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Sample records for adaptive lattice notch

  1. A gradient-adaptive lattice-based complex adaptive notch filter

    NASA Astrophysics Data System (ADS)

    Zhu, Rui; Yang, Feiran; Yang, Jun

    2016-12-01

    This paper presents a new complex adaptive notch filter to estimate and track the frequency of a complex sinusoidal signal. The gradient-adaptive lattice structure instead of the traditional gradient one is adopted to accelerate the convergence rate. It is proved that the proposed algorithm results in unbiased estimations by using the ordinary differential equation approach. The closed-form expressions for the steady-state mean square error and the upper bound of step size are also derived. Simulations are conducted to validate the theoretical analysis and demonstrate that the proposed method generates considerably better convergence rates and tracking properties than existing methods, particularly in low signal-to-noise ratio environments.

  2. Adaptive comb filtering for motion artifact reduction from PPG with a structure of adaptive lattice IIR notch filter.

    PubMed

    Lee, Boreom; Kee, Youngwook; Han, Jonghee; Yi, Won Jin

    2011-01-01

    Photoplethysmographic (PPG) signal can provide important information about cardiovascular and respiratory conditions of individuals in a hospital or daily life. However, PPG can be distorted by motion artifacts significantly. Therefore, the reduction of the effects of motion artifacts is very important procedure for monitoring cardio-respiratory system by PPG. There have been many adaptive techniques to reduce motion artifacts from PPG signal including normalized least mean squares (NLMS) method, recursive least squares (RLS) filter, and Kalman filter. In the present study, we propose the adaptive comb filter (ACF) for reducing the effects of motion artifacts from PPG signal. ACF with adaptive lattice infinite impulse response (IIR) notch filter (ALNF) successfully reduced the motion artifacts from the quasi-periodic PPG signal.

  3. Unbalance vibration suppression for AMBs system using adaptive notch filter

    NASA Astrophysics Data System (ADS)

    Chen, Qi; Liu, Gang; Han, Bangcheng

    2017-09-01

    The unbalance of rotor levitated by active magnetic bearings (AMBs) will cause synchronous vibration which greatly degrade the performance at high speeds in the rotating machinery. To suppress the unbalance vibration without angular velocity information, a novel modified adaptive notch filter (ANF) with phase shift in the AMBs system is presented in this study. Firstly, a 4-degree-of-freedom (DOF) radial unbalanced AMB rotor system is described and analyzed, and the solution of rotor vibration displacement is compared with the experimental data to verify the preciseness of the dynamic model. Then the principle and structure of the proposed notch filter used for the frequency estimation and online identification of synchronous component are presented. As well, the convergence property of the algorithm is investigated. In addition, the stability analysis of the closed-loop AMB system with the proposed ANF is conducted. Simulation and experiments on an AMB driveline system demonstrate the effectiveness and the adaptive characteristics of the proposed ANF on the elimination of synchronous controlled current in a widely operating speed range.

  4. Bimaterial lattices as thermal adapters and actuators

    NASA Astrophysics Data System (ADS)

    Toropova, Marina M.; Steeves, Craig A.

    2016-11-01

    The goal of this paper is to demonstrate how anisotropic biomaterial lattices can be used in thermal actuation. Compared to other lattices with tailored thermal expansion, the anisotropy of these bimaterial lattices makes them uniquely suitable for use as thermal actuators. Each individual cell, and hence lattices consisting of such cells, can be designed with widely different predetermined coefficients of thermal expansion (CTE) in different directions, enabling complex shape changes appropriate for actuation with either passive or active control. The lattices are composed of planar non-identical cells that each consist of a skewed hexagon surrounding an irregular triangle. The cells and all members of any cell are connected to each other by pins so that they have no rotational constraints and are able to expand or contract freely. In this case, the skew angles of the hexagon and the ratio of the CTEs of the two component materials determine the overall performance of the lattice. At its boundaries, the lattice is connected to substrates by pins and configured such that the CTE between two neighboring lattice vertices coincides with the CTE of the adjacent substrate. Provided the boundary behavior of the lattice is matched to the thermal properties of the substrates, temperature changes in the structure produce thermal strains without producing any corresponding stresses. Such lattices can be used in three different ways: as adaptive elements for stress-free connection of components with different CTEs; for fine tuning of structures; and as thermally driven actuators. In this paper, we demonstrate some concepts for lattice configurations that produce thermally-driven displacements that enable several actuators: a switch, a valve and tweezers.

  5. Adaptive filtering for the lattice Boltzmann method

    NASA Astrophysics Data System (ADS)

    Marié, Simon; Gloerfelt, Xavier

    2017-03-01

    In this study, a new selective filtering technique is proposed for the Lattice Boltzmann Method. This technique is based on an adaptive implementation of the selective filter coefficient σ. The proposed model makes the latter coefficient dependent on the shear stress in order to restrict the use of the spatial filtering technique in sheared stress region where numerical instabilities may occur. Different parameters are tested on 2D test-cases sensitive to numerical stability and on a 3D decaying Taylor-Green vortex. The results are compared to the classical static filtering technique and to the use of a standard subgrid-scale model and give significant improvements in particular for low-order filter consistent with the LBM stencil.

  6. A Novel Adaptive Frequency Estimation Algorithm Based on Interpolation FFT and Improved Adaptive Notch Filter

    NASA Astrophysics Data System (ADS)

    Shen, Ting-ao; Li, Hua-nan; Zhang, Qi-xin; Li, Ming

    2017-02-01

    The convergence rate and the continuous tracking precision are two main problems of the existing adaptive notch filter (ANF) for frequency tracking. To solve the problems, the frequency is detected by interpolation FFT at first, which aims to overcome the convergence rate of the ANF. Then, referring to the idea of negative feedback, an evaluation factor is designed to monitor the ANF parameters and realize continuously high frequency tracking accuracy. According to the principle, a novel adaptive frequency estimation algorithm based on interpolation FFT and improved ANF is put forward. Its basic idea, specific measures and implementation steps are described in detail. The proposed algorithm obtains a fast estimation of the signal frequency, higher accuracy and better universality qualities. Simulation results verified the superiority and validity of the proposed algorithm when compared with original algorithms.

  7. Progress in adaptive control of flexible spacecraft using lattice filters

    NASA Technical Reports Server (NTRS)

    Sundararajan, N.; Montgomery, R. C.

    1985-01-01

    This paper reviews the use of the least square lattice filter in adaptive control systems. Lattice filters have been used primarily in speech and signal processing, but they have utility in adaptive control because of their order-recursive nature. They are especially useful in dealing with structural dynamics systems wherein the order of a controller required to damp a vibration is variable depending on the number of modes significantly excited. Applications are presented for adaptive control of a flexible beam. Also, difficulties in the practical implementation of the lattice filter in adaptive control are discussed.

  8. Adaptive digital notch filter design on the unit circle for the removal of powerline noise from biomedical signals.

    PubMed

    Ferdjallah, M; Barr, R E

    1994-06-01

    This paper investigates adaptive digital notch filters for the elimination of powerline noise from biomedical signals. Since the distribution of the frequency variation of the powerline noise may or may not be centered at 60 Hz, three different adaptive digital notch filters are considered. For the first case, an adaptive FIR second-order digital notch filter is designed to track the center frequency variation. For the second case, the zeroes of an adaptive IIR second-order digital notch filter are fixed on the unit circle and the poles are adapted to find an optimum bandwidth to eliminate the noise to a pre-defined attenuation level. In the third case, both the poles and zeroes of the adaptive IIR second-order filter are adapted to track the center frequency variation within an optimum bandwidth. The adaptive process is considerably simplified by designing the notch filters by pole-zero placement on the unit circle using some suggested rules. A constrained least mean-squared (CLMS) algorithm is used for the adaptive process. To evaluate their performance, the three adaptive notch filters are applied to a powerline noise sample and to a noisy EEG as an illustration of a biomedical signal.

  9. [Research of adaptive notch filter based on QRD-LS algorithm for power line interference in ECG].

    PubMed

    Wang, Shuyan; Dong, Jian; Guan, Xin

    2008-10-01

    In this paper, an adaptive notch filter based on QRD-LS algorithm for power line interference in ECG is researched. It can automatically eliminate the power line interference in order to improve the signal-to-interference ratio. Furthermore, QLD-LS algorithm, which is recursive least-squares minimization using systolic arrays, is employed to adjust the weight vector. Compared with the adaptive notch filter based on LMS (least mean square) algorithm, it has good robustness. Simulation examples confirm the results. QRD-LS adaptive notch filter has better performance in comparison with LMS method.

  10. 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.

  11. Adaptive IIR-Notch Filter for RFI Suppression in a Radio Detection of Cosmic Rays

    NASA Astrophysics Data System (ADS)

    Szadkowski, Zbigniew

    2017-06-01

    Radio stations can observe radio signals caused by coherent emissions due to geomagnetic radiation and charge excess processes mainly in the frequency band from 30 to 80 MHz. This range is highly contaminated by human-made radio frequency interference (RFI). In order to improve the signal-to-noise ratio, RFI filters are used to suppress this contamination. Infinite impulse response (IIR)-notch filters operate with fixed parameters and suppress several narrow bands. IIR filters are generally potentially unstable due to feedbacks; however, they are much shorter and more power efficient than finite impulse response filters. We implemented an NIOS virtual processor calculating new set of IIR filter coefficients, which are reloaded dynamically on-the-fly. Spectrum analysis of the 30-80-MHz band can also be supported by the Altera IP Cores. The NIOS adjusts the new coefficients of the filter checking whether the poles are inside the unique complex radius (a condition of stability) as well as tuning the width of the notch filter. Practical implementation was tested in the laboratory with signal and pattern generators. Laboratory results are very promising. The IIR filter follows the drifting frequencies over very wide ranges (even 15 MHz for investigated range of 30-80 MHz), keeping a suppression factor on a very high level (≥10). The novelty of this paper is an introduction of the adaptive IIR-notch filter, which has not been used in any previous experiment.

  12. Load-Adapted Design of Generative Manufactured Lattice Structures

    NASA Astrophysics Data System (ADS)

    Reinhart, Gunther; Teufelhart, Stefan

    Additive layer manufacturing offers many opportunities for the production of lightweight components, because of the high geometrical freedom that can be realized in comparison to conventional manufacturing processes. This potential gets demonstrated at the example of a bending beam. Therefore, a topology optimization is performed as well as the use of periodically arranged lattice structures. The latter ones show the constraint, that shear forces in the struts reduce the stiffness of the lattice. To avoid this, the structure has to be adapted to the flux of force. This thesis is supported by studies on a torqueloaded shaft.

  13. 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.

  14. 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.

  15. Parameter testing for lattice filter based adaptive modal control systems

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

    For Large Space Structures (LSS), an adaptive control system is highly desirable. The present investigation is concerned with an 'indirect' adaptive control scheme wherein the system order, mode shapes, and modal amplitudes are estimated on-line using an identification scheme based on recursive, least-squares, lattice filters. Using the identified model parameters, a modal control law based on a pole-placement scheme with the objective of vibration suppression is employed. A method is presented for closed loop adaptive control of a flexible free-free beam. The adaptive control scheme consists of a two stage identification scheme working in series and a modal pole placement control scheme. The main conclusion from the current study is that the identified parameters cannot be directly used for controller design purposes.

  16. Parameter testing for lattice filter based adaptive modal control systems

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

    For Large Space Structures (LSS), an adaptive control system is highly desirable. The present investigation is concerned with an 'indirect' adaptive control scheme wherein the system order, mode shapes, and modal amplitudes are estimated on-line using an identification scheme based on recursive, least-squares, lattice filters. Using the identified model parameters, a modal control law based on a pole-placement scheme with the objective of vibration suppression is employed. A method is presented for closed loop adaptive control of a flexible free-free beam. The adaptive control scheme consists of a two stage identification scheme working in series and a modal pole placement control scheme. The main conclusion from the current study is that the identified parameters cannot be directly used for controller design purposes.

  17. Building block for an orthonormal-lattice-filter adaptive network

    NASA Astrophysics Data System (ADS)

    Gabriel, W. F.

    1980-07-01

    The recent algorithm for a multistage multichannel orthonormal lattice filter proposed by M. Aftab Alam is a welcome addition to the library of adaptive-processing algorithms and provides a flexible alternative to the conventional approach of an optimum Weiner filter. This algorithm is based on a Gram-Schmidt orthonormalization procedure which is similar to cascade adaptive processing techniques described in earlier works. One of the most desirable features of this type of processing network is that it can be implemented with simple one-stage orthogonal-filter building blocks which directly filter the input data samples. These building blocks are the major subject of this report, and a particular configuration is developed based on a modified version of the familiar Howells-Applebaum algorithm. It can be implemented in either analog or digital form, data storage is not required, it is unconditionally stable, speed of convergence is no longer a problem, and the design is simple. The performance characteristics of a complete orthogonal-lattice-filter network operating in the spacial domain were simulated for example cases of one, two, and three strong incoherent signal sources spaced within a beamwidth for a eight-element linear-array antenna. The adaptive spacial filter patterns and the transient responses demonstrate that the building block has sufficient transient-response speed and control to permit full use of the processing capabilities inherent in a Gram-Schmidt cascade network.

  18. Adaptation of the chevron-notch beam fracture toughness method to specimens harvested from diesel particulate filters

    DOE PAGES

    Wereszczak, Andrew; Jadaan, Osama; Modugno, Max; ...

    2017-01-18

    In this paper, the apparent fracture toughness of a porous cordierite ceramic was estimated using a large specimen whose geometry was inspired by the ASTM-C1421-standardized chevron-notch beam. In this paper, using the same combination of experiment and analysis used to develop the standardized chevron-notch test for small, monolithic ceramic bend bars, an apparent fracture toughness of 0.6 and 0.9 MPa√m were estimated for an unaged and aged cordierite diesel particulate filter structure, respectively. Finally, the effectiveness and simplicity of this adapted specimen geometry and test method lends itself to the evaluation of (macroscopic) apparent fracture toughness of an entire porous-ceramic,more » diesel particulate filter structure.« less

  19. 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.

  20. 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.

  1. Improvement of Accuracy for Continuous Mass Measurement in Checkweighers with an Adaptive Notch Filter

    NASA Astrophysics Data System (ADS)

    Umemoto, Toshitaka; Kamon, Morihito; Kagawa, Yoichiro

    As manufacturing processes are steadily automatized, quick and accurate mass measurement systems are in great demand. In this respect, recently, active belt conveyer ‘checkweigher’ is used by many enterprises. This system possesses a serious technical problem, in which three types of mechanical noises, that is, proper vibration, motor vibration, and belt pulley vibration, are included in detection signals. The noises should be removed to increase the accuracy. In the current mass measurement system, ‘moving average method’ is applied for the aim. However, it is not enough to realize the quick and accurate measurement. Very recently, we applied ‘frequency analysis method’ using the complex LMS algorithm for this problem. Only a signal in the stable time had to be used for real-time processing with this method. In this study, therefore, we decreased the moving average filters and increased the adjustment notch filters.

  2. 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.

  3. An adaptive variational Quasicontinuum methodology for lattice networks with localized damage

    NASA Astrophysics Data System (ADS)

    Rokoš, O.; Peerlings, R. H. J.; Zeman, J.; Beex, L. A. A.

    2017-10-01

    Lattice networks with dissipative interactions can be used to describe the mechanics of discrete meso-structures of materials such as 3D-printed structures and foams. This contribution deals with the crack initiation and propagation in such materials and focuses on an adaptive multiscale approach that captures the spatially evolving fracture. Lattice networks naturally incorporate non-locality, large deformations, and dissipative mechanisms taking place inside fracture zones. Because the physically relevant length scales are significantly larger than those of individual interactions, discrete models are computationally expensive. The Quasicontinuum (QC) method is a multiscale approach specifically constructed for discrete models. This method reduces the computational cost by fully resolving the underlying lattice only in regions of interest, while coarsening elsewhere. In this contribution, the (variational) QC is applied to damageable lattices for engineering-scale predictions. To deal with the spatially evolving fracture zone, an adaptive scheme is proposed. Implications induced by the adaptive procedure are discussed from the energy-consistency point of view, and theoretical considerations are demonstrated on two examples. The first one serves as a proof of concept, illustrates the consistency of the adaptive schemes, and presents errors in energies. The second one demonstrates the performance of the adaptive QC scheme for a more complex problem.

  4. A New Adaptive Structural Signature for Symbol Recognition by Using a Galois Lattice as a Classifier.

    PubMed

    Coustaty, M; Bertet, K; Visani, M; Ogier, J

    2011-08-01

    In this paper, we propose a new approach for symbol recognition using structural signatures and a Galois lattice as a classifier. The structural signatures are based on topological graphs computed from segments which are extracted from the symbol images by using an adapted Hough transform. These structural signatures-that can be seen as dynamic paths which carry high-level information-are robust toward various transformations. They are classified by using a Galois lattice as a classifier. The performance of the proposed approach is evaluated based on the GREC'03 symbol database, and the experimental results we obtain are encouraging.

  5. Adaptive control of a flexible beam using least square lattice filters

    NASA Technical Reports Server (NTRS)

    Sundararajan, N.; Montgomery, R. C.

    1983-01-01

    This paper presents an indirect adaptive control scheme for the control of flexible structures using recursive least square lattice filters. The identification scheme uses lattice filters which provide an on-line estimate of the number of modes, mode shapes and modal amplitudes. These modes are coupled and a transformation to decouple them in order to obtain the natural modes is presented. The decoupled modal amplitude time series are then used in an equation error identification scheme to identify the model parameters in an autoregressive moving average (ARMA) form. The control is based on modal pole placement scheme with the objective of vibration suppression. The control gains are calculated based on the identified ARMA parameters. Before using the identified parameters for control, detailed testing and validation procedures are carried out on the identified parameters. The full adaptive control scheme is demonstrated using the simulation for the 12 foot free-free beam apparatus at NASA Langley Research Center.

  6. Scapular Notching.

    PubMed

    Dare, David; Dines, Joshua S; Tebo, Collin; Edwards, T Bradley; Craig, Edward V; Dines, David M

    2016-01-01

    Developed in 1985, the Grammont-style reverse total shoulder arthroplasty offered a biomechanical advantage for the deltoid muscle as well as predictably reduced pain and improved shoulder function in rotator cuff-deficient shoulders. Despite favorable outcomes, reverse total shoulder arthroplasty is associated with a unique set of complications, one of which is scapular notching. Scapular notching is believed to be a result of mechanical impingement of the humeral component on the lateral scapular pillar. Although it appears that scapular notching progresses with time, its effect on implant survivorship and clinical outcomes is unknown. Factors associated with scapular notching are categorized into several groups, including patient-specific risk factors, surgical approach and technique, and prosthetic design. Surgical strategies to reduce the rate of scapular notching include inferior positioning of the glenosphere, inferior tilting of the glenosphere, and increasing the size of the glenosphere. A lateralized center of rotation and a decreased humeral shaft-neck angle also decrease the incidence of scapular notching. As the indications for reverse total shoulder arthroplasty expand, it is important for orthopaedic surgeons to understand the etiology and incidence, predictive factors, and clinical relevance of scapular notching as well as strategies to avoid it.

  7. Stomaching Notch

    PubMed Central

    Yin, Xiaolei; Karp, Jeffrey M

    2015-01-01

    The self-renewal and differentiation of tissue stem cells must be tightly controlled. Unrestrained self-renewal leads to over-proliferation of stem cells, which may cause tumor formation, while uncontrolled differentiation leads to depletion of the stem cell pool. In this issue of The EMBO Journal, Demitrack et al (2015) show that the Notch pathway is a key regulator of Lgr5 antral stem cell self-renewal and differentiation. Notch signaling controls the proliferation and differentiation of stem cells as well as gastric tissue growth, while uncontrolled Notch activity in stem cells leads to polyp formation. PMID:26358838

  8. Lattice reconfiguration and phononic band-gap adaptation via origami folding

    NASA Astrophysics Data System (ADS)

    Thota, M.; Li, S.; Wang, K. W.

    2017-02-01

    We introduce a framework of utilizing origami folding to redistribute the inclusions of a phononic structure to achieve significant phononic band-gap adaptation. Cylindrical inclusions are attached to the vertices of a Miura-Ori sheet, whose 1 degree-of-freedom rigid folding can enable fundamental reconfigurations in the underlying periodic architecture via switching between different Bravais lattice types. Such a reconfiguration can drastically change the wave propagation behavior in terms of band gap and provide a scalable and practical means for broadband wave tailoring.

  9. A piezo-shunted kirigami auxetic lattice for adaptive elastic wave filtering

    NASA Astrophysics Data System (ADS)

    Ouisse, Morvan; Collet, Manuel; Scarpa, Fabrizio

    2016-11-01

    Tailoring the dynamical behavior of wave-guide structures can provide an efficient and physically elegant approach for optimizing mechanical components with regards to vibroacoustic propagation. Architectured materials as pyramidal core kirigami cells combined with smart systems may represent a promising way to improve the vibroacoustic quality of structural components. This paper describes the design and modeling of a pyramidal core with auxetic (negative Poisson’s ratio) characteristics and distributed shunted piezoelectric patches that allow for wave propagation control. The core is produced using a kirigami technique, inspired by the cutting/folding processes of the ancient Japanese art. The kirigami structure has a pyramidal unit cell shape that creates an in-plane negative Poisson’s ratio macroscopic behavior. This structure exhibits in-plane elastic properties (Young’s and shear modulus) which are higher than the out-of-plane ones, and hence this lattice has very specific properties in terms of wave propagation that are investigated in this work. The short-circuited configuration is first analyzed, before using negative capacitance and resistance as a shunt which provides impressive band gaps in the low frequency range. All configurations are investigated by using a full analysis of the Brillouin zone, rendering possible the deep understanding of the dynamical properties of the smart lattice. The results are presented in terms of dispersion and directivity diagrams, and the smart lattice shows quite interesting properties for the adaptive filtering of elastic waves at low frequencies bandwidths.

  10. 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.

  11. 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.

  12. Notch filter

    NASA Technical Reports Server (NTRS)

    Shelton, G. B. (Inventor)

    1977-01-01

    A notch filter for the selective attenuation of a narrow band of frequencies out of a larger band was developed. A helical resonator is connected to an input circuit and an output circuit through discrete and equal capacitors, and a resistor is connected between the input and the output circuits.

  13. 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.

  14. Predictive wind turbine simulation with an adaptive lattice Boltzmann method for moving boundaries

    NASA Astrophysics Data System (ADS)

    Deiterding, Ralf; Wood, Stephen L.

    2016-09-01

    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 that are able to transport wakes without significant artificial decay over distances of several rotor diameters. We have developed 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 paper describes the employed computational techniques and presents validation simulations for the Mexnext benchmark experiments as well as simulations of the wake propagation in the Scaled Wind Farm Technology (SWIFT) array consisting of three Vestas V27 turbines in triangular arrangement.

  15. Nonlinear waves in lattice materials: Adaptively augmented directivity and functionality enhancement by modal mixing

    NASA Astrophysics Data System (ADS)

    Ganesh, R.; Gonella, S.

    2017-02-01

    The motive of this work is to understand the complex spatial characteristics of finite-amplitude elastic wave propagation in periodic structures and leverage the unique opportunities offered by nonlinearity to activate complementary functionalities and design adaptive spatial wave manipulators. The underlying assumption is that the magnitude of wave propagation is small with respect to the length scale of the structure under consideration, albeit large enough to elicit the effects of finite deformation. We demonstrate that the interplay of dispersion, nonlinearity and modal complexity involved in the generation and propagation of higher harmonics gives rise to secondary wave packets that feature multiple characteristics, one of which conforms to the dispersion relation of the corresponding linear structure. This provides an opportunity to engineer desired wave characteristics through a geometric and topological design of the unit cell, and results in the ability to activate complementary functionalities, typical of high frequency regimes, while operating at low frequencies of excitation - an effect seldom observed in linear periodic structures. The ability to design adaptive switches is demonstrated here using lattice configurations whose response is characterized by geometric and/or material nonlinearities.

  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. 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.

  18. Experimental Results: Detection and Tracking of Low SNR Sinusoids Using Real-Time LMS and RLS Lattice Adaptive Line Enhancers.

    DTIC Science & Technology

    1991-08-01

    DETECTION AND TRACKING OF LOW SNR SINUSOIDS USING REAL-TIMNE LMS AND RI S LATTIICE, ADAPTIVE LINE PR: SSWh ENHANCRS RE: 0300000liN 6 AIJTHCRISI WVl: D68...RESULTS: DETECTION AND TRACKING OF LOW SNR SINUSOIDS USING REAL-TIME LMS AND RLS LATTICE ADAPTIVE LINE ENHANCERS i f. Terence R. Albert, Hana Abusalem...obtained from a real-time custom hardware SNR sinusoids and filter parameters such as system using 32-bit IEEE floating point filter length, and adaption

  19. Finite-difference lattice Boltzmann method with a block-structured adaptive-mesh-refinement technique.

    PubMed

    Fakhari, Abbas; Lee, Taehun

    2014-03-01

    An adaptive-mesh-refinement (AMR) algorithm for the finite-difference lattice Boltzmann method (FDLBM) is presented in this study. The idea behind the proposed AMR is to remove the need for a tree-type data structure. Instead, pointer attributes are used to determine the neighbors of a certain block via appropriate adjustment of its children identifications. As a result, the memory and time required for tree traversal are completely eliminated, leaving us with an efficient algorithm that is easier to implement and use on parallel machines. To allow different mesh sizes at separate parts of the computational domain, the Eulerian formulation of the streaming process is invoked. As a result, there is no need for rescaling the distribution functions or using a temporal interpolation at the fine-coarse grid boundaries. The accuracy and efficiency of the proposed FDLBM AMR are extensively assessed by investigating a variety of vorticity-dominated flow fields, including Taylor-Green vortex flow, lid-driven cavity flow, thin shear layer flow, and the flow past a square cylinder.

  20. Finite-difference lattice Boltzmann method with a block-structured adaptive-mesh-refinement technique

    NASA Astrophysics Data System (ADS)

    Fakhari, Abbas; Lee, Taehun

    2014-03-01

    An adaptive-mesh-refinement (AMR) algorithm for the finite-difference lattice Boltzmann method (FDLBM) is presented in this study. The idea behind the proposed AMR is to remove the need for a tree-type data structure. Instead, pointer attributes are used to determine the neighbors of a certain block via appropriate adjustment of its children identifications. As a result, the memory and time required for tree traversal are completely eliminated, leaving us with an efficient algorithm that is easier to implement and use on parallel machines. To allow different mesh sizes at separate parts of the computational domain, the Eulerian formulation of the streaming process is invoked. As a result, there is no need for rescaling the distribution functions or using a temporal interpolation at the fine-coarse grid boundaries. The accuracy and efficiency of the proposed FDLBM AMR are extensively assessed by investigating a variety of vorticity-dominated flow fields, including Taylor-Green vortex flow, lid-driven cavity flow, thin shear layer flow, and the flow past a square cylinder.

  1. 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.

  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. A notch sweeter.

    PubMed

    Irvine, Kenneth D

    2008-01-25

    Notch is a key signaling protein mediating cell-fate decisions during development. In this issue, Acar et al. (2008) describe a new gene called rumi that is required for Notch signaling in Drosophila. This gene encodes an O-glucosyltransferase that attaches glucose sugars to serine residues in the multiple EGF domains of the extracellular region of Notch. This modification by Rumi likely influences Notch folding and trafficking.

  4. A novel algorithm for notch detection

    NASA Astrophysics Data System (ADS)

    Acosta, C.; Salazar, D.; Morales, D.

    2013-06-01

    It is common knowledge that DFM guidelines require revisions to design data. These guidelines impose the need for corrections inserted into areas within the design data flow. At times, this requires rather drastic modifications to the data, both during the layer derivation or DRC phase, and especially within the RET phase. For example, OPC. During such data transformations, several polygon geometry changes are introduced, which can substantially increase shot count, geometry complexity, and eventually conversion to mask writer machine formats. In this resulting complex data, it may happen that notches are found that do not significantly contribute to the final manufacturing results, but do in fact contribute to the complexity of the surrounding geometry, and are therefore undesirable. Additionally, there are cases in which the overall figure count can be reduced with minimum impact in the quality of the corrected data, if notches are detected and corrected. Case in point, there are other cases where data quality could be improved if specific valley notches are filled in, or peak notches are cut out. Such cases generally satisfy specific geometrical restrictions in order to be valid candidates for notch correction. Traditional notch detection has been done for rectilinear data (Manhattan-style) and only in axis-parallel directions. The traditional approaches employ dimensional measurement algorithms that measure edge distances along the outside of polygons. These approaches are in general adaptations, and therefore ill-fitted for generalized detection of notches with strange shapes and in strange rotations. This paper covers a novel algorithm developed for the CATS MRCC tool that finds both valley and/or peak notches that are candidates for removal. The algorithm is generalized and invariant to data rotation, so that it can find notches in data rotated in any angle. It includes parameters to control the dimensions of detected notches, as well as algorithm tolerances

  5. 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

  6. The QR-Decomposition Based Least-Squares Lattice Algorithm for Adaptive Filtering

    DTIC Science & Technology

    1990-07-01

    Copyright © Controller HMSO London 1990 THIS PAGE IS LEFT BLANI( INTENTIONALLY CONTENTS 1. INTRODUCION ...bring together the work of Lewis [9] and McWhiner[ 14]. Lewis began with the standard (covariance domain) multi-channel least squares lattice equations...decomposition. As the bulk of the calculation is exactly the computation of the reflection coefficients. Lewis pmoceeded no further with this re-formu

  7. Waveform frequency notching

    DOEpatents

    Doerry, Armin W.; Andrews, John

    2017-05-09

    The various technologies presented herein relate to incorporating one or more notches into a radar spectrum, whereby the notches relate to one or more frequencies for which no radar transmission is to occur. An instantaneous frequency is monitored and if the frequency is determined to be of a restricted frequency, then a radar signal can be modified. Modification can include replacing the signal with a signal having a different instantaneous amplitude, a different instantaneous phase, etc. The modification can occur in a WFS prior to a DAC, as well as prior to a sin ROM component and/or a cos ROM component. Further, the notch can be dithered to enable formation of a deep notch. The notch can also undergo signal transitioning to enable formation of a deep notch. The restricted frequencies can be stored in a LUT against which an instantaneous frequency can be compared.

  8. Adaptive multichannel sequential lattice prediction filtering method for ARMA spectrum estimation in subbands

    NASA Astrophysics Data System (ADS)

    Ozden, Mehmet Tahir

    2013-12-01

    A multichannel characterization for autoregressive moving average (ARMA) spectrum estimation in subbands is considered in this article. The fullband ARMA spectrum estimation can be realized in two-channels as a special form of this characterization. A complete orthogonalization of input multichannel data is accomplished using a modified form of sequential processing multichannel lattice stages. Matrix operations are avoided, only scalar operations are used, and a multichannel ARMA prediction filter with a highly modular and suitable structure for VLSI implementations is achieved. Lattice reflection coefficients for autoregressive (AR) and moving average (MA) parts are simultaneously computed. These coefficients are then converted to process parameters using a newly developed Levinson-Durbin type multichannel conversion algorithm. Hence, a novel method for spectrum estimation in subbands as well as in fullband is developed. The computational complexity is given in terms of model order parameters, and comparisons with the complexities of nonparametric methods are provided. In addition, the performance is visually and statistically compared against those of the nonparametric methods under both stationary and nonstationary conditions.

  9. 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.

  10. Notch-Nrf2 Axis: Regulation of Nrf2 Gene Expression and Cytoprotection by Notch Signaling

    PubMed Central

    Skoko, John J.; Chartoumpekis, Dionysios V.; Kimura, Shoko; Slocum, Stephen L.; Noda, Kentaro; Palliyaguru, Dushani L.; Fujimuro, Masahiro; Boley, Patricia A.; Tanaka, Yugo; Shigemura, Norihisa; Biswal, Shyam; Yamamoto, Masayuki; Kensler, Thomas W.

    2014-01-01

    The Notch signaling pathway enables regulation and control of development, differentiation, and homeostasis through cell-cell communication. Our investigation shows that Notch signaling directly activates the Nrf2 stress adaptive response pathway through recruitment of the Notch intracellular domain (NICD) transcriptosome to a conserved Rbpjκ site in the promoter of Nrf2. Stimulation of Notch signaling through Notch ligand expression in cells and by overexpression of the NICD in RosaNICD/−::AlbCre mice in vivo induces expression of Nrf2 and its target genes. Continuous and transient NICD expression in the liver produces a Notch-dependent cytoprotective response through direct transcriptional activation of Nrf2 signaling to rescue mice from acute acetaminophen toxicity. This response can be reversed upon genetic disruption of Nrf2. Morphological studies showed that the characteristic phenotype of high-density intrahepatic bile ducts and enlarged liver in RosaNICD/−::AlbCre mice could be at least partially reversed after Nrf2 disruption. Furthermore, the liver and bile duct phenotypes could be recapitulated with constitutive activation of Nrf2 signaling in Keap1F/F::AlbCre mice. It appears that Notch-to-Nrf2 signaling is another important determinant in liver development and function and promotes cell-cell cytoprotective signaling responses. PMID:24298019

  11. 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.

  12. Notch2 activation ameliorates nephrosis

    NASA Astrophysics Data System (ADS)

    Tanaka, Eriko; Asanuma, Katsuhiko; Kim, Eunhee; Sasaki, Yu; Trejo, Juan Alejandro Oliva; Seki, Takuto; Nonaka, Kanae; Asao, Rin; Nagai-Hosoe, Yoshiko; Akiba-Takagi, Miyuki; Hidaka, Teruo; Takagi, Masatoshi; Koyanagi, Akemi; Mizutani, Shuki; Yagita, Hideo; Tomino, Yasuhiko

    2014-02-01

    Activation of Notch1 and Notch2 has been recently implicated in human glomerular diseases. Here we show that Notch2 prevents podocyte loss and nephrosis. Administration of a Notch2 agonistic monoclonal antibody ameliorates proteinuria and glomerulosclerosis in a mouse model of nephrosis and focal segmental glomerulosclerosis. In vitro, the specific knockdown of Notch2 increases apoptosis in damaged podocytes, while Notch2 agonistic antibodies enhance activation of Akt and protect damaged podocytes from apoptosis. Treatment with triciribine, an inhibitor of Akt pathway, abolishes the protective effect of the Notch2 agonistic antibody. We find a positive linear correlation between the number of podocytes expressing activated Notch2 and the number of residual podocytes in human nephrotic specimens. Hence, specific activation of Notch2 rescues damaged podocytes and activating Notch2 may represent a novel clinical strategy for the amelioration of nephrosis and glomerulosclerosis.

  13. Building a biomedical tokenizer using the token lattice design pattern and the adapted Viterbi algorithm

    PubMed Central

    2011-01-01

    Background Tokenization is an important component of language processing yet there is no widely accepted tokenization method for English texts, including biomedical texts. Other than rule based techniques, tokenization in the biomedical domain has been regarded as a classification task. Biomedical classifier-based tokenizers either split or join textual objects through classification to form tokens. The idiosyncratic nature of each biomedical tokenizer’s output complicates adoption and reuse. Furthermore, biomedical tokenizers generally lack guidance on how to apply an existing tokenizer to a new domain (subdomain). We identify and complete a novel tokenizer design pattern and suggest a systematic approach to tokenizer creation. We implement a tokenizer based on our design pattern that combines regular expressions and machine learning. Our machine learning approach differs from the previous split-join classification approaches. We evaluate our approach against three other tokenizers on the task of tokenizing biomedical text. Results Medpost and our adapted Viterbi tokenizer performed best with a 92.9% and 92.4% accuracy respectively. Conclusions Our evaluation of our design pattern and guidelines supports our claim that the design pattern and guidelines are a viable approach to tokenizer construction (producing tokenizers matching leading custom-built tokenizers in a particular domain). Our evaluation also demonstrates that ambiguous tokenizations can be disambiguated through POS tagging. In doing so, POS tag sequences and training data have a significant impact on proper text tokenization. PMID:21658288

  14. A Block-Structured Adaptive Mesh Refinement Technique with a Finite-Difference-Based Lattice Boltzmann Method

    NASA Astrophysics Data System (ADS)

    Fakhari, Abbas; Lee, Taehun

    2013-11-01

    A novel adaptive mesh refinement (AMR) algorithm for the numerical solution of fluid flow problems is presented in this study. The proposed AMR algorithm can be used to solve partial differential equations including, but not limited to, the Navier-Stokes equations using an AMR technique. Here, the lattice Boltzmann method (LBM) is employed as a substitute of the nearly incompressible Navier-Stokes equations. Besides its simplicity, the proposed AMR algorithm is straightforward and yet efficient. The idea is to remove the need for a tree-type data structure by using the pointer attributes in a unique way, along with an appropriate adjustment of the child block's IDs, to determine the neighbors of a certain block. Thanks to the unique way of invoking pointers, there is no need to construct a quad-tree (in 2D) or oct-tree (in 3D) data structure for maintaining the connectivity data between different blocks. As a result, the memory and time required for tree traversal are completely eliminated, leaving us with a clean and efficient algorithm that is easier to implement and use on parallel machines. Several benchmark studies are carried out to assess the accuracy and efficiency of the proposed AMR-LBM, including lid-driven cavity flow, vortex shedding past a square cylinder, and Kelvin-Helmholtz instability for single-phase and multiphase fluids.

  15. 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

  16. Comparative Notched Box Plots.

    DTIC Science & Technology

    1983-06-01

    provides a 95.1% confidence interval. See Noether (1976, Table E). Furthermore, this notch is not necessarily sym- metric about the sample median as in...distribution of the sign test). ( Noether 1976, Chapter 12; Lehmann 1975, Chapter 4; Hollander and Wolfe 1972, Chapter 3.) Thus, exact rather than approximate...binomial with parameters n and .5, i.e., b(n, .5). We will refer to dx as the notch depth. Noether (1978, Table E) provides the d. values; otherwise, they

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. Inland notches micromorphology

    NASA Astrophysics Data System (ADS)

    Brook, Anna; Ben-Binyamin, Atzmon; Shtober-Zisu, Nurit

    2017-04-01

    Inland notches are well known phenomenon in Israel and can be found mostly along the mountainous backbone, developed in hard limestone or dolomite rocks within the Mediterranean climate zone and up to the desert fringe. LiDAR technology presents an opportunity to study the fine scale rock surface within the notch and its texture patterns. De-trending of the LiDAR reconstructed DEM to a local trend, surface roughness, was achieved by fitting a normalized surface to all measured ground points within the roughness neighborhood. Micro-topography plays an important role for modelling geomorphology dynamics, resulting in improved estimates for micro stream lines network and topographic erosion as well as mineral accumulation or deposition. Clearly, dissolution occurs whenever rock and solvent meet; thus water and moisture's crucial role in the decay of carbonate rocks results in texture and roughness variability. Study aims is to generate high resolution normalized DEM models using a terrestrial LiDAR, redefining the texture and roughness within the notch while assessing weathering processes caused by water. Plan curvature is the second derivative of slope taken perpendicular to its direction. It influences convergence and divergence of flow and it emphasizes the ridges and valleys across the surface. Concaved classified areas were tested against all planar curvature areas to distinguish them as unique areas based on their texture co-occurrence measures (GLCM). Overall negative curvature pixels show poor separability, in both TD and JM separation tests, while classes of curvature degree describe a positive trend showing medium and high concavity as unique areas. Study aims to link classified areas as the basic micro infrastructure for water flow, potential runoff flow and further accumulation of minerals. On the other hand, positive values of Plan curvature present the convexity of rock surface to imply diverging flow, thus describing the watershed line within the micro

  3. Lattice-adaptive kinetic Monte Carlo (LA-KMC) for simulating solute segregation/depletion at interfaces

    NASA Astrophysics Data System (ADS)

    Castin, N.; Fernandez, J. R.; Terentyev, D.; Malerba, L.; Pasianot, R. C.

    2014-06-01

    We propose a novel approach for simulating, with atomistic kinetic Monte Carlo, the segregation or depletion of solute atoms at interfaces, via transport by vacancies. Differently from classical lattice KMC, no assumption is made regarding the crystallographic structure. The model can thus potentially be applied to any type of interfaces, e.g. grain boundaries. Fully off-lattice KMC models were already proposed in the literature, but are rather demanding in CPU time, mainly because of the necessity to perform static relaxation several times at every step of the simulation, and to calculate migration energies between different metastable states. In our LA-KMC model, we aim at performing static relaxation only once per step at the most, and define possible transitions to other metastable states following a generic predefined procedure. The corresponding migration energies can then be calculated using artificial neural networks, trained to predict them as a function of a full description of the local atomic environment, in term of both the exact location in space of atoms and in term of their chemical nature. Our model is thus a compromise between fully off-lattice and fully on-lattice models: (a) The description of the system is not bound to strict assumptions, but is readapted automatically performing the minimum required amount of static relaxation; (b) The procedure to define transition events is not guaranteed to find all important transitions, and is thereby potentially disregarding some mechanisms of system evolution. This shortcoming is in fact classical to non-fully off-lattice models, but is in our case limited thanks to the application of relaxation at every step; (c) Computing time is largely reduced thanks to the use of neural network to calculate the migration energies. In this presentation, we show the premises of this novel approach, in the case of grain-boundaries for bcc Fe-Cr alloys.

  4. A hybrid wavelet-based adaptive immersed boundary finite-difference lattice Boltzmann method for two-dimensional fluid-structure interaction

    NASA Astrophysics Data System (ADS)

    Cui, Xiongwei; Yao, Xiongliang; Wang, Zhikai; Liu, Minghao

    2017-03-01

    A second generation wavelet-based adaptive finite-difference Lattice Boltzmann method (FD-LBM) is developed in this paper. In this approach, the adaptive wavelet collocation method (AWCM) is firstly, to the best of our knowledge, incorporated into the FD-LBM. According to the grid refinement criterion based on the wavelet amplitudes of density distribution functions, an adaptive sparse grid is generated by the omission and addition of collocation points. On the sparse grid, the finite differences are used to approximate the derivatives. To eliminate the special treatments in using the FD-based derivative approximation near boundaries, the immersed boundary method (IBM) is also introduced into FD-LBM. By using the adaptive technique, the adaptive code requires much less grid points as compared to the uniform-mesh code. As a consequence, the computational efficiency can be improved. To justify the proposed method, a series of test cases, including fixed boundary cases and moving boundary cases, are invested. A good agreement between the present results and the data in previous literatures is obtained, which demonstrates the accuracy and effectiveness of the present AWCM-IB-LBM.

  5. Notch Charge-Coupled Devices

    NASA Technical Reports Server (NTRS)

    Janesick, James

    1992-01-01

    Notch charge-coupled devices are imaging arrays of photodetectors designed to exhibit high charge-transfer efficiencies necessary for operation in ultra-large array, and less vulnerable to degradation by energetic protons, neutrons, and electrons. Main channel of horizontal register includes deep narrow inner channel (notch). Small packets of charge remain confined to notch. Larger packets spill into rest of channel; transferred in usual way. Degradation of charge-transfer efficiency by energetic particles reduced.

