosis of NIHL. The aim of this study was to describe the prevalence of notched audiograms among railway personnel with and without noise exposure to better assess the usefulness of such notches in the diagnosis of NIHL. Design: The most recent audiogram from 1994 to 2011 of a total of 12,055 railway workers, age 20 to 65 years, was obtained from the medical records of the occupational health service of the Norwegian State Railways (NSB). The prevalences of three types of notched audiograms, Coles notch, notch index, and 4 kHz notch, were computed, in relation to age, sex, and occupational noise exposure. Results: Coles notch in either ear was found in 63% of the male railway maintenance workers, exposed to noise levels of 75 to 90 dB(A), compared with 53% of the non-noise exposed (<70 dB(A)) traffic controllers (p < 0.001). The corresponding figures for the 4 kHz notch were 31% versus 21% (p < 0.001). For the notch index, 61% of the exposed and 51% of the controls had a notched audiogram (p < 0.001). For female workers, the prevalence of audiometric notches was lower, and the differences between noise exposed and nonexposed was smaller than those in men. Increasing age led to an increased prevalence of notches. Conclusions: Audiometric notches commonly occur among both noise-exposed and those not exposed to noise in railway personnel. The usefulness of audiometric notches in the diagnosis of NIHL is therefore limited. PMID:25470371

  14. Lattice-induced nonadiabatic frequency shifts in optical lattice clocks

    SciTech Connect

    Beloy, K.

    2010-09-15

    We consider the frequency shift in optical lattice clocks which arises from the coupling of the electronic motion to the atomic motion within the lattice. For the simplest of three-dimensional lattice geometries this coupling is shown to affect only clocks based on blue-detuned lattices. We have estimated the size of this shift for the prospective strontium lattice clock operating at the 390-nm blue-detuned magic wavelength. The resulting fractional frequency shift is found to be on the order of 10{sup -18} and is largely overshadowed by the electric quadrupole shift. For lattice clocks based on more complex geometries or other atomic systems, this shift could potentially be a limiting factor in clock accuracy.

  15. An analysis of the load-bearing capacity of members of square cross section with a series of perpendicular notches

    NASA Astrophysics Data System (ADS)

    Miastkowski, Jozef; Szczebiot, Ryszard

    The authors analyze the load-bearing capacity of structural members with square cross sections which have been weakened on their perimeters by a series of perpendicular notches. The analysis is based on complete solutions for axisymmetric bars with perpendicular notches and estimates of load-bearing capacity obtained from kinematically acceptable failure mechanisms. A procedure for determining the optimal distance (spacing) between the notches in the case of bars weakened by a series of perpendicular notches is described. The practical value of the analysis presented was confirmed by the results of experiments conducted on aluminum alloy test pieces of square cross section for plastic working weakened by two peripheral perpendicular notches.

  16. Single identities for lattice theory and for weakly associative lattices

    SciTech Connect

    McCune, W.; Padmanabhan, R.

    1995-03-13

    We present a single identity for the variety of all lattices that is much simpler than those previously known to us. We also show that the variety of weakly associative lattices is one-based, and we present a generalized one-based theorem for subvarieties of weakly associative lattices that can be defined with absorption laws. The automated theorem-proving program OTTER was used in substantial way to obtain the results.

  17. RNA folding on the 3D triangular lattice

    PubMed Central

    2009-01-01

    Background Difficult problems in structural bioinformatics are often studied in simple exact models to gain insights and to derive general principles. Protein folding, for example, has long been studied in the lattice model. Recently, researchers have also begun to apply the lattice model to the study of RNA folding. Results We present a novel method for predicting RNA secondary structures with pseudoknots: first simulate the folding dynamics of the RNA sequence on the 3D triangular lattice, next extract and select a set of disjoint base pairs from the best lattice conformation found by the folding simulation. Experiments on sequences from PseudoBase show that our prediction method outperforms the HotKnot algorithm of Ren, Rastegari, Condon and Hoos, a leading method for RNA pseudoknot prediction. Our method for RNA secondary structure prediction can be adapted into an efficient reconstruction method that, given an RNA sequence and an associated secondary structure, finds a conformation of the sequence on the 3D triangular lattice that realizes the base pairs in the secondary structure. We implemented a suite of computer programs for the simulation and visualization of RNA folding on the 3D triangular lattice. These programs come with detailed documentation and are accessible from the companion website of this paper at http://www.cs.usu.edu/~mjiang/rna/DeltaIS/. Conclusion Folding simulation on the 3D triangular lattice is effective method for RNA secondary structure prediction and lattice conformation reconstruction. The visualization software for the lattice conformations of RNA structures is a valuable tool for the study of RNA folding and is a great pedagogic device. PMID:19891777

  18. Canonical Notch signaling plays an instructive role in auditory supporting cell development

    PubMed Central

    Campbell, Dean P.; Chrysostomou, Elena; Doetzlhofer, Angelika

    2016-01-01

    The auditory sensory epithelium, composed of mechano-sensory hair cells (HCs) and highly specialized glial-like supporting cells (SCs), is critical for our ability to detect sound. SCs provide structural and functional support to HCs and play an essential role in cochlear development, homeostasis and repair. Despite their importance, however, surprisingly little is known about the molecular mechanisms guiding SC differentiation. Here, we provide evidence that in addition to its well-characterized inhibitory function, canonical Notch signaling plays a positive, instructive role in the differentiation of SCs. Using γ-secretase inhibitor DAPT to acutely block canonical Notch signaling, we identified a cohort of Notch-regulated SC-specific genes, with diverse functions in cell signaling, cell differentiation, neuronal innervation and synaptogenesis. We validated the newly identified Notch-regulated genes in vivo using genetic gain (Emx2Cre/+; Rosa26N1ICD/+) and loss-of-function approaches (Emx2Cre/+; Rosa26DnMAML1/+). Furthermore, we demonstrate that Notch over-activation in the differentiating murine cochlea (Emx2Cre/+; Rosa26N1ICD/+) actively promotes a SC-specific gene expression program. Finally, we show that outer SCs –so called Deiters’ cells are selectively lost by prolonged reduction (Emx2Cre/+; Rosa26DnMAML1/+/+) or abolishment of canonical Notch signaling (Fgfr3-iCreER; Rbpj−/Δ), indicating a critical role for Notch signaling in Deiters’ cell development. PMID:26786414

  19. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells.

    PubMed

    Ponnurangam, Sivapriya; Dandawate, Prasad R; Dhar, Animesh; Tawfik, Ossama W; Parab, Rajashri R; Mishra, Prabhu Dutt; Ranadive, Prafull; Sharma, Rajiv; Mahajan, Girish; Umar, Shahid; Weir, Scott J; Sugumar, Aravind; Jensen, Roy A; Padhye, Subhash B; Balakrishnan, Arun; Anant, Shrikant; Subramaniam, Dharmalingam

    2016-01-19

    Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1-4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins. PMID:26673007

  20. Alterations in cellular metabolome after pharmacological inhibition of Notch in glioblastoma cells.

    PubMed

    Kahlert, Ulf D; Cheng, Menglin; Koch, Katharina; Marchionni, Luigi; Fan, Xing; Raabe, Eric H; Maciaczyk, Jarek; Glunde, Kristine; Eberhart, Charles G

    2016-03-01

    Notch signaling can promote tumorigenesis in the nervous system and plays important roles in stem-like cancer cells. However, little is known about how Notch inhibition might alter tumor metabolism, particularly in lesions arising in the brain. The gamma-secretase inhibitor MRK003 was used to treat glioblastoma neurospheres, and they were subdivided into sensitive and insensitive groups in terms of canonical Notch target response. Global metabolomes were then examined using proton magnetic resonance spectroscopy, and changes in intracellular concentration of various metabolites identified which correlate with Notch inhibition. Reductions in glutamate were verified by oxidation-based colorimetric assays. Interestingly, the alkylating chemotherapeutic agent temozolomide, the mTOR-inhibitor MLN0128, and the WNT inhibitor LGK974 did not reduce glutamate levels, suggesting that changes to this metabolite might reflect specific downstream effects of Notch blockade in gliomas rather than general sequelae of tumor growth inhibition. Global and targeted expression analyses revealed that multiple genes important in glutamate homeostasis, including glutaminase, are dysregulated after Notch inhibition. Treatment with an allosteric inhibitor of glutaminase, compound 968, could slow glioblastoma growth, and Notch inhibition may act at least in part by regulating glutaminase and glutamate. PMID:26422827

  1. Feasibility of a bilateral 4000–6000 Hz notch as a phenotype for genetic association analysis

    PubMed Central

    Phillips, Susan L.; Richter, Scott J.; Teglas, Sandra L.; Bhatt, Ishan S.; Morehouse, Robin C.; Hauser, Elizabeth R.; Henrich, Vincent C.

