Light-based Modeling and Control of Circadian Rhythm

DTIC Science & Technology

2016-08-29

the foundation of the full research. 1. Circadian phase estimation and control: Demonstrate the applicability of the adaptive notch filter (ANF) to...the adaptive notch filter (ANF) to extract circadian phase from noisy Drosophila locomotive activity measurements and the efficacy of using the ANF...full research. 1. Circadian phase estimation and control: Demonstrate the applicability of the adaptive notch filter (ANF) to extract circadian

Design and manufacture of super-multilayer optical filters based on PARMS technology

NASA Astrophysics Data System (ADS)

Lü, Shaobo; Wang, Ruisheng; Ma, Jing; Jiang, Chao; Mu, Jiali; Zhao, Shuaifeng; Yin, Xiaojun

2018-04-01

Three multilayer interference optical filters, including a UV band-pass, a VIS dual-band-pass and a notch filter, were designed by using Ta2O5, Nb2O5, Al2O3 and SiO2 as high- and low-index materials. During the design of the coating process, a hybrid optical monitoring and RATE-controlled layer thickness control scheme was adopted. The coating process was simulated by using the optical monitoring system (OMS) Simulator, and the simulation result indicated that the layer thickness can be controlled within an error of less than ±0.1%. The three filters were manufactured on a plasma-assisted reactive magnetic sputtering (PARMS) coating machine. The measurements indicate that for the UV band-pass filter, the peak transmittance is higher than 95% and the blocking density is better than OD6 in the 300-1100 nm region, whereas for the dual-band-pass filter, the center wavelength positioning accuracy of the two passbands are less than ±2 nm, the peak transmittance is higher than 95% and blocking density is better than OD6 in the 300-950 nm region. Finally, for the notch filter, the minimum transmittance rates are >90% and >94% in the visible and near infrared, respectively, and the blocking density is better than OD5.5 at 808 nm.

Raman Laser Spectrometer internal Optical Head current status: opto-mechanical redesign to minimize the excitation laser trace

NASA Astrophysics Data System (ADS)

Sanz, Miguel; Ramos, Gonzalo; Moral, Andoni; Pérez, Carlos; Belenguer, Tomás; del Rosario Canchal, María; Zuluaga, Pablo; Rodriguez, Jose Antonio; Santiago, Amaia; Rull, Fernando; Instituto Nacional de Técnica Aeroespacial (INTA); Ingeniería de Sistemas para la Defesa de España S.A. (ISDEFE)

2016-10-01

Raman Laser Spectrometer (RLS) is the Pasteur Payload instruments of the ExoMars mission, within the ESA's Aurora Exploration Programme, that will perform for the first time in an out planetary mission Raman spectroscopy. RLS is composed by SPU (Spectrometer Unit), iOH (Internal Optical Head), and ICEU (Instrument Control and Excitation Unit). iOH focuses the excitation laser on the samples (excitation path), and collects the Raman emission from the sample (collection path, composed on collimation system and filtering system). The original design presented a high laser trace reaching to the detector, and although a certain level of laser trace was required for calibration purposes, the high level degrades the Signal to Noise Ratio confounding some Raman peaks.The investigation revealing that the laser trace was not properly filtered as well as the iOH opto-mechanical redesign are reported on. After the study of the Long Pass Filters Optical Density (OD) as a function of the filtering stage to the detector distance, a new set of filters (Notch filters) was decided to be evaluated. Finally, and in order to minimize the laser trace, a new collection path design (mainly consisting on that the collimation and filtering stages are now separated in two barrels, and on the kind of filters to be used) was required. Distance between filters and collimation stage first lens was increased, increasing the OD. With this new design and using two Notch filters, the laser trace was reduced to assumable values, as can be observed in the functional test comparison also reported on this paper.

Devices based on surface plasmon interference filters

NASA Technical Reports Server (NTRS)

Wang, Yu (Inventor)

2001-01-01

Devices based on surface plasmon filters having at least one metal-dielectric interface to support surface plasmon waves. A multi-layer-coupled surface plasmon notch filter is provided to have more than two symmetric metal-dielectric interfaces coupled with one another to produce a transmission spectral window with desired spectral profile and bandwidth. Such notch filters can form various color filtering devices for color flat panel displays.

Liquid crystal photonic bandgap fiber components

NASA Astrophysics Data System (ADS)

Scolari, L.; Alkeskjold, T. T.; Noordegraaf, D.; Tartarini, G.; Bassi, P.; Bjarklev, A.

2007-11-01

Liquid crystal photonic bandgap fibers represent a promising platform for the design of all-in-fiber optical devices, which show a high degree of tunability and exhibit novel optical properties for the manipulation of guided light. In this review paper we present tunable fiber devices for spectral filtering, such as Gaussian filters and notch filters, and devices for polarization control and analysis, such as birefringence control devices and switchable and rotatable polarizers.

The Impact of Volume Phase Holographic Filters and Gratings on the Development of Raman Instrumentation

ERIC Educational Resources Information Center

Owen, Harry

2007-01-01

Volume phase holographic (VPH) optical elements have made a major contribution to Raman spectroscopy by providing notch filters, and VPH gratings that provide remarkable performance advantages over previous technologies. Holographic notch filters have eliminated Rayleigh scattered laser light from single monochromators, thereby contributing to the…

47 CFR 15.611 - General technical requirements.

Code of Federal Regulations, 2011 CFR

2011-10-01

... spectrum by licensed services. These techniques may include adaptive or “notch” filtering, or complete... frequencies below 30 MHz, when a notch filter is used to avoid interference to a specific frequency band, the... below the applicable part 15 limits. (ii) For frequencies above 30 MHz, when a notch filter is used to...

A mean-based filter to remove power line harmonic noise from seismic reflection data

NASA Astrophysics Data System (ADS)

Karslı, Hakan; Dondurur, Derman

2018-06-01

Power line harmonic noise generated by power lines during the seismic data acquisition in land and marine seismic surveys generally appears as a single frequency with 50/60 Hz (or multiples of these frequencies) and contaminates seismic data leading to complicate the identification of fine details in the data. Commonly applied method during seismic data processing to remove the harmonic noise is classical notch filter (or very narrow band-stop filter), however, it also attenuates all recorded data around the notch frequencies and results in a complete loss of available information which corresponds to fine details in the seismic data. In this study, we introduce an application of the algorithm of iterative trimmed and truncated mean filter method (ITTM) to remove the harmonic noise from seismic data, and here, we name the method as local ITTM (LITTM) since we applied it to the seismic data locally in spectral domain. In this method, an optimal value is iteratively searched depending on a threshold value by trimming and truncating process for the spectral amplitude samples within the specified spectral window. Therefore, the LITTM filter converges to the median, but, there is no need to sort the data as in the case of conventional median filters. On the other hand, the LITTM filtering process doesn't require any reference signal or a precise estimate of the fundamental frequency of the harmonic noise, and only approximate frequency band of the noise within the amplitude spectra is considered. The only required parameter of the method is the width of this frequency band in the spectral domain. The LITTM filter is first applied to synthetic data and then we analyze a real marine dataset to compare the quality of the output after removing the power line noise by classical notch, median and proposed LITTM filters. We observe that the power line harmonic noise is completely filtered out by LITTM filter, and unlike the conventional notch filter, without any damage on the available frequencies around the notch frequency band. It also provides a more balanced amplitude spectrum since it does not produce amplitude notches in the spectrum.

Tunable THz notch filter with a single groove inside parallel-plate waveguides.

PubMed

Lee, Eui Su; Jeon, Tae-In

2012-12-31

A single groove in a parallel-plate waveguide (PPWG) has been applied to a tunable terahertz (THz) notch filter with a transverse-electromagnetic (TEM) mode. When the air gap between the metal plates of the PPWG is controlled from 60 to 240 μm using a motor controlled translation stage or a piezo-actuator, the resonant frequency of the notch filter is changed from 1.75 up to 0.62 THz, respectively. Therefore, the measured tunable sensitivity of the notch filter increases to 6.28 GHz/μm. The measured resonant frequencies were found to be in good agreement with the calculation using an effective groove depth. Using a finite-difference time-domain (FDTD) simulation, we also demonstrate that the sensitivity of a THz microfluidic sensor can be increased via a small air gap, a narrow groove width, and a deep groove depth.

Inductive displacement sensors with a notch filter for an active magnetic bearing system.

PubMed

Chen, Seng-Chi; Le, Dinh-Kha; Nguyen, Van-Sum

2014-07-15

Active magnetic bearing (AMB) systems support rotating shafts without any physical contact, using electromagnetic forces. Each radial AMB uses two pairs of electromagnets at opposite sides of the rotor. This allows the rotor to float in the air gap, and the machine to operate without frictional losses. In active magnetic suspension, displacement sensors are necessary to detect the radial and axial movement of the suspended object. In a high-speed rotating machine equipped with an AMB, the rotor bending modes may be limited to the operating range. The natural frequencies of the rotor can cause instability. Thus, notch filters are a useful circuit for stabilizing the system. In addition, commercial displacement sensors are sometimes not suitable for AMB design, and cannot filter the noise caused by the natural frequencies of rotor. Hence, implementing displacement sensors based on the AMB structure is necessary to eliminate noises caused by natural frequency disturbances. The displacement sensor must be highly sensitive in the desired working range, and also exhibit a low interference noise, high stability, and low cost. In this study, we used the differential inductive sensor head and lock-in amplifier for synchronous demodulation. In addition, an active low-pass filter and a notch filter were used to eliminate disturbances, which caused by natural frequencies. As a consequence, the inductive displacement sensor achieved satisfactory linearity, high sensitivity, and disturbance elimination. This sensor can be easily produced for AMB applications. A prototype of these displacement sensors was built and tested.

Spectral analysis and filtering techniques in digital spatial data processing

USGS Publications Warehouse

Pan, Jeng-Jong

1989-01-01

A filter toolbox has been developed at the EROS Data Center, US Geological Survey, for retrieving or removing specified frequency information from two-dimensional digital spatial data. This filter toolbox provides capabilities to compute the power spectrum of a given data and to design various filters in the frequency domain. Three types of filters are available in the toolbox: point filter, line filter, and area filter. Both the point and line filters employ Gaussian-type notch filters, and the area filter includes the capabilities to perform high-pass, band-pass, low-pass, and wedge filtering techniques. These filters are applied for analyzing satellite multispectral scanner data, airborne visible and infrared imaging spectrometer (AVIRIS) data, gravity data, and the digital elevation models (DEM) data. -from Author

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 formed off axis - that is, away from the occulting spot - so that they become refocused onto the final image plane.

An Improved Filtering Method for Quantum Color Image in Frequency Domain

NASA Astrophysics Data System (ADS)

Li, Panchi; Xiao, Hong

2018-01-01

In this paper we investigate the use of quantum Fourier transform (QFT) in the field of image processing. We consider QFT-based color image filtering operations and their applications in image smoothing, sharpening, and selective filtering using quantum frequency domain filters. The underlying principle used for constructing the proposed quantum filters is to use the principle of the quantum Oracle to implement the filter function. Compared with the existing methods, our method is not only suitable for color images, but also can flexibly design the notch filters. We provide the quantum circuit that implements the filtering task and present the results of several simulation experiments on color images. The major advantages of the quantum frequency filtering lies in the exploitation of the efficient implementation of the quantum Fourier transform.

Circuit for detecting initial systole and dicrotic notch. [for monitoring arterial pressure

NASA Technical Reports Server (NTRS)

Gebben, V. D.; Webb, J. A., Jr. (Inventor)

1974-01-01

Circuitry is disclosed for processing an arterial pressure waveform to produce during any one cycle a pulse corresponding to the initial systole and a pulse corresponding to the dicrotic notch. In a first channel, an electrical analog of the arterial pressure waveform is filtered and then compared to the original waveform to produce an initial systole signal. In a second channel, the analog is differentiated, filtered, and fed through a gate controlled by pulses from the first channel to produce an electrical pulse corresponding to the dicrotic notch.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wereszczak, Andrew; Jadaan, Osama; Modugno, Max

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

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

A human auditory tuning curves matched wavelet function.

PubMed

Abolhassani, Mohammad D; Salimpour, Yousef

2008-01-01

This paper proposes a new quantitative approach to the problem of matching a wavelet function to a human auditory tuning curves. The auditory filter shapes were derived from the psychophysical measurements in normal-hearing listeners using the variant of the notched-noise method for brief signals in forward and simultaneous masking. These filters were used as templates for the designing a wavelet function that has the maximum matching to a tuning curve. The scaling function was calculated from the matched wavelet function and by using these functions, low pass and high pass filters were derived for the implementation of a filter bank. Therefore, new wavelet families were derived.

Compact electromagnetic bandgap structures for notch band in ultra-wideband applications.

PubMed

Rotaru, Mihai; Sykulski, Jan

2010-01-01

This paper introduces a novel approach to create notch band filters in the front-end of ultra-wideband (UWB) communication systems based on electromagnetic bandgap (EBG) structures. The concept presented here can be implemented in any structure that has a microstrip in its configuration. The EBG structure is first analyzed using a full wave electromagnetic solver and then optimized to work at WLAN band (5.15-5.825 GHz). Two UWB passband filters are used to demonstrate the applicability and effectiveness of the novel EBG notch band feature. Simulation results are provided for two cases studied.

Compact Electromagnetic Bandgap Structures for Notch Band in Ultra-Wideband Applications

PubMed Central

Rotaru, Mihai; Sykulski, Jan

2010-01-01

This paper introduces a novel approach to create notch band filters in the front-end of ultra-wideband (UWB) communication systems based on electromagnetic bandgap (EBG) structures. The concept presented here can be implemented in any structure that has a microstrip in its configuration. The EBG structure is first analyzed using a full wave electromagnetic solver and then optimized to work at WLAN band (5.15–5.825 GHz). Two UWB passband filters are used to demonstrate the applicability and effectiveness of the novel EBG notch band feature. Simulation results are provided for two cases studied. PMID:22163430

FM notch filter in front - and - behind the low noise amplifier of a Callisto Radio Spectrometer in Gauribidanur, India

NASA Astrophysics Data System (ADS)

Monstein, C.

2014-03-01

In the framework of IHY2007 a Callisto spectrometer [Benz(2004)] was installed and set into operation at the location of the solar heliograph in Gauribidanur, India. At that time the level of radio frequency interference (RFI) was amazingly low. In recent years more and more FM broadcast transmitters were installed with high power compared to the requirements of radio astronomical observations. So, the spectral observations with Callisto experienced more and more interference by these FM transmitters. Recently an FM-notch filter was installed between the low noise amplifier and Callisto, but it did not work out. The notch filter was then moved to the input of the LNA and the result was much better, as expected from theoretical concepts.

DC-pass filter design with notch filters superposition for CPW rectenna at low power level

NASA Astrophysics Data System (ADS)

Rivière, J.; Douyère, A.; Alicalapa, F.; Luk, J.-D. Lan Sun

2016-03-01

In this paper the challenging coplanar waveguide direct current (DC) pass filter is designed, analysed, fabricated and measured. As the ground plane and the conductive line are etched on the same plane, this technology allows the connection of series and shunt elements to the active devices without via holes through the substrate. Indeed, this study presents the first step in the optimization of a complete rectenna in coplanar waveguide (CPW) technology: key element of a radio frequency (RF) energy harvesting system. The measurement of the proposed filter shows good performance in the rejection of F0=2.45 GHz and F1=4.9 GHz. Additionally, a harmonic balance (HB) simulation of the complete rectenna is performed and shows a maximum RF-to-DC conversion efficiency of 37% with the studied DC-pass filter for an input power of 10 µW at 2.45 GHz.

A novel filter bank for biotelemetry.

PubMed

Karagözoglu, B

2001-03-01

In a multichannel biotelemetry system, signals taken from a patient are distributed along the available frequency range (bandwidth) of the system through frequency-division-multiplexing, and combined into a single composite signal. Biological signals that are limited to low frequencies (below 10 Hz) modulate the frequencies of respective sub-carriers. Other biological signals are carried in amplitude-modulated forms. It is recognized that recovering original signals from a composite signal at the receiver side is a technical challenge when a telemetry system with narrow bandwidth capacity is used, since such a system leaves little frequency spacing between information channels. A filter bank is therefore utilized for recovering biological signals that are transmitted. The filter bank contains filter units comprising switched-capacitor filter integrated circuits. The filters have two distinct and opposing outputs (band-stop (notch) and band-pass). Since most biological signals are at low frequencies, and modulated signals occupy a narrow band around the carrier, notch filters can be used to efficiently stop signals in the narrow frequency range. Once the interim channels are removed, other channels become well separated from each other, and band-pass filters can select them. In the proposed system, efficient filtering of closely packed channels is achieved, with low interference, from neighboring channels. The filter bank is applied to a system that carries four biological signals and a battery status indicator signal. Experimental results reinforce theoretical predictions that the filter bank successfully de-multiplexes closely packed information channels with low crosstalk between them. It is concluded that the proposed filter bank allows utilization of cost-effective multichannel biotelemetry systems that are designed around commercial audio devices, and that it can be readily adapted to a broad range of physiological recording requirements.

Integrated optic single-ring filter for narrowband phase demodulation

NASA Astrophysics Data System (ADS)

Madsen, C. K.

2017-05-01

Integrated optic notch filters are key building blocks for higher-order spectral filter responses and have been demonstrated in many technology platforms from dielectrics (such as Si3N4) to semiconductors (Si photonics). Photonic-assisted RF processing applications for notch filters include identifying and filtering out high-amplitude, narrowband signals that may be interfering with the desired signal, including undesired frequencies detected in radar and free-space optical links. The fundamental tradeoffs for bandwidth and rejection depth as a function of the roundtrip loss and coupling coefficient are investigated along with the resulting spectral phase response for minimum-phase and maximum-phase responses compared to the critical coupling condition and integration within a Mach Zehnder interferometer. Based on a full width at half maximum criterion, it is shown that maximum-phase responses offer the smallest bandwidths for a given roundtrip loss. Then, a new role for passive notch filters in combination with high-speed electro-optic phase modulation is explored around narrowband phase-to-amplitude demodulation using a single ring operating on one sideband. Applications may include microwave processing and instantaneous frequency measurement (IFM) for radar, space and defense applications.

Continuously tunable optical notch filter and band-pass filter systems that cover the visible to near-infrared spectral ranges.

PubMed

Jeong, Mi-Yun; Mang, Jin Yeob

2018-03-10

Spatially continuous tunable optical notch and band-pass filter systems that cover the visible (VIS) and near-infrared (NIR) spectral ranges from ∼460  nm to ∼1,000  nm are realized by combining left- and right-handed circular cholesteric liquid crystal (CLC) wedge cells with continuous pitch gradient. The notch filter system is polarization independent in all of the spectral ranges. The band-pass filter system, when the left- and right-handed CLCs are arranged in a row, is polarization independent, while when they are arranged at right angles, they are polarization dependent; furthermore, the full-width at half-maximum of the band-pass filter can be changed reversibly from the original bandwidth of 36 nm to 16 nm. Depending on the CLC materials, this strategy could be applied to the UV, VIS, and IR spectral ranges. Due to the high performance in the broad spectral range, cost-effective facile fabrication process, simple mechanical control, and small size, it is expected that our optical tunable filter strategies could become one of the key parts of laser-based Raman spectroscopy, fluorescence, life science devices, optical communication systems, astronomical telescopes, and so forth.

Low-cost, high-fidelity, adaptive cancellation of periodic 60 Hz noise.

PubMed

Wesson, Kyle D; Ochshorn, Robert M; Land, Bruce R

2009-12-15

A common method to eliminate unwanted power line interference in neurobiology laboratories where sensitive electronic signals are measured is with a notch filter. However a fixed-frequency notch filter cannot remove all power line noise contamination since inherent frequency and phase variations exist in the contaminating signal. One way to overcome the limitations of a fixed-frequency notch filter is with adaptive noise cancellation. Adaptive noise cancellation is an active approach that uses feedback to create a signal that when summed with the contaminated signal destructively interferes with the noise component leaving only the desired signal. We have implemented an optimized least mean square adaptive noise cancellation algorithm on a low-cost 16 MHz, 8-bit microcontroller to adaptively cancel periodic 60 Hz noise. In our implementation, we achieve between 20 and 25 dB of cancellation of the fundamental 60 Hz noise component.

Fully tunable 360° microwave photonic phase shifter based on a single semiconductor optical amplifier.

PubMed

Sancho, Juan; Lloret, Juan; Gasulla, Ivana; Sales, Salvador; Capmany, José

2011-08-29

A fully tunable microwave photonic phase shifter involving a single semiconductor optical amplifier (SOA) is proposed and demonstrated. 360° microwave phase shift has been achieved by tuning the carrier wavelength and the optical input power injected in an SOA while properly profiting from the dispersion feature of a conveniently designed notch filter. It is shown that the optical filter can be advantageously employed to switch between positive and negative microwave phase shifts. Numerical calculations corroborate the experimental results showing an excellent agreement.

Fiber-distributed Ultra-wideband noise radar with steerable power spectrum and colorless base station.

PubMed

Zheng, Jianyu; Wang, Hui; Fu, Jianbin; Wei, Li; Pan, Shilong; Wang, Lixian; Liu, Jianguo; Zhu, Ninghua

2014-03-10

A fiber-distributed Ultra-wideband (UWB) noise radar was achieved, which consists of a chaotic UWB noise source based on optoelectronic oscillator (OEO), a fiber-distributed transmission link, a colorless base station (BS), and a cross-correlation processing module. Due to a polarization modulation based microwave photonic filter and an electrical UWB pass-band filter embedded in the feedback loop of the OEO, the power spectrum of chaotic UWB signal could be shaped and notch-filtered to avoid the spectrum-overlay-induced interference to the narrow band signals. Meanwhile, the wavelength-reusing could be implemented in the BS by means of the distributed polarization modulation-to-intensity modulation conversion. The experimental comparison for range finding was carried out as the chaotic UWB signal was notch-filtered at 5.2 GHz and 7.8 GHz or not. Measured results indicate that space resolution with cm-level could be realized after 3-km fiber transmission thanks to the excellent self-correlation property of the UWB noise signal provided by the OEO. The performance deterioration of the radar raised by the energy loss of the notch-filtered noise signal was negligible.

Binocular contrast-gain control for natural scenes: Image structure and phase alignment.

PubMed

Huang, Pi-Chun; Dai, Yu-Ming

2018-05-01

In the context of natural scenes, we applied the pattern-masking paradigm to investigate how image structure and phase alignment affect contrast-gain control in binocular vision. We measured the discrimination thresholds of bandpass-filtered natural-scene images (targets) under various types of pedestals. Our first experiment had four pedestal types: bandpass-filtered pedestals, unfiltered pedestals, notch-filtered pedestals (which enabled removal of the spatial frequency), and misaligned pedestals (which involved rotation of unfiltered pedestals). Our second experiment featured six types of pedestals: bandpass-filtered, unfiltered, and notch-filtered pedestals, and the corresponding phase-scrambled pedestals. The thresholds were compared for monocular, binocular, and dichoptic viewing configurations. The bandpass-filtered pedestal and unfiltered pedestals showed classic dipper shapes; the dipper shapes of the notch-filtered, misaligned, and phase-scrambled pedestals were weak. We adopted a two-stage binocular contrast-gain control model to describe our results. We deduced that the phase-alignment information influenced the contrast-gain control mechanism before the binocular summation stage and that the phase-alignment information and structural misalignment information caused relatively strong divisive inhibition in the monocular and interocular suppression stages. When the pedestals were phase-scrambled, the elimination of the interocular suppression processing was the most convincing explanation of the results. Thus, our results indicated that both phase-alignment information and similar image structures cause strong interocular suppression. Copyright © 2018 Elsevier Ltd. All rights reserved.

Comparison of methods for removing electromagnetic noise from electromyographic signals.

PubMed

Defreitas, Jason M; Beck, Travis W; Stock, Matt S

2012-02-01

The purpose of this investigation was to compare three different methods of removing noise from monopolar electromyographic (EMG) signals: (a) electrical shielding with a Faraday cage, (b) denoising with a digital notch-filter and (c) applying a bipolar differentiation with another monopolar EMG signal. Ten men and ten women (mean age = 24.0 years) performed isometric muscle actions of the leg extensors at 10-100% of their maximal voluntary contraction on two separate occasions. One trial was performed inside a Faraday tent (a flexible Faraday cage made from conductive material), and the other was performed outside the Faraday tent. The EMG signals collected outside the Faraday tent were analyzed three separate ways: as a raw signal, as a bipolar signal, and as a signal digitally notch filtered to remove 60 Hz noise and its harmonics. The signal-to-noise ratios were greatest after notch-filtering (range: 3.0-33.8), and lowest for the bipolar arrangement (1.6-10.2). Linear slope coefficients for the EMG amplitude versus force relationship were also used to compare the methods of noise removal. The results showed that a bipolar arrangement had a significantly lower linear slope coefficient when compared to the three other conditions (raw, notch and tent). These results suggested that an appropriately filtered monopolar EMG signal can be useful in situations that require a large pick-up area. Furthermore, although it is helpful, a Faraday tent (or cage) is not required to achieve an appropriate signal-to-noise ratio, as long as the correct filters are applied.

A robust high-order lattice adaptive notch filter and its application to narrowband noise cancellation

NASA Astrophysics Data System (ADS)

Kim, Seong-woo; Park, Young-cheol; Seo, Young-soo; Youn, Dae Hee

2014-12-01

In this paper, we propose a high-order lattice adaptive notch filter (LANF) that can robustly track multiple sinusoids. Unlike the conventional cascade structure, the proposed high-order LANF has robust tracking characteristics regardless of the frequencies of reference sinusoids and initial notch frequencies. The proposed high-order LANF is applied to a narrowband adaptive noise cancellation (ANC) to mitigate the effect of the broadband disturbance in the reference signal. By utilizing the gradient adaptive lattice (GAL) ANC algorithm and approximately combining it with the proposed high-order LANF, a computationally efficient narrowband ANC system is obtained. Experimental results demonstrate the robustness of the proposed high-order LANF and the effectiveness of the obtained narrowband ANC system.