  6. Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis

    PubMed Central

    Gifford, Gail B; Demitrack, Elise S; Keeley, Theresa M; Tam, Andrew; La Cunza, Nilsa; Dedhia, Priya H; Spence, Jason R; Simeone, Diane M; Saotome, Ichiko; Louvi, Angeliki; Siebel, Christian W; Samuelson, Linda C

    2016-01-01

    Objective We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue. Design Mice were treated with the pan-Notch inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches. Organoids were established from mouse and human antral glands; growth and differentiation were measured after treatment with Notch inhibitors. Results Notch1 and Notch2 are the predominant Notch receptors expressed in mouse and human antral tissue and organoid cultures. Combined inhibition of Notch1 and Notch2 in adult mice led to decreased epithelial cell proliferation, including reduced proliferation of LGR5 stem cells, and increased apoptosis, similar to the response to global Notch inhibition with DBZ. Less pronounced effects were observed after inhibition of individual receptors. Notch pathway inhibition with DBZ or combined inhibition of Notch1 and Notch2 led to increased differentiation of all gastric antral lineages, with remodelling of cells to express secretory products normally associated with other regions of the GI tract, including intestine. Analysis of mouse and human organoids showed that Notch signalling through Notch1 and Notch2 is intrinsic to the epithelium and required for organoid growth. Conclusions Notch signalling is required to maintain gastric antral stem cells. Notch1 and Notch2 are the primary Notch receptors regulating epithelial cell homoeostasis in mouse and human stomach. PMID:26933171

  7. Notch as a tumour suppressor.

    PubMed

    Nowell, Craig S; Radtke, Freddy

    2017-03-01

    The Notch signalling cascade is an evolutionarily conserved pathway that has a crucial role in regulating development and homeostasis in various tissues. The cellular processes and events that it controls are diverse, and continued investigation over recent decades has revealed how the role of Notch signalling is multifaceted and highly context dependent. Consistent with the far-reaching impact that Notch has on development and homeostasis, aberrant activity of the pathway is also linked to the initiation and progression of several malignancies, and Notch can in fact be either oncogenic or tumour suppressive depending on the tissue and cellular context. The Notch pathway therefore represents an important target for therapeutic agents designed to treat many types of cancer. In this Review, we focus on the latest developments relating specifically to the tumour-suppressor activity of Notch signalling and discuss the potential mechanisms by which Notch can inhibit carcinogenesis in various tissues. Potential therapeutic strategies aimed at restoring or augmenting Notch-mediated tumour suppression will also be highlighted.

  8. 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

  9. Notch Signaling Inhibits Axon Regeneration

    PubMed Central

    Bejjani, Rachid El; Hammarlund, Marc

    2013-01-01

    Summary Many neurons have limited capacity to regenerate their axons after injury. Neurons in the mammalian CNS do not regenerate, and even neurons in the PNS often fail to regenerate to their former targets. This failure is likely due in part to pathways that actively restrict regeneration; however, only a few factors that limit regeneration are known. Here, using single-neuron analysis of regeneration in vivo, we show that Notch/lin-12 signaling inhibits the regeneration of mature C. elegans neurons. Notch signaling suppresses regeneration by acting autonomously in the injured cell to prevent growth cone formation. The metalloprotease and gamma-secretase cleavage events that lead to Notch activation during development are also required for its activity in regeneration. Furthermore, blocking Notch activation immediately after injury improves regeneration. Our results define a novel, post-developmental role for the Notch pathway as a repressor of axon regeneration in vivo. PMID:22284182

  10. 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.

  11. Jammed lattice sphere packings

    NASA Astrophysics Data System (ADS)

    Kallus, Yoav; Marcotte, Étienne; Torquato, Salvatore

    2013-12-01

    We generate and study an ensemble of isostatic jammed hard-sphere lattices. These lattices are obtained by compression of a periodic system with an adaptive unit cell containing a single sphere until the point of mechanical stability. We present detailed numerical data about the densities, pair correlations, force distributions, and structure factors of such lattices. We show that this model retains many of the crucial structural features of the classical hard-sphere model and propose it as a model for the jamming and glass transitions that enables exploration of much higher dimensions than are usually accessible.

  12. Role of Glycosylation of Notch in Development

    PubMed Central

    Takeuchi, Hideyuki; Haltiwanger, Robert S.

    2010-01-01

    The Notch pathway is one of the major signaling pathways required for proper development in metazoans. Notch activity is regulated at numerous levels, and increasing evidence reveals the importance of “protein glycosylation” (modification of Notch receptors with sugars) for its regulation. In this review we summarize the significance of the Notch pathway in development and the players responsible for its glycosylation, and then discuss the molecular mechanisms by which protein glycosylation may regulate Notch function. PMID:20226260

  13. Notch1 and notch2 have opposite effects on embryonal brain tumor growth.

    PubMed

    Fan, Xing; Mikolaenko, Irina; Elhassan, Ihab; Ni, Xingzhi; Wang, Yunyue; Ball, Douglas; Brat, Daniel J; Perry, Arie; Eberhart, Charles G

    2004-11-01

    The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P = 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.

  14. 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

  15. Adaptive Notch Filter Suppression of Bending Modes.

    DTIC Science & Technology

    1980-12-01

    December 1980 Author Y / V ’ SApproved by: / T v bThesis Advisor Second Reader Chairman, Department of El cal Engineering Dean of Science and...SIMULATION MODEL 99 C. SIMULATION CONDITIONS ------------ 99 D. SIMULATION RESULTS -- ------------- 102 i, oL5 [,, V . CONCLUSIONS AND RECOMMENDATIONS...mass in slug K@ Pitch autopilot attitude gain Kre Pitch autopilot rate gain V Vehicle velocity in ft/second Damping ratio , W Undamped natural frequency

  16. 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.

  17. Notch, lipids, and endothelial cells

    PubMed Central

    Briot, Anaïs; Bouloumié, Anne; Iruela-Arispe, M. Luisa

    2017-01-01

    Purpose of review Notch signaling is an evolutionary conserved pathway critical for cardiovascular development and angiogenesis. More recently, the contribution of Notch signaling to the homeostasis of the adult vasculature has emerged as an important novel paradigm, but much remains to be understood. Recent findings Recent findings shed light on the impact of Notch in vascular and immune responses to microenvironmental signals as well as on the onset of atherosclerosis. In the past year, studies in human and mice explored the role of Notch in the maintenance of a nonactivated endothelium. Novel pieces of evidence suggest that this pathway is sensitive to environmental factors, including inflammatory mediators and diet-derived by-products. Summary An emerging theme is the ability of Notch to respond to changes in the microenvironment, including glucose and lipid metabolites. In turn, alterations in Notch enable an important link between metabolism and transcriptional changes, thus this receptor appears to function as a metabolic sensor with direct implications to gene expression. PMID:27454451

  18. Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis.

    PubMed

    Gifford, Gail B; Demitrack, Elise S; Keeley, Theresa M; Tam, Andrew; La Cunza, Nilsa; Dedhia, Priya H; Spence, Jason R; Simeone, Diane M; Saotome, Ichiko; Louvi, Angeliki; Siebel, Christian W; Samuelson, Linda C

    2017-06-01

    We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue. Mice were treated with the pan-Notch inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches. Organoids were established from mouse and human antral glands; growth and differentiation were measured after treatment with Notch inhibitors. Notch1 and Notch2 are the predominant Notch receptors expressed in mouse and human antral tissue and organoid cultures. Combined inhibition of Notch1 and Notch2 in adult mice led to decreased epithelial cell proliferation, including reduced proliferation of LGR5 stem cells, and increased apoptosis, similar to the response to global Notch inhibition with DBZ. Less pronounced effects were observed after inhibition of individual receptors. Notch pathway inhibition with DBZ or combined inhibition of Notch1 and Notch2 led to increased differentiation of all gastric antral lineages, with remodelling of cells to express secretory products normally associated with other regions of the GI tract, including intestine. Analysis of mouse and human organoids showed that Notch signalling through Notch1 and Notch2 is intrinsic to the epithelium and required for organoid growth. Notch signalling is required to maintain gastric antral stem cells. Notch1 and Notch2 are the primary Notch receptors regulating epithelial cell homoeostasis in mouse and human stomach. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  19. NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus.

    PubMed

    Demitrack, Elise S; Gifford, Gail B; Keeley, Theresa M; Horita, Nobukatsu; Todisco, Andrea; Turgeon, D Kim; Siebel, Christian W; Samuelson, Linda C

    2017-02-01

    The Notch signaling pathway is known to regulate stem cells and epithelial cell homeostasis in gastrointestinal tissues; however, Notch function in the corpus region of the stomach is poorly understood. In this study we examined the consequences of Notch inhibition and activation on cellular proliferation and differentiation and defined the specific Notch receptors functioning in the mouse and human corpus. Notch pathway activity was observed in the mouse corpus epithelium, and gene expression analysis revealed NOTCH1 and NOTCH2 to be the predominant Notch receptors in both mouse and human. Global Notch inhibition for 5 days reduced progenitor cell proliferation in the mouse corpus, as well as in organoids derived from mouse and human corpus tissue. Proliferation effects were mediated through both NOTCH1 and NOTCH2 receptors, as demonstrated by targeting each receptor alone or in combination with Notch receptor inhibitory antibodies. Analysis of differentiation by marker expression showed no change to the major cell lineages; however, there was a modest increase in the number of transitional cells coexpressing markers of mucous neck and chief cells. In contrast to reduced proliferation after pathway inhibition, Notch activation in the adult stomach resulted in increased proliferation coupled with reduced differentiation. These findings suggest that NOTCH1 and NOTCH2 signaling promotes progenitor cell proliferation in the mouse and human gastric corpus, which is consistent with previously defined roles for Notch in promoting stem and progenitor cell proliferation in the intestine and antral stomach. Here we demonstrate that the Notch signaling pathway is essential for proliferation of stem cells in the mouse and human gastric corpus. We identify NOTCH1 and NOTCH2 as the predominant Notch receptors expressed in both mouse and human corpus and show that both receptors are required for corpus stem cell proliferation. We show that chronic Notch activation in corpus stem

  20. Analytical and experimental investigation of the notched strength of thick laminates with surface notches

    NASA Technical Reports Server (NTRS)

    Harris, Charles E.; Nottorf, Eric W.; Morris, Don H.

    1988-01-01

    Experimental and analytical investigations of the fracture of a graphite/epoxy laminate with part-through semielliptic surface notches have been conducted. Experimental values of notched strength were determined for a variety of notch aspect ratios and notch depths. Analytical predictions of laminate failure were obtained from three different models. The three models were equally successful in predicting the fracture of laminates with deep notches. The experimental results of laminates with shallow notches indicated more notch sensitivity (that is greater strength reduction) than did the analytical models.

  1. Notch Signaling: Piercing a Harness of Simplicity.

    PubMed

    Helbig, Christina; Amsen, Derk

    2015-11-17

    The Notch pathway is an attractive therapeutic target for treatment of cancer and T cell-mediated pathology, but Notch inhibition leads to many side effects. Pinnell et al. (2015) demonstrate that oncogenic functions can be separated biochemically from other functions of Notch, opening new options for more selective targeting of this pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. The Influence of Notches Under Static Stress

    NASA Technical Reports Server (NTRS)

    Matthaes, K

    1938-01-01

    From the described experiments it is seen that notches are a potential source of strength decrease even under static stress, which the designer must take into consideration. Section I is a general treatment of notch influence under the various types of stresses. Section II treats the influence of notches in thin sheet as is used in airplane construction.

  3. Social Security: The Notch Issue.

    DTIC Science & Technology

    1988-03-24

    changes to the benefit formula should be made and, if so, what form they should take. Notch May Affect It has been claimed that the notch affects...Another factor was a form of "bracket creep" due to the fixed wage brackets or bendpoints in the benefit formula. As an individual’s wages rose, so...Security Taxes; lBenefit Formula Differential, 96th Congress, ist ’,sion. Skpt. 27, 1979. 𔃼The form of the transition provisions was debated

  4. Necking and notch strengthening in metallic glass with symmetric sharp-and-deep notches.

    PubMed

    Sha, Z D; Pei, Q X; Liu, Z S; Zhang, Y W; Wang, T J

    2015-05-29

    Notched metallic glasses (MGs) have received much attention recently due to their intriguing mechanical properties compared to their unnotched counterparts, but so far no fundamental understanding of the correlation between failure behavior and notch depth/sharpness exists. Using molecular dynamics simulations, we report necking and large notch strengthening in MGs with symmetric sharp-and-deep notches. Our work reveals that the failure mode and strength of notched MGs are strongly dependent on the notch depth and notch sharpness. By increasing the notch depth and the notch sharpness, we observe a failure mode transition from shear banding to necking, and also a large notch strengthening. This necking is found to be caused by the combined effects of large stress gradient at the notch roots and the impingement and subsequent arrest of shear bands emanating from the notch roots. The present study not only shows the failure mode transition and the large notch strengthening in notched MGs, but also provides significant insights into the deformation and failure mechanisms of notched MGs that may offer new strategies for the design and engineering of MGs.

  5. Necking and notch strengthening in metallic glass with symmetric sharp-and-deep notches

    PubMed Central

    Sha, Z. D.; Pei, Q. X.; Liu, Z. S.; Zhang, Y. W.; Wang, T. J.

    2015-01-01

    Notched metallic glasses (MGs) have received much attention recently due to their intriguing mechanical properties compared to their unnotched counterparts, but so far no fundamental understanding of the correlation between failure behavior and notch depth/sharpness exists. Using molecular dynamics simulations, we report necking and large notch strengthening in MGs with symmetric sharp-and-deep notches. Our work reveals that the failure mode and strength of notched MGs are strongly dependent on the notch depth and notch sharpness. By increasing the notch depth and the notch sharpness, we observe a failure mode transition from shear banding to necking, and also a large notch strengthening. This necking is found to be caused by the combined effects of large stress gradient at the notch roots and the impingement and subsequent arrest of shear bands emanating from the notch roots. The present study not only shows the failure mode transition and the large notch strengthening in notched MGs, but also provides significant insights into the deformation and failure mechanisms of notched MGs that may offer new strategies for the design and engineering of MGs. PMID:26022224

  6. 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.

  7. Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain development.

    PubMed

    Irvin, D K; Zurcher, S D; Nguyen, T; Weinmaster, G; Kornblum, H I

    2001-07-23

    The Notch-DSL signaling system consists of multiple receptors and ligands, and plays many roles in development. The function of Notch receptors and ligands in mammalian brain, however, is poorly understood. In the current study, we examined the expression patterns for three receptors of this system, Notch1, 2, and 3, in late embryonic and postnatal rat brain by in situ hybridization. The three receptors have overlapping but different patterns of expression. Messenger RNA for all three proteins is found in postnatal central nervous system (CNS) germinal zones and, in early postnatal life, within numerous cells throughout the CNS. Within zones of cellular proliferation of the postnatal brain, Notch1 mRNA is found in both the subventricular and the ventricular germinal zones, whereas Notch2 and Notch3 mRNAs are more highly localized to the ventricular zones. Both Notch1 and Notch3 mRNAs are expressed along the inner aspect of the dentate gyrus, a site of adult neurogenesis. Notch2 mRNA is expressed in the external granule cell layer of the developing cerebellum. In several brain areas, Notch1 and Notch2 mRNAs are relatively concentrated in white matter, whereas Notch3 mRNA is not. Neurosphere cultures (which contain CNS stem cells), purified astrocyte cultures, and striatal neuron-enriched cultures express Notch1 mRNA. However, in these latter cultures, Notch1 mRNA is produced by nestin-containing cells, rather than by postmitotic neurons. Taken together, these results support multiple roles for Notch1, 2, and 3 receptor activation during CNS development, particularly during gliogenesis. Copyright 2001 Wiley-Liss, Inc.

  8. 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.

  9. Notch signaling in cerebrovascular diseases (Review)

    PubMed Central

    Cai, Zhiyou; Zhao, Bin; Deng, Yanqing; Shangguan, Shouqin; Zhou, Faming; Zhou, Wenqing; Li, Xiaoli; Li, Yanfeng; Chen, Guanghui

    2016-01-01

    The Notch signaling pathway is a crucial regulator of numerous fundamental cellular processes. Increasing evidence suggests that Notch signaling is involved in inflammation and oxidative stress, and thus in the progress of cerebrovascular diseases. In addition, Notch signaling in cerebrovascular diseases is associated with apoptosis, angiogenesis and the function of blood-brain barrier. Despite the contradictory results obtained to date as to whether Notch signaling is harmful or beneficial, the regulation of Notch signaling may provide a novel strategy for the treatment of cerebrovascular diseases. PMID:27574001

  10. Biaxial Fatigue Cracking from Notch

    DTIC Science & Technology

    2013-03-04

    UNCLASSIFIED UNCLASSIFIED NAVAL AIR WARFARE CENTER AIRCRAFT DIVISION PATUXENT RIVER, MARYLAND TECHNICAL REPORT REPORT NO... AIRCRAFT DIVISION PATUXENT RIVER, MARYLAND NAWCADPAX/TR-2013/32 4 March 2013 BIAXIAL FATIGUE CRACKING FROM NOTCH by Eun U. Lee...Materials Engineering Division Naval Air Warfare Center Aircraft Division NAWCADPAX/TR-2013/32 i REPORT DOCUMENTATION PAGE Form Approved OMB

  11. Notch Signaling in Bone Regeneration

    DTIC Science & Technology

    2011-10-01

    Notch delivery, a large animal model (e.g., sheep ) could be developed and tested in another 2 years. Within five years, we will have a product to...phenotype ( macrophage , endothelial cell, osteoblast, chondrocyte) using dual antibody labeling with antibodies for specific cell types. Additionally, we

  12. Turn It Down a Notch

    PubMed Central

    Carrieri, Francesca A.; Dale, Jacqueline Kim

    2017-01-01

    In the developing vertebrate embryo, segmentation initiates through the formation of repeated segments, or somites, on either side of the posterior neural tube along the anterior to posterior axis. The periodicity of somitogenesis is regulated by a molecular oscillator, the segmentation clock, driving cyclic gene expression in the unsegmented paraxial mesoderm, from which somites derive. Three signaling pathways underlie the molecular mechanism of the oscillator: Wnt, FGF, and Notch. In particular, Notch has been demonstrated to be an essential piece in the intricate somitogenesis regulation puzzle. Notch is required to synchronize oscillations between neighboring cells, and is moreover necessary for somite formation and clock gene oscillations. Following ligand activation, the Notch receptor is cleaved to liberate the active intracellular domain (NICD) and during somitogenesis NICD itself is produced and degraded in a cyclical manner, requiring tightly regulated, and coordinated turnover. It was recently shown that the pace of the segmentation clock is exquisitely sensitive to levels/stability of NICD. In this review, we focus on what is known about the mechanisms regulating NICD turnover, crucial to the activity of the pathway in all developmental contexts. To date, the regulation of NICD stability has been attributed to phosphorylation of the PEST domain which serves to recruit the SCF/Sel10/FBXW7 E3 ubiquitin ligase complex involved in NICD turnover. We will describe the pathophysiological relevance of NICD-FBXW7 interaction, whose defects have been linked to leukemia and a variety of solid cancers. PMID:28149836

  13. Anabolic actions of Notch on mature bone

    PubMed Central

    Liu, Peng; Ping, Yilin; Ma, Meng; Zhang, Demao; Liu, Connie; Zaidi, Samir; Gao, Song; Ji, Yaoting; Lou, Feng; Yu, Fanyuan; Lu, Ping; Stachnik, Agnes; Bai, Mingru; Wei, Chengguo; Zhang, Liaoran; Wang, Ke; Chen, Rong; New, Maria I.; Rowe, David W.; Yuen, Tony; Sun, Li; Zaidi, Mone

    2016-01-01

    Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response. PMID:27036007

  14. 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

  15. Conditional deletion of Notch1 and Notch2 genes in excitatory neurons of postnatal forebrain does not cause neurodegeneration or reduction of Notch mRNAs and proteins.

    PubMed

    Zheng, Jin; Watanabe, Hirotaka; Wines-Samuelson, Mary; Zhao, Huailong; Gridley, Thomas; Kopan, Raphael; Shen, Jie

    2012-06-08

    Activation of Notch signaling requires intramembranous cleavage by γ-secretase to release the intracellular domain. We previously demonstrated that presenilin and nicastrin, components of the γ-secretase complex, are required for neuronal survival in the adult cerebral cortex. Here we investigate whether Notch1 and/or Notch2 are functional targets of presenilin/γ-secretase in promoting survival of excitatory neurons in the adult cerebral cortex by generating Notch1, Notch2, and Notch1/Notch2 conditional knock-out (cKO) mice. Unexpectedly, we did not detect any neuronal degeneration in the adult cerebral cortex of these Notch cKO mice up to ∼2 years of age, whereas conditional inactivation of presenilin or nicastrin using the same αCaMKII-Cre transgenic mouse caused progressive, striking neuronal loss beginning at 4 months of age. More surprisingly, we failed to detect any reduction of Notch1 and Notch2 mRNAs and proteins in the cerebral cortex of Notch1 and Notch2 cKO mice, respectively, even though Cre-mediated genomic deletion of the floxed Notch1 and Notch2 exons clearly took place in the cerebral cortex of these cKO mice. Furthermore, introduction of Cre recombinase into primary cortical cultures prepared from postnatal floxed Notch1/Notch2 pups, where Notch1 and Notch2 are highly expressed, completely eliminated their expression, indicating that the floxed Notch1 and Notch2 alleles can be efficiently inactivated in the presence of Cre. Together, these results demonstrate that Notch1 and Notch2 are not involved in the age-related neurodegeneration caused by loss of presenilin or γ-secretase and suggest that there is no detectable expression of Notch1 and Notch2 in pyramidal neurons of the adult cerebral cortex.

  16. 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. © 2016 American Heart Association, Inc.

  17. 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.

  18. Phosphorylation-dependent regulation of Notch1 signaling: the fulcrum of Notch1 signaling.

    PubMed

    Lee, Hye-Jin; Kim, Mi-Yeon; Park, Hee-Sae

    2015-08-01

    Notch signaling plays a pivotal role in cell fate determination, cellular development, cellular self-renewal, tumor progression, and has been linked to developmental disorders and carcinogenesis. Notch1 is activated through interactions with the ligands of neighboring cells, and acts as a transcriptional activator in the nucleus. The Notch1 intracellular domain (Notch1-IC) regulates the expression of target genes related to tumor development and progression. The Notch1 protein undergoes modification after translation by posttranslational modification enzymes. Phosphorylation modification is critical for enzymatic activation, complex formation, degradation, and subcellular localization. According to the nuclear cycle, Notch1-IC is degraded by E3 ligase, FBW7 in the nucleus via phosphorylation-dependent degradation. Here, we summarize the Notch signaling pathway, and resolve to understand the role of phosphorylation in the regulation of Notch signaling as well as to understand its relation to cancer.

  19. The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo.

    PubMed

    Monet, Marie; Domenga, Valérie; Lemaire, Barbara; Souilhol, Céline; Langa, Francina; Babinet, Charles; Gridley, Thomas; Tournier-Lasserve, Elisabeth; Cohen-Tannoudji, Michel; Joutel, Anne

    2007-04-15

    Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy (CADASIL) is the most prominent known cause of inherited stroke and vascular dementia in human adult. The disease gene, NOTCH3, encodes a transmembrane receptor primarily expressed in arterial smooth muscle cells (SMC). Pathogenic mutations lead to an odd number of cysteine residues within the NOTCH3 extracellular domain (NOTCH3(ECD)), and are associated with progressive accumulation of NOTCH3(ECD) at the SMC plasma membrane. The murine homolog, Notch3, is dispensable for viability but required post-natally for the elaboration and maintenance of arteries. How CADASIL-associated mutations impact NOTCH3 function remains a fundamental, yet unresolved issue. Particularly, whether NOTCH3(ECD) accumulation may titrate the ligand and inhibit the normal pathway is unknown. Herein, using genetic analyses in the mouse, we assessed the functional significance of an archetypal CADASIL-associated mutation (R90C), in vivo, in brain arteries. We show that transgenic mouse lines expressing either the wild-type human NOTCH3 or the mutant R90C human NOTCH3, at comparable and physiological levels, can rescue the arterial defects of Notch3-/- mice to similar degrees. In vivo assessment of NOTCH3/RBP-Jk activity provides evidence that the mutant NOTCH3 protein exhibits normal level of activity in brain arteries. Remarkably, the mutant NOTCH3 protein remains functional and does not exhibit dominant negative interfering activity, even when NOTCH3(ECD) accumulates. Collectively, these data suggest a model that invokes novel pathogenic roles for the mutant NOTCH3 protein rather than compromised NOTCH3 function as the primary determinant of the CADASIL arteriopathy.

  20. Notch in Pathological Angiogenesis and Lymphangiogenesis

    DTIC Science & Technology

    2012-05-01

    agent known as Notch1 decoy (hN1DFc). Activation or inactivation of Notch changes the gene profile of LEC and changes their in vitro behavior. An...induced transcripts for direct targets such as Hey1 and Hey2 (data not shown), as well as the LEC gene VEGFR-3 (Figure 2a). Interestingly, Notch...activity may interfere with tumor (lymph)angiogenesis by disrupting expression and activity of EC genes . To that end, we have created a treatment

  1. 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

  2. Notch in Pathological Angiogenesis and Lymphangiogenesis

    DTIC Science & Technology

    2011-05-01

    have created a treatment agent known as Notch1 decoy (hN1DFc). Activation of Notch changes the gene profile of LEC and changes their in vitro...and lymphangiogenesis by disrupting expression and activity of EC genes . To that end, we have created a treatment agent known as Notch1 decoy (hN1DFc...We hypothesized that inhibiting Notch activity may disrupt tumor (lymph)angiogenesis by changing expression and activity of EC genes . To that end, we

  3. Zebrafish phenotypic screen identifies novel Notch antagonists.

    PubMed

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  4. Hypoxia, notch signalling, and prostate cancer.

    PubMed

    Marignol, Laure; Rivera-Figueroa, Karla; Lynch, Thomas; Hollywood, Donal

    2013-07-01

    The notch signalling pathway is involved in differentiation, proliferation, angiogenesis, vascular remodelling, and apoptosis. Deregulated expression of notch receptors, ligands, and targets is observed in many solid tumours, including prostate cancer. Hypoxia is a common feature of prostate tumours, leading to increased gene instability, reduced treatment response, and increased tumour aggressiveness. The notch signalling pathway is known to regulate vascular cell fate and is responsive to hypoxia-inducible factors. Evidence to date suggests similar, therapeutically exploitable, behaviour of notch-activated and hypoxic prostate cancer cells.

  5. Notch Promotes Radioresistance of Glioma Stem Cells

    PubMed Central

    Wang, Jialiang; Wakeman, Timothy P.; Latha, Justin D.; Hjelmeland, Anita B.; Wang, Xiao-Fan; White, Rebekah R.; Rich, Jeremy N.; Sullenger, Bruce A.

    2009-01-01

    Radiotherapy represents the most effective nonsurgical treatments for gliomas. Yet, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radioresistance in gliomas and breast cancers. The Notch pathway is critically implicated in stem cell fate determination and cancer. In this study, we showed that inhibition of Notch pathway with gamma-secretase inhibitors (GSIs) rendered the glioma stem cells more sensitive to radiation at clinically relevant doses. GSIs enhanced radiation-induced cell death and impaired clonogenic survival of glioma stem cells, but not non-stem glioma cells. Similarly, knockdown of Notch1 or Notch2 increased radiosensitivity of glioma stem cells. The specificity of the radiosensitizing effects of GSIs was confirmed by expression of the constitutively active intracellular domains of Notch1 or Notch2 that protected glioma stem cells against radiation. Notch inhibition with GSIs did not alter the DNA damage response of glioma stem cells following radiation, but rather impaired radiation-induced Akt activation and upregulated levels of the truncated apoptotic isoform of Mcl-1 (Mcl-1s). Taken together, our results suggest a critical role of Notch to promote radioresistance of glioma stem cells. Inhibition of Notch signaling holds promise to improve the efficiency of current radiotherapy in glioma treatment. PMID:19921751

  6. 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

  7. 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

  8. Notch1 controls development of the extravillous trophoblast lineage in the human placenta

    PubMed Central

    Haider, Sandra; Meinhardt, Gudrun; Saleh, Leila; Fiala, Christian; Pollheimer, Jürgen; Knöfler, Martin

    2016-01-01

    Development of the human placenta and its different epithelial trophoblasts is crucial for a successful pregnancy. Besides fusing into a multinuclear syncytium, the exchange surface between mother and fetus, progenitors develop into extravillous trophoblasts invading the maternal uterus and its spiral arteries. Migration into these vessels promotes remodelling and, as a consequence, adaption of blood flow to the fetal–placental unit. Defects in remodelling and trophoblast differentiation are associated with severe gestational diseases, such as preeclampsia. However, mechanisms controlling human trophoblast development are largely unknown. Herein, we show that Notch1 is one such critical regulator, programming primary trophoblasts into progenitors of the invasive differentiation pathway. At the 12th wk of gestation, Notch1 is exclusively detected in precursors of the extravillous trophoblast lineage, forming cell columns anchored to the uterine stroma. At the 6th wk, Notch1 is additionally expressed in clusters of villous trophoblasts underlying the syncytium, suggesting that the receptor initiates the invasive differentiation program in distal regions of the developing placental epithelium. Manipulation of Notch1 in primary trophoblast models demonstrated that the receptor promotes proliferation and survival of extravillous trophoblast progenitors. Notch1 intracellular domain induced genes associated with stemness of cell columns, myc and VE-cadherin, in Notch1− fusogenic precursors, and bound to the myc promoter and enhancer region at RBPJκ cognate sequences. In contrast, Notch1 repressed syncytialization and expression of TEAD4 and p63, two regulators controlling self-renewal of villous cytotrophoblasts. Our results revealed Notch1 as a key factor promoting development of progenitors of the extravillous trophoblast lineage in the human placenta. PMID:27849611

  9. Notch Signaling Functions in Retinal Pericyte Survival

    PubMed Central

    Arboleda-Velasquez, Joseph F.; Primo, Vincent; Graham, Mark; James, Alexandra; Manent, Jan; D'Amore, Patricia A.

    2014-01-01

    Purpose. Pericytes, the vascular cells that constitute the outer layer of capillaries, have been shown to have a crucial role in vascular development and stability. Loss of pericytes precedes endothelial cell dysfunction and vascular degeneration in small-vessel diseases, including diabetic retinopathy. Despite their clinical relevance, the cellular pathways controlling survival of retinal pericytes remain largely uncharacterized. Therefore, we investigated the role of Notch signaling, a master regulator of cell fate decisions, in retinal pericyte survival. Methods. A coculture system of ligand-dependent Notch signaling was developed using primary cultured retinal pericytes and a mesenchymal cell line derived from an inducible mouse model expressing the Delta-like 1 Notch ligand. This model was used to examine the effect of Notch activity on pericyte survival using quantitative PCR (qPCR) and a light-induced cell death assay. The effect of Notch gain- and loss-of-function was analyzed in monocultures of retinal pericytes using antibody arrays to interrogate the expression of apoptosis-related proteins. Results. Primary cultured retinal pericytes differentially expressed key molecules of the Notch pathway and displayed strong expression of canonical Notch/RBPJK (recombination signal-binding protein 1 for J-kappa) downstream targets. A gene expression screen using gain- and loss-of-function approaches identified genes relevant to cell survival as downstream targets of Notch activity in retinal pericytes. Ligand-mediated Notch activity protected retinal pericytes from light-induced cell death. Conclusions. Our results have identified signature genes downstream of Notch activity in retinal pericytes and suggest that tight regulation of Notch signaling is crucial for pericyte survival. PMID:25015359

  10. Lattice overview

    SciTech Connect

    Creutz, M.

    1984-01-01

    After reviewing some recent developments in supercomputer access, the author discusses a few areas where perturbation theory and lattice gauge simulations make contact. The author concludes with a brief discussion of a deterministic dynamics for the Ising model. This may be useful for numerical studies of nonequilibrium phenomena. 13 references.

  11. 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

  12. Active notch filter network with variable notch depth, width and frequency

    NASA Technical Reports Server (NTRS)

    Black, J. M. (Inventor)

    1980-01-01

    An active notch filter having independently adjustable notch frequency, width, and depth is provided by three equal capacitors connected in series with an operational amplifier (connected in a voltage follower configuration), a potentiometer across the series connected capacitors for notch depth adjustment, and a potentiometer (for notch frequency connected across the center capacitor); with its tap connected to receive a voltage feedback signal from a variable voltage divider comprised of another potentiometer for notch width. Adjusting the voltage dividing potentiometer will independently set the notch width, and adjusting the tap on the potentiometer across the center capacitor will independently adjust the notch frequency of the filter. A second operational amplifier connected in a voltage follower configuration may be used to connect the voltage divider output to the adjustable tap of the potentiometer across the center capacitor.

  13. Fracture analysis of notched composites

    NASA Technical Reports Server (NTRS)

    Deale, F.

    1985-01-01

    The problem of part-through cracks emanating from a central notch in a composite laminate is considered. The composite laminate is modeled as an orthotropic plate and along the branches, it is assumed that the stresses are carried by the fibers only. The stresses along the uncracked portions are assumed to be proportional to the crack opening displacement at the point. After formulating the branched crack problem, the model is applied to a(+45 deg)25 composite laminate. The stress concentration factors for the fibers are computed for various values of the spring constant K. Sample results showing the crack opening displacement are also displayed.

  14. Deuterium reveals the dynamics of notch activation.

    PubMed

    Raphael, Kopan

    2011-04-13

    Notch activation requires unfolding of a juxtamembrane negative regulatory domain (NRR). Tiyanont et al. (2011) analyzed the dynamics of NRR unfolding in the presence of EGTA. As predicted from the crystal structure and deletion analyses, the lin-Notch repeats unfold first, facilitating access by ADAM proteases. Surprisingly, the heterodimerization domain remains stable.

  15. Targeting Notch to overcome radiation resistance.

    PubMed

    Yahyanejad, Sanaz; Theys, Jan; Vooijs, Marc

    2016-02-16

    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.

  16. p53 regulates thymic Notch1 activation.

    PubMed

    Laws, Amy M; Osborne, Barbara A

    2004-03-01

    Notch is crucial for multiple stages of T cell development, including the CD4+CD8+ double positive (DP)/CD8+ single positive (SP) transition, but regulation of Notchactivation is not well understood. p53 regulates Presenilin1 (PS1) expression, and PS1 cleaves Notch, releasing its intracellular domain (NIC), leading to the expression of downstream targets, e.g. the HES1 gene. We hypothesize that p53 regulates Notch activity during T cell development. We found that Notch1 expression and activation were negatively regulated by p53in several thymoma lines. Additionally, NIC was elevated in Trp53(-/-) thymocytes as compared to Trp53(+/+) thymocytes. To determine if elevated Notch1 activation in Trp53(-/-) thymocytes had an effect on T cell development, CD4 and CD8 expression were analyzed. The CD4+ SP/CD8+ SP T cell ratio was decreased in Trp53(-/-) splenocytes and thymocytes. This alteration in T cell development correlated with the increased Notch1 activation observed in the absence of p53. These data indicate that p53 negatively regulates Notch1 activation during T cell development. Skewing of T cell development toward CD8+SP T cells in Trp53(-/-) mice is reminiscent of the phenotype of NIC-overexpressing mice. Thus, we suggest that p53 plays a role in T cell development, in part by regulating Notch1 activation.

  17. Notch signaling in development and cancer.

    PubMed

    Bolós, Victoria; Grego-Bessa, Joaquín; de la Pompa, José Luis

    2007-05-01

    Notch is an evolutionarily conserved local cell signaling mechanism that participates in a variety of cellular processes: cell fate specification, differentiation, proliferation, apoptosis, adhesion, epithelial-mesenchymal transition, migration, and angiogenesis. These processes can be subverted in Notch-mediated pathological situations. In the first part of this review, we will discuss the role of Notch in vertebrate central nervous system development, somitogenesis, cardiovascular and endocrine development, with attention to the mechanisms by which Notch regulates cell fate specification and patterning in these tissues. In the second part, we will review the molecular aspects of Notch-mediated neoplasias, where Notch can act as an oncogene or as a tumor suppressor. From all these studies, it becomes evident that the outcome of Notch signaling is strictly context-dependent and differences in the strength, timing, cell type, and context of the signal may affect the final outcome. It is essential to understand how Notch integrates inputs from other signaling pathways and how specificity is achieved, because this knowledge may be relevant for future therapeutic applications.

  18. 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

  19. Identification of Domains for Efficient Notch Signaling Activity in Immobilized Notch Ligand Proteins.

    PubMed

    Liu, Ledi; Wada, Hiroe; Matsubara, Natsuki; Hozumi, Katsuto; Itoh, Motoyuki

    2017-04-01

    Notch is a critical signaling pathway that controls cell fate and tissue homeostasis, but the functional characterization of Notch ligand domains that activate Notch receptors remains incomplete. Here, we established a method for immobilizing Notch ligand proteins onto beads to measure time-dependent Notch activity after the addition of Notch ligand-coated beads. A comparison between activities by the Notch ligand found on the cell surface to that of the ligand immobilized on beads showed that immobilized Notch ligand protein produces comparable signal activity during the first 10 h. Follow-up truncation studies showed that the N-terminal epidermal growth factor (EGF) repeat three region of delta like canonical Notch ligand 4 (DLL4) or jagged 1 (JAG1) is the minimum region for activating Notch signaling, and the DLL4 EGF repeat three domain may have a role in activation through a mechanism other than by increasing binding affinity. In addition, we found that reconstruction of the DLL4 delta and OSM-11 (DOS) motif (N257P) resulted in an increase in both binding affinity and signaling activity, which suggests that the role of the DOS motif is conserved among Notch ligands. Furthermore, active DLL4 protein on beads promoted T cell differentiation or inhibited B cell differentiation in vitro, whereas JAG1 proteins on beads did not have any effect. Taken together, our findings provide unambiguous evidence for the role of different Notch ligands and their domains in Notch signal activation, and may be potential tools for controlling Notch signaling activation. J. Cell. Biochem. 118: 785-796, 2017. © 2016 Wiley Periodicals, Inc.

  20. [Abnormal Notch-Hes Signaling Pathways and Acute Leukemia -Review].

    PubMed

    Gu, Zhen-Yang; Wang, Li; Gao, Chun-Ji

    2017-02-01

    The abnormal activation of Notch signaling is closely related to the development of acute leukemia (AL). The core elements of the Notch signaling system include Notch receptors, Notch ligands, CSL DNA-binding proteins, and effectors like target genes. Any factors, which affect ligands, receptors, signal transducers and effectors, can influence the signal transduction of Notch signaling greatly. Based on the role of Notch signaling in AL, several targeted drugs against Notch upstream signaling have been developed. However, due to the complexity and pleiotropic effects of Notch upstream signaling, these targeted drugs display strong side effects. Thus, Hes (Hairy Enhancer of Split) factors as a primary Notch effector, also play an important role in the pathogenesis of AL. This review summarizes recent progresses on Notch-Hes signaling in AL, hopping to provide references for further excavation of the Notch-Hes signaling, and lay foundations for developing the next generation of targeted drugs.

  1. The Notch pathway in colorectal cancer.

    PubMed

    Vinson, Kaitlyn E; George, Dennis C; Fender, Alexander W; Bertrand, Fred E; Sigounas, George

    2016-04-15

    Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. It is also the third most common cancer diagnosis among men, and the second most common cancer diagnosis among women. Globally, CRC can account for nearly 694,000 annual deaths. It is widely appreciated that CRC is the result of dysregulated cellular pathways that promote an inappropriate stem-cell-like phenotype, apoptotic resistance, unchecked proliferation and metastatic spread. While no single pathway is responsible for all of these attributes, an array of recent studies suggests a pivotal role for abnormal Notch-1 signaling in CRC, in part due to interconnectivity of Notch with other pathways. This review will summarize recent evidence for a role of Notch signaling in CRC, will consider interconnectivity between Notch and other pathways involved in CRC and will discuss the possible utility of targeting Notch as a CRC therapeutic.

  2. Notch signaling in the developing cardiovascular system.

    PubMed

    Niessen, Kyle; Karsan, Aly

    2007-07-01

    The Notch proteins encompass a family of transmembrane receptors that have been highly conserved through evolution as mediators of cell fate. Recent findings have demonstrated a critical role of Notch in the developing cardiovascular system. Notch signaling has been implicated in the endothelial-to-mesenchymal transition during development of the heart valves, in arterial-venous differentiation, and in remodeling of the primitive vascular plexus. Mutations of Notch pathway components in humans are associated with congenital defects of the cardiovascular system such as Alagille syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and bicuspid aortic valves. This article focuses on the role of the Notch pathway in the developing cardiovascular system and congenital human cardiovascular diseases.

  3. 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

  4. Lattice fermions

    NASA Technical Reports Server (NTRS)

    Wilczek, Frank

    1987-01-01

    A simple heuristic proof of the Nielsen-Ninomaya theorem is given. A method is proposed whereby the multiplication of fermion species on a lattice is reduced to the minimal doubling, in any dimension, with retention of appropriate chiral symmetries. Also, it is suggested that use of spatially thinned fermion fields is likely to be a useful and appropriate approximation in QCD - in any case, it is a self-checking one.

  5. The Expression of Notch 1 and Notch 3 in Gallbladder Cancer and Their Clinicopathological Significance.

    PubMed

    Liu, Luyao; Yang, Zhu-Lin; Wang, Chunwei; Miao, Xiongying; Liu, Zhiyu; Li, Daiqiang; Zou, Qiong; Li, Jinghe; Liang, Lufeng; Zeng, Guixiang; Chen, Senlin

    2016-07-01

    Gallbladder cancers (GBCs) are highly malignant gastrointestinal cancers. The biological makers for the prognosis and targeting therapy of GBCs have not been established. The protein expression of Notch 1 and Notch 3 in 46 squamous cell/adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (AC) was measured using immunohistochemistry. Positive Notch 1 and Notch 3 expression in both SC/ASC and AC was significantly associated with large tumor size, invasion, metastasis, and low surgical curability (P < 0.05 or P < 0.01). Univariate Kaplan-Meier analysis showed that positive Notch 1 and Notch 3 expression was significantly associated with mean survival of SC/ASC and AC patients (P < 0.01 or P < 0.001). Multivariate Cox regression analysis showed that positive Notch 1 and Notch 3 expression, as well as low differentiation, large tumor size, high TNM stage, invasion, lymph node metastasis, and surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Positive Notch 1 and Notch 3 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in both SC/ASC and AC patients.

  6. Optical Transversal Processor For Notch Filtering

    NASA Astrophysics Data System (ADS)

    Lugt, A. V.

    1984-06-01

    A frequency domain implementation of an optical transversal processor has been described previously. Since this system uses Bragg cells both as the delay line and as the accumulators that provide the tap weights, a key question concerns the effect the finite integration times have on the perfor-mance of the system. Computer programs were written to simulate an adaptive notch filtering application; the measure of performance is the correlation coefficient for the residual signal and the desired received signal. The correlation coefficient was increased significantly by tapering the accumulators so that the readaptation phenomena caused by large values leaving the accumulator are minimized. Several examples of the performance are given as a function of the number of taps, the length and degree of taper of the accumulator, the feedback gain, and the number of iterations. The results show that a finite accumulator is not a serious drawback, particularly for those applications in which the system must operate in a rapidly changing environment. The performance of the system then approaches that of one having an infinite accumulator with the gain adjusted to give equivalent tracking performance.

  7. Notch regulation of gastrointestinal stem cells.

    PubMed

    Demitrack, Elise S; Samuelson, Linda C

    2016-09-01

    The gastrointestinal (GI) tract epithelium is continuously replenished by actively cycling stem and progenitor cells. These cell compartments are regulated to balance proliferation and stem cell renewal with differentiation into the various mature cell types to maintain tissue homeostasis. In this topical review we focus on the role of the Notch signalling pathway to regulate GI stem cell function in adult small intestine and stomach. We first present the current view of stem and progenitor cell populations in these tissues and then summarize the studies that have established the Notch pathway as a key regulator of gastric and intestinal stem cell function. Notch signalling has been shown to be a niche factor required for maintenance of GI stem cells in both tissues. In addition, Notch has been described to regulate epithelial cell differentiation. Recent studies have revealed key similarities and differences in how Notch regulates stem cell function in the stomach compared to intestine. We summarize the literature regarding Notch regulation of GI stem cell proliferation and differentiation, highlighting tissue-specific functions to compare and contrast Notch in the stomach and intestine. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

  8. Notch regulation of gastrointestinal stem cells

    PubMed Central

    Demitrack, Elise S.