    2016-01-01

    Objective Noise-induced hearing loss (NIHL) is a worldwide health problem and a growing concern among young people. Although some people appear to be more susceptible to NIHL, genetic association studies lack a specific phenotype. We tested the feasibility of a bilateral 4000–6000 Hz audiometric notch as a phenotype for identifying genetic contributions to hearing loss in young adults. Design A case-control-control study was conducted to examine selected SNPs in 52 genes previously associated with hearing loss and/or expressed in the cochlea. A notch was defined as a minimum of a 15-dB drop at 4000–6000 Hz from the previous best threshold with a 5-dB ‘recovery’ at 8000 Hz. Study sample Participants were 252 individuals of European descent taken from a population of 640 young adults who are students of classical music. Participants were grouped as No-notch (NN), Unilateral Notch (UN), or Bilateral Notch (BN). Results The strongest evidence of a genetic association with the 4000–6000 Hz notch was a nonsynonymous SNP variant in the ESRR? gene (rs61742642:C>T, P386S). Carriers of the minor allele accounted for 26% of all bilateral losses. Conclusion This study indicates that the 4000–6000 Hz bilateral notch is a feasible phenotype for identifying genetic susceptibility to hearing loss. PMID:25938503

  2. Requirement of HDAC6 for activation of Notch1 by TGF-β1.

    PubMed

    Deskin, Brian; Lasky, Joseph; Zhuang, Yan; Shan, Bin

    2016-01-01

    TGF-β1 is enriched in the tumor microenvironment and acts as a key inducer of epithelial to mesenchymal transition (EMT) in lung cancer. The NOTCH signaling pathway is conserved across species and is an essential pathway for development, cell differentiation, and cancer biology. Dysregulation of Notch signaling is a common feature of non-small cell lung cancer (NSCLC) and is correlated with poor prognosis. Crosstalk exists between the NOTCH and TGF-β signaling pathways in EMT. Herein we report that histone deacetylase 6 (HDAC6) modulates TGF-β1-mediated activation of the Notch pathway. HDAC6, a primarily cytoplasmic deacetylase, mediates TGF-β1-induced EMT in human lung cancer cells. Inhibition of HDAC6 with a small molecule inhibitor, namely tubacin or with siRNA attenuated TGF-β1-induced Notch-1 signaling. We show that TGFβ-1-induced EMT is accompanied by rapid HDAC6-dependent deacetylation of heat shock protein 90 (HSP90). Consistently, inhibition of HSP90 with its small molecule inhibitor 17AAG attenuated expression of TGF-β1-induced Notch-1 target genes, HEY-1 and HES-1. These findings reveal a novel function of HDAC6 in EMT via mediating the TGF-β-Notch signaling cascade, and support HDAC6 as a key regulator of TGFβ-induced EMT in NSCLC. This work suggests that HDAC6 may be an attractive therapeutic target against tumor progression and metastasis. PMID:27499032

  3. The Notch Ligand Jagged1 as a Target for Anti-Tumor Therapy

    PubMed Central

    Li, Demin; Masiero, Massimo; Banham, Alison H.; Harris, Adrian L.

    2014-01-01

    The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signaling has been implicated in various aspects of cancer biology; as a consequence, pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better-defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1), is overexpressed in many cancer types, and plays an important role in several aspects of tumor biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumor growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis, and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumor microenvironment components such as tumor vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumor biology, and its potential as a therapeutic target. PMID:25309874

  4. Alterations in cellular metabolome after pharmacological inhibition of Notch in glioblastoma cells

    PubMed Central

    Kahlert, Ulf D.; Cheng, Menglin; Koch, Katharina; Marchionni, Luigi; Fan, Xing; Raabe, Eric H.; Maciaczyk, Jarek; Glunde, Kristine; Eberhart, Charles G.

    2016-01-01

    Notch signaling can promote tumorigenesis in the nervous system and plays important roles in stem-like cancer cells. However, little is known about how Notch inhibition might alter tumor metabolism, particularly in lesions arising in the brain. The gamma-secretase inhibitor MRK003 was used to treat glioblastoma neurospheres, and they were subdivided into sensitive and insensitive groups in terms of canonical Notch target response. Global metabolomes were then examined using proton magnetic resonance spectroscopy, and changes in intracellular concentration of various metabolites identified which correlate with Notch inhibition. Reductions in glutamate were verified by oxidation-based colorimetric assays. Interestingly, the alkylating chemotherapeutic agent temozolomide, the mTOR-inhibitor MLN0128, and the WNT inhibitor LGK974 did not reduce glutamate levels, suggesting that changes to this metabolite might reflect specific downstream effects of Notch blockade in gliomas rather than general sequelae of tumor growth inhibition. Global and targeted expression analyses revealed that multiple genes important in glutamate homeostasis, including glutaminase, are dysregulated after Notch inhibition. Treatment with an allosteric inhibitor of glutaminase, compound 968, could slow glioblastoma growth, and Notch inhibition may act at least in part by regulating glutaminase and glutamate. PMID:26422827

  5. Canonical Notch signaling plays an instructive role in auditory supporting cell development.

    PubMed

    Campbell, Dean P; Chrysostomou, Elena; Doetzlhofer, Angelika

    2016-01-01

    The auditory sensory epithelium, composed of mechano-sensory hair cells (HCs) and highly specialized glial-like supporting cells (SCs), is critical for our ability to detect sound. SCs provide structural and functional support to HCs and play an essential role in cochlear development, homeostasis and repair. Despite their importance, however, surprisingly little is known about the molecular mechanisms guiding SC differentiation. Here, we provide evidence that in addition to its well-characterized inhibitory function, canonical Notch signaling plays a positive, instructive role in the differentiation of SCs. Using γ-secretase inhibitor DAPT to acutely block canonical Notch signaling, we identified a cohort of Notch-regulated SC-specific genes, with diverse functions in cell signaling, cell differentiation, neuronal innervation and synaptogenesis. We validated the newly identified Notch-regulated genes in vivo using genetic gain (Emx2(Cre/+); Rosa26(N1ICD/+)) and loss-of-function approaches (Emx2(Cre/+); Rosa26(DnMAML1/+)). Furthermore, we demonstrate that Notch over-activation in the differentiating murine cochlea (Emx2(Cre/+); Rosa26(N1ICD/+)) actively promotes a SC-specific gene expression program. Finally, we show that outer SCs -so called Deiters' cells are selectively lost by prolonged reduction (Emx2(Cre/+); Rosa26(DnMAML1/+/+)) or abolishment of canonical Notch signaling (Fgfr3-iCreER; Rbpj(-/Δ)), indicating a critical role for Notch signaling in Deiters' cell development. PMID:26786414

  6. Epidermal Notch1 recruits RORγ+ group 3 innate lymphoid cells to orchestrate normal skin repair

    PubMed Central

    Li, Zhi; Hodgkinson, Tom; Gothard, Elizabeth J.; Boroumand, Soulmaz; Lamb, Rebecca; Cummins, Ian; Narang, Priyanka; Sawtell, Amy; Coles, Jenny; Leonov, German; Reboldi, Andrea; Buckley, Christopher D.; Cupedo, Tom; Siebel, Christian; Bayat, Ardeshir; Coles, Mark C.; Ambler, Carrie A.

    2016-01-01

    Notch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal. Epidermal Notch induces recruitment of immune cell subsets including RORγ+ ILC3s into wounded dermis; RORγ+ ILC3s are potent sources of IL17F in wounds and control immunological and epidermal cell responses. Mice deficient for RORγ+ ILC3s heal wounds poorly resulting from delayed epidermal proliferation and macrophage recruitment in a CCL3-dependent process. Notch1 upregulates TNFα and the ILC3 recruitment chemokines CCL20 and CXCL13. TNFα, as a Notch1 effector, directs ILC3 localization and rates of wound healing. Altogether these findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair. PMID:27099134

  7. Drosophila EHBP1 regulates Scabrous secretion during Notch-mediated lateral inhibition

    PubMed Central

    Giagtzoglou, Nikolaos; Li, Tongchao; Yamamoto, Shinya; Bellen, Hugo J.

    2013-01-01

    Summary Notch signaling is an evolutionarily conserved pathway that plays a central role in numerous developmental and disease processes. The versatility of the Notch pathway relies on the activity of context-dependent regulators. These include rab11, sec15, arp3 and Drosophila EHBP1 (dEHBP1), which control Notch signaling and cell fate acquisition in asymmetrically dividing mechanosensory lineages by regulating the trafficking of the ligand Delta. Here, we show that dEHBP1 also controls the specification of R8 photoreceptors, as its loss results in the emergence of supernumerary R8 photoreceptors. Given the requirements for Notch signaling during lateral inhibition, we propose that dEHBP1 regulates distinct aspects of Notch signaling in different developmental contexts. We show that dEHBP1 regulates the exocytosis of Scabrous, a positive regulator of Notch signaling. In conclusion, dEHBP1 provides developmental versatility of intercellular signaling by regulating the trafficking of distinct Notch signaling components. PMID:23788431

  8. Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy.