Ultrasound Transducer and System for Real-Time Simultaneous Therapy and Diagnosis for Noninvasive Surgery of Prostate Tissue

PubMed Central

Jeong, Jong Seob; Chang, Jin Ho; Shung, K. Kirk

2009-01-01

For noninvasive treatment of prostate tissue using high intensity focused ultrasound (HIFU), this paper proposes a design of an integrated multi-functional confocal phased array (IMCPA) and a strategy to perform both imaging and therapy simultaneously with this array. IMCPA is composed of triple-row phased arrays: a 6 MHz array in the center row for imaging and two 4 MHz arrays in the outer rows for therapy. Different types of piezoelectric materials and stack configurations may be employed to maximize their respective functionalities, i.e., therapy and imaging. Fabrication complexity of IMCPA may be reduced by assembling already constructed arrays. In IMCPA, reflected therapeutic signals may corrupt the quality of imaging signals received by the center row array. This problem can be overcome by implementing a coded excitation approach and/or a notch filter when B-mode images are formed during therapy. The 13-bit Barker code, which is a binary code with unique autocorrelation properties, is preferred for implementing coded excitation, although other codes may also be used. From both Field II simulation and experimental results, whether these remedial approaches would make it feasible to simultaneously carry out imaging and therapy by IMCPA was verifeid. The results showed that the 13-bit Barker code with 3 cycles per bit provided acceptable performances. The measured −6 dB and −20 dB range mainlobe widths were 0.52 mm and 0.91 mm, respectively, and a range sidelobe level was measured to be −48 dB regardless of whether a notch filter was used. The 13-bit Barker code with 2 cycles per bit yielded −6dB and −20dB range mainlobe widths of 0.39 mm and 0.67 mm. Its range sidelobe level was found to be −40 dB after notch filtering. These results indicate the feasibility of the proposed transducer design and system for real-time imaging during therapy. PMID:19811994

Ultrasound transducer and system for real-time simultaneous therapy and diagnosis for noninvasive surgery of prostate tissue.

PubMed

Jeong, Jong Seob; Chang, Jin Ho; Shung, K Kirk

2009-09-01

For noninvasive treatment of prostate tissue using high-intensity focused ultrasound this paper proposes a design of an integrated multifunctional confocal phased array (IMCPA) and a strategy to perform both imaging and therapy simultaneously with this array. IMCPA is composed of triple-row phased arrays: a 6-MHz array in the center row for imaging and two 4-MHz arrays in the outer rows for therapy. Different types of piezoelectric materials and stack configurations may be employed to maximize their respective functionalities, i.e., therapy and imaging. Fabrication complexity of IMCPA may be reduced by assembling already constructed arrays. In IMCPA, reflected therapeutic signals may corrupt the quality of imaging signals received by the center-row array. This problem can be overcome by implementing a coded excitation approach and/or a notch filter when B-mode images are formed during therapy. The 13-bit Barker code, which is a binary code with unique autocorrelation properties, is preferred for implementing coded excitation, although other codes may also be used. From both Field II simulation and experimental results, we verified whether these remedial approaches would make it feasible to simultaneously carry out imaging and therapy by IMCPA. The results showed that the 13-bit Barker code with 3 cycles per bit provided acceptable performances. The measured -6 dB and -20 dB range mainlobe widths were 0.52 mm and 0.91 mm, respectively, and a range sidelobe level was measured to be -48 dB regardless of whether a notch filter was used. The 13-bit Barker code with 2 cycles per bit yielded -6 dB and -20 dB range mainlobe widths of 0.39 mm and 0.67 mm. Its range sidelobe level was found to be -40 dB after notch filtering. These results indicate the feasibility of the proposed transducer design and system for real-time imaging during therapy.

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.

The role of low-spatial frequencies in lexical decision and masked priming.

PubMed

Boden, C; Giaschi, D

2009-04-01

Spatial frequency filtering was used to test the hypotheses that low-spatial frequency information in printed text can: (1) lead to a rapid lexical decision or (2) facilitate word recognition. Adult proficient readers made lexical decisions in unprimed and masked repetition priming experiments with unfiltered, low-pass, high-pass and notch filtered letter strings. In the unprimed experiments, a filtered target was presented for 105 or 400 ms followed by a pattern mask. Sensitivity (d') was lowest for the low-pass filtered targets at both durations with a bias towards a 'non-word' response. Sensitivity was higher in the high-pass and notch filter conditions. In the priming experiments, a forward mask was followed by a filtered prime then an unfiltered target. Primed words, but not non-words, were identified faster than unprimed words in both the low-pass and high-pass filtered conditions. These results do not support a unique role for low-spatial frequency information in either facilitating or making rapid lexical decisions.

Compact triple band-stop filter using novel epsilon-shaped metamaterial with lumped capacitor

NASA Astrophysics Data System (ADS)

Ali, W. A. E.; Hamdalla, M. Z. M.

2018-04-01

This paper presents the design of a novel epsilon-shaped metamaterial unit cell structure that is applicable for single-band and multi-band applications. A closed-form formulas to control the resonance frequencies of the proposed design are included. The proposed unit cell, which exhibits negative permeability at its frequency bands, is etched from the ground plane to form a band-stop filter. The filter design is constructed to validate the band-notched characteristics of the proposed unit cell. A lumped capacitor is inserted for size reduction purpose in addition to multi-resonance generation. The fundamental resonance frequency is translated from 3.62 GHz to 2.45 GHz, which means that the filter size will be more compact (more than 32% size reduction). The overall size of the proposed filter is 13 × 6 × 1.524 mm3, where the electrical size is 0.221λg × 0.102λg × 0.026λg at the lower frequency band (2.45 GHz). Two other resonance frequencies are generated at 5.3 GHz and 9.2 GHz, which confirm the multi-band behavior of the proposed filter. Good agreement between simulated and measured characteristics of the fabricated filter prototype is achieved.

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

PubMed

Verhein, Kirsten C; McCaw, Zachary; Gladwell, Wesley; Trivedi, Shweta; Bushel, Pierre R; Kleeberger, Steven R

2015-08-01

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. Wild-type (WT), Notch3 (Notch3-/-), and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hr. 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. 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.

Digital hum filtering

USGS Publications Warehouse

Knapp, R.W.; Anderson, N.L.

1994-01-01

Data may be overprinted by a steady-state cyclical noise (hum). Steady-state indicates that the noise is invariant with time; its attributes, frequency, amplitude, and phase, do not change with time. Hum recorded on seismic data usually is powerline noise and associated higher harmonics; leakage from full-waveform rectified cathodic protection devices that contain the odd higher harmonics of powerline frequencies; or vibrational noise from mechanical devices. The fundamental frequency of powerline hum may be removed during data acquisition with the use of notch filters. Unfortunately, notch filters do not discriminate signal and noise, attenuating both. They also distort adjacent frequencies by phase shifting. Finally, they attenuate only the fundamental mode of the powerline noise; higher harmonics and frequencies other than that of powerlines are not removed. Digital notch filters, applied during processing, have many of the same problems as analog filters applied in the field. The method described here removes hum of a particular frequency. Hum attributes are measured by discrete Fourier analysis, and the hum is canceled from the data by subtraction. Errors are slight and the result of the presence of (random) noise in the window or asynchrony of the hum and data sampling. Error is minimized by increasing window size or by resampling to a finer interval. Errors affect the degree of hum attenuation, not the signal. The residual is steady-state hum of the same frequency. ?? 1994.

A Compact Multiple Notched Ultra-Wide Band Antenna with an Analysis of the CSRR-TO-CSRR Coupling for Portable UWB Applications.

PubMed

Rahman, MuhibUr; Ko, Dong-Sik; Park, Jung-Dong

2017-09-25

We present a compact ultra-wideband (UWB) antenna integrated with sharp notches with a detailed analysis of the mutual coupling of the multiple notch resonators. By utilizing complementary split ring resonators (CSRR) on the radiating semi-circular patch, we achieve the sharp notch-filtering of various bands within the UWB band without increasing the antenna size. The notched frequency bands include WiMAX, INSAT, and lower and upper WLAN. In order to estimate the frequency shifts of the notch due to the coupling of the nearby CSRRs, an analysis of the coupling among the multiple notch resonators is carried out and we construct the lumped-circuit equivalent model. The time domain analysis of the proposed antenna is performed to show its validity on the UWB application. The measured frequency response of the input port corresponds quite well with the calculations and simulations. The radiation pattern of the implemented quad-notched UWB antenna is nearly omnidirectional in the passband.

A Compact Multiple Notched Ultra-Wide Band Antenna with an Analysis of the CSRR-TO-CSRR Coupling for Portable UWB Applications

PubMed Central

Ko, Dong-Sik

2017-01-01

We present a compact ultra-wideband (UWB) antenna integrated with sharp notches with a detailed analysis of the mutual coupling of the multiple notch resonators. By utilizing complementary split ring resonators (CSRR) on the radiating semi-circular patch, we achieve the sharp notch-filtering of various bands within the UWB band without increasing the antenna size. The notched frequency bands include WiMAX, INSAT, and lower and upper WLAN. In order to estimate the frequency shifts of the notch due to the coupling of the nearby CSRRs, an analysis of the coupling among the multiple notch resonators is carried out and we construct the lumped-circuit equivalent model. The time domain analysis of the proposed antenna is performed to show its validity on the UWB application. The measured frequency response of the input port corresponds quite well with the calculations and simulations. The radiation pattern of the implemented quad-notched UWB antenna is nearly omnidirectional in the passband. PMID:28946658

Development of a Comb Limiter Combiner with Sub band Known Interference Cancellation

DTIC Science & Technology

2017-10-17

Juarez, Head 55190 Networks Division ACRONYMS ABSF absorptive bandstop filters ATP applied thin films BAW bulk acoustic waves BPF bandpass filter ...BSF bandstop filters CW continuous wave CWSP Commercial Wideband Satellite Program DAC digital to analog converter DAC digital to analog converter...8 3.2 FREQUENCY AGILE ABSORPTIVE NOTCH FILTERS ................................................. 9 3.3 INTEGRATION OF

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.

Rapid estimation of high-parameter auditory-filter shapes

PubMed Central

Shen, Yi; Sivakumar, Rajeswari; Richards, Virginia M.

2014-01-01

A Bayesian adaptive procedure, the quick-auditory-filter (qAF) procedure, was used to estimate auditory-filter shapes that were asymmetric about their peaks. In three experiments, listeners who were naive to psychoacoustic experiments detected a fixed-level, pure-tone target presented with a spectrally notched noise masker. The qAF procedure adaptively manipulated the masker spectrum level and the position of the masker notch, which was optimized for the efficient estimation of the five parameters of an auditory-filter model. Experiment I demonstrated that the qAF procedure provided a convergent estimate of the auditory-filter shape at 2 kHz within 150 to 200 trials (approximately 15 min to complete) and, for a majority of listeners, excellent test-retest reliability. In experiment II, asymmetric auditory filters were estimated for target frequencies of 1 and 4 kHz and target levels of 30 and 50 dB sound pressure level. The estimated filter shapes were generally consistent with published norms, especially at the low target level. It is known that the auditory-filter estimates are narrower for forward masking than simultaneous masking due to peripheral suppression, a result replicated in experiment III using fewer than 200 qAF trials. PMID:25324086

Pulsed ultrasonic comb filtering effect and its applications in the measurement of sound velocity and thickness of thin plates.

PubMed

Liu, Jingfei; Declercq, Nico F

2017-03-01

An analytical and experimental study of the pulsed ultrasonic comb filtering effect is presented in this work intending to provide a fundamental tool for data analysis and phenomenon understanding in pulsed ultrasonics. The basic types of comb filter, feedforward and feedback filters, are numerically simulated and demonstrated. The characteristic features of comb filters, which include the formula for determining the locations of the spectral peaks or notches and the relationship between its temporal characteristics (relative time delay between constituent pulses) and its spectral characteristics (frequency interval between peaks or notches), are theoretically derived. To demonstrate the applicability of the comb filtering effect, it is applied to measuring the sound velocities and thickness of a thin plate sample. It is proven that the comb filtering effect based method not only is capable of accurate measurements, but also has advantages over the conventional time-of-flight based method in thin plate measurements. Furthermore, the principles developed in this study have potential applications in any pulsed ultrasonic cases where the output signal shows comb filter features. Copyright © 2016 Elsevier B.V. All rights reserved.

Engineering Filters for Reducing Spontaneous Emission in cQED

NASA Astrophysics Data System (ADS)

Bronn, Nicholas; Masluk, Nicholas; Srinivasan, Srikanth; Chow, Jerry; Abraham, David; Rothwell, Mary; Keefe, George; Gambetta, Jay; Steffen, Matthias; Lirakis, Chris

2014-03-01

Inserting a notch filter between a qubit and the external environment at the qubit frequency can significantly suppress spontaneous emission mediated by the cavity (``Purcell effect''). In order to realize this filtering in multi-qubit architectures, where space comes at a premium, we will present a filter with minimal space requirements. We acknowledge support from IARPA under contract W911NF-10-1-0324.

Experimental demonstration of optical stealth transmission over wavelength-division multiplexing network.

PubMed

Zhu, Huatao; Wang, Rong; Pu, Tao; Fang, Tao; Xiang, Peng; Zheng, Jilin; Tang, Yeteng; Chen, Dalei

2016-08-10

We propose and experimentally demonstrate an optical stealth transmission system over a 200 GHz-grid wavelength-division multiplexing (WDM) network. The stealth signal is processed by spectral broadening, temporal spreading, and power equalizing. The public signal is suppressed by multiband notch filtering at the stealth channel receiver. The interaction between the public and stealth channels is investigated in terms of public-signal-to-stealth-signal ratio, data rate, notch-filter bandwidth, and public channel number. The stealth signal can transmit over 80 km single-mode fiber with no error. Our experimental results verify the feasibility of optical steganography used over the existing WDM-based optical network.

From Broadband to Electrochromic Notch Filters with Printed Monochiral Carbon Nanotubes

PubMed Central

2018-01-01

Dense layers of semiconducting single-walled carbon nanotubes (SWNTs) serve as electrochromic (EC) materials in the near-infrared with high optical density and high conductivity. EC cells with tunable notch filter properties instead of broadband absorption are created via highly selective dispersion of specific semiconducting SWNTs through polymer-wrapping followed by deposition of thick films by aerosol-jet printing. A simple planar geometry with spray-coated mixed SWNTs as the counter electrode renders transparent metal oxides redundant and facilitates complete bleaching within a few seconds through iongel electrolytes with high ionic conductivities. Monochiral (6,5) SWNT films as working electrodes exhibit a narrow absorption band at 997 nm (full width at half-maximum of 55–73 nm) with voltage-dependent optical densities between 0.2 and 4.5 and a modulation depth of up to 43 dB. These (6,5) SWNT notch filters can retain more than 95% of maximum bleaching for several hours under open-circuit conditions. In addition, different levels of transmission can be set by applying constant low voltage (1.5 V) pulses with modulated width or by a given number of fixed short pulses. PMID:29521086

Enhancement of the Comb Filtering Selectivity Using Iterative Moving Average for Periodic Waveform and Harmonic Elimination

PubMed Central

Wu, Yan; Aarts, Ronald M.

2018-01-01

A recurring problem regarding the use of conventional comb filter approaches for elimination of periodic waveforms is the degree of selectivity achieved by the filtering process. Some applications, such as the gradient artefact correction in EEG recordings during coregistered EEG-fMRI, require a highly selective comb filtering that provides effective attenuation in the stopbands and gain close to unity in the pass-bands. In this paper, we present a novel comb filtering implementation whereby the iterative filtering application of FIR moving average-based approaches is exploited in order to enhance the comb filtering selectivity. Our results indicate that the proposed approach can be used to effectively approximate the FIR moving average filter characteristics to those of an ideal filter. A cascaded implementation using the proposed approach shows to further increase the attenuation in the filter stopbands. Moreover, broadening of the bandwidth of the comb filtering stopbands around −3 dB according to the fundamental frequency of the stopband can be achieved by the novel method, which constitutes an important characteristic to account for broadening of the harmonic gradient artefact spectral lines. In parallel, the proposed filtering implementation can also be used to design a novel notch filtering approach with enhanced selectivity as well. PMID:29599955

A Novel Complex-Coefficient In-Band Interference Suppression Algorithm for Cognitive Ultra-Wide Band Wireless Sensors Networks.

PubMed

Xiong, Hailiang; Zhang, Wensheng; Xu, Hongji; Du, Zhengfeng; Tang, Huaibin; Li, Jing

2017-05-25

With the rapid development of wireless communication systems and electronic techniques, the limited frequency spectrum resources are shared with various wireless devices, leading to a crowded and challenging coexistence circumstance. Cognitive radio (CR) and ultra-wide band (UWB), as sophisticated wireless techniques, have been considered as significant solutions to solve the harmonious coexistence issues. UWB wireless sensors can share the spectrum with primary user (PU) systems without harmful interference. The in-band interference of UWB systems should be considered because such interference can severely affect the transmissions of UWB wireless systems. In order to solve the in-band interference issues for UWB wireless sensor networks (WSN), a novel in-band narrow band interferences (NBIs) elimination scheme is proposed in this paper. The proposed narrow band interferences suppression scheme is based on a novel complex-coefficient adaptive notch filter unit with a single constrained zero-pole pair. Moreover, in order to reduce the computation complexity of the proposed scheme, an adaptive complex-coefficient iterative method based on two-order Taylor series is designed. To cope with multiple narrow band interferences, a linear cascaded high order adaptive filter and a cyclic cascaded high order matrix adaptive filter (CCHOMAF) interference suppression algorithm based on the basic adaptive notch filter unit are also presented. The theoretical analysis and numerical simulation results indicate that the proposed CCHOMAF algorithm can achieve better performance in terms of average bit error rate for UWB WSNs. The proposed in-band NBIs elimination scheme can significantly improve the reception performance of low-cost and low-power UWB wireless systems.

A Novel Complex-Coefficient In-Band Interference Suppression Algorithm for Cognitive Ultra-Wide Band Wireless Sensors Networks

PubMed Central

Xiong, Hailiang; Zhang, Wensheng; Xu, Hongji; Du, Zhengfeng; Tang, Huaibin; Li, Jing

2017-01-01

With the rapid development of wireless communication systems and electronic techniques, the limited frequency spectrum resources are shared with various wireless devices, leading to a crowded and challenging coexistence circumstance. Cognitive radio (CR) and ultra-wide band (UWB), as sophisticated wireless techniques, have been considered as significant solutions to solve the harmonious coexistence issues. UWB wireless sensors can share the spectrum with primary user (PU) systems without harmful interference. The in-band interference of UWB systems should be considered because such interference can severely affect the transmissions of UWB wireless systems. In order to solve the in-band interference issues for UWB wireless sensor networks (WSN), a novel in-band narrow band interferences (NBIs) elimination scheme is proposed in this paper. The proposed narrow band interferences suppression scheme is based on a novel complex-coefficient adaptive notch filter unit with a single constrained zero-pole pair. Moreover, in order to reduce the computation complexity of the proposed scheme, an adaptive complex-coefficient iterative method based on two-order Taylor series is designed. To cope with multiple narrow band interferences, a linear cascaded high order adaptive filter and a cyclic cascaded high order matrix adaptive filter (CCHOMAF) interference suppression algorithm based on the basic adaptive notch filter unit are also presented. The theoretical analysis and numerical simulation results indicate that the proposed CCHOMAF algorithm can achieve better performance in terms of average bit error rate for UWB WSNs. The proposed in-band NBIs elimination scheme can significantly improve the reception performance of low-cost and low-power UWB wireless systems. PMID:28587085

Tunable graphene-based mid-infrared plasmonic multispectral and narrow band-stop filter

NASA Astrophysics Data System (ADS)

Wang, Xianjun; Meng, Hongyun; Liu, Shuai; Deng, Shuying; Jiao, Tao; Wei, Zhongchao; Wang, Faqiang; Tan, Chunhua; Huang, Xuguang

2018-04-01

In this paper, we numerically investigate the band-stop properties of single- or few-layers doped graphene ribbon arrays operating in the mid-infrared region by finite-difference time-domain method (FDTD). A perfect band-stop filter with extinction ratio (ER) ∼17 dB, 3 dB bandwidth ∼200 nm and the resonance notch located at 6.64 μm can be achieved. And desired working regions can be obtained by tuning the Fermi level (E f ) of the graphene ribbons and the geometrical parameters of the structure. Besides, by tuning the Fermi level of odd or even graphene ribbons with terminal gate voltage, we can achieve a dual-circuit switch with four states combinations of on-to-off. Furthermore, the multiple filter notches can be achieved by stacking few-layers structure, and the filter dips can be dynamically tuned to achieve the tunability and selective characteristics by tuning the Fermi-level of the graphene ribbons in the system. We believe that our proposal has the potential applications in selective filters and active plasmonic switching in the mid-infrared region.

High-Speed Digital-Image Data Acquisition, Processing, and Visualization System for Turbulent Mixing and Combustion

DTIC Science & Technology

2007-05-25

of-the-art optical filters. Specifically, a FF01 -510/84 Semrock green band-pass filter (transmission >95% with 1% standard deviation between 467nm...used to reject the UV laser light (-390nm) exciting the CH radicals, and a NF0I-532U Semrock notch filter (transmission ə 04 % at 527nm, and >95

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

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.

Two-Stage Processing of Sounds Explains Behavioral Performance Variations due to Changes in Stimulus Contrast and Selective Attention: An MEG Study

PubMed Central

Kauramäki, Jaakko; Jääskeläinen, Iiro P.; Hänninen, Jarno L.; Auranen, Toni; Nummenmaa, Aapo; Lampinen, Jouko; Sams, Mikko

2012-01-01

Selectively attending to task-relevant sounds whilst ignoring background noise is one of the most amazing feats performed by the human brain. Here, we studied the underlying neural mechanisms by recording magnetoencephalographic (MEG) responses of 14 healthy human subjects while they performed a near-threshold auditory discrimination task vs. a visual control task of similar difficulty. The auditory stimuli consisted of notch-filtered continuous noise masker sounds, and of 1020-Hz target tones occasionally () replacing 1000-Hz standard tones of 300-ms duration that were embedded at the center of the notches, the widths of which were parametrically varied. As a control for masker effects, tone-evoked responses were additionally recorded without masker sound. Selective attention to tones significantly increased the amplitude of the onset M100 response at 100 ms to the standard tones during presence of the masker sounds especially with notches narrower than the critical band. Further, attention modulated sustained response most clearly at 300–400 ms time range from sound onset, with narrower notches than in case of the M100, thus selectively reducing the masker-induced suppression of the tone-evoked response. Our results show evidence of a multiple-stage filtering mechanism of sensory input in the human auditory cortex: 1) one at early (100 ms) latencies bilaterally in posterior parts of the secondary auditory areas, and 2) adaptive filtering of attended sounds from task-irrelevant background masker at longer latency (300 ms) in more medial auditory cortical regions, predominantly in the left hemisphere, enhancing processing of near-threshold sounds. PMID:23071654

An Adaptive Filter for the Removal of Drifting Sinusoidal Noise Without a Reference.

PubMed

Kelly, John W; Siewiorek, Daniel P; Smailagic, Asim; Wang, Wei

2016-01-01

This paper presents a method for filtering sinusoidal noise with a variable bandwidth filter that is capable of tracking a sinusoid's drifting frequency. The method, which is based on the adaptive noise canceling (ANC) technique, will be referred to here as the adaptive sinusoid canceler (ASC). The ASC eliminates sinusoidal contamination by tracking its frequency and achieving a narrower bandwidth than typical notch filters. The detected frequency is used to digitally generate an internal reference instead of relying on an external one as ANC filters typically do. The filter's bandwidth adjusts to achieve faster and more accurate convergence. In this paper, the focus of the discussion and the data is physiological signals, specifically electrocorticographic (ECoG) neural data contaminated with power line noise, but the presented technique could be applicable to other recordings as well. On simulated data, the ASC was able to reliably track the noise's frequency, properly adjust its bandwidth, and outperform comparative methods including standard notch filters and an adaptive line enhancer. These results were reinforced by visual results obtained from real ECoG data. The ASC showed that it could be an effective method for increasing signal to noise ratio in the presence of drifting sinusoidal noise, which is of significant interest for biomedical applications.

Application of LC and LCoS in Multispectral Polarized Scene Projector (MPSP)

NASA Astrophysics Data System (ADS)

Yu, Haiping; Guo, Lei; Wang, Shenggang; Lippert, Jack; Li, Le

2017-02-01

A Multispectral Polarized Scene Projector (MPSP) had been developed in the short-wave infrared (SWIR) regime for the test & evaluation (T&E) of spectro-polarimetric imaging sensors. This MPSP generates multispectral and hyperspectral video images (up to 200 Hz) with 512×512 spatial resolution with active spatial, spectral, and polarization modulation with controlled bandwidth. It projects input SWIR radiant intensity scenes from stored memory with user selectable wavelength and bandwidth, as well as polarization states (six different states) controllable on a pixel level. The spectral contents are implemented by a tunable filter with variable bandpass built based on liquid crystal (LC) material, together with one passive visible and one passive SWIR cholesteric liquid crystal (CLC) notch filters, and one switchable CLC notch filter. The core of the MPSP hardware is the liquid-crystal-on-silicon (LCoS) spatial light modulators (SLMs) for intensity control and polarization modulation.