    2016-01-01

    Abstract The gastrointestinal (GI) tract epithelium is continuously replenished by actively cycling stem and progenitor cells. These cell compartments are regulated to balance proliferation and stem cell renewal with differentiation into the various mature cell types to maintain tissue homeostasis. In this topical review we focus on the role of the Notch signalling pathway to regulate GI stem cell function in adult small intestine and stomach. We first present the current view of stem and progenitor cell populations in these tissues and then summarize the studies that have established the Notch pathway as a key regulator of gastric and intestinal stem cell function. Notch signalling has been shown to be a niche factor required for maintenance of GI stem cells in both tissues. In addition, Notch has been described to regulate epithelial cell differentiation. Recent studies have revealed key similarities and differences in how Notch regulates stem cell function in the stomach compared to intestine. We summarize the literature regarding Notch regulation of GI stem cell proliferation and differentiation, highlighting tissue‐specific functions to compare and contrast Notch in the stomach and intestine. PMID:26848053

  9. BMP and Notch interaction in CRC subtypes.

    PubMed

    Irshad, Shazia; Bansal, Mukesh; Guarnieri, Paolo; Davis, Hayley; Zen, Ayman Al Haj; Baran, Brygida; Pinna, Claudia Maria Assunta; Rahman, Haseeb; Biswas, Sujata; Bardella, Chiara; Jeffery, Rosemary; Wang, Lai Mun; East, James Edward; Lewis, Annabelle; Tomlinson, Ian; Leedham, Simon John

    2017-03-15

    The functional role of Bone Morphogenetic Protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localisation was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRC, but was conserved specifically in mesenchymal subtype tumours, where it interacts with Notch to induce an EMT phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal subtype tumours promotes synergistic BMP/Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed.

  10. Notch: From Neural Development to Neurological Disorders

    PubMed Central

    Lathia, Justin D.; Mattson, Mark P.; Cheng, Aiwu

    2015-01-01

    Notch is an integral membrane protein that functions as receptor for ligands such as jagged and delta that are associated with the surface of neighboring cells. Upon ligand binding, notch is proteolytically cleaved within its transmembrane domain by presenilin-1 (the enzymatic component of the γ-secretase complex) resulting in the release of a notch intracellular domain (NICD) which translocates to the nucleus where it regulates gene expression. Notch signaling plays multiple roles in the development of the central nervous system (CNS) including regulating neural stem cell (NSC) proliferation, survival, self-renewal and differentiation. Notch is also present in postmitotic neurons in the adult CNS wherein its activation influences structural and functional plasticity including processes involved in learning and memory. Recent findings suggest that notch signaling in neurons, glia and NSCs may be involved in pathological changes that occur in disorders such as stroke, Alzheimer’s disease and CNS tumors. Studies of animal models suggest the potential of agents that target notch signaling as therapeutic interventions for several different CNS disorders. PMID:19094054

  11. The role of Notch signaling in kidney podocytes.

    PubMed

    Asanuma, Katsuhiko; Oliva Trejo, Juan Alejandro; Tanaka, Eriko

    2017-02-01

    The Notch signaling pathway is a basic cell-to-cell communication mechanism. This pathway is activated by the interaction between Notch receptors and the ligands of adjacent cells. Once activated, Notch receptors are cleaved and the intracellular domains translocate into the nucleus, where the transcription of target genes starts. In the mammalian kidney, Notch receptors are activated during nephrogenesis. Afterwards, in the mature glomeruli, the Notch pathway becomes silent. However, many researchers have reported the activation of Notch receptors in mature podocytes under pathological conditions. In this review, we discuss the role of Notch signaling in podocytes.

  12. 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.

  13. Not(ch) just development: Notch signalling in the adult brain

    PubMed Central

    Ables, Jessica L.; Breunig, Joshua J.; Eisch, Amelia J.; Rakic, Pasko

    2011-01-01

    The Notch pathway is often regarded as a developmental pathway, but components of Notch signalling are expressed and active in the adult brain. With the advent of more sophisticated genetic manipulations, evidence has emerged that suggests both conserved and novel roles for Notch signalling in the adult brain. Not surprisingly, Notch is a key regulator of adult neural stem cells, but it is increasingly clear that Notch signalling also has roles in the regulation of migration, morphology, synaptic plasticity and survival of immature and mature neurons. Understanding the many functions of Notch signalling in the adult brain, and its dysfunction in neurodegenerative disease and malignancy, is crucial to the development of new therapeutics that are centred around this pathway. PMID:21505516

  14. Notch and the awesome power of genetics.

    PubMed

    Greenwald, Iva

    2012-07-01

    Notch is a receptor that mediates cell-cell interactions in animal development, and aberrations in Notch signal transduction can cause cancer and other human diseases. Here, I describe the major advances in the Notch field from the identification of the first mutant in Drosophila almost a century ago through the elucidation of the unusual mechanism of signal transduction a little over a decade ago. As an essay for the GENETICS Perspectives series, it is my personal and critical commentary as well as an historical account of discovery.

  15. Notch and the Awesome Power of Genetics

    PubMed Central

    Greenwald, Iva

    2012-01-01

    Notch is a receptor that mediates cell–cell interactions in animal development, and aberrations in Notch signal transduction can cause cancer and other human diseases. Here, I describe the major advances in the Notch field from the identification of the first mutant in Drosophila almost a century ago through the elucidation of the unusual mechanism of signal transduction a little over a decade ago. As an essay for the GENETICS Perspectives series, it is my personal and critical commentary as well as an historical account of discovery. PMID:22785620

  16. Fracture modes in notched angleplied composite laminates

    NASA Technical Reports Server (NTRS)

    Irvine, T. B.; Ginty, C. A.

    1984-01-01

    The Composite Durability Structural Analysis (CODSTRAN) computer code is used to determine composite fracture. Fracture modes in solid and notched, unidirectional and angleplied graphite/epoxy composites were determined by using CODSTRAN. Experimental verification included both nondestructive (ultrasonic C-Scanning) and destructive (scanning electron microscopy) techniques. The fracture modes were found to be a function of ply orientations and whether the composite is notched or unnotched. Delaminations caused by stress concentrations around notch tips were also determined. Results indicate that the composite mechanics, structural analysis, laminate analysis, and fracture criteria modules embedded in CODSTRAN are valid for determining composite fracture modes.

  17. The Role of Notch Signaling Pathway in Breast Cancer Pathogenesis

    DTIC Science & Technology

    2004-07-01

    coexpression of a constitutively active form of Notch1 in immortalized breast epithelial HMLE cells expressing low levels of oncogenic Ras rendered them...the Notch-Ras pathway interaction revealed that nuclear localization of Notch1 is essential for this cooperation. Dissection of Ras-pathways using the...activates Raf/MAPK pathway, formed efficient colonies with activated Notch1 . Interestingly, I found that expression of activated Notch1 rendered the

  18. Cis-interactions between Notch and its ligands block ligand-independent Notch activity

    PubMed Central

    Palmer, William Hunt; Jia, Dongyu; Deng, Wu-Min

    2014-01-01

    The Notch pathway is integrated into numerous developmental processes and therefore is fine-tuned on many levels, including receptor production, endocytosis, and degradation. Notch is further characterized by a twofold relationship with its Delta-Serrate (DSL) ligands, as ligands from opposing cells (trans-ligands) activate Notch, whereas ligands expressed in the same cell (cis-ligands) inhibit signaling. We show that cells without both cis- and trans-ligands can mediate Notch-dependent developmental events during Drosophila oogenesis, indicating ligand-independent Notch activity occurs when the receptor is free of cis- and trans-ligands. Furthermore, cis-ligands can reduce Notch activity in endogenous and genetically induced situations of elevated trans-ligand-independent Notch signaling. We conclude that cis-expressed ligands exert their repressive effect on Notch signaling in cases of trans-ligand-independent activation, and propose a new function of cis-inhibition which buffers cells against accidental Notch activity. DOI: http://dx.doi.org/10.7554/eLife.04415.001 PMID:25486593

  19. 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

  20. Notch sensitivity of space shuttle tile materials

    NASA Technical Reports Server (NTRS)

    Newman, J. C., Jr.

    1980-01-01

    Tests were conducted at room temperature to determine the notch sensitivity of the thermal protection tile for the space shuttle. Two types of RSI tile were studied: LI-900 and LI-2200. Three point bend specimens were cut from discarded tiles in the in-plane (ip) and through-the-thickness (ttt) directions. They were tested with or without a sharp notch. The LI-900 (ip and ttt) specimens were not very notch sensitive, but the LI-2200 (ip and ttt) specimens were. The LI-2200 material showed about a 35 percent reduction in strength due to the presence of the notch. This reduction in strength should be considered in the design of mechanically fastened tile concepts.

  1. 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.

  2. Notch Signaling in Vascular Smooth Muscle Cells.

    PubMed

    Baeten, J T; Lilly, B

    2017-01-01

    The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease.

  3. 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.

  4. Molecular Determinants of NOTCH4 Transcription in Vascular Endothelium

    PubMed Central

    Wu, Jing; Iwata, Fumiko; Grass, Jeffrey A.; Osborne, Cameron S.; Elnitski, Laura; Fraser, Peter; Ohneda, Osamu; Yamamoto, Masayuki; Bresnick, Emery H.

    2005-01-01

    The process whereby the primitive vascular network develops into the mature vasculature, known as angiogenic vascular remodeling, is controlled by the Notch signaling pathway. Of the two mammalian Notch receptors expressed in vascular endothelium, Notch1 is broadly expressed in diverse cell types, whereas Notch4 is preferentially expressed in endothelial cells. As mechanisms that confer Notch4 expression were unknown, we investigated how NOTCH4 transcription is regulated in human endothelial cells and in transgenic mice. The NOTCH4 promoter and the 5′ portion of NOTCH4 assembled into an endothelial cell-specific histone modification pattern. Analysis of NOTCH4 primary transcripts in human umbilical vein endothelial cells by RNA fluorescence in situ hybridization revealed that 36% of the cells transcribed one or both NOTCH4 alleles. The NOTCH4 promoter was sufficient to confer endothelial cell-specific transcription in transfection assays, but intron 1 or upstream sequences were required for expression in the vasculature of transgenic mouse embryos. Cell-type-specific activator protein 1 (AP-1) complexes occupied NOTCH4 chromatin and conferred endothelial cell-specific transcription. Vascular angiogenic factors activated AP-1 and reprogrammed the endogenous NOTCH4 gene in HeLa cells from a repressed to a transcriptionally active state. These results reveal an AP-1-Notch4 pathway, which we propose to be crucial for transducing angiogenic signals and to be deregulated upon aberrant signal transduction in cancer. PMID:15684396

  5. Notch-dependent control of myelopoiesis is regulated by fucosylation

    PubMed Central

    Li, Lebing Wei; Yan, Quanjian; Petryniak, Bronislawa; Man, Yunfang; Su, Charles; Shim, Jeongsup; Chervin, Stephanie; Lowe, John B.

    2008-01-01

    Cell-cell contact–dependent mechanisms that modulate proliferation and/or differentiation in the context of hematopoiesis include mechanisms characteristic of the interactions between members of the Notch family of signal transduction molecules and their ligands. Whereas Notch family members and their ligands clearly modulate T lymphopoietic decisions, evidence for their participation in modulating myelopoiesis is much less clear, and roles for posttranslational control of Notch-dependent signal transduction in myelopoiesis are unexplored. We report here that a myeloproliferative phenotype in FX−/− mice, which are conditionally deficient in cellular fucosylation, is consequent to loss of Notch-dependent signal transduction on myeloid progenitor cells. In the context of a wild-type fucosylation phenotype, we find that the Notch ligands suppress myeloid differentiation of progenitor cells and enhance expression of Notch target genes. By contrast, fucosylation-deficient myeloid progenitors are insensitive to the suppressive effects of Notch ligands on myelopoiesis, do not transcribe Notch1 target genes when cocultured with Notch ligands, and have lost the wild-type Notch ligand-binding phenotype. Considered together, these observations indicate that Notch-dependent signaling controls myelopoiesis in vivo and in vitro and identifies a requirement for Notch fucosylation in the expression of Notch ligand binding activity and Notch signaling efficiency in myeloid progenitors. PMID:18359890

  6. 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.

  7. Notch down-regulation by endocytosis is essential for pigment cell determination and survival in the Drosophila retina.

    PubMed

    Peralta, Susana; Gómez, Yolanda; González-Gaitán, Marcos A; Moya, Fernando; Vinós, Javier

    2009-01-01

    The clathrin heavy chain is a fundamental element in endocytosis and therefore, in the internalization of several cell-surface receptors through which cells interact with their environment. Here we show that the only non-lethal mutant allele of the clathrin heavy chain identified to date in metazoans, the Drosophila Chc(4), involves the substitution of a residue at the knee region of the molecule that impairs clathrin-dependent endocytosis. We have investigated the consequences of this endocytic defect in Drosophila retinal development and found that it produces an inhibition of programmed cell death in the retinal lattice, followed by widespread death of interommatidial pigment cells once retinal development has been completed. Through genetic interactions and transgenic analyses, we show that Chc(4) phenotypes are caused by a Notch receptor gain-of-function, providing a dramatic example of the importance of Notch down-regulation by endocytosis. An increase in Notch signaling is also observed in Drosophila wings in response to the mutant clathrin, suggesting that Notch levels are controlled by clathrin-dependent endocytosis. We discuss the implications of these findings for current models on eye-development and for the role of endocytosis in Notch signaling.

  8. MAGP2 controls Notch via interactions with RGD binding integrins: Identification of a novel ECM-integrin-Notch signaling axis.

    PubMed

    Deford, Peter; Brown, Kasey; Richards, Rae Lee; King, Aric; Newburn, Kristin; Westover, Katherine; Albig, Allan R

    2016-02-01

    Canonical Notch signaling involves Notch receptor activation via interaction with cell surface bound Notch ligand. Recent findings also indicate that Notch signaling may be modulated by cross-talk with other signaling mechanisms. The ECM protein MAGP2 was previously shown to regulate Notch in a cell type dependent manner, although the molecular details of this interaction have not been dissected. Here, we report that MAGP2 cell type specific control of Notch is independent of individual Notch receptor-ligand combinations but dependent on interaction with RGD binding integrins. Overexpressed MAGP2 was found to suppress transcriptional activity from the Notch responsive Hes1 promoter activity in endothelial cells, while overexpression of a RGD→RGE MAGP2 mutant increased Notch signaling in the same cell type. This effect was not unique to MAGP2 since the RGD domain of the ECM protein EGFL7 was also found to be an important modulator of Hes1 promoter activity. Independently of MAGP2 or EGFL7, inhibition of RGD-binding integrins with soluble RGD peptides also increased accumulation of active N1ICD fragments and Notch responsive promoter activity independently of changes in Notch1, Jag1, or Dll4 expression. Finally, β1 or β3 integrin blocking antibodies also enhanced Notch signaling. Collectively, these results answer the question of how MAGP2 controls cell type dependent Notch signaling, but more importantly uncover a new mechanism to understand how extracellular matrices and cellular environments impact Notch signaling.

  9. Differential Regulation of NOTCH2 and NOTCH3 Contribute to Their Unique Functions in Vascular Smooth Muscle Cells*

    PubMed Central

    Baeten, Jeremy T.; Lilly, Brenda

    2015-01-01

    Notch signaling is a key regulator of vascular smooth muscle cell (VSMC) phenotypes, including differentiation, proliferation, and cell survival. However, the exact contribution of the individual Notch receptors has not been thoroughly delineated. In this study, we identify unique roles for NOTCH2 and NOTCH3 in regulating proliferation and cell survival in cultured VSMCs. Our results indicate that NOTCH2 inhibits PDGF-B-dependent proliferation and its expression is decreased by PDGF-B. In contrast, NOTCH3 promotes proliferation and receptor expression is increased by PDGF-B. Additionally, data show that NOTCH3, but not NOTCH2 protects VSMCs from apoptosis and apoptosis mediators degrade NOTCH3 protein. We identified three pro-survival genes specifically regulated by NOTCH3 in cultured VSMCs and in mouse aortas. This regulation is mediated through MAP kinase signaling, which we demonstrate can be activated by NOTCH3, but not NOTCH2. Overall, this study highlights discrete roles for NOTCH2 and NOTCH3 in VSMCs and connects these roles to specific upstream regulators that control their expression. PMID:25957400

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

    PubMed

    Colin, Jérôme

    2012-06-06

    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.

  11. ADAM Proteases: Ligand Processing and Modulation of the Notch Pathway

    PubMed Central

    Zolkiewska, Anna

    2009-01-01

    ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step of the regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. PMID:18344021

  12. Plane elastostatic analysis of V-notched plates.

    NASA Technical Reports Server (NTRS)

    Gross, B.; Mendelson, A.

    1972-01-01

    Solutions are given for several plane elastostatic problems of plates having a V-notch on one edge, and subjected to a variety of boundary conditions. The effect of the magnitude of the V-notch angle and specimen geometry on stress intensity factors KI and KII are obtained for unloaded notch surfaces. There is less than one per cent difference in opening model stress intensity factor in going from a zero degree notch angle to a 30 degree notch angle. Notch opening displacements at the plate edge were measured experimentally, and the results obtained were in excellent agreement with the computed results.

  13. Notch Signaling Regulates Antigen Sensitivity of Naive CD4+ T Cells by Tuning Co-stimulation

    PubMed Central

    Laky, Karen; Evans, Sharron; Perez-Diez, Ainhoa

    2015-01-01

    SUMMARY Adaptive immune responses begin when naive CD4+ T cells engage peptide+major histocompatibility complex class II and co-stimulatory molecules on antigen-presenting cells (APCs). Notch signaling can influence effector functions in differentiated CD4+ T helper and T regulatory cells. Whether and how ligand-induced Notch signaling influences the initial priming of CD4+ T cells has not been addressed. We have found that Delta Like Ligand 4 (DLL4)-induced Notch signaling potentiates phosphatidylinositol 3-OH kinase (PI3K)-dependent signaling downstream of the T cell receptor+CD28, allowing naive CD4+ T cells to respond to lower doses of antigen. In vitro, DLL4-deficient APCs were less efficient stimulators of CD4+ T cell activation, metabolism, proliferation, and cytokine secretion. With deletion of DLL4 from CD11c+ APCs in vivo, these deficits translated to an impaired ability to mount an effective CD4+-dependent anti-tumor response. These data implicate Notch signaling as an important regulator of adaptive immune responses. PMID:25607460

  14. Targeting Notch to target cancer stem cells.

    PubMed

    Pannuti, Antonio; Foreman, Kimberly; Rizzo, Paola; Osipo, Clodia; Golde, Todd; Osborne, Barbara; Miele, Lucio

    2010-06-15

    The cellular heterogeneity of neoplasms has been at the center of considerable interest since the "cancer stem cell hypothesis", originally formulated for hematologic malignancies, was extended to solid tumors. The origins of cancer "stem" cells (CSC) or tumor-initiating cells (TIC; henceforth referred to as CSCs) and the methods to identify them are hotly debated topics. Nevertheless, the existence of subpopulations of tumor cells with stem-like characteristics has significant therapeutic implications. The stem-like phenotype includes indefinite self-replication, pluripotency, and, importantly, resistance to chemotherapeutics. Thus, it is plausible that CSCs, regardless of their origin, may escape standard therapies and cause disease recurrences and/or metastasis after apparently complete remissions. Consequently, the idea of selectively targeting CSCs with novel therapeutics is gaining considerable interest. The Notch pathway is one of the most intensively studied putative therapeutic targets in CSC, and several investigational Notch inhibitors are being developed. However, successful targeting of Notch signaling in CSC will require 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 prove safe and effective. Additionally, to determine which patients are most likely to benefit from treatment with Notch-targeting therapeutics, reliable biomarkers to measure pathway activity in CSC from specific tumors will have to be identified and validated. This article summarizes the most recent developments in the field of Notch-targeted cancer therapeutics, with emphasis on CSC.

  15. Notch receptor expression in human brain arteriovenous malformations.

    PubMed

    Hill-Felberg, Sandra; Wu, Hope Hueizhi; Toms, Steven A; Dehdashti, Amir R

    2015-08-01

    The roles of the Notch pathway proteins in normal adult vascular physiology and the pathogenesis of brain arteriovenous malformations are not well-understood. Notch 1 and 4 have been detected in human and mutant mice vascular malformations respectively. Although mutations in the human Notch 3 gene caused a genetic form of vascular stroke and dementia, its role in arteriovenous malformations development has been unknown. In this study, we performed immunohistochemistry screening on tissue microarrays containing eight surgically resected human brain arteriovenous malformations and 10 control surgical epilepsy samples. The tissue microarrays were evaluated for Notch 1-4 expression. We have found that compared to normal brain vascular tissue Notch-3 was dramatically increased in brain arteriovenous malformations. Similarly, Notch 4 labelling was also increased in vascular malformations and was confirmed by western blot analysis. Notch 2 was not detectable in any of the human vessels analysed. Using both immunohistochemistry on microarrays and western blot analysis, we have found that Notch-1 expression was detectable in control vessels, and discovered a significant decrease of Notch 1 expression in vascular malformations. We have demonstrated that Notch 3 and 4, and not Notch 1, were highly increased in human arteriovenous malformations. Our findings suggested that Notch 4, and more importantly, Notch 3, may play a role in the development and pathobiology of human arteriovenous malformations.

  16. Notch1 functions as a tumor suppressor in mouse skin.

    PubMed

    Nicolas, Michael; Wolfer, Anita; Raj, Kenneth; Kummer, J Alain; Mill, Pleasantine; van Noort, Mascha; Hui, Chi-chung; Clevers, Hans; Dotto, G Paolo; Radtke, Freddy

    2003-03-01

    Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.

  17. Differential expression of Notch family members in astrocytomas and medulloblastomas.

    PubMed

    Xu, Peng; Yu, Shizhu; Jiang, Rongcai; Kang, Chunsheng; Wang, Guangxiu; Jiang, Hao; Pu, Peiyu

    2009-12-01

    Notch signaling pathway plays an integral role in determining cell fates in development. Growing evidence demonstrates that Notch signaling pathway has versatile effects in tumorigenesis depending on the tumor type, grade and stage. Notch signaling pathway is deregulated in some brain tumors. To examine the differential expression of Notch family members (Notch1, 2, 3, 4) in human astrocytomas and medulloblastomas, and to evaluate their roles in the development of both tumor types. Immunohistochemical staining and Western blot analysis were used to detect Notch1, 2, 3, 4 expression in tissue microarray and freshly resected tissue samples of normal brain, astrocytomas and medulloblastomas. Notch family members were not expressed or barely detectable in normal brain tissues. Notch1, 3, 4 were highly expressed but Notch2 was not expressed in astrocytomas. The percentage of immunopositive tumor cells and level of Notch1 expression was increased with tumor grade. In addition, overexpression of Notch2 was detected in medulloblastomas in contrast to low or no expression of Notch1, 3, 4. Differential expression of Notch1, 2, 3, 4 is detected in astrocytomas and medulloblastomas, that may be related to their different roles playing in the development of brain tumors.

  18. Notched delta, phenotype, and Angelman syndrome.

    PubMed

    Korff, Christian M; Kelley, Kent R; Nordli, Douglas R

    2005-08-01

    The notched delta pattern is one of the characteristic EEG features found in Angelman syndrome patients. The purpose of this study was to evaluate the possibility of using the notched delta pattern as a detection tool for Angelman syndrome patients by analyzing its frequency in a tertiary care pediatric center, its specificity for Angelman syndrome, and the age at which it was observed. The authors performed a retrospective review of the video-EEG recordings of all the patients who had either the notched delta pattern or a phenotype consistent with Angelman syndrome. The notched delta was observed in 1.1% of all the EEGs performed. Its specificity for Angelman syndrome was evaluated at 38%. The youngest age at which it was noted was 14 months. The results indicate that the notched delta pattern is relatively rare, but more frequent than expected, and is easily recognizable. The pattern was observed not only in Angelman syndrome patients, but also in children with a spectrum of conditions wider than reported. It is a powerful detection tool for Angelman syndrome when correlated to a suggestive phenotype, and the association of these features should raise suspicion for Angelman syndrome in both infants and adults.

  19. 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.

  20. Complex regulation of HSC emergence by the Notch signaling pathway

    PubMed Central

    Butko, Emerald; Pouget, Claire; Traver, David

    2016-01-01

    Hematopoietic stem cells are formed during embryonic development, and serve as the foundation of the definitive blood program for life. Notch signaling has been well established as an essential direct contributor to HSC specification. However, several recent studies have indicated that the contribution of Notch signaling is complex. HSC specification requires multiple Notch signaling inputs, some received directly by hematopoietic precursors, and others that occur indirectly within neighboring somites. Of note, proinflammatory signals provided by primitive myeloid cells are needed for HSC specification via upregulation of the Notch pathway in hemogenic endothelium. In addition to multiple requirements for Notch activation, recent studies indicate that Notch signaling must subsequently be repressed to permit HSC emergence. Finally, Notch must then be reactivated to maintain HSC fate. In this review, we discuss the growing understanding of the dynamic contributions of Notch signaling to the establishment of hematopoiesis during development. PMID:26586199

  1. Rabconnectin-3 is a functional regulator of mammalian Notch signaling.

    PubMed

    Sethi, Nilay; Yan, Yan; Quek, Debra; Schupbach, Trudi; Kang, Yibin

    2010-11-05

    The Notch signaling pathway is important for cell fate decisions in embryonic development and adult life. Defining the functional importance of the Notch pathway in these contexts requires the elucidation of essential signal transduction components that have not been fully characterized. Here, we show that Rabconnectin-3B is required for the Notch pathway in mammalian cells. siRNA-mediated silencing of Rabconnectin-3B in mammalian cells attenuated Notch signaling and disrupted the activation and nuclear accumulation of the Notch target Hes1. Rabconnectin-3B knockdown also disrupted V-ATPase activity in mammalian cells, consistent with previous observations in Drosophila. Pharmacological inhibition of the V-ATPase complex significantly reduced Notch signaling in mammalian cells. Finally, Rabconnectin-3B knockdown phenocopied functional disruption of Notch signaling during osteoclast differentiation. Collectively, these findings define an important role for Rabconnectin-3 and V-ATPase activity in the Notch signaling pathway in mammalian cells.

  2. Notch in mammary gland development and breast cancer.

    PubMed

    Politi, Katerina; Feirt, Nikki; Kitajewski, Jan

    2004-10-01

    Notch signaling has been implicated in many processes including cell fate determination and oncogenesis. In mice, the Notch1 and Notch4 genes are both targets for insertion and rearrangement by the mouse mammary tumor virus and these mutations promote epithelial mammary tumorigenesis. Moreover, expression of a constitutively active form of Notch4 in mammary epithelial cells inhibits epithelial differentiation and leads to tumor formation in this organ. These data implicate the Notch pathway in breast tumorigenesis and provide the foundation for future experiments that will aid in our understanding of the role of Notch in human breast cancer development. Here, we review studies of mammary tumorigenesis induced by Notch in mouse and in vitro culture models providing evidence that Notch activation is a causal factor in human breast cancer.

  3. Laser notching ceramics for reliable fracture toughness testing

    DOE PAGES

    Barth, Holly D.; Elmer, John W.; Freeman, Dennis C.; ...

    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

  4. 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.

  5. The Role of Adaptive Photorefractive Power Limiting on Acousto-Optic Radio Frequency (RF) Signal Excision

    DTIC Science & Technology

    2001-12-01

    Adaptive RF interference reduction for broadband communication systems continues to be problematic. The acousto - optic RF signal excision system...novel photorefractive optical power limiting device to achieve adaptive notch filtering, and multi- channel acousto - optic deflection to achieve angle...of-arrival signal discrimination at the notch filter. This dissertation describes basic principles of acousto - optic RF signal excision, including

  6. Emerin suppresses Notch signaling by restricting the Notch intracellular domain to the nuclear membrane.

    PubMed

    Lee, Byongsun; Lee, Tae-Hee; Shim, Jaekyung

    2017-02-01

    Emerin is an inner nuclear membrane protein that is involved in maintaining the mechanical integrity of the nuclear membrane. Increasing evidence supports the involvement of emerin in the regulation of gene expression; however, its precise function remains to be elucidated. Here, we show that emerin downregulated genes downstream of Notch signaling, which are activated exclusively by the Notch intracellular domain (NICD). Deletion mutant experiments revealed that the transmembrane domain of emerin is important for the inhibition of Notch signaling. Emerin interacted directly and colocalized with the NICD at the nuclear membrane. Emerin knockdown induced the phosphorylation of ERK and AKT, increased endogenous Notch signaling, and inhibited hydrogen peroxide-induced apoptosis in HeLa cells. Notably, the downregulation of barrier-to-autointegration factor (BAF) or lamin A/C increased Notch signaling by inducing the release of emerin into the cytosol, implying that nuclear membrane-bound emerin acts as an endogenous inhibitor of Notch signaling. Taken together, our results indicate that emerin negatively regulates Notch signaling by promoting the retention of the NICD at the nuclear membrane. This mechanism could constitute a new therapeutic target for the treatment of emerin-related diseases.

  7. Notch1 hallmarks fibrillary depositions in sporadic Alzheimer's disease.

    PubMed

    Brai, Emanuele; Alina Raio, Noemi; Alberi, Lavinia

    2016-07-01

    Notch1 signaling is a cellular cascade with a fundamental role from brain development to adult brain function. Reduction in Notch1 affects synaptic plasticity, memory and olfaction. On the other hand, Notch1 overactivation after brain injury is detrimental for neuronal survival. Some familial Alzheimer's disease (FAD) mutations in Presenilins can affect Notch1 processing/activation. Others report that Notch1 is overexpressed in sporadic Alzheimer's disease (AD). These works indicate that imbalances in Notch1 may be implicated in AD pathophysiology. In this study, we addressed whether Notch1 alteration can be considered a hallmark of AD. Immunohistochemical analysis of Notch1 on cortical and hippocampal tissue from post-mortem patients indicates an accumulation of Notch1 in plaque-like structures in the brain parenchyma of subjects with sporadic AD. Further analysis shows that displaced Notch1 is associated with fibrillary tangles/plaques. Biochemical validation confirms an accumulation of Notch1 in cytosolic brain fractions. This increase in protein is not accompanied with a raise in the Notch1 targets Hes1 and Hey1. Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma. Our research indicates that Notch1 is significantly displaced and accumulated in fibrillary structures in the susceptible hippocampal and cortical regions of sporadic AD patients. The dominant deposition of Notch1 in the brain parenchyma and its general signal reduction in neurons is consistent in all the AD patients analyzed and suggests that Notch1 may potentially be considered a novel hallmark of AD.

  8. The Role of Notch Signaling Pathway in Breast Cancer Pathogenesis

    DTIC Science & Technology

    2005-07-01

    proteins are activated upon binding to ligands of the Delta/Serrate family. In previous experiments I had found that activated allele of Notch1 cooperates...breast cancer cells, I tested whether ErbB2 overexpression will cooperate with Notch in HMLE cells. While overexpression of activated Notch1 failed to...tumorigenic behavior. 15. SUBJECT TERMS Notch, Ras, signaling, transformation, tumorigenesis 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  9. Comparative analysis of Notch1 and Notch2 binding sites in the genome of BxPC3 pancreatic cancer cells.

    PubMed

    Liu, Hao; Zhou, Ping; Lan, Hong; Chen, Jia; Zhang, Yu-Xiang

    2017-01-01

    Notch signaling plays a key role in the development of pancreatic cancer. Among the four identified Notch receptors, Notch1 and Notch2 share the highest homology. Notch1 has been reported to be an oncogene but some reports indicate that Notch2, not Notch1, plays a key role in pancreatic carcinogenesis. As both are transcription factors, examination of their genomic binding sites might reveal interesting functional differences between them. Notch proteins do not have DNA-binding domain. In the canonical Notch signaling pathway, ligand binding induces the release and nuclear translocation of Notch receptor intracellular domains (NICDs), which then interact with the transcription factor CSL, resulting in subsequent activation of the canonical Notch target genes. We investigated the binding site profiles of Notch1and Notch2 in the BxPC3 genome using CHIP-Seq and bioinfomatics. We found that Notch1, Notch2 and CSL generally bound to different target genes. We also found that only a small subset of Notch1 and Notch2 binding sites overlap with that of CSL, but about half of the CSL binding overlap with that of Notch1 or Notch2, indicating most Notch signaling activities are CSL-independent.

  10. Comparative analysis of Notch1 and Notch2 binding sites in the genome of BxPC3 pancreatic cancer cells

    PubMed Central

    Liu, Hao; Zhou, Ping; Lan, Hong; Chen, Jia; Zhang, Yu-xiang

    2017-01-01

    Notch signaling plays a key role in the development of pancreatic cancer. Among the four identified Notch receptors, Notch1 and Notch2 share the highest homology. Notch1 has been reported to be an oncogene but some reports indicate that Notch2, not Notch1, plays a key role in pancreatic carcinogenesis. As both are transcription factors, examination of their genomic binding sites might reveal interesting functional differences between them. Notch proteins do not have DNA-binding domain. In the canonical Notch signaling pathway, ligand binding induces the release and nuclear translocation of Notch receptor intracellular domains (NICDs), which then interact with the transcription factor CSL, resulting in subsequent activation of the canonical Notch target genes. We investigated the binding site profiles of Notch1and Notch2 in the BxPC3 genome using CHIP-Seq and bioinfomatics. We found that Notch1, Notch2 and CSL generally bound to different target genes. We also found that only a small subset of Notch1 and Notch2 binding sites overlap with that of CSL, but about half of the CSL binding overlap with that of Notch1 or Notch2, indicating most Notch signaling activities are CSL-independent. PMID:28123599

  11. Improved Notch Filter For Synchronous-Response Control

    NASA Technical Reports Server (NTRS)

    Johnson, Bruce G.; Downer, James R.; Eisenhaure, David B.; Hockney, Richard; Misovec, Kathleen

    1991-01-01

    Tracking differential-notch filter (TDNF) developed to retain good synchronous-response performance of notch filter, but with vastly improved stability properties. Measurement error perfectly filtered from feedback signal used to drive compensator. Provides good stability of simple lead/lag compensator combined with good synchronous-response performance gained by addition of notch filter.

  12. 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.

  13. O-Fucose Modulates Notch-Controlled Blood Lineage Commitment

    PubMed Central

    Yan, Quanjian; Yao, David; Wei, Lebing L.; Huang, Yuanshuai; Myers, Jay; Zhang, Lihua; Xin, Wei; Shim, Jeongsup; Man, Yunfang; Petryniak, Bronislawa; Gerson, Stanton; Lowe, John B.; Zhou, Lan

    2010-01-01

    Notch receptors are cell surface molecules essential for cell fate determination. Notch signaling is subject to tight regulation at multiple levels, including the posttranslational modification of Notch receptors by O-linked fucosylation, a reaction that is catalyzed by protein O-fucosyltransferase-1 (Pofut1). Our previous studies identified a myeloproliferative phenotype in mice conditionally deficient in cellular fucosylation that is attributable to a loss of Notch-dependent suppression of myelopoiesis. Here, we report that hematopoietic stem cells deficient in cellular fucosylation display decreased frequency and defective repopulating ability as well as decreased lymphoid but increased myeloid developmental potential. This phenotype may be attributed to suppressed Notch ligand binding and reduced downstream signaling of Notch activity in hematopoietic stem cells. Consistent with this finding, we further demonstrate that mouse embryonic stem cells deficient in Notch1 (Notch1−/−) or Pofut1 (Pofut1−/−) fail to generate T lymphocytes but differentiate into myeloid cells while coculturing with Notch ligand–expressing bone marrow stromal cells in vitro. Moreover, in vivo hematopoietic reconstitution of CD34+ progenitor cells derived from either Notch1−/− or Pofut1−/− embryonic stem cells show enhanced granulopoiesis with depressed lymphoid lineage development. Together, these results indicate that Notch signaling maintains hematopoietic lineage homeostasis by promoting lymphoid development and suppressing overt myelopoiesis, in part through processes controlled by O-linked fucosylation of Notch receptors. PMID:20363915

  14. Activation of the NOTCH pathway in Head and Neck Cancer

    PubMed Central

    Sun, Wenyue; Gaykalova, Daria A.; Ochs, Michael F.; Mambo, Elizabeth; Arnaoutakis, Demetri; Liu, Yan; Loyo, Myriam; Agrawal, Nishant; Howard, Jason; Li, Ryan; Ahn, Sun; Fertig, Elana; Sidransky, David; Houghton, Jeffery; Buddavarapu, Kalyan; Sanford, Tiffany; Choudhary, Ashish; Darden, Will; Adai, Alex; Latham, Gary; Bishop, Justin; Sharma, Rajni; Westra, William H.; Hennessey, Patrick; Chung, Christine H.; Califano, Joseph A.

    2014-01-01

    NOTCH1 mutations have been reported to occur in 10 to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of these mutations, we embarked upon a comprehensive study of NOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation and mutation analyses. Copy number increases were identified in NOTCH pathway genes including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1 mutations in 4/37 of the tumors analyzed, with none of these tumors exhibiting HES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptors mutations but a larger subset exhibiting other NOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently. PMID:24351288

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

    PubMed

    Capaccione, Kathleen M; Pine, Sharon R

    2013-07-01

    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.

  16. Recent advances on NOTCH signaling in T-ALL.

    PubMed

    Tzoneva, Gannie; Ferrando, Adolfo A

    2012-01-01

    NOTCH1 receptor signaling plays a central role in T-cell lineage specification and in supporting the growth and proliferation of immature T-cell progenitors in the thymus during lymphoid development. In T-cell acute lymphoblastic leukemia (T-ALL), a tumor resulting from the malignant transformation of T-cell progenitors, aberrant and constitutively active NOTCH1 signaling triggered by activating mutations in the NOTCH1 gene contributes to oncogenic transformation and is a hallmark of this disease. Most notably, small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease. In addition, a number of emerging anti-NOTCH therapeutic strategies including anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs and glucocorticoids, have recently been proposed. Finally, the identification of NOTCH1 mutations in solid tumors and chronic lymphocytic leukemias has increased even further the clinical relevance of NOTCH signaling as a therapeutic target in human cancer. Here we review our current understanding of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 in T-ALL and the therapeutic and prognostic implications of NOTCH1 mutations in T-ALL.

  17. Interactions between fibroblast growth factors and Notch regulate neuronal differentiation.

    PubMed

    Faux, C H; Turnley, A M; Epa, R; Cappai, R; Bartlett, P F

    2001-08-01

    The differentiation of precursor cells into neurons has been shown to be influenced by both the Notch signaling pathway and growth factor stimulation. In this study, the regulation of neuronal differentiation by these mechanisms was examined in the embryonic day 10 neuroepithelial precursor (NEP) population. By downregulating Notch1 expression and by the addition of a Delta1 fusion protein (Delta Fc), it was shown that signaling via the Notch pathway inhibited neuron differentiation in the NEP cells, in vitro. The expression of two of the Notch receptor homologs, Notch1 and Notch3, and the ligand Delta1 in these NEP cells was found to be influenced by a number of different growth factors, indicating a potential interaction between growth factors and Notch signaling. Interestingly, none of the growth factors examined promoted neuron differentiation; however, the fibroblast growth factors (FGFs) 1 and 2 potently inhibited differentiation. FGF1 and FGF2 upregulated the expression of Notch and decreased expression of Delta1 in the NEP cells. In addition, the inhibitory response of the cells to the FGFs could be overcome by downregulating Notch1 expression and by disrupting Notch cleavage and signaling by the ablation of the Presenilin1 gene. These results indicate that FGF1 and FGF2 act via the Notch pathway, either directly or indirectly, to inhibit differentiation. Thus, signaling through the Notch receptor may be a common regulator of neuronal differentiation within the developing forebrain.

  18. Reduced Notch signaling leads to renal cysts and papillary microadenomas.

    PubMed

    Surendran, Kameswaran; Selassie, Meron; Liapis, Helen; Krigman, Hannah; Kopan, Raphael

    2010-05-01

    The formation of proximal nephron segments requires canonical Notch2 signaling, but other functions of Notch signaling during renal development are incompletely understood. Here, we report that proximal tubules forming with reduced Notch signaling, resulting from delayed conditional inactivation of Notch1 and/or Notch2, are prone to cyst formation and tubular epithelial stratification. Conditional inactivation of the DNA binding factor RBP-J, which mediates Notch signaling, also resulted in multiple congenital cysts arising from the proximal tubule. Moreover, a few stratified foci/microadenomas containing hyperproliferative cells, resembling precursors of papillary renal cell carcinoma, formed in these proximal tubules. Epithelial stratification correlated neither with reduced expression of the transcriptional regulator of ciliary proteins TCF2/HNF1beta nor with loss of apical-basal polarity. Instead, Notch signaling helped to restrict the orientation of epithelial mitotic spindles to a plane parallel to the basement membrane during nephron elongation. In the absence of Notch, random spindle orientation may explain the epithelial stratification and cyst formation. Furthermore, post hoc analysis of human class 1 papillary renal cell carcinoma revealed reduced Notch activity in these tumors, resulting from abundant expression of a potent inhibitor of canonical Notch signaling, KyoT3/FHL1B. In summary, these data suggest that canonical Notch signaling maintains the alignment of cell division in the proximal tubules during nephrogenesis and that perturbations in Notch signaling may lead to cystic renal disease and tumorigenesis.

  19. Reduced Notch Signaling Leads to Renal Cysts and Papillary Microadenomas

    PubMed Central

    Surendran, Kameswaran; Selassie, Meron; Liapis, Helen; Krigman, Hannah

    2010-01-01

    The formation of proximal nephron segments requires canonical Notch2 signaling, but other functions of Notch signaling during renal development are incompletely understood. Here, we report that proximal tubules forming with reduced Notch signaling, resulting from delayed conditional inactivation of Notch1 and/or Notch2, are prone to cyst formation and tubular epithelial stratification. Conditional inactivation of the DNA binding factor RBP-J, which mediates Notch signaling, also resulted in multiple congenital cysts arising from the proximal tubule. Moreover, a few stratified foci/microadenomas containing hyperproliferative cells, resembling precursors of papillary renal cell carcinoma, formed in these proximal tubules. Epithelial stratification correlated neither with reduced expression of the transcriptional regulator of ciliary proteins TCF2/HNF1β nor with loss of apical-basal polarity. Instead, Notch signaling helped to restrict the orientation of epithelial mitotic spindles to a plane parallel to the basement membrane during nephron elongation. In the absence of Notch, random spindle orientation may explain the epithelial stratification and cyst formation. Furthermore, post hoc analysis of human class 1 papillary renal cell carcinoma revealed reduced Notch activity in these tumors, resulting from abundant expression of a potent inhibitor of canonical Notch signaling, KyoT3/FHL1B. In summary, these data suggest that canonical Notch signaling maintains the alignment of cell division in the proximal tubules during nephrogenesis and that perturbations in Notch signaling may lead to cystic renal disease and tumorigenesis. PMID:20378824

  20. 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

  1. HES6 promotes prostate cancer aggressiveness independently of Notch signalling.

    PubMed

    Carvalho, Filipe L F; Marchionni, Luigi; Gupta, Anuj; Kummangal, Basheer A; Schaeffer, Edward M; Ross, Ashley E; Berman, David M

    2015-07-01

    Notch signalling is implicated in the pathogenesis of a variety of cancers, but its role in prostate cancer is poorly understood. However, selected Notch pathway members are overrepresented in high-grade prostate cancers. We comprehensively profiled Notch pathway components in prostate cells and found prostate cancer-specific up-regulation of NOTCH3 and HES6. Their expression was particularly high in androgen responsive lines. Up- and down-regulating Notch in these cells modulated expression of canonical Notch targets, HES1 and HEY1, which could also be induced by androgen. Surprisingly, androgen treatment also suppressed Notch receptor expression, suggesting that androgens can activate Notch target genes in a receptor-independent manner. Using a Notch-sensitive Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) reporter assay, we found that basal levels of Notch signalling were significantly lower in prostate cancer cells compared to benign cells. Accordingly pharmacological Notch pathway blockade did not inhibit cancer cell growth or viability. In contrast to canonical Notch targets, HES6, a HES family member known to antagonize Notch signalling, was not regulated by Notch signalling, but relied instead on androgen levels, both in cultured cells and in human cancer tissues. When engineered into prostate cancer cells, reduced levels of HES6 resulted in reduced cancer cell invasion and clonogenic growth. By molecular profiling, we identified potential roles for HES6 in regulating hedgehog signalling, apoptosis and cell migration. Our results did not reveal any cell-autonomous roles for canonical Notch signalling in prostate cancer. However, the results do implicate HES6 as a promoter of prostate cancer progression.