    PubMed

    Abravanel, Daniel L; Belka, George K; Pan, Tien-chi; Pant, Dhruv K; Collins, Meredith A; Sterner, Christopher J; Chodosh, Lewis A

    2015-06-01

    Breast cancer mortality is principally due to recurrent tumors that arise from a reservoir of residual tumor cells that survive therapy. Remarkably, breast cancers can recur after extended periods of clinical remission, implying that at least some residual tumor cells pass through a dormant phase prior to relapse. Nevertheless, the mechanisms that contribute to breast cancer recurrence are poorly understood. Using a mouse model of recurrent mammary tumorigenesis in combination with bioinformatics analyses of breast cancer patients, we have identified a role for Notch signaling in mammary tumor dormancy and recurrence. Specifically, we found that Notch signaling is acutely upregulated in tumor cells following HER2/neu pathway inhibition, that Notch signaling remains activated in a subset of dormant residual tumor cells that persist following HER2/neu downregulation, that activation of Notch signaling accelerates tumor recurrence, and that inhibition of Notch signaling by either genetic or pharmacological approaches impairs recurrence in mice. Consistent with these findings, meta-analysis of microarray data from over 4,000 breast cancer patients revealed that elevated Notch pathway activity is independently associated with an increased rate of recurrence. Together, these results implicate Notch signaling in tumor recurrence from dormant residual tumor cells and provide evidence that dormancy is a targetable stage of breast cancer progression. PMID:25961456

  9. The Vacuolar ATPase a2-subunit regulates Notch signaling in triple-negative breast cancer cells

    PubMed Central

    Pamarthy, Sahithi; Jaiswal, Mukesh K.; Kulshreshtha, Arpita; Katara, Gajendra K.; Gilman-Sachs, Alice; Beaman, Kenneth D.

    2015-01-01

    Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer with poor prognosis for which no targeted therapies are currently available. Notch signaling has been implicated in breast cancer but the factors that control Notch in TNBC are unknown. Because the Vacuolar ATPase has been shown to be important in breast cancer invasiveness, we investigated the role of a2-subunit isoform of Vacuolar ATPase (a2V) in regulating Notch signaling in TNBC. Confocal microscopy revealed that among all the ‘a’ subunit isoforms, a2V was uniquely expressed on the plasma membrane of breast cancer cells. Both a2V and NOTCH1 were elevated in TNBC tumors tissues and cell lines. a2V knockdown by siRNA as well as V-ATPase inhibition by Bafilomycin A1 (Baf A1) in TNBC cell lines enhanced Notch signaling by increasing the expression of Notch1 intracellular Domain (N1ICD). V-ATPase inhibition blocked NICD degradation by disrupting autophagy and lysosomal acidification as demonstrated by accumulation of LC3B and diminished expression of LAMP1 respectively. Importantly, treatment with Baf A1 or anti-a2V, a novel-neutralizing antibody against a2V hindered cell migration of TNBC cells. Our findings indicate that a2V regulates Notch signaling through its role in endolysosomal acidification and emerges as a potential target for TNBC. PMID:26418877

  10. Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair.

    PubMed

    Li, Zhi; Hodgkinson, Tom; Gothard, Elizabeth J; Boroumand, Soulmaz; Lamb, Rebecca; Cummins, Ian; Narang, Priyanka; Sawtell, Amy; Coles, Jenny; Leonov, German; Reboldi, Andrea; Buckley, Christopher D; Cupedo, Tom; Siebel, Christian; Bayat, Ardeshir; Coles, Mark C; Ambler, Carrie A

    2016-01-01

    Notch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal. Epidermal Notch induces recruitment of immune cell subsets including RORγ(+) ILC3s into wounded dermis; RORγ(+) ILC3s are potent sources of IL17F in wounds and control immunological and epidermal cell responses. Mice deficient for RORγ(+) ILC3s heal wounds poorly resulting from delayed epidermal proliferation and macrophage recruitment in a CCL3-dependent process. Notch1 upregulates TNFα and the ILC3 recruitment chemokines CCL20 and CXCL13. TNFα, as a Notch1 effector, directs ILC3 localization and rates of wound healing. Altogether these findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair. PMID:27099134

  11. Notch signaling in group 3 innate lymphoid cells modulates their plasticity.

    PubMed

    Chea, Sylvestre; Perchet, Thibaut; Petit, Maxime; Verrier, Thomas; Guy-Grand, Delphine; Banchi, Elena-Gaia; Vosshenrich, Christian A J; Di Santo, James P; Cumano, Ana; Golub, Rachel

    2016-01-01

    The Notch signaling pathway is conserved throughout evolution, and it controls various processes, including cell fate determination, differentiation, and proliferation. Innate lymphoid cells (ILCs) are lymphoid cells lacking antigen receptors that fulfill effector and regulatory functions in innate immunity and tissue remodeling. Type 3 ILCs (ILC3s) reinforce the epithelial barrier and maintain homeostasis with intestinal microbiota. We demonstrated that the population of natural cytotoxicity receptor-positive (NCR(+)) ILC3s in mice is composed of two subsets that have distinct developmental requirements. A major subset depended on the activation of Notch2 in NCR(-) ILC3 precursors in the lamina propria of the small intestine to stimulate expression of the genes encoding the transcription factors T-bet, RORγt, and aryl hydrocarbon receptor (AhR). Notch signaling contributed to the transition of NCR(-) cells into NCR(+) cells, the more proinflammatory subset, in a cell-autonomous manner. In the absence of Notch signaling, this subset of NCR(-) ILC3s did not acquire the gene expression profile of NCR(+) ILC3s. A second subset of NCR(+) ILC3s did not depend on Notch for their development or for increased transcription factor abundance; however, their production of cytokines and cell surface abundance of NCRs were decreased in the absence of Notch signaling. Together, our data suggest that Notch is a regulator of the plasticity of ILC3s by controlling NCR(+) cell fate. PMID:27141929

  12. Notch maintains Drosophila type II neuroblasts by suppressing expression of the Fez transcription factor Earmuff.

    PubMed

    Li, Xiaosu; Xie, Yonggang; Zhu, Sijun

    2016-07-15

    Notch signaling is crucial for maintaining neural stem cell (NSC) self-renewal and heterogeneity; however, the underlying mechanism is not well understood. In Drosophila, loss of Notch prematurely terminates the self-renewal of larval type II neuroblasts (NBs, the Drosophila NSCs) and transforms type II NBs into type I NBs. Here, we demonstrate that Notch maintains type II NBs by suppressing the activation of earmuff (erm) by Pointed P1 (PntP1). We show that loss of Notch or components of its canonical pathway leads to PntP1-dependent ectopic Erm expression in type II NBs. Knockdown of Erm significantly rescues the loss-of-Notch phenotypes, and misexpression of Erm phenocopies the loss of Notch. Ectopically expressed Erm promotes the transformation of type II NBs into type I NBs by inhibiting PntP1 function and expression in type II NBs. Our work not only elucidates a key mechanism of Notch-mediated maintenance of type II NB self-renewal and identity, but also reveals a novel function of Erm. PMID:27151950

  13. The Notch Intracellular Domain Has an RBPj-Independent Role during Mouse Hair Follicular Development.

    PubMed

    Turkoz, Mustafa; Townsend, R Reid; Kopan, Raphael

    2016-06-01

    Ligand-dependent activation, γ-secretase-processed cleavage, and recombining binding protein Jk (RBPj)-mediated downstream transcriptional activities of Notch receptors constitute the "canonical" Notch signaling pathway, which is essential for skin organogenesis. However, in Msx2-Cre mice, keratinocyte-specific deletion of the Rbpj gene in utero produced a significantly milder phenotype than either global Notch or γ-secretase loss. Herein, we investigated the underlying mechanisms for this apparent noncanonical signal using mouse genetics. We found no evidence that ligand back-signaling contributed to skin organogenesis. The perdurance of RBPj protein did not establish an epigenetic memory of a canonical signal in the youngest epidermal stem cells, and Notch targets were not derepressed. We provide evidence that γ-secretase-dependent but RBPj-independent Notch intracellular domain activity operating in the first hair follicles is responsible for a delay in follicular destruction, which results in lower serum thymic stromal lymphopoietin levels, milder B-cell lymphoproliferative disease, and improved survival in Msx2-Cre(+/tg);Rbpj(f/f) mice. Minimal amounts of the Notch intracellular domain were sufficient for rescue, which was not mediated by transcription, suggesting that the Notch intracellular domain is acting through a novel mechanism. PMID:26940862

  14. EGCG Attenuates Uric Acid-Induced Inflammatory and Oxidative Stress Responses by Medicating the NOTCH Pathway

    PubMed Central

    Xie, Hua; Sun, Jianqin; Chen, Yanqiu; Zong, Min; Li, Shijie; Wang, Yan

    2015-01-01

    Background. The aim of this study is to investigate whether (-)-epigallocatechin-3-gallate (EGCG) can prevent the UA-induced inflammatory effect of human umbilical vein endothelial cells (HUVEC) and the involved mechanisms in vitro. Methods. HUVEC were subjected to uric acid (UA) with or without EGCG treatment. RT-PCR and western blots were performed to determine the level of inflammation marker. The antioxidant activity was evaluated by measuring scavenged reactive oxygen species (ROS). Functional studies of the role of Notch-1 in HUVEC lines were performed using RNA interference analyses. Results. UA significantly increased the expressions of IL-6, ICAM-1, TNF-α, and MCP-1 and the production of ROS in HUVEC. Meanwhile, the expression of Notch-1 and its downstream effects significantly increased. Using siRNA, inhibition of Notch-1 signaling significantly impeded the expressions of inflammatory cytokines under UA treatment. Interestingly, EGCG suppressed the expressions of inflammatory cytokines and the generation of ROS. Western blot analysis of Notch-1 showed that EGCG significantly decreased the expressions of inflammatory cytokines through Notch-1 signaling pathways. Conclusions. In summary, our findings indicated that Notch-1 plays an important role in the UA-induced inflammatory response, and the downregulation of Notch-1 by EGCG could be an effective approach to decrease inflammation and oxidative stress induced by UA. PMID:26539255

  15. Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling.