Lifetime Fluorescence and Raman Imaging for Detection of Wound Failure and Heterotopic Ossification

DTIC Science & Technology

2015-12-01

containing ten bandpass filters ( Semrock Fluorescence filters) centered at: 407nm, 434 nm, 465 nm, 494 nm, 520 nm, 542 nm, 572 nm, 605 nm, 652 nm, 676 nm...meat (~2 - 3 mm thickness), and a bottom piece (~8 mm). The system was built around an 852 nm tunable narrow-band optical filter ( Semrock , LL01-852...optical filters to block light that falls outside the detection band: 785 nm notch filter ( Semrock , NF03-785E-25), and a bandpass filter at 842 nm

Lifetime Fluorescence and Raman Imaging for Detection of Wound Failure and Heterotopic Ossification

DTIC Science & Technology

2014-10-01

Filter Wheel) containing ten bandpass filters ( Semrock Fluorescence filters) centered at: 407nm, 434 nm, 465 nm, 494 nm, 520 nm, 542 nm, 572 nm...and a bottom piece (~8 mm). The system was built around an 852 nm tunable narrow-band optical filter ( Semrock , LL01-852-25) mounted in front of...light that falls outside the detection band: 785 nm notch filter ( Semrock , NF03-785E-25), and a bandpass filter at 842 nm ( Semrock , FF01-842/56-25

Adaptive HIFU noise cancellation for simultaneous therapy and imaging using an integrated HIFU/imaging transducer

PubMed Central

Jeong, Jong Seob; Cannata, Jonathan Matthew; Shung, K Kirk

2010-01-01

It was previously demonstrated that it is feasible to simultaneously perform ultrasound therapy and imaging of a coagulated lesion during treatment with an integrated transducer that is capable of high intensity focused ultrasound (HIFU) and B-mode ultrasound imaging. It was found that coded excitation and fixed notch filtering upon reception could significantly reduce interference caused by the therapeutic transducer. During HIFU sonication, the imaging signal generated with coded excitation and fixed notch filtering had a range side-lobe level of less than −40 dB, while traditional short-pulse excitation and fixed notch filtering produced a range side-lobe level of −20 dB. The shortcoming is, however, that relatively complicated electronics may be needed to utilize coded excitation in an array imaging system. It is for this reason that in this paper an adaptive noise canceling technique is proposed to improve image quality by minimizing not only the therapeutic interference, but also the remnant side-lobe ‘ripples’ when using the traditional short-pulse excitation. The performance of this technique was verified through simulation and experiments using a prototype integrated HIFU/imaging transducer. Although it is known that the remnant ripples are related to the notch attenuation value of the fixed notch filter, in reality, it is difficult to find the optimal notch attenuation value due to the change in targets or the media resulted from motion or different acoustic properties even during one sonication pulse. In contrast, the proposed adaptive noise canceling technique is capable of optimally minimizing both the therapeutic interference and residual ripples without such constraints. The prototype integrated HIFU/imaging transducer is composed of three rectangular elements. The 6 MHz center element is used for imaging and the outer two identical 4 MHz elements work together to transmit the HIFU beam. Two HIFU elements of 14.4 mm × 20.0 mm dimensions could increase the temperature of the soft biological tissue from 55 °C to 71 °C within 60 s. Two types of experiments for simultaneous therapy and imaging were conducted to acquire a single scan-line and B-mode image with an aluminum plate and a slice of porcine muscle, respectively. The B-mode image was obtained using the single element imaging system during HIFU beam transmission. The experimental results proved that the combination of the traditional short-pulse excitation and the adaptive noise canceling method could significantly reduce therapeutic interference and remnant ripples and thus may be a better way to implement real-time simultaneous therapy and imaging. PMID:20224162

Adaptive HIFU noise cancellation for simultaneous therapy and imaging using an integrated HIFU/imaging transducer.

PubMed

Jeong, Jong Seob; Cannata, Jonathan Matthew; Shung, K Kirk

2010-04-07

It was previously demonstrated that it is feasible to simultaneously perform ultrasound therapy and imaging of a coagulated lesion during treatment with an integrated transducer that is capable of high intensity focused ultrasound (HIFU) and B-mode ultrasound imaging. It was found that coded excitation and fixed notch filtering upon reception could significantly reduce interference caused by the therapeutic transducer. During HIFU sonication, the imaging signal generated with coded excitation and fixed notch filtering had a range side-lobe level of less than -40 dB, while traditional short-pulse excitation and fixed notch filtering produced a range side-lobe level of -20 dB. The shortcoming is, however, that relatively complicated electronics may be needed to utilize coded excitation in an array imaging system. It is for this reason that in this paper an adaptive noise canceling technique is proposed to improve image quality by minimizing not only the therapeutic interference, but also the remnant side-lobe 'ripples' when using the traditional short-pulse excitation. The performance of this technique was verified through simulation and experiments using a prototype integrated HIFU/imaging transducer. Although it is known that the remnant ripples are related to the notch attenuation value of the fixed notch filter, in reality, it is difficult to find the optimal notch attenuation value due to the change in targets or the media resulted from motion or different acoustic properties even during one sonication pulse. In contrast, the proposed adaptive noise canceling technique is capable of optimally minimizing both the therapeutic interference and residual ripples without such constraints. The prototype integrated HIFU/imaging transducer is composed of three rectangular elements. The 6 MHz center element is used for imaging and the outer two identical 4 MHz elements work together to transmit the HIFU beam. Two HIFU elements of 14.4 mm x 20.0 mm dimensions could increase the temperature of the soft biological tissue from 55 degrees C to 71 degrees C within 60 s. Two types of experiments for simultaneous therapy and imaging were conducted to acquire a single scan-line and B-mode image with an aluminum plate and a slice of porcine muscle, respectively. The B-mode image was obtained using the single element imaging system during HIFU beam transmission. The experimental results proved that the combination of the traditional short-pulse excitation and the adaptive noise canceling method could significantly reduce therapeutic interference and remnant ripples and thus may be a better way to implement real-time simultaneous therapy and imaging.

Waterfall notch-filtering for restoration of acoustic backscatter records from Admiralty Bay, Antarctica

NASA Astrophysics Data System (ADS)

Fonseca, Luciano; Hung, Edson Mintsu; Neto, Arthur Ayres; Magrani, Fábio José Guedes

2018-06-01

A series of multibeam sonar surveys were conducted from 2009 to 2013 around Admiralty Bay, Shetland Islands, Antarctica. These surveys provided a detailed bathymetric model that helped understand and characterize the bottom geology of this remote area. Unfortunately, the acoustic backscatter records registered during these bathymetric surveys were heavily contaminated with noise and motion artifacts. These artifacts persisted in the backscatter records despite the fact that the proper acquisition geometry and the necessary offsets and delays were applied during the survey and in post-processing. These noisy backscatter records were very difficult to interpret and to correlate with gravity-core samples acquired in the same area. In order to address this issue, a directional notch-filter was applied to the backscatter waterfall in the along-track direction. The proposed filter provided better estimates for the backscatter strength of each sample by considerably reducing residual motion artifacts. The restoration of individual samples was possible since the waterfall frame of reference preserves the acquisition geometry. Then, a remote seafloor characterization procedure based on an acoustic model inversion was applied to the restored backscatter samples, generating remote estimates of acoustic impedance. These remote estimates were compared to Multi Sensor Core Logger measurements of acoustic impedance obtained from gravity core samples. The remote estimates and the Core Logger measurements of acoustic impedance were comparable when the shallow seafloor was homogeneous. The proposed waterfall notch-filtering approach can be applied to any sonar record, provided that we know the system ping-rate and sampling frequency.

Effect of efferent activation on binaural frequency selectivity.

PubMed

Verhey, Jesko L; Kordus, Monika; Drga, Vit; Yasin, Ifat

2017-07-01

Binaural notched-noise experiments indicate a reduced frequency selectivity of the binaural system compared to monaural processing. The present study investigates how auditory efferent activation (via the medial olivocochlear system) affects binaural frequency selectivity in normal-hearing listeners. Thresholds were measured for a 1-kHz signal embedded in a diotic notched-noise masker for various notch widths. The signal was either presented in phase (diotic) or in antiphase (dichotic), gated with the noise. Stimulus duration was 25 ms, in order to avoid efferent activation due to the masker or the signal. A bandpass-filtered noise precursor was presented prior to the masker and signal stimuli to activate the efferent system. The silent interval between the precursor and the masker-signal complex was 50 ms. For comparison, thresholds for detectability of the masked signal were also measured in a baseline condition without the precursor and, in addition, without the masker. On average, the results of the baseline condition indicate an effectively wider binaural filter, as expected. For both signal phases, the addition of the precursor results in effectively wider filters, which is in agreement with the hypothesis that cochlear gain is reduced due to the presence of the precursor. Copyright © 2017 Elsevier B.V. All rights reserved.

The Width of the Auditory Filter in Children.

ERIC Educational Resources Information Center

Irwin, R. J.; And Others

1986-01-01

Because young children have poorer auditory temporal resolution than older children, a study measured the auditory filters of two 6-year-olds, two 10-year-olds, and two adults by having them detect a 400-ms sinusoid centered in a spectral notch in a band of noise. (HOD)

Photonic ring resonator filters for astronomical OH suppression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellis, S. C.; Kuhlmann, S.; Kuehn, K.

Ring resonators provide a means of filtering specific wavelengths from a waveguide, and optionally dropping the filtered wavelengths into a second waveguide. Both of these features are potentially useful for astronomical instruments. In this paper we focus on their use as notch filters to remove the signal from atmospheric OH emission lines from astronomical spectra. We derive the design requirements for ring resonators for OH suppression from theory and finite difference time domain simulations. We find that rings with small radii (< 10 μm) are required to provide an adequate free spectral range, leading to high index contrast materials suchmore » as Si and Si 3N 4. Critically coupled rings with high self-coupling coefficients should provide the necessary Q factors, suppression depth, and throughput for efficient OH suppression, but will require post-inscription tuning of the coupling and the resonant wavelengths. The overall prospects for the use of ring resonators in astronomical instruments is promising, provided efficient fibre-chip coupling can be achieved.« less

Photonic ring resonator filters for astronomical OH suppression

DOE PAGES

Ellis, S. C.; Kuhlmann, S.; Kuehn, K.; ...

2017-01-01

Ring resonators provide a means of filtering specific wavelengths from a waveguide, and optionally dropping the filtered wavelengths into a second waveguide. Both of these features are potentially useful for astronomical instruments. In this paper we focus on their use as notch filters to remove the signal from atmospheric OH emission lines from astronomical spectra. We derive the design requirements for ring resonators for OH suppression from theory and finite difference time domain simulations. We find that rings with small radii (< 10 μm) are required to provide an adequate free spectral range, leading to high index contrast materials suchmore » as Si and Si 3N 4. Critically coupled rings with high self-coupling coefficients should provide the necessary Q factors, suppression depth, and throughput for efficient OH suppression, but will require post-inscription tuning of the coupling and the resonant wavelengths. The overall prospects for the use of ring resonators in astronomical instruments is promising, provided efficient fibre-chip coupling can be achieved.« less

Flexible RF filter using a nonuniform SCISSOR.

PubMed

Zhuang, Leimeng

2016-03-15

This work presents a flexible radiofrequency (RF) filter using an integrated microwave photonic circuit that comprises a nonuniform side-coupled integrated spaced sequence of resonators (N-SCISSOR). The filter passband can be reconfigured by varying the N-SCISSOR parameters. When employing a dual-parallel Mach-Zechnder modulator, the filter is also able to perform frequency down-conversion. In the experiment, various filter response shapes are shown, ranging from a flat-top band-pass filter to a total opposite high-rejection (>40  dB) notch filter, with a frequency coverage of greater than two octaves. The frequency down-conversion function is also demonstrated.

MM5 Modeling of the Madden Julian Oscillation in the Indian and West Pacific Oceans: Implications of 30 70-Day Boundary Effects on MJO Development.

NASA Astrophysics Data System (ADS)

Gustafson, William I., Jr.; Weare, Bryan C.

2004-03-01

The results of an experiment designed to isolate the initiation phase of the Madden Julian oscillation (MJO) from 30 70-day boundary effects is presented. The technique used to accomplish this involves employing the fifth-generation Pennsylvania State University National Center for Atmospheric Research (PSU NCAR) Mesoscale Model (MM5), as first presented in the companion paper to this paper. Two runs, each 2 yr long, are integrated forward from 1 June 1990. The first run, called the control, uses the unmodified National Centers for Environmental Prediction (NCEP) NCAR reanalysis (NRA) dataset for boundary conditions. The second run, called the notched, uses the same NRA dataset for the boundary conditions, with the exception that all signals with periodicities in the 30 70-day range have been removed. Any signals in the 30 70-day range subsequently generated by the notched run are then solely due to signals generated from within the model domain or from signals entering through the domain boundaries with frequencies outside of the MJO band. Comparisons between 2-yr means from each run indicate that filtering the boundaries does not significantly modify the model climatology. The mean wind structure, thermodynamic state, and outgoing longwave radiation (OLR) are almost identical in the control and notched runs. A 30 70-day bandpass filter is used to isolate MJO-like signals in the runs. Comparisons of 30 70-day bandpassed zonal wind, moist static energy (MSE), and OLR reveal that the notched run develops many of the expected characteristics of MJO episodes, but with a weaker signal. Large-scale, organized structures develop that possess seasonal shifts in amplitude, mirroring observed MJO activity, have opposite wind directions in the upper and lower troposphere, and propagate eastward during most strong episodes. The results suggest that neither remnants from previous MJO episodes nor extratropical feedbacks within the MJO time band are necessary for MJO initiation. However, the control run is more organized than the notched run, implying that 30 70 signals outside the model domain influence the MJO signal. There is also some evidence that the recharge discharge mechanism plays a role in MJO formation.

Enhanced thermomechanical stability on laser-induced damage by functionally graded layers in quasi-rugate filters

NASA Astrophysics Data System (ADS)

Pu, Yunti; Ma, Ping; Lv, Liang; Zhang, Mingxiao; Lu, Zhongwen; Qiao, Zhao; Qiu, Fuming

2018-05-01

Ta2O5-SiO2 quasi-rugate filters with a reasonable optimization of rugate notch filter design were prepared by ion-beam sputtering. The optical properties and laser-induced damage threshold are studied. Compared with the spectrum of HL-stacks, the spectrum of quasi-rugate filters have weaker second harmonic peaks and narrower stopbands. According to the effect of functionally graded layers (FGLs), 1-on-1 and S-on-1 Laser induced damage threshold (LIDT) of quasi-rugate filters are about 22% and 50% higher than those of HL stacks, respectively. Through the analysis of the damage morphologies, laser-induced damage of films under nanosecond multi-pulse are dominated by a combination of thermal shock stress and thermomechanical instability due to nodules. Compared with catastrophic damages, the damage sits of quasi-rugate filters are developed in a moderate way. The damage growth behavior of defect-induced damage sites have been effectively restrained by the structure of FGLs. Generally, FGLs are used to reduce thermal stress by the similar thermal-expansion coefficients of neighboring layers and solve the problems such as instability and cracking raised by the interface discontinuity of nodular boundaries, respectively.

Metal Standards for Waveguide Characterization of Materials

NASA Technical Reports Server (NTRS)

Lambert, Kevin M.; Kory, Carol L.

2009-01-01

Rectangular-waveguide inserts that are made of non-ferromagnetic metals and are sized and shaped to function as notch filters have been conceived as reference standards for use in the rectangular- waveguide method of characterizing materials with respect to such constitutive electromagnetic properties as permittivity and permeability. Such standards are needed for determining the accuracy of measurements used in the method, as described below. In this method, a specimen of a material to be characterized is cut to a prescribed size and shape and inserted in a rectangular- waveguide test fixture, wherein the specimen is irradiated with a known source signal and detectors are used to measure the signals reflected by, and transmitted through, the specimen. Scattering parameters [also known as "S" parameters (S11, S12, S21, and S22)] are computed from ratios between the transmitted and reflected signals and the source signal. Then the permeability and permittivity of the specimen material are derived from the scattering parameters. Theoretically, the technique for calculating the permeability and permittivity from the scattering parameters is exact, but the accuracy of the results depends on the accuracy of the measurements from which the scattering parameters are obtained. To determine whether the measurements are accurate, it is necessary to perform comparable measurements on reference standards, which are essentially specimens that have known scattering parameters. To be most useful, reference standards should provide the full range of scattering-parameter values that can be obtained from material specimens. Specifically, measurements of the backscattering parameter (S11) from no reflection to total reflection and of the forward-transmission parameter (S21) from no transmission to total transmission are needed. A reference standard that functions as a notch (band-stop) filter can satisfy this need because as the signal frequency is varied across the frequency range for which the filter is designed, the scattering parameters vary over the ranges of values between the extremes of total reflection and total transmission. A notch-filter reference standard in the form of a rectangular-waveguide insert that has a size and shape similar to that of a material specimen is advantageous because the measurement configuration used for the reference standard can be the same as that for a material specimen. Typically a specimen is a block of material that fills a waveguide cross-section but occupies only a small fraction of the length of the waveguide. A reference standard of the present type (see figure) is a metal block that fills part of a waveguide cross section and contains a slot, the long dimension of which can be chosen to tailor the notch frequency to a desired value. The scattering parameters and notch frequency can be estimated with high accuracy by use of commercially available electromagnetic-field-simulating software. The block can be fabricated to the requisite precision by wire electrical-discharge machining. In use, the accuracy of measurements is determined by comparison of (1) the scattering parameters calculated from the measurements with (2) the scattering parameters calculated by the aforementioned software.

An Active Filter Primer, Mod 1.

DTIC Science & Technology

1983-02-01

D-Element Phase Shifting Super-Capacitor Delay Network Frequency Domain Filtering 20...Response A-44 O-OF-3 Notch Response A-45 1-Pole 1-Zero All-Pass Response A-46 2-Pole 2-Zero 90°-Phase-Difference Network Response. . . . A-47 A-13...Delagrange, "A Useful Filter Family," NSWC WOL TR 75-170. 7. E. A. Guillemin, Synthesis of Passive Networks , Wiley, 1957. 8. Harry Y-F. Lam, Analog and

Application of optical broadband monitoring to quasi-rugate filters by ion-beam sputtering

NASA Astrophysics Data System (ADS)

Lappschies, Marc; Görtz, Björn; Ristau, Detlev

2006-03-01

Methods for the manufacture of rugate filters by the ion-beam-sputtering process are presented. The first approach gives an example of a digitized version of a continuous-layer notch filter. This method allows the comparison of the basic theory of interference coatings containing thin layers with practical results. For the other methods, a movable zone target is employed to fabricate graded and gradual rugate filters. The examples demonstrate the potential of broadband optical monitoring in conjunction with the ion-beam-sputtering process. First-characterization results indicate that these types of filter may exhibit higher laser-induced damage-threshold values than those of classical filters.

A reconfigurable microwave photonic filter with flexible tunability using a multi-wavelength laser and a multi-channel phase-shifted fiber Bragg grating

NASA Astrophysics Data System (ADS)

Shi, Nuannuan; Hao, Tengfei; Li, Wei; Zhu, Ninghua; Li, Ming

2018-01-01

We propose a photonic scheme to realize a reconfigurable microwave photonic filter (MPF) with flexible tunability using a multi-wavelength laser (MWL) and a multi-channel phase-shifted fiber Bragg grating (PS-FBG). The proposed MPF is capable of performing reconfigurability including single bandpass filter, two independently bandpass filter and a flat-top bandpass filter. The performance such as the central frequency and the bandwidth of passband is tuned by controlling the wavelengths of the MWL. In the MPF, The light waves from a MWL are sent to a phase modulator (PM) to generate the phase-modulated optical signals. By applying a multi-channel PS-FBG, which has a series of narrow notches in the reflection spectrum with the free spectral range (FSR) of 0.8 nm, the +1st sidebands are removed in the notches and the phased-modulated signals are converted to the intensity-modulated signals without beating signals generation between each two optical carriers. The proposed MPF is also experimentally verified. The 3-dB bandwidth of the MPF is broadened from 35 MHz to 135 MHz and the magnitude deviation of the top from the MPF is less than 0.2 dB within the frequency tunable range from 1 GHz to 5 GHz.

Enhancing inhibition-induced plasticity in tinnitus--spectral energy contrasts in tailor-made notched music matter.

PubMed

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

2015-01-01

Chronic tinnitus seems to be caused by reduced inhibition among frequency selective neurons in the auditory cortex. One possibility to reduce tinnitus perception is to induce inhibition onto over-activated neurons representing the tinnitus frequency via tailor-made notched music (TMNM). Since lateral inhibition is modifiable by spectral energy contrasts, the question arises if the effects of inhibition-induced plasticity can be enhanced by introducing increased spectral energy contrasts (ISEC) in TMNM. Eighteen participants suffering from chronic tonal tinnitus, pseudo randomly assigned to either a classical TMNM or an ISEC-TMNM group, listened to notched music for three hours on three consecutive days. The music was filtered for both groups by introducing a notch filter centered at the individual tinnitus frequency. For the ISEC-TMNM group a frequency bandwidth of 3/8 octaves on each side of the notch was amplified, additionally, by about 20 dB. Before and after each music exposure, participants rated their subjectively perceived tinnitus loudness on a visual analog scale. During the magnetoencephalographic recordings, participants were stimulated with either a reference tone of 500 Hz or a test tone with a carrier frequency representing the individual tinnitus pitch. Perceived tinnitus loudness was significantly reduced after TMNM exposure, though TMNM type did not influence the loudness ratings. Tinnitus related neural activity in the N1m time window and in the so called tinnitus network comprising temporal, parietal and frontal regions was reduced after TMNM exposure. The ISEC-TMNM group revealed even enhanced inhibition-induced plasticity in a temporal and a frontal cortical area. Overall, inhibition of tinnitus related neural activity could be strengthened in people affected with tinnitus by increasing spectral energy contrast in TMNM, confirming the concepts of inhibition-induced plasticity via TMNM and spectral energy contrasts.

Enhancing Inhibition-Induced Plasticity in Tinnitus – Spectral Energy Contrasts in Tailor-Made Notched Music Matter

PubMed Central

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

2015-01-01

Chronic tinnitus seems to be caused by reduced inhibition among frequency selective neurons in the auditory cortex. One possibility to reduce tinnitus perception is to induce inhibition onto over-activated neurons representing the tinnitus frequency via tailor-made notched music (TMNM). Since lateral inhibition is modifiable by spectral energy contrasts, the question arises if the effects of inhibition-induced plasticity can be enhanced by introducing increased spectral energy contrasts (ISEC) in TMNM. Eighteen participants suffering from chronic tonal tinnitus, pseudo randomly assigned to either a classical TMNM or an ISEC-TMNM group, listened to notched music for three hours on three consecutive days. The music was filtered for both groups by introducing a notch filter centered at the individual tinnitus frequency. For the ISEC-TMNM group a frequency bandwidth of 3/8 octaves on each side of the notch was amplified, additionally, by about 20 dB. Before and after each music exposure, participants rated their subjectively perceived tinnitus loudness on a visual analog scale. During the magnetoencephalographic recordings, participants were stimulated with either a reference tone of 500 Hz or a test tone with a carrier frequency representing the individual tinnitus pitch. Perceived tinnitus loudness was significantly reduced after TMNM exposure, though TMNM type did not influence the loudness ratings. Tinnitus related neural activity in the N1m time window and in the so called tinnitus network comprising temporal, parietal and frontal regions was reduced after TMNM exposure. The ISEC-TMNM group revealed even enhanced inhibition-induced plasticity in a temporal and a frontal cortical area. Overall, inhibition of tinnitus related neural activity could be strengthened in people affected with tinnitus by increasing spectral energy contrast in TMNM, confirming the concepts of inhibition-induced plasticity via TMNM and spectral energy contrasts. PMID:25951605

Destriping AIS data using Fourier filtering techniques

NASA Technical Reports Server (NTRS)

Hlavka, C.

1986-01-01

Airborne Imaging Spectrometers (AIS) data collected in 1984 and 1985 showed pronounced striping in the vertical and horizontal directions. This striping reduced the signal to noise ratio so that features of the spectra of forest canopies were obscured or altered by noise. This noise was removed by application of a notch filter to the Fourier transform of the imagery in each waveband.

Wideband Bandpass Filter with High Selectivity and an Adjustable Notched-band Adopting a Multi-mode Resonator

NASA Astrophysics Data System (ADS)

Ma, Xing-Bing; Jiang, Ting

2018-04-01

A wideband bandpass filter (BPF) with an adjustable notched-band and high selectivity is proposed. The proposed BPF consists of a multi-mode resonator (MMR), two λ/2 resonators, and I/O feed lines with 50 ohm characteristic impedance. The MMR, connected as a whole by a wide stub, is composed of one I-shaped resonator and two open-loop resonators. Tightly coupling is built between MMR and λ/2 resonators. I/O feed lines are directly connected with two λ/2 resonators, respectively. Due to the use of tapped-line coupling, one transmission zero (TZ) is formed near low-edge of aim passband. High-edge of passband with one attendant TZ can be tuned to desired location by adjusting bottom-side position of used wide stub or bottom-side length of I-shaped resonator in MMR. The top-side length of I-shaped resonator is applied to improve upper stopband performance and shift undesired resonant mode of MMR near high-edge of aim passband to proper frequency point. The notched-band in aim passband is dominated by top-side position of wide stub in MMR. Good agreement is observed between simulated and measured results.

Travelling wave resonators fabricated with low-loss hydrogenated amorphous silicon

NASA Astrophysics Data System (ADS)

Lipka, Timo; Amthor, Julia; Trieu, Hoc Khiem; Müller, Jörg

2013-05-01

Low-loss hydrogenated amorphous silicon is employed for the fabrication of various planar integrated travelling wave resonators. Microring, racetrack, and disk resonators of different dimensions were fabricated with CMOS-compatible processes and systematically investigated. The key properties of notch filter ring resonators as extinction ratio, Q-factor, free spectral range, and the group refractive index were determined for resonators of varying radius, thereby achieving critically coupled photonic systems with high extinction ratios of about 20 dB for both polarizations. Racetrack resonators that are arranged in add/drop configuration and high quality factor microdisk resonators were optically characterized, with the microdisks exhibiting Q-factors of greater than 100000. Four-channel add/drop wavelength-division multiplexing filters that are based on cascaded racetrack resonators are studied. The design, the fabrication, and the optical characterization are presented.

On-Chip Hardware for Cell Monitoring: Contact Imaging and Notch Filtering

DTIC Science & Technology

2005-07-07

a polymer carrier. Spectrophotometer chosen and purchased for testing optical filters and materials. Characterization and comparison of fabricated...reproducibility of behavior. Multi-level SU8 process developed. Optimization of actuator for closing vial lids and development of lid sealing technology is...bending angles characterized as a function of temperature in NaDBS solution. " Photopatternable polymers are a viable interim packaging solution; through

Photonic crystal nanocavity assisted rejection ratio tunable notch microwave photonic filter

PubMed Central

Long, Yun; Xia, Jinsong; Zhang, Yong; Dong, Jianji; Wang, Jian

2017-01-01

Driven by the increasing demand on handing microwave signals with compact device, low power consumption, high efficiency and high reliability, it is highly desired to generate, distribute, and process microwave signals using photonic integrated circuits. Silicon photonics offers a promising platform facilitating ultracompact microwave photonic signal processing assisted by silicon nanophotonic devices. In this paper, we propose, theoretically analyze and experimentally demonstrate a simple scheme to realize ultracompact rejection ratio tunable notch microwave photonic filter (MPF) based on a silicon photonic crystal (PhC) nanocavity with fixed extinction ratio. Using a conventional modulation scheme with only a single phase modulator (PM), the rejection ratio of the presented MPF can be tuned from about 10 dB to beyond 60 dB. Moreover, the central frequency tunable operation in the high rejection ratio region is also demonstrated in the experiment. PMID:28067332

Photonic crystal nanocavity assisted rejection ratio tunable notch microwave photonic filter

NASA Astrophysics Data System (ADS)

Long, Yun; Xia, Jinsong; Zhang, Yong; Dong, Jianji; Wang, Jian

2017-01-01

Driven by the increasing demand on handing microwave signals with compact device, low power consumption, high efficiency and high reliability, it is highly desired to generate, distribute, and process microwave signals using photonic integrated circuits. Silicon photonics offers a promising platform facilitating ultracompact microwave photonic signal processing assisted by silicon nanophotonic devices. In this paper, we propose, theoretically analyze and experimentally demonstrate a simple scheme to realize ultracompact rejection ratio tunable notch microwave photonic filter (MPF) based on a silicon photonic crystal (PhC) nanocavity with fixed extinction ratio. Using a conventional modulation scheme with only a single phase modulator (PM), the rejection ratio of the presented MPF can be tuned from about 10 dB to beyond 60 dB. Moreover, the central frequency tunable operation in the high rejection ratio region is also demonstrated in the experiment.