  2. Molecular Pathways of Notch Signaling in Vascular Smooth Muscle Cells

    PubMed Central

    Boucher, Joshua; Gridley, Thomas; Liaw, Lucy

    2012-01-01

    Notch signaling in the cardiovascular system is important during embryonic development, vascular repair of injury, and vascular pathology in humans. The vascular smooth muscle cell (VSMC) expresses multiple Notch receptors throughout its life cycle, and responds to Notch ligands as a regulatory mechanism of differentiation, recruitment to growing vessels, and maturation. The goal of this review is to provide an overview of the current understanding of the molecular basis for Notch regulation of VSMC phenotype. Further, we will explore Notch interaction with other signaling pathways important in VSMC. PMID:22509166

  3. Notch pathway is dispensable for adipocyte specification.

    PubMed

    Nichols, Amy M; Pan, Yonghua; Herreman, An; Hadland, Brandon K; De Strooper, Bart; Kopan, Raphael; Huppert, Stacey S

    2004-09-01

    In the past decade we have witnessed an epidemic of obesity in developed countries. Therefore, understanding the mechanisms involved in regulation of body weight is becoming an increasingly important goal shared by the public and the scientific community. The key to fat deposition is the adipocyte, a specialized cell that plays a critical role in energy balance and appetite regulation. Much of our knowledge of adipogenesis comes from studies using preadipocytic cell lines that have provided important information regarding molecular control of adipocyte differentiation. However, they fall short of revealing how naive cells acquire competence for adipogenesis. Studies in preadipocytes indicate that the Notch pathway plays a role in regulating adipogenesis (Garces et al.: J Biol Chem 272:29729-29734, 1997). Given the known biological functions of Notch in mediating cell fate decisions (Artavanis-Tsakonas et al.: Science 284:770-776, 1999), we wished to test the hypothesis that the Notch pathway is required for this cellular program by examining adipogenesis in several genetic loss-of-function models that encompass the entire pathway. We conclude that the "canonical" Notch signaling pathway is dispensable for adipocyte specification and differentiation from either mesenchymal or epithelial progenitors.

  4. 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.

  5. Notch and VEGF Interactions in Breast Cancer

    DTIC Science & Technology

    2006-04-01

    induces VEGFR-3 expression in cultured endothelial cells, we want to test whether blocking Notch activity suppressed tumor growth and pathological...Y.W., Shawber, C., Paty, P. and Barany , F. (2005) Accurate multiplexed detection of methylation status in CpG islands of candidate genes using a

  6. Notch3 Interactome Analysis Identified WWP2 as a Negative Regulator of Notch3 Signaling in Ovarian Cancer

    PubMed Central

    Guan, Bin; Wu, Ren-Chin; Zhu, Heng; Blackshaw, Seth; Shih, Ie-Ming; Wang, Tian-Li

    2014-01-01

    The Notch3 signaling pathway is thought to play a critical role in cancer development, as evidenced by the Notch3 amplification and rearrangement observed in human cancers. However, the molecular mechanism by which Notch3 signaling contributes to tumorigenesis is largely unknown. In an effort to identify the molecular modulators of the Notch3 signaling pathway, we screened for Notch3-intracellular domain (N3-ICD) interacting proteins using a human proteome microarray. Pathway analysis of the Notch3 interactome demonstrated that ubiquitin C was the molecular hub of the top functional network, suggesting the involvement of ubiquitination in modulating Notch3 signaling. Thereby, we focused on functional characterization of an E3 ubiquitin-protein ligase, WWP2, a top candidate in the Notch3 interactome list. Co-immunoprecipitation experiments showed that WWP2 interacted with N3-ICD but not with intracellular domains from other Notch receptors. Wild-type WWP2 but not ligase-deficient mutant WWP2 increases mono-ubiquitination of the membrane-tethered Notch3 fragment, therefore attenuating Notch3 pathway activity in cancer cells and leading to cell cycle arrest. The mono-ubiquitination by WWP2 may target an endosomal/lysosomal degradation fate for Notch3 as suggested by the fact that the process could be suppressed by the endosomal/lysosomal inhibitor. Analysis of The Cancer Genome Atlas dataset showed that the majority of ovarian carcinomas harbored homozygous or heterozygous deletions in WWP2 locus, and there was an inverse correlation in the expression levels between WWP2 and Notch3 in ovarian carcinomas. Furthermore, ectopic expression of WWP2 decreased tumor development in a mouse xenograft model and suppressed the Notch3-induced phenotypes including increase in cancer stem cell-like cell population and platinum resistance. Taken together, our results provide evidence that WWP2 serves as a tumor suppressor by negatively regulating Notch3 signaling in ovarian cancer

  7. Inhibitory role of Notch1 in calcific aortic valve disease.

    PubMed

    Acharya, Asha; Hans, Chetan P; Koenig, Sara N; Nichols, Haley A; Galindo, Cristi L; Garner, Harold R; Merrill, Walter H; Hinton, Robert B; Garg, Vidu

    2011-01-01

    Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.

  8. Kuz and TACE can activate Notch independent of ligand

    PubMed Central

    Delwig, Anton; Rand, Matthew D.

    2010-01-01

    A central mechanism in activation of the Notch signaling pathway is cleavage of the Notch receptor by ADAM metalloproteases. ADAMs also cleave Delta, the ligand for Notch, thereby downregulating Notch signals. Two ADAMs, Kuzbanian (Kuz) and TNF-α converting enzyme (TACE), are known to process both Delta and Notch, yet the role of these cleavages in signal propagation has remained controversial. Using an in-vitro model, we show that Kuz regulates Notch signaling primarily by activating the receptor and has little overall effect on signaling via disabling Delta. We confirm that Kuz-dependent activation of Notch requires stimulation of Notch by Delta. However, over-expression of Kuz gives ligand-independent Notch activation. In contrast, TACE, which is elevated in expression in developing Drosophila nervous system, can efficiently activate Notch in a ligand-independent manner. Altogether, these data demonstrate the potential for Kuz and TACE to participate in context- and mechanism-specific modes of Notch activation. PMID:18535782

  9. NOTCHing the bone: insights into multi-functionality.

    PubMed

    Engin, Feyza; Lee, Brendan

    2010-02-01

    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. (c) 2009 Elsevier Inc. All rights reserved.

  10. Notch signaling in the brain: in good and bad times.

    PubMed

    Alberi, Lavinia; Hoey, Sarah E; Brai, Emanuele; Scotti, Alessandra L; Marathe, Swananda

    2013-06-01

    Notch signaling is an evolutionarily conserved pathway, which is fundamental for neuronal development and specification. In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimer's disease and ischemic injury. The molecular mechanisms by which Notch displays these functions in the mature brain are not fully understood, but are currently the subject of intense research. In this review, we will discuss old and novel Notch targets and molecular mediators that contribute to Notch function in the mature brain and will summarize recent findings that explore the two facets of Notch signaling in brain physiology and pathology. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Notch filtering the nuclear environment of a spin qubit

    NASA Astrophysics Data System (ADS)

    Malinowski, Filip K.; Martins, Frederico; Nissen, Peter D.; Barnes, Edwin; Cywiński, Łukasz; Rudner, Mark S.; Fallahi, Saeed; Gardner, Geoffrey C.; Manfra, Michael J.; Marcus, Charles M.; Kuemmeth, Ferdinand

    2017-01-01

    Electron spins in gate-defined quantum dots provide a promising platform for quantum computation. In particular, spin-based quantum computing in gallium arsenide takes advantage of the high quality of semiconducting materials, reliability in fabricating arrays of quantum dots and accurate qubit operations. However, the effective magnetic noise arising from the hyperfine interaction with uncontrolled nuclear spins in the host lattice constitutes a major source of decoherence. Low-frequency nuclear noise, responsible for fast (10 ns) inhomogeneous dephasing, can be removed by echo techniques. High-frequency nuclear noise, recently studied via echo revivals, occurs in narrow-frequency bands related to differences in Larmor precession of the three isotopes 69Ga, 71Ga and 75As (refs 15,16,17). Here, we show that both low- and high-frequency nuclear noise can be filtered by appropriate dynamical decoupling sequences, resulting in a substantial enhancement of spin qubit coherence times. Using nuclear notch filtering, we demonstrate a spin coherence time (T2) of 0.87 ms, five orders of magnitude longer than typical exchange gate times, and exceeding the longest coherence times reported to date in Si/SiGe gate-defined quantum dots.

  12. Notch filtering the nuclear environment of a spin qubit.

    PubMed

    Malinowski, Filip K; Martins, Frederico; Nissen, Peter D; Barnes, Edwin; Cywiński, Łukasz; Rudner, Mark S; Fallahi, Saeed; Gardner, Geoffrey C; Manfra, Michael J; Marcus, Charles M; Kuemmeth, Ferdinand

    2017-01-01

    Electron spins in gate-defined quantum dots provide a promising platform for quantum computation. In particular, spin-based quantum computing in gallium arsenide takes advantage of the high quality of semiconducting materials, reliability in fabricating arrays of quantum dots and accurate qubit operations. However, the effective magnetic noise arising from the hyperfine interaction with uncontrolled nuclear spins in the host lattice constitutes a major source of decoherence. Low-frequency nuclear noise, responsible for fast (10 ns) inhomogeneous dephasing, can be removed by echo techniques. High-frequency nuclear noise, recently studied via echo revivals, occurs in narrow-frequency bands related to differences in Larmor precession of the three isotopes (69)Ga, (71)Ga and (75)As (refs 15,16,17). Here, we show that both low- and high-frequency nuclear noise can be filtered by appropriate dynamical decoupling sequences, resulting in a substantial enhancement of spin qubit coherence times. Using nuclear notch filtering, we demonstrate a spin coherence time (T2) of 0.87 ms, five orders of magnitude longer than typical exchange gate times, and exceeding the longest coherence times reported to date in Si/SiGe gate-defined quantum dots.

  13. 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.

  14. Prognostic values of Notch receptors in breast cancer.

    PubMed

    Xu, Junming; Song, Fangbin; Jin, Tao; Qin, Jun; Wu, Junyi; Wang, Min; Wang, Ye; Liu, Jun

    2016-02-01

    Notch receptors are frequently deregulated in several human malignancies including human breast cancer. Activation of Notch has been reported to cause mammary carcinomas in mice. However, the prognostic value of individual Notch receptors in breast cancer (BC) patients remains elusive. In the current study, we investigated the prognostic value of Notch receptors in human BC patients. More specifically, we investigated the prognostic value of four Notch receptors in breast cancer patients through "the Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information are from a total of 3554 breast cancer patients. Our results showed that Notch1 messenger RNA (mRNA) high expression was correlated to worsen overall survival (OS) in PgR-negative BC patients. Notch2, Notch3, and Notch4 mRNA high expressions were found to be correlated to better OS for all breast cancer patients. Notch2 was also found to be correlated to better OS in lymph node-negative breast cancer patients and HER2-positive breast cancer patients. These results will be useful for better understanding of the heterogeneity and complexity in the molecular biology of breast cancer and for developing tools to more accurately predict their prognosis and design their customized treatment strategies.

  15. Notch as a Driver of Gastric Epithelial Cell Proliferation.

    PubMed

    Demitrack, Elise S; Samuelson, Linda C

    2017-05-01

    The gastric epithelium is sustained by a population of stem cells that replenish the various mature epithelial lineages throughout adulthood. Regulation of stem and progenitor cell proliferation occurs via basic developmental signaling pathways, including the Notch pathway, which recently was described to promote gastric stem cell proliferation in both mice and human beings. Current cancer theory proposes that adult stem cells that maintain gastrointestinal tissues accumulate mutations that promote cancerous growth, and that basic signaling pathways, such as Notch, which stimulate stem cell proliferation, can promote tumorigenesis. Accordingly, constitutive Notch activation leads to unchecked cellular proliferation and gastric tumors in genetic mouse models. Furthermore, there is emerging evidence suggesting that the Notch pathway may be activated in some human gastric cancers, supporting a potential role for Notch in gastric tumorigenesis. In this review, we first summarize the current understanding of gastric stem cells defined by genetic mouse studies, followed by discussion of the literature regarding Notch pathway regulation of gastric stem cell function in the mouse and human beings. Notch action to maintain gastric epithelial cell homeostasis and the cellular consequences of dysregulated signaling to promote tumorigenesis are discussed, including studies associating Notch activation with human gastric cancer. Finally, we compare and contrast Notch function in the stomach with other gastrointestinal tissues, including the intestine, to highlight the sensitivity of the stomach to Notch-induced tumors.

  16. Functional Roles of Notch Signaling in the cnidarian Nematostella vectensis

    PubMed Central

    Marlow, Heather; Roettinger, Eric; Boekhout, Michiel; Martindale, Mark Q.

    2013-01-01

    Notch signaling is among the oldest of known Metazoan signaling pathways and is used in a multitude of developmental contexts to effect cellular differentiation, specification and the maintenance of stem cell state. Here we report the isolation and expression of the canonical Notch signaling pathway in the early branching metazoan Nematostella vectensis (Anthozoa, Cnidaria) during embryonic and larval development. We have used pharmacological treatment, morpholino knockdown, and dominant negative misexpression experiments to demonstrate that Notch signaling acts to mediate cnidogenesis, the development of cnidarian-specific neural effecter cells. Notch signaling often results in the transcriptional activation of NvHes genes, a conserved family of bHLH transcription factors. A loss of Notch signaling through use of pharmacological inhibition or knock-down of the Notch effecter gene Suppressor of Hairless Su(H) similarly results in a loss of cnidocyte cell fate. We also provide evidence that Notch signaling is responsible for certain aspects of neurogenesis in developing N. vectensis planula in which disruption of Notch cleavage via the pharmacological agent DAPT results in increased expression of neural marker genes in vivo. This data suggests that Notch signaling acting on components of the developing nervous system is an ancient role of this pathway. The shared requirement of Notch signaling for the development of both cnidocytes and neurons further supports the hypothesis that cnidocytes and neurons share common origins as multifunctional sensory-effecter cells. PMID:22155407

  17. Inferior scapular notching following encore reverse shoulder prosthesis.

    PubMed

    Levy, Jonathan; Blum, Sara

    2009-10-01

    Inferior scapular notching following reverse shoulder arthroplasty has been described using devices with a center of rotation located at the glenoid. Notching is typically seen within the first few months. To date, the only prosthesis without a reported case of scapular notching is the Encore Reverse Shoulder Prosthesis (RSP) (DJO Surgical, Austin, Texas). We present the first reported case of inferior scapular notching with the Encore RSP seen in a patient treated using an alternative glenosphere (36 minus 4) with a center of rotation 2 mm lateral to the glenoid. The glenosphere was implanted using previously described techniques to avoid scapular notching: inferior tilt and inferior translation with overhang of the glenosphere. Inferior scapular notching was not observed at 1-year follow-up. However, at 2-year follow-up, radiographs revealed Sirveaux Grade 2 scapular notching. This case illustrates that using a glenosphere with a center of rotation at or near the glenoid places the shoulder at risk for scapular notching. When choosing this type of design, the treating surgeon must maintain a high index of suspicion for scapular notching as intermediate and long-term follow-up radiographs are reviewed. Scapular notching for these devices may develop later than devices with a center of rotation at the glenoid.

  18. Notch signaling and new therapeutic options in liver disease.

    PubMed

    Morell, Carola Maria; Strazzabosco, Mario

    2014-04-01

    Notch signaling is a crucial determinant of cell fate decision during development and disease in several organs. Notch effects are strictly dependent on the cellular context in which it is activated. In the liver, Notch signaling is involved in biliary tree development and tubulogenesis. Recent advances have shed light on Notch as a critical player in liver regeneration and repair, as well as in liver metabolism and inflammation and cancer. Notch signaling is finely regulated at several levels. The complexity of the pathway provides several possible targets for development of therapeutic agents able to inhibit Notch. Recent reports have shown that persistent activation of Notch signaling is associated with liver malignancies, particularly hepatocellular with stem cell features and cholangiocarcinoma. These novel findings suggest that interfering with the aberrant activation of the Notch pathway may have therapeutic relevance. However, further studies are needed to clarify the mechanisms regulating physiologic and pathologic Notch activation in the adult liver, to better understand the mechanistic role(s) of Notch in liver diseases and to develop safe and specific therapeutic agents.

  19. Emerging roles of Notch signaling in liver disease

    PubMed Central

    Geisler, Fabian; Strazzabosco, Mario

    2014-01-01

    This review critically discusses the most recent advances on the role of Notch signaling in liver development, homeostasis and disease. It is now clear that the significance of Notch in determining mammalian cell fates and functions extends beyond development, and Notch is a major regular of organ homeostasis. Moreover, Notch signaling is reactivated upon injury and regulates the complex interactions between the distinct cellular types involved in the repair process. Notch is also involved in the regulation of liver metabolism, inflammation and cancer. The net effects of Notch signaling are highly variable and finely regulated at multiple levels, but also depend on the specific cellular context in which Notch is activated. Persistent activation of Notch signaling is associated with liver malignancies, such as hepatocellular carcinoma with stem cell features and intrahepatic cholangiocarcinoma. The complexity of the pathway provides several possible targets for agents able to inhibit Notch. However, further cell- and context-specific in depth understanding of Notch signaling in liver homeostasis and disease will be essential to translate these concepts into the clinical practice and be able to predict benefits and risks of evolving therapies. PMID:24930574

  20. Dynamics of notch expression during murine prostate development and tumorigenesis.

    PubMed

    Shou, J; Ross, S; Koeppen, H; de Sauvage, F J; Gao, W Q

    2001-10-01

    Notch signaling has been widely demonstrated to be responsible for cell fate determination during normal development and implicated in human T-cell leukemia and mouse mammary carcinomas. Here we show that Notch signaling may be involved in prostatic development and cancer cell growth. In situ hybridization and reverse transcription-PCR analyses revealed that Notch1 was expressed in prostate epithelial cells during normal development and in prostate cancer cells. Characterization of Notch1-green fluorescent protein transgenic mice, in which the expression of reporter green fluorescent protein is under the control of the Notch1 promoter, indicated that Notch1-expressing cells were associated with the basal epithelial cell population in the prostate. Examination of the transgenic adenocarcinoma of the mouse prostate showed that expression of Notch1 was elevated in malignant prostatic epithelial cells of primary and metastatic tumors. Expression of Notch ligands, however, was low or undetectable in cultured prostate cancer cells or in malignant prostatic epithelial cells in transgenic adenocarcinoma of the mouse prostate. Furthermore, overexpression of a constitutively active form of Notch1 inhibited the proliferation of various prostate cancer cells, including DU145, LNCaP, and PC3 cells. Taken together, our data indicate for the first time that Notch signaling may play a role in murine prostatic development and tumorigenesis.

  1. Notch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing.

    PubMed

    Kimball, Andrew S; Joshi, Amrita D; Boniakowski, Anna E; Schaller, Matthew; Chung, Jooho; Allen, Ronald; Bermick, Jennifer; Carson, William F; Henke, Peter K; Maillard, Ivan; Kunkel, Steve L; Gallagher, Katherine A

    2017-01-01

    Macrophages are essential immune cells necessary for regulated inflammation during wound healing. Recent studies have identified that Notch plays a role in macrophage-mediated inflammation. Thus, we investigated the role of Notch signaling on wound macrophage phenotype and function during normal and diabetic wound healing. We found that Notch receptor and ligand expression are dynamic in wound macrophages during normal healing. Mice with a myeloid-specific Notch signaling defect (DNMAML(floxed)Lyz2(Cre+) ) demonstrated delayed early healing (days 1-3) and wound macrophages had decreased inflammatory gene expression. In our physiologic murine model of type 2 diabetes (T2D), Notch receptor expression was significantly increased in wound macrophages on day 6, following the initial inflammatory phase of wound healing, corresponding to increased inflammatory cytokine expression. This increase in Notch1 and Notch2 was also observed in human monocytes from patients with T2D. Further, in prediabetic mice with a genetic Notch signaling defect (DNMAML(floxed)Lyz2(Cre+) on a high-fat diet), improved wound healing was seen at late time points (days 6-7). These findings suggest that Notch is critical for the early inflammatory phase of wound healing and directs production of macrophage-dependent inflammatory mediators. These results identify that canonical Notch signaling is important in directing macrophage function in wound repair and define a translational target for the treatment of non-healing diabetic wounds.

  2. Notch signaling in prostate cancer: refining a therapeutic opportunity

    PubMed Central

    Su, Qingtai; Xin, Li

    2016-01-01

    Summary Notch is an evolutionarily conserved signaling pathway that plays a critical role in specifying cell fate and regulating tissue homeostasis and carcinogenesis. Studies using organ cultures and genetically engineered mouse models have demonstrated that Notch signaling regulates prostate development and homeostasis. However, the role of the Notch signaling pathway in prostate cancer remains inconclusive. Many published studies have documented consistent deregulation of major Notch signaling components in human prostate cancer cell lines, mouse models for prostate cancers, and human prostate cancer specimens at both the mRNA and the protein levels. However, functional studies in human cancer cells by modulation of Notch pathway elements suggest both tumor suppressive and oncogenic roles of Notch. These controversies may originate from our inadequate understanding of the regulation of Notch signaling under versatile genetic contexts, and reflect the multifaceted and pleiotropic roles of Notch in regulating different aspects of prostate cancer cell biology, such as proliferation, metastasis, and chemo-resistance. Future comprehensive studies using various mouse models for prostate cancer may help clarify the role of Notch signaling in prostate cancer and provide a solid basis for determining whether and how Notch should be employed as a therapeutic target for prostate cancer. PMID:26521657

  3. Targeting Notch signaling as a novel therapy for retinoblastoma

    PubMed Central

    Asnaghi, Laura; Tripathy, Arushi; Yang, Qian; Kaur, Harpreet; Hanaford, Allison; Yu, Wayne; Eberhart, Charles G.

    2016-01-01

    Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma. PMID:27661116

  4. Mutations of NOTCH3 in childhood pulmonary arterial hypertension

    PubMed Central

    Chida, Ayako; Shintani, Masaki; Matsushita, Yoshihisa; Sato, Hiroki; Eitoku, Takahiro; Nakayama, Tomotaka; Furutani, Yoshiyuki; Hayama, Emiko; Kawamura, Yoichi; Inai, Kei; Ohtsuki, Shinichi; Saji, Tsutomu; Nonoyama, Shigeaki; Nakanishi, Toshio

    2014-01-01

    Mutations of BMPR2 and other TGF-β superfamily genes have been reported in pulmonary arterial hypertension (PAH). However, 60–90% of idiopathic PAH cases have no mutations in these genes. Recently, the expression of NOTCH3 was shown to be increased in the pulmonary artery smooth muscle cells of PAH patients. We sought to investigate NOTCH3 and its target genes in PAH patients and clarify the role of NOTCH3 signaling. We screened for mutations in NOTCH3, HES1, and HES5 in 41 PAH patients who had no mutations in BMPR2, ALK1, endoglin, SMAD1/4/8, BMPR1B, or Caveolin-1. Two novel missense mutations (c.2519 G>A p.G840E, c.2698 A>C p.T900P) in NOTCH3 were identified in two PAH patients. We performed functional analysis using stable cell lines expressing either wild-type or mutant NOTCH3. The protein-folding chaperone GRP78/BiP was colocalized with wild-type NOTCH3 in the endoplasmic reticulum, whereas the majority of GRP78/BiP was translocated into the nuclei of cells expressing mutant NOTCH3. Cell proliferation and viability were higher for cells expressing mutant NOTCH3 than for those expressing wild-type NOTCH3. We identified novel NOTCH3 mutations in PAH patients and revealed that these mutations were involved in cell proliferation and viability. NOTCH3 mutants induced an impairment in NOTCH3-HES5 signaling. The results may contribute to the elucidation of PAH pathogenesis. PMID:24936512

  5. Phototunable reflection notches of cholesteric liquid crystals

    NASA Astrophysics Data System (ADS)

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

    2008-09-01

    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.

  6. 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.

  7. Notch Activation Induces Endothelial Cell Senescence and Pro-inflammatory Response: Implication of Notch Signaling in Atherosclerosis

    PubMed Central

    Liu, Zhao-Jun; Tan, Yurong; Beecham, Gary W.; Seo, David M.; Tian, Runxia; Li, Yan; Vazquez-Padron, Roberto I.; Pericak-Vance, Margaret; Vance, Jeffery M.; Goldschmidt-Clermont, Pascal J.; Livingstone, Alan S.; Velazquez, Omaida C.

    2012-01-01

    Objective Notch signaling plays pivotal roles in the pathogenesis of vascular disease. However, little is known about its role in atherosclerosis. We sought to investigate the potential involvement of the Notch signaling in atherosclerosis. Methods Expression of Notch pathway components in mouse and human aorta with or without atherosclerosis plaque was examined by immuno-histochemistry. Expression of Notch target genes in young versus aged human endothelial cells (EC) was examined by PCRArray and immunoblot. In vitro loss- and gain-of-function approaches were utilized to evaluate the role of Notch signaling in inducing EC senescence and secretion of pro-inflammatory cytokines by ProteinArray. Notch gene profile was studied in 1054 blood samples of patients with coronary artery disease (CAD). Genotyping was performed using the Genome-Wide Single Nucleotide Polymorphism (SNP) Array. Results Notch pathway components were upregulated in luminal EC at atherosclerotic lesions from mouse and human aortas. In addition, the Notch pathway was activated in aged but not young human EC. Enforced Notch activation resulted in EC senescence and significantly upregulated expression of several molecules implicated in the inflammatory response (IL-6/IL-8/IL-1α/RANTES/ICAM-1). The upregulated IL-6 was partially responsible for mediating leukocyte transendothelial migration. Genetic association analysis detected, of 82 SNPs across 6 Notch pathway genes analyzed, 4 SNPs with nominal association with CAD burden. Conclusion Notch pathway is activated in luminal EC at atherosclerotic plaques and results in pro-inflammatory response and senescence of EC. Notch signaling may be linked to human CAD risk. These findings implicate a potential involvement of Notch signaling in atherosclerosis. PMID:23078884

  8. Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes

    PubMed Central

    2012-01-01

    Introduction Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis. Methods Mouse bone marrow-derived macrophages or human peripheral blood monocytes were used as osteoclast precursors and cultured with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) to induce osteoclasts. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. K/BxN serum-induced arthritic mice and ovariectomized mice were treated with anti-mouse Delta-like 1 (Dll1) blocking monoclonal antibody (mAb). Results Blockade of a Notch ligand Dll1 with mAb inhibited osteoclastogenesis and, conversely, immobilized Dll1-Fc fusion protein enhanced it in both mice and humans. In contrast, blockade of a Notch ligand Jagged1 enhanced osteoclastogenesis and immobilized Jagged1-Fc suppressed it. Enhancement of osteoclastogenesis by agonistic anti-Notch2 mAb suggested that Dll1 promoted osteoclastogenesis via Notch2, while suppression by agonistic anti-Notch1 mAb suggested that Jagged1 suppressed osteoclastogenesis via Notch1. Inhibition of Notch signaling by a gamma-secretase inhibitor suppressed osteoclastogenesis, implying that Notch2/Dll1-mediated enhancement was dominant. Actually, blockade of Dll1 ameliorated arthritis induced by K/BxN serum transfer, reduced the number of osteoclasts in the affected joints and suppressed ovariectomy-induced bone loss. Conclusions The differential regulation of osteoclastogenesis by Notch2/Dll1 and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients. PMID:22390640

  9. Dynamic chromatin regulation at Notch target genes

    PubMed Central

    Giaimo, Benedetto Daniele; Oswald, Franz; Borggrefe, Tilman

    2017-01-01

    ABSTRACT RBPJ is the central transcription factor that controls the Notch-dependent transcriptional response by coordinating repressing histone H3K27 deacetylation and activating histone H3K4 methylation. Here, we discuss the molecular mechanisms how RBPJ interacts with opposing NCoR/HDAC-corepressing or KMT2D/UTX-coactivating complexes and how this is controlled by phosphorylation of chromatin modifiers. PMID:28027012

  10. 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

  11. Notch signal integration in the vasculature during remodeling

    PubMed Central

    Rostama, Bahman; Peterson, Sarah M.; Vary, Calvin P. H.; Liaw, Lucy

    2014-01-01

    Notch signaling plays many important roles in homeostasis and remodeling in the vessel wall, and serves a critical role in the communication between endothelial cells and smooth muscle cells. Within blood vessels, Notch signaling integrates with multiple pathways by mechanisms including direct protein-protein interaction, cooperative or synergistic regulation of signal cascades, and co-regulation of transcriptional targets. After establishment of the mature blood vessel, the spectrum and intensity of Notch signaling changes during phases of active remodeling or disease progression. These changes can be mediated by regulation via microRNAs and protein stability or signaling, and corresponding changes in complementary signaling pathways. Notch also affects endothelial cells on a systems level by regulating key metabolic components. This review will outline the most recent findings of Notch activity in blood vessels, with a focus on how Notch signals integrate with other molecular signaling pathways controlling vascular phenotype. PMID:25464152

  12. Direct inhibition of the NOTCH transcription factor complex.

    PubMed

    Moellering, Raymond E; Cornejo, Melanie; Davis, Tina N; Del Bianco, Cristina; Aster, Jon C; Blacklow, Stephen C; Kung, Andrew L; Gilliland, D Gary; Verdine, Gregory L; Bradner, James E

    2009-11-12

    Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.

  13. Notch Signaling Proteins: Legitimate Targets for Cancer Therapy

    PubMed Central

    Wang, Zhiwei; Li, Yiwei; Sarkar, Fazlul H.

    2011-01-01

    Proteins and small peptides (growth factors and hormones) are key molecules in maintaining cellular homeostasis. To that end, Notch signaling pathway proteins are known to play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis, and thus it has been suggested that Notch may be responsible for the development and progression of human malignancies. Therefore, the Notch signaling pathway proteins may present novel therapeutic targets, which could have promising therapeutic impact on eradicating human malignancies. This review describes the role of Notch signaling pathway proteins in cancer and how its deregulation is involved in tumor development and progression leading to metastasis and the ultimate demise of patients diagnosed with cancer. Further, we summarize the role of several Notch inhibitors especially “natural agents” that could represent novel therapeutic strategies targeting Notch signaling toward better treatment outcome of patients diagnosed with cancer. PMID:20491628

  14. Direct inhibition of the NOTCH transcription factor complex

    PubMed Central

    Moellering, Raymond E.; Cornejo, Melanie; Davis, Tina N.; Del Bianco, Cristina; Aster, Jon C.; Blacklow, Stephen C.; Kung, Andrew L.; Gilliland, D. Gary; Verdine, Gregory L.; Bradner, James E.

    2010-01-01

    Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized α-helical peptides that target a critical protein–protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL. PMID:19907488

  15. Notch signaling in cancer stem cells.

    PubMed

    Wang, Jialiang; Sullenger, Bruce A; Rich, Jeremy N

    2012-01-01

    Subpopulations of cancer cells with stem cell-like characteristics, termed cancer stem cells, have been identified in a wide range of human cancers. Cancer stem cells are defined by their ability to self-renew as well as recapitulate the original heterogeneity of cancer cells in culture and in serial xenotransplants. Not only are cancer stem cells highly tumorigenic, but these cells are implicated in tumor resistance to conventional chemotherapy and radiotherapy, thus highlighting their significance as therapeutic targets. Considerable similarities have been found between cancer stem cells and normal stem cells on their dependence on certain signaling pathways. More specifically, the core stem cell signaling pathways, such as the Wnt, Notch and Hedgehog pathways, also critically regulate the self-renewal and survival of cancer stem cells. While the oncogenic functions of Notch pathway have been well documented, its role in cancer stem cells is just emerging. In this chapter, we will discuss recent advances in cancer stem cell research and highlight the therapeutic potential of targeting Notch in cancer stem cells.

  16. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development.

    PubMed

    Yun, Theodore J; Bevan, Michael J

    2003-06-15

    We have characterized the function of Notch-regulated ankyrin-repeat protein (Nrarp) in mouse cell lines and in hematopoietic stem cells (HSCs). Nrarp overexpression is able to block Notch-induced activation of CBF-1. In AKR1010 thymoma cells, Nrarp overexpression blocks CBF-1-dependent transcriptional activation of Notch-responsive genes and inhibits phenotypic changes associated with Notch activation. Enforced expression of Nrarp in mouse HSCs results in a profound block in T lineage commitment and progression through early stages of thymocyte maturation. In contrast, Deltex-1 overexpression in HSCs can also block T lineage commitment but not progression through the early double negative stages of thymocyte maturation. The different effects of Deltex-1 and Nrarp overexpression suggest that alternate Notch signaling pathways mediate T vs B lineage commitment and thymocyte maturation.

  17. Elastoplastic notch root strains - Measurements versus finite-element predictions

    NASA Technical Reports Server (NTRS)

    Tregoning, R. L.

    1992-01-01

    A study intended to experimentally and computationally probe the nature of the elastoplastic strain fields created by notches with various levels of constraint is presented. An interferometric strain/displacement gage is used to measure both the axial and lateral strain at the center of a machined and polished notch. The monotonic response of various notches is determined using 3D finite-element calculations.

  18. Microstructure-Sensitive Fatigue Design of Notched Components

    DTIC Science & Technology

    2015-01-26

    Office P.O. Box 12211 Research Triangle Park, NC 27709-2211 High cycle fatigue, faigue notch factor , probabilistic mesomechanics, crystal plasticity...crystal plasticity finite element or closed-form solution was also developed as a more robust approach for determining the fatigue notch factor than...Owolabi, Horace Whitworth. On the concept of fatigue notch factor , JP journal of solids and structures, (05 2012): 63. doi: Gbadebo Owolabi, Horace

  19. Role of Notch Signaling in Human Breast Cancer Pathogenesis

    DTIC Science & Technology

    2006-11-01

    allele of Notch1 cooperates with low levels of oncogenic Ras expressing HMLE cells(termed HMLER). Further investigations revealed that Notch-IC...transformation, tumorigenesis , 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC...15. Number of Pages (count all pages including appendices) 9 Notch, Ras, signaling, transformation, tumorigenesis , 16. Price Code (Leave Blank) 17

  20. Notch signaling and the determination of appendage identity

    PubMed Central

    Kurata, Shoichiro; Go, Masahiro J.; Artavanis-Tsakonas, Spyros; Gehring, Walter J.

    2000-01-01

    The Notch signaling pathway defines an evolutionarily conserved cell–cell interaction mechanism that throughout development controls the ability of precursor cells to respond to developmental signals. Here we show that Notch signaling regulates the expression of the master control genes eyeless, vestigial, and Distal-less, which in combination with homeotic genes induce the formation of eyes, wings, antennae, and legs. Therefore, Notch is involved in a common regulatory pathway for the determination of the various Drosophila appendages. PMID:10681430

  1. 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.

  2. Notch signaling: its roles and therapeutic potential in hematological malignancies.

    PubMed

    Gu, Yisu; Masiero, Massimo; Banham, Alison H

    2016-05-17

    Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway.

  3. Notch signaling regulates gastric antral LGR5 stem cell function.

    PubMed

    Demitrack, Elise S; Gifford, Gail B; Keeley, Theresa M; Carulli, Alexis J; VanDussen, Kelli L; Thomas, Dafydd; Giordano, Thomas J; Liu, Zhenyi; Kopan, Raphael; Samuelson, Linda C

    2015-10-14

    The major signaling pathways regulating gastric stem cells are unknown. Here we report that Notch signaling is essential for homeostasis of LGR5(+) antral stem cells. Pathway inhibition reduced proliferation of gastric stem and progenitor cells, while activation increased proliferation. Notch dysregulation also altered differentiation, with inhibition inducing mucous and endocrine cell differentiation while activation reduced differentiation. Analysis of gastric organoids demonstrated that Notch signaling was intrinsic to the epithelium and regulated growth. Furthermore, in vivo Notch manipulation affected the efficiency of organoid initiation from glands and single Lgr5-GFP stem cells, suggesting regulation of stem cell function. Strikingly, constitutive Notch activation in LGR5(+) stem cells induced tissue expansion via antral gland fission. Lineage tracing using a multi-colored reporter demonstrated that Notch-activated stem cells rapidly generate monoclonal glands, suggesting a competitive advantage over unmanipulated stem cells. Notch activation was associated with increased mTOR signaling, and mTORC1 inhibition normalized NICD-induced increases in proliferation and gland fission. Chronic Notch activation induced undifferentiated, hyper-proliferative polyps, suggesting that aberrant activation of Notch in gastric stem cells may contribute to gastric tumorigenesis. © 2015 The Authors.

  4. Stage-specific effects of Notch activation during skeletal myogenesis

    PubMed Central

    Bi, Pengpeng; Yue, Feng; Sato, Yusuke; Wirbisky, Sara; Liu, Weiyi; Shan, Tizhong; Wen, Yefei; Zhou, Daoguo; Freeman, Jennifer; Kuang, Shihuan

    2016-01-01

    Skeletal myogenesis involves sequential activation, proliferation, self-renewal/differentiation and fusion of myogenic stem cells (satellite cells). Notch signaling is known to be essential for the maintenance of satellite cells, but its function in late-stage myogenesis, i.e. post-differentiation myocytes and post-fusion myotubes, is unknown. Using stage-specific Cre alleles, we uncovered distinct roles of Notch1 in mononucleated myocytes and multinucleated myotubes. Specifically, constitutive Notch1 activation dedifferentiates myocytes into Pax7 quiescent satellite cells, leading to severe defects in muscle growth and regeneration, and postnatal lethality. By contrast, myotube-specific Notch1 activation improves the regeneration and exercise performance of aged and dystrophic muscles. Mechanistically, Notch1 activation in myotubes upregulates the expression of Notch ligands, which modulate Notch signaling in the adjacent satellite cells to enhance their regenerative capacity. These results highlight context-dependent effects of Notch activation during myogenesis, and demonstrate that Notch1 activity improves myotube’s function as a stem cell niche. DOI: http://dx.doi.org/10.7554/eLife.17355.001 PMID:27644105

  5. Notch signaling: its roles and therapeutic potential in hematological malignancies

    PubMed Central

    Gu, Yisu

    2016-01-01

    Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway. PMID:26934331

  6. 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

  7. Stra13 regulates satellite cell activation by antagonizing Notch signaling

    PubMed Central

    Sun, Hong; Li, Li; Vercherat, Cécile; Gulbagci, Neriman Tuba; Acharjee, Sujata; Li, Jiali; Chung, Teng-Kai; Thin, Tin Htwe; Taneja, Reshma

    2007-01-01

    Satellite cells play a critical role in skeletal muscle regeneration in response to injury. Notch signaling is vital for satellite cell activation and myogenic precursor cell expansion but inhibits myogenic differentiation. Thus, precise spatial and temporal regulation of Notch activity is necessary for efficient muscle regeneration. We report that the basic helix-loop-helix transcription factor Stra13 modulates Notch signaling in regenerating muscle. Upon injury, Stra13−/− mice exhibit increased cellular proliferation, elevated Notch signaling, a striking regeneration defect characterized by degenerated myotubes, increased mononuclear cells, and fibrosis. Stra13−/− primary myoblasts also exhibit enhanced Notch activity, increased proliferation, and defective differentiation. Inhibition of Notch signaling ex vivo and in vivo ameliorates the phenotype of Stra13−/− mutants. We demonstrate in vitro that Stra13 antagonizes Notch activity and reverses the Notch-imposed inhibition of myogenesis. Thus, Stra13 plays an important role in postnatal myogenesis by attenuating Notch signaling to reduce myoblast proliferation and promote myogenic differentiation. PMID:17502421

  8. 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

  9. Osteotomy for Sigmoid Notch Obliquity and Ulnar Positive Variance

    PubMed Central

    Dickson, Lisa M.; Tham, Stephen K. Y.

    2014-01-01

    Background Several causes of ulnar wrist pain have been described. One uncommon cause is ulnar carpal abutment associated with a notable distally facing sigmoid notch (reverse obliquity). Such an abnormality cannot be treated with ulnar shortening alone because it will result in incongruity of the distal radioulnar joint (DRUJ). Case Description A 23-year-old woman presented with ulnar wrist pain aggravated by forearm rotation. Ten years earlier she had sustained a distal radius fracture that was conservatively treated. Examination revealed mild tenderness at the DRUJ and decreased wrist flexion and grip strength on the affected side. Radiographic examination demonstrated 1 cm ulnar positive variance, ulnar styloid nonunion, and a 37° reverse obliquity of the sigmoid notch. The patient was treated with ulnar shortening and rotation sigmoid notch osteotomy to realign the sigmoid notch with the ulnar head. Literature Review Sigmoid notch incongruity is one of several causes of wrist pain after distal radius fracture. Traditional salvage options for DRUJ arthritis may result in loss of grip strength, painful ulnar shaft instability, or reossification and are not acceptable options in the young patient. Sigmoid notch osteotomy or osteoplasty have been described to correct the shape of the sigmoid notch in the axial plane. Clinical Relevance We report a coronal plane osteotomy of the sigmoid notch to treat reverse obliquity of the sigmoid notch associated with ulnar carpal abutment. The rotation osteotomy described is particularly useful for patients in whom a salvage procedure is not warranted. PMID:24533247

  10. A review of chevron-notched fracture specimens

    NASA Technical Reports Server (NTRS)

    Newman, J. C., Jr.

    1984-01-01

    The historical development of chevron notched fracture specimens is reviewed. Stress intensity factors and load line displacement solutions proposed for some of these specimens are compared. The original bend bar configurations up to the present day short rod and bar specimens are reviewed. The results of an analytical round robin that was conducted on chevron-notched specimens are presented. In the round robin, stress-intensity factors for either the chevron notched round rod or square bar specimens were calculated. The consensus stress intensity factor (compliance) solution for these specimens is assessed. The stress intensity factor solutions proposed for three and four point bend chevron notched specimens are reviewed.

  11. 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

  12. 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

  13. 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.

  14. Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration

    PubMed Central

    Carulli, Alexis J.; Keeley, Theresa M.; Demitrack, Elise S.; Chung, Jooho; Maillard, Ivan; Samuelson, Linda C.

    2015-01-01

    The Notch signaling pathway regulates intestinal epithelial cell homeostasis, including stem cell maintenance, progenitor cell proliferation and differentiation. Notch1 and Notch2 receptors are expressed in the epithelium, but individual contributions to these functions are unclear. We used genetic deletion to define receptor roles on stem cell function, cell proliferation/differentiation, and repair after injury. Loss of Notch1 induced a transient secretory cell hyperplasia that spontaneously resolved over time. In contrast, deletion of Notch2 had no secretory cell effect. Compound deletions of Notch1 and Notch2 resulted in a more severe secretory cell hyperplasia than deletion of Notch1 alone. Furthermore, only double deletion of Notch1 and Notch2 decreased cell proliferation, suggesting a low threshold for maintenance of proliferation compared to differentiation. Stem cells were affected by deletion of Notch1, with reduced expression of Olfm4 and fewer LGR5+ stem cells. Deletion of Notch2 had no apparent affect on stem cell homeostasis. However, we observed impaired crypt regeneration after radiation in both Notch1- and Notch2-deleted intestine, suggesting that higher Notch activity is required post-injury. These findings suggest that Notch1 is the primary receptor regulating intestinal stem cell function and that Notch1 and Notch2 together regulate epithelial cell proliferation, cell fate determination, and post-injury regeneration. PMID:25835502

  15. Progress Report on Alloy 617 Notched Specimen Testing

    SciTech Connect

    McMurtrey, Michael David; Wright, Richard Neil; Lillo, Thomas Martin

    2016-08-01

    Creep behavior of Alloy 617 has been extensively characterized to support the development of a draft Code Case to qualify Alloy 617 in Section III division 5 of the ASME Boiler and Pressure Vessel Code. This will allow use of Alloy 617 in construction of nuclear reactor components at elevated temperatures and longer periods of time (up to 950°C and 100,000 hours). Prior to actual use, additional concerns not considered in the ASME code need to be addressed. Code Cases are based largely on uniaxial testing of smooth gage specimens. In service conditions, components will generally be under multi axial loading. There is also the concern of the behavior at discontinuities, such as threaded components. To address the concerns of multi axial creep behavior and at geometric discontinuities, notched specimens have been designed to create conditions representative of the states that service components experience. Two general notch geometries have been used for these series of tests: U notch and V notch specimens. The notches produce a tri axial stress state, though not uniform across the specimen. Characterization of the creep behavior of the U notch specimens and the creep rupture behavior of the V notch specimens provides a good approximation of the behavior expected of actual components. Preliminary testing and analysis have been completed and are reported in this document. This includes results from V notch specimens tested at 900°C and 800°C. Failure occurred in the smooth gage section of the specimen rather than at the root of the notch, though some damage was present at the root of the notch, where initial stress was highest. This indicates notch strengthening behavior in this material at these temperatures.