    PubMed

    Gomez-Lamarca, Maria J; Snowdon, Laura A; Seib, Ekatarina; Klein, Thomas; Bray, Sarah J

    2015-07-20

    Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur. PMID:26169355

  16. Aberrant Notch signaling in glioblastoma stem cells contributes to tumor recurrence and invasion.

    PubMed

    Yu, Jian-Bo; Jiang, Hao; Zhan, Ren-Ya

    2016-08-01

    Upregulation of the Notch signaling pathway in cancer stem cells and side population (SP) cells has a major role in maintenance, self-renewal and chemoresistance. The present study isolated a cancer stem cell-like SP accounting for 4.1% of a glioblastoma cell population using a Hoechst 33342 dye exclusion assay. In this glioblastoma SP, the expression of of Notch1 signaling proteins Notch1 intracellular domain and Hes‑1 was markedly upregulated. Furthermore, knockdown of Notch1 by RNA interference significantly diminished the neurosphere formation ability, self‑renewal and chemoresistance of the SP cells. In addition, the expression of the stem‑cell surface genes Oct‑4, Sox2 and Nanog in SP cells was significantly reduced and the sensitivity to the SP cells to chemotherapeutics was enhanced following Notch1 knockdown. In conclusion, the results of the present study suggested that upregulation of Notch1 is involved in the chemotherapy resistance and tumor recurrence of glioblastoma. Hence, the development of novel anti‑cancer drugs targeting the Notch1 signaling pathway may be a promising strategy for curing glioblastoma. PMID:27315154

  17. Requirement of HDAC6 for activation of Notch1 by TGF-β1

    PubMed Central

    Deskin, Brian; Lasky, Joseph; Zhuang, Yan; Shan, Bin

    2016-01-01

    TGF-β1 is enriched in the tumor microenvironment and acts as a key inducer of epithelial to mesenchymal transition (EMT) in lung cancer. The NOTCH signaling pathway is conserved across species and is an essential pathway for development, cell differentiation, and cancer biology. Dysregulation of Notch signaling is a common feature of non-small cell lung cancer (NSCLC) and is correlated with poor prognosis. Crosstalk exists between the NOTCH and TGF-β signaling pathways in EMT. Herein we report that histone deacetylase 6 (HDAC6) modulates TGF-β1-mediated activation of the Notch pathway. HDAC6, a primarily cytoplasmic deacetylase, mediates TGF-β1-induced EMT in human lung cancer cells. Inhibition of HDAC6 with a small molecule inhibitor, namely tubacin or with siRNA attenuated TGF-β1-induced Notch-1 signaling. We show that TGFβ-1-induced EMT is accompanied by rapid HDAC6-dependent deacetylation of heat shock protein 90 (HSP90). Consistently, inhibition of HSP90 with its small molecule inhibitor 17AAG attenuated expression of TGF-β1-induced Notch-1 target genes, HEY-1 and HES-1. These findings reveal a novel function of HDAC6 in EMT via mediating the TGF-β-Notch signaling cascade, and support HDAC6 as a key regulator of TGFβ-induced EMT in NSCLC. This work suggests that HDAC6 may be an attractive therapeutic target against tumor progression and metastasis. PMID:27499032

  18. Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury.

    PubMed

    Sörensen-Zender, Inga; Rong, Song; Susnik, Nathan; Zender, Steffen; Pennekamp, Petra; Melk, Anette; Haller, Hermann; Schmitt, Roland

    2014-04-15

    The aging kidney has a diminished regenerative potential and an increased tendency to develop tubular atrophy and fibrosis after acute injury. In this study, we found that activation of tubular epithelial Notch1 signaling was prolonged in the aging kidney after ischemia/reperfusion (IR) damage. To analyze the consequences of sustained Notch activation, we generated mice with conditional inducible expression of Notch1 intracellular domain (NICD) in proximal tubules. NICD kidneys were analyzed 1 and 4 wk after renal IR. Conditional NICD expression was associated with aggravated tubular damage, a fibrotic phenotype, and the expression of cellular senescence markers p21 and p16(INK4a). In wild-type mice pharmacological inhibition of Notch using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) improved tubulo-interstitial damage and antagonized the prosenescent pathway activation after IR. In vitro, activation of Notch signaling with delta-like-ligand-4 caused prosenescent changes in tubular cells while inhibition with DAPT attenuated these changes. In conclusion, our data suggest that sustained epithelial Notch activation after IR might contribute to the inferior outcome of old kidneys after injury. Sustained epithelial activation of Notch is associated with a prosenescent phenotype and maladaptive repair. PMID:24573392

  19. Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling

    PubMed Central

    Gomez-Lamarca, Maria J.; Snowdon, Laura A.; Seib, Ekatarina; Klein, Thomas

    2015-01-01

    Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised. Strikingly, when the retromer component Vps26 was depleted at the same time, Notch no longer accumulated and instead was ectopically activated. Likewise, depletion of ESCRT-0 components Hrs or Stam in combination with Rme-8 also led to high levels of ectopic Notch activity. Together, these results highlight the importance of Rme-8 in coordinating normal endocytic recycling route and reveal that its absence predisposes toward conditions in which pathological Notch signaling can occur. PMID:26169355

  20. miR-935 suppresses gastric signet ring cell carcinoma tumorigenesis by targeting Notch1 expression.

    PubMed

    Yan, Chao; Yu, Jianchun; Kang, Weiming; Liu, Yuqin; Ma, Zhiqiang; Zhou, Li

    2016-01-29

    Gastric signet ring cell carcinoma (GSRCC) is a unique pathological type of gastric carcinoma that is extremely invasive and has a poor prognosis. Expression of microRNAs (miRNAs) has been closely linked to the carcinogenesis of gastric cancer and has been considered as a powerful prognostic marker. The function of miR-935 has never been reported in cancer before. We found, using microRNA array, that expression of miR-935 in GSRCC cell lines is lower than in non-GSRCC cell lines, and enhanced expression of miR-935 in GSRCC cell-lines inhibit cell proliferation, migration and invasion. We also identified Notch1 as a direct target of miR-935. Knockdown of Notch1 reduced proliferation, migration/invasion of GSRCC cells, and overexpression Notch1's activated form (Notch intracellular domain) could rescue miR-935's tumor suppressive effect on GSRCC. Expression of miR-935 was lower in gastric carcinoma tissue than in paired normal tissue samples, and lower in GSRCC than in non-GSRCC. Our results demonstrate the inverse correlation between the expression of miR-935 and Notch1 in gastric tissues. We conclude that miR-935 inhibits gastric carcinoma cell proliferation, migration and invasion by targeting Notch1, suggesting potential applications of the miR-935-Notch1 pathway in gastric cancer clinical diagnosis and therapeutics, especially in gastric signet ring cell carcinoma. PMID:26742429

  1. miRNA-34c regulates Notch signaling during bone development

    PubMed Central

    Bae, Yangjin; Yang, Tao; Zeng, Huan-Chang; Campeau, Philippe M.; Chen, Yuqing; Bertin, Terry; Dawson, Brian C.; Munivez, Elda; Tao, Jianning; Lee, Brendan H.

    2012-01-01

    During bone homeostasis, osteoblast and osteoclast differentiation is coupled and regulated by multiple signaling pathways and their downstream transcription factors. Here, we show that microRNA 34 (miR-34) is significantly induced by BMP2 during osteoblast differentiation. In vivo, osteoblast-specific gain of miR-34c in mice leads to an age-dependent osteoporosis due to the defective mineralization and proliferation of osteoblasts and increased osteoclastogenesis. In osteoblasts, miR-34c targets multiple components of the Notch signaling pathway, including Notch1, Notch2 and Jag1 in a direct manner, and influences osteoclast differentiation in a non-cell-autonomous fashion. Taken together, our results demonstrate that miR-34c is critical during osteoblastogenesis in part by regulating Notch signaling in bone homeostasis. Furthermore, miR-34c-mediated post-transcriptional regulation of Notch signaling in osteoblasts is one possible mechanism to modulate the proliferative effect of Notch in the committed osteoblast progenitors which may be important in the pathogenesis of osteosarcomas. Therefore, understanding the functional interaction of miR-34 and Notch signaling in normal bone development and in bone cancer could potentially lead to therapies modulating miR-34 signaling. PMID:22498974

  2. Transient inactivation of Notch signaling synchronizes differentiation of neural progenitor cells

    PubMed Central

    Nelson, Branden R.; Hartman, Byron H.; Georgi, Sean A.; Lan, Michael S.; Reh, Thomas A.