Photonic crystal nanocavity assisted rejection ratio tunable notch microwave photonic filter.

PubMed

Long, Yun; Xia, Jinsong; Zhang, Yong; Dong, Jianji; Wang, Jian

2017-01-09

Driven by the increasing demand on handing microwave signals with compact device, low power consumption, high efficiency and high reliability, it is highly desired to generate, distribute, and process microwave signals using photonic integrated circuits. Silicon photonics offers a promising platform facilitating ultracompact microwave photonic signal processing assisted by silicon nanophotonic devices. In this paper, we propose, theoretically analyze and experimentally demonstrate a simple scheme to realize ultracompact rejection ratio tunable notch microwave photonic filter (MPF) based on a silicon photonic crystal (PhC) nanocavity with fixed extinction ratio. Using a conventional modulation scheme with only a single phase modulator (PM), the rejection ratio of the presented MPF can be tuned from about 10 dB to beyond 60 dB. Moreover, the central frequency tunable operation in the high rejection ratio region is also demonstrated in the experiment.

Frequency tracking and variable bandwidth for line noise filtering without a reference.

PubMed

Kelly, John W; Collinger, Jennifer L; Degenhart, Alan D; Siewiorek, Daniel P; Smailagic, Asim; Wang, Wei

2011-01-01

This paper presents a method for filtering line noise using an adaptive noise canceling (ANC) technique. This method effectively eliminates the sinusoidal contamination while achieving a narrower bandwidth than typical notch filters and without relying on the availability of a noise reference signal as ANC methods normally do. A sinusoidal reference is instead digitally generated and the filter efficiently tracks the power line frequency, which drifts around a known value. The filter's learning rate is also automatically adjusted to achieve faster and more accurate convergence and to control the filter's bandwidth. In this paper the focus of the discussion and the data will be electrocorticographic (ECoG) neural signals, but the presented technique is applicable to other recordings.

SPS pilot signal design and power transponder analysis, volume 2, phase 3

NASA Technical Reports Server (NTRS)

Lindsey, W. C.; Scholtz, R. A.; Chie, C. M.

1980-01-01

The problem of pilot signal parameter optimization and the related problem of power transponder performance analysis for the Solar Power Satellite reference phase control system are addressed. Signal and interference models were established to enable specifications of the front end filters including both the notch filter and the antenna frequency response. A simulation program package was developed to be included in SOLARSIM to perform tradeoffs of system parameters based on minimizing the phase error for the pilot phase extraction. An analytical model that characterizes the overall power transponder operation was developed. From this model, the effects of different phase noise disturbance sources that contribute to phase variations at the output of the power transponders were studied and quantified. Results indicate that it is feasible to hold the antenna array phase error to less than one degree per power module for the type of disturbances modeled.

Parameter Identification

DTIC Science & Technology

1979-11-01

Science Aeronautique, Vol. 6, pp. 38-49, 1950. 9. Anon.: "Methods of testing at constant attitude", ICAO Circular 16-AN/13, 1951. 10. H.L. Jonkers...spectral density analysis, it was determined that a notch filter at 17.7 hertz and a third-order Butterworth low-pass filter with a break frequency of 20...of the effects of specific errors, they are circular in nature and do not address the basic theoretical problem. Therefore, the Cramer-Rao bound

Flexible stator control on the Galileo spacecraft

NASA Technical Reports Server (NTRS)

Kopf, E. H.; Brown, T. K.; Marsh, E. L.

1979-01-01

Galileo is a dual-spin spacecraft designed to deliver a probe to Jupiter and then orbit the planet. The stator, or despun section, contains four flexible modes below 10 Hz and the despun actuator is separated from the inertial sensors by this flexibility. Control loop separation by bandwidth proved unacceptable due to performance requirements. To obtain the desired performance, a control scheme was devised which consists of three parts. First, flexibility damping and control notch filtering are accomplished by phase locked loop techniques. Second, slewing maneuvers are produced by torque profiles which are nonexcitatory to the structure. Finally, a low bandwidth perturbation controller is supplied to remove spacecraft disturbances.

Infrared techniques for detecting carbonization at onset of device failure

NASA Astrophysics Data System (ADS)

Farr, Norman; Sinofsky, Edward L.

1997-05-01

We describe the design, and development of an infrared detection system which detects the onset of carbonization of fluoropolymers in the presence of up to 60 watts of 1.06 micrometer laser energy. This system is used to shut down a therapeutic laser system before significant damage is done to a laser delivery device and patient. Black body radiation emitting from the diffusion tip is transmitted, backwards, through the same optical fiber as the therapeutic wavelength. Using a high power 1.06 micrometer laser mirror at 45 degrees, most of the 1.06 micrometer light is reflected while the black body radiation is passed to a holographic notch filter which further filters the signal. Still more filtering was needed before the 1.1 to 2 micrometer signal could be detected within the presence the therapeutic light using an extended indium gallium arsenide photodetector. There was still a significant detected offset which increased with laser power which necessitated a means to automatically null the offset for different laser power settings. The system is designed to be used with any unmodified laser system. It interfaces directly to or in series with most common external safety interlocks and can be used with various diffusing tips, probes or bare fibers.

Dynamic tunable notch filters for the Antarctic Impulsive Transient Antenna (ANITA)

NASA Astrophysics Data System (ADS)

Allison, P.; Banerjee, O.; Beatty, J. J.; Connolly, A.; Deaconu, C.; Gordon, J.; Gorham, P. W.; Kovacevich, M.; Miki, C.; Oberla, E.; Roberts, J.; Rotter, B.; Stafford, S.; Tatem, K.; Batten, L.; Belov, K.; Besson, D. Z.; Binns, W. R.; Bugaev, V.; Cao, P.; Chen, C.; Chen, P.; Chen, Y.; Clem, J. M.; Cremonesi, L.; Dailey, B.; Dowkontt, P. F.; Hsu, S.; Huang, J.; Hupe, R.; Israel, M. H.; Kowalski, J.; Lam, J.; Learned, J. G.; Liewer, K. M.; Liu, T. C.; Ludwig, A. B.; Matsuno, S.; Mulrey, K.; Nam, J.; Nichol, R. J.; Novikov, A.; Prohira, S.; Rauch, B. F.; Ripa, J.; Romero-Wolf, A.; Russell, J.; Saltzberg, D.; Seckel, D.; Shiao, J.; Stockham, J.; Stockham, M.; Strutt, B.; Varner, G. S.; Vieregg, A. G.; Wang, S.; Wissel, S. A.; Wu, F.; Young, R.

2018-06-01

The Antarctic Impulsive Transient Antenna (ANITA) is a NASA long-duration balloon experiment with the primary goal of detecting ultra-high-energy (> 1018eV) neutrinos via the Askaryan Effect. The fourth ANITA mission, ANITA-IV, recently flew from Dec 2 to Dec 29, 2016. For the first time, the Tunable Universal Filter Frontend (TUFF) boards were deployed for mitigation of narrow-band, anthropogenic noise with tunable, switchable notch filters. The TUFF boards also performed second-stage amplification by approximately 45 dB to boost the ∼ μV-level radio frequency (RF) signals to ∼ mV-level for digitization, and supplied power via bias tees to the first-stage, antenna-mounted amplifiers. The other major change in signal processing in ANITA-IV is the resurrection of the 90 ° hybrids deployed previously in ANITA-I, in the trigger system, although in this paper we focus on the TUFF boards. During the ANITA-IV mission, the TUFF boards were successfully operated throughout the flight. They contributed to a factor of 2.8 higher total instrument livetime on average in ANITA-IV compared to ANITA-III due to reduction of narrow-band, anthropogenic noise before a trigger decision is made.

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 (T 2 ) 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.

Design of band-notched antenna with DG-CEBG

NASA Astrophysics Data System (ADS)

Jaglan, Naveen; Kanaujia, Binod Kumar; Gupta, Samir Dev; Srivastava, Shweta

2018-01-01

Ultra-wideband (UWB) disc monopole antenna with crescent shaped slot for double band-notched features is presented. Planned antenna discards worldwide interoperability for microwave access (WiMAX) band (3.3-3.6 GHz) and wireless local area network (WLAN) band (5-6 GHz). Defected ground compact electromagnetic band gap (DG-CEBG) designs are used to accomplish band notches in WiMAX and WLAN bands. Defected ground planes are utilised to achieve compactness in electromagnetic band gap (EBG) structures. The proposed WiMAX and WLAN DG-CEBG designs show a compactness of around 46% and 50%, respectively, over mushroom EBG structures. Parametric analyses of DG-CEBG design factors are carried out to control the notched frequencies. Stepwise notch transition from upper to lower frequencies is presented with incremental inductance augmentation. The proposed antenna is made-up on low-cost FR-4 substrate of complete extents as (42 × 50 × 1.6) mm3.Fabricated sample antenna shows excellent consistency in simulated and measured outcomes.

Therapeutic targeting of NOTCH1 signaling in T-ALL

PubMed Central

Palomero, Teresa; Ferrando, Adolfo

2010-01-01

The recent identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias (T-ALL) has brought major interest towards targeting the NOTCH signaling pathway in this disease. Small molecule γ-secretase inhibitors (GSIs) which block a critical proteolytic step required for NOTCH1 activation can effectively block the activity of NOTCH1 mutant alleles. However, the clinical development of GSIs has been hampered by their low cytotoxicity against human T-ALL and the development of significant gastrointestinal toxicity derived from inhibition of NOTCH signaling in the gut. Improved understanding of the oncogenic mechanisms of NOTCH1 and the effects of NOTCH inhibition in leukemic cells and the intestinal epithelium are required for the design of effective anti-NOTCH1 therapies in T-ALL. PMID:19778842

Guided-mode resonance reflection and transmission filters in the optical and microwave spectral ranges

NASA Astrophysics Data System (ADS)

Tibuleac, Sorin

In this dissertation, new reflection and transmission filters are developed and characterized in the optical and microwave spectral regions. These guided-mode resonance (GMR) filters are implemented by integrating diffraction gratings into classical thin-film multilayers to produce high efficiency filter response and low sidebands extended over a large spectral range. Diffraction from phase-shifted gratings and gratings with different periods is analyzed using rigorous coupled-wave theory yielding a new approach to filter linewidth broadening, line-shaping, and multi-line filters at normal incidence. New single-grating transmission filters presented have narrow linewidth, high peak transmittance, and low sideband reflectance. A comparison with classical thin-film filters shows that GMR devices require significantly fewer layers to obtain narrow linewidth and high peak response. All-dielectric microwave frequency- selective surfaces operating in reflection or transmission are shown to be realizable with only a few layers using common microwave materials. Single-layer and multilayer waveguide gratings operating as reflection and transmission filters, respectively, were built and tested in the 4-20 GHz frequency range. The presence of GMR notches and peaks is clearly established by the experimental results, and their spectral location and lineshape found to be in excellent agreement with the theoretical predictions. A new computer program using genetic algorithms and rigorous coupled-wave analysis was developed for optimization of multilayer structures containing homogeneous and diffractive layers. This program was utilized to find GMR filters possessing features not previously known. Thus, numerous examples of transmission filters with peaks approaching 100%, narrow linewidths (~0.03%), and low sidebands have been found in structures containing only 1-3 layers. A new type of GMR device integrating a waveguide grating with subwavelength period on the endface of an optical fiber is developed for high-resolution biomedical or chemical sensors and spectral filtering applications. Diffraction gratings with submicron periods exhibiting high efficiencies have been recorded for the first time on coated and uncoated endfaces of single-mode and multimode fibers. Guided-mode resonance transmittance notches of ~18% were experimentally obtained with structures consisting of photoresist gratings on thin films of Si3N4 deposited on optical fiber endfaces.

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.

Extraction of user's navigation commands from upper body force interaction in walker assisted gait.

PubMed

Frizera Neto, Anselmo; Gallego, Juan A; Rocon, Eduardo; Pons, José L; Ceres, Ramón

2010-08-05

The advances in technology make possible the incorporation of sensors and actuators in rollators, building safer robots and extending the use of walkers to a more diverse population. This paper presents a new method for the extraction of navigation related components from upper-body force interaction data in walker assisted gait. A filtering architecture is designed to cancel: (i) the high-frequency noise caused by vibrations on the walker's structure due to irregularities on the terrain or walker's wheels and (ii) the cadence related force components caused by user's trunk oscillations during gait. As a result, a third component related to user's navigation commands is distinguished. For the cancelation of high-frequency noise, a Benedict-Bordner g-h filter was designed presenting very low values for Kinematic Tracking Error ((2.035 +/- 0.358).10(-2) kgf) and delay ((1.897 +/- 0.3697).10(1)ms). A Fourier Linear Combiner filtering architecture was implemented for the adaptive attenuation of about 80% of the cadence related components' energy from force data. This was done without compromising the information contained in the frequencies close to such notch filters. The presented methodology offers an effective cancelation of the undesired components from force data, allowing the system to extract in real-time voluntary user's navigation commands. Based on this real-time identification of voluntary user's commands, a classical approach to the control architecture of the robotic walker is being developed, in order to obtain stable and safe user assisted locomotion.

Effect of ECG filter settings on J-waves.

PubMed

Nakagawa, Mikiko; Tsunemitsu, Chie; Katoh, Sayo; Kamiyama, Yukari; Sano, Nario; Ezaki, Kaori; Miyazaki, Hiroko; Teshima, Yasushi; Yufu, Kunio; Takahashi, Naohiko; Saikawa, Tetsunori

2014-01-01

While J-waves were observed in healthy populations, variations in their reported incidence may be partly explicable by the ECG filter setting. We obtained resting 12-lead ECG recordings in 665 consecutive patients and enrolled 112 (56 men, 56 women, mean age 59.3±16.1years) who manifested J-waves on ECGs acquired with a 150-Hz low-pass filter. We then studied the J-waves on individual ECGs to look for morphological changes when 25-, 35-, 75-, 100-, and 150Hz filters were used. The notching observed with the 150-Hz filter changed to slurring (42%) or was eliminated (28%) with the 25-Hz filter. Similarly, the slurring seen with the 150-Hz filter was eliminated on 71% of ECGs recorded with the 25-Hz filter. The amplitude of J-waves was significantly lower with 25- and 35-Hz than 75-, 100-, and 150-Hz filters (p<0.0001). The ECG filter setting significantly affects the J-wave morphology. © 2013.

Redesign of the End Group in the 3.9 GHz LCLS-II Cavity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lunin, Andrei; Gonin, Ivan; Khabiboulline, Timergali

Development and production of Linac Coherent Light Source II (LCLS-II) is underway. The central part of LCLS-II is a continuous wave superconducting RF (CW SCRF) electron linac. The 3.9 GHz third harmonic cavity similar to the XFEL design will be used in LCLS-II for linearizing the longitudinal beam profile*. The initial design of the 3.9 GHz cavity developed for XFEL project has a large, 40 mm, beam pipe aperture for better higher-order mode (HOM) damping. It is resulted in dipole HOMs with frequencies nearby the operating mode, which causes difficulties with HOM coupler notch filter tuning. The CW linac operationmore » requires an extra caution in the design of the HOM coupler in order to prevent its possible overheating. In this paper we present the modified 3.9 GHz cavity End Group for meeting the LCLS-II requirements« less

Modifying high-order aeroelastic math model of a jet transport using maximum likelihood estimation

NASA Technical Reports Server (NTRS)

Anissipour, Amir A.; Benson, Russell A.

1989-01-01

The design of control laws to damp flexible structural modes requires accurate math models. Unlike the design of control laws for rigid body motion (e.g., where robust control is used to compensate for modeling inaccuracies), structural mode damping usually employs narrow band notch filters. In order to obtain the required accuracy in the math model, maximum likelihood estimation technique is employed to improve the accuracy of the math model using flight data. Presented here are all phases of this methodology: (1) pre-flight analysis (i.e., optimal input signal design for flight test, sensor location determination, model reduction technique, etc.), (2) data collection and preprocessing, and (3) post-flight analysis (i.e., estimation technique and model verification). In addition, a discussion is presented of the software tools used and the need for future study in this field.

Magnetoresistance effect in permalloy nanowires with various types of notches

NASA Astrophysics Data System (ADS)

Gao, Y.; You, B.; Wang, J.; Yuan, Y.; Wei, L. J.; Tu, H. Q.; Zhang, W.; Du, J.

2018-05-01

Suppressing the stochastic domain wall (DW) motion in magnetic nanowires is of great importance for designing DW-related spintronic devices. In this work, we have investigated the pinning/depinning processes of DWs in permalloy nanowires with three different types of notches by using longitudinal magnetoresistance (MR) measurement. The averaged MR curves demonstrate that the stochastic DW depinning is suppressed partly or even completely by a transversely asymmetric notch. The single-shot MR curves show that how the resistance changes with the applied field also depends strongly on the notch type while the DW is pinned around the notch. In the case of two depinning fields, larger (smaller) change of resistance always corresponds to larger (smaller) depinning field, regardless of the notch type. These phenomena can be understood by that the spin structure around the notch changes differently with the notch type when the DW is traveling through the notch.

Techniques for optically compressing light intensity ranges

DOEpatents

Rushford, Michael C.

1989-01-01

A pin hole camera assembly for use in viewing an object having a relatively large light intensity range, for example a crucible containing molten uranium in an atomic vapor laser isotope separator (AVLIS) system is disclosed herein. The assembly includes means for optically compressing the light intensity range appearing at its input sufficient to make it receivable and decipherable by a standard video camera. A number of different means for compressing the intensity range are disclosed. These include the use of photogray glass, the use of a pair of interference filters, and the utilization of a new liquid crystal notch filter in combination with an interference filter.

Techniques for optically compressing light intensity ranges

DOEpatents

Rushford, M.C.

1989-03-28

A pin hole camera assembly for use in viewing an object having a relatively large light intensity range, for example a crucible containing molten uranium in an atomic vapor laser isotope separator (AVLIS) system is disclosed herein. The assembly includes means for optically compressing the light intensity range appearing at its input sufficient to make it receivable and decipherable by a standard video camera. A number of different means for compressing the intensity range are disclosed. These include the use of photogray glass, the use of a pair of interference filters, and the utilization of a new liquid crystal notch filter in combination with an interference filter. 18 figs.

Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-ALL

PubMed Central

Palomero, Teresa; Ferrando, Adolfo

2008-01-01

The identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias and lymphomas (T-ALL) has brought much interest in inhibiting NOTCH1 signaling as therapeutic target in this disease. Small molecule inhibitors of the γ-secretase complex, which mediates a critical proteolytic cleavage required for NOTCH1 activation, hold the promise of becoming an effective molecular therapy against relapsed and refractory T-ALL. Recent progress in the elucidation of the transcriptional regulatory networks downstream of oncogenic NOTCH1 has uncovered a central role of NOTCH1 signaling in promoting leukemic cell growth and revealed an intricate circuitry that connects NOTCH1 signaling with MYC and the PI3K-AKT signaling pathway. The identification of the downstream effector pathways controlled by NOTCH1 should pave the way for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL. PMID:18765521

STS-99 Shuttle Radar Topography Mission Stability and Control

NASA Technical Reports Server (NTRS)

Hamelin, Jennifer L.; Jackson, Mark C.; Kirchwey, Christopher B.; Pileggi, Roberto A.

2001-01-01

The Shuttle Radar Topography Mission (SRTM) flew aboard Space Shuttle Endeavor February 2000 and used interferometry to map 80% of the Earth's landmass. SRTM employed a 200-foot deployable mast structure to extend a second antenna away from the main antenna located in the Shuttle payload bay. Mapping requirements demanded precision pointing and orbital trajectories from the Shuttle on-orbit Flight Control System (PCS). Mast structural dynamics interaction with the FCS impacted stability and performance of the autopilot for attitude maneuvers and pointing during mapping operations. A damper system added to ensure that mast tip motion remained with in the limits of the outboard antenna tracking system while mapping also helped to mitigate structural dynamic interaction with the FCS autopilot. Late changes made to the payload damper system, which actually failed on-orbit, required a redesign and verification of the FCS autopilot filtering schemes necessary to ensure rotational control stability. In-flight measurements using three sensors were used to validate models and gauge the accuracy and robustness of the pre-mission notch filter design.

Design and validation of a wearable "DRL-less" EEG using a novel fully-reconfigurable architecture.

PubMed

Mahajan, Ruhi; Morshed, Bashir I; Bidelman, Gavin M

2016-08-01

The conventional EEG system consists of a driven-right-leg (DRL) circuit, which prohibits modularization of the system. We propose a Lego-like connectable fully reconfigurable architecture of wearable EEG that can be easily customized and deployed at naturalistic settings for collecting neurological data. We have designed a novel Analog Front End (AFE) that eliminates the need for DRL while maintaining a comparable signal quality of EEG. We have prototyped this AFE for a single channel EEG, referred to as Smart Sensing Node (SSN), that senses brain signals and sends it to a Command Control Node (CCN) via an I2C bus. The AFE of each SSN (referential-montage) consists of an off-the-shelf instrumentation amplifier (gain=26), an active notch filter fc = 60Hz), 2nd-order active Butterworth low-pass filter followed by a passive low pass filter (fc = 47.5 Hz, gain = 1.61) and a passive high pass filter fc = 0.16 Hz, gain = 0.83). The filtered signals are digitized using a low-power microcontroller (MSP430F5528) with a 12-bit ADC at 512 sps, and transmitted to the CCN every 1 s at a bus rate of 100 kbps. The CCN can further transmit this data wirelessly using Bluetooth to the paired computer at a baud rate of 115.2 kbps. We have compared temporal and frequency-domain EEG signals of our system with a research-grade EEG. Results show that the proposed reconfigurable EEG captures comparable signals, and is thus promising for practical routine neurological monitoring in non-clinical settings where a flexible number of EEG channels are needed.

A critical role of Notch signaling in osteosarcoma invasion and metastasis

PubMed Central

Zhang, Pingyu; Yang, Yanwen; Zweidler-McKay, Patrick A.; Hughes, Dennis P.M.

2010-01-01

Purpose Notch signaling is an important mediator of growth and survival in several cancer types, with Notch pathway genes functioning as oncogenes or tumor suppressors in different cancers. However, the role of Notch in osteosarcoma is unknown. Experimental Design We assessed the expression of Notch pathway genes in human osteosarcoma cell lines and patient samples. We then employed pharmacologic and retroviral manipulation of the Notch pathway and studied the impact on osteosarcoma cell proliferation, survival, anchorage-independent growth, invasion and metastasis in vitro and in vivo. Results Notch pathway genes, including Notch ligand DLL1, Notch 1 and 2, and the Notch target gene HES1 were expressed in osteosarcoma cells, and expression of HES1 was associated with invasive and metastatic potential. Blockade of Notch pathway signaling with a small molecule inhibitor of gamma secretase eliminated invasion in matrigel without affecting cell proliferation, survival, or anchorage-independent growth. Manipulation of Notch and HES1 signaling demonstrated a crucial role for HES1 in osteosarcoma invasiveness and metastasis in vivo. Conclusion These studies identify a new invasion and metastasis-regulating pathway in osteosarcoma and define a novel function for the Notch pathway: regulation of metastasis. Since the Notch pathway can be inhibited pharmacologically, these findings point toward possible new treatments to reduce invasion and metastasis in osteosarcoma. PMID:18483362

A median-Gaussian filtering framework for Moiré pattern noise removal from X-ray microscopy image.

PubMed

Wei, Zhouping; Wang, Jian; Nichol, Helen; Wiebe, Sheldon; Chapman, Dean

2012-02-01

Moiré pattern noise in Scanning Transmission X-ray Microscopy (STXM) imaging introduces significant errors in qualitative and quantitative image analysis. Due to the complex origin of the noise, it is difficult to avoid Moiré pattern noise during the image data acquisition stage. In this paper, we introduce a post-processing method for filtering Moiré pattern noise from STXM images. This method includes a semi-automatic detection of the spectral peaks in the Fourier amplitude spectrum by using a local median filter, and elimination of the spectral noise peaks using a Gaussian notch filter. The proposed median-Gaussian filtering framework shows good results for STXM images with the size of power of two, if such parameters as threshold, sizes of the median and Gaussian filters, and size of the low frequency window, have been properly selected. Copyright © 2011 Elsevier Ltd. All rights reserved.

Interferometric interrogation of π-phase shifted fiber Bragg grating sensors

NASA Astrophysics Data System (ADS)

Srivastava, Deepa; Tiwari, Umesh; Das, Bhargab

2018-03-01

Interferometric interrogation technique realized for conventional fiber Bragg grating (FBG) sensors is historically known to offer the highest sensitivity measurements, however, it has not been yet explored for π-phase-shifted FBG (πFBG) sensors. This, we believe, is due to the complex nature of the reflection/transmission spectrum of a πFBG, which cannot be directly used for interferometric interrogation purpose. Therefore, we propose here an innovative as well as simple concept towards this direction, wherein, the transmission spectrum of a πFBG sensor is optically filtered using a specially designed fiber grating. The resulting filtered spectrum retains the entire characteristics of a πFBG sensor and hence the filtered spectrum can be interrogated with interferometric principles. Furthermore, due to the extremely narrow transmission notch of a πFBG sensor, a fiber interferometer can be realized with significantly longer path difference. This leads to substantially enhanced detection limit as compared to sensors based on a regular FBG of similar length. Theoretical analysis demonstrates that high resolution weak dynamic strain measurement down to 4 pε /√{ Hz } is easily achievable. Preliminary experimental results are also presented as proof-of-concept of the proposed interrogation principle.