  16. 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

    2015-10-16

    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.

  17. The EMMA Lattice

    NASA Astrophysics Data System (ADS)

    Berg, J. Scott

    2008-02-01

    EMMA is a 10 to 20 MeV electron ring designed to test our understanding of beam dynamics in a relativistic linear non-scaling fixed field alternating gradient accelerator (FFAG). I will give a basic review of the EMMA lattice parameters. Then I will review the different lattice configurations that we would like to have for EMMA. Finally, I will briefly discuss the process of commissioning each lattice configuration.

  18. Quantitative dissection of the Notch:CSL interaction: insights into the Notch-mediated transcriptional switch.

    PubMed

    Lubman, Olga Y; Ilagan, Ma Xenia G; Kopan, Raphael; Barrick, Doug

    2007-01-19

    Complex formation between the intracellular domain of the Notch receptor (NICD) and the transcription factor CSL is indispensable for transcriptional activation. To understand how NICD displaces CSL-associated co-repressors, we have quantified the binding of different Notch1 ICD regions to a key interaction domain (the beta trefoil domain, or BTD) of human CSL. Electrophoresis, scattering, and titration calorimetry indicate that NICD and BTD combine to form a 1:1 heterodimer. Neither the Notch1 ankyrin domain (ANK) nor C-terminal region contributes binding energy towards BTD. In contrast, binding energy is attributed largely to a short segment including the conserved WFP sequence motif within the RAM region (the approximately 140 residue polypeptide segment N-terminal to the ANK domain); substitution of this motif substantially reduces affinity. Short (< or =25 residues) WFP-containing peptides encoded by the four mammalian Notch genes have similar affinities to BTD; thus, activity differences between paralogues either result from other regions of NICD and CSL or from differences in interaction with downstream components. The importance of RAM was demonstrated by the ability of a short RAM peptides to dissociate NICD:CSL interaction in cellular lysates. These results support an emerging molecular mechanism for the displacement of co-repressors from DNA-bound CSL by NICD.

  19. Quantitative Dissection of the Notch:CSL Interaction: Insights into the Notch Transcriptional Switch

    PubMed Central

    Lubman, Olga Y.; Ilagan, Ma. Xenia G.; Kopan, Raphael; Barrick, Doug

    2007-01-01

    Complex formation between the intracellular domain of the Notch receptor (NICD) and the transcription factor CSL is indispensable for transcriptional activation. To understand how NICD displaces CSL-associated co-repressors, we have quantified the binding of different Notch1 ICD regions to a key interaction domain (the beta trefoil domain, or BTD) of human CSL. Electrophoresis, scattering, and titration calorimetry indicate that NICD and BTD combine to form a 1:1 heterodimer. Neither the Notch1 ankyrin domain (ANK) nor C-terminal region contributes binding energy towards BTD. In contrast, binding energy is attributed largely to a short segment including the conserved WFP sequence motif within the RAM region (the ~140 residue polypeptide segment N-terminal to the ANK domain); substitution of this motif substantially reduces affinity. Short (≤ 25 residues) WFP-containing peptides encoded by the four mammalian Notch genes have similar affinities to BTD; thus, activity differences between paralogues either result from other regions of NICD and CSL or from differences in interaction with downstream components. The importance of RAM was demonstrated by the ability of a short RAM peptides to dissociate NICD:CSL interaction in cellular lysates. These results support an emerging molecular mechanism for the displacement of co-repressors from DNA-bound CSL by NICD. PMID:17070841

  20. Chimeric analysis of Notch2 function: a role for Notch2 in the development of the roof plate of the mouse brain.

    PubMed

    Kadokawa, Yuzo; Marunouchi, Tohru

    2002-10-01

    Notch proteins are transmembrane receptors involved in cell-fate determination throughout development. Targeted disruption of either the Notch1 or Notch2 gene in mice results in embryonic lethality around embryonic day (E) 10.5 with widespread cell death. Although Notch1-deficient mice show disorganized somitogenesis, Notch2 mutants did not show definitive abnormalities in any tissue expressing high levels of the Notch2 gene, including the central nervous system. To study Notch2 function in development beyond the embryonic lethal stage, we performed chimeric analysis between Notch2 mutant and wild-type mouse embryos. Chimeric embryos developed normally and homozygous Notch2 mutant-specific cell death was not observed. Although chimeric embryos showed normal mosaicism until E9.5 in all tissues studied to date, Notch2 homozygous mutant cells failed to contribute to formation of the roof plate of the diencephalon and mesencephalon at later developmental stages, when Notch2 is normally expressed at high levels at there. Furthermore, Notch2 heterozygous mutant cells were also excluded from the roof plate of the chimera, however, Notch2 heterozygous mutant mice developed normally. We also showed that Wnt-1 and Mash1 expression patterns at the roof plate were disorganized in Notch2 homozygous mutant embryos. These results indicate that Notch2 plays an important role in development of the roof plate of the diencephalon and mesencephalon, and suggest that cellular rearrangement is involved in this process.

  1. Mid-latitude hiss and plasmaspheric notch

    NASA Astrophysics Data System (ADS)

    Masson, A.; Inan, U.; Laakso, H.; Décréau, P.; Santolik, O.

    2004-12-01

    A newly identified whistler mode ELF/VLF emission, observed by the Cluster satellites, will be presented. In the vicinity of the plasmapause, around the geomagnetic equator, the four Cluster satellites often observe banded hiss-like electromagnetic emissions (BHE). Their frequency bandwidth is always in between the lower hybrid resonance and the electron gyrofrequency, from 2 kHz to 10 kHz. Based on two years of data measured by three waves experiments on Cluster (WHISPER, STAFF and WBD), the following properties of the BHE waves have been deduced: (i) their location is strongly correlated with the position of the plasmapause, (ii) no MLT dependence has been found, (iii) their spectral width is generally 1 to 2 kHz, and (iv) the central frequency of their emission band varies from 2 kHz to 10 kHz. All these features suggest that BHE are in fact mid-latitude hiss emissions (MLH). MLH have been rarely observed on a regular basis at such altitude. Based on this survey, the central frequency of mid-latitude hiss is shown to be correlated with the Kp index. This suggests either that these banded emissions are generated in a given f/fce range, or that there is a Kp dependent Doppler shift between the satellites and a possible moving source of the MLH Mid-latitude hiss case events observed within density depletion known as plasmaspheric notch (observed by the EUV instrument on IMAGE) will be presented. A recent study showed that plasmaspheric notch plays a crucial role in the generation of higher frequency emissions such as kilometric continuum. The role of plasmaspheric notch in the generation and/or the amplification of mid-latitude hiss will be addressed.

  2. A structure for digital notch filters

    NASA Technical Reports Server (NTRS)

    Abu-El-haija, A. I.; Peterson, A. M.

    1979-01-01

    Narrow-band digital notch filters have their poles near the unit circle. As the sampling rate is increased, the poles move towards Z = +1. Implementing such filters requires long registers to overcome the sensitivity and roundoff errors. A filter structure based on digital incremental computers is proposed which has low sensitivity and round-off errors, and simple hardware implementation. The filter structure can be directly used on differentially pulse-code modulated signals. Hardware multipliers are not required as the poles approach z = +1, and excellent results can be obtained using multipliers with very short word lengths, or with small size read-only memories.

  3. The Role of Adams in Notch Signaling

    PubMed Central

    Groot, Arjan J.; Vooijs, Marc A.

    2014-01-01

    Regulated intramembrane proteolysis (RIP) is a highly conserved signaling paradigm whereby membrane-bound signaling proteins are cleaved in their transmembrane region and then released into the cytoplasm to act as signaling molecules. In most if not all cases intramembrane cleavage is preceded and regulated by a membrane proximal cleavage step called “ectodomain shedding”. Here we will review the role of ectodomain shedding in RIP of the NOTCH signaling pathway, a highly conserved cell-cell communication pathway that mediates cell fate decisions during development and in adult tissues. PMID:22399336

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. The role of NOTCH1 signaling in T-ALL.

    PubMed

    Ferrando, Adolfo A

    2009-01-01

    The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule gamma-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.

  9. 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.

  10. Autophagy negatively regulates tumor cell proliferation through phosphorylation dependent degradation of the Notch1 intracellular domain

    PubMed Central

    Ahn, Ji-Seon; Ann, Eun-Jung; Kim, Mi-Yeon; Yoon, Ji-Hye; Lee, Hye-Jin; Jo, Eun-Hye; Lee, Keesook; Lee, Ji Shin; Park, Hee-Sae

    2016-01-01

    Autophagy is a highly conserved mechanism that degrades long-lived proteins and dysfunctional organelles, and contributes to cell fate. In this study, autophagy attenuates Notch1 signaling by degrading the Notch1 intracellular domain (Notch1-IC). Nutrient-deprivation promotes Notch1-IC phosphorylation by MEKK1 and phosphorylated Notch1-IC is recognized by Fbw7 E3 ligase. The ubiquitination of Notch1-IC by Fbw7 is essential for the interaction between Notch1-IC and p62 and for the formation of aggregates. Inhibition of Notch1 signaling prevents the transformation of breast cancer cells, tumor progression, and metastasis. The expression of Notch1 and p62 is inversely correlated with Beclin1 expression in human breast cancer patients. These results show that autophagy inhibits Notch1 signaling by promoting Notch1-IC degradation and therefore plays a role in tumor suppression. PMID:27806347

  11. Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis.

    PubMed

    Thomas, Marsha M; Zhang, Yaqing; Mathew, Esha; Kane, Kevin T; Maillard, Ivan; Pasca di Magliano, Marina

    2014-11-22

    Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer. To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis. We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation

  12. [Role of the Notch receptors in intercellular communication].

    PubMed

    Seugnet, L; Simpson, P

    1996-04-01

    The Notch gene was discovered in Drosophila at the beginning of the century and is currently the subject of intensive investigation, not only in invertebrates but also in vertebrates where remarkably well conserved homologues have been recently found. Notch encodes a new kind of cellular receptor whose functioning is still unclear and plays a role in a large number of cell interactions throughout development and in tissue renewal in the adult. Detailed study in invertebrates of some of these interactions has led to the identification of other genes required for transduction of the signal initiated by the receptor. Notch is always involved in processes where cells have the potential to choose between several different programmes of differentiation. Cells adopt a specific developmental pathway as a result of the inhibition of some programmes through Notch signalling. In this review we discuss the contribution of different experimental models to an understanding of the role of Notch in intercellular signalling.

  13. 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

  14. Botch (NPG7) Promotes Neurogenesis by Antagonizing Notch

    PubMed Central

    Chi, Zhikai; Zhang, Jianmin; Tokunaga, Akinori; Harraz, Maged M.; Byrne, Sean T.; Dolinko, Andrew; Xu, Jing; Blackshaw, Seth; Gaiano, Nicholas; Dawson, Ted M.; Dawson, Valina L.

    2012-01-01

    SUMMARY Regulation of self-renewal and differentiation of neural stem cells is still poorly understood. Here we investigate the role of a developmentally expressed protein, Botch, which blocks Notch, in neocortical development. Downregulation of Botch in vivo leads to cellular retention in the ventricular and subventricular zones, whereas overexpression of Botch drives neural stem cells into the intermediate zone and cortical plate. In vitro neurosphere and differentiation assays indicate that Botch regulates neurogenesis by promoting neuronal differentiation. Botch prevents cell surface presentation of Notch by inhibiting the S1 furin-like cleavage of Notch, maintaining Notch in the immature full-length form. Understanding the function of Botch expands our knowledge regarding both the regulation of Notch signaling and the complex signaling mediating neuronal development. PMID:22445366

  15. fringe and Notch specify polar cell fate during Drosophila oogenesis.

    PubMed

    Grammont, M; Irvine, K D

    2001-06-01

    fringe encodes a glycosyltransferase that modulates the ability of the Notch receptor to be activated by its ligands. We describe studies of fringe function during early stages of Drosophila oogenesis. Animals mutant for hypomorphic alleles of fringe contain follicles with an incorrect number of germline cells, which are separated by abnormally long and disorganized stalks. Analysis of clones of somatic cells mutant for a null allele of fringe localizes the requirement for fringe in follicle formation to the polar cells, and demonstrates that fringe is required for polar cell fate. Clones of cells mutant for Notch also lack polar cells and the requirement for Notch in follicle formation appears to map to the polar cells. Ectopic expression of fringe or of an activated form of Notch can generate an extra polar cell. Our results indicate that fringe plays a key role in positioning Notch activation during early oogenesis, and establish a function for the polar cells in separating germline cysts into individual follicles.

  16. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis

    PubMed Central

    South, Andrew P; Purdie, Karin J; Watt, Stephen A; Haldenby, Sam; den Breems, Nicoline; Dimon, Michelle; Arron, Sarah T; Kluk, Michael J; Aster, Jon C; McHugh, Angela; Xue, Dylan J; Dayal, Jasbani HS; Robinson, Kim S; Rizvi, SM Hasan

    2014-01-01

    Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors. Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis. Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin. Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin. Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC. PMID:24662767

  17. Notch signaling during cell fate determination in the inner ear

    PubMed Central

    Kiernan, Amy

    2013-01-01

    In the inner ear, Notch signaling has been proposed to specify the sensory regions, as well as regulate the differentiation of hair cells and supporting cell within those regions. In addition, Notch plays an important role in otic neurogenesis, by determining which cells differentiate as neurons, sensory cells and non-sensory cells. Here, I review the evidence for the complex and myriad roles Notch participates in during inner ear development. A particular challenge for those studying ear development and Notch is to decipher how activation of a single pathway can lead to different outcomes within the ear, which may include changes in the intrinsic properties of the cell, Notch modulation, and potential non-canonical pathways. PMID:23578865

  18. Notch is required for long-term memory in Drosophila.

    PubMed

    Presente, Asaf; Boyles, Randy S; Serway, Christine N; de Belle, J Steven; Andres, Andrew J

    2004-02-10

    A role for Notch in the elaboration of existing neural processes is emerging that is distinct from the increasingly well understood function of this gene in binary cell-fate decisions. Several research groups, by using a variety of organisms, have shown that Notch is important in the development of neural ultrastructure. Simultaneously, Presenilin (Psn) was identified both as a key mediator of Notch signaling and as a site of genetic lesions that cause early-onset Alzheimer's disease. Here we demonstrate that Notch loss of function produces memory deficits in Drosophila melanogaster. The effects are specific to long-term memory, which is thought to depend on ultrastructural remodeling. We propose that Notch plays an important role in the neural plasticity underlying consolidated memory.

  19. Notch is required for long-term memory in Drosophila

    PubMed Central

    Presente, Asaf; Boyles, Randy S.; Serway, Christine N.; de Belle, J. Steven; Andres, Andrew J.

    2004-01-01

    A role for Notch in the elaboration of existing neural processes is emerging that is distinct from the increasingly well understood function of this gene in binary cell-fate decisions. Several research groups, by using a variety of organisms, have shown that Notch is important in the development of neural ultrastructure. Simultaneously, Presenilin (Psn) was identified both as a key mediator of Notch signaling and as a site of genetic lesions that cause early-onset Alzheimer's disease. Here we demonstrate that Notch loss of function produces memory deficits in Drosophila melanogaster. The effects are specific to long-term memory, which is thought to depend on ultrastructural remodeling. We propose that Notch plays an important role in the neural plasticity underlying consolidated memory. PMID:14752200

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

    PubMed

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

    2015-03-01

    Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). 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 jagged1 (Jag1) in a mouse model of primary liver cancer driven by v-akt murine thymoma viral oncogene homolog and neuroblastoma RAS viral oncogene homolog (NRas). We show that inhibition of Notch2 reduces tumor burden by eliminating highly malignant HCC- and CCA-like tumors. Inhibition of the Notch ligand, Jag1, had a similar effect, consistent with Jag1 acting in cooperation with Notch2. This effect was specific to Notch2, because 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. 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. © 2014 by the American Association for the Study of Liver Diseases.

  1. Dissipative photonic lattice solitons.

    PubMed

    Ultanir, Erdem A; Stegeman, George I; Christodoulides, Demetrios N

    2004-04-15

    We show that discrete dissipative optical lattice solitons are possible in waveguide array configurations that involve periodically patterned semiconductor optical amplifiers and saturable absorbers. The characteristics of these low-power soliton states are investigated, and their propagation constant eigenvalues are mapped on Floquet-Bloch band diagrams. The prospect of observing such low-power dissipative lattice solitons is discussed in detail.

  2. Notch Signaling Regulates Ovarian Follicle Formation and Coordinates Follicular Growth

    PubMed Central

    Vanorny, Dallas A.; Prasasya, Rexxi D.; Chalpe, Abha J.; Kilen, Signe M.

    2014-01-01

    Ovarian follicles form through a process in which somatic pregranulosa cells encapsulate individual germ cells from germ cell syncytia. Complementary expression of the Notch ligand, Jagged1, in germ cells and the Notch receptor, Notch2, in pregranulosa cells suggests a role for Notch signaling in mediating cellular interactions during follicle assembly. Using a Notch reporter mouse, we demonstrate that Notch signaling is active within somatic cells of the embryonic ovary, and these cells undergo dramatic reorganization during follicle histogenesis. This coincides with a significant increase in the expression of the ligands, Jagged1 and Jagged2; the receptor, Notch2; and the target genes, Hes1 and Hey2. Histological examination of ovaries from mice with conditional deletion of Jagged1 within germ cells (J1 knockout [J1KO]) or Notch2 within granulosa cells (N2 knockout [N2KO]) reveals changes in follicle dynamics, including perturbations in the primordial follicle pool and antral follicle development. J1KO and N2KO ovaries also contain multi-oocytic follicles, which represent a failure to resolve germ cell syncytia, and follicles with enlarged oocytes but lacking somatic cell growth, signifying a potential role of Notch signaling in follicle activation and the coordination of follicle development. We also observed decreased cell proliferation and increased apoptosis in the somatic cells of both conditional knockout lines. As a consequence of these defects, J1KO female mice are subfertile; however, N2KO female mice remain fertile. This study demonstrates important functions for Jagged1 and Notch2 in the resolution of germ cell syncytia and the coordination of somatic and germ cell growth within follicles of the mouse ovary. PMID:24552588

  3. 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

  4. Grid refinement for entropic lattice Boltzmann models.

    PubMed

    Dorschner, B; Frapolli, N; Chikatamarla, S S; Karlin, I V

    2016-11-01

    We propose a multidomain grid refinement technique with extensions to entropic incompressible, thermal, and compressible lattice Boltzmann models. Its validity and accuracy are assessed by comparison to available direct numerical simulation and experiment for the simulation of isothermal, thermal, and viscous supersonic flow. In particular, we investigate the advantages of grid refinement for the setups of turbulent channel flow, flow past a sphere, Rayleigh-Bénard convection, as well as the supersonic flow around an airfoil. Special attention is paid to analyzing the adaptive features of entropic lattice Boltzmann models for multigrid simulations.

  5. Benchmark notch test for life prediction

    NASA Technical Reports Server (NTRS)

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

    1982-01-01

    Aircraft gas turbine engine components are subjected to severe stress, temperature, and environmental conditions. Economic and reliabilty demands have prompted inordinate effort in development of analytic methods to predict stresses and strains in aircraft engines. There remains, however, the need to check or verify these analytical methodologies against actual experimental data measurements. The laser interferometric strain displacement gage was recognized as having the potential to accomplish this task and was employed in this program. The actual strains incurred at the root of a discontinuity in cyclically loaded test samples subjected to inelastic deformation at high temperature where creep deformation readily occur were measured. The steady-state, cyclic stress-strain response at the root of the discontinuity in the tested samples was analyzed for comparison with the measured results. A comprehensive set of local notch root strain measurements for a variety of load patterns in an Inconel 718 notch specimen at 649 C (1200 F) was obtained and documented using the laser interferometric strain displacement gage.

  6. Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice

    PubMed Central

    McCaw, Zachary; Gladwell, Wesley; Trivedi, Shweta; Bushel, Pierre R.; Kleeberger, Steven R.

    2015-01-01

    Background Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation. Methods Wild-type (WT), Notch3 (Notch3–/–), and Notch4 (Notch4–/–) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6–72 hr. Results Relative to air-exposed controls, ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4–/– compared with WT and Notch3–/– mice. Significantly greater mean numbers of BALF neutrophils were found in Notch3–/– and Notch4–/– mice compared with WT mice after ozone exposure. Expression of whole lung Tnf was significantly increased after ozone in Notch3–/– and Notch4–/– mice, and was significantly greater in Notch3–/– compared with WT mice. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member. Conclusions These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation. Citation Verhein KC, McCaw Z, Gladwell W, Trivedi S, Bushel PR, Kleeberger SR. 2015. Novel roles for Notch3 and Notch4 receptors in gene expression and susceptibility to ozone-induced lung inflammation in mice. Environ Health Perspect 123:799–805; http://dx.doi.org/10.1289/ehp.1408852 PMID:25658374

  7. Chip physically interacts with Notch and their stoichiometry is critical for Notch function in wing development and cell proliferation in Drosophila.

    PubMed

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

    2015-04-01

    Notch signaling plays a fundamental role both in metazoan cell fate determination and in the establishment of distinct developmental cell lineages. In a yeast two-hybrid screen, we identified Chip as a binding partner of Notch. Thus, we investigated the functional significance of Notch and Chip interactions. Co-immunoprecipitation and GST pull-down experiments confirmed the physical interaction between Notch and Chip. Immunostaining revealed that Chip and Notch-intracellular domain (Notch-ICD) co-localized in cell nuclei. Loss-of-function and gain-of-function analyses of Chip were carried out using FLP/FRT and GAL4-UAS systems, respectively. Immunostaining and real-time PCR were performed to analyze the role of Chip on Notch-induced cell proliferation. Here, we report transcriptional cofactor Chip as a novel binding partner of Notch. Chip and Notch also showed strong genetic interactions, and Chip mutant clones in the dorsal compartment induced ectopic wing margins by ectopic expression of Notch and its targets, Wg and Cut. Our analyses revealed that stoichiometry of Notch and Chip is critical at the dorso-ventral (DV) boundary for wing margin formation. In addition, overexpression of Chip can rescue Notch-induced cell proliferation in larval imaginal discs. Our results indicate that Notch function in the DV boundary area is presumably dependent on Notch-Chip heterodimer formation. In addition, overexpression of Chip can rescue Notch-induced cell proliferation, presumably through titration of overexpressed Notch-ICD by excess Chip molecules. The present study reveals that Chip is a novel interacting partner of Notch and it plays a major role in Notch-induced DV margin formation and cell proliferation. Copyright © 2015. Published by Elsevier B.V.

  8. 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.

  9. Notch modulates VEGF action in endothelial cells by inducing Matrix Metalloprotease activity

    PubMed Central

    2011-01-01

    Background In the vasculature, Notch signaling functions as a downstream effecter of Vascular Endothelial Growth Factor (VEGF) signaling. VEGF regulates sprouting angiogenesis in part by inducing and activating matrix metalloproteases (MMPs). This study sought to determine if VEGF regulation of MMPs was mediated via Notch signaling and to determine how Notch regulation of MMPs influenced endothelial cell morphogenesis. Methods and Results We assessed the relationship between VEGF and Notch signaling in cultured human umbilical vein endothelial cells. Overexpression of VEGF-induced Notch4 and the Notch ligand, Dll4, activated Notch signaling, and altered endothelial cell morphology in a fashion similar to that induced by Notch activation. Expression of a secreted Notch antagonist (Notch1 decoy) suppressed VEGF-mediated activation of endothelial Notch signaling and endothelial morphogenesis. We demonstrate that Notch mediates VEGF-induced matrix metalloprotease activity via induction of MMP9 and MT1-MMP expression and activation of MMP2. Introduction of a MMP inhibitor blocked Notch-mediated endothelial morphogenesis. In mice, analysis of VEGF-induced dermal angiogenesis demonstrated that the Notch1 decoy reduced perivascular MMP9 expression. Conclusions Taken together, our data demonstrate that Notch signaling can act downstream of VEGF signaling to regulate endothelial cell morphogenesis via induction and activation of specific MMPs. In a murine model of VEGF-induced dermal angiogenesis, Notch inhibition led to reduced MMP9 expression. PMID:21349159

  10. Role of Notch and its oncogenic signaling crosstalk in breast cancer

    PubMed Central

    Guo, Shanchun; Liu, Mingli; Gonzalez-Perez, Ruben R.

    2011-01-01

    The Notch signaling plays a key role in cell differentiation, survival, and proliferation through diverse mechanisms. Notch signaling is also involved in vasculogenesis and angiogenesis. Moreover, Notch expression is regulated by hypoxia and inflammatory cytokines (IL-1, IL-6 and leptin). Entangled crosstalk between Notch and other developmental signaling (Hedgehog and Wnt), and signaling triggered by growth factors, estrogens and oncogenic kinases, could impact on Notch targeted genes. Thus, alterations of the Notch signaling can lead to a variety of disorders, including human malignancies. Notch signaling is activated by ligand binding, followed by ADAM/Tumor necrosis factor-α-converting enzyme (TACE) metalloprotease and γ-secretase cleavages that produce the Notch intracellular domain (NICD). Translocation of NICD into the nucleus induces the transcriptional activation of Notch target genes. The relationships between Notch deregulated signaling, cancer stem cells and the carcinogenesis process reinforced by Notch crosstalk with many oncogenic signaling pathways suggest that Notch signaling may be a critical drug target for breast and other cancers. Since current status of knowledge in this field changes quickly, our insight should be continuously revised. In this review, we will focus on recent advancements in identification of aberrant Notch signaling in breast cancer and the possible underlying mechanisms, including potential role of Notch in breast cancer stem cells, tumor angiogenesis, as well as its crosstalk with other oncogenic signaling pathways in breast cancer. We will also discuss the prognostic value of Notch proteins and therapeutic potential of targeting Notch signaling for cancer treatment. PMID:21193018

  11. Quasicrystallography from Bn lattices

    NASA Astrophysics Data System (ADS)

    Koca, M.; Koca, N. O.; Al-Mukhaini, A.; Al-Qanabi, A.

    2014-11-01

    We present a group theoretical analysis of the hypercubic lattice described by the affine Coxeter-Weyl group Wa (Bn). An h-fold symmetric quasicrystal structure follows from the hyperqubic lattice whose point group is described by the Coxeter-Weyl group W (Bn) with the Coxeter number h=2n. Higher dimensional cubic lattices are explicitly constructed for n = 4,5,6 by identifying their rank-3 Coxeter subgroups and maximal dihedral subgroups. Decomposition of their Voronoi cells under the respective rank-3 subgroups W (A3), W (H2)×W (A1) and W (H3)lead to the rhombic dodecahedron, rhombic icosahedron and rhombic triacontahedron respectively. Projection of the lattice B4 describes a quasicrystal structure with 8-fold symmetry. The B5 lattice leads to quasicrystals with both 5fold and 10 fold symmetries. The lattice B6 projects on a 12-fold symmetric quasicrystal as well as a 3D icosahedral quasicrystal depending on the choice of subspace of projections. The projected sets of lattice points are compatible with the available experimental data.

  12. Superalloy Lattice Block Structures

    NASA Technical Reports Server (NTRS)

    Whittenberger, J. D.; Nathal, M. V.; Hebsur, M. G.; Kraus, D. L.

    2003-01-01

    In their simplest form, lattice block panels are produced by direct casting and result in lightweight, fully triangulated truss-like configurations which provide strength and stiffness [2]. The earliest realizations of lattice block were made from A1 and steels, primarily under funding from the US Navy [3]. This work also showed that the mechanical efficiency (eg., specific stiffness) of lattice block structures approached that of honeycomb structures [2]. The lattice architectures are also less anisotropic, and the investment casting route should provide a large advantage in cost and temperature capability over honeycombs which are limited to alloys that can be processed into foils. Based on this early work, a program was initiated to determine the feasibility of extending the high temperature superalloy lattice block [3]. The objective of this effort was to provide an alternative to intermetallics and composites in achieving a lightweight high temperature structure without sacrificing the damage tolerance and moderate cost inherent in superalloys. To establish the feasibility of the superalloy lattice block concept, work was performed in conjunction with JAMCORP, Inc. Billerica, MA, to produce a number of lattice block panels from both IN71 8 and Mar-M247.

  13. 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.

  14. 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.

  15. Notch signalling in placental development and gestational diseases.

    PubMed

    Haider, S; Pollheimer, J; Knöfler, M

    2017-01-16

    Activation of Notch signalling upon cell-cell contact of neighbouring cells controls a plethora of cellular processes such as stem cell maintenance, cell lineage determination, cell proliferation, and survival. Accumulating evidence suggests that the pathway also critically regulates these events during placental development and differentiation. Herein, we summarize our present knowledge about Notch signalling in murine and human placentation and discuss its potential role in the pathophysiology of gestational disorders. Studies in mice suggest that Notch controls trophectoderm formation, decidualization, placental branching morphogenesis and endovascular trophoblast invasion. In humans, the particular signalling cascade promotes formation of the extravillous trophoblast lineage and regulates trophoblast proliferation, survival and differentiation. Expression patterns as well as functional analyses indicate distinct roles of Notch receptors in different trophoblast subtypes. Altered effects of Notch signalling have been detected in choriocarcinoma cells, consistent with its role in cancer development and progression. Moreover, deregulation of Notch signalling components were observed in pregnancy disorders such as preeclampsia and fetal growth restriction. In summary, Notch plays fundamental roles in different developmental processes of the placenta. Abnormal signalling through this pathway could contribute to the pathogenesis of gestational diseases with aberrant placentation and trophoblast function.

  16. Biological therapy induces expression changes in Notch pathway in psoriasis.

    PubMed

    Skarmoutsou, Evangelia; Trovato, Chiara; Granata, Mariagrazia; Rossi, Giulio A; Mosca, Ambra; Longo, Valentina; Gangemi, Pietro; Pettinato, Maurizio; D'Amico, Fabio; Mazzarino, Maria Clorinda

    2015-12-01

    Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

  17. Notch Signaling Pathway Regulates Progesterone Secretion in Murine Luteal Cells.

    PubMed

    Wang, Jing; Liu, Shuangmei; Peng, Lichao; Dong, Qiming; Bao, Riqiang; Lv, Qiulan; Tang, Min; Hu, Chuan; Li, Gang; Liang, Shangdong; Zhang, Chunping

    2015-10-01

    Notch signaling is an evolutionarily conserved pathway, which involves in various cell life activities. Other studies and our report showed that the Notch signaling plays very important role in follicle development in mammalian ovaries. In luteal cells, Notch ligand, delta-like ligand 4, is involved in normal luteal vasculature. In this study, murine luteal cells were cultured in vitro and treated with Notch signaling inhibitors, L-658,458 and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester (DAPT). We found that L-658,458 and DAPT treatment decrease basal and human chorionic gonadotropin (hCG)-stimulated progesterone secretion. On the contrary, overexpression of intracellular domain of Notch3 increased basal and hCG-stimulated progesterone secretion. Further studies demonstrated that Notch signaling regulated the expression of steroidogenic acute regulatory protein and CYP11A, 2 key enzymes for progesterone synthesis. In conclusion, Notch signaling plays important role in regulating progesterone secretion in murine luteal cells.

  18. 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. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  19. Notch3 drives development and progression of cholangiocarcinoma.

    PubMed

    Guest, Rachel V; Boulter, Luke; Dwyer, Benjamin J; Kendall, Timothy J; Man, Tak-Yung; Minnis-Lyons, Sarah E; Lu, Wei-Yu; Robson, Andrew J; Gonzalez, Sofia Ferreira; Raven, Alexander; Wojtacha, Davina; Morton, Jennifer P; Komuta, Mina; Roskams, Tania; Wigmore, Stephen J; Sansom, Owen J; Forbes, Stuart J

    2016-10-25

    The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent.

  20. 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

  1. Impaired endolysosomal function disrupts Notch signaling in optic nerve astrocytes

    PubMed Central

    Valapala, Mallika; Hose, Stacey; Gongora, Celine; Dong, Lijin; Wawrousek, Eric F.; Zigler, J. Samuel; Sinha, Debasish

    2013-01-01

    Astrocytes migrate from the optic nerve into the inner retina, forming a template upon which retinal vessels develop. In the Nuc1 rat, mutation in the gene encoding βA3/A1-crystallin disrupts both Notch signaling in astrocytes and formation of the astrocyte template. Here we show that loss of βA3/A1-crystallin in astrocytes does not impede Notch ligand binding or extracellular cleavages. However, it affects V-ATPase activity, thereby compromising acidification of the endolysosomal compartments, leading to reduced γ-secretase-mediated processing and release of the Notch intracellular domain (NICD). Lysosomal-mediated degradation of Notch is also impaired. These defects decrease the level of NICD in the nucleus, inhibiting expression of Notch target genes. Overexpression of βA3/A1-crystallin in those same astrocytes restored V-ATPase activity and normal endolysosomal acidification, thereby increasing the levels of γ-secretase to facilitate optimal Notch signaling. We postulate that βA3/A1-crystallin is essential for normal endolysosomal acidification, and thereby, normal activation of Notch signaling in astrocytes. PMID:23535650

  2. Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration.

    PubMed

    Zhao, Long; Borikova, Asya L; Ben-Yair, Raz; Guner-Ataman, Burcu; MacRae, Calum A; Lee, Richard T; Burns, C Geoffrey; Burns, Caroline E

    2014-01-28

    The human heart's failure to replace ischemia-damaged myocardium with regenerated muscle contributes significantly to the worldwide morbidity and mortality associated with coronary artery disease. Remarkably, certain vertebrate species, including the zebrafish, achieve complete regeneration of amputated or injured myocardium through the proliferation of spared cardiomyocytes. Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. Here, we report that cardiac regeneration in zebrafish relies on Notch signaling. Following amputation of the zebrafish ventricular apex, Notch receptor expression becomes activated specifically in the endocardium and epicardium, but not the myocardium. Using a dominant negative approach, we discovered that suppression of Notch signaling profoundly impairs cardiac regeneration and induces scar formation at the amputation site. We ruled out defects in endocardial activation, epicardial activation, and dedifferentiation of compact myocardial cells as causative for the regenerative failure. Furthermore, coronary endothelial tubes, which we lineage traced from preexisting endothelium in wild-type hearts, formed in the wound despite the myocardial regenerative failure. Quantification of myocardial proliferation in Notch-suppressed hearts revealed a significant decrease in cycling cardiomyocytes, an observation consistent with a noncell autonomous requirement for Notch signaling in cardiomyocyte proliferation. Unexpectedly, hyperactivation of Notch signaling also suppressed cardiomyocyte proliferation and heart regeneration. Taken together, our data uncover the exquisite sensitivity of regenerative cardiomyocyte proliferation to perturbations in Notch signaling.

  3. Notch3 marks clonogenic mammary luminal progenitor cells in vivo

    PubMed Central

    Lafkas, Daniel; Rodilla, Veronica; Huyghe, Mathilde; Mourao, Larissa; Kiaris, Hippokratis

    2013-01-01

    The identity of mammary stem and progenitor cells remains poorly understood, mainly as a result of the lack of robust markers. The Notch signaling pathway has been implicated in mammary gland development as well as in tumorigenesis in this tissue. Elevated expression of the Notch3 receptor has been correlated to the highly aggressive “triple negative” human breast cancer. However, the specific cells expressing this Notch paralogue in the mammary gland remain unknown. Using a conditionally inducible Notch3-CreERT2SAT transgenic mouse, we genetically marked Notch3-expressing cells throughout mammary gland development and followed their lineage in vivo. We demonstrate that Notch3 is expressed in a highly clonogenic and transiently quiescent luminal progenitor population that gives rise to a ductal lineage. These cells are capable of surviving multiple successive pregnancies, suggesting a capacity to self-renew. Our results also uncover a role for the Notch3 receptor in restricting the proliferation and consequent clonal expansion of these cells. PMID:24100291

  4. Notch3 marks clonogenic mammary luminal progenitor cells in vivo.

    PubMed

    Lafkas, Daniel; Rodilla, Veronica; Huyghe, Mathilde; Mourao, Larissa; Kiaris, Hippokratis; Fre, Silvia

    2013-10-14

    The identity of mammary stem and progenitor cells remains poorly understood, mainly as a result of the lack of robust markers. The Notch signaling pathway has been implicated in mammary gland development as well as in tumorigenesis in this tissue. Elevated expression of the Notch3 receptor has been correlated to the highly aggressive "triple negative" human breast cancer. However, the specific cells expressing this Notch paralogue in the mammary gland remain unknown. Using a conditionally inducible Notch3-CreERT2(SAT) transgenic mouse, we genetically marked Notch3-expressing cells throughout mammary gland development and followed their lineage in vivo. We demonstrate that Notch3 is expressed in a highly clonogenic and transiently quiescent luminal progenitor population that gives rise to a ductal lineage. These cells are capable of surviving multiple successive pregnancies, suggesting a capacity to self-renew. Our results also uncover a role for the Notch3 receptor in restricting the proliferation and consequent clonal expansion of these cells.

  5. 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.

  6. Notch signaling promotes osteoclast maturation and resorptive activity

    PubMed Central

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

    2015-01-01

    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

  7. Notch3 drives development and progression of cholangiocarcinoma

    PubMed Central

    Guest, Rachel V.; Dwyer, Benjamin J.; Kendall, Timothy J.; Man, Tak-Yung; Minnis-Lyons, Sarah E.; Lu, Wei-Yu; Robson, Andrew J.; Gonzalez, Sofia Ferreira; Raven, Alexander; Wojtacha, Davina; Morton, Jennifer P.; Komuta, Mina; Roskams, Tania; Wigmore, Stephen J.; Sansom, Owen J.; Forbes, Stuart J.

    2016-01-01

    The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent. PMID:27791012

  8. Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning.

    PubMed

    Shaya, Oren; Binshtok, Udi; Hersch, Micha; Rivkin, Dmitri; Weinreb, Sheila; Amir-Zilberstein, Liat; Khamaisi, Bassma; Oppenheim, Olya; Desai, Ravi A; Goodyear, Richard J; Richardson, Guy P; Chen, Christopher S; Sprinzak, David

    2017-03-13

    During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes.

  9. Mutations in NOTCH1 Cause Adams-Oliver Syndrome

    PubMed Central

    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.

    2014-01-01

    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

  10. 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

  11. HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.

    PubMed

    Fan, Yan; Gao, Xiang; Chen, Jinhui; Liu, Ying; He, Johnny J

    2016-11-02

    Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene Hes1 promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hes1 transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics.

  12. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways

    PubMed Central

    Shi, Shaolin; Stanley, Pamela

    2003-01-01

    Notch receptor signaling regulates cell growth and differentiation, and core components of Notch signaling pathways are conserved from Drosophila to humans. Fringe glycosyltransferases are crucial modulators of Notch signaling that act on epidermal growth factor (EGF)-like repeats in the Notch receptor extracellular domain. The substrate of Fringe is EGF-O-fucose and the transfer of fucose to Notch by protein O-fucosyltransferase 1 is necessary for Fringe to function. O-fucose also occurs on Cripto and on Notch ligands. Here we show that mouse embryos lacking protein O-fucosyltransferase 1 die at midgestation with severe defects in somitogenesis, vasculogenesis, cardiogenesis, and neurogenesis. The phenotype is similar to that of embryos lacking downstream effectors of all Notch signaling pathways such as presenilins or RBP-Jκ, and is different from Cripto, Notch receptor, Notch ligand, or Fringe null phenotypes. Protein O-fucosyltransferase 1 is therefore an essential core member of Notch signaling pathways in mammals. PMID:12697902

  13. Notchless encodes a novel WD40-repeat-containing protein that modulates Notch signaling activity.

    PubMed Central

    Royet, J; Bouwmeester, T; Cohen, S M

    1998-01-01

    Signaling by Notch family receptors is involved in many cell-fate decisions during development. Several modifiers of Notch activity have been identified, suggesting that regulation of Notch signaling is complex. In a genetic screen for modifiers of Notch activity, we identified a gene encoding a novel WD40-repeat protein. The gene is called Notchless, because loss-of-function mutant alleles dominantly suppress the wing notching caused by certain Notch alleles. Reducing Notchless activity increases Notch activity. Overexpression of Notchless in Xenopus or Drosophila appears to have a dominant-negative effect in that it also increases Notch activity. Biochemical studies show that Notchless binds to the cytoplasmic domain of Notch, suggesting that it serves as a direct regulator of Notch signaling activity. PMID:9857191

  14. Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway.

    PubMed

    Baek, Sang-Hyun; Kim, Mi-Yeon; Mo, Jung-Soon; Ann, Eun-Jung; Lee, Kyu Shik; Park, Ji-Hye; Kim, Jin-Young; Seo, Mi-Sun; Choi, Eui-Ju; Park, Hee-Sae

    2007-09-18

    The Notch signaling pathway appears to perform an important function in the determination of cell fate and in differentiation, in a wide variety of organisms and cell types. In this study, we provide evidence that the inactivation of Notch signaling by zinc is achieved via a PI3K-Akt-dependent, cytoplasmic retention of Notch1-IC and RBP-Jk. Extracellular zinc has been determined to inhibit constitutive active mutants of both Notch1 (DeltaEN1) and Notch1-IC-mediated transcription. However, in such cases, neither the cleavage pattern of Notch nor the protein stability of Notch1-IC and RBP-Jk was found to have significantly changed. With regard to the modulation of Notch signaling, zinc appears to exert a significant negative influence on the binding occurring between Notch1 and RBP-Jk, both in vivo and in vitro. The zinc-induced inhibition of Notch signaling can be rescued via pretreatment with wortmannin or LY294002, both of which are specific PI3K signaling pathway inhibitors. Furthermore, we ascertained that zinc triggers the cytoplasmic retention of Notch1-IC and RBP-Jk, and that cytoplasmic retention could be rescued via treatment with wortmannin. Overall, we have determined that an important relationship exists between zinc and the Notch1 signaling pathway, and that this relationship is intimately involved with the cytoplasmic retention of Notch and RBP-Jk.

  15. Emerging role of Notch in stem cells and cancer.

    PubMed

    Wang, Zhiwei; Li, Yiwei; Banerjee, Sanjeev; Sarkar, Fazlul H

    2009-06-28

    The Notch signaling pathway is known to be responsible for maintaining a balance between cell proliferation and death and, as such, plays important roles in the formation of many types of human tumors. Recently, Notch signaling pathway has been shown to control stem cell self-renewal and multi-potency. As many cancers are thought to be developed from a number of cancer stem-like cells, which are also known to be linked with the acquisition of epithelial-mesenchymal transition (EMT); and thus suggesting an expanding role of Notch signaling in human tumor progression.

  16. Fracture behavior of notched sheet-molding-compound composites

    NASA Astrophysics Data System (ADS)

    Nagoh, Satoshi; Choi, Nak-Sam; Takahashi, Kiyoshi

    1992-05-01

    The effect of notched tip radius on the fracture behavior of compact tension type specimens of sheet-molding compound composites was studied. For specimens were rho of 0.56 or less, a main crack initiated at the notch tip and grew in parallel with the generation of many subcracks surrounding the main crack tip. For rho of 2.1 mm, subcracks propagated in radial directions during main crack growth. With increasing notch tip radius, little increase in the maximum load, acoustic emission (AE) cumulative event count, and standard deviations of AE source locations was observed.