    2007-01-01

    Summary In the developing nervous system, the balance between proliferation and differentiation is critical to generate the appropriate numbers and types of neurons and glia. Notch signaling maintains the progenitor pool throughout this process. While many components of the Notch pathway have been identified, the downstream molecular events leading to neural differentiation are not well understood. We have taken advantage of a small molecule inhibitor, DAPT, to block Notch activity in retinal progenitor cells, and analyzed the resulting molecular and cellular changes over time. DAPT treatment causes a massive, coordinated differentiation of progenitors that produces cell types appropriate for their developmental stage. Transient exposure of retina to DAPT for specific time periods allowed us to define the period of Notch inactivation that is required for a permanent commitment to differentiate. Inactivation of Notch signaling revealed a cascade of proneural bHLH transcription factor gene expression that correlates with stages in progenitor cell differentiation. Microarray/QPCR analysis confirms the changes in Notch signaling components, and reveals new molecular targets for investigating neuronal differentiation. Thus, transient inactivation of Notch signaling synchronizes progenitor cell differentiation, and allows for a systematic analysis of key steps in this process. PMID:17280659

  3. Thermodynamics of lattice OCD

    SciTech Connect

    Matsuoka, H.

    1985-01-01

    The thermodynamic consequences of QCD are explored in the framework of lattice gauge theory. Attention is focused upon the nature of the chiral symmetry restoration transition at finite temperature and at finite baryon density, and possible strategies for identifying relevant thermodynamic phases are discussed. Some numerical results are presented on the chiral symmetry restoration in the SU(2) gauge theory at high baryon density. The results suggest that with T approx. = 110 MeV there is a second order restoration transition at the critical baryon density n/sub B//sup c/ approx. = 0.62 fm/sup -3/.

  4. Selective suppression of Notch1 inhibits proliferation of renal cell carcinoma cells through JNK/p38 pathway.

    PubMed

    Wu, Kerong; Hu, Linkun; Hou, Jianquan

    2016-05-01

    The present study was performed to explore the effects of Notch1 inhibition selectively by siRNA on the proliferation and cell cycle of renal carcinoma cells. Human renal carcinoma cell lines, 786-0 and Caki-1, were treated with Si-Notch1 or negative control (NC). RT-PCR and western blotting were used to confirm the efficiency of siRNA on Notch1 expression. MTT, cell cycle analysis, colony formation as well as migration and invasion assays were performed. The expression levels of p38 and SAPK/JNK were measured by western blotting. For both cell lines, as compared with the NC group, the cell growth was markedly reduced, and colony formation was restricted in the Si-Notch1‑treated group. After incubated with Si-Notch1 or NC for 48 h, Si-Notch1-treated cells arrested the cell cycle at G1/S phase. The Si-Notch1 group also had a reduced rate of migration as well as invasion. Moreover, we observed a reduction in p-SAPK/JNK and p-p38 in Si-Notch1 transfected cells. The present study indicated that Notch signaling is important in the tumorigenesis of renal cell carcinoma. Notch1 may be a potential therapeutic regimen towards renal cell carcinoma, and JNK/p38 may serve as an important molecular mechanism for Notch1-mediated carcinogenesis. PMID:26986634

  5. Notch1 is associated with the multidrug resistance of hypoxic osteosarcoma by regulating MRP1 gene expression.

    PubMed

    Li, C; Guo, D; Tang, B; Zhang, Y; Zhang, K; Nie, L

    2016-01-01

    Hypoxia and Notch signaling pathway are closely related and both participate in cell proliferation and drug resistance of tumors. However, the molecular mechanisms of hypoxia and Notch signaling pathway in cell proliferation and drug resistance of osteosarcoma (OS) remain unclear. In this study, to further evaluate the role of hypoxia and Notch1 on drug resistance of OS, we investigated the influence of inhibiting Notch1 pathway by Notch1 small interference RNA (siRNA) on human MG-63 OS cells in hypoxia. Our data showed that hypoxia promoted OS cell proliferation, induced the G0/G1-S-G2/M phase transition, and increased multidrug resistance of human OS cells. Western blot analysis suggested that hypoxia increased the expression of HIF-1α, Notch1, and multidrug resistance protein-1 (MRP1) in human OS cells. Notch1 siRNA inhibits proliferation and increases apoptosis of hypoxic OS cells. Finally, these hypoxic OS cells can be sensitized to multidrug treatment through inhibition of the Notch protein expression by siRNA. Repression of the Notch protein expression resulted in down-regulation of MRP1 protein. These data support the conclusion that Notch signaling is up-regulated in human OS cells under hypoxia and Notch1 may represent a viable target to overcome chemoresistant OS cells in a hypoxic niche by regulating MRP1 gene expression. PMID:27468877

  6. Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways

    SciTech Connect

    Talora, Claudio; Cialfi, Samantha; Segatto, Oreste; Morrone, Stefania; Kim Choi, John; Frati, Luigi; Paolo Dotto, Gian; Gulino, Alberto; Screpanti, Isabella . E-mail: isabella.screpanti@uniroma1.it

    2005-05-01

    Notch signaling plays a key role in cell-fate determination and differentiation in different organisms and cell types. Several reports suggest that Notch signaling may be involved in neoplastic transformation. However, in primary keratinocytes, Notch1 can function as a tumor suppressor. Similarly, in HPV-positive cervical cancer cells, constitutively active Notch1 signaling was found to cause growth suppression. Activated Notch1 in these cells represses viral E6/E7 expression through AP-1 down-modulation, resulting in increased p53 expression and a block of pRb hyperphosphorylation. Here we show that in cervical cancer cell lines in which Notch1 ability to repress AP-1 activity is impaired, Notch1-enforced expression elicits an alternative pathway leading to growth arrest. Indeed, activated Notch1 signaling suppresses activity of the helix-loop-helix transcription factor E47, via ERK1/2 activation, resulting in inhibition of cell cycle progression. Moreover, we found that RBP-J{kappa}-dependent Notch signaling is specifically repressed in cervical cancer cells and this repression could provide one such mechanism that needs to be activated for cervical carcinogenesis. Finally, we show that inhibition of endogenous Notch1 signaling, although results in a proliferative advantage, sensitizes cervical cancer cell lines to drug-induced apoptosis. Together, our results provide novel molecular insights into Notch1-dependent growth inhibitory effects, counteracting the transforming potential of HPV.

  7. NOTCH3 Is Induced in Cancer-Associated Fibroblasts and Promotes Angiogenesis in Oral Squamous Cell Carcinoma

    PubMed Central

    Kayamori, Kou; Katsube, Ken-ichi; Sakamoto, Kei; Ohyama, Yoshio; Hirai, Hideaki; Yukimori, Akane; Ohata, Yae; Akashi, Takumi; Saitoh, Masao; Harada, Kiyoshi; Harada, Hiroyuki; Yamaguchi, Akira

    2016-01-01

    Recent studies have shown that Notch signaling is involved in many types of cancers, including oral squamous cell carcinomas (OSCCs). However, the role of Notch signaling in the tumor microenvironment is not yet fully understood. In this study, we investigated the roles of NOTCH3 signaling in cancer associated fibroblasts (CAFs) in OSCCs. Immunohistochemical study of 93 human tongue OSCC cases indicated that about one third of OSCCs showed NOTCH3 expression in CAFs, and that this expression significantly correlated with tumor-size. In vitro study showed that OSCC cell lines, especially HO1-N-1 cells stimulated NOTCH3 expression in normal human dermal fibroblasts (NHDFs) through direct cell-to-cell contact. Immunohistochemical and morphometric analysis using human OSCC samples demonstrated that NOTCH3 expression in CAFs significantly correlated with micro-vessel density in cancer stroma. In vitro angiogenesis assays involving co-culture of NHDFs with HO1-N-1 and human umbilical endothelial cells (HUVECs), and NOTCH3 knockdown in NHDFs using siRNA, demonstrated that HO1-N-1 cells significantly promoted tube formation dependent on NOTCH3-expression in NHDFs. Moreover, NOTCH3 expression in CAFs was related to poor prognosis of the OSCC patients. This work provides a new insight into the role of Notch signaling in CAFs associated with tumor angiogenesis and the possibility of NOTCH3-targeted molecular therapy in OSCCs. PMID:27124156

  8. Notched bar Izod impact properties of zinc die castings

    SciTech Connect

    Schrems, K.K.; Dogan, O.N.; Goodwin, F.E.

    2007-03-01

    Notched bar Izod impact testing of zinc die cast Alloy 3, Alloy 5, ZA-8, and AcuZinc 5 was performed at five temperatures between -40\\mDC and room temperature in accordance with ASTM E23 for impact testing of metallic materials. A direct comparison between ASTM D256 for impact testing of plastics and ASTM E23 was performed using continuously cast zinc specimens of Alloy 5 and ZA-8 at -40\\mDC and room temperature. There are differences in sample sizes, impact velocity, and striker geometry between the two tests. Bulk zinc tested according to ASTM E23 resulted in higher impact energies at -40\\mDC and lower impact energies at room temperature then did the same alloys when tested according to ASTM D256.