Various design approaches to achieve electric field-driven segmented folding actuation of electroactive polymer (EAP) sheets

NASA Astrophysics Data System (ADS)

Ahmed, Saad; Hong, Jonathan; Zhang, Wei; Kopatz, Jessica; Ounaies, Zoubeida; Frecker, Mary

2018-03-01

Electroactive polymer (EAPs) based technologies have shown promise in areas such as artificial muscles, aerospace, medical and soft robotics. In this work, we demonstrate ways to harness on-demand segmented folding actuation from pure bending of relaxor-ferroelectric P(VDF-TrFE-CTFE) based films, using various design approaches, such as `stiffener' and `notch' based approaches. The in-plane actuation of the P(VDF-TrFE-CTFE) is converted into bending actuation using unimorph configurations, where one passive substrate layer is attached to the active polymer. First, we experimentally show that placement of thin metal strips as stiffener in between active EAPs and passive substrates leads to segmented actuation as opposed to pure bending actuation; stiffeners made of different materials, such as nickel, copper and aluminum, are studied which reveals that a higher Young's modulus favors more pronounced segmented actuation. Second, notched samples are prepared by mounting passive substrate patches of various materials on top of the passive layers of the unimorph EAP actuators. Effect of notch materials, size of the notches and position of the notches on the folding actuation are studied. The motion of the human finger inspires a finger-like biomimetic actuator, which is realized by assigning multiple notches on the structure; finite element analysis (FEA) is also performed using COMSOL Multiphysics software for the notched finger actuator. Finally, a versatile soft-gripper is developed using the notched approach to demonstrate the capability of a properly designed EAP actuator to hold objects of various sizes and shapes.

Model of rotary-actuated flexible beam with notch filter vibration suppression controller and torque feedforward load compensation controller

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bills, K.C.; Kress, R.L.; Kwon, D.S.

1994-12-31

This paper describes ORNL`s development of an environment for the simulation of robotic manipulators. Simulation includes the modeling of kinematics, dynamics, sensors, actuators, control systems, operators, and environments. Models will be used for manipulator design, proposal evaluation, control system design and analysis, graphical preview of proposed motions, safety system development, and training. Of particular interest is the development of models for robotic manipulators having at least one flexible link. As a first application, models have been developed for the Pacific Northwest Laboratory`s Flexible Beam Test Bed (PNL FBTB), which is a 1-Degree-of-Freedom, flexible arm with a hydraulic base actuator. ORNLmore » transferred control algorithms developed for the PNL FBTB to controlling IGRIP models. A robust notch filter is running in IGRIP controlling a full dynamics model of the PNL test bed. Model results provide a reasonable match to the experimental results (quantitative results are being determined) and can run on ORNL`s Onyx machine in approximately realtime. The flexible beam is modeled as six rigid sections with torsional springs between each segment. The spring constants were adjusted to match the physical response of the flexible beam model to the experimental results. The controller is able to improve performance on the model similar to the improvement seen on the experimental system. Some differences are apparent, most notably because the IGRIP model presently uses a different trajectory planner than the one used by ORNL on the PNL test bed. In the future, the trajectory planner will be modified so that the experiments and models are the same. The successful completion of this work provides the ability to link C code with IGRIP, thus allowing controllers to be developed, tested, and tuned in simulation and then ported directly to hardware systems using the C language.« less

Design and performance of the collective Thomson scattering receiver at ASDEX Upgrade.

PubMed

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

2012-01-01

Here we present the design of the fast-ion collective Thomson scattering receiver for millimeter wave radiation installed at ASDEX Upgrade, a tokamak for fusion plasma experiments. The receiver can detect spectral power densities of a few eV against the electron cyclotron emission background on the order of 100 eV under presence of gyrotron stray radiation that is several orders of magnitude stronger than the signal to be detected. The receiver down converts the frequencies of scattered radiation (100-110 GHz) to intermediate frequencies (IF) (4.5-14.5 GHz) by heterodyning. The IF signal is divided into 50 IF channels tightly spaced in frequency space. The channels are terminated by square-law detector diodes that convert the signal power into DC voltages. We present measurements of the transmission characteristics and performance of the main receiver components operating at mm-wave frequencies (notch, bandpass, and lowpass filters, a voltage-controlled variable attenuator, and an isolator), the down-converter unit, and the IF components (amplifiers, bandpass filters, and detector diodes). Furthermore, we determine the performance of the receiver as a unit through spectral response measurements and find reasonable agreement with the expectation based on the individual component measurements.

Design and Realization of a Planar Ultrawideband Antenna with Notch Band at 3.5 GHz

PubMed Central

2014-01-01

A small antenna with single notch band at 3.5 GHz is designed for ultrawideband (UWB) communication applications. The fabricated antenna comprises a radiating monopole element and a perfectly conducting ground plane with a wide slot. To achieve a notch band at 3.5 GHz, a parasitic element has been inserted in the same plane of the substrate along with the radiating patch. Experimental results shows that, by properly adjusting the position of the parasitic element, the designed antenna can achieve an ultrawide operating band of 3.04 to 11 GHz with a notched band operating at 3.31–3.84 GHz. Moreover, the proposed antenna achieved a good gain except at the notched band and exhibits symmetric radiation patterns throughout the operating band. The prototype of the proposed antenna possesses a very compact size and uses simple structures to attain the stop band characteristic with an aim to lessen the interference between UWB and worldwide interoperability for microwave access (WiMAX) band. PMID:25133245

Origin of anomalous inverse notch effect in bulk metallic glasses

NASA Astrophysics Data System (ADS)

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

2015-11-01

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

Three genes in the human MHC class III region near the junction with the class II: Gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sugaya, K.; Fukagawa, T.; Matsumoto, K.

Cosmid walking of about 250 kb from MHC class III gene CYP21 to class II was conducted. The gene for receptor of advanced glycosylation end products of proteins (RAGE, a member of immunoglobulin super-family molecules), the PBX2 homeobox gene designated HOX12, and the human counterpart of the mouse mammary tumor gene int-3 were found. The contiguous RAGE and HOX12 genes were completely sequenced, and the human int-3 counterpart was partially sequenced and assigned to a Notch homolog. This human Notch homolog, designated NOTCH3, showed both the intracellular portion present in the mouse int-3 sequence and the extracellular portion absent inmore » the int-3. It thus corresponds to the intact form of a Notch-type transmembrane protein. About 20 kb of dense Alu clustering was found just centromeric to the NOTCH3. 48 refs., 9 figs., 2 tabs.« less

Method of recording bioelectrical signals using a capacitive coupling

NASA Astrophysics Data System (ADS)

Simon, V. A.; Gerasimov, V. A.; Kostrin, D. K.; Selivanov, L. M.; Uhov, A. A.

2017-11-01

In this article a technique for the bioelectrical signals acquisition by means of the capacitive sensors is described. A feedback loop for the ultra-high impedance biasing of the input instrumentation amplifier, which provides receiving of the electrical cardiac signal (ECS) through a capacitive coupling, is proposed. The mains 50/60 Hz noise is suppressed by a narrow-band stop filter with an independent notch frequency and quality factor tuning. Filter output is attached to a ΣΔ analog-to-digital converter (ADC), which acquires the filtered signal with a 24-bit resolution. Signal processing board is connected through universal serial bus interface to a personal computer, where ECS in a digital form is recorded and processed.

A simple system for 160GHz optical terahertz wave generation and data modulation

NASA Astrophysics Data System (ADS)

Li, Yihan; He, Jingsuo; Sun, Xueming; Shi, Zexia; Wang, Ruike; Cui, Hailin; Su, Bo; Zhang, Cunlin

2018-01-01

A simple system based on two cascaded Mach-Zehnder modulators, which can generate 160GHz optical terahertz waves from 40GHz microwave sources, is simulated and tested in this paper. Fiber grating filter is used in the system to filter out optical carrier. By properly adjusting the modulator DC bias voltages and the signal voltages and phases, 4-tupling optical terahertz wave can be generated with fiber grating. This notch fiber grating filter is greatly suitable for terahertz over fiber (TOF) communication system. This scheme greatly reduces the cost of long-distance terahertz communication. Furthermore, 10Gbps digital signal is modulated in the 160GHz optical terahertz wave.

A simple nonlocal damage model for predicting failure of notched laminates

NASA Technical Reports Server (NTRS)

Kennedy, T. C.; Nahan, M. F.

1995-01-01

The ability to predict failure loads in notched composite laminates is a requirement in a variety of structural design circumstances. A complicating factor is the development of a zone of damaged material around the notch tip. The objective of this study was to develop a computational technique that simulates progressive damage growth around a notch in a manner that allows the prediction of failure over a wide range of notch sizes. This was accomplished through the use of a relatively simple, nonlocal damage model that incorporates strain-softening. This model was implemented in a two-dimensional finite element program. Calculations were performed for two different laminates with various notch sizes under tensile loading, and the calculations were found to correlate well with experimental results.

Notch2 and Notch3 suppress the proliferation and mediate invasion of trophoblast cell lines

PubMed Central

Zhao, Wei-Xiu; Wu, Zhen-Ming; Liu, Wei

2017-01-01

ABSTRACT Notch signaling pathways play important roles in cell fate and many diseases, including preeclampsia, the dysregulation of which may be the main cause of maternal mortality. This study aimed to investigate the roles of Notch2 and Notch3 in proliferation and invasion in trophoblast cell lines (BeWo and JAR). Small hairpin RNAs targeting Notch2/Notch3 and Notch2/Notch3-overexpression vectors were designed, constructed and transfected into BeWo and JAR cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were then used to detect Notch2 and Notch3 mRNA and protein levels, and confirm the efficiency of silence and overexpression. Flow cytometry assays were conducted to evaluate the cell cycle of the two cell lines, and transwell assays were used to detect migration and invasion. Western blot analysis was also performed to show the alteration of the cell lines' physiological activities at protein level. When Notch2 was downregulated in BeWo cells, proliferation was dramatically promoted, while migration and invasion were significantly inhibited. When Notch2 was upregulated in JAR cells, proliferation was inhibited, but migration and invasion were promoted. After overexpression of Notch3 in BeWo cells, proliferation was downregulated, but migration and invasion were both upregulated. By contrast, the silencing of Notch3 expression in JAR cells significantly enhanced proliferation, but suppressed migration and invasion. These data indicated that Notch2 and Notch3 mediate the invasion and migration of BeWo and JAR cells, and may play a potential role in early onset severe preeclampsia. PMID:28606936

Notch2 and Notch3 suppress the proliferation and mediate invasion of trophoblast cell lines.

PubMed

Zhao, Wei-Xiu; Wu, Zhen-Ming; Liu, Wei; Lin, Jian-Hua

2017-08-15

Notch signaling pathways play important roles in cell fate and many diseases, including preeclampsia, the dysregulation of which may be the main cause of maternal mortality. This study aimed to investigate the roles of Notch2 and Notch3 in proliferation and invasion in trophoblast cell lines (BeWo and JAR). Small hairpin RNAs targeting Notch2/Notch3 and Notch2/Notch3-overexpression vectors were designed, constructed and transfected into BeWo and JAR cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were then used to detect Notch2 and Notch3 mRNA and protein levels, and confirm the efficiency of silence and overexpression. Flow cytometry assays were conducted to evaluate the cell cycle of the two cell lines, and transwell assays were used to detect migration and invasion. Western blot analysis was also performed to show the alteration of the cell lines' physiological activities at protein level.When Notch2 was downregulated in BeWo cells, proliferation was dramatically promoted, while migration and invasion were significantly inhibited. When Notch2 was upregulated in JAR cells, proliferation was inhibited, but migration and invasion were promoted. After overexpression of Notch3 in BeWo cells, proliferation was downregulated, but migration and invasion were both upregulated. By contrast, the silencing of Notch3 expression in JAR cells significantly enhanced proliferation, but suppressed migration and invasion. These data indicated that Notch2 and Notch3 mediate the invasion and migration of BeWo and JAR cells, and may play a potential role in early onset severe preeclampsia. © 2017. Published by The Company of Biologists Ltd.

Pixel level optical-transfer-function design based on the surface-wave-interferometry aperture

PubMed Central

Zheng, Guoan; Wang, Yingmin; Yang, Changhuei

2010-01-01

The design of optical transfer function (OTF) is of significant importance for optical information processing in various imaging and vision systems. Typically, OTF design relies on sophisticated bulk optical arrangement in the light path of the optical systems. In this letter, we demonstrate a surface-wave-interferometry aperture (SWIA) that can be directly incorporated onto optical sensors to accomplish OTF design on the pixel level. The whole aperture design is based on the bull’s eye structure. It composes of a central hole (diameter of 300 nm) and periodic groove (period of 560 nm) on a 340 nm thick gold layer. We show, with both simulation and experiment, that different types of optical transfer functions (notch, highpass and lowpass filter) can be achieved by manipulating the interference between the direct transmission of the central hole and the surface wave (SW) component induced from the periodic groove. Pixel level OTF design provides a low-cost, ultra robust, highly compact method for numerous applications such as optofluidic microscopy, wavefront detection, darkfield imaging, and computational photography. PMID:20721038

The Significance of Notch1 Compared with Notch3 in High Metastasis and Poor Overall Survival in Hepatocellular Carcinoma

PubMed Central

Li, Qingjun; Sun, Wei; Zhang, Yong; Wang, Desheng; Dou, Kefeng

2013-01-01

Background The prognosis for patients with hepatocellular carcinoma (HCC) is poor, and the mechanisms underlying the development of HCC remain unclear. Notch1 and Notch3 may be involved in malignant transformation, although their roles remain unknown. Materials and Methods HCC tissues were stained with anti-Notch1 or -Notch3 antibody. The migration and invasion capacities of the cells were measured with transwell cell culture chambers. RT-PCR was used to measure the expression of Notch1 and Notch3 mRNA. Additionally, western blot analysis was used to assess the protein expression of Notch1, Notch3, CD44v6, E-cadherin, matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA). RNA interference was used to down-regulate the expression of Notch1 and Notch3. Cell viability was assessed using MTT. Results Based on immunohistochemistry, high Notch1 expression was correlated with tumor size, tumor grade, metastasis, venous invasion and AJCC TNM stage. High Notch3 expression was only strongly correlated with metastasis, venous invasion and satellite lesions. Kaplan-Meier curves demonstrated that patients with high Notch1 or Notch3 expression were at a significantly increased risk for shortened survival time. In vitro, the down-regulation of Notch1 decreased the migration and invasion capacities of HCC cells by regulating CD44v6, E-cadherin, MMP-2, MMP-9, and uPA via the COX-2 and ERK1/2 pathways. Down-regulation of Notch3 only decreased the invasion capacity of HCC cells by regulating MMP-2 and MMP-9 via the ERK1/2 pathway. Conclusions Based on the migration and invasion of HCC, we hypothesize that targeting Notch1 may be more useful than Notch3 for designing novel preventive and therapeutic strategies for HCC in the near future. PMID:23468978

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 and data reach.

Wave detection in acceleration plethysmogram.

PubMed

Ahn, Jae Mok

2015-04-01

Acceleration plethysmogram (APG) obtained from the second derivative of photoplethysmography (PPG) is used to predict risk factors for atherosclerosis with age. This technique is promising for early screening of atherosclerotic pathologies. However, extraction of the wave indices of APG signals measured from the fingertip is challenging. In this paper, the development of a wave detection algorithm including a preamplifier based on a microcontroller that can detect the a, b, c, and d wave indices is proposed. The 4(th) order derivative of a PPG under real measurements of an APG waveform was introduced to clearly separate the components of the waveform, and to improve the rate of successful wave detection. A preamplifier with a Sallen-Key low pass filter and a wave detection algorithm with programmable gain control, mathematical differentials, and a digital IIR notch filter were designed. The frequency response of the digital IIR filter was evaluated, and a pulse train consisting of a specific area in which the wave indices existed was generated. The programmable gain control maintained a constant APG amplitude at the output for varying PPG amplitudes. For 164 subjects, the mean values and standard deviation of the a wave index corresponding to the magnitude of the APG signal were 1,106.45 and ±47.75, respectively. We conclude that the proposed algorithm and preamplifier designed to extract the wave indices of an APG in real-time are useful for evaluating vascular aging in the cardiovascular system in a simple healthcare device.

The Prevalence of Notched Audiograms in a Cross-Sectional Study of 12,055 Railway Workers

PubMed Central

Skogstad, Marit; Johnsen, Torstein Seip; Engdahl, Bo; Tambs, Kristian

2015-01-01

Objective: Noise-induced hearing loss (NIHL) is one of the most reported occupational diseases internationally. The occurrence of audiometric notches is emphasized in both American and European guidelines for the diagnosis of NIHL. The aim of this study was to describe the prevalence of notched audiograms among railway personnel with and without noise exposure to better assess the usefulness of such notches in the diagnosis of NIHL. Design: The most recent audiogram from 1994 to 2011 of a total of 12,055 railway workers, age 20 to 65 years, was obtained from the medical records of the occupational health service of the Norwegian State Railways (NSB). The prevalences of three types of notched audiograms, Coles notch, notch index, and 4 kHz notch, were computed, in relation to age, sex, and occupational noise exposure. Results: Coles notch in either ear was found in 63% of the male railway maintenance workers, exposed to noise levels of 75 to 90 dB(A), compared with 53% of the non-noise exposed (<70 dB(A)) traffic controllers (p < 0.001). The corresponding figures for the 4 kHz notch were 31% versus 21% (p < 0.001). For the notch index, 61% of the exposed and 51% of the controls had a notched audiogram (p < 0.001). For female workers, the prevalence of audiometric notches was lower, and the differences between noise exposed and nonexposed was smaller than those in men. Increasing age led to an increased prevalence of notches. Conclusions: Audiometric notches commonly occur among both noise-exposed and those not exposed to noise in railway personnel. The usefulness of audiometric notches in the diagnosis of NIHL is therefore limited. PMID:25470371

Comparison of across-frequency integration strategies in a binaural detection model.

PubMed

Breebaart, Jeroen

2013-11-01

Breebaart et al. [J. Acoust. Soc. Am. 110, 1089-1104 (2001)] reported that the masker bandwidth dependence of detection thresholds for an out-of-phase signal and an in-phase noise masker (N0Sπ) can be explained by principles of integration of information across critical bands. In this paper, different methods for such across-frequency integration process are evaluated as a function of the bandwidth and notch width of the masker. The results indicate that an "optimal detector" model assuming independent internal noise in each critical band provides a better fit to experimental data than a best filter or a simple across-frequency integrator model. Furthermore, the exponent used to model peripheral compression influences the accuracy of predictions in notched conditions.

Ultra-wide-range measurements of thin-film filter optical density over the visible and near-infrared spectrum.

PubMed

Lequime, Michel; Liukaityte, Simona; Zerrad, Myriam; Amra, Claude

2015-10-05

We present the improved structure and operating principle of a spectrophotometric mean that allows us for the recording of the transmittance of a thin-film filter over an ultra-wide range of optical densities (from 0 to 11) between 400 and 1000 nm. The operation of this apparatus is based on the combined use of a high power supercontinuum laser source, a tunable volume hologram filter, a standard monochromator and a scientific grade CCD camera. The experimentally recorded noise floor is in good accordance with the optical density values given by the theoretical approach. A demonstration of the sensitivity gain provided by this new set-up with respect to standard spectrophotometric means is performed via the characterization of various types of filters (band-pass, long-pass, short-pass, and notch).

Wide-range tuning of polymer microring resonators by the photobleaching of CLD-1 chromophores

NASA Astrophysics Data System (ADS)

Poon, Joyce K. S.; Huang, Yanyi; Paloczi, George T.; Yariv, Amnon; Zhang, Cheng; Dalton, Larry R.

2004-11-01

We present a simple and effective method for the postfabrication trimming of optical microresonators. We photobleach CLD-1 chromophores to tune the resonance wavelengths of polymer microring resonator optical notch filters. A maximum wavelength shift of -8.73 nm is observed. The resonators are fabricated with a soft-lithography molding technique and have an intrinsic Q value of 2.6×10^4 and a finesse of 9.3. The maximum extinction ratio of the resonator filters is -34 dB, indicating that the critical coupling condition has been satisfied.

Design of UWB Monopole Antenna with Dual Notched Bands Using One Modified Electromagnetic-Bandgap Structure

PubMed Central

Xu, Ziqiang

2013-01-01

A modified electromagnetic-bandgap (M-EBG) structure and its application to planar monopole ultra-wideband (UWB) antenna are presented. The proposed M-EBG which comprises two strip patch and an edge-located via can perform dual notched bands. By properly designing and placing strip patch near the feedline, the proposed M-EBG not only possesses a simple structure and compact size but also exhibits good band rejection. Moreover, it is easy to tune the dual notched bands by altering the dimensions of the M-EBG. A demonstration antenna with dual band-notched characteristics is designed and fabricated to validate the proposed method. The results show that the proposed antenna can satisfy the requirements of VSWR < 2 over UWB 3.1–10.6 GHz, except for the rejected bands of the world interoperability for microwave access (WiMAX) and the wireless local area network (WLAN) at 3.5 GHz and 5.5 GHz, respectively. PMID:24170984

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.

Bmp2 and Notch cooperate to pattern the embryonic endocardium.

PubMed

Papoutsi, T; Luna-Zurita, L; Prados, B; Zaffran, S; de la Pompa, J L

2018-05-31

Signaling interactions between myocardium and endocardium pattern embryonic cardiac regions, instructing their development to fulfill specific functions in the mature heart. We show that ectopic Bmp2 expression in the mouse chamber myocardium changes the transcriptional signature of adjacent chamber endocardial cells into valve tissue, and enables them to undergo epithelial-mesenchyme transition. This induction is independent of valve myocardium specification and requires high levels of Notch1 activity. Biochemical experiments suggest that Bmp2-mediated Notch1 induction is achieved through transcriptional activation of the Notch ligand Jag1, and physical interaction of Smad1/5 with the intracellular domain of the Notch1 receptor. Thus, widespread myocardial Bmp2 and endocardial Notch signaling drive presumptive ventricular endocardium to differentiate into valve endocardium. Understanding the molecular basis of valve development is instrumental to designing therapeutic strategies for congenital heart valve defects. © 2018. Published by The Company of Biologists Ltd.

46 CFR 154.610 - Design temperature not colder than 0 °C (32 °F).

Code of Federal Regulations, 2011 CFR

2011-10-01

... Charpy V-notch impact energy must be determined for: (1) Each plate as rolled; and (2) Each five short... orientation and required impact energy of a 10 mm × 10 mm (0.394 in. × 0.394 in.) Charpy V-notch specimen must... temperature of the Charpy V-notch specimens is as follows: Material Thickness Test Temperature t≤20 mm (0.788...

Adaptive linear predictor FIR filter based on the Cyclone V FPGA with HPS to reduce narrow band RFI in AERA radio detection of cosmic rays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szadkowski, Zbigniew

We present the new approach to a filtering of radio frequency interferences (RFI) in the Auger Engineering Radio Array (AERA) which study the electromagnetic part of the Extensive Air Showers. The radio stations can observe radio signals caused by coherent emissions due to geomagnetic radiation and charge excess processes. AERA observes frequency band from 30 to 80 MHz. This range is highly contaminated by human-made RFI. In order to improve the signal to noise ratio RFI filters are used in AERA to suppress this contamination. The first kind of filter used by AERA was the Median one, based on themore » Fast Fourier Transform (FFT) technique. The second one, which is currently in use, is the infinite impulse response (IIR) notch filter. The proposed new filter is a finite impulse response (FIR) filter based on a linear prediction (LP). A periodic contamination hidden in a registered signal (digitized in the ADC) can be extracted and next subtracted to make signal cleaner. The FIR filter requires a calculation of n=32, 64 or even 128 coefficients (dependent on a required speed or accuracy) by solving of n linear equations with coefficients built from the covariance Toeplitz matrix. This matrix can be solved by the Levinson recursion, which is much faster than the Gauss procedure. The filter has been already tested in the real AERA radio stations on Argentinean pampas with a very successful results. The linear equations were solved either in the virtual soft-core NIOSR processor (implemented in the FPGA chip as a net of logic elements) or in the external Voipac PXA270M ARM processor. The NIOS processor is relatively slow (50 MHz internal clock), calculations performed in an external processor consume a significant amount of time for data exchange between the FPGA and the processor. Test showed a very good efficiency of the RFI suppression for stationary (long-term) contaminations. However, we observed a short-time contaminations, which could not be suppressed either by the IIR-notch filter or by the FIR filter based on the linear predictions. For the LP FIR filter the refreshment time of the filter coefficients was to long and filter did not keep up with the changes of a contamination structure, mainly due to a long calculation time in a slow processors. We propose to use the Cyclone V SE chip with embedded micro-controller operating with 925 MHz internal clock to significantly reduce a refreshment time of the FIR coefficients. The lab results are promising. (authors)« less

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.

46 CFR 38.05-1 - Design and construction of vessels-general-TB/ALL.

Code of Federal Regulations, 2011 CFR

2011-10-01

... of cargo tanks and piping shall have adequate notch toughness at the service temperature. Where a... sufficient notch toughness at the lowest temperature which may result during the containment of leakage cargo...

Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma

PubMed Central

Hassan, Khaled A.; Wang, Luo; Korkaya, Hasan; Chen, Guoan; Maillard, Ivan; Beer, David G.; Kalemkerian, Gregory P.; Wicha, Max S.

2013-01-01

Purpose The cancer stem cell theory postulates that tumors contain a subset of cells with stem cell properties of self-renewal, differentiation and tumor-initiation. The purpose of this study is to determine the role of Notch activity in identifying lung cancer stem cells. Experimental Design We investigated the role of Notch activity in lung adenocarcinoma utilizing a Notch GFP-reporter construct and a gamma-secretase inhibitor (GSI), which inhibits Notch pathway activity. Results Transduction of lung cancer cells with Notch GFP-reporter construct identified a subset of cells with high Notch activity (GFP-bright). GFP-bright cells had the ability to form more tumor spheres in serum-free media, and were able to generate both GFP-bright and GFP-dim (lower Notch activity) cell populations. GFP-bright cells were resistant to chemotherapy and were tumorigenic in serial xenotransplantation assays. Tumor xenografts of mice treated with GSI had decreased expression of downstream effectors of Notch pathway and failed to regenerate tumors upon reimplantation in NOD/SCID mice. Using multivariate analysis, we detected a statistically significant correlation between poor clinical outcome and Notch activity (reflected in increased Notch ligand expression or decreased expression of the negative modulators), in a group of 441 lung adenocarcinoma patients. This correlation was further confirmed in an independent group of 89 adenocarcinoma patients where Hes-1 overexpression correlated with poor overall survival. Conclusions Notch activity can identify lung cancer stem cell-like population and its inhibition may be an appropriate target for treating lung adenocarcinoma. PMID:23444212

NOTCH3 Is a Prognostic Factor That Promotes Glioma Cell Proliferation, Migration and Invasion via Activation of CCND1 and EGFR

PubMed Central

Alqudah, Mohammad A. Y.; Agarwal, Supreet; Al-Keilani, Maha S.; Sibenaller, Zita A.; Ryken, Timothy C.; Assem, Mahfoud

2013-01-01

Using a GWA analysis of a comprehensive glioma specimen population, we identified whole gain of chromosome 19 as one of the major chromosomal aberrations that correlates to patients’ outcomes. Our analysis of significant loci revealed for the first time NOTCH3 as one of the most significant amplification. NOTCH3 amplification is associated with worse outcome compared to tumors with non-amplified locus. NOTCH receptors (NOTCH1-4) are key positive regulators of cell-cell interactions, angiogenesis, cell adhesion and stem cell niche development which have been shown to play critical roles in several human cancers. Our objective is to determine the molecular roles of NOTCH3 in glioma pathogenesis and aggressiveness. Here we show for the first time that NOTCH3 plays a major role in glioma cell proliferation, cell migration, invasion and apoptosis. Therefore, our study uncovers the prognostic value and the oncogenic function of NOTCH3 in gliomagenesis and supports NOTCH3 as a promising target of therapy in high grade glioma. Our studies allowed the identification of a subset of population that may benefit from GSI- or anti-NOTCH3- based therapies. This may lead to the design of novel strategies to improve therapeutic outcome of patients with glioma by establishing medical and scientific basis for personalized chemotherapies. PMID:24143218

Expression of Jagged1/Notch3 Signaling Pathway and their Relationship with the Tumor Angiogenesis in TNBC.