  17. SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling.

    PubMed

    Zhu, Xiaolong; Ding, Sha; Qiu, Cong; Shi, Yanna; Song, Lin; Wang, Yueyue; Wang, Yuewen; Li, Jinying; Wang, Yiran; Sun, Yi; Qin, Lingfeng; Chen, Jun; Simons, Michael; Min, Wang; Yu, Luyang

    2017-09-01

    The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders. The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)-deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a

  18. 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

  19. Targeting the Notch signaling pathway in cancer therapeutics.

    PubMed

    Guo, Huajiao; Lu, Yi; Wang, Jianhua; Liu, Xia; Keller, Evan T; Liu, Qian; Zhou, Qinghua; Zhang, Jian

    2014-11-01

    Despite advances in surgery, imaging, chemotherapy, and radiotherapy, the poor overall cancer-related death rate remains unacceptable. Novel therapeutic strategies are desperately needed. Nowadays, targeted therapy has become the most promising therapy and a welcome asset to the cancer therapeutic arena. There is a large body of evidence demonstrating that the Notch signaling pathway is critically involved in the pathobiology of a variety of malignancies. In this review, we provide an overview of emerging data, highlight the mechanism of the Notch signaling pathway in the development of a wide range of cancers, and summarize recent progress in therapeutic targeting of the Notch signaling pathway.

  20. Strength and Stiffness Analysis of Notched, Green Oak Pallet Stringers.

    DTIC Science & Technology

    1984-12-01

    1D-AI49 579 STRENGTH AND STIFFNESS ANALYSIS OF NOTCHED GREEN OAK i/i PALLET STRINGERS(U) FOREST PRODUCTS LAB MADISON NI T D GERHARDT DEC 84 FSRN-FPL...Notched, Green Research Oak Pallet Stringers Terry D. Gerhardt DTIC SELECT L- JAN 29 19M D 01 DIRBTO EA-f A. 85 0 15 Aproe 101 puli 90100t~NSTTM...board feet of lumber was converted to The author thanks Tom Foley of Foley and Sons, 258 million pallets in 1980, design information for notched

  1. 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.

  2. Role of Notch/VEGF-Receptor 3 in Breast Tumor Angiogenesis and Lymphangiogenesis

    DTIC Science & Technology

    2006-05-01

    in a murine mammary tumor model. In aim 1, to study the role for notch in murine mammary tumorigenesis , progress has been made in developing two new...ACCOMPLISHMENTS • Developed a EF-1-flox-NotchIC mouse line that expresses an activated form of Notch1 with within the murine vasculature when...interaction between Notch and VEGFR-3 in breast cancer. To study the role for notch in murine mammary tumorigenesis , progress has been made in developing

  3. Progressive Damage Modeling of Notched Composites

    NASA Technical Reports Server (NTRS)

    Aitharaju, Venkat; Aashat, Satvir; Kia, Hamid; Satyanarayana, Arunkumar; Bogert, Philip

    2016-01-01

    There is an increased interest in using non-crimp fabric reinforced composites for primary and secondary structural weight savings in high performance automobile applications. However, one of the main challenges in implementing these composites is the lack of understanding of damage progression under a wide variety of loading conditions for general configurations. Towards that end, researchers at GM and NASA are developing new damage models to predict accurately the progressive failure of these composites. In this investigation, the developed progressive failure analysis model was applied to study damage progression in center-notched and open-hole tension specimens for various laminate schemes. The results of a detailed study with respect to the effect of element size on the analysis outcome are presented.

  4. 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.

  5. Modeling notch signaling in normal and neoplastic hematopoiesis: global gene expression profiling in response to activated notch expression.

    PubMed

    Ganapati, Uma; Tan, Hongying Tina; Lynch, Maureen; Dolezal, Milana; de Vos, Sven; Gasson, Judith C

    2007-08-01

    In normal hematopoiesis, proliferation is tightly linked to differentiation in ways that involve cell-cell interaction with stromal elements in the bone marrow stem cell niche. Numerous in vitro and in vivo studies strongly support a role for Notch signaling in the regulation of stem cell renewal and hematopoiesis. Not surprisingly, mutations in the Notch gene have been linked to a number of types of malignancies. To better define the function of Notch in both normal and neoplastic hematopoiesis, a tetracycline-inducible system regulating expression of a ligand-independent, constitutively active form of Notch1 was introduced into murine E14Tg2a embryonic stem cells. During coculture, OP9 stromal cells induce the embryonic stem cells to differentiate first to hemangioblasts and subsequently to hematopoietic stem cells. Our studies indicate that activation of Notch signaling in flk+ hemangioblasts dramatically reduces their survival and proliferative capacity and lowers the levels of hematopoietic stem cell markers CD34 and c-Kit and the myeloid marker CD11b. Global gene expression profiling of day 8 hematopoietic progenitors in the absence and presence of activated Notch yield candidate genes required for normal hematopoietic differentiation, as well as putative downstream targets of oncogenic forms of Notch including the noncanonical Wnts Wnt4 and 5A. Disclosure of potential conflicts of interest is found at the end of this article.

  6. 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.

  7. Root lattices and quasicrystals

    NASA Astrophysics Data System (ADS)

    Baake, M.; Joseph, D.; Kramer, P.; Schlottmann, M.

    1990-10-01

    It is shown that root lattices and their reciprocals might serve as the right pool for the construction of quasicrystalline structure models. All noncrystallographic symmetries observed so far are covered in minimal embedding with maximal symmetry.

  8. Root lattices and quasicrystals

    NASA Astrophysics Data System (ADS)

    Baake, M.; Joseph, D.; Kramer, P.; Schlottmann, M.

    1990-10-01

    It is shown how root lattices and their reciprocals might serve as the right pool for the construction of quasicrystalline structure models. All non-periodic symmetries observed so far are covered in minimal embedding with maximal symmetry.

  9. 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.

  10. Asymptotic energy of lattices

    NASA Astrophysics Data System (ADS)

    Yan, Weigen; Zhang, Zuhe

    2009-04-01

    The energy of a simple graph G arising in chemical physics, denoted by E(G), is defined as the sum of the absolute values of eigenvalues of G. As the dimer problem and spanning trees problem in statistical physics, in this paper we propose the energy per vertex problem for lattice systems. In general for a type of lattice in statistical physics, to compute the entropy constant with toroidal, cylindrical, Mobius-band, Klein-bottle, and free boundary conditions are different tasks with different hardness and may have different solutions. We show that the energy per vertex of plane lattices is independent of the toroidal, cylindrical, Mobius-band, Klein-bottle, and free boundary conditions. In particular, the asymptotic formulae of energies of the triangular, 33.42, and hexagonal lattices with toroidal, cylindrical, Mobius-band, Klein-bottle, and free boundary conditions are obtained explicitly.

  11. 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.

  12. Hybrid lattice Boltzmann method on overlapping grids.

    PubMed

    Di Ilio, G; Chiappini, D; Ubertini, S; Bella, G; Succi, S

    2017-01-01

    In this work, a hybrid lattice Boltzmann method (HLBM) is proposed, where the standard lattice Boltzmann implementation based on the Bhatnagar-Gross-Krook (LBGK) approximation is combined together with an unstructured finite-volume lattice Boltzmann model. The method is constructed on an overlapping grid system, which allows the coexistence of a uniform lattice nodes spacing and a coordinate-free lattice structure. The natural adaptivity of the hybrid grid system makes the method particularly suitable to handle problems involving complex geometries. Moreover, the provided scheme ensures a high-accuracy solution near walls, given the capability of the unstructured submodel of achieving the desired level of refinement in a very flexible way. For these reasons, the HLBM represents a prospective tool for solving multiscale problems. The proposed method is here applied to the benchmark problem of a two-dimensional flow past a circular cylinder for a wide range of Reynolds numbers and its numerical performances are measured and compared with the standard LBGK ones.

  13. Hybrid lattice Boltzmann method on overlapping grids

    NASA Astrophysics Data System (ADS)

    Di Ilio, G.; Chiappini, D.; Ubertini, S.; Bella, G.; Succi, S.

    2017-01-01

    In this work, a hybrid lattice Boltzmann method (HLBM) is proposed, where the standard lattice Boltzmann implementation based on the Bhatnagar-Gross-Krook (LBGK) approximation is combined together with an unstructured finite-volume lattice Boltzmann model. The method is constructed on an overlapping grid system, which allows the coexistence of a uniform lattice nodes spacing and a coordinate-free lattice structure. The natural adaptivity of the hybrid grid system makes the method particularly suitable to handle problems involving complex geometries. Moreover, the provided scheme ensures a high-accuracy solution near walls, given the capability of the unstructured submodel of achieving the desired level of refinement in a very flexible way. For these reasons, the HLBM represents a prospective tool for solving multiscale problems. The proposed method is here applied to the benchmark problem of a two-dimensional flow past a circular cylinder for a wide range of Reynolds numbers and its numerical performances are measured and compared with the standard LBGK ones.

  14. Additive lattice kirigami.

    PubMed

    Castle, Toen; Sussman, Daniel M; Tanis, Michael; Kamien, Randall D

    2016-09-01

    Kirigami uses bending, folding, cutting, and pasting to create complex three-dimensional (3D) structures from a flat sheet. In the case of lattice kirigami, this cutting and rejoining introduces defects into an underlying 2D lattice in the form of points of nonzero Gaussian curvature. A set of simple rules was previously used to generate a wide variety of stepped structures; we now pare back these rules to their minimum. This allows us to describe a set of techniques that unify a wide variety of cut-and-paste actions under the rubric of lattice kirigami, including adding new material and rejoining material across arbitrary cuts in the sheet. We also explore the use of more complex lattices and the different structures that consequently arise. Regardless of the choice of lattice, creating complex structures may require multiple overlapping kirigami cuts, where subsequent cuts are not performed on a locally flat lattice. Our additive kirigami method describes such cuts, providing a simple methodology and a set of techniques to build a huge variety of complex 3D shapes.

  15. Additive lattice kirigami

    PubMed Central

    Castle, Toen; Sussman, Daniel M.; Tanis, Michael; Kamien, Randall D.

    2016-01-01

    Kirigami uses bending, folding, cutting, and pasting to create complex three-dimensional (3D) structures from a flat sheet. In the case of lattice kirigami, this cutting and rejoining introduces defects into an underlying 2D lattice in the form of points of nonzero Gaussian curvature. A set of simple rules was previously used to generate a wide variety of stepped structures; we now pare back these rules to their minimum. This allows us to describe a set of techniques that unify a wide variety of cut-and-paste actions under the rubric of lattice kirigami, including adding new material and rejoining material across arbitrary cuts in the sheet. We also explore the use of more complex lattices and the different structures that consequently arise. Regardless of the choice of lattice, creating complex structures may require multiple overlapping kirigami cuts, where subsequent cuts are not performed on a locally flat lattice. Our additive kirigami method describes such cuts, providing a simple methodology and a set of techniques to build a huge variety of complex 3D shapes. PMID:27679822

  16. 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

  17. A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis.

    PubMed

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

    2015-07-21

    Loss of NOTCH signaling in postnatal murine joints results in osteoarthritis, indicating a requirement for NOTCH during maintenance of joint cartilage. However, NOTCH signaling components are substantially increased in abundance in posttraumatic osteoarthritis in humans and mice, suggesting either a reparative or a pathological role for NOTCH activation in osteoarthritis. We investigated a potential dual role for NOTCH in joint maintenance and osteoarthritis by generating two mouse models overexpressing the NOTCH1 intracellular domain (NICD) within postnatal joint cartilage. The first mouse model exhibited sustained NOTCH activation to resemble pathological NOTCH signaling, whereas the second model had transient NOTCH activation, which more closely reflected physiological NOTCH signaling. Sustained NOTCH signaling in joint cartilage led to an early and progressive osteoarthritic-like pathology, whereas transient NOTCH activation enhanced the synthesis of cartilage matrix and promoted joint maintenance under normal physiological conditions. Through RNA-sequencing, immunohistochemical, and biochemical approaches, we identified several targets that could be responsible for NOTCH-mediated cartilage degradation, fibrosis, and osteoarthritis progression. These targets included components of the interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase signaling pathways, which may also contribute to the posttraumatic development of osteoarthritis. Together, these data suggest a dual role for the NOTCH pathway in joint cartilage, and they identify downstream effectors of NOTCH signaling as potential targets for disease-modifying osteoarthritis drugs.

  18. Solitons in spiraling Vogel lattices.

    PubMed

    Kartashov, Yaroslav V; Vysloukh, Victor A; Torner, Lluis

    2013-01-15

    We address light propagation in Vogel optical lattices and show that such lattices support a variety of stable soliton solutions in both self-focusing and self-defocusing media, whose propagation constants belong to domains resembling gaps in the spectrum of a truly periodic lattice. The azimuthally rich structure of Vogel lattices allows generation of spiraling soliton motion.

  19. Alpinetin targets glioma stem cells by suppressing Notch pathway.

    PubMed

    Wang, Jianpeng; Yan, Zhiyong; Liu, Xia; Che, Shusheng; Wang, Chao; Yao, Weicheng

    2016-07-01

    Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti-tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy.

  20. Double-notch single-pumper fluid mounts

    NASA Astrophysics Data System (ADS)

    Vahdati, Nader

    2005-07-01

    Passive fluid mounts are widely used in the automotive and aerospace applications to isolate the cabin from the engine noise and vibration. In the case of aerospace fixed wing applications, when fluid mounts are used, they are placed in between the engine and the fuselage, and the notch frequency of each fluid mount is tuned to either N1 frequency (engine low speed shaft imbalance excitation frequency) or to N2 frequency (engine high speed shaft imbalance excitation frequency) at the cruise condition. Since current passive fluid mount designs have only one notch, isolation is only possible at N1 or at N2, but not both. Here, in this paper, a double-notch passive fluid mount design will be presented, which has two notch frequencies, and therefore can provide vibration and noise isolation at two frequencies. In this paper, the new fluid mount design concept and its mathematical model and simulation results will be presented.

  1. 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

  2. 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.

  3. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL.

    PubMed

    Rutten, Julie W; Haan, Joost; Terwindt, Gisela M; van Duinen, Sjoerd G; Boon, Elles M J; Lesnik Oberstein, Saskia A J

    2014-06-01

    CADASIL is an autosomal dominant inherited disease, characterized by mid-adult onset of cerebrovascular disease and dementia. CADASIL is caused by mutations in the NOTCH3 gene, which encodes the NOTCH3 protein. Pathogenic mutations in CADASIL are highly distinctive in the sense that they lead to the loss or gain of a cysteine residue in 1 of the 34 EGFr domains of the NOTCH3 protein. The majority are missense mutations, but small deletions, insertions and splice-site mutations have been reported, which typically also lead to a numerical cysteine alteration. Whether numerical cysteine-altering mutations are a rule in CADASIL remains subject of debate, as there are reports suggesting pathogenicity of other types of mutations. However, for most of these the association with CADASIL was later revoked or is questionable. Here, we discuss and provide recommendations for the interpretation of NOTCH3 mutations in the diagnosis of CADASIL.

  4. CADASIL with a novel NOTCH3 mutation (Cys478Tyr).

    PubMed

    Ozaki, Kokoro; Irioka, Takashi; Ishikawa, Kinya; Mizusawa, Hidehiro

    2015-03-01

    Recently, an increasing number of NOTCH3 mutations have been described to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here, we report 2 CADASIL patients from a Japanese family, who were found to possess a novel NOTCH3 mutation. The proband only had chronic headache, and her mother had previously suffered a minor stroke. Although the patients' clinical symptoms were mild, their distinctive magnetic resonance imaging (MRI) features suggested CADASIL. Genetic analysis revealed that both patients had a novel heterozygous NOTCH3 mutation (p.Cys478Tyr) leading to stereotypical cysteine loss. The present finding suggests that genetic testing for NOTCH3 mutations in patients with distinctive MRI features, even if the symptoms are as mild as chronic headache, should help to broaden the mutational and clinical spectrum of CADASIL.

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

    PubMed

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

    2016-08-03

    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.

  6. 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

  7. 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

  8. Analyzing the posttranslational modification status of Notch using mass spectrometry.

    PubMed

    Kakuda, Shinako; Haltiwanger, Robert S

    2014-01-01

    Notch is modified by multiple types of posttranslational modifications, most of which are known to affect Notch function. The extracellular domain (ECD) is modified with N-glycosylation and at least three types of O-glycosylation (O-fucose, O-glucose, and O-GlcNAc), while the intracellular domain is hydroxylated, phosphorylated, and ubiquitinated. In order to analyze the structure and function of the O-glycans decorating the ECD, we have developed semiquantitative mass spectral methods for identifying modifications at individual sites on Notch that are generally applicable to most posttranslational modifications. Here we describe the expression and purification of Notch ECD fragments, digestion of the fragments with proteases to prepare for mass spectral analysis, and identification of peptides modified with O-glycans using mass spectrometry.

  9. 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

  10. Notch signaling promotes nephrogenesis by downregulating Six2

    PubMed Central

    Chung, Eunah; Deacon, Patrick; Marable, Sierra; Shin, Juhyun

    2016-01-01

    During nephrogenesis, multipotent mesenchymal nephron progenitors develop into distinct epithelial segments. Each nephron segment has distinct cell types and physiological function. In the current model of kidney development, Notch signaling promotes the formation of proximal tubules and represses the formation of distal tubules. Here, we present a novel role of Notch in nephrogenesis. We show in mice that differentiation of nephron progenitors requires downregulation of Six2, a transcription factor required for progenitor maintenance, and that Notch signaling is necessary and sufficient for Six2 downregulation. Furthermore, we find that nephron progenitors lacking Notch signaling fail to differentiate into any nephron segments, not just proximal tubules. Our results demonstrate how cell fates of progenitors are regulated by a transcription factor governing progenitor status and by a differentiation signal in nephrogenesis. PMID:27633993

  11. Detail view of exterior siding and "notching" at south corner ...

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

    Detail view of exterior siding and "notching" at south corner - Glacier Park Villas, Edna Sears Graham Cabin, South of Lake McDonald Lodge on Lake Mcdonald Lodge Loop Road, Lake McDonald, Flathead County, MT

  12. Can Sonography Distinguish a Supraorbital Notch From a Foramen?

    PubMed

    Garg, Ravi K; Lee, Kenneth S; Kohn, Sarah C; Baskaya, Mustafa K; Afifi, Ahmed M

    2015-11-01

    Diagnostic tools for evaluating the supraorbital rim in preparation for nerve decompression surgery in patients with chronic headaches are currently limited. We evaluated the use of sonography to diagnose the presence of a supraorbital notch or foramen in 11 cadaver orbits. Sonographic findings were assessed by dissecting cadaver orbits to determine whether a notch or foramen was present. Sonography correctly diagnosed the presence of a supraorbital notch in 7 of 7 cases and correctly diagnosed a supraorbital foramen in 4 of 4 cases. We found that sonography had 100% sensitivity in diagnosing a supraorbital notch and foramen. This tool may therefore be helpful in characterizing the supraorbital rim preoperatively and may influence the decision to use a transpalpebral or endoscopic approach for supraorbital nerve decompression as well as the decision to use local or general anesthesia.

  13. 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

  14. The Pathogenic Role of Notch Activation in Podocytes

    PubMed Central

    Niranjan, Thiruvur; Murea, Mariana; Susztak, Katalin

    2010-01-01

    Podocytes play a key role in the maintenance of glomerular filtration barrier. Depletion or dysregulative mechanisms of podocytes can lead to the development of glomerulosclerosis. Signaling pathways that control these processes in podocytes are not fully understood. Recent studies from our and other laboratories found that genes that belong to the Notch pathway are regulated in patients and in animal models of renal disease. Genetic studies performed on mice with conditional expression of active Notch1 protein showed massive albuminuria, glomerulosclerosis ultimately renal failure and death of the animals. Gamma secretase inhibitors and genetic deletion of Notch transcriptional binding partner (Rbpj) protected animals from nephrotic syndrome. Further studies are needed to define whether the activation of Notch pathway in podocytes represents a common pathomechanism in glomerular injury and its potential to be a therapeutic target for the treatment of chronic kidney disease. PMID:19293596

  15. 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.

  16. 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.

  17. Roundoff error effects on spatial lattice algorithm

    NASA Technical Reports Server (NTRS)

    An, S. H.; Yao, K.

    1986-01-01

    The floating-point roundoff error effect under finite word length limitations is analyzed for the time updates of reflection coefficients in the spatial lattice algorithm. It is shown that recursive computation is superior to direct computation under finite word length limitations. Moreover, the forgetting factor, which is conventionally used to smooth the time variations of the inputs, is also a crucial parameter in the consideration of the system stability and adaptability under finite word length constraints.

  18. 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

  19. 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

  20. 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

  1. Non-degradative ubiquitination of the Notch1 receptor by the E3 ligase MDM2 activates the Notch signalling pathway.

    PubMed

    Pettersson, Susanne; Sczaniecka, Matylda; McLaren, Lorna; Russell, Fiona; Gladstone, Karen; Hupp, Ted; Wallace, Maura

    2013-03-15

    The Notch receptor is necessary for modulating cell fate decisions throughout development, and aberrant activation of Notch signalling has been associated with many diseases, including tumorigenesis. The E3 ligase MDM2 (murine double minute 2) plays a role in regulating the Notch signalling pathway through its interaction with NUMB. In the present study we report that MDM2 can also exert its oncogenic effects on the Notch signalling pathway by directly interacting with the Notch 1 receptor through dual-site binding. This involves both the N-terminal and acidic domains of MDM2 and the RAM [RBP-Jκ (recombination signal-binding protein 1 for Jκ)-associated molecule] and ANK (ankyrin) domains of Notch 1. Although the interaction between Notch1 and MDM2 results in ubiquitination of Notch1, this does not result in degradation of Notch1, but instead leads to activation of the intracellular domain of Notch1. Furthermore, MDM2 can synergize with Notch1 to inhibit apoptosis and promote proliferation. This highlights yet another target for MDM2-mediated ubiquitination that results in activation of the protein rather than degradation and makes MDM2 an attractive target for drug discovery for both the p53 and Notch signalling pathways.

  2. Adaptive noncolocated velocity feedback for vibration damping

    NASA Technical Reports Server (NTRS)

    Bayard, David S.; Spanos, John T.

    1990-01-01

    A method is proposed for adaptive noncolocated velocity feedback control of flexible structure vibrations. The approach, denoted as auto-tuning, is to drive the system into a sequence of controlled oscillations to provide accurate knowledge of the plant characteristics in the vicinity of the phase cross-over frequencies. An allpass phase notch filter cascade is used as the control architecture to phase stabilize each destabilizing mode in the plant transfer function. The allpass phase notch filter cascade is tuned precisely by the information extracted from the controlled oscillations.

  3. 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.

  4. Lateral inhibition of Notch signaling in neoplastic cells

    PubMed Central

    Heth, Jason A.; Muraszko, Karin M.; Fan, Xing; Bar, Eli E.; Eberhart, Charles G.

    2015-01-01

    During normal development, heterogeneous expression of Notch ligands can result in pathway suppression in the signal-sending cell, a process known as lateral inhibition. It is unclear if an analogous phenomenon occurs in malignant cells. We observed significant induction of Notch ligands in glioblastoma neurospheres and pancreatic carcinoma cells cultured in low oxygen, suggesting that this phenomenon could occur around hypoxic regions. To model lateral inhibition in these tumors, the ligand Jagged1 was overexpressed in glioblastoma and pancreatic carcinoma cells, resulting in overall induction of pathway targets. However, when ligand high and ligand low cells from a single line were co-cultured and then separated, we noted suppression of Notch pathway targets in the former and induction in the latter, suggesting that neoplastic lateral inhibition can occur. We also found that repression of Notch pathway targets in signal-sending cells may occur through the activity of a Notch ligand intracellular domain, which translocates into the nucleus. Understanding how this neoplastic lateral inhibition process functions in cancer cells may be important in targeting ligand driven Notch signaling in solid tumors. PMID:25557173

  5. Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.

    PubMed

    Rutten, Julie W; Boon, Elles M J; Liem, Michael K; Dauwerse, Johannes G; Pont, Margot J; Vollebregt, Ellen; Maat-Kievit, Anneke J; Ginjaar, Hendrika B; Lakeman, Phillis; van Duinen, Sjoerd G; Terwindt, Gisela M; Lesnik Oberstein, Saskia A J

    2013-11-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by stereotyped missense mutations in NOTCH3. Whether these mutations lead to the CADASIL phenotype via a neomorphic effect, or rather by a hypomorphic effect, is subject of debate. Here, we report two novel NOTCH3 mutations, both leading to a premature stop codon with predicted loss of NOTCH3 function. The first mutation, c.307C>T, p.Arg103*, was detected in two brothers aged 50 and 55 years, with a brain MRI and skin biopsy incompatible with CADASIL. The other mutation was found in a 40-year-old CADASIL patient compound heterozygous for a pathogenic NOTCH3 mutation (c.2129A>G, p.Tyr710Cys) and an intragenic frameshift deletion. The deletion was inherited from his father, who did not have the skin biopsy abnormalities seen in CADASIL patients. These individuals with rare NOTCH3 mutations indicate that hypomorphic NOTCH3 alleles do not cause CADASIL.

  6. Notched K-wire for low thermal damage bone drilling.

    PubMed

    Liu, Yao; Belmont, Barry; Wang, Yiwen; Tai, Bruce; Holmes, James; Shih, Albert

    2017-07-01

    The Kirschner wire (K-wire) is a common bone drilling tool in orthopedic surgery to affix fractured bone. Significant heat is produced due to both the cutting and the friction between the K-wire and the bone debris during drilling. Such heat can result in high temperatures, leading to osteonecrosis and other secondary injuries. To reduce thermal injury and other high-temperature associated complications, a new K-wire design with three notches along the three-plane trocar tip fabricated using a thin micro-saw tool is studied. These notches evacuate bone debris and reduce the clogging and heat generation during bone drilling. A set of four K-wires, one without notches and three notched, with depths of 0.5, 0.75, and 1mm, are evaluated. Bone drilling experiments conducted on bovine cortical bone show that notched K-wires could effectively decrease the temperature, thrust force, and torque during bone drilling. K-wires with notches 1mm deep reduced the thrust force and torque by approximately 30%, reduced peak temperatures by 43%, and eliminated blackened burn marks in bone. This study demonstrates that a simple modification of the tip of K-wires can effectively reduce bone temperatures during drilling. Copyright © 2017 IPEM. Published by Elsevier Ltd. All rights reserved.

  7. Deadpan contributes to the robustness of the notch response.

    PubMed

    Babaoğlan, A Burcu; Housden, Ben E; Furriols, Marc; Bray, Sarah J

    2013-01-01

    Notch signaling regulates many fundamental events including lateral inhibition and boundary formation to generate very reproducible patterns in developing tissues. Its targets include genes of the bHLH hairy and Enhancer of split [E(spl)] family, which contribute to many of these developmental decisions. One member of this family in Drosophila, deadpan (dpn), was originally found to have functions independent of Notch in promoting neural development. Employing genome-wide chromatin-immunoprecipitation we have identified several Notch responsive enhancers in dpn, demonstrating its direct regulation by Notch in a range of contexts including the Drosophila wing and eye. dpn expression largely overlaps that of several E(spl) genes and the combined knock-down leads to more severe phenotypes than either alone. In addition, Dpn contributes to the establishment of Cut expression at the wing dorsal-ventral (D/V) boundary; in its absence Cut expression is delayed. Furthermore, over-expression of Dpn inhibits expression from E(spl) gene enhancers, but not vice versa, suggesting that dpn contributes to a feed-back mechanism that limits E(spl) gene expression following Notch activation. Thus the combined actions of dpn and E(spl) appear to provide a mechanism that confers an initial rapid output from Notch activity which becomes self-limited via feedback between the targets.

  8. Notch signaling in stomach epithelial stem cell homeostasis

    PubMed Central

    Kim, Tae-Hee

    2011-01-01

    The mammalian adult gastric epithelium self-renews continually through the activity of stem cells located in the isthmus of individual gland units. Mechanisms facilitating stomach stem and progenitor cell homeostasis are unknown. Here, we show that Notch signaling occurs in the mouse stomach epithelium during development and becomes restricted mainly to the isthmus in adult glands, akin to its known localization in the proliferative compartment of intestinal villi. Using genetic and chemical inhibition, we demonstrate that Notch signaling is required to maintain the gastric stem cell compartment. Activation of Notch signaling in lineage-committed stomach epithelial cells is sufficient to induce dedifferentiation into stem and/or multipotential progenitors that populate the mucosa with all major cell types. Prolonged Notch activation within dedifferentiated parietal cells eventually enhances cell proliferation and induces adenomas that show focal Wnt signaling. In contrast, Notch activation within native antral stomach stem cells does not affect cell proliferation. These results establish a role for Notch activity in the foregut and highlight the importance of cellular context in gastric tumorigenesis. PMID:21402740

  9. Dynamic binding of RBPJ is determined by Notch signaling status

    PubMed Central

    Castel, David; Mourikis, Philippos; Bartels, Stefanie J.J.; Brinkman, Arie B.; Tajbakhsh, Shahragim; Stunnenberg, Hendrik G.

    2013-01-01

    Notch signaling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighboring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and, together with the transcription factor moiety of Notch (NICD), regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole-genome binding profiles were generated for RBPJ; its coactivator, p300; NICD; and the histone H3 modifications H3 Lys 4 trimethylation (H3K4me3), H3 Lys 4 monomethylation (H3K4me1), and histone H3 Lys 27 acetylation (H3K27ac) in myogenic cells under active or inhibitory Notch signaling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300 and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signaling mediate their activities and consequently impact on cell fate decisions. PMID:23651858

  10. 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

  11. Cytoskeletal protection: acting on notch to prevent neuronal dysfunction.

    PubMed

    Bonini, Sara Anna; Ferrari-Toninelli, Giulia; Maccarinelli, Giuseppina; Bettinsoli, Paola; Montinaro, Mery; Memo, Maurizio

    2014-01-01

    Functional and structural plasticity is a fundamental property of the brain involving chemical, electrical, molecular and cellular responses and leading to reorganization of connections within a brain region and/or between brain regions. The Notch pathway has been recognized as one of the main contributors in regulating neural development and has been proposed as a key mediator in neuroplasticity. We supported this concept, demonstrating that Notch plays a role in determining the only possible 'cell fate' decisions in post-mitotic mature neurons: synaptic remodelling or neurite extension/retraction. We demonstrated that Notch pathway activation causes a decrease in neurite branching and a loss of varicosities, with consequent reduction in the release of neurotransmitters. Furthermore, in dysfunctional neurons that present Notch pathway hyper-activation, neuronal morphology was reverted by Notch-inhibiting agents. Potentially, a better understanding of the molecular events participating in neuroplasticity may provide relevant information for innovative therapeutic approaches in a variety of neurological disorders. Hence, we propose a Notch-signalling fine-tuned manipulation as a novel approach to modulate neuronal cytoskeleton plasticity in order to prevent dysfunctional structural plasticity in neurodegenerative diseases.

  12. Thermodynamic binding analysis of Notch transcription complexes from Drosophila melanogaster

    PubMed Central

    Contreras, Ashley N; Yuan, Zhenyu; Kovall, Rhett A

    2015-01-01

    Notch is an intercellular signaling pathway that is highly conserved in metazoans and is essential for proper cellular specification during development and in the adult organism. Misregulated Notch signaling underlies or contributes to the pathogenesis of many human diseases, most notably cancer. Signaling through the Notch pathway ultimately results in changes in gene expression, which is regulated by the transcription factor CSL. Upon pathway activation, CSL forms a ternary complex with the intracellular domain of the Notch receptor (NICD) and the transcriptional coactivator Mastermind (MAM) that activates transcription from Notch target genes. While detailed in vitro studies have been conducted with mammalian and worm orthologous proteins, less is known regarding the molecular details of the Notch ternary complex in Drosophila. Here we thermodynamically characterize the assembly of the fly ternary complex using isothermal titration calorimetry. Our data reveal striking differences in the way the RAM (RBP-J associated molecule) and ANK (ankyrin) domains of NICD interact with CSL that is specific to the fly. Additional analysis using cross-species experiments suggest that these differences are primarily due to fly CSL, while experiments using point mutants show that the interface between fly CSL and ANK is likely similar to the mammalian and worm interface. Finally, we show that the binding of the fly RAM domain to CSL does not affect interactions of the corepressor Hairless with CSL. Taken together, our data suggest species-specific differences in ternary complex assembly that may be significant in understanding how CSL regulates transcription in different organisms. PMID:25650119

  13. 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.

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

    PubMed Central

    Gama-Norton, Leonor; Ferrando, Eva; Ruiz-Herguido, Cristina; 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

  15. Notch1 signaling stimulates proliferation of immature cardiomyocytes

    PubMed Central

    Collesi, Chiara; Zentilin, Lorena; Sinagra, Gianfranco; Giacca, Mauro

    2008-01-01

    The identification of the molecular mechanisms controlling cardiomyocyte proliferation during the embryonic, fetal, and early neonatal life appears of paramount interest in regard to exploiting this information to promote cardiac regeneration. Here, we show that the proliferative potential of neonatal rat cardiomyocytes is powerfully stimulated by the sustained activation of the Notch pathway. We found that Notch1 is expressed in proliferating ventricular immature cardiac myocytes (ICMs) both in vitro and in vivo, and that the number of Notch1-positive cells in the heart declines with age. Notch1 expression in ICMs paralleled the expression of its Jagged1 ligand on non-myocyte supporting cells. The inhibition of Notch signaling in ICMs blocked their proliferation and induced apoptosis; in contrast, its activation by Jagged1 or by the constitutive expression of its activated form using an adeno-associated virus markedly stimulated proliferative signaling and promoted ICM expansion. Maintenance or reactivation of Notch signaling in cardiac myocytes might represent an interesting target for innovative regenerative therapy. PMID:18824567

  16. 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.

  17. Role of Delta-Notch signaling in cerebral cavernous malformations.

    PubMed

    Kar, Souvik; Baisantry, Arpita; Nabavi, Arya; Bertalanffy, Helmut

    2016-10-01

    Cerebral cavernous malformations (CCM) commonly known as cavernous hemangioma are associated with abnormally enlarged thin-walled blood vessels. As a result, these dilated capillaries are prone to leakage and result in hemorrhages. Clinically, such hemorrhages lead to severe headaches, focal neurological deficits, and epileptic seizures. CCM is caused by loss of function mutations in one of the three well-known CCM genes: Krev interaction trapped 1 (KRIT1), OSM, and programmed cell death 10 (PDCD10). Loss of CCM genes have been shown to be synergistically related to decreased Notch signaling and excessive angiogenesis. Despite recent evidences indicating that Notch signaling plays a pivotal role in regulating angiogenesis, the role of Notch in CCM development and progression is still not clear. Here, we provide an update literature review on the current knowledge of the structure of Notch receptor and its ligands, its relevance to angiogenesis and more precisely to CCM pathogenesis. In addition to reviewing the current literatures, this review will also focus on the cross talk between Delta-Notch and vascular endothelial growth factor (VEGF) signaling in angiogenesis and in CCM pathogenesis. Understanding the role of Notch signaling in CCM development and progression might help provide a better insight for novel anti-angiogenic therapies.

  18. 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.

  19. In vivo Mapping of Notch Pathway Activity in Normal and Stress Hematopoiesis

    PubMed Central

    Gao, Jie; Tikhonova, Anastasia; Loizou, Evangelia; Manet, Jan; van Handel, Ben; Ibrahim, Sherif; Greve, Jeffrey; Mikkola, Hanna; Artavanis-Tsakonas, Spyros; Aifantis, Iannis

    2013-01-01

    SUMMARY Accumulating evidence suggests that Notch signaling is active at multiple points during hematopoiesis. Until recently, the majority of such studies focused on Notch signaling in lymphocyte differentiation and knowledge of individual Notch receptor roles has been limited due to a paucity of genetic tools available. In this manuscript we generate and describe animal models to identify and fate-map stem and progenitor cells expressing each Notch receptor, delineate Notch pathway activation, and perform in vivo gain and loss of function studies dissecting Notch signaling in early hematopoiesis. These models provide comprehensive genetic maps of lineage-specific Notch receptor expression and activation in hematopoietic stem and progenitor cells. Moreover, they establish a previously unknown role for Notch signaling in the commitment of blood progenitors towards the erythrocytic lineage and link Notch signaling to optimal organismal response to stress erythropoiesis. PMID:23791481

  20. In vivo mapping of notch pathway activity in normal and stress hematopoiesis.

    PubMed

    Oh, Philmo; Lobry, Camille; Gao, Jie; Tikhonova, Anastasia; Loizou, Evangelia; Manet, Jan; van Handel, Ben; Ibrahim, Sherif; Greve, Jeffrey; Mikkola, Hanna; Artavanis-Tsakonas, Spyros; Aifantis, Iannis

    2013-08-01

    Accumulating evidence suggests that Notch signaling is active at multiple points during hematopoiesis. Until recently, the majority of such studies focused on Notch signaling in lymphocyte differentiation and knowledge of individual Notch receptor roles has been limited due to a paucity of genetic tools available. In this manuscript we generate and describe animal models to identify and fate-map stem and progenitor cells expressing each Notch receptor, delineate Notch pathway activation, and perform in vivo gain- and loss-of-function studies dissecting Notch signaling in early hematopoiesis. These models provide comprehensive genetic maps of lineage-specific Notch receptor expression and activation in hematopoietic stem and progenitor cells. Moreover, they establish a previously unknown role for Notch signaling in the commitment of blood progenitors toward the erythrocytic lineage and link Notch signaling to optimal organismal response to stress erythropoiesis. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma.

    PubMed

    Mazur, Pawel K; Einwächter, Henrik; Lee, Marcel; Sipos, Bence; Nakhai, Hassan; Rad, Roland; Zimber-Strobl, Ursula; Strobl, Lothar J; Radtke, Freddy; Klöppel, Günter; Schmid, Roland M; Siveke, Jens T

    2010-07-27

    Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in KrasG12D-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial-mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.

  2. 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

  3. 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.

  4. The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia.

    PubMed

    Suresh, Sukanya; McCallum, Lynn; Crawford, Lisa J; Lu, Wan Hua; Sharpe, Daniel J; Irvine, Alexandra E

    2013-11-01

    Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3(rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05).Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML.

  5. NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells.

    PubMed

    Hayashi, Yoshihiro; Osanai, Makoto; Lee, Gang-Hong

    2015-10-01

    The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1‑positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells.

  6. Heterogeneity of breast cancer stem cells as evidenced with Notch-dependent and Notch-independent populations.

    PubMed

    Wong, Nelson K Y; Fuller, Megan; Sung, Sandy; Wong, Fred; Karsan, Aly

    2012-10-01

    Studies have suggested the potential importance of Notch signaling to the cancer stem cell population in some tumors, but it is not known whether all cells in the cancer stem cell fraction require Notch activity. To address this issue, we blocked Notch activity in MCF-7 cells by expressing a dominant-negative MAML-GFP (dnMAML) construct, which inhibits signaling through all Notch receptors, and quantified the effect on tumor-initiating activity. Inhibition of Notch signaling reduced primary tumor sphere formation and side population. Functional quantification of tumor-initiating cell numbers in vivo showed a significant decrease, but not a complete abrogation, of these cells in dnMAML-expressing cells. Interestingly, when assessed in secondary assays in vitro or in vivo, there was no difference in tumor-initiating activity between the dnMAML-expressing cells and control cells. The fact that a subpopulation of dnMAML-expressing cells was capable of forming primary and secondary tumors indicates that there are Notch-independent tumor-initiating cells in the breast cancer cell line MCF-7. Our findings thus provide direct evidence for a heterogeneous cancer stem cell pool, which will require combination therapies against multiple oncogenic pathways to eliminate the tumor-initiating cell population.

  7. NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers.

    PubMed

    Wang, Hongfang; Zang, Chongzhi; Taing, Len; Arnett, Kelly L; Wong, Yinling Joey; Pear, Warren S; Blacklow, Stephen C; Liu, X Shirley; Aster, Jon C

    2014-01-14

    The main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic NOTCH1-binding sites cooccupy chromatin domains defined by constitutive binding of CCCTC binding factor, which appears to restrict the regulatory potential of dynamic NOTCH1 sites. More remarkably, the majority of dynamic NOTCH1 sites lie in superenhancers, distal elements with exceptionally broad and high levels of H3K27ac. Changes in Notch occupancy produces dynamic alterations in H3K27ac levels across the entire breadth of superenhancers and in the promoters of Notch target genes. These findings link regulation of superenhancer function to NOTCH1, a master regulatory factor and potent oncoprotein in the context of immature T cells, and delineate a generally applicable roadmap for identifying functional Notch sites in cellular genomes.

  8. Crosstalk between PKCα and Notch-4 in endocrine-resistant breast cancer cells

    PubMed Central

    Yun, J; Pannuti, A; Espinoza, I; Zhu, H; Hicks, C; Zhu, X; Caskey, M; Rizzo, P; D'Souza, G; Backus, K; Denning, M F; Coon, J; Sun, M; Bresnick, E H; Osipo, C; Wu, J; Strack, P R; Tonetti, D A; Miele, L

    2013-01-01

    The Notch pathway is functionally important in breast cancer. Notch-1 has been reported to maintain an estrogen-independent phenotype in estrogen receptor α (ERα)+ breast cancer cells. Notch-4 expression correlates with Ki67. Notch-4 also plays a key role in breast cancer stem-like cells. Estrogen-independent breast cancer cell lines have higher Notch activity than estrogen-dependent lines. Protein kinase Cα (PKCα) overexpression is common in endocrine-resistant breast cancers and promotes tamoxifen (TAM)-resistant growth in breast cancer cell lines. We tested whether PKCα overexpression affects Notch activity and whether Notch signaling contributes to endocrine resistance in PKCα-overexpressing breast cancer cells.Analysis of published microarray data from ERα+ breast carcinomas shows that PKCα expression correlates strongly with Notch-4. Real-time reverse transcription PCR and immunohistochemistry on archival specimens confirmed this finding. In a PKCα-overexpressing, TAM-resistant T47D model, PKCα selectively increases Notch-4, but not Notch-1, expression in vitro and in vivo. This effect is mediated by activator protein-1 (AP-1) occupancy of the Notch-4 promoter. Notch-4 knockdown inhibits estrogen-independent growth of PKCα-overexpressing T47D cells, whereas Notch-4IC expression stimulates it. Gene expression profiling shows that multiple genes and pathways associated with endocrine resistance are induced in Notch-4IC- and PKCα-expressing T47D cells. In PKCα-overexpressing T47D xenografts, an orally active γ-secretase inhibitor at clinically relevant doses significantly decreased estrogen-independent tumor growth, alone and in combination with TAM. In conclusion, PKCα overexpression induces Notch-4 through AP-1. Notch-4 promotes estrogen-independent, TAM-resistant growth and activates multiple pathways connected with endocrine resistance and chemoresistance. Notch inhibitors should be clinically evaluated in PKCα- and Notch-4-overexpressing

  9. NOTCH1–RBPJ complexes drive target gene expression through dynamic interactions with superenhancers

    PubMed Central

    Wang, Hongfang; Zang, Chongzhi; Taing, Len; Arnett, Kelly L.; Wong, Yinling Joey; Pear, Warren S.; Blacklow, Stephen C.; Liu, X. Shirley; Aster, Jon C.