  9. Notch-independent RBPJ controls angiogenesis in the adult heart

    PubMed Central

    Díaz-Trelles, Ramón; Scimia, Maria Cecilia; Bushway, Paul; Tran, Danh; Monosov, Anna; Monosov, Edward; Peterson, Kirk; Rentschler, Stacey; Cabrales, Pedro; Ruiz-Lozano, Pilar; Mercola, Mark

    2016-01-01

    Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury. PMID:27357444

  10. Unusual Morphological Alteration in Sigmoid Notch: An Insight Through CBCT.

    PubMed

    Gupta, Anjali; Kant, Sanchita; Phulambrikar, Tushar; Kode, Manasi; Singh, Siddharth Kumar

    2015-12-01

    The Temporomandibular Joint (TMJ) is a ginglymo-diarthrodial joint known to be the most complex joint in human body. Growth disturbances, owing to genetic influences or trauma during the intrauterine life or during early developmental age may lead to morphological and functional variations in the mandible resulting in developmental anomaly. We report a rare case of altered sigmoid notch morphology on the right side and condylar hypoplasia on the left side, not related to any clear pathological disorder. Cone Beam Computed Tomography (CBCT) was helpful in evaluating this case. This case of unknown aetiology was thoroughly examined; based on clinical and radiographic findings, we suggest that this case is of congenital origin. PMID:26816996

  11. Exceptionally tough and notch-insensitive magnetic hydrogels.

    PubMed

    Haider, Hussain; Yang, Can Hui; Zheng, Wen Jiang; Yang, Jian Hai; Wang, Mei Xiang; Yang, Sen; Zrínyi, Miklós; Osada, Yoshihito; Suo, Zhigang; Zhang, Qiqing; Zhou, Jinxiong; Chen, Yong Mei

    2015-11-14

    Most existing magnetic hydrogels are weak and brittle. The development of strong and tough magnetic hydrogels would extend their applications into uncultivated areas, such as in actuators for soft machines and guided catheters for magnetic navigation systems, which is still a big challenge. Here a facile and versatile approach to fabricating highly stretchable, exceptionally tough and notch-insensitive magnetic hydrogels, Fe(3)O(4)@Fe-alginate/polyacrylamide (PAAm), is developed, by dispersing alginate-coated Fe(3)O(4) nanoparticles into the interpenetrating polymer networks of alginate and PAAm, with hybrid physical and chemical crosslinks. A cantilever bending beam actuator as well as a proof-of-concept magnetically guided hydrogel catheter is demonstrated. The method proposed in this work can be integrated into other strong and tough magnetic hydrogels for the development of novel hydrogel nanocomposites with both desirable functionality and superior mechanical properties. PMID:26350404

  12. Morphological Examination of the Obturator Notch and Canal in Cervidae

    PubMed Central

    TAE, Hyun-Jin; PARK, Byung-Yong; KIM, In-Shik; AHN, Dongchoon

    2014-01-01

    ABSTRACT The purpose of this study was to investigate gross findings of the obturator notch (ON) and obturator canal (OC) in Cervidae. A total of 183 pelvic girdles from 26 species of deer were examined, and the obturator canal (OC) was classified into 4 types based on the degree of separation from the obturator foramen (OF). The deep ON was observed primarily in the subfamily Capreolinae (telemetacarpal deer). The small bony OC was frequently observed in Hydropotes inermis, Mazama gouazoubira and Ozotoceros bezoarticus. A canal without a tubercle or bony bridge structure was mainly observed in the subfamily Cervinae (plesiometacarpal deer). These results suggest that the deep ONs or the OCs separated by bony structures are more common in telemetacarpal rather than plesiometacarpal deer. PMID:24430657

  13. Fracture toughness of brittle materials determined with chevron notch specimens

    NASA Technical Reports Server (NTRS)

    Shannon, J. L., Jr.; Bubsey, R. T.; Pierce, W. S.; Munz, D.

    1981-01-01

    Short bar, short rod, and four-point-bend chevron-notch specimens were used to determine the plane strain fracture toughness of hot-pressed silicon nitride and sintered aluminum oxide brittle ceramics. The unique advantages of this specimen type are: (1) the production of a sharp natural crack during the early stage of test loading, so that no precracking is required, and (2) the load passes through a maximum at a constant, material-independent crack length-to-width ratio for a specific geometry, so that no post-test crack measurement is required. The plane strain fracture toughness is proportional to the maximum test load and functions of the specimen geometry and elastic compliance. Although results obtained for silicon nitride are in good mutual agreement and relatively free of geometry and size effects, aluminum oxide results were affected in both these respects by the rising crack growth resistance curve of the material.

  14. Unusual Morphological Alteration in Sigmoid Notch: An Insight Through CBCT

    PubMed Central

    Gupta, Anjali; Phulambrikar, Tushar; Kode, Manasi; Singh, Siddharth Kumar

    2015-01-01

    The Temporomandibular Joint (TMJ) is a ginglymo-diarthrodial joint known to be the most complex joint in human body. Growth disturbances, owing to genetic influences or trauma during the intrauterine life or during early developmental age may lead to morphological and functional variations in the mandible resulting in developmental anomaly. We report a rare case of altered sigmoid notch morphology on the right side and condylar hypoplasia on the left side, not related to any clear pathological disorder. Cone Beam Computed Tomography (CBCT) was helpful in evaluating this case. This case of unknown aetiology was thoroughly examined; based on clinical and radiographic findings, we suggest that this case is of congenital origin. PMID:26816996

  15. TNFα and Endothelial Cells Modulate Notch Signaling in the Bone Marrow Microenvironment during Inflammation

    PubMed Central

    Fernandez, Luis; Rodriguez, Sonia; Huang, Hui; Chora, Angelo; Mumaw, Christin; Cruz, Eugenia; Pollok, Karen; Cristina, Filipa; Price, Joanne E.; Ferkowicz, Michael J.; Scadden, David T.; Clauss, Matthias; Cardoso, Angelo A.; Carlesso, Nadia

    2009-01-01

    Objective Homeostasis of the hematopoietic compartment is challenged and maintained during conditions of stress by mechanisms that are poorly defined. To understand how the bone marrow (BM) microenvironment influences hematopoiesis, we explored the role of Notch signaling and bone marrow endothelial cells in providing microenvironmental cues to hematopoietic cells in the presence of inflammatory stimuli. Methods The human BM endothelial cell line BMEC and primary human BM endothelial cells were analyzed for expression of Notch ligands and the ability to expand hematopoietic progenitors in an in vitro co-culture system. In vivo experiments were carried out to identify modulation of Notch signaling in BM endothelial and hematopoietic cells in mice challenged with TNFα or LPS, or in Tie2-tmTNFα transgenic mice characterized by constitutive TNFα activation. Results BM endothelial cells were found to express Jagged ligands and to greatly support progenitor’s colony-forming ability. This effect was markedly decreased by Notch antagonists and augmented by increasing levels of Jagged2. Physiologic upregulation of Jagged2 expression on BMEC was observed upon TNFα activation. Injection of TNFα or LPS upregulated 3 to 4 fold Jagged2 expression on murine BM endothelial cells in vivo and resulted in increased Notch activation on murine hematopoietic stem/progenitor cells. Similarly, constitutive activation of endothelial cells in Tie2-tmTNFα mice was characterized by increased expression of Jagged2 and by augmented Notch activation on hematopoietic stem/progenitor cells. Conclusions Our results provide the first evidence that BM endothelial cells promote expansion of hematopoietic progenitor cells by a Notch-dependent mechanism and that TNFα and LPS can modulate the levels of Notch ligand expression and Notch activation in the bone marrow microenvironment in vivo. PMID:18439488

  16. Immunohistochemical expression of aberrant Notch-1 signaling in vitiligo: an implication for pathogenesis.

    PubMed

    Seleit, Iman; Bakry, Ola Ahmed; Abdou, Asmaa Gaber; Dawoud, Noha Mohammed

    2014-06-01

    The etiopathogenetic mechanisms leading to pigment loss in vitiligo are not fully understood. Notch signaling is required for development and maintenance of melanocyte lineage and acts as a key component among keratinocyte-melanocyte interactions. The current study aimed to investigate the possible role of Notch signaling and its effect on the whole melanocyte lineage in vitiligo and correlating it with the different clinicopathologic parameters. Using immunohistochemical technique, Notch-1 expression was evaluated in 50 lesional and 20 perilesional biopsies of patients with vitiligo in comparison with 20 normal skin biopsies as a control group. Lesional biopsies were stained with human melanoma black-45 and tyrosinase-related protein-2 to demonstrate the melanocyte lineage. Membranous and/or nuclear expression of Notch-1 was in favor of control and perilesional skin, whereas cytoplasmic expression appeared only in vitiliginous lesions (P < .05). Membranous and/or nuclear expression of Notch-1 was significantly associated with epidermal human melanoma black-45 positivity (P = .01) and percentage of expression in both epidermis (P = .02) and hair follicles (P = .03) of lesional skin. Cytoplasmic pattern of Notch-1 expression in epidermis was significantly found in lesions with white hair (P = .04) and in cases with marked keratinocyte vacuolization (P = .03). Segmental and acrofacial vitiligo were associated with mild to moderate Notch-1 intensity, whereas generalized vitiligo was associated with strong intensity of expression (P = .02). In conclusion, Notch-1 signaling is inactivated in vitiligo with consequent loss of epidermal and/or follicular active melanocytes. Aberrant Notch signaling in vitiliginous white hair and acral and segmental vitiligo may be the cause of their treatment resistance. PMID:24560443