PubMed

Xue, Siliang; He, Lang; Zhang, Xiao; Zhou, Jin; Li, Fanghua; Wang, Xiaoshan

2017-02-01

Jagged1/Notch3 signaling pathway plays a key role in angiogenesis of breast cancer, but little is known in TNBC. This study was designed to investigate the expression of Jagged1/Notch3 mRNA and protein in TNBC, analyze their correlations with clinicopathological characteristics and prognosis. Moreover, the interrelationship among Jagged1/Notch3 and VEGF was initially evaluated. Jagged1/Notch3 mRNA and protein expression levels were determined by Q-RT-PCR and Western blotting. Additionally, Immunohistochemistry for Jagged1/Notch3 was detected by Ventana platform, VEGF and CD34 was performed using the EnVision/HRP technique. mRNA transcriptionof Jagged1/Notch3 was in accord with protein expression. TNBC patients with positive Jagged1 expression had poorer DFS (p = 0.008) and OS (p = 0.004). Jagged1 expression was independent predictors of OS (p = 0.038). The expression of VEGF was positively correlative to MVD (p = 0.018), MVD was significantly associated with Jagged1 (p <0.0001) and Notch3 (p <0.0001). The expression of Jagged1/Notch3 has no correlation with VEGF, only in positive VEGF expression of TNBC patients Jagged1/Notch3 had influence on DFS and OS (p <0.05). Jagged1/Notch3 was -expressed at both the mRNA and protein levels, Jagged1 served as an independent predictor of poor prognosis. We speculate that there is a cross-talk between Jagged1/Notch3 and VEGF in TNBC angiogenesis. Jagged1/Notch3 is expected to be an important signaling pathway for TNBC progression and a potential target for TNBC neovascularization therapy. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

Biomechanical evaluation of different designs of glenospheres in the SMR reverse total shoulder prosthesis: range of motion and risk of scapular notching.

PubMed

Chou, Justin; Malak, Sharif F; Anderson, Iain A; Astley, Tim; Poon, Peter C

2009-01-01

Reverse total shoulder arthroplasty is a treatment option for cuff tear arthropathy. Scapular notching remains a concern. This biomechanical study compared the range-of-motion in different designs of glenospheres and hence the relative risk of scapular notching. A precision coordinate device was used to investigate four different designs of glenospheres (SMR prosthesis); 36 mm concentric (Standard), 36 mm eccentric, 44 mm concentric, and 44 mm eccentric glenospheres. The centre of rotation in each design was first established. The position of the humeral prosthesis was recorded in the plane of the scapula to compare the degree of adduction and the total range-of-motion. Eccentric glenospheres were found to improve range-of-motion by allowing a higher degree of adduction. Larger diameter glenospheres were found to improve range-of-motion by increasing adduction and abduction. Compared to the 36 mm concentric (standard) glenosphere, the 36 mm eccentric glenosphere improved adduction by 14.5 degrees, the 44 mm concentric glenosphere improved adduction by 11.6 degrees, the 44 mm eccentric glenosphere improved adduction by 17.7 degrees. Eccentric glenospheres with a center-of-rotation placed more inferiorly were shown to improve adduction. This design may reduce the clinical incidence of scapular notching.

The acoustical cues to sound location in the Guinea pig (cavia porcellus)

PubMed Central

Greene, Nathanial T; Anbuhl, Kelsey L; Williams, Whitney; Tollin, Daniel J.

2014-01-01

There are three main acoustical cues to sound location, each attributable to space-and frequency-dependent filtering of the propagating sound waves by the outer ears, head, and torso: Interaural differences in time (ITD) and level (ILD) as well as monaural spectral shape cues. While the guinea pig has been a common model for studying the anatomy, physiology, and behavior of binaural and spatial hearing, extensive measurements of their available acoustical cues are lacking. Here, these cues were determined from directional transfer functions (DTFs), the directional components of the head-related transfer functions, for eleven adult guinea pigs. In the frontal hemisphere, monaural spectral notches were present for frequencies from ~10 to 20 kHz; in general, the notch frequency increased with increasing sound source elevation and in azimuth toward the contralateral ear. The maximum ITDs calculated from low-pass filtered (2 kHz cutoff frequency) DTFs were ~250 µs, whereas the maximum ITD measured with low frequency tone pips was over 320 µs. A spherical head model underestimates ITD magnitude under normal conditions, but closely approximates values when the pinnae were removed. Interaural level differences (ILDs) strongly depended on location and frequency; maximum ILDs were < 10 dB for frequencies < 4 kHz and were as large as 40 dB for frequencies > 10 kHz. Removal of the pinna reduced the depth and sharpness of spectral notches, altered the acoustical axis, and reduced the acoustical gain, ITDs, and ILDs; however, spectral shape features and acoustical gain were not completely eliminated, suggesting a substantial contribution of the head and torso in altering the sounds present at the tympanic membrane. PMID:25051197

Advanced Simultion of Digital Filters.

DTIC Science & Technology

1980-09-01

pass filter. Fig ures 7-3a through 7-3T show a band-reject or notch fi I ter. The secondary ptrnose of the chanter is to show the user the general...directly and oerforming the convolution in the frequency domain by multiplying the DFT’s. The relation between the circular and linear convolution could...aa0Y O. .0..40Z). rNa 0 0 * *.-- IX zI. Wj-40 * (JNWU xo0-4 1 .0 -1 ctU.v WIW(’.+ i44 4#W(. W I-. M -P Z0~~..UI~ Z *3rc.0joj-oy *I X *IJ0- *I>W>Z~ -4

A high temperature superconductor notch filter for the Sardinia Radio Telescope

NASA Astrophysics Data System (ADS)

Bolli, Pietro; Cresci, Luca; Huang, Frederick; Mariotti, Sergio; Panella, Dario

2018-04-01

A High Temperature Superconductor filter operating in the C-band between 4200 and 5600 MHz has been developed for one of the radio astronomical receivers of the Sardinia Radio Telescope. The motivation was to attenuate an interference from a weather radar at 5640 MHz, whose power level exceeds the linear region of the first active stages of the receiver. A very sharp transition after the nominal maximum passband frequency is reached by combining a 6th order band-pass filter with a 6th order stop-band. This solution is competitive with an alternative layout based on a cascaded triplet filter. Three units of the filter have been measured with two different calibration approaches to investigate pros and cons of each, and data repeatability. The final performance figures of the filters are: ohmic losses of the order of 0.15-0.25 dB, matching better than -15 dB, and -30 dB attenuation at 5640 MHz. Finally, a more accurate model of the connection between external connector and microstrip shows a better agreement between simulations and experimental data.

Progress Report on Alloy 617 Notched Specimen Testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 axialmore » 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.« less

Evaluation of a new baseplate in reverse total shoulder arthroplasty - comparison of biomechanical testing of stability with roentgenological follow up criteria.

PubMed

Irlenbusch, U; Kohut, G

2015-04-01

To minimize notching problem associated with reversed prostheses, inferior positioning of base plate is recommended. This reduces the risk of notching, but does not eliminate it completely. Both polyethylene/PE-induced osteolysis and implant-to-bone or implant-to-implant contact may still occur, contributing to the risk of screw-breakage and resulting long-term failure. Therefore, the stability and integration of a newly developed base plate without inferior screw and inversion of bearing materials was investigated. Biomechanical assessment of primary stability of the two types of glenoid baseplate (1- and 2-pegged) was carried out according to ASTM F-2028-02 (American Society for Testing and Materials). Patients with a follow-up period of at least 2 years were clinically (n=78) and for most of them radiologically (n=61) examined. The X-rays were evaluated for loosening and scapular notching. The mean values of micromotions after 100,000 cycles showed no relevant differences between the 2-peg and the 1-peg base plates (47 μm for the 2-peg design and 43 μm for the 1-peg design), i.e. both were below the borderline for secure Osseointegration of 150 μm. Radiologically, no signs of loosening or radiolucent lines/RLL were found for both base plates. The mean incidence of inferior scapular notching was 23.6% (42 mm glenoid sphere: 15.8%). Only grade 1 and grade 2 notching was observed. Additionally as result of absence of PE-induced osteolysis shape, size, borderline and location of notching differed from those observed with conventional reverse total shoulder arthroplasty bearing materials. In combination with modified inferior operating technique, the newly designed implant has the potential to reduce the incidence of scapular notching and to avoid both PE-induced osteolysis and metal-screw contact. The new design did not compromise stability of the base plate in any way during the investigation period, as demonstrated both by the data from the biomechanical investigation and also by the radiological follow-up. Level III, case-control study. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Tension fracture of laminates for transport fuselage. Part 1: Material screening

NASA Technical Reports Server (NTRS)

Walker, T. H.; Avery, W. B.; Ilcewicz, L. B.; Poe, C. C., Jr.; Harris, C. E.

1992-01-01

Transport fuselage structures are designed to contain pressure following a large penetrating damage event. Applications of composites to fuselage structures require a database and supporting analysis on tension damage tolerance. Tests with 430 fracture specimens were used to accomplish the following: (1) identify critical material and laminate variables affecting notch sensitivity; (2) evaluate composite failure criteria; and (3) recommend a screening test method. Variables studied included fiber type, matrix toughness, lamination manufacturing process, and intraply hybridization. The laminates found to have the lowest notch sensitivity were manufactured using automated tow placement. This suggests a possible relationship between the stress distribution and repeatable levels of material inhomogeneity that are larger than found in traditional tape laminates. Laminates with the highest notch sensitivity consisted of toughened matrix materials that were resistant to a splitting phenomena that reduces stress concentrations in major load bearing plies. Parameters for conventional fracture criteria were found to increase with crack length for the smallest notch sizes studied. Most material and laminate combinations followed less than a square root singularity for the largest crack sizes studied. Specimen geometry, notch type, and notch size were evaluated in developing a screening test procedure. Traitional methods of correcting for specimen finite width were found to be lacking. Results indicate that a range of notch sizes must be tested to determine notch sensitivity. Data for a single small notch size (0.25 in. diameter) was found to give no indication of the sensitivity of a particular material and laminate layup to larger notch sizes.

Extreme temperature robust optical sensor designs and fault-tolerant signal processing

DOEpatents

Riza, Nabeel Agha [Oviedo, FL; Perez, Frank [Tujunga, CA

2012-01-17

Silicon Carbide (SiC) probe designs for extreme temperature and pressure sensing uses a single crystal SiC optical chip encased in a sintered SiC material probe. The SiC chip may be protected for high temperature only use or exposed for both temperature and pressure sensing. Hybrid signal processing techniques allow fault-tolerant extreme temperature sensing. Wavelength peak-to-peak (or null-to-null) collective spectrum spread measurement to detect wavelength peak/null shift measurement forms a coarse-fine temperature measurement using broadband spectrum monitoring. The SiC probe frontend acts as a stable emissivity Black-body radiator and monitoring the shift in radiation spectrum enables a pyrometer. This application combines all-SiC pyrometry with thick SiC etalon laser interferometry within a free-spectral range to form a coarse-fine temperature measurement sensor. RF notch filtering techniques improve the sensitivity of the temperature measurement where fine spectral shift or spectrum measurements are needed to deduce temperature.

A compact new incoherent Thomson scattering diagnostic for low-temperature plasma studies

NASA Astrophysics Data System (ADS)

Vincent, Benjamin; Tsikata, Sedina; Mazouffre, Stéphane; Minea, Tiberiu; Fils, Jérôme

2018-05-01

Incoherent Thomson scattering (ITS) has a long history of application for the determination of electron density and temperature in dense fusion plasmas, and in recent years, has been increasingly extended to studies in low-temperature plasma environments. In this work, the design and preliminary implementation of a new, sensitive and uniquely compact ITS platform known as Thomson scattering experiments for low temperature ion sources are described. Measurements have been performed on a hollow cathode plasma source, providing access to electron densities as low as 1016 m‑3 and electron temperatures of a few eV and below. This achievement has been made possible by the implementation of a narrow volume Bragg grating notch filter for the attenuation of stray light, a feature which guarantees compactness and reduced transmission losses in comparison to standard ITS platforms.

Mitigation of stimulated Raman scattering in high power fiber lasers using transmission gratings

NASA Astrophysics Data System (ADS)

Heck, Maximilian; Bock, Victor; Krämer, Ria G.; Richter, Daniel; Goebel, Thorsten A.; Matzdorf, Christian; Liem, Andreas; Schreiber, Thomas; Tünnermann, Andreas; Nolte, Stefan

2018-02-01

The average output power of fiber lasers have been scaled deep into the kW regime within the recent years. However a further scaling is limited due to nonlinear effects like stimulated Raman scattering (SRS). Using the special characteristics of femtosecond laser pulse written transmission fiber gratings, it is possible to realize a notch filter that mitigates efficiently this negative effect by coupling the Raman wavelength from the core into the cladding of the fiber. To the best of our knowledge, we realized for the first time highly efficient gratings in large mode area (LMA) fibers with cladding diameters up to 400 μm. The resonances show strong attenuation at design wavelength and simultaneously low out of band losses. A high power fiber amplifier with an implemented passive fiber grating is shown and its performance is carefully investigated.

A Fixed-Lag Kalman Smoother to Filter Power Line Interference in Electrocardiogram Recordings.

PubMed

Warmerdam, G J J; Vullings, R; Schmitt, L; Van Laar, J O E H; Bergmans, J W M

2017-08-01

Filtering power line interference (PLI) from electrocardiogram (ECG) recordings can lead to significant distortions of the ECG and mask clinically relevant features in ECG waveform morphology. The objective of this study is to filter PLI from ECG recordings with minimal distortion of the ECG waveform. In this paper, we propose a fixed-lag Kalman smoother with adaptive noise estimation. The performance of this Kalman smoother in filtering PLI is compared to that of a fixed-bandwidth notch filter and several adaptive PLI filters that have been proposed in the literature. To evaluate the performance, we corrupted clean neonatal ECG recordings with various simulated PLI. Furthermore, examples are shown of filtering real PLI from an adult and a fetal ECG recording. The fixed-lag Kalman smoother outperforms other PLI filters in terms of step response settling time (improvements that range from 0.1 to 1 s) and signal-to-noise ratio (improvements that range from 17 to 23 dB). Our fixed-lag Kalman smoother can be used for semi real-time applications with a limited delay of 0.4 s. The fixed-lag Kalman smoother presented in this study outperforms other methods for filtering PLI and leads to minimal distortion of the ECG waveform.

Tension fracture of laminates for transport fuselage. Part 1: Material screening

NASA Technical Reports Server (NTRS)

Walker, T. H.; Avery, W. B.; Ilcewicz, L. B.; Poe, C. C., Jr.; Harris, C. E.

1992-01-01

Transport fuselage structures are designed to contain pressure following a large penetrating damage event. Application of composites to fuselage structures requires a data base and supporting analysis on tension damage tolerance. Tests with 430 fracture specimens were used to accomplish the following: (1) identify critical material and laminate variables affecting notch sensitivity, (2) evaluate composite failure criteria, and (3) recommend a screening test method. Variables studied included fiber type, matrix toughness, lamination manufacturing process, and intraply hybridization. The laminates found to have the lowest notch sensitivity were manufactured using automated tow placement. This suggests a possible relationship between the stress distribution and repeatable levels of material inhomogeneity that are larger than found in traditional tape laminates. Laminates with the highest notch sensitivity consisted of toughened matrix materials that were resistant to a splitting phenomena that reduces stress concentrations in load bearing plies. Parameters for conventional fracture criteria were found to increase with the crack length of the smallest notch sizes studied. Most materials and laminate combinations followed less than a square root singularity for the largest crack sizes studied. Specimen geometry, notch type, and notch size were evaluated in developing a screening test procedure. Results indicate that a range of notch sizes must be tested to determine notch sensitivity.

Effects of spectral smearing on performance of the spectral ripple and spectro-temporal ripple tests.

PubMed

Narne, Vijaya Kumar; Sharma, Mridula; Van Dun, Bram; Bansal, Shalini; Prabhu, Latika; Moore, Brian C J

2016-12-01

The main aim of this study was to use spectral smearing to evaluate the efficacy of a spectral ripple test (SRt) using stationary sounds and a recent variant with gliding ripples called the spectro-temporal ripple test (STRt) in measuring reduced spectral resolution. In experiment 1 the highest detectable ripple density was measured using four amounts of spectral smearing (unsmeared, mild, moderate, and severe). The thresholds worsened with increasing smearing and were similar for the SRt and the STRt across the three conditions with smearing. For unsmeared stimuli, thresholds were significantly higher (better) for the STRt than for the SRt. An amplitude fluctuation at the outputs of simulated (gammatone) auditory filters centered above 6400 Hz was identified as providing a potential detection cue for the STRt stimuli. Experiment 2 used notched noise with energy below and above the passband of the SRt and STRt stimuli to reduce confounding cues in the STRt. Thresholds were almost identical for the STRt and SRt for both unsmeared and smeared stimuli, indicating that the confounding cue for the STRt was eliminated by the notched noise. Thresholds obtained with notched noise present could be predicted reasonably accurately using an excitation-pattern model.

Adaptive Same Frequency Repeater (SFR) Study

DTIC Science & Technology

1976-03-01

Formulation 13 (2) Evaluation of the Steady State Weights!.’.’.’!.*!!."!! 21 (3) Evaluation of the Composite Transfer Function.... 2^ (4) Simplified...well as possible the amplitude and phase of the composite coupling path. Because the coupling paths have frequency-dependent transfer functions...34), (35) and the notch filter and channel transfer .’unctions (3fi) and (39). The composite transfer function Hc(f ’ ^’.f) is then found and

Bat noseleaf model: echolocation function, design considerations, and experimental verification.

PubMed

Kuc, Roman

2011-05-01

This paper describes a possible bat noseleaf echolocation function that improves target elevation resolution. Bats with a protruding noseleaf can rotate the lancet to act as an acoustic mirror that reflects the nostril emission, modeled as a virtual nostril that produces a delayed emission. The cancellation of the nostril and virtual nostril components at a target produces a sharp spectral notch whose frequency location relates to target elevation. This notch can be observed directly from the swept-frequency emission waveform, suggesting cochlear processing capabilities. Physical acoustic principles indicate the design considerations and trade-offs that a bat can accomplish through noseleaf shape and emission characteristics. An experimental model verifies the analysis and exhibits an elevation versus notch frequency sensitivity of approximately 1°/kHz.

Tunable negative-tap photonic microwave filter based on a cladding-mode coupler and an optically injected laser of large detuning.

PubMed

Chan, Sze-Chun; Liu, Qing; Wang, Zhu; Chiang, Kin Seng

2011-06-20

A tunable negative-tap photonic microwave filter using a cladding-mode coupler together with optical injection locking of large wavelength detuning is demonstrated. Continuous and precise tunability of the filter is realized by physically sliding a pair of bare fibers inside the cladding-mode coupler. Signal inversion for the negative tap is achieved by optical injection locking of a single-mode semiconductor laser. To couple light into and out of the cladding-mode coupler, a pair of matching long-period fiber gratings is employed. The large bandwidth of the gratings requires injection locking of an exceptionally large wavelength detuning that has never been demonstrated before. Experimentally, injection locking with wavelength detuning as large as 27 nm was achieved, which corresponded to locking the 36-th side mode. Microwave filtering with a free-spectral range tunable from 88.6 MHz to 1.57 GHz and a notch depth larger than 35 dB was obtained.

A novel design solution to the fraenal notch of maxillary dentures.

PubMed

White, J A P; Bond, I P; Jagger, D C

2013-09-01

This study investigates a novel design feature for the fraenal notch of maxillary dentures, using computational and experimental methods, and shows that its use could significantly increase the longevity of the prosthesis. A two-step process can be used to create the design feature with current denture base materials, but would be highly dependent on the individual skill of the dental technician. Therefore, an alternative form of manufacture, multi-material additive layer manufacture (or '3D printing'), has been proposed as a future method for the direct production of complete dentures with multi-material design features.

Notch1 is a prognostic factor that is distinctly activated in the classical and proneural subtype of glioblastoma and that promotes glioma cell survival via the NF-κB(p65) pathway.

PubMed

Hai, Long; Zhang, Chen; Li, Tao; Zhou, Xingchen; Liu, Bo; Li, Shuai; Zhu, Meng; Lin, Yu; Yu, Shengping; Zhang, Kai; Ren, Bingcheng; Ming, Haolang; Huang, Yubao; Chen, Lei; Zhao, Pengfei; Zhou, Hua; Jiang, Tao; Yang, Xuejun

2018-02-06

Glioblastomas (GBMs) are the most prevalent and devastating primary intracranial malignancies and have extensive heterogeneity. Notch1 signaling is a more complex process in the development of numerous cell and tissue types, including gliomagenesis and progression, and is upregulated in glioma-initiating cells. However, the contradictory expression of Notch1 among lower grade gliomas and GBMs confounds our understanding of GBM biology and has made identifying effective therapies difficult. In this study, we validated that Notch1 and NF-κB(p65) are highly expressed in the classical and proneural subtypes of GBM using the data set from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). DAPT and shRNA targeting Notch1 decreased NF-κB(p65) expression, suppressed cell proliferation, and induced apoptosis of GBM cells in vitro and in vivo. Furthermore, we illustrated that the intracellular Notch could bind with NF-κB(p65) in GBM cells. These findings suggest that the cross-talk between Notch1 signaling and NF-κB(p65) could contribute to the proliferation and apoptosis of glioma, and this discovery could help drive the design of more effective therapies in Notch1-targeted clinical trials.

A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia

PubMed Central

Petroni, Roberta Cardoso; Muto, Nair Hideko; Sitnik, Roberta; de Carvalho, Flavia Pereira; Bacal, Nydia Strachman; Velloso, Elvira Deolinda Rodrigues Pereira; Oliveira, Gislaine Borba; Pinho, João Renato Rebello; Torres, Davi Coe; Mansur, Marcela Braga; Hassan, Rocio; Lorand-Metze, Irene Gyongyvér Heidemarie; Chiattone, Carlos Sérgio; Hamerschlak, Nelson; Mangueira, Cristovão Luis Pitangueira

2016-01-01

Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions. PMID:28074183

Multiplex CARS imaging with spectral notch shaped laser pulses delivered by optical fibers.

PubMed

Oh, Seung Ryeol; Park, Joo Hyun; Kim, Kyung-Soo; Lee, Jae Yong; Kim, Soohyun

2017-12-11

We present an experimental demonstration of single-pulse coherent anti-Stokes Raman spectroscopy (CARS) using a spectrally shaped broadband laser that is delivered by an optical fiber to a sample at its distal end. The optical fiber consists of a fiber Bragg grating component to serve as a narrowband notch filter and a combined large-mode-area fiber to transmit such shaped ultrashort laser pulses without spectral distortion in a long distance. Experimentally, our implementation showed a capability to measure CARS spectra of various samples with molecular vibrations in the fingerprint region. Furthermore, CARS imaging of poly(methyl methacrylate) bead samples was carried out successfully under epi-CARS geometry in which backward-scattered CARS signals were collected into a multimode optical fiber. A compatibility of single-pulse CARS scheme with fiber optics, verified in this study, implies a potential for future realization of compact all-fiber CARS spectroscopic imaging systems.

Cooling system for a gas turbine using a cylindrical insert having V-shaped notch weirs

DOEpatents

Grondahl, Clayton M.; Germain, Malcolm R.

1981-01-01

An improved cooling system for a gas turbine is disclosed. A plurality of V-shaped notch weirs are utilized to meter a coolant liquid from a pool of coolant into a plurality of platform and airfoil coolant channels formed in the buckets of the turbine. The V-shaped notch weirs are formed in a separately machined cylindrical insert and serve to desensitize the flow of coolant into the individual platform and airfoil coolant channels to design tolerances and non-uniform flow distribution.

New notch weir system designed to pass shad through Potomac Dam

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1996-08-01

This article discusses the design and functional characteristics of a notch and three-weir labyrinth fish passage facility at Little Falls Dam. Most effective at low-head hydroelectric power plants, the weir system will reduce flow velocities to a value thought to be low enough for healthy shad to swim against. It is felt that this system will re-establish the shad population in a 10-mile stretch of the Patomac River near Washington.

Integrable microwave filter based on a photonic crystal delay line.

PubMed

Sancho, Juan; Bourderionnet, Jerome; Lloret, Juan; Combrié, Sylvain; Gasulla, Ivana; Xavier, Stephane; Sales, Salvador; Colman, Pierre; Lehoucq, Gaelle; Dolfi, Daniel; Capmany, José; De Rossi, Alfredo

2012-01-01

The availability of a tunable delay line with a chip-size footprint is a crucial step towards the full implementation of integrated microwave photonic signal processors. Achieving a large and tunable group delay on a millimetre-sized chip is not trivial. Slow light concepts are an appropriate solution, if propagation losses are kept acceptable. Here we use a low-loss 1.5 mm-long photonic crystal waveguide to demonstrate both notch and band-pass microwave filters that can be tuned over the 0-50-GHz spectral band. The waveguide is capable of generating a controllable delay with limited signal attenuation (total insertion loss below 10 dB when the delay is below 70 ps) and degradation. Owing to the very small footprint of the delay line, a fully integrated device is feasible, also featuring more complex and elaborate filter functions.

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.

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...

Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions.

PubMed

Askew, Caitlin; Intskirveli, Irakli; Metherate, Raju

2017-01-01

Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral "notch" of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.