    2014-01-01

    The main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic NOTCH1-binding sites cooccupy chromatin domains defined by constitutive binding of CCCTC binding factor, which appears to restrict the regulatory potential of dynamic NOTCH1 sites. More remarkably, the majority of dynamic NOTCH1 sites lie in superenhancers, distal elements with exceptionally broad and high levels of H3K27ac. Changes in Notch occupancy produces dynamic alterations in H3K27ac levels across the entire breadth of superenhancers and in the promoters of Notch target genes. These findings link regulation of superenhancer function to NOTCH1, a master regulatory factor and potent oncoprotein in the context of immature T cells, and delineate a generally applicable roadmap for identifying functional Notch sites in cellular genomes. PMID:24374627

  10. Lattice studies of baryons

    SciTech Connect

    David Richards

    2004-10-01

    This talk describes progress at understanding the properties of the nucleon and its excitations from lattice QCD. I begin with a review of recent lattice results for the lowest-lying states of the excited baryon spectrum. The need to approach physical values of the light quark masses is emphasized, enabling the effects of the pion cloud to be revealed. I then outline the development of techniques that will enable the extraction of the masses of the higher resonances, and describe how such calculations provide insight into the structure of the hadrons. Finally, I discuss direct probes of the quark and gluon structure of baryons through the lattice measurement of the moments of quark distributions and of Generalized Parton Distributions.

  11. Crossing on hyperbolic lattices

    NASA Astrophysics Data System (ADS)

    Gu, Hang; Ziff, Robert M.

    2012-05-01

    We divide the circular boundary of a hyperbolic lattice into four equal intervals and study the probability of a percolation crossing between an opposite pair as a function of the bond occupation probability p. We consider the {7,3} (heptagonal), enhanced or extended binary tree (EBT), the EBT-dual, and the {5,5} (pentagonal) lattices. We find that the crossing probability increases gradually from 0 to 1 as p increases from the lower pl to the upper pu critical values. We find bounds and estimates for the values of pl and pu for these lattices and identify the self-duality point p* corresponding to where the crossing probability equals 1/2. Comparison is made with recent numerical and theoretical results.

  12. Lattice gauge theories

    NASA Astrophysics Data System (ADS)

    Weisz, Peter; Majumdar, Pushan

    2012-03-01

    Lattice gauge theory is a formulation of quantum field theory with gauge symmetries on a space-time lattice. This formulation is particularly suitable for describing hadronic phenomena. In this article we review the present status of lattice QCD. We outline some of the computational methods, discuss some phenomenological applications and a variety of non-perturbative topics. The list of references is severely incomplete, the ones we have included are text books or reviews and a few subjectively selected papers. Kronfeld and Quigg (2010) supply a reasonably comprehensive set of QCD references. We apologize for the fact that have not covered many important topics such as QCD at finite density and heavy quark effective theory adequately, and mention some of them only in the last section "In Brief". These topics should be considered in further Scholarpedia articles.

  13. 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.

  14. 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

  15. 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.

  16. Optical Lattice Clocks

    NASA Astrophysics Data System (ADS)

    Oates, Chris

    2012-06-01

    Since they were first proposed in 2003 [1], optical lattice clocks have become one of the leading technologies for the next generation of atomic clocks, which will be used for advanced timing applications and in tests of fundamental physics [2]. These clocks are based on stabilized lasers whose frequency is ultimately referenced to an ultra-narrow neutral atom transition (natural linewidths << 1 Hz). To suppress the effects of atomic motion/recoil, the atoms in the sample (˜10^4 atoms) are confined tightly in the potential wells of an optical standing wave (lattice). The wavelength of the lattice light is tuned to its ``magic'' value so as to yield a vanishing net AC Stark shift for the clock transition. As a result lattice clocks have demonstrated the capability of generating high stability clock signals with small absolute uncertainties (˜ 1 part in 10^16). In this presentation I will first give an overview of the field, which now includes three different atomic species. I will then use experiments with Yb performed in our laboratory to illustrate the key features of a lattice clock. Our research has included the development of state-of-the-art optical cavities enabling ultra-high-resolution optical spectroscopy (1 Hz linewidth). Together with the large atom number in the optical lattice, we are able to achieve very low clock instability (< 0.3 Hz in 1 s) [3]. Furthermore, I will show results from some of our recent investigations of key shifts for the Yb lattice clock, including high precision measurements of ultracold atom-atom interactions in the lattice and the dc Stark effect for the Yb clock transition (necessary for the evaluation of blackbody radiation shifts). [4pt] [1] H. Katori, M. Takamoto, V. G. Pal'chikov, and V. D. Ovsiannikov, Phys. Rev. Lett. 91, 173005 (2003). [0pt] [2] Andrei Derevianko and Hidetoshi Katori, Rev. Mod. Phys. 83, 331 (2011). [0pt] [3] Y. Y. Jiang, A. D. Ludlow, N. D. Lemke, R. W. Fox, J. A. Sherman, L.-S. Ma, and C. W. Oates

  17. Design of optical notch filter based on Michelson Gires-Tournois interferometer

    NASA Astrophysics Data System (ADS)

    Guo, Sen; Zhang, Juan; Li, Xue

    2011-01-01

    Based on digital signal processing theory, a novel method of designing optical notch filter is presented for Michelson interferometer with Gires-Tournois Etalon. The method is not only effective and simple, but also can be used to implement the designing of the optical notch filter which has arbitrary numbers of notch points in one free spectrum range. As a designing example, the optical notch filter with one notch point is given in the paper. The change of output intensity spectrum is also investigated for the reflection coefficient of the mirror and the distance between the mirrors deviating from the ideal value, finally the tuning characteristics of the notch filter is discussed.

  18. Design of optical notch filter based on Michelson Gires-Tournois interferometer

    NASA Astrophysics Data System (ADS)

    Guo, Sen; Zhang, Juan; Li, Xue

    2010-12-01

    Based on digital signal processing theory, a novel method of designing optical notch filter is presented for Michelson interferometer with Gires-Tournois Etalon. The method is not only effective and simple, but also can be used to implement the designing of the optical notch filter which has arbitrary numbers of notch points in one free spectrum range. As a designing example, the optical notch filter with one notch point is given in the paper. The change of output intensity spectrum is also investigated for the reflection coefficient of the mirror and the distance between the mirrors deviating from the ideal value, finally the tuning characteristics of the notch filter is discussed.

  19. The effect of residual stresses induced by prestraining on fatigue life of notched specimens

    NASA Astrophysics Data System (ADS)

    Sadeler, R.; Ozel, A.; Kaymaz, I.; Totik, Y.

    2005-06-01

    The effect of tensile prestraining-induced residual stress on the fatigue life of notched steel parts was investigated. The study was performed on AISI 4140 steel. Rotating bending fatigue tests were carried out on semicircular notched specimens with different notch radii in the as-quenched and tempered conditions. Metallography of the specimens was performed by means of light optical microscopy. The finite-element method was used to evaluate the residual stress distribution near the notch region. Fatigue tests revealed fatigue life improvement for notched specimens, which changes depending on the notch radii and applied stress. Scanning electron microscopy was used to examine the fracture surfaces of the specimens.

  20. 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.

  1. Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling.

    PubMed

    Muguruma, Yukari; Hozumi, Katsuto; Warita, Hiroyuki; Yahata, Takashi; Uno, Tomoko; Ito, Mamoru; Ando, Kiyoshi

    2016-10-13

    Adult bone mass is maintained through a balance of the activities of osteoblasts and osteoclasts. Although Notch signaling has been shown to maintain bone homeostasis by controlling the commitment, differentiation, and function of cells in both the osteoblast and osteoclast lineages, the precise mechanisms by which Notch performs such diverse and complex roles in bone physiology remain unclear. By using a transgenic approach that modified the expression of delta-like 1 (DLL1) or Jagged1 (JAG1) in an osteoblast-specific manner, we investigated the ligand-specific effects of Notch signaling in bone homeostasis. This study demonstrated for the first time that the proper regulation of DLL1 expression, but not JAG1 expression, in osteoblasts is essential for the maintenance of bone remodeling. DLL1-induced Notch signaling was responsible for the expansion of the bone-forming cell pool by promoting the proliferation of committed but immature osteoblasts. However, DLL1-Notch signaling inhibited further differentiation of the expanded osteoblasts to become fully matured functional osteoblasts, thereby substantially decreasing bone formation. Osteoblast-specific expression of DLL1 did not alter the intrinsic differentiation ability of cells of the osteoclast lineage. However, maturational arrest of osteoblasts caused by the DLL1 transgene impaired the maturation and function of osteoclasts due to a failed osteoblast-osteoclast coupling, resulting in severe suppression of bone metabolic turnover. Taken together, DLL1-mediated Notch signaling is critical for proper bone remodeling as it regulates the differentiation and function of both osteoblasts and osteoclasts. Our study elucidates the importance of ligand-specific activation of Notch signaling in the maintenance of bone homeostasis. This article is protected by copyright. All rights reserved.

  2. Mutational analysis of NOTCH1, 2, 3 and 4 genes in common solid cancers and acute leukemias.

    PubMed

    Lee, Sung Hak; Jeong, Eun Goo; Yoo, Nam Jin; Lee, Sug Hyung

    2007-12-01

    NOTCH proteins (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) play crucial roles in embryonic development. Also, mounting evidence indicates that NOTCH contributes to the pathogenesis of hematopoietic and solid malignancies. Recent studies reported a high incidence of gain-of-function mutations of the NOTCH1 gene in T-cell acute lymphoblastic leukemias (ALL). To see whether NOTCH1 mutation occurs in other malignancies, we analyzed NOTCH1 for the detection of somatic mutations in 334 malignancies, including 48 lung, 48 breast, 48 colorectal and 48 gastric carcinomas, and 142 acute leukemias (105 acute myelogenous leukemias, 32 B-ALLs and 4 T-ALLs) by single-strand conformation polymorphism assay. Also, to see whether other NOTCH genes harbor somatic mutations, we analyzed NOTCH2, NOTCH3 and NOTCH4 genes in the same tissue samples. Overall, we detected three NOTCH mutations in the cancers, which consisted of one NOTCH1 mutation in the T-ALLs (25.0%), one NOTCH2 mutation in the breast carcinomas (2.1%), and one NOTCH3 mutation in the colorectal carcinomas (2.0%). There was no NOTCH mutation in other malignancies analyzed. Our data indicate that NOTCH1 is mutated in T-ALL, but not in other common human cancers, and that NOTCH2, NOTCH3 and NOTH4 genes are rarely mutated in common human cancers. Despite the importance of NOTCH activation in many types of human cancers, mutation of NOTCH genes, except for NOTCH1 mutation in T-ALL, may not play an important role in the tumorigenesis of common cancers.

  3. Cell-cell contact area affects Notch signaling and Notch-dependent patterning

    PubMed Central

    Shaya, Oren; Binshtok, Udi; Hersch, Micha; Rivkin, Dmitri; Weinreb, Sheila; Amir-Zilberstein, Liat; Khamaisi, Bassma; Oppenheim, Olya; Desai, Ravi A.; Goodyear, Richard J.; Richardson, Guy P.; Chen, Christopher S.; Sprinzak, David

    2017-01-01

    Summary During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from microns to tens of microns. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes. PMID:28292428

  4. Notch3 activation is sufficient but not required for inducing human T-lineage specification.

    PubMed

    Waegemans, Els; Van de Walle, Inge; De Medts, Jelle; De Smedt, Magda; Kerre, Tessa; Vandekerckhove, Bart; Leclercq, Georges; Wang, Tao; Plum, Jean; Taghon, Tom

    2014-12-15

    Although the role for the individual Notch receptors in early hematopoiesis have been thoroughly investigated in mouse, studies in human have been mostly limited to the use of pan-Notch inhibitors. However, such studies in human are important to predict potential side effects of specific Notch receptor blocking reagents because these are currently being considered as therapeutic tools to treat various Notch-dependent diseases. In this study, we studied the individual roles of Notch1 and Notch3 in early human hematopoietic lineage decisions, particularly during T-lineage specification. Although this process in mice is solely dependent on Notch1 activation, we recently reported Notch3 expression in human uncommitted thymocytes, raising the possibility that Notch3 mediates human T-lineage specification. Although expression of a constitutive activated form of Notch3 (ICN3) results in the induction of T-lineage specification in human CD34(+) hematopoietic progenitor cells, similar to ICN1 overexpression, loss-of-function studies using blocking Abs reveal that only Notch1, but not Notch3, is critical in this process. Blocking of Notch1 activation in OP9-DLL4 cocultures resulted in a complete block in T-lineage specification and induced monocytic and plasmacytoid dendritic cell differentiation instead. In fetal thymus organ cultures, impeded Notch1 activation resulted in B and dendritic cell development. In contrast, Notch3 blocking Abs only marginally affected T-lineage specification and hematopoietic differentiation with a slight increase in monocyte development. No induction of B or dendritic cell development was observed. Thus, our results unambiguously reveal a nonredundant role for Notch1 in human T-lineage specification, despite the expression of other Notch receptors. Copyright © 2014 by The American Association of Immunologists, Inc.

  5. Notch protection against apoptosis in T-ALL cells mediated by GIMAP5.

    PubMed

    Chadwick, Nicholas; Zeef, Leo; Portillo, Virginia; Boros, Joanna; Hoyle, Sarah; van Doesburg, Jaap C L; Buckle, Anne-Marie

    2010-10-15

    Recent studies have highlighted the role of Notch signalling in the development of T cell acute lymphoblasic leukaemia (T-ALL). Over-expression of Notch3 and gain of function mutations in the Notch1 gene have been reported. The aims of this study were to determine the effect of Notch signalling on apoptosis in human T-ALL cell lines and to identify targets of Notch signalling that may mediate this effect. Functional studies showed that inhibition of Notch signalling using gamma secretase inhibitors promoted glucocorticoid-induced apoptosis in cells carrying gain of function mutations in Notch1. Moreover, ectopic expression of constitutively activated Notch provided protection against glucocorticoid-induced apoptosis, indicating that signalling via Notch may also contribute to the development of T-ALL by conferring resistance to apoptosis. Microarray analysis revealed that GIMAP5, a gene coding for an anti-apoptotic intracellular protein, is upregulated by Notch in T-ALL cell lines. Knockdown of GIMAP5 expression using siRNA promoted glucocorticoid-induced apoptosis in T-ALL cells carrying gain of function mutations in Notch1 and in T-ALL cells engineered to express ectopic constitutively activated Notch indicating that Notch signalling protects T-ALL cells from apoptosis by upregulating the expression of GIMAP5.

  6. Computed tomographic evaluation of the canine intercondylar notch in normal and cruciate deficient stifles.

    PubMed

    Lewis, B A; Allen, D A; Henrikson, T D; Lehenbauer, T W

    2008-01-01

    In the human and veterinary orthopaedic literature it has been implied that intercondylar notch stenosis is a mechanical factor in cranial cruciate ligament rupture and intraarticular graft failure. The patients in this study were classified as normal (32), unilateral cruciate rupture (23), or bilateral cruciate rupture (17). The dogs were placed under general anaesthesia and both stifles were scanned via computed tomography (CT) as previously described. Three CT slices at predetermined levels were evaluated within the notch. Measurements included opening notch angle, notch width and height, condyle width, and notch width index (notch width/condyle width) at two different heights within the notch. Intercondylar notch measurements at the most cranial extent were significantly more narrow in unilateral and bilaterally affected stifles when compared to the normal population. Significant differences were noted in the opening notch angle (ONA), notch width index (NWI), NWI at two thirds notch height (NWI2/3), and tibial slope index (TSI). No significant differences were noted between unilateral and bilateral affected stifles. Increased mechanical contact of the cranial cruciate ligament with a stenotic intercondylar notch may predispose the ligament to mechanical wear and structural weakening. Intercondylar notch measurements have been used as a tool to predict the risk of anterior cruciate ligament injury in young human athletes, and to assess the risk factors for intra-articular graft replacements. Our findings may be useful in developing similar predictive models using stifle CT scans.

  7. Significance of Notch1-signaling pathway in human pancreatic development and carcinogenesis.

    PubMed

    Hu, Huankai; Zhou, Lan; Awadallah, Amad; Xin, Wei

    2013-05-01

    In animal studies, Notch1-signaling pathway plays an important role in the pancreatic embryogenesis by promoting pancreatic progenitor cells self-renewal and exocrine linage development. The persistent activation of Notch pathway could arrest the organ development and keep cells at an undifferentiated stage. Studies have shown that Notch1-signaling pathway is upregulated in invasive pancreatic ductal adenocarcinoma (PDAC). Here we examined the expression pattern of Notch1 and Hes1 in human fetal pancreatic tissues to elucidate the role of Notch1 in human pancreatic embryonic development. We also compared Notch1 expression in tissues from PDAC, chronic pancreatitis and pancreatic intraepithelial neoplasm. Our data show that Notch1/Hes1-signaling pathway is activated during early pancreatic embryogenesis and reaches the highest at birth. After pancreas is fully developed, Notch1/Hes1 pathway is inactivated even though Notch1 protein cell-surface expression is upregulated. We also showed that the expression of both Notch1 and Hes1 are present in 50% (33/66) of PDACs, but not in pancreatic intraepithelial neoplasms. These findings indicate that Notch1 activation is only apparent in late stage of pancreatic carcinogenesis, suggesting that treatment with Notch-signaling inhibitors including γ-secretase should be selectively used for PDACs with confirmed Notch1-signaling activation.

  8. 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.

  9. 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).

  10. Generalizing Word Lattice Translation

    DTIC Science & Technology

    2008-02-01

    demonstrate substantial gains for Chinese -English and Arabic -English translation. Keywords: word lattice translation, phrase-based and hierarchical...introduce in reordering models. Our experiments evaluating the approach demonstrate substantial gains for Chinese -English and Arabic -English translation. 15...Section 4 presents two applications of the noisier channel paradigm, demonstrating substantial performance gains in Arabic -English and Chinese -English

  11. Moving embedded lattice solitons.

    PubMed

    Malomed, B A; Fujioka, J; Espinosa-Cerón, A; Rodríguez, R F; González, S

    2006-03-01

    It was recently proved that solitons embedded in the spectrum of linear waves may exist in discrete systems, and explicit solutions for isolated unstable embedded lattice solitons (ELS) of a differential-difference version of a higher-order nonlinear Schrodinger equation were found [Gonzalez-Perez-Sandi, Fujioka, and Malomed, Physica D 197, 86 (2004)]. The discovery of these ELS gives rise to relevant questions such as the following: (1) Are there continuous families of ELS? (2) Can ELS be stable? (3) Is it possible for ELS to move along the lattice? (4) How do ELS interact? The present work addresses these questions by showing that a novel equation (a discrete version of a complex modified Korteweg-de Vries equation that includes next-nearest-neighbor couplings) has a two-parameter continuous family of exact ELS. These solitons can move with arbitrary velocities across the lattice, and the numerical simulations demonstrate that these ELS are completely stable. Moreover, the numerical tests show that these ELS are robust enough to withstand collisions, and the result of a collision is only a shift in the positions of the solitons. The model may apply to the description of a Bose-Einstein condensate with dipole-dipole interactions between the atoms, trapped in a deep optical-lattice potential.

  12. Career Ladders and Lattices.

    ERIC Educational Resources Information Center

    Dory, Fran

    1975-01-01

    The first part of this report discusses the career lattice concept in the Career Opportunities Program (COP), a concept which represents the marriage of two career development ideas--upward mobility and task differentiation at separate levels. It explains that by combining task differentiation and upward mobility, a system can effectively reduce a…

  13. 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.

  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. Phenomenology Using Lattice QCD

    NASA Astrophysics Data System (ADS)

    Gupta, R.

    2005-08-01

    This talk provides a brief summary of the status of lattice QCD calculations of the light quark masses and the kaon bag parameter BK. Precise estimates of these four fundamental parameters of the standard model, i.e., mu, md, ms and the CP violating parameter η, help constrain grand unified models and could provide a window to new physics.

  17. Phenomenology Using Lattice QCD

    NASA Astrophysics Data System (ADS)

    Gupta, R.

    This talk provides a brief summary of the status of lattice QCD calculations of the light quark masses and the kaon bag parameter BK. Precise estimates of these four fundamental parameters of the standard model, i.e., mu, md, ms and the CP violating parameter η, help constrain grand unified models and could provide a window to new physics.

  18. Rigidity of lattice domes

    NASA Technical Reports Server (NTRS)

    Savelyev, V. A.

    1979-01-01

    The means of ensuring total rigidity of lattice domes, using comparison with solid shells of 1-3 layers are discussed. Irregularities of manufacture, processing, and other factors are considered, as they relate to diminution of rigidity. The discussion uses the concepts of upper and lower critical loads on the structure in question.

  19. p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating with the Notch Transcriptional Complex via MAML1†

    PubMed Central

    Yun, Jieun; Espinoza, Ingrid; Pannuti, Antonio; Romero, Damian; Martinez, Luis; Caskey, Mary; Stanculescu, Adina; Bocchetta, Maurizio; Rizzo, Paola; Band, Vimla; Band, Hamid; Kim, Hwan Mook; Park, Song-Kyu; Kang, Keon Wook; Avantaggiati, Maria Laura; Gomez, Christian R.; Golde, Todd; Osborne, Barbara; Miele, Lucio

    2015-01-01

    p53 and Notch-1 play important roles in breast cancer biology. Notch-1 inhibits p53 activity in cervical and breast cancer cells. Conversely, p53 inhibits Notch activity in T-cells but stimulates it in human keratinocytes. Notch co-activator MAML1 binds p53 and functions as a p53 co-activator. We studied the regulation of Notch signaling by p53 in MCF-7 cells and normal human mammary epithelial cells (HMEC). Results show that overexpression of p53 or activation of endogenous p53 with Nutlin-3 inhibits Notch-dependent transcriptional activity and Notch target expression in a dose-dependent manner. This effect could be partially rescued by transfection of MAML1 but not p300. Standard and quantitative co-immunoprecipitation experiments readily detected a complex containing p53 and Notch-1 in MCF-7 cells. Formation of this complex was inhibited by dominant negative MAML1 (DN-MAML1) and stimulated by wild-type MAML1. Standard and quantitative far-Western experiments showed a complex including p53, Notch-1 and MAML1. Chromatin immunoprecipitation (ChIP) experiments showed that p53 can associate with Notch-dependent HEY1 promoter and this association is inhibited by DN-MAML1 and stimulated by wild-type MAML1. Our data support a model in which p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. In our cellular models, the effect of this association is to inhibit Notch-dependent transcription. Our data suggest that p53-null breast cancers may lack this Notch-modulatory mechanism, and that therapeutic strategies that activate wild-type p53 can indirectly cause inhibition of Notch transcriptional activity. PMID:26033683

  20. p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating With the Notch Transcriptional Complex Via MAML1.

    PubMed

    Yun, Jieun; Espinoza, Ingrid; Pannuti, Antonio; Romero, Damian; Martinez, Luis; Caskey, Mary; Stanculescu, Adina; Bocchetta, Maurizio; Rizzo, Paola; Band, Vimla; Band, Hamid; Kim, Hwan Mook; Park, Song-Kyu; Kang, Keon Wook; Avantaggiati, Maria Laura; Gomez, Christian R; Golde, Todd; Osborne, Barbara; Miele, Lucio

    2015-12-01

    p53 and Notch-1 play important roles in breast cancer biology. Notch-1 inhibits p53 activity in cervical and breast cancer cells. Conversely, p53 inhibits Notch activity in T-cells but stimulates it in human keratinocytes. Notch co-activator MAML1 binds p53 and functions as a p53 co-activator. We studied the regulation of Notch signaling by p53 in MCF-7 cells and normal human mammary epithelial cells (HMEC). Results show that overexpression of p53 or activation of endogenous p53 with Nutlin-3 inhibits Notch-dependent transcriptional activity and Notch target expression in a dose-dependent manner. This effect could be partially rescued by transfection of MAML1 but not p300. Standard and quantitative co-immunoprecipitation experiments readily detected a complex containing p53 and Notch-1 in MCF-7 cells. Formation of this complex was inhibited by dominant negative MAML1 (DN-MAML1) and stimulated by wild-type MAML1. Standard and quantitative far-Western experiments showed a complex including p53, Notch-1, and MAML1. Chromatin immunoprecipitation (ChIP) experiments showed that p53 can associate with Notch-dependent HEY1 promoter and this association is inhibited by DN-MAML1 and stimulated by wild-type MAML1. Our data support a model in which p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. In our cellular models, the effect of this association is to inhibit Notch-dependent transcription. Our data suggest that p53-null breast cancers may lack this Notch-modulatory mechanism, and that therapeutic strategies that activate wild-type p53 can indirectly cause inhibition of Notch transcriptional activity.

  1. Notch Signaling is Essential for Ventricular Chamber Development

    PubMed Central

    Grego-Bessa, Joaquín; Luna-Zurita, Luis; Monte, Gonzalo del; Bolós, Victoria; Melgar, Pedro; Arandilla, Alejandro; Garratt, Alistair N.; Zang, Heesuk; Mukouyama, Yoh-suke; Chen, Hanying; Shou, Weinian; Ballestar, Esteban; Esteller, Manel; Rojas, Ana; Pérez-Pomares, José María; de la Pompa, José Luis

    2009-01-01

    Summary Ventricular chamber morphogenesis, first manifested by trabeculae formation, is crucial for cardiac function and embryonic viability and depends on cellular interactions between endocardium and myocardium. We show that ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, attenuated EphrinB2, NRG1 and BMP10 expression and signaling and decreased myocardial proliferation. Functional and molecular analyses show that Notch inhibition prevents EphrinB2 expression and that EphrinB2 is a direct Notch target acting upstream of NRG1 in the ventricles. However, BMP10 levels are found to be independent of both EphrinB2 and NRG1 during trabeculation. Accordingly, exogenous BMP10 rescues the myocardial proliferative defect of in vitro cultured RBPJk mutants, while exogenous NRG1 rescues differentiation in parallel. We suggest that during trabeculation Notch independently regulates cardiomyocyte proliferation and differentiation, two exquisitely balanced processes whose perturbation may result in congenital heart disease. PMID:17336907

  2. Notch signaling is essential for ventricular chamber development.

    PubMed

    Grego-Bessa, Joaquín; Luna-Zurita, Luis; del Monte, Gonzalo; Bolós, Victoria; Melgar, Pedro; Arandilla, Alejandro; Garratt, Alistair N; Zang, Heesuk; Mukouyama, Yoh-Suke; Chen, Hanying; Shou, Weinian; Ballestar, Esteban; Esteller, Manel; Rojas, Ana; Pérez-Pomares, José María; de la Pompa, José Luis

    2007-03-01

    Ventricular chamber morphogenesis, first manifested by trabeculae formation, is crucial for cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. We show that ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, attenuated EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation. Functional and molecular analyses show that Notch inhibition prevents EphrinB2 expression, and that EphrinB2 is a direct Notch target acting upstream of NRG1 in the ventricles. However, BMP10 levels are found to be independent of both EphrinB2 and NRG1 during trabeculation. Accordingly, exogenous BMP10 rescues the myocardial proliferative defect of in vitro-cultured RBPJk mutants, while exogenous NRG1 rescues differentiation in parallel. We suggest that during trabeculation Notch independently regulates cardiomyocyte proliferation and differentiation, two exquisitely balanced processes whose perturbation may result in congenital heart disease.

  3. Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice

    PubMed Central

    Yue, Feng; Karki, Anju; Castro, Beatriz; Wirbisky, Sara E.; Bidwell, Christopher A.; Freeman, Jennifer L.

    2016-01-01

    Liposarcomas (LPSs) are the most common soft-tissue cancer. Because of the lack of animal models, the cellular origin and molecular regulation of LPS remain unclear. Here, we report that mice with adipocyte-specific activation of Notch signaling (Ad/N1ICD) develop LPS with complete penetrance. Lineage tracing confirms the adipocyte origin of Ad/N1ICD LPS. The Ad/N1ICD LPS resembles human dedifferentiated LPS in histological appearance, anatomical localization, and gene expression signature. Before transformation, Ad/N1ICD adipocytes undergo dedifferentiation that leads to lipodystrophy and metabolic dysfunction. Although concomitant Pten deletion normalizes the glucose metabolism of Ad/N1ICD mice, it dramatically accelerates the LPS prognosis and malignancy. Transcriptomes and lipidomics analyses indicate that Notch activation suppresses lipid metabolism pathways that supply ligands to Pparγ, the master regulator of adipocyte homeostasis. Accordingly, synthetic Pparγ ligand supplementation induces redifferentiation of Ad/N1ICD adipocytes and tumor cells, and prevents LPS development in Ad/N1ICD mice. Importantly, the Notch target HES1 is abundantly expressed in human LPS, and Notch inhibition suppresses the growth of human dedifferentiated LPS xenografts. Collectively, ectopic Notch activation is sufficient to induce dedifferentiation and tumorigenic transformation of mature adipocytes in mouse. PMID:27573812

  4. 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'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. 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.

  6. IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression.

    PubMed

    Liu, Mo; Lee, Dung-Fang; Chen, Chun-Te; Yen, Chia-Jui; Li, Long-Yuan; Lee, Hong-Jen; Chang, Chun-Ju; Chang, Wei-Chao; Hsu, Jung-Mao; Kuo, Hsu-Ping; Xia, Weiya; Wei, Yongkun; Chiu, Pei-Chun; Chou, Chao-Kai; Du, Yi; Dhar, Debanjan; Karin, Michael; Chen, Chung-Hsuan; Hung, Mien-Chie

    2012-01-27

    Proinflammatory cytokine TNFα plays critical roles in promoting malignant cell proliferation, angiogenesis, and tumor metastasis in many cancers. However, the mechanism of TNFα-mediated tumor development remains unclear. Here, we show that IKKα, an important downstream kinase of TNFα, interacts with and phosphorylates FOXA2 at S107/S111, thereby suppressing FOXA2 transactivation activity and leading to decreased NUMB expression, and further activates the downstream NOTCH pathway and promotes cell proliferation and tumorigenesis. Moreover, we found that levels of IKKα, pFOXA2 (S107/111), and activated NOTCH1 were significantly higher in hepatocellular carcinoma tumors than in normal liver tissues and that pFOXA2 (S107/111) expression was positively correlated with IKKα and activated NOTCH1 expression in tumor tissues. Therefore, dysregulation of NUMB-mediated suppression of NOTCH1 by TNFα/IKKα-associated FOXA2 inhibition likely contributes to inflammation-mediated cancer pathogenesis. Here, we report a TNFα/IKKα/FOXA2/NUMB/NOTCH1 pathway that is critical for inflammation-mediated tumorigenesis and may provide a target for clinical intervention in human cancer.

  7. Reconfigurable UWB Bandpass Filter with Flexible Notch Characteristics

    NASA Astrophysics Data System (ADS)

    Dhwaj, Kirti

    The thesis reports a compact tunable ultra-wideband (UWB) notch filter using hybrid microstrip and coplanar waveguide (CPW) structure. The tunable notch is implemented to filter out the wireless local area network (WLAN) channels from 5GHz to 6GHz. The proposed structure utilizes the resonance of open ended stubs to achieve transmission zeroes in the filter passband. Varactors and by-pass capacitors are then introduced for dynamic tunability of notch. Further, the electromagnetic decoupling of the two resonators leads to tunable bandwidth of notch. DC bias circuitry is implemented to control the varactor capacitances. Rejection levels up to 25 dB are attained using this technique while maintaining insertion loss levels below 2.5 dB in the passband. The reconfigurability of bandwidth is shown by maintaining a constant bandwidth of 150 MHz across the WLAN band for the notch. The filter achieves an excellent wide bandwidth (from 2.5 GHz to 8.5 GHz) using multimode-resonator (MMR) based topology which makes the filter one wavelength long at the central frequency.

  8. Structural Analysis Uncovers Lipid-Binding Properties of Notch Ligands

    PubMed Central

    Chillakuri, Chandramouli R.; Sheppard, Devon; Ilagan, Ma. Xenia G.; Holt, Laurie R.; Abbott, Felicity; Liang, Shaoyan; Kopan, Raphael; Handford, Penny A.; Lea, Susan M.

    2013-01-01

    Summary The Notch pathway is a core cell-cell signaling system in metazoan organisms with key roles in cell-fate determination, stem cell maintenance, immune system activation, and angiogenesis. Signals are initiated by extracellular interactions of the Notch receptor with Delta/Serrate/Lag-2 (DSL) ligands, whose structure is highly conserved throughout evolution. To date, no structure or activity has been associated with the extreme N termini of the ligands, even though numerous mutations in this region of Jagged-1 ligand lead to human disease. Here, we demonstrate that the N terminus of human Jagged-1 is a C2 phospholipid recognition domain that binds phospholipid bilayers in a calcium-dependent fashion. Furthermore, we show that this activity is shared by a member of the other class of Notch ligands, human Delta-like-1, and the evolutionary distant Drosophila Serrate. Targeted mutagenesis of Jagged-1 C2 domain residues implicated in calcium-dependent phospholipid binding leaves Notch interactions intact but can reduce Notch activation. These results reveal an important and previously unsuspected role for phospholipid recognition in control of this key signaling system. PMID:24239355

  9. 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.

  10. Notch signaling controls sprouting angiogenesis of endometriotic lesions.

    PubMed

    Körbel, Christina; Gerstner, Miriam D; Menger, Michael D; Laschke, Matthias W

    2017-10-09

    Angiogenesis is essential for the engraftment and growth of endometriotic lesions. In this study, we analyzed whether this process is regulated by Notch signaling. Endometriotic lesions were induced by endometrial tissue transplantation into dorsal skinfold chambers of C57BL/6 mice, which were treated with the γ-secretase inhibitor DAPT or vehicle. Vascularization, morphology, and proliferation of the newly developing lesions were analyzed using intravital fluorescence microscopy, histology, and immunohistochemistry over 14 days. Inhibition of Notch signaling by DAPT significantly increased the number of angiogenic sprouts within the endometrial grafts during the first days after transplantation when compared to vehicle-treated controls. This was associated with an accelerated vascularization, as indicated by a higher functional microvessel density of DAPT-treated lesions on day 6. However, inhibition of Notch signaling did not affect the morphology and proliferating activity of the lesions, as previously described for tumors. Both DAPT- and vehicle-treated lesions finally consisted of cyst-like dilated glands, which were surrounded by a well-vascularized stroma and contained comparable numbers of proliferating cell nuclear antigen-positive cells. These findings demonstrate that sprouting angiogenesis in endometriotic lesions is controlled by Notch signaling. However, inhibition of Notch signaling does not have beneficial therapeutic effects on lesion development.

  11. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone.

    PubMed

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

    2014-03-20

    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.

  12. Localization oscillation in antidot lattices

    NASA Astrophysics Data System (ADS)

    Uryu, S.; Ando, T.

    1998-06-01

    The Anderson localization in square and hexagonal antidot lattices is numerically studied with the use of a Thouless number method. It is revealed that localization is very sensitive to the aspect ratio between the antidot diameter and the lattice constant. In a hexagonal lattice, both the Thouless number and the localization length oscillate with the period equal to the Al’tshuler-Aronov-Spivak oscillation. The oscillation is quite weak in a square lattice.

  13. [Research Progress on Notch Signal Pathway in Acute Graft-Versus-Host Disease -Review].

    PubMed

    Guo, Dong-Mei; Li, Ban-Ban; Li, Chun-Pu; Teng, Qing-Liang

    2017-02-01

    The Notch signaling pathway is a highly conserved cell signaling system that plays an essential role in many biological processes. Notch signaling regulates multiple aspects of hematopoiesis, especially during T cell develop-ment. Recent data suggest that Notch also regulates mature T cell differentiation and function. The latest data show that Notch also plays an essential role in alloreactive T cells mediating acute graft-versus-host disease (aGVHD), the most severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notch inhibition in donor-derived T cells or blockade of individual Notch ligands and receptors after transplantation can reduce GVHD severity and mortality in mouse models of allo-HSCT, without causing global immunosuppression. These findings indicate Notch in T cells as an attractive therapeutic target to control aGVHD. In this article, the pathophysiology of aGVHD, the Notch signal pathway and aGVHD are reviewed.

  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. Notch Ligand Endocytosis Generates Mechanical Pulling Force Dependent on Dynamin, Epsins and Actin

    PubMed Central

    Meloty-Kapella, Laurence; Shergill, Bhupinder; Kuon, Jane; Botvinick, Elliot; Weinmaster, Gerry

    2012-01-01

    SUMMARY Notch signaling induced by cell surface ligands is critical to development and maintenance of many eukaryotic organisms. Notch and its ligands are integral membrane proteins that facilitate direct cell-cell interactions to activate Notch proteolysis and release the intracellular domain that directs Notch-specific cellular responses. Genetic studies suggest Notch ligands require endocytosis, ubiquitylation and epsin endocytic adaptors to activate signaling, yet the exact role ligand endocytosis serves remains unresolved. Here we characterize a molecularly distinct mode of clathrin-mediated endocytosis requiring ligand ubiquitylation, epsins and actin for ligand cells to activate signaling in Notch cells. Using a cell-bead optical tweezers system, we obtained evidence for cell-mediated mechanical force dependent on this distinct mode of ligand endocytosis. We propose mechanical pulling force produced by endocytosis of Notch-bound ligand drives conformational changes in Notch that permit activating proteolysis. PMID:22658936

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

    PubMed

    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

  17. 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

  18. 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.

  19. Hyper-Activation of Notch3 Amplifies the Proliferative Potential of Rhabdomyosarcoma Cells

    PubMed Central

    Vella, Serena; Adesso, Laura; Ciarapica, Roberta; Verginelli, Federica; Pannuti, Antonio; Citti, Arianna; Boldrini, Renata; Milano, Giuseppe M.; Cacchione, Antonella; Ferrari, Andrea; Collini, Paola; Rosolen, Angelo; Bisogno, Gianni; Alaggio, Rita; Inserra, Alessandro; Locatelli, Mattia; Stifani, Stefano; Screpanti, Isabella; Miele, Lucio; Locatelli, Franco; Rota, Rossella

    2014-01-01

    Rhabdomyosarcoma (RMS) is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells. PMID:24797362

  20. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality.

    PubMed

    Hamada, Y; Kadokawa, Y; Okabe, M; Ikawa, M; Coleman, J R; Tsujimoto, Y

    1999-08-01

    Notch family genes encode transmembrane proteins involved in cell-fate determination. Using gene targeting procedures, we disrupted the mouse Notch2 gene by replacing all but one of the ankyrin repeat sequences in the cytoplasmic domain with the E. coli (beta)-galactosidase gene. The mutant Notch2 gene encodes a 380 kDa Notch2-(beta)-gal fusion protein with (beta)-galactosidase activity. Notch2 homozygous mutant mice die prior to embryonic day 11.5, whereas heterozygotes show no apparent abnormalities and are fully viable. Analysis of Notch2 expression patterns, revealed by X-gal staining, demonstrated that the Notch2 gene is expressed in a wide variety of tissues including neuroepithelia, somites, optic vesicles, otic vesicles, and branchial arches, but not heart. Histological studies, including in situ nick end labeling procedures, showed earlier onset and higher incidence of apoptosis in homozygous mutant mice than in heterozygotes or wild type mice. Dying cells were particularly evident in neural tissues, where they were seen as early as embryonic day 9.5 in Notch2-deficient mice. Cells from Notch2 mutant mice attach and grow normally in culture, demonstrating that Notch2 deficiency does not interfere with cell proliferation and that expression of the Notch2-(beta)-gal fusion protein is not toxic per se. In contrast to Notch1-deficient mice, Notch2 mutant mice did not show disorganized somitogenesis, nor did they fail to properly regulate the expression of neurogenic genes such as Hes-5 or Mash1. In situ hybridization studies show no indication of altered Notch1 expression patterns in Notch2 mutant mice. The results indicate that Notch2 plays an essential role in postimplantation development in mice, probably in some aspect of cell specification and/or differentiation, and that the ankyrin repeats are indispensable for its function.

  1. Notch receptor expression in neurogenic regions of the adult zebrafish brain.

    PubMed

    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 [Formula: see text] 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 [Formula: see text] cells. In this region notch3 expression is mostly in Bergmann glia and at low levels in few PCNA [Formula: see text] 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.

  2. 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

  3. 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.

  4. Role of Notch signaling pathway in pancreatic cancer

    PubMed Central

    Gao, Jiankun; Long, Bo; Wang, Zhiwei

    2017-01-01

    Pancreatic cancer (PC) is one of the highly aggressive malignancies in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of PC, such as JNK, PI3K/AKT, Rho GTPase, Hedgehog (Hh) and Skp2. In recent years, accumulated evidence has demonstrated that Notch signaling pathway plays critical roles in the development and progression of PC. Therefore, in this review we discuss the recent literature regarding the function and regulation of Notch in the pathogenesis of PC. Moreover, we describe that Notch signaling pathway could be down-regulated by its inhibitors or natural compounds, which could be a novel approach for the treatment of PC patients. PMID:28337369

  5. 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

    2014-09-08

    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.

  6. Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk.

    PubMed

    Kim, Mi-Yeon; Mo, Jung-Soon; Ann, Eun-Jung; Yoon, Ji-Hye; Jung, Jane; Choi, Yun-Hee; Kim, Su-Man; Kim, Hwa-Young; Ahn, Ji-Seon; Kim, Hangun; Kim, Kwonseop; Hoe, Hyang-Sook; Park, Hee-Sae

    2011-06-01

    The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC-RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.

  7. Evidence of non-canonical NOTCH signaling: Delta-like 1 homolog (DLK1) directly interacts with the NOTCH1 receptor in mammals.

    PubMed

    Traustadóttir, Gunnhildur Ásta; Jensen, Charlotte H; Thomassen, Mads; Beck, Hans Christian; Mortensen, Sussi B; Laborda, Jorge; Baladrón, Victoriano; Sheikh, Søren P; Andersen, Ditte C

    2016-04-01

    Canonical NOTCH signaling, known to be essential for tissue development, requires the Delta-Serrate-LAG2 (DSL) domain for NOTCH to interact with its ligand. However, despite lacking DSL, Delta-like 1 homolog (DLK1), a protein that plays a significant role in mammalian development, has been suggested to interact with NOTCH1 and act as an antagonist. This non-canonical interaction is, however controversial, and evidence for a direct interaction, still lacking in mammals. In this study, we elucidated the putative DLK1-NOTCH1 interaction in a mammalian context. Taking a global approach and using Dlk1(+/+) and Dlk1(-/-) mouse tissues at E16.5, we demonstrated that several NOTCH signaling pathways indeed are affected by DLK1 during tissue development, and this was supported by a lower activation of NOTCH1 protein in Dlk1(+/+) embryos. Likewise, but using a distinct Dlk1-manipulated (siRNA) setup in a mammalian cell line, NOTCH signaling was substantially inhibited by DLK1. Using a mammalian two-hybrid system, we firmly established that the effect of DLK1 on NOTCH signaling was due to a direct interaction between DLK1 and NOTCH1. By careful dissection of this mechanism, we found this interaction to occur between EGF domains 5 and 6 of DLK1 and EGF domains 10-15 of NOTCH1. Thus, our data provide the first evidence for a direct interaction between DLK1 and NOTCH1 in mammals, and substantiate that non-canonical NOTCH ligands exist, adding to the complexity of NOTCH signaling.

  8. 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.