  17. Withaferin A inhibits in vivo growth of breast cancer cells accelerated by Notch2 knockdown.

    PubMed

    Kim, Su-Hyeong; Hahm, Eun-Ryeong; Arlotti, Julie A; Samanta, Suman K; Moura, Michelle B; Thorne, Stephen H; Shuai, Yongli; Anderson, Carolyn J; White, Alexander G; Lokshin, Anna; Lee, Joomin; Singh, Shivendra V

    2016-05-01

    The present study offers novel insights into the molecular circuitry of accelerated in vivo tumor growth by Notch2 knockdown in triple-negative breast cancer (TNBC) cells. Therapeutic vulnerability of Notch2-altered growth to a small molecule (withaferin A, WA) is also demonstrated. MDA-MB-231 and SUM159 cells were used for the xenograft studies. A variety of technologies were deployed to elucidate the mechanisms underlying tumor growth augmentation by Notch2 knockdown and its reversal by WA, including Fluorescence Molecular Tomography for measurement of tumor angiogenesis in live mice, Seahorse Flux analyzer for ex vivo measurement of tumor metabolism, proteomics, and Luminex-based cytokine profiling. Stable knockdown of Notch2 resulted in accelerated in vivo tumor growth in both cells reflected by tumor volume and/or latency. For example, the wet tumor weight from mice bearing Notch2 knockdown MDA-MB-231 cells was about 7.1-fold higher compared with control (P < 0.0001). Accelerated tumor growth by Notch2 knockdown was highly sensitive to inhibition by a promising steroidal lactone (WA) derived from a medicinal plant. Molecular underpinnings for tumor growth intensification by Notch2 knockdown included compensatory increase in Notch1 activation, increased cellular proliferation and/or angiogenesis, and increased plasma or tumor levels of growth stimulatory cytokines. WA administration reversed many of these effects providing explanation for its remarkable anti-cancer efficacy. Notch2 functions as a tumor growth suppressor in TNBC and WA offers a novel therapeutic strategy for restoring this function. PMID:27097807

  18. Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia

    PubMed Central

    2012-01-01

    Background Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether NOTCH1 mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases. Methods T-ALL subtypes, status of SIL-TAL1 fusion, ectopic expression of TLX3, and mutations in FBXW7, KRAS, PTEN and NOTCH1 were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test. Results The frequencies of mutations were 43.5% for NOTCH1, while FBXW7, KRAS and PTEN exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of NOTCH1 mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between NOTCH1 mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. SIL-TAL1 was identified as an adverse prognostic factor. NOTCH1 mutation status was not associated with outcome, while the presence of NOTCH1 complex mutations (indels) were associated with a longer overall survival (p = 0.031) than point mutations. Conclusion NOTCH1 mutations alone or in combination with FBXW7 did not impact T-ALL prognosis. Nevertheless, complex NOTCH1 mutations appear to have a positive impact on OS and the SIL-TAL1 fusion was validated as a negative prognostic marker in our series of T-ALL. PMID:22225590

  19. Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.

    PubMed

    Ali, Syed A; Justilien, Verline; Jamieson, Lee; Murray, Nicole R; Fields, Alan P

    2016-03-14

    We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC. PMID:26977885

  20. Notch-mediated lateral inhibition regulates proneural wave propagation when combined with EGF-mediated reaction diffusion.

    PubMed

    Sato, Makoto; Yasugi, Tetsuo; Minami, Yoshiaki; Miura, Takashi; Nagayama, Masaharu

    2016-08-30

    Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt and pepper patterns during various developmental processes. However, how Notch signaling behaves in combination with other signaling systems remains elusive. The wave of differentiation in the Drosophila visual center or "proneural wave" accompanies Notch activity that is propagated without the formation of a salt and pepper pattern, implying that Notch does not form a feedback loop of lateral inhibition during this process. However, mathematical modeling and genetic analysis clearly showed that Notch-mediated lateral inhibition is implemented within the proneural wave. Because partial reduction in EGF signaling causes the formation of the salt and pepper pattern, it is most likely that EGF diffusion cancels salt and pepper pattern formation in silico and in vivo. Moreover, the combination of Notch-mediated lateral inhibition and EGF-mediated reaction diffusion enables a function of Notch signaling that regulates propagation of the wave of differentiation. PMID:27535937

  1. Notching and anterior beveling on fossil horse incisors: Indicators of domestication?

    NASA Astrophysics Data System (ADS)

    Rogers, Richard A.; Rogers, Laurine A.

    1988-01-01

    One of the lines of evidence cited for possible late Pleistocene human control of horses has been the presence of notching and anterior beveling on horse incisor teeth recovered from upper and middle Paleolithic sites in Europe. Similar forms of wear have been found on the incisor teeth of wild horses from early and middle Pleistocene deposits in North America. Notching appears partly due to malocclusion and chipping. The causes of beveling are less certain but may involve the eating of bark. Therefore, the presence of notching and anterior beveling on horse incisor teeth may not be a reliable indicator of human control.

  2. Effect of microstructure and notch root radius on fracture toughness of an aluminum metal matrix composite

    NASA Technical Reports Server (NTRS)

    Manoharan, M.; Lewandowski, J. J.

    1989-01-01

    Recent results on the effects of matrix aging condition (matrix temper) and notch root radius on the measured fracture toughness of a SiC particulate reinforced aluminum alloy are reviewed. Stress intensity factors at catastrophic fracture were obtained for both underaged and overaged composites reveal. The linear relation found between apparent fracture toughness and the square root of the notch root radius implies a linear dependence of the crack opening displacement on the notch root radius. The results suggest a strain controlled fracture process, and indicate that there are differences in the fracture micromechanisms of the two aging conditions.

  3. Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation

    PubMed Central

    2011-01-01

    Background Pancreas cancer is one of most aggressive human cancers with the survival rate for patients with metastatic pancreas cancer at 5-6 months. The poor survival demonstrates a clear need for better target identification, drug development and new therapeutic strategies. Recent discoveries have shown that the role for Notch pathway is important in both development and cancer. Its contribution to oncogenesis also involves crosstalks with other growth factor pathways, such as Akt and its modulator, PTEN. The mounting evidence supporting a role for Notch in cancer promotion and survival suggests that targeting this pathway alone or in combination with other therapeutics represents a promising therapeutic strategy. Results Using a pancreas cancer tissue microarray, we noted that Jagged1, Notch3 and Notch4 are overexpressed in pancreas tumors (26%, 84% and 31% respectively), whereas Notch1 is expressed in blood vessels. While there was no correlation between Notch receptor expression and survival, stage or tumor grade, Notch3 was associated with Jagged1 and EGFR expression, suggesting a unique relationship between Notch3 and Jagged1. Inhibition of the Notch pathway genetically and with gamma-secretase inhibitor (GSI) resulted in tumor suppression and enhanced cell death. The observed anti-tumor activity appeared to be through Akt and modulation of PTEN phosphorylation. We discovered that transcriptional regulation of RhoA by Notch is important for PTEN phosphorylation. Finally, the mTOR inhibitor Rapamycin enhanced the effect of GSI on RhoA expression, resulting in down regulation of phospho-Akt and increased in vitro tumor cytotoxity. Conclusions Notch pathway plays an important role in maintaining pancreas tumor phenotype. Targeting this pathway represents a reasonable strategy for the treatment of pancreas cancers. Notch modulates the Akt pathway through regulation of PTEN phosphorylation, an observation that has not been made previously. Furthermore, we

  4. Matrix fatigue crack development in a notched continuous fiber SCS-6/Ti-15-3 composite

    NASA Technical Reports Server (NTRS)

    Hillberry, B. M.; Johnson, W. S.

    1990-01-01

    In this study the extensive matrix fatigue cracking that has been observed in notched SCS-6/Ti-15-3 composites is investigated. Away from the notch a uniform spacing of the fatigue cracks develops. Closer to the notch, fiber-matrix debonding which occurs increases the crack spacing. Crack spacing and debond length determined from shear-lag cylinder models compare favorably with experimental observations. Scanning electron microscope (SEM) fractography showed that the principal fatigue crack initiation occurred around the zero degree fibers. Interface failure in the 90 degree plies does not lead to the development of the primary fatigue cracking.

  5. Matrix fatigue crack development in a notched continuous fiber SCS-6/Ti-15-3 composite

    NASA Technical Reports Server (NTRS)

    Hillberry, B. M.; Johnson, W. S.