Notch-modifying xylosyltransferase-substrate complexes support an SNi-like retaining mechanism

PubMed Central

Yu, Hongjun; Takeuchi, Megumi; LeBarron, Jamie; Kantharia, Joshua; London, Erwin; Bakker, Hans; Haltiwanger, Robert S.; Li, Huilin; Takeuchi, Hideyuki

2015-01-01

A major remaining question in glycobiology is how a glycosyltransferase (GT) that retains the anomeric linkage of a sugar catalyzes the reaction. Xylosideα1–3 Xylosyltransferase (XXYLT1) is a retaining GT that regulates Notch receptor activation by adding xylose to the Notch extracellular domain. Here, using natural acceptor and donor substrates and active Mus musculus XXYLT1, we report a series of crystallographic snapshots along the reaction, including an unprecedented natural and competent Michaelis reaction complex for retaining enzymes. These structures strongly support the SNi-like reaction as the retaining mechanism for XXYLT1. Unexpectedly the Epidermal Growth Factor-like repeat acceptor substrate undergoes a large conformational change upon binding to the active site, providing a structural basis for substrate specificity. Our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations where dysregulation of Notch is known to cause cancer or developmental disorders. PMID:26414444

Notch-modifying xylosyltransferase structures support an S Ni-like retaining mechanism

DOE PAGES

Yu, Hongjun; Li, Huilin; Takeuchi, Megumi; ...

2015-09-28

A major question remaining in glycobiology is how a glycosyltransferase (GT) that retains the anomeric linkage of a sugar catalyzes the reaction. Xyloside α-1,3-xylosyltransferase (XXYLT1) is a retaining GT that regulates Notch receptor activation by adding xylose to the Notch extracellular domain. Here, using natural acceptor and donor substrates and active Mus musculus XXYLT1, we report a series of crystallographic snapshots along the reaction, including an unprecedented natural and competent Michaelis reaction complex for retaining enzymes. These structures strongly support the SNi-like reaction as the retaining mechanism for XXYLT1. Unexpectedly, the epidermal growth factor–like repeat acceptor substrate undergoes a largemore » conformational change upon binding to the active site, providing a structural basis for substrate specificity. As a result, our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations in which Notch dysregulation is known to cause cancer or developmental disorders.« less

Notch-modifying xylosyltransferase structures support an S Ni-like retaining mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Hongjun; Li, Huilin; Takeuchi, Megumi

A major question remaining in glycobiology is how a glycosyltransferase (GT) that retains the anomeric linkage of a sugar catalyzes the reaction. Xyloside α-1,3-xylosyltransferase (XXYLT1) is a retaining GT that regulates Notch receptor activation by adding xylose to the Notch extracellular domain. Here, using natural acceptor and donor substrates and active Mus musculus XXYLT1, we report a series of crystallographic snapshots along the reaction, including an unprecedented natural and competent Michaelis reaction complex for retaining enzymes. These structures strongly support the SNi-like reaction as the retaining mechanism for XXYLT1. Unexpectedly, the epidermal growth factor–like repeat acceptor substrate undergoes a largemore » conformational change upon binding to the active site, providing a structural basis for substrate specificity. As a result, our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations in which Notch dysregulation is known to cause cancer or developmental disorders.« less

Modeling and design of a two-axis elliptical notch flexure hinge

NASA Astrophysics Data System (ADS)

Wu, Jianwei; Zhang, Yin; Lu, Yunfeng; Wen, Zhongpu; Bin, Deer; Tan, Jiubin

2018-04-01

As an important part of the joule balance system, the two-axis elliptical notch flexure hinge (TENFH) which typically consists of two single-axis elliptical notch flexure hinges was studied. First, a 6 degrees of freedom (6-DOF) compliance model was established based on the coordinate transformation method. In addition, the maximum stress of the TENFH was derived. The compliance and maximum stress model was verified using finite element analysis simulation. To decouple the attitude of the suspended coil system and reduce the offset between the centroid of the suspended coil mechanism and the mass comparator in the joule balance system, a new mechanical structure of TENFH was designed based on the compliance model and stress model proposed in this paper. The maximum rotation range is up to 10°, and the axial load is more than 5 kg, which meets the requirements of the system. The compliance model was also verified by deformation experimentation with the designed TENFH.

An Evaluation of Top Notch Fundamentals B: A Four Phase Study

ERIC Educational Resources Information Center

Ahmadi, Marzie

2016-01-01

Textbooks play an important role in educational contexts especially in EFL contexts their role are more highlighted. Textbook evaluation in any type, predictive or retrospective, is a necessary part of curriculum design and in this sense is a worthwhile means of conducting research. Recently, Top Notch series have become widely used in Iranian…

Clinical Impact of De-Regulated Notch-1 and Notch-3 in the Development and Progression of HPV-Associated Different Histological Subtypes of Precancerous and Cancerous Lesions of Human Uterine Cervix

PubMed Central

Tripathi, Richa; Rath, Gayatri; Jawanjal, Poonam; Sharma, Shweta; Singhal, Pallavi; Bhambhani, Suresh; Hussain, Showket; Bharadwaj, Mausumi

2014-01-01

Background Cervical cancer is the leading cause of cancer related deaths among women in India. Limited reports are available for Notch-1 and Notch-3 protein in cervical carcinoma, which play crucial role in cell proliferation, differentiation, and apoptosis. Methods This study was designed to evaluate the role of Notch-1 and Notch-3 with context to HPV infection in cervical carcinoma. A total of 168 tissue biopsy samples comprising of tumor specimens (n = 98), precancer (n = 30) and non-neoplastic cervical tissues (n = 40) were screened for HPV infection by PCR and expression of Notch-1 and Notch-3 protein by Immunohistochemistry and Immunoblotting. Results 80% (24/30) were found to be positive for HPV in precancer and 86.7% (85/98) in cancer patients. Notch-1 expression of precancer and cancer cases was found to be significantly down-regulated with severity of disease in nuclear (3.43±0.29; 2.04±0.19, p = 0.0001, p = 0.0001) and cytoplasm (3.07±0.29; 2.29±0.17, p = 0.0001, p = 0.0001) obtained from different stages as compared to normal cervix tissue (5.40±0.19, 4.97±0.15; p<0.001; p<0.001). However, Notch-3 expression of above cases was significantly up-regulated with severity of disease and showed intense nuclear (4.17±0.39; 4.74±0.18, p = 0.0001, p = 0.0001) and cytoplasm (3.67±0.36; 4.48±0.18, p = 0.0001, p = 0.0001) of different stages as compared to normal cervix tissue (0.95±0.20, 0.70±0.20; p<0.001; p<0.001) respectively. Conclusions These findings suggest that Notch-1 and Notch-3 may play an important role with synergistic effect of HPV in regulating development and proliferation of cervical cancer through the deregulation of Notch signalling. This study also shows the clinical utility of both proteins which may be used as predictable biomarkers in diagnosing different histological sub-types of HPV associated cervical cancer. Nevertheless, abnormal activation of this pathway may provide legitimate targets for cervical cancer therapy. PMID:24905589

Clinical impact of de-regulated Notch-1 and Notch-3 in the development and progression of HPV-associated different histological subtypes of precancerous and cancerous lesions of human uterine cervix.

PubMed

Tripathi, Richa; Rath, Gayatri; Jawanjal, Poonam; Sharma, Shweta; Singhal, Pallavi; Bhambhani, Suresh; Hussain, Showket; Bharadwaj, Mausumi

2014-01-01

Cervical cancer is the leading cause of cancer related deaths among women in India. Limited reports are available for Notch-1 and Notch-3 protein in cervical carcinoma, which play crucial role in cell proliferation, differentiation, and apoptosis. This study was designed to evaluate the role of Notch-1 and Notch-3 with context to HPV infection in cervical carcinoma. A total of 168 tissue biopsy samples comprising of tumor specimens (n = 98), precancer (n = 30) and non-neoplastic cervical tissues (n = 40) were screened for HPV infection by PCR and expression of Notch-1 and Notch-3 protein by Immunohistochemistry and Immunoblotting. 80% (24/30) were found to be positive for HPV in precancer and 86.7% (85/98) in cancer patients. Notch-1 expression of precancer and cancer cases was found to be significantly down-regulated with severity of disease in nuclear (3.43±0.29; 2.04±0.19, p = 0.0001, p = 0.0001) and cytoplasm (3.07±0.29; 2.29±0.17, p = 0.0001, p = 0.0001) obtained from different stages as compared to normal cervix tissue (5.40±0.19, 4.97±0.15; p<0.001; p<0.001). However, Notch-3 expression of above cases was significantly up-regulated with severity of disease and showed intense nuclear (4.17±0.39; 4.74±0.18, p = 0.0001, p = 0.0001) and cytoplasm (3.67±0.36; 4.48±0.18, p = 0.0001, p = 0.0001) of different stages as compared to normal cervix tissue (0.95±0.20, 0.70±0.20; p<0.001; p<0.001) respectively. These findings suggest that Notch-1 and Notch-3 may play an important role with synergistic effect of HPV in regulating development and proliferation of cervical cancer through the deregulation of Notch signalling. This study also shows the clinical utility of both proteins which may be used as predictable biomarkers in diagnosing different histological sub-types of HPV associated cervical cancer. Nevertheless, abnormal activation of this pathway may provide legitimate targets for cervical cancer therapy.

rotational Raman spectroscopy methods for probing energy thermalisation processes during spin-exchange optical pumping

NASA Astrophysics Data System (ADS)

Newton, Hayley; Walkup, Laura L.; Whiting, Nicholas; West, Linda; Carriere, James; Havermeyer, Frank; Ho, Lawrence; Morris, Peter; Goodson, Boyd M.; Barlow, Michael J.

2014-05-01

Spin-exchange optical pumping (SEOP) has been widely used to produce enhancements in nuclear spin polarisation for hyperpolarised noble gases. However, some key fundamental physical processes underlying SEOP remain poorly understood, particularly in regards to how pump laser energy absorbed during SEOP is thermalised, distributed and dissipated. This study uses in situ ultra-low frequency Raman spectroscopy to probe rotational temperatures of nitrogen buffer gas during optical pumping under conditions of high resonant laser flux and binary Xe/N2 gas mixtures. We compare two methods of collecting the Raman scattering signal from the SEOP cell: a conventional orthogonal arrangement combining intrinsic spatial filtering with the utilisation of the internal baffles of the Raman spectrometer, eliminating probe laser light and Rayleigh scattering, versus a new in-line modular design that uses ultra-narrowband notch filters to remove such unwanted contributions. We report a ~23-fold improvement in detection sensitivity using the in-line module, which leads to faster data acquisition and more accurate real-time monitoring of energy transport processes during optical pumping. The utility of this approach is demonstrated via measurements of the local internal gas temperature (which can greatly exceed the externally measured temperature) as a function of incident laser power and position within the cell.

Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept.

PubMed

Rutten, Julie W; Dauwerse, Hans G; Peters, Dorien J M; Goldfarb, Andrew; Venselaar, Hanka; Haffner, Christof; van Ommen, Gert-Jan B; Aartsma-Rus, Annemieke M; Lesnik Oberstein, Saskia A J

2016-04-01

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, is a hereditary cerebral small vessel disease caused by characteristic cysteine altering missense mutations in the NOTCH3 gene. NOTCH3 mutations in CADASIL result in an uneven number of cysteine residues in one of the 34 epidermal growth factor like-repeat (EGFr) domains of the NOTCH3 protein. The consequence of an unpaired cysteine residue in an EGFr domain is an increased multimerization tendency of mutant NOTCH3, leading to toxic accumulation of the protein in the (cerebro)vasculature, and ultimately reduced cerebral blood flow, recurrent stroke and vascular dementia. There is no therapy to delay or alleviate symptoms in CADASIL. We hypothesized that exclusion of the mutant EGFr domain from NOTCH3 would abolish the detrimental effect of the unpaired cysteine and thus prevent toxic NOTCH3 accumulation and the negative cascade of events leading to CADASIL. To accomplish this NOTCH3 cysteine correction by EGFr domain exclusion, we used pre-mRNA antisense-mediated skipping of specific NOTCH3 exons. Selection of these exons was achieved using in silico studies and based on the criterion that skipping of a particular exon or exon pair would modulate the protein in such a way that the mutant EGFr domain is eliminated, without otherwise corrupting NOTCH3 structure and function. Remarkably, we found that this strategy closely mimics evolutionary events, where the elimination and fusion of NOTCH EGFr domains led to the generation of four functional NOTCH homologues. We modelled a selection of exon skip strategies using cDNA constructs and show that the skip proteins retain normal protein processing, can bind ligand and be activated by ligand. We then determined the technical feasibility of targeted NOTCH3 exon skipping, by designing antisense oligonucleotides targeting exons 2-3, 4-5 and 6, which together harbour the majority of distinct CADASIL-causing mutations. Transfection of these antisense oligonucleotides into CADASIL patient-derived cerebral vascular smooth muscle cells resulted in successful exon skipping, without abrogating NOTCH3 signalling. Combined, these data provide proof of concept for this novel application of exon skipping, and are a first step towards the development of a rational therapeutic approach applicable to up to 94% of CADASIL-causing mutations. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Spectral Structure Of Phase-Induced Intensity Noise In Recirculating Delay Lines

NASA Astrophysics Data System (ADS)

Tur, M.; Moslehi, B.; Bowers, J. E.; Newton, S. A.; Jackson, K. P.; Goodman, J. W.; Cutler, C. C.; Shaw, H. J.

1983-09-01

The dynamic range of fiber optic signal processors driven by relatively incoherent multimode semiconductor lasers is shown to be severely limited by laser phase-induced noise. It is experimentally demonstrated that while the noise power spectrum of differential length fiber filters is approximately flat, processors with recirculating loops exhibit noise with a periodically structured power spectrum with notches at zero frequency as well as at all other multiples of 1/(loop delay). The experimental results are aug-mented by a theoretical analysis.

Burst Testing of Triaxial Braided Composite Tubes

NASA Technical Reports Server (NTRS)

Salem, J. A.; Bail, J. L.; Wilmoth, N. G.; Ghosn, L. J.; Kohlman, L. W.; Roberts, G. D.; Martin, R. E.

2014-01-01

Applications using triaxial braided composites are limited by the materials transverse strength which is determined by the delamination capacity of unconstrained, free-edge tows. However, structural applications such as cylindrical tubes can be designed to minimize free edge effects and thus the strength with and without edge stresses is relevant to the design process. The transverse strength of triaxial braided composites without edge effects was determined by internally pressurizing tubes. In the absence of edge effects, the axial and transverse strength were comparable. In addition, notched specimens, which minimize the effect of unconstrained tow ends, were tested in a variety of geometries. Although the commonly tested notch geometries exhibited similar axial and transverse net section failure strength, significant dependence on notch configuration was observed. In the absence of unconstrained tows, failure ensues as a result of bias tow rotation, splitting, and fracture at cross-over regions.

Design features and results from fatigue reliability research machines.

NASA Technical Reports Server (NTRS)

Lalli, V. R.; Kececioglu, D.; Mcconnell, J. B.

1971-01-01

The design, fabrication, development, operation, calibration and results from reversed bending combined with steady torque fatigue research machines are presented. Fifteen-centimeter long, notched, SAE 4340 steel specimens are subjected to various combinations of these stresses and cycled to failure. Failure occurs when the crack in the notch passes through the specimen automatically shutting down the test machine. These cycles-to-failure data are statistically analyzed to develop a probabilistic S-N diagram. These diagrams have many uses; a rotating component design example given in the literature shows that minimum size and weight for a specified number of cycles and reliability can be calculated using these diagrams.

Notched Audiograms and Noise Exposure History in Older Adults

PubMed Central

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

2009-01-01

OBJECTIVE Using data from a population-based cohort study, we compared four published algorithms for identifying notched audiograms, along with how their resulting classifications compare with noise exposure history. DESIGN Four algorithms: 1) Coles, Lutman & Buffin (2000), 2) McBride & Williams (2001), 3) Dobie & Rabinowitz (2002), and 4) Hoffman et al. (2006) were used to identify notched audiograms. Audiometric evaluations were collected as part of the Epidemiology of Hearing Loss Study 10-year follow-up examinations, in Beaver Dam, WI (2003–2005, n=2395). Detailed noise exposure histories were collected by interview at the baseline examination (1993–95) and updated at subsequent visits. An extensive history of occupational noise exposure, participation in noisy hobbies, and firearm usage were used to evaluate consistency of the notch classifications with history of noise exposure. RESULTS The prevalence of notched audiograms varied greatly by definition (31.7%, 25.9%, 47.2%, and 11.7% for methods 1, 2, 3, and 4, respectively). In this cohort, a history of noise exposure was common (56.2% for occupational noise, 71.7% for noisy hobbies, 13.4% for firearms, 81.2% for any of these three sources). Among participants with a notched audiogram, almost one third did not have a history of occupational noise exposure (31.4%, 33.0%, 32.5%, and 28.1% for methods 1, 2, 3, and 4, respectively) and approximately 11% did not have a history of exposure to any of the three sources of noise (11.5%, 13.6%, 10.3%, and 7.6%). Discordance was greater among women than men. CONCLUSIONS These results suggest that there is poor agreement across existing algorithms for audiometric notches. In addition, notches can occur in the absence of a positive noise history. In the absence of an objective consensus definition of a notched audiogram, and in light of the degree of discordance in women between noise history and notches by each of these algorithms, researchers should be cautious about classifying noise-induced hearing loss by notched audiograms. PMID:19633561

Active integrated filters for RF-photonic channelizers.

PubMed

El Nagdi, Amr; Liu, Ke; LaFave, Tim P; Hunt, Louis R; Ramakrishna, Viswanath; Dabkowski, Mieczyslaw; MacFarlane, Duncan L; Christensen, Marc P

2011-01-01

A theoretical study of RF-photonic channelizers using four architectures formed by active integrated filters with tunable gains is presented. The integrated filters are enabled by two- and four-port nano-photonic couplers (NPCs). Lossless and three individual manufacturing cases with high transmission, high reflection, and symmetric couplers are assumed in the work. NPCs behavior is dependent upon the phenomenon of frustrated total internal reflection. Experimentally, photonic channelizers are fabricated in one single semiconductor chip on multi-quantum well epitaxial InP wafers using conventional microelectronics processing techniques. A state space modeling approach is used to derive the transfer functions and analyze the stability of these filters. The ability of adapting using the gains is demonstrated. Our simulation results indicate that the characteristic bandpass and notch filter responses of each structure are the basis of channelizer architectures, and optical gain may be used to adjust filter parameters to obtain a desired frequency magnitude response, especially in the range of 1-5 GHz for the chip with a coupler separation of ∼9 mm. Preliminarily, the measurement of spectral response shows enhancement of quality factor by using higher optical gains. The present compact active filters on an InP-based integrated photonic circuit hold the potential for a variety of channelizer applications. Compared to a pure RF channelizer, photonic channelizers may perform both channelization and down-conversion in an optical domain.

CPW fed UWB antenna with enhanced bandwidth & dual band notch characteristics

NASA Astrophysics Data System (ADS)

Jangid, K. G.; Jain, P. K.; Sharma, B. R.; Saxena, V. K.; Kulhar, V. S.; Bhatnagar, D.

2018-05-01

This paper reports the design and performance of CPW fed UWB antenna having two U-shaped slots etched in the radiating structure. UWB performance of proposed structure is obtained through the truncated shape of the patch and L-slits etched in ground plane. By applying two U- shaped slots in a radiating patch, we achieved dual notch band characteristics. The proposed antenna is simulated by applying CST Microwave Studio simulator. This antenna provides wide impedance bandwidth of 12.585 GHz (2.74GHz - 15.325 GHz) with dual notched band characteristics. This antenna may be proved as a useful structure for modern wireless communication systems including UWB band.

A Novel Design of Frequency Reconfigurable Antenna for UWB Application

NASA Astrophysics Data System (ADS)

Yang, Xiaolin; Yu, Ziliang; Wu, Zheng; Shen, Huajiao

2016-09-01

In this paper, we present a novel frequency reconfigurable antenna which could be easily operate in a single notched-band (WiMAX (3.3-3.6 GHz)) UWB frequency band, another single notched-band (WLAN (5-6 GHz)) UWB frequency band and the dual band-notched UWB frequency band (the stopband covers the WiMAX (3.3-3.6 GHz) and WLAN (5-6 GHz)). The reconfigurability is achieved by changing the states of PIN diodes. The simulated results are in agreement well with the measured results. And the measured patterns are slightly changed with antenna reconfiguration. The proposed antenna is a good candidate for various UWB applications.

Relationship between notch strengthening threshold and mechanical property for ductile cast iron

NASA Astrophysics Data System (ADS)

Ikeda, T.; Noda, N.-A.; Sano, Y.; Umetani, T.; Kai, N.

2018-06-01

In this study, dynamic tensile tests were conducted at the various strain rates and temperatures for traditional ductile cast iron. Then, the notch strength {σ }{{B}}{{noth}} and the static tensile strength at room temperature {σ }{{B,}\\quad {{RT}}}{{smooth}} were discussed in terms of the strain rate- temperature parameter R, which is known to be useful for evaluating the combined influence of strain rate and temperature. This study focuses on the notch strengthening threshold R ≧ R th where {σ }{{B}}{{noth}} is larger than {σ }{{B,}\\quad {{RT}}}{{smooth}} and therefore notched components can be used safely. In other words, if R ≧ R th, {σ }{{B,}\\quad {{RT}}}{{smooth}} can be used to evaluate notched components in mechanical design to prevent the instantaneous fracture. In this study, it was found that the R th value can be predicted from the static tensile property and Brinell hardness. Since the traditional ductile cast iron considered in this paper has a broad range of mechanical properties, the present approach and discussion can be applied to evaluate other materials under various temperature and strain rate.

Comparison of Signal Response Between EDM Notch and Cracks in Eddy-Current Testing

NASA Technical Reports Server (NTRS)

Kane, Mary; Koshti, Ajay

2008-01-01

In the field of ET an eddy-current instrument is calibrated on a manufactured notch that is designed to simulate a defect in a part. The calibrated instrument is then used to scan parts with the assumption that any response that is over half the amplitude of the notch signal is taken to be defective. The purpose of this study is to attempt a direct comparison of the signal response observed from an EDM notch to a crack of the same size. To make this comparison test equipment will be set up and calibrated as per normal inspection procedures. Once this has been achieved both notches and as many different sizes of crack specimens will be scanned and the data recorded. This data will then be analyzed to provide a comparison of the response. The results should also provide information that shows it is acceptable to use the half-amplitude method for determining if a part is defective. The tests will be performed on two different materials commonly inspected, titanium and aluminum. This will allow a comparison of the results between materials.

Novel candidate genes may be possible predisposing factors revealed by whole exome sequencing in familial esophageal squamous cell carcinoma.

PubMed

Forouzanfar, Narjes; Baranova, Ancha; Milanizadeh, Saman; Heravi-Moussavi, Alireza; Jebelli, Amir; Abbaszadegan, Mohammad Reza

2017-05-01

Esophageal squamous cell carcinoma is one of the deadliest of all the cancers. Its metastatic properties portend poor prognosis and high rate of recurrence. A more advanced method to identify new molecular biomarkers predicting disease prognosis can be whole exome sequencing. Here, we report the most effective genetic variants of the Notch signaling pathway in esophageal squamous cell carcinoma susceptibility by whole exome sequencing. We analyzed nine probands in unrelated familial esophageal squamous cell carcinoma pedigrees to identify candidate genes. Genomic DNA was extracted and whole exome sequencing performed to generate information about genetic variants in the coding regions. Bioinformatics software applications were utilized to exploit statistical algorithms to demonstrate protein structure and variants conservation. Polymorphic regions were excluded by false-positive investigations. Gene-gene interactions were analyzed for Notch signaling pathway candidates. We identified novel and damaging variants of the Notch signaling pathway through extensive pathway-oriented filtering and functional predictions, which led to the study of 27 candidate novel mutations in all nine patients. Detection of the trinucleotide repeat containing 6B gene mutation (a slice site alteration) in five of the nine probands, but not in any of the healthy samples, suggested that it may be a susceptibility factor for familial esophageal squamous cell carcinoma. Noticeably, 8 of 27 novel candidate gene mutations (e.g. epidermal growth factor, signal transducer and activator of transcription 3, MET) act in a cascade leading to cell survival and proliferation. Our results suggest that the trinucleotide repeat containing 6B mutation may be a candidate predisposing gene in esophageal squamous cell carcinoma. In addition, some of the Notch signaling pathway genetic mutations may act as key contributors to esophageal squamous cell carcinoma.

The parameters effect on the structural performance of damaged steel box beam using Taguchi method

NASA Astrophysics Data System (ADS)

El-taly, Boshra A.; Abd El Hameed, Mohamed F.

2018-03-01

In the current study, the influence of notch or opening parameters and the positions of the applied load on the structural performance of steel box beams up to failure was investigated using Finite Element analysis program, ANSYS. The Taguchi-based design of experiments technique was used to plan the current study. The plan included 12 box steel beams; three intact beams, and nine damaged beams (with opening) in the beams web. The numerical studies were conducted under varying the spacing between the two concentrated point loads (location of applied loads), the notch (opening) position, and the ratio between depth and width of the notch with a constant notch area. According to Taguchi analysis, factor X (location of the applied loads) was found the highest contributing parameters for the variation of the ultimate load, vertical deformation, shear stresses, and the compressive normal stresses.

Internal-short-mitigating current collector for lithium-ion battery

NASA Astrophysics Data System (ADS)

Wang, Meng; Le, Anh V.; Noelle, Daniel J.; Shi, Yang; Meng, Y. Shirley; Qiao, Yu

2017-05-01

Mechanical abuse often causes thermal runaway of lithium-ion battery (LIB). When a LIB cell is impacted, radial cracks can be formed in the current collector, separating the electrode into petals. As separator ruptures, the petals on positive and negative electrodes may contact each other, forming internal short circuit (ISC). In this study, we conducted an experimental investigation on LIB coin cells with current collectors modified by surface notches. Our testing results showed that as the current collector contained appropriate surface notches, the cracking mode of electrode in a damaged LIB cell could be adjusted. Particularly, if a complete circumferential crack was generated, the petals would be cut off, which drastically reduced the area of electrode involved in ISC and the associated heat generation rate. A parameterized study was performed to analysis various surface-notch configurations. We identified an efficient surface-notch design that consistently led to trivial temperature increase of ISC.

Time-frequency model for echo-delay resolution in wideband biosonar.