  9. Retrospective analysis of vocal cord-to-suprasternal notch distance

    PubMed Central

    Kim, Hyerim; Chang, Jee-Eun; Ryu, Jung-Hee; Jung, Haesun; Min, Seong-Won; Lee, Jung-Man; Hwang, Jin-Young

    2017-01-01

    Abstract Endotracheal tube (ETT) positioning using the cuff ballottement test, which confirms that the inflated cuff is positioned at the suprasternal notch with squeezing or inflating a pilot balloon, has been reported to be a simple and reliable method of preventing endobronchial intubation. However, in patients with a short vocal cord-to-suprasternal notch, ETT placement using the cuff ballottement test can cause vocal cord injury. In the present study, we assessed the distance from a point 15 mm below the vocal cord to the suprasternal notch (VSD-15), the safe position for ETT cuff placement above the suprasternal notch, and investigated variables for predicting VSD-15. We retrospectively examined neck computed tomography in 427 adult patients and measured VSD-15 and the distance from the thyroid notch to the suprasternal notch (TSD). Patient height, weight, sex, and age were also recorded. In total, 47 patients (11.0%) showed a VSD-15 shorter than 45 mm. VSD-15 significantly correlated with TSD (r = 0.778, P < 0.001) and height (r = 0.312, P < 0.001), and inversely correlated with age (r = −0.321, P < 0.001). In multiple linear regression models, a formula was obtained for VSD-15 (VSD-15 [mm] = −6.220 + 0.744 × TSD [mm] + 0.092 × height [cm] − 0.065 × age [years], R2 = 0.621). The cuff ballottement test should be used cautiously in patients with a predicted short VSD-15. VSD-15 can be predicted from TSD, height, and age. PMID:28207550

  10. Honokiol Inhibits Melanoma Stem Cells by Targeting Notch Signaling

    PubMed Central

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

    2016-01-01

    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

  11. The pathological significance of Notch1 in oral squamous cell carcinoma.

    PubMed

    Yoshida, Ryoji; Nagata, Masashi; Nakayama, Hideki; Niimori-Kita, Kanako; Hassan, Wael; Tanaka, Takuji; Shinohara, Masanori; Ito, Takaaki

    2013-10-01

    Notch signaling has been reported to be involved in several types of malignant tumors; however, the role and activation mechanism of Notch signaling in oral squamous cell carcinoma (OSCC) remains poorly characterized. The purpose of this study was to elucidate the pathological significance of Notch signaling and its activation mechanism in the development and progression of OSCC. In this study, we showed that the expression of Notch1 and intracellular Notch domain (NICD) are upregulated in OSCCs. In addition, Notch1 and NICD were found to be characteristically localized at the invasive tumor front. TNF-α, a major inflammatory cytokine, significantly activated Notch signaling in vitro. In a clinicopathological analysis, Notch1 expression correlated with both the T-stage and the clinical stage. Furthermore, loss of Notch1 expression correlated with the inhibition of cell proliferation and TNF-α-dependent invasiveness in an OSCC cell line. In addition, γ-secretase inhibitor (GSI) prevented cell proliferation and TNF-α-dependent invasion of OSCC cells in vitro. These results indicate that altered expression of Notch1 is associated with increased cancer progression and that Notch1 regulates the steps involved in cell metastasis in OSCC. Moreover, inactivating Notch signaling with GSI could therefore be a useful approach for treating patients with OSCC.

  12. Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia.

    PubMed

    Liu, Hudan; Chiang, Mark Y; Pear, Warren S

    2011-08-01

    NOTCH1 plays a central role in T-cell development and, when aberrantly activated, in acute T-cell lymphoblastic leukemia (T-ALL). As a transmembrane receptor that is ultimately converted into a transcription factor, NOTCH1 directly activates a spectrum of target genes, which function to mediate NOTCH1 signaling in normal or transformed T cells. During physiologic T-cell development, NOTCH1 has important functions in cell fate determination, proliferation, survival and metabolism. Activating NOTCH1 mutations occur in more than half of human patients with T-ALL, suggesting an important role for aberrant NOTCH1 signaling in the pathogenesis of this disease. Inhibiting NOTCH1 signaling in patient-derived cell lines and murine T-ALLs leads to growth arrest and/or apoptosis suggesting that NOTCH1 inhibitors can improve T-ALL treatment. However, there are challenges to translate NOTCH1 inhibitors to the clinic because of toxicity and resistance. This review focuses on molecular mechanisms of oncogenic NOTCH1 signaling, molecular and functional analysis of NOTCH1 transcriptional targets in T-ALL, and recent advances in therapeutic targeting of NOTCH1.

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

    PubMed

    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. 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.

  14. Notch-1 regulates transcription of the epidermal growth factor receptor through p53.

    PubMed

    Purow, Benjamin W; Sundaresan, Tilak K; Burdick, Michael J; Kefas, Benjamin A; Comeau, Laurey D; Hawkinson, Michael P; Su, Qin; Kotliarov, Yuri; Lee, Jeongwu; Zhang, Wei; Fine, Howard A

    2008-05-01

    The Notch pathway plays a key role in the development and is increasingly recognized for its importance in cancer. We demonstrated previously the overexpression of Notch-1 and its ligands in gliomas and showed that their knockdown inhibits glioma cell proliferation and survival. To elucidate the mechanisms downstream of Notch-1 in glioma cells, we performed microarray profiling of glioma cells transfected with Notch-1 small interfering RNA. Notable among downregulated transcripts was the epidermal growth factor receptor (EGFR), known to be overexpressed or amplified in gliomas and prominent in other cancers as well. Further studies confirmed that Notch-1 inhibition decreased EGFR messenger RNA (mRNA) and EGFR protein in glioma and other cell lines. Transfection with Notch-1 increased EGFR expression. Additionally, we found a significant correlation in levels of EGFR and Notch-1 mRNA in primary high-grade human gliomas. Subsequent experiments showed that p53, an activator of the EGFR promoter, is regulated by Notch-1. Experiments with p53-positive and -null cell lines confirmed that p53 partially mediates the effects of Notch-1 on EGFR expression. These results show for the first time that Notch-1 upregulates EGFR expression and also demonstrate Notch-1 regulation of p53 in gliomas. These observations have significant implications for understanding the mechanisms of Notch in cancer and development.

  15. Regulation of Notch signaling during T- and B-cell development by O-fucose glycans.

    PubMed

    Stanley, Pamela; Guidos, Cynthia J

    2009-07-01

    Notch signaling is required for the development of all T cells and marginal zone (MZ) B cells. Specific roles in T- and B-cell differentiation have been identified for different Notch receptors, the canonical Delta-like (Dll) and Jagged (Jag) Notch ligands, and downstream effectors of Notch signaling. Notch receptors and ligands are post-translationally modified by the addition of glycans to extracellular domain epidermal growth factor-like (EGF) repeats. The O-fucose glycans of Notch cell-autonomously modulate Notch-ligand interactions and the strength of Notch signaling. These glycans are initiated by protein O-fucosyltransferase 1 (Pofut1), and elongated by the transfer of N-acetylglucosamine (GlcNAc) to the fucose by beta1,3GlcNAc-transferases termed lunatic, manic, or radical fringe. This review discusses T- and B-cell development from progenitors deficient in O-fucose glycans. The combined data show that Lfng and Mfng regulate T-cell development by enhancing the interactions of Notch1 in T-cell progenitors with Dll4 on thymic epithelial cells. In the spleen, Lfng and Mfng cooperate to modify Notch2 in MZ B progenitors, enhancing their interaction with Dll1 on endothelial cells and regulating MZ B-cell production. Removal of O-fucose affects Notch signaling in myelopoiesis and lymphopoiesis, and the O-fucose glycan in the Notch1 ligand-binding domain is required for optimal T-cell development.

  16. 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.

  17. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Notch1-mediated signaling regulates proliferation of porcine satellite cells (PSCs).

    PubMed

    Qin, Lili; Xu, Jian; Wu, Zhenfang; Zhang, Zhe; Li, Jiaqi; Wang, Chong; Long, Qiaoming

    2013-02-01

    Notch signaling is an evolutionarily conserved cell-cell communication mechanism involved in the regulation of cell proliferation, differentiation and fate decisions of mammalian cells. In the present study, we investigated the possible requirement for Notch signaling in the proliferation and differentiation of porcine satellite cells. We show that Notch1, 2 and 3 are expressed in cultured porcine satellite cells. Knock-down of NOTCH1, but not NOTCH2 and NOTCH3, decreases the proliferation of porcine satellite cells. In contrast, enhancement of NOTCH1 expression via treatment of porcine satellite cells with recombinant NF-κB increases the proliferation of porcine satellite cells. The alteration of porcine satellite cell proliferation is associated with significant changes in the expression of cell cycle related genes (cyclin B1, D1, D2, E1 and p21), myogenic regulatory factors (MyoD and myogenin) and the Notch effector Hes5. In addition, alteration of Notch1 expression in porcine satellite cells causes changes in the expression of GSK3β-3. Taken together, these findings suggest that of the four notch-related genes, Notch1is likely to be required for regulating the proliferation and therefore the maintenance of porcine satellite cells in vivo, and do so through activation of the Notch effector gene Hes5.

  19. Biological Lattice Gas Models

    NASA Astrophysics Data System (ADS)

    Alber, Mark S.; Kiskowski, Maria; Jiang, Yi; Newman, Stuart

    Modelling pattern formation and morphogenesis are fundamental problems in biology. One useful approach is lattice gas cellular automata (LGCA) model. This paper reviews several stochastic lattice gas models for pattern formation in myxobacteria fruiting body morphogenesis and vertebrate limb skeletogenesis. The fruiting body formation in myxobacteria is a complex morphological process that requires the organized, collective effort of tens of thousands of cells. It provides new insight into collective microbial behavior since myxobacteria morphogenic pattern formation is governed by cell-cell interactions rather than chemotaxis. We describe LGCA models for the aggregation stage of the fruiting body formation. Limb bud precartilage mesenchymal cells in micromass culture undergo chondrogenic pattern formation, which results in the formation of regularly-spaced "islands" of cartilage analogous to the cartilage primordia of the developing limb skeleton. An LGCA model, based on reaction-diffusion coupling and cell-matrix adhesion, is described for this process.

  20. 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.

  1. Parametric lattice Boltzmann method

    NASA Astrophysics Data System (ADS)

    Shim, Jae Wan

    2017-06-01

    The discretized equilibrium distributions of the lattice Boltzmann method are presented by using the coefficients of the Lagrange interpolating polynomials that pass through the points related to discrete velocities and using moments of the Maxwell-Boltzmann distribution. The ranges of flow velocity and temperature providing positive valued distributions vary with regulating discrete velocities as parameters. New isothermal and thermal compressible models are proposed for flows of the level of the isothermal and thermal compressible Navier-Stokes equations. Thermal compressible shock tube flows are simulated by only five on-lattice discrete velocities. Two-dimensional isothermal and thermal vortices provoked by the Kelvin-Helmholtz instability are simulated by the parametric models.

  2. Fractional lattice charge transport

    PubMed Central

    Flach, Sergej; Khomeriki, Ramaz

    2017-01-01

    We consider the dynamics of noninteracting quantum particles on a square lattice in the presence of a magnetic flux α and a dc electric field E oriented along the lattice diagonal. In general, the adiabatic dynamics will be characterized by Bloch oscillations in the electrical field direction and dispersive ballistic transport in the perpendicular direction. For rational values of α and a corresponding discrete set of values of E(α) vanishing gaps in the spectrum induce a fractionalization of the charge in the perpendicular direction - while left movers are still performing dispersive ballistic transport, the complementary fraction of right movers is propagating in a dispersionless relativistic manner in the opposite direction. Generalizations and the possible probing of the effect with atomic Bose-Einstein condensates and photonic networks are discussed. Zak phase of respective band associated with gap closing regime has been computed and it is found converging to π/2 value. PMID:28102302

  3. 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.

  4. Instantons on the lattice

    NASA Astrophysics Data System (ADS)

    Fucito, F.; Solomon, S.

    By modifying the lattice action of spin and gauge models we insure that the system cannot tunnel between topological sectors by local Monte Carlo (MC) steps. We insure the correct weight of the topological sectors in the statistical sum by considering global MC steps. This strategy permits us to study the effects of topological objects in ϑ-vacua, < Q2> scaling and chiral symmetry breaking in a straightforward way.

  5. Charmonium from Lattice QCD

    SciTech Connect

    Jozef Dudek

    2007-08-05

    Charmonium is an attractive system for the application of lattice QCD methods. While the sub-threshold spectrum has been considered in some detail in previous works, it is only very recently that excited and higher-spin states and further properties such as radiative transitions and two-photon decays have come to be calculated. I report on this recent progress with reference to work done at Jefferson Lab.

  6. 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.

  7. Notch sensitivity of hydrogenated oxygen-strengthened titanium

    NASA Technical Reports Server (NTRS)

    Wasz, M. L.; Ko, C. C.; Brotzen, F. R.; Mclellan, R. B.

    1990-01-01

    While earlier studies have shown that the tensile properties and fracture test intensity factors of oxygen-strengthened Ti remain nearly unaffected by the presence of about 70 ppm (weight) hydrogen, the Charpy V-notch test-determined impact properties of oxygen-bearing Ti are strongly affected by the presence of hydrogen. The present study establishes that, concurrently with the strengthening effect of oxygen, there is a substantial lowering of ductility. The presence of hydrogen has virtually no effect on the notch strength of Ti alloys of either low or high oxygen content, where hydrogen contents lie in the 25-80 range.

  8. 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

  9. Design of optical notch filters using apodized thickness modulation.

    PubMed

    Lyngnes, Ove; Kraus, James

    2014-02-01

    An apodized thickness design method for discrete layer notch filters is presented. The method produces error tolerant designs with low ripple in the passband regions without any additional numerical optimization. Several apodization functions including Gaussian, cosine squared, as well as quintic are considered. Theoretical and experimental results from ion beam deposited sample designs for single-notch as well as multinotch filters are presented. Good agreement is observed between the theoretical design and the experimental measurement even when the deposition process is only controlled on time. This demonstrates the low layer error sensitivity of the apodized designs.

  10. 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.

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

    PubMed

    McBride, D I; Williams, S

    2001-01-01

    To investigate the relation between different types of exposure to noise and a classic sign of noise induced hearing loss (NIHL), the audiometric notch. 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. 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. 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 confirming the diagnosis, the 6 kHz notch is variable and of

  12. 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.

  13. Immunohistochemical tools and techniques to visualize Notch in Drosophila melanogaster.

    PubMed

    Tognon, Emiliana; Vaccari, Thomas

    2014-01-01

    The ability to accurately visualize proteins in Drosophila tissues is critical for studying their abundance and localization relative to the morphology of cells during tissue development and homeostasis. Here we describe the procedure to visualize Notch localization in whole-mount preparations of several Drosophila organs using confocal microscopy. The use of monoclonal antibodies directed to distinct portions of Notch allows one to follow the fate of the receptor during constitutive and inductive processes. The protocol described here can be used to co-label with antibodies recognizing markers of subcellular compartments in wild-type as well as mutant tissues.

  14. Lattice dynamics of coesite.

    PubMed

    Wehinger, Björn; Bosak, Alexeï; Chumakov, Aleksandr; Mirone, Alessandro; Winkler, Björn; Dubrovinsky, Leonid; Dubrovinskaia, Natalia; Brazhkin, Vadim; Dyuzheva, Tatiana; Krisch, Michael

    2013-07-10

    The lattice dynamics of coesite has been studied by a combination of diffuse x-ray scattering, inelastic x-ray scattering and ab initio lattice dynamics calculations. The combined technique gives access to the full lattice dynamics in the harmonic description and thus eventually provides detailed information on the elastic properties, the stability and metastability of crystalline systems. The experimentally validated calculation was used for the investigation of the eigenvectors, mode character and their contribution to the density of vibrational states. High-symmetry sections of the reciprocal space distribution of diffuse scattering and inelastic x-ray scattering spectra as well as the density of vibrational states and the dispersion relation are reported and compared to the calculation. A critical point at the zone boundary is found to contribute strongly to the main peak of the low-energy part in the density of vibrational states. Comparison with the most abundant SiO2 polymorph--α-quartz--reveals similarities and distinct differences in the low-energy vibrational properties.

  15. Digital lattice gauge theories

    NASA Astrophysics Data System (ADS)

    Zohar, Erez; Farace, Alessandro; Reznik, Benni; Cirac, J. Ignacio

    2017-02-01

    We propose a general scheme for a digital construction of lattice gauge theories with dynamical fermions. In this method, the four-body interactions arising in models with 2 +1 dimensions and higher are obtained stroboscopically, through a sequence of two-body interactions with ancillary degrees of freedom. This yields stronger interactions than the ones obtained through perturbative methods, as typically done in previous proposals, and removes an important bottleneck in the road towards experimental realizations. The scheme applies to generic gauge theories with Lie or finite symmetry groups, both Abelian and non-Abelian. As a concrete example, we present the construction of a digital quantum simulator for a Z3 lattice gauge theory with dynamical fermionic matter in 2 +1 dimensions, using ultracold atoms in optical lattices, involving three atomic species, representing the matter, gauge, and auxiliary degrees of freedom, that are separated in three different layers. By moving the ancilla atoms with a proper sequence of steps, we show how we can obtain the desired evolution in a clean, controlled way.

  16. 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.

  17. Topological lattice actions

    NASA Astrophysics Data System (ADS)

    Bietenholz, W.; Gerber, U.; Pepe, M.; Wiese, U.-J.

    2010-12-01

    We consider lattice field theories with topological actions, which are invariant against small deformations of the fields. Some of these actions have infinite barriers separating different topological sectors. Topological actions do not have the correct classical continuum limit and they cannot be treated using perturbation theory, but they still yield the correct quantum continuum limit. To show this, we present analytic studies of the 1-d O(2) and O(3) model, as well as Monte Carlo simulations of the 2-d O(3) model using topological lattice actions. Some topological actions obey and others violate a lattice Schwarz inequality between the action and the topological charge Q. Irrespective of this, in the 2-d O(3) model the topological susceptibility {χ_t} = {{{left< {{Q^2}} rightrangle }} left/ {V} right.} is logarithmically divergent in the continuum limit. Still, at non-zero distance the correlator of the topological charge density has a finite continuum limit which is consistent with analytic predictions. Our study shows explicitly that some classically important features of an action are irrelevant for reaching the correct quantum continuum limit.

  18. Hadroquarkonium from lattice QCD

    NASA Astrophysics Data System (ADS)

    Alberti, Maurizio; Bali, Gunnar S.; Collins, Sara; Knechtli, Francesco; Moir, Graham; Söldner, Wolfgang

    2017-04-01

    The hadroquarkonium picture [S. Dubynskiy and M. B. Voloshin, Phys. Lett. B 666, 344 (2008), 10.1016/j.physletb.2008.07.086] provides one possible interpretation for the pentaquark candidates with hidden charm, recently reported by the LHCb Collaboration, as well as for some of the charmoniumlike "X , Y , Z " states. In this picture, a heavy quarkonium core resides within a light hadron giving rise to four- or five-quark/antiquark bound states. We test this scenario in the heavy quark limit by investigating the modification of the potential between a static quark-antiquark pair induced by the presence of a hadron. Our lattice QCD simulations are performed on a Coordinated Lattice Simulations (CLS) ensemble with Nf=2 +1 flavors of nonperturbatively improved Wilson quarks at a pion mass of about 223 MeV and a lattice spacing of about a =0.0854 fm . We study the static potential in the presence of a variety of light mesons as well as of octet and decuplet baryons. In all these cases, the resulting configurations are favored energetically. The associated binding energies between the quarkonium in the heavy quark limit and the light hadron are found to be smaller than a few MeV, similar in strength to deuterium binding. It needs to be seen if the small attraction survives in the infinite volume limit and supports bound states or resonances.

  19. 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

  20. A new approach for modelling lattice energy in finite crystal domains

    NASA Astrophysics Data System (ADS)

    Bilotsky, Y.; Gasik, M.

    2015-09-01

    Evaluation of internal energy in a crystal lattice requires precise calculation of lattice sums. Such evaluation is a problem in the case of small (nano) particles because the traditional methods are usually effective only for infinite lattices and are adapted to certain specific potentials. In this work, a new method has been developed for calculation of lattice energy. The method is a generalisation of conventional geometric probability techniques for arbitrary fixed lattices in a finite crystal domain. In our model, the lattice energy for wide range of two- body central interaction potentials (including long-range Coulomb potential) has been constructed using absolutely convergent sums. No artificial cut-off potential or periodical extension of the domain (which usually involved for such calculations) have been made for calculation of the lattice energy under this approach. To exemplify the applications of these techniques, the energy of Coulomb potential has been plotted as the function of the domain size.

  1. 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.

  2. 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

  3. 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.

  4. Using singularities to detect and describe a notch in a pipe

    NASA Astrophysics Data System (ADS)

    Stoyko, D. K.; Popplewell, N.; Shah, A. H.

    2013-01-01

    A hybrid Semi-Analytical Finite Element (SAFE) and standard finite element procedure is adopted to locally detect and characterize an outer surface breaking, axisymmetric notch in an otherwise infinitely long steel pipe. Numerical simulations demonstrate that interactions between incident, dispersive ultrasonic guided waves and the notch change a radial displacement's temporal history and introduce singularities in the previously unblemished pipe's Frequency Response Function (FRF). The new singularities indicate the presence of a nearby notch. Furthermore, the frequency differences between the singularities of the unblemished and blemished pipes are shown to reflect the axisymmetric notch's dimensions. The conceptually straightforward but computationally expensive extension to nonaxisymmetric notches is also suggested.

  5. 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

  6. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.

    PubMed

    Nam, Yunsun; Sliz, Piotr; Song, Luyan; Aster, Jon C; Blacklow, Stephen C

    2006-03-10

    Notch receptors transduce essential developmental signals between neighboring cells by forming a complex that leads to transcription of target genes upon activation. We report here the crystal structure of a Notch transcriptional activation complex containing the ankyrin domain of human Notch1 (ANK), the transcription factor CSL on cognate DNA, and a polypeptide from the coactivator Mastermind-like-1 (MAML-1). Together, CSL and ANK create a groove to bind the MAML-1 polypeptide as a kinked, 70 A helix. The composite binding surface likely restricts the recruitment of MAML proteins to promoters on which Notch:CSL complexes have been preassembled, ensuring tight transcriptional control of Notch target genes.

  7. 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.

  8. Lattice topology dictates photon statistics.

    PubMed

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

    2017-08-21

    Propagation of coherent light through a disordered network is accompanied by randomization and possible conversion into thermal light. Here, we show that network topology plays a decisive role in determining the statistics of the emerging field if the underlying lattice is endowed with chiral symmetry. In such lattices, eigenmode pairs come in skew-symmetric pairs with oppositely signed eigenvalues. By examining one-dimensional arrays of randomly coupled waveguides arranged on linear and ring topologies, we are led to a remarkable prediction: the field circularity and the photon statistics in ring lattices are dictated by its parity while the same quantities are insensitive to the parity of a linear lattice. For a ring lattice, adding or subtracting a single lattice site can switch the photon statistics from super-thermal to sub-thermal, or vice versa. This behavior is understood by examining the real and imaginary fields on a lattice exhibiting chiral symmetry, which form two strands that interleave along the lattice sites. These strands can be fully braided around an even-sited ring lattice thereby producing super-thermal photon statistics, while an odd-sited lattice is incommensurate with such an arrangement and the statistics become sub-thermal.

  9. 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

  10. Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity.

    PubMed

    D'Angelo, Rosemarie C; Ouzounova, Maria; Davis, April; Choi, Daejin; Tchuenkam, Stevie M; Kim, Gwangil; Luther, Tahra; Quraishi, Ahmed A; Senbabaoglu, Yasin; Conley, Sarah J; Clouthier, Shawn G; Hassan, Khaled A; Wicha, Max S; Korkaya, Hasan

    2015-03-01

    Developmental pathways such as Notch play a pivotal role in tissue-specific stem cell self-renewal as well as in tumor development. However, the role of Notch signaling in breast cancer stem cells (CSC) remains to be determined. We utilized a lentiviral Notch reporter system to identify a subset of cells with a higher Notch activity (Notch(+)) or reduced activity (Notch(-)) in multiple breast cancer cell lines. Using in vitro and mouse xenotransplantation assays, we investigated the role of the Notch pathway in breast CSC regulation. Breast cancer cells with increased Notch activity displayed increased sphere formation as well as expression of breast CSC markers. Interestingly Notch(+) cells displayed higher Notch4 expression in both basal and luminal breast cancer cell lines. Moreover, Notch(+) cells demonstrated tumor initiation capacity at serial dilutions in mouse xenografts, whereas Notch(-) cells failed to generate tumors. γ-Secretase inhibitor (GSI), a Notch blocker but not a chemotherapeutic agent, effectively targets these Notch(+) cells in vitro and in mouse xenografts. Furthermore, elevated Notch4 and Hey1 expression in primary patient samples correlated with poor patient survival. Our study revealed a molecular mechanism for the role of Notch-mediated regulation of breast CSCs and provided a compelling rationale for CSC-targeted therapeutics.

  11. Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity

    PubMed Central

    Davis, April; Choi, Daejin; Tchuenkam, Stevie M.; Kim, Gwangil; Luther, Tahra; Quraishi, Ahmed A.; Senbabaoglu, Yasin; Conley, Sarah J.; Clouthier, Shawn G.; Hassan, Khaled A.; Wicha, Max S.; Korkaya, Hasan

    2015-01-01

    Developmental pathways such as Notch play a pivotal role in tissue specific stem cell self-renewal as well as in tumor development. However, the role of Notch signaling in breast cancer stem cells (CSC) remains to be determined. We utilized a lentiviral Notch reporter system to identify a subset of cells with a higher Notch activity (Notch+) or reduced activity (Notch-) in multiple breast cancer cell lines. Using in vitro and mouse xenotransplantation assays we investigated the role of Notch pathway in breast CSC regulation. Breast cancer cells with increased Notch activity displayed increased sphere formation as well as expression of breast CSC markers. Interestingly Notch+ cells displayed higher Notch4 expression in both basal and luminal breast cancer cell lines. Moreover, Notch+ cells demonstrated tumor initiation capacity at serial dilutions in mouse xenografts while Notch- cells failed to generate tumors. Gamma-secretase inhibitor (GSI), a Notch blocker but not a chemotherapeutic agent effectively targets these Notch+ cells in vitro and in mouse xenografts. Furthermore, elevated Notch4 and Hey1 expression in primary patient samples correlated with poor patient survival. Our studies reveal molecular mechanism for the role of Notch mediated regulation of breast CSCs and provide a compelling rationale for CSC targeted therapeutics. PMID:25673823

  12. 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.

  13. Finite-element analysis of end-notch flexure specimens

    NASA Technical Reports Server (NTRS)

    Mall, S.; Kochhar, N. K.

    1986-01-01

    A finite-element analysis of the end-notch flexure specimen for Mode II interlaminar fracture toughness measurement was conducted. The effects of friction between the crack faces and large deflection on the evaluation of G(IIc) from this specimen were investigated. Results of this study are presented in this paper.

  14. 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.

  15. Finite element analysis of end notch flexure specimen

    NASA Technical Reports Server (NTRS)

    Mall, S.; Kochhar, N. K.

    1986-01-01

    A finite element analysis of the end notch flexure specimen for mode II interlaminar fracture toughness measurement was conducted. The effect of friction between the crack faces and large deflection on the evaluation of G sub IIc from this specimen were investigated. Results of this study are presented in this paper.

  16. 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.

  17. Notch Inhibits Yorkie Activity in Drosophila Wing Discs

    PubMed Central

    Djiane, Alexandre; Zaessinger, Sophie; Babaoğlan, A. Burcu; Bray, Sarah J.

    2014-01-01

    During development, tissues and organs must coordinate growth and patterning so they reach the right size and shape. During larval stages, a dramatic increase in size and cell number of Drosophila wing imaginal discs is controlled by the action of several signaling pathways. Complex cross-talk between these pathways also pattern these discs to specify different regions with different fates and growth potentials. We show that the Notch signaling pathway is both required and sufficient to inhibit the activity of Yorkie (Yki), the Salvador/Warts/Hippo (SWH) pathway terminal transcription activator, but only in the central regions of the wing disc, where the TEAD factor and Yki partner Scalloped (Sd) is expressed. We show that this cross-talk between the Notch and SWH pathways is mediated, at least in part, by the Notch target and Sd partner Vestigial (Vg). We propose that, by altering the ratios between Yki, Sd and Vg, Notch pathway activation restricts the effects of Yki mediated transcription, therefore contributing to define a zone of low proliferation in the central wing discs. PMID:25157415

  18. 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

  19. Impacts of wildlife viewing at Dixville Notch Wildlife Viewing Area

    Treesearch

    Judith K. Silverberg; Peter J. Pekins; Robert A. Robertson

    2002-01-01

    Dixville Notch Wildlife Viewing Area provided an opportunity to examine the motivations, knowledge level and attitudes of wildlife viewers as well as the response of wildlife to observation and other human caused stimuli at a designated wildlife viewing site. Using integrated social science and biological information allowed recommendations to be made for managing...

  20. An environmental Wnt16/Notch pathway specifies haematopoietic stem cells

    PubMed Central

    Clements, Wilson K.; Kim, Albert D.; Ong, Karen G.; Moore, John C.; Lawson, Nathan; Traver, David

    2011-01-01

    Haematopoietic stem cells (HSCs) are a self-renewing population that continuously replenish all blood and immune cells during the lifetime of an individual1, 2. HSCs are used clinically to treat a wide array of diseases, including acute leukaemias and congenital blood disorders, but obtaining suitable numbers of cells and finding immune compatible donors remain serious problems. These concerns have led to an interest in the conversion of embryonic stem cells or induced pluripotent stem cells into HSCs, which is not possible using current methodologies. To accomplish this goal, it is critical to understand the native mechanisms involved in specification of HSCs during embryonic development. Here we demonstrate that Wnt16 controls a novel genetic regulatory network required for HSC specification. Non-canonical signaling by Wnt16 is required for somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), and these ligands are in turn required for establishment of definitive haematopoiesis. Notch signalling downstream of Dlc/Dld is earlier than, and distinct from known cell-autonomous requirements for Notch, strongly suggesting that novel Notch-dependent relay signal(s) induce the first HSCs in parallel to other established pathways. Our results demonstrate that somite-specific gene expression is required for the production of haemogenic endothelium. PMID:21654806

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

    NASA Astrophysics Data System (ADS)

    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.

    2016-09-01

    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.

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

    SciTech Connect

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

    1991-10-01

    A fast notch'' current has been produced on the (4 {mu}H) hardcore central conductor (C. M. Greenfield, M. E. Koepke, and F. L. Ribe, Phys. Fluids B {bold 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 ({tau}{sub 1/4} = 14 {mu}s) brought to a crowbarred dc value (20 kA) and then quickly ({tau}{sub 1/4} = 1.3 {mu}s) 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.

  3. Dynamics of lattice kinks

    NASA Astrophysics Data System (ADS)

    Kevrekidis, P. G.; Weinstein, M. I.

    2000-08-01

    We consider a class of Hamiltonian nonlinear wave equations governing a field defined on a spatially discrete one-dimensional lattice, with discreteness parameter, d= h-1, where h>0 is the lattice spacing. The specific cases we consider in detail are the discrete sine-Gordon (SG) and discrete φ4 models. For finite d and in the continuum limit ( d→∞) these equations have static kink-like (heteroclinic) states which are stable. In contrast to the continuum case, due to the breaking of Lorentz invariance, discrete kinks cannot be “Lorentz boosted” to obtain traveling discrete kinks. Peyrard and Kruskal pioneered the study of how a kink, initially propagating in the lattice, dynamically adjusts in the absence of an available family of traveling kinks. We study in detail the final stages of the discrete kink’s evolution during which it is pinned to a specified lattice site (equilibrium position in the Peierls-Nabarro barrier). We find the following: For d sufficiently large (sufficiently small lattice spacing), the state of the system approaches an asymptotically stable ground state static kink (centered between lattice sites). For d sufficiently small, d< d*, the static kink bifurcates to one or more time-periodic states. For the discrete φ4 we have wobbling kinks which have the same spatial symmetry as the static kink as well as “ g-wobblers” and “ e-wobblers”, which have different spatial symmetry. In the discrete SG case, the “ e-wobbler” has the spatial symmetry of the kink, whereas the “ g-wobbler” has the opposite one. These time-periodic states may be regarded as a class of discrete breather/topological defect states; they are spatially localized and time-periodic oscillations mounted on a static kink background. The large time limit of solutions with initial data near a kink is marked by damped oscillation about one of these two types of asymptotic states. In case (1) we compute the characteristics of the damped oscillation

  4. Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis.

    PubMed

    Hu, Biao; Wu, Zhe; Bai, David; Liu, Tianju; Ullenbruch, Matthew R; Phan, Sem H

    2015-11-01

    Notch signaling pathway is involved in the regulation of cell fate, differentiation, proliferation, and apoptosis in development and disease. Previous studies suggest the importance of Notch1 in myofibroblast differentiation in lung alveogenesis and fibrosis. However, direct in vivo evidence of Notch1-mediated myofibroblast differentiation is lacking. In this study, we examined the effects of conditional mesenchymal-specific deletion of Notch1 on pulmonary fibrosis. Crossing of mice bearing the floxed Notch1 gene with α2(I) collagen enhancer-Cre-ER(T)-bearing mice successfully generated progeny with a conditional knockout (CKO) of Notch1 in collagen I-expressing (mesenchymal) cells on treatment with tamoxifen (Notch1 CKO). Because Notch signaling is known to be activated in the bleomycin model of pulmonary fibrosis, control and Notch1 CKO mice were analyzed for their responses to bleomycin treatment. The results showed significant attenuation of pulmonary fibrosis in CKO relative to control mice, as examined by collagen deposition, myofibroblast differentiation, and histopathology. However, there were no significant differences in inflammatory or immune cell influx between bleomycin-treated CKO and control mouse lungs. Analysis of isolated lung fibroblasts confirmed absence of Notch1 expression in cells from CKO mice, which contained fewer myofibroblasts and significantly diminished collagen I expression relative to those from control mice. These findings revealed an essential role for Notch1-mediated myofibroblast differentiation in the pathogenesis of pulmonary fibrosis.

  5. Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins.

    PubMed

    Wilkin, Marian B; Carbery, Ann-Marie; Fostier, Maggy; Aslam, Hanna; Mazaleyrat, Sabine L; Higgs, Jenny; Myat, Anna; Evans, Dana A P; Cornell, Michael; Baron, Martin

    2004-12-29

    The Notch receptor mediates a short-range signal that regulates many cell fate decisions. The misregulation of Notch has been linked to cancer and to developmental disorders. Upon binding to its ligands, Delta (Dl) or Serrate (Ser), the Notch ectodomain is shed by the action of an ADAM protease. The Notch intracellular domain is subsequently released proteolytically from the membrane by Presenilin and translocates to the nucleus to activate the transcription factor, Suppressor of Hairless. We show in Drosophila that Notch signaling is limited by the activity of two Nedd4 family HECT domain proteins, Suppressor of deltex [Su(dx)] and DNedd4. We rule out models by which Su(dx) downregulates Notch through modulating Deltex or by limiting the adherens junction accumulation of Notch. Instead, we show that Su(dx) regulates the postendocytic sorting of Notch within the early endosome to an Hrs- and ubiquitin-enriched subdomain en route to the late endosome. We propose a model in which endocytic sorting of Notch mediates a decision between its activation and downregulation. Such intersections between trafficking routes may provide key points at which other signals can modulate Notch activity in both normal development and in the pathological misactivation of Notch.

  6. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer

    PubMed Central

    Rodilla, Verónica; Villanueva, Alberto; Obrador-Hevia, Antonia; Robert-Moreno, Àlex; Fernández-Majada, Vanessa; Grilli, Andrea; López-Bigas, Nuria; Bellora, Nicolás; Albà, M. Mar; Torres, Ferran; Duñach, Mireia; Sanjuan, Xavier; Gonzalez, Sara; Gridley, Thomas; Capella, Gabriel; Bigas, Anna; Espinosa, Lluís

    2009-01-01

    Notch has been linked to β-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/β-catenin (down-regulated when blocking Wnt/β-catenin) that are directly regulated by Notch (repressed by γ-secretase inhibitors and up-regulated by active Notch1 in the absence of β-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through β-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/β-catenin pathway in tumors implanted s.c. in nude mice. Crossing APCMin/+ with Jagged1+/Δ mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear β-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by β-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways. PMID:19325125

  7. 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

    2015-05-29

    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.

  8. Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression

    PubMed Central

    Franciosa, G; Diluvio, G; Gaudio, F Del; Giuli, M V; Palermo, R; Grazioli, P; Campese, A F; Talora, C; Bellavia, D; D'Amati, G; Besharat, Z M; Nicoletti, C; Siebel, C W; Choy, L; Rustighi, A; Sal, G Del; Screpanti, I; Checquolo, S

    2016-01-01

    Deregulated Notch signaling is associated with T-cell Acute Lymphoblastic Leukemia (T-ALL) development and progression. Increasing evidence reveals that Notch pathway has an important role in the invasion ability of tumor cells, including leukemia, although the underlying molecular mechanisms remain mostly unclear. Here, we show that Notch3 is a novel target protein of the prolyl-isomerase Pin1, which is able to regulate Notch3 protein processing and to stabilize the cleaved product, leading to the increased expression of the intracellular domain (N3IC), finally enhancing Notch3-dependent invasiveness properties. We demonstrate that the combined inhibition of Notch3 and Pin1 in the Notch3-overexpressing human leukemic TALL-1 cells reduces their high invasive potential, by decreasing the expression of the matrix metalloprotease MMP9. Consistently, Pin1 depletion in a mouse model of Notch3-induced T-ALL, by reducing N3IC expression and signaling, impairs the expansion/invasiveness of CD4+CD8+ DP cells in peripheral lymphoid and non-lymphoid organs. Notably, in in silico gene expression analysis of human T-ALL samples we observed a significant correlation between Pin1 and Notch3 expression levels, which may further suggest a key role of the newly identified Notch3-Pin1 axis in T-ALL aggressiveness and progression. Thus, combined suppression of Pin1 and Notch3 proteins may be exploited as an additional target therapy for T-ALL. PMID:26876201

  9. 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.

  10. Delta activity independent of its activity as a ligand of Notch

    PubMed Central

    Mok, Lee-Peng; Qin, Tielin; Bardot, Boris; LeComte, Matthew; Homayouni, Asal; Ahimou, Francois; Wesley, Cedric

    2005-01-01

    Background Delta, Notch, and Scabrous often function together to make different cell types and refine tissue patterns during Drosophila development. Delta is known as the ligand that triggers Notch receptor activity. Scabrous is known to bind Notch and promote Notch activity in response to Delta. It is not known if Scabrous binds Delta or Delta has activity other than its activity as a ligand of Notch. It is very difficult to clearly determine this binding or activity in vivo as all Notch, Delta, and Scabrous activities are required simultaneously or successively in an inter-dependent manner. Results Using Drosophila cultured cells we show that the full length Delta promotes accumulation of Daughterless protein, fringe RNA, and pangolin RNA in the absence of Scabrous or Notch. Scabrous binds Delta and suppresses this activity even though it increases the level of the Delta intracellular domain. We also show that Scabrous can promote Notch receptor activity, in the absence of Delta. Conclusion Delta has activity that is independent of its activity as a ligand of Notch. Scabrous suppresses this Delta activity. Scabrous also promotes Notch activity that is dependent on Delta's ligand activity. Thus, Notch, Delta, and Scabrous might function in complex combinatorial or mutually exclusive interactions during development. The data reported here will be of significant help in understanding these interactions in vivo. PMID:15760463

  11. NOTCH1 gain of function in germ cells causes failure of spermatogenesis in male mice.

    PubMed

    Huang, Zaohua; Rivas, Bryan; Agoulnik, Alexander I

    2013-01-01

    NOTCH1 is a member of the NOTCH receptor family, a group of single-pass trans-membrane receptors. NOTCH signaling is highly conserved in evolution and mediates communication between adjacent cells. NOTCH receptors have been implicated in cell fate determination, as well as maintenance and differentiation of stem cells. In the mammalian testis expression of NOTCH1 in somatic and germ cells has been demonstrated, however its role in spermatogenesis was not clear. To study the significance of NOTCH1 in germ cells, we applied a cre/loxP approach in mice to induce NOTCH1 gain- or loss-of function specifically in male germ cells. Using a Stra8-icre transgene we produced mice with conditional activation of the NOTCH1 intracellular domain (NICD) in germ cells. Spermatogenesis in these mutants was progressively affected with age, resulting in decreased testis weight and sperm count. Analysis of downstream target genes of NOTCH1 signaling showed an increased expression of Hes5, with a reduction of the spermatogonial differentiation marker, Neurog3 expression in the mutant testis. Apoptosis was significantly increased in mouse germ cells with the corresponding elevation of pro-apoptotic Trp53 and Trp63 genes' expression. We also showed that the conditional germ cell-specific ablation of Notch1 had no effect on spermatogenesis or male fertility. Our data suggest the importance of NOTCH signaling regulation in male germ cells for their survival and differentiation.

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

    PubMed

    Watanabe, Kazuhide; Nagaoka, Tadahiro; Lee, Joseph M; Bianco, Caterina; Gonzales, Monica; Castro, Nadia P; Rangel, Maria Cristina; Sakamoto, Kei; Sun, Youping; Callahan, Robert; Salomon, David S

    2009-11-02

    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.

  13. 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

  14. 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.

  15. 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

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

    PubMed

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

    2008-02-01

    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.

  17. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer.

    PubMed

    Rodilla, Verónica; Villanueva, Alberto; Obrador-Hevia, Antonia; Robert-Moreno, Alex; Fernández-Majada, Vanessa; Grilli, Andrea; López-Bigas, Nuria; Bellora, Nicolás; Albà, M Mar; Torres, Ferran; Duñach, Mireia; Sanjuan, Xavier; Gonzalez, Sara; Gridley, Thomas; Capella, Gabriel; Bigas, Anna; Espinosa, Lluís

    2009-04-14

    Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC(Min/+) with Jagged1(+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.

  18. Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex.

    PubMed

    Han, Xiaoqing; Ranganathan, Prathibha; Tzimas, Christos; Weaver, Kelly L; Jin, Ke; Astudillo, Luisana; Zhou, Wen; Zhu, Xiaoxia; Li, Bin; Robbins, David J; Capobianco, Anthony J

    2017-09-01

    It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19(Arf) and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis.Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Mol Cancer Res; 15(9); 1173-83. ©2017 AACR. ©2017 American Association for Cancer Research.

  19. Thermodynamics of the Relationship between Lattice Energy and Lattice Enthalpy

    NASA Astrophysics Data System (ADS)

    Jenkins, H. Donald B.

    2005-06-01

    Incorporation of lattice potential energy, U POT , within a Born Fajans Haber thermochemical cycle based on enthalpy changes necessitates correction of the energy of the lattice to an enthalpy term, Δ H L . For a lattice containing p i ions of type i in the formula unit, the lattice enthalpy is given by Δ H L = U POT + ∑ s i [( c i /2) - 2] RT where R is the gas constant (= 8.314 J K -1 mol -1 ), T is the absolute temperature, and c i is defined according as to whether the ion i is monatomic ( c i = 3), linear polyatomic ( c i = 5), or polyatomic ( c i = 6), respectively.

  20. Understanding tidal notch development: examples from tropical and Mediterranean coasts.

    NASA Astrophysics Data System (ADS)

    Moses, Cherith; Furlani, Stefano; Kazmer, Miklos

    2017-04-01

    It has been suggested that tropical rock coasts exhibit morphological features that are different compared to other climatic regimes. But tidal notches, recesses extending along marine cliffs, are common to both tropical and Mediterranean coasts, and develop because of higher erosion rates in the intertidal zone compared to the supratidal or subtidal zone. They are widely used as geomorphological indicators of sea level change and tectonic movement. For this purpose their formation is usually associated with wave erosion, although the role of bioerosion and weathering, e.g. solution, are sometimes given more importance. In some cases wave erosion may simply remove weathered materials rather than directly eroding the rock e.g. on granite and sandstone coasts. Rock type is also thought to be important in the development of tidal notches, with those developed on limestone coasts said to provide more reliable indicators than other rock types. As well as indicating the vertical position of former sea levels, tidal notches have also been used to estimate the duration of stillstands (e.g. on harder limestones) and to calculate the periodicity of cliff-falls (e.g. on softer limestones). Despite their importance, the genesis, rate of development and global variations in morphology of tidal notches are still not fully understood. We assess present understanding of the roles of climate, tidal range, wave conditions and rock type by reviewing studies of morphology, rates and modes of tidal notch development on Mediterranean and tropical coasts. There is a dearth of quantitative data and so we present notch erosion rates directly measured using the Micro Erosion Meter (MEM) and Traversing MEM (TMEM) on limestone on the Northern Adriatic and Andaman Sea coasts: the former collected over > 10 years on the Trieste and Istrian coasts and > 3 years on an experimental vertical slab in the Gulf of Trieste; the latter over a 10 year period at Krabi in Southern Thailand. We relate these