    1990-01-01

    In this study the extensive matrix fatigue cracking that has been observed in notched SCS-6/Ti-15-3 composites is investigated. Away from the notch uniform spacing of the fatigue cracks develops. Closer to the notch, fiber-matrix debonding which occurs increases the crack spacing. Crack spacing and debond length determined from shear-lag cylinder models compare favorably with experimental observations. Scanning electron microscope (SEM) fractography showed that the principal fatigue crack initiation occurred around the zero degree fibers. Interface failure in the 90 degree plies does not lead to the development of the primary fatigue cracking.

  6. Tunable microwave photonic notch filter based on sliced broadband optical source.

    PubMed

    Yu, Yang; Li, Shangyuan; Zheng, Xiaoping; Zhang, Hanyi; Zhou, Bingkun

    2015-09-21

    A microwave photonic filter is demonstrated with both tunable center frequency and bandwidth. This filter is switchable from all-pass, bandpass to notch filter, and the notch filter is a result of the subtraction of a bandpass filter from an all-pass filter based on a balanced photodetector. The all-pass filter is achieved based on a single wavelength radio over fiber link, and the bandpass one is acquired by using the spectrum-sliced broadband optical source. Theoretical analysis and experimental results show that both the center frequency and the bandwidth of the notch filter can be widely tuned. PMID:26406636

  7. Ultra-high peak rejection notch microwave photonic filter using a single silicon microring resonator.

    PubMed

    Long, Yun; Wang, Jian

    2015-07-13

    We propose a simple scheme to realize ultra-high peak rejection notch microwave photonic filter (MPF) based on a single silicon microring resonator (MRR). Using the combination of a conventional phase modulator (PM), a tunable bandpass filter (TBF), and a silicon MRR to manipulate the phase and amplitude of optical sidebands resulting in a signal cancellation at the RF notch filter frequency, we experimentally demonstrate a notch MPF with an ultra-high peak rejection beyond 60 dB. The frequency tunability of the proposed ultra-high peak rejection MPF is also demonstrated in the experiment. PMID:26191836

  8. A macro-micromechanics analysis of a notched metal matrix composite

    NASA Technical Reports Server (NTRS)

    Bigelow, Catherine A.; Naik, Rajiv A.

    1992-01-01

    Macro- and micromechanics analysis were conducted to determine the matrix and fiber behaviors near the notch in a center-notched metal-matrix composite. In this approach, the macrolevel analysis models the entire notched specimen using a 3D finite element program that uses the vanishing-fiber-diameter model to simulate the elastic-plastic behavior of the matrix and the elastic behavior of the fiber. The microlevel behavior is analyzed using a discrete fiber-matrix model containing one fiber and the surrounding matrix. The viability of this analysis is demonstrated using results for a boron/aluminum monolayer.

  9. Three-dimensional vibrations of cylindrical elastic solids with V-notches and sharp radial cracks

    NASA Astrophysics Data System (ADS)

    McGee, O. G.; Kim, J. W.

    2010-02-01

    This paper provides free vibration data for cylindrical elastic solids, specifically thick circular plates and cylinders with V-notches and sharp radial cracks, for which no extensive previously published database is known to exist. Bending moment and shear force singularities are known to exist at the sharp reentrant corner of a thick V-notched plate under transverse vibratory motion, and three-dimensional (3-D) normal and transverse shear stresses are known to exist at the sharp reentrant terminus edge of a V-notched cylindrical elastic solid under 3-D free vibration. A theoretical analysis is done in this work utilizing a variational Ritz procedure including these essential singularity effects. The procedure incorporates a complete set of admissible algebraic-trigonometric polynomials in conjunction with an admissible set of " edge functions" that explicitly model the 3-D stress singularities which exist along a reentrant terminus edge (i.e., α>180°) of the V-notch. The first set of polynomials guarantees convergence to exact frequencies, as sufficient terms are retained. The second set of edge functions—in addition to representing the corner stress singularities—substantially accelerates the convergence of frequency solutions. This is demonstrated through extensive convergence studies that have been carried out by the investigators. Numerical analysis has been carried out and the results have been given for cylindrical elastic solids with various V-notch angles and depths. The relative depth of the V-notch is defined as (1- c/ a), and the notch angle is defined as (360°- α). For a very small notch angle (1° or less), the notch may be regarded as a "sharp radial crack." Accurate (four significant figure) frequencies are presented for a wide spectrum of notch angles (360°- α), depths (1- c/ a), and thickness ratios ( a/ h for plates and h/ a for cylinders). An extended database of frequencies for completely free thick sectorial, semi-circular, and

  10. Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human

    PubMed Central

    Kushwah, Rahul; Guezguez, Borhane; Lee, Jung Bok; Hopkins, Claudia I; Bhatia, Mickie

    2014-01-01

    The Notch signaling pathway is evolutionarily conserved across species and plays an important role in regulating cell differentiation, proliferation, and survival. It has been implicated in several different hematopoietic processes including early hematopoietic development as well as adult hematological malignancies in humans. This review focuses on recent developments in understanding the role of Notch signaling in the human hematopoietic system with an emphasis on hematopoietic initiation from human pluripotent stem cells and regulation within the bone marrow. Based on recent insights, we summarize potential strategies for treatment of human hematological malignancies toward the concept of targeting Notch signaling for fate regulation. PMID:25252682

  11. Distinct prognostic values of four-Notch-receptor mRNA expression in ovarian cancer.

    PubMed

    Zhou, Xinling; Teng, Lingling; Wang, Min

    2016-05-01

    Notch signaling pathway includes ligands and Notch receptors, which are frequently deregulated in several human malignancies including ovarian cancer. Aberrant activation of Notch signaling has been linked to ovarian carcinogenesis and progression. In the current study, we used the "Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information from a total of 1306 ovarian cancer patients were used to access the prognostic value of four Notch receptors in ovarian cancer patients. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Notch1 messenger RNA (mRNA) high expression was not found to be correlated to overall survival (OS) for all ovarian cancer, as well as in serous and endometrioid cancer patients followed for 20 years. However, Notch1 mRNA high expression is significantly associated with worsen OS in TP53 wild-type ovarian cancer patients, while it is significantly associated with better OS in TP53 mutation-type ovarian cancer patients. Notch2 mRNA high expression was found to be significantly correlated to worsen OS for all ovarian cancer patients, as well as in grade II ovarian cancer patients. Notch3 mRNA high expression was found to be significantly correlated to better OS for all ovarian cancer patients, but not in serous cancer patients and endometrioid cancer patients. Notch4 mRNA high expression was not found to be significantly correlated to OS for all ovarian cancer patients, serous cancer patients, and endometrioid cancer patients. These results indicate that there are distinct prognostic values of four Notch receptors in ovarian cancer. This information will be useful for better understanding of the heterogeneity and complexity in the molecular biology of ovarian cancer and for developing tools to more accurately predict their prognosis. Based on our results, Notch1 could be a potential drug target of TP53 wild-type ovarian cancer and Notch2 could be a potential drug

  12. A fractographic investigation of the influence of stacking sequence on the strength of notched laminated composites

    NASA Technical Reports Server (NTRS)

    Harris, Charles E.; Morris, Don H.

    1987-01-01

    The fracture behavior of T300/5208 CFRP laminate panels with 12 different combinations of ply orientation and stacking sequence is investigated experimentally, using optical microscopy, SEM, and X-ray radiography to characterize the notch-tip damage zones and fracture surfaces of center-cracked tension specimens subjected to tensile loading at constant crosshead displacement rate 20 micron/s. The results are presented graphically and analyzed in detail. Significant differences in notched strength are found for different ply fiber orientations and stacking sequences; the laminates with few major delaminations had a greater percentage of fracture due to broken fibers and also higher notched strength.

  13. Lattice polymer automata

    SciTech Connect

    Rasmussen, S. |; Smith, J.R. |

    1995-05-01

    We present a new style of molecular dynamics and self-assembly simulation, the Lattice Polymer Automaton (LPA). In the LPA all interactions, including electromagnetic forces, are decomposed and communicated via propagating particles, {open_quotes}photons.{close_quotes} The monomer-monomer bondforces, the molecular excluded volume forces, the longer range intermolecular forces, and the polymer-solvent interactions may all be modeled with propagating particles. The LPA approach differs significantly from both of the standard approaches, Monte Carlo lattice methods and Molecular Dynamics simulations. On the one hand, the LPA provides more realism than Monte Carlo methods, because it produces a time series of configurations of a single molecule, rather than a set of causally unrelated samples from a distribution of configurations. The LPA can therefore be used directly to study dynamical properties; one can in fact watch polymers move in real time. On the other hand, the LPA is fully discrete, and therefore much simpler than traditional Molecular Dynamics models, which are continuous and operate on much shorter time scales. Due to this simplicity it is possible to simulate longer real time periods, which should enable the study of molecular self-organization on workstations supercomputers are not needed.

  14. Ehrlichia chaffeensis TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival

    PubMed Central

    Lina, Taslima T.; Dunphy, Paige S.; Luo, Tian

    2016-01-01

    ABSTRACT Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP) effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD) occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40%) were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs) against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activa