PubMed

Neretti, Nicola; Sanderson, Mark I; Intrator, Nathan; Simmons, James A

2003-04-01

A time/frequency model of the bat's auditory system was developed to examine the basis for the fine (approximately 2 micros) echo-delay resolution of big brown bats (Eptesicus fuscus), and its performance at resolving closely spaced FM sonar echoes in the bat's 20-100-kHz band at different signal-to-noise ratios was computed. The model uses parallel bandpass filters spaced over this band to generate envelopes that individually can have much lower bandwidth than the bat's ultrasonic sonar sounds and still achieve fine delay resolution. Because fine delay separations are inside the integration time of the model's filters (approximately 250-300 micros), resolving them means using interference patterns along the frequency dimension (spectral peaks and notches). The low bandwidth content of the filter outputs is suitable for relay of information to higher auditory areas that have intrinsically poor temporal response properties. If implemented in fully parallel analog-digital hardware, the model is computationally extremely efficient and would improve resolution in military and industrial sonar receivers.

A Pole-Zero Filter Cascade Provides Good Fits to Human Masking Data and to Basilar Membrane and Neural Data

NASA Astrophysics Data System (ADS)

Lyon, Richard F.

2011-11-01

A cascade of two-pole-two-zero filters with level-dependent pole and zero dampings, with few parameters, can provide a good match to human psychophysical and physiological data. The model has been fitted to data on detection threshold for tones in notched-noise masking, including bandwidth and filter shape changes over a wide range of levels, and has been shown to provide better fits with fewer parameters compared to other auditory filter models such as gammachirps. Originally motivated as an efficient machine implementation of auditory filtering related to the WKB analysis method of cochlear wave propagation, such filter cascades also provide good fits to mechanical basilar membrane data, and to auditory nerve data, including linear low-frequency tail response, level-dependent peak gain, sharp tuning curves, nonlinear compression curves, level-independent zero-crossing times in the impulse response, realistic instantaneous frequency glides, and appropriate level-dependent group delay even with minimum-phase response. As part of exploring different level-dependent parameterizations of such filter cascades, we have identified a simple sufficient condition for stable zero-crossing times, based on the shifting property of the Laplace transform: simply move all the s-domain poles and zeros by equal amounts in the real-s direction. Such pole-zero filter cascades are efficient front ends for machine hearing applications, such as music information retrieval, content identification, speech recognition, and sound indexing.

Modeling and Application of Piezoelectric Materials in Repair of Engineering Structures

NASA Astrophysics Data System (ADS)

Wu, Nan

The shear horizontal wave propagation and vibration of piezoelectric coupled structures under an open circuit electrical boundary condition are studied. Following the studies on the dynamic response of piezoelectric coupled structures, the repair of both crack/notch and delaminated structures using piezoelectric materials are conducted. The main contribution was the proposed the active structural repair design using piezoelectric materials for different structures. An accurate model for the piezoelectric effect on the shear wave propagation is first proposed to guide the application of piezoelectric materials as sensors and actuators in the repair of engineering structures. A vibration analysis of a circular steel substrate surface bonded by a piezoelectric layer with open circuit is presented. The mechanical models and solutions for the wave propagation and vibration analysis of piezoelectric coupled structures are established based on the Kirchhoff plate model and Maxwell equation. Following the studies of the dynamic response of piezoelectric coupled structures, a close-loop feedback control repair methodology is proposed for a vibrating delaminated beam structure by using piezoelectric patches. The electromechanical characteristic of the piezoelectric material is employed to induce a local shear force above the delamination area via an external actuation voltage, which is designed as a feedback of the deflection of a vibrating beam and a delaminated plate, to reduce the stress singularity around the delamination tips. Furthermore, an experimental realization of an effective repair of a notched cantilever beam structure subjected to a dynamic loading by use of piezoelectric patches is reported. A small piezoelectric patch used as a sensor is placed on the notch position to monitor the severity of the stress singularity around the notch area by measuring the charge output on the sensor, and a patch used as an actuator is located around the notch area to generate a required bending moment by employing an actuation voltage to reduce the stress singularity at the notch position. The actuation voltage on the actuator is designed from a feedback circuit process. Through the analytical model, FEM simulation and experimental studies, the active structural repair method using piezoelectric materials is realized and proved to be feasible and practical.

The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

PubMed Central

Zuurbier, Linda; Petricoin, Emanuel F.; Vuerhard, Maartje J.; Calvert, Valerie; Kooi, Clarissa; Buijs-Gladdines, Jessica G.C.A.M.; Smits, Willem K.; Sonneveld, Edwin; Veerman, Anjo J.P.; Kamps, Willem A.; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

2012-01-01

Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. Design and Methods The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors. PMID:22491738

A comparison of angle-beam shear wave scattering from hidden defects in single-and double-layer plates

NASA Astrophysics Data System (ADS)

Maki, Carson T.; Michaels, Jennifer E.; Weng, Yu

2018-04-01

Quantification of shear wave scattering from hidden defects is challenging because it is difficult to separate defect-scattered waves from waves that are scattered from benign structural features such as interfaces and fastener holes. It is even more difficult for the case of a crack emanating from a through-hole because there is complicated scattering from both the hole and the crack. This present work reports the results of a study that considers measurements from several far-surface notches emanating from through-holes in an aluminum plate both before and after a second plate is bonded to the back surface of the first plate. Measurements are also made of scattering from just a through-hole in both the single and bonded plates as a basis for comparison. The presence of the second layer provides a path for energy to leak out of the first plate, which can reduce the scattered energy. The recorded data show that notch scattering is clearly visible in the wavefield data for all of the notched holes. This scattering is quantified by first applying frequency-wavenumber filtering to extract shear waves of interest, and then computing scattered energy as a function of direction. Results for the different specimens are reported and compared to show the differences in scattering caused by the presence of the second layer.

Structural Efficiency and Behavior of Pristine and Notched Stitched Structure

NASA Technical Reports Server (NTRS)

Jegley, Dawn C.

2011-01-01

Two driving factors in aircraft panel design are structural efficiency and response to in-service damage. Stitching through the thickness can improve both of these considerations. Combining stitching with a post-buckling design approach can provide additional improvements. The buckling behavior of stitched structure is considered since lighter structures can be achieved if local skin buckling is allowed to occur at less than design ultimate load. Through-the-thickness stitching can suppress delamination between skin and flange, thereby allowing the structure to reliably carry load into the postbuckling range. Hat-stiffened and rod-stiffened panels in which the skin and flanges were stitched together through-the-thickness prior to curing are considered through experiment and analysis. In both types of panels no mechanical fasteners were used for the assembly. Specimens were loaded to failure in axial compression. In this study all specimens buckled in the skin between the stiffeners and continued to carry load. In addition, the behavior of panels with a severed stringer or notch are considered. Failure loads and strain distributions in the notched panel are compared to those in the unnotched panel.

Synthetic Human NOTCH1 EGF Modules Unraveled Molecular Mechanisms for the Structural and Functional Roles of Calcium Ions and O-Glycans in the Ligand-Binding Region.

PubMed

Hayakawa, Shun; Koide, Ryosuke; Hinou, Hiroshi; Nishimura, Shin-Ichiro

2016-02-09

The Notch signaling pathway is an evolutionarily highly conserved mechanism that operates across multicellular organisms and is critical for cell-fate decisions during development and homeostasis in most tissues. Notch signaling is modified by posttranslational glycosylations of the Notch extracellular EGF-like domain. To evaluate the structural and functional roles of various glycoforms at multiple EGF domains in the human Notch transmembrane receptor, we established a universal method for the construction of NOTCH1 EGF modules displaying the desired O-glycans at the designated glycosylation sites. The versatility of this strategy was demonstrated by the rapid and highly efficient synthesis of NOTCH1 EGF12 concurrently having a β-D-glucopyranose-initiated glycan (Xylα1 → 3Xylα1 → 3Glcβ1 →) at Ser458 and α-L-fucopyranose-initiated glycan (Neu5Acα2 → 3Galβ1 → 4GlcNAcβ1 → 3Fucα1 →) at Thr466. The efficiency of the proper folding of the glycosylated EGF12 was markedly enhanced in the presence of 5 mM CaCl2. A nuclear magnetic resonance study revealed the existence of strong nuclear Overhauser effects between key sugar moieties and neighboring amino acid residues, indicating that both O-glycans contribute independently to the intramolecular stabilization of the antiparallel β-sheet structure in the ligand-binding region of EGF12. A preliminary test using synthetic human NOTCH1 EGF modules showed significant inhibitory effects on the proliferation and adhesiveness of human breast cancer cell line MCF-7 and lung adenocarcinoma epithelial cell line A549, demonstrating for the first time evidence that exogenously applied synthetic EGF modules have the ability to interact with intrinsic Notch ligands on the surface of cancer cells.

Instantaneous and Frequency-Warped Signal Processing Techniques for Auditory Source Separation.

NASA Astrophysics Data System (ADS)

Wang, Avery Li-Chun

This thesis summarizes several contributions to the areas of signal processing and auditory source separation. The philosophy of Frequency-Warped Signal Processing is introduced as a means for separating the AM and FM contributions to the bandwidth of a complex-valued, frequency-varying sinusoid p (n), transforming it into a signal with slowly-varying parameters. This transformation facilitates the removal of p (n) from an additive mixture while minimizing the amount of damage done to other signal components. The average winding rate of a complex-valued phasor is explored as an estimate of the instantaneous frequency. Theorems are provided showing the robustness of this measure. To implement frequency tracking, a Frequency-Locked Loop algorithm is introduced which uses the complex winding error to update its frequency estimate. The input signal is dynamically demodulated and filtered to extract the envelope. This envelope may then be remodulated to reconstruct the target partial, which may be subtracted from the original signal mixture to yield a new, quickly-adapting form of notch filtering. Enhancements to the basic tracker are made which, under certain conditions, attain the Cramer -Rao bound for the instantaneous frequency estimate. To improve tracking, the novel idea of Harmonic -Locked Loop tracking, using N harmonically constrained trackers, is introduced for tracking signals, such as voices and certain musical instruments. The estimated fundamental frequency is computed from a maximum-likelihood weighting of the N tracking estimates, making it highly robust. The result is that harmonic signals, such as voices, can be isolated from complex mixtures in the presence of other spectrally overlapping signals. Additionally, since phase information is preserved, the resynthesized harmonic signals may be removed from the original mixtures with relatively little damage to the residual signal. Finally, a new methodology is given for designing linear-phase FIR filters which require a small fraction of the computational power of conventional FIR implementations. This design strategy is based on truncated and stabilized IIR filters. These signal-processing methods have been applied to the problem of auditory source separation, resulting in voice separation from complex music that is significantly better than previous results at far lower computational cost.

Biochemical Characterization and Cellular Effects of CADASIL Mutants of NOTCH3

PubMed Central

Meng, He; Zhang, Xiaojie; Yu, Genggeng; Lee, Soo Jung; Chen, Y. Eugene; Prudovsky, Igor; Wang, Michael M.

2012-01-01

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the best understood cause of dominantly inherited stroke and results from NOTCH3 mutations that lead to NOTCH3 protein accumulation and selective arterial smooth muscle degeneration. Previous studies show that NOTCH3 protein forms multimers. Here, we investigate protein interactions between NOTCH3 and other vascular Notch isoforms and characterize the effects of elevated NOTCH3 on smooth muscle gene regulation. We demonstrate that NOTCH3 forms heterodimers with NOTCH1, NOTCH3, and NOTCH4. R90C and C49Y mutant NOTCH3 form complexes which are more resistant to detergents than wild type NOTCH3 complexes. Using quantitative NOTCH3-luciferase clearance assays, we found significant inhibition of mutant NOTCH3 clearance. In coculture assays of NOTCH function, overexpressed wild type and mutant NOTCH3 significantly repressed NOTCH-regulated smooth muscle transcripts and potently impaired the activity of three independent smooth muscle promoters. Wildtype and R90C recombinant NOTCH3 proteins applied to cell cultures also blocked canonical Notch fuction. We conclude that CADASIL mutants of NOTCH3 complex with NOTCH1, 3, and 4, slow NOTCH3 clearance, and that overexpressed wild type and mutant NOTCH3 protein interfere with key NOTCH-mediated functions in smooth muscle cells. PMID:23028706

Effects of varying Notch1 signal strength on embryogenesis and vasculogenesis in compound mutant heterozygotes

PubMed Central

2010-01-01

Background Identifying developmental processes regulated by Notch1 can be addressed in part by characterizing mice with graded levels of Notch1 signaling strength. Here we examine development in embryos expressing various combinations of Notch1 mutant alleles. Mice homozygous for the hypomorphic Notch112f allele, which removes the single O-fucose glycan in epidermal growth factor-like repeat 12 (EGF12) of the Notch1 ligand binding domain (lbd), exhibit reduced growth after weaning and defective T cell development. Mice homozygous for the inactive Notch1lbd allele express Notch1 missing an ~20 kDa internal segment including the canonical Notch1 ligand binding domain, and die at embryonic day ~E9.5. The embryonic and vascular phenotypes of compound heterozygous Notch112f/lbd embryos were compared with Notch1+/12f, Notch112f/12f, and Notch1lbd/lbd embryos. Embryonic stem (ES) cells derived from these embryos were also examined in Notch signaling assays. While Notch1 signaling was stronger in Notch112f/lbd compound heterozygotes compared to Notch1lbd/lbd embryos and ES cells, Notch1 signaling was even stronger in embryos carrying Notch112f and a null Notch1 allele. Results Mouse embryos expressing the hypomorphic Notch112f allele, in combination with the inactive Notch1lbd allele which lacks the Notch1 ligand binding domain, died at ~E11.5-12.5. Notch112f/lbd ES cells signaled less well than Notch112f/12f ES cells but more strongly than Notch1lbd/lbd ES cells. However, vascular defects in Notch112f/lbd yolk sac were severe and similar to Notch1lbd/lbd yolk sac. By contrast, vascular disorganization was milder in Notch112f/lbd compared to Notch1lbd/lbd embryos. The expression of Notch1 target genes was low in Notch112f/lbd yolk sac and embryo head, whereas Vegf and Vegfr2 transcripts were increased. The severity of the compound heterozygous Notch112f/lbd yolk sac phenotype suggested that the allelic products may functionally interact. By contrast, compound heterozygotes with Notch112f in combination with a Notch1 null allele (Notch1tm1Con) were capable of surviving to birth. Conclusions Notch1 signaling in Notch112f/lbd compound heterozygous embryos is more defective than in compound heterozygotes expressing a hypomorphic Notch112f allele and a Notch1 null allele. The data suggest that the gene products Notch1lbd and Notch112f interact to reduce the activity of Notch112f. PMID:20346184

NOTCH-Mediated Maintenance and Expansion of Human Bone Marrow Stromal/Stem Cells: A Technology Designed for Orthopedic Regenerative Medicine

PubMed Central

Dong, Yufeng; Long, Teng; Wang, Cuicui; Mirando, Anthony J.; Chen, Jianquan; O’Keefe, Regis J.

2014-01-01

Human bone marrow-derived stromal/stem cells (BMSCs) have great therapeutic potential for treating skeletal disease and facilitating skeletal repair, although maintaining their multipotency and expanding these cells ex vivo have proven difficult. Because most stem cell-based applications to skeletal regeneration and repair in the clinic would require large numbers of functional BMSCs, recent research has focused on methods for the appropriate selection, expansion, and maintenance of BMSC populations during long-term culture. We describe here a novel biological method that entails selection of human BMSCs based on NOTCH2 expression and activation of the NOTCH signaling pathway in cultured BMSCs via a tissue culture plate coated with recombinant human JAGGED1 (JAG1) ligand. We demonstrate that transient JAG1-mediated NOTCH signaling promotes human BMSC maintenance and expansion while increasing their skeletogenic differentiation capacity, both ex vivo and in vivo. This study is the first of its kind to describe a NOTCH-mediated methodology for the maintenance and expansion of human BMSCs and will serve as a platform for future clinical or translational studies aimed at skeletal regeneration and repair. PMID:25368376

Dual Band Notched EBG Structure based UWB MIMO/Diversity Antenna with Reduced Wide Band Electromagnetic Coupling

NASA Astrophysics Data System (ADS)

Jaglan, Naveen; Kanaujia, Binod Kumar; Gupta, Samir Dev; Srivastava, Shweta

2017-10-01

A dual band-notched MIMO/Diversity antenna is proposed in this paper. The proposed antenna ensures notches in WiMAX band (3.3-3.6 GHz) besides WLAN band (5-6 GHz). Mushroom Electromagnetic Band Gap (EBG) arrangements are employed for discarding interfering frequencies. The procedure followed to attain notches is antenna shape independent with established formulas. The electromagnetic coupling among two narrowly set apart Ultra-Wide Band (UWB) monopoles is reduced by means of decoupling bands and slotted ground plane. Monopoles are 90° angularly parted with steps on the radiator. This aids to diminish mutual coupling and also adds in the direction of impedance matching by long current route. S21 or else mutual coupling of fewer than 15 dB is established over antenna operating range. Two-port envelope correlation coefficient is lower than 0.02 in UWB range of 3.1 GHz-10.6 GHz. The shifting in notch frequencies by varying variables in formulas is also reported. The suggested antenna is designed on low budget FR-4 substrate with measurements as (58 × 45 × 1.6) mm3. Simulated and measured results of fabricated antenna are found to be in close agreement.

A CPW-fed circular wide-slot UWB antenna with wide tunable and flexible reconfigurable dual notch bands.

PubMed

Li, Yingsong; Li, Wenxing; Ye, Qiubo

2013-01-01

A coplanar waveguide (CPW)-fed circular slot antenna with wide tunable dual band-notched function and frequency reconfigurable characteristic is designed, and its performance is verified experimentally for ultra-wideband (UWB) communication applications. The dual band-notched function is achieved by using a T-shaped stepped impedance resonator (T-SIR) inserted inside the circular ring radiation patch and by etching a parallel stub loaded resonator (PSLR) in the CPW transmission line, while the wide tunable bands can be implemented by adjusting the dimensions of the T-SIR and the PSLR. The notch band reconfigurable characteristic is realized by integrating three switches into the T-SIR and the PSLR. The numerical and experimental results show that the proposed antenna has a wide bandwidth ranging from 2.7 GHz to 12 GHz with voltage standing wave ratio (VSWR) less than 2, except for the two notch bands operating at 3.8-5.9 GHz and 7.7-9.2 GHz, respectively. In addition, the proposed antenna has been optimized to a compact size and can provide omnidirectional radiation patterns, which are suitable for UWB communication applications.

A CPW-Fed Circular Wide-Slot UWB Antenna with Wide Tunable and Flexible Reconfigurable Dual Notch Bands

PubMed Central

Li, Yingsong; Li, Wenxing; Ye, Qiubo

2013-01-01

A coplanar waveguide (CPW)-fed circular slot antenna with wide tunable dual band-notched function and frequency reconfigurable characteristic is designed, and its performance is verified experimentally for ultra-wideband (UWB) communication applications. The dual band-notched function is achieved by using a T-shaped stepped impedance resonator (T-SIR) inserted inside the circular ring radiation patch and by etching a parallel stub loaded resonator (PSLR) in the CPW transmission line, while the wide tunable bands can be implemented by adjusting the dimensions of the T-SIR and the PSLR. The notch band reconfigurable characteristic is realized by integrating three switches into the T-SIR and the PSLR. The numerical and experimental results show that the proposed antenna has a wide bandwidth ranging from 2.7 GHz to 12 GHz with voltage standing wave ratio (VSWR) less than 2, except for the two notch bands operating at 3.8–5.9 GHz and 7.7–9.2 GHz, respectively. In addition, the proposed antenna has been optimized to a compact size and can provide omnidirectional radiation patterns, which are suitable for UWB communication applications. PMID:24222733

The Least Mean Squares Adaptive FIR Filter for Narrow-Band RFI Suppression in Radio Detection of Cosmic Rays

NASA Astrophysics Data System (ADS)

Szadkowski, Zbigniew; Głas, Dariusz

2017-06-01

Radio emission from the extensive air showers (EASs), initiated by ultrahigh-energy cosmic rays, was theoretically suggested over 50 years ago. However, due to technical limitations, successful collection of sufficient statistics can take several years. Nowadays, this detection technique is used in many experiments consisting in studying EAS. One of them is the Auger Engineering Radio Array (AERA), located within the Pierre Auger Observatory. AERA focuses on the radio emission, generated by the electromagnetic part of the shower, mainly in geomagnetic and charge excess processes. The frequency band observed by AERA radio stations is 30-80 MHz. Thus, the frequency range is contaminated by human-made and narrow-band radio frequency interferences (RFIs). Suppression of contaminations is very important to lower the rate of spurious triggers. There are two kinds of digital filters used in AERA radio stations to suppress these contaminations: the fast Fourier transform median filter and four narrow-band IIR-notch filters. Both filters have worked successfully in the field for many years. An adaptive filter based on a least mean squares (LMS) algorithm is a relatively simple finite impulse response (FIR) filter, which can be an alternative for currently used filters. Simulations in MATLAB are very promising and show that the LMS filter can be very efficient in suppressing RFI and only slightly distorts radio signals. The LMS algorithm was implemented into a Cyclone V field programmable gate array for testing the stability, RFI suppression efficiency, and adaptation time to new conditions. First results show that the FIR filter based on the LMS algorithm can be successfully implemented and used in real AERA radio stations.

Figures of merit for microwave photonic phase shifters based on semiconductor optical amplifiers.

PubMed

Sancho, Juan; Lloret, Juan; Gasulla, Ivana; Sales, Salvador; Capmany, José

2012-05-07

We theoretically and experimentally compare the performance of two fully tunable phase shifter structures based on semiconductor optical amplifiers (SOA) by means of several figures of merit common to microwave photonic systems. A single SOA stage followed by a tailored notch filter is compared with a cascaded implementation comprising three SOA-based phase shifter stages. Attention is focused on the assessment of the RF net gain, noise figure and nonlinear distortion. Recommendations on the performance optimization of this sort of approaches are detailed.

A 2D Electron Density and Plasma Current Density Diagnostic for Opening Switches

DTIC Science & Technology

2006-02-01

x, y)) can be recovered by taking the inverse transform of C(f - f,, y), and calculating the inverse tangent of the ratio of its real and imaginary...parts, 27rfox + (x,y) = tan-1 [Re(IT)/Im(IT)], (7) where IT represents the inverse transform of C(f - fo, y). There are a number of options available...notch filtering around f, before the inverse transform is taken. However, since frequency space is discrete due to the discrete nature of the FFT, we

NASA Tech Briefs, August 2004

NASA Technical Reports Server (NTRS)

2004-01-01

Topics covered include: Data Relay Board with Protocol for High-Speed, Free-Space Optical Communications; Software and Algorithms for Biomedical Image Data Processing and Visualization; Rapid Chemometric Filtering of Spectral Data; Prioritizing Scientific Data for Transmission; Determining Sizes of Particles in a Flow from DPIV Data; Faster Processing for Inverting GPS Occultation Data; FPGA-Based, Self-Checking, Fault-Tolerant Computers; Ultralow-Power Digital Correlator for Microwave Polarimetry; Grounding Headphones for Protection Against ESD; Lightweight Stacks of Direct Methanol Fuel Cells; Highly Efficient Vector-Inversion Pulse Generators; Estimating Basic Preliminary Design Performances of Aerospace Vehicles; Framework for Development of Object-Oriented Software; Analyzing Spacecraft Telecommunication Systems; Collaborative Planning of Robotic Exploration; Tools for Administration of a UNIX-Based Network; Preparing and Analyzing Iced Airfoils; Evaluating Performance of Components; Fuels Containing Methane of Natural Gas in Solution; Direct Electrolytic Deposition of Mats of MnxOy Nanowires; Bubble Eliminator Based on Centrifugal Flow; Inflatable Emergency Atmospheric-Entry Vehicles; Lightweight Deployable Mirrors with Tensegrity Supports; Centrifugal Adsorption Cartridge System; Ultrasonic Apparatus for Pulverizing Brittle Material; Transplanting Retinal Cells using Bucky Paper for Support; Using an Ultrasonic Instrument to Size Extravascular Bubbles; Coronagraphic Notch Filter for Raman Spectroscopy; On-the-Fly Mapping for Calibrating Directional Antennas; Working Fluids for Increasing Capacities of Heat Pipes; Computationally-Efficient Minimum-Time Aircraft Routes in the Presence of Winds; Liquid-Metal-Fed Pulsed Plasma Thrusters; Personal Radiation Protection System; and Attitude Control for a Solar-Sail Spacecraft.

Effects of Notch2 and Notch3 on Cell Proliferation and Apoptosis of Trophoblast Cell Lines.

PubMed

Zhao, Wei-Xiu; Zhuang, Xu; Huang, Tao-Tao; Feng, Ran; Lin, Jian-Hua

2015-01-01

To investigate the effect of Notch2 and Notch3 on cell proliferation and apoptosis of two trophoblast cell lines, BeWo and JAR. Notch2 and Notch3 expression in BeWo and JAR cells was upregulated or downregulated using lentivirus-mediated overexpression or RNA interference. The effect of Notch2 and Notch3 on cell proliferation was assessed by the CCK-8 assay. The effect of Notch2 and Notch3 on the apoptosis of BeWo and JAR cells was evaluated by flow cytometry using the Annexin V-PE Apoptosis kit. Lentivirus-based overexpression vectors were constructed by cloning the full-length coding sequences of human Notch2 and Notch3 C-terminally tagged with GFP or GFP alone (control) into a lentivirus-based expression vector. Lentivirus-based gene silencing vectors were prepared by cloning small interfering sequences targeting human Notch2 and Notch3 and scrambled control RNA sequence into a lentivirus-based gene knockdown vector. The effect of Notch2 and Notch3 on cell proliferation was assessed by the CCK-8 assay. And the effect of Notch2 and Notch3 on the apoptosis of BeWo and JAR cells was evaluated by flow cytometry using the Annexin V PE Apoptosis kit. We found that the downregulation of Notch2 and Notch3 gene expression in BeWo and JAR cells resulted in an increase in cell proliferation, while upregulation of Notch3 and Notch2 expression led to a decrease in cell proliferation. Moreover, the overexpression of Notch3 and Notch2 in BeWo and JAR cells reduced apoptosis in these trophoblast cell lines, whereas apoptosis was increased in the cells in which the expression of Notch3 and Notch2 was downregulated. Notch2 and Notch3 inhibited both cell proliferation and cell apoptosis in BeWo and JAR trophoblast cell lines.

Research and development of a control system for multi axis cooperative motion based on PMAC

NASA Astrophysics Data System (ADS)

Guo, Xiao-xiao; Dong, Deng-feng; Zhou, Wei-hu

2017-10-01

Based on Programmable Multi-axes Controller (PMAC), a design of a multi axis motion control system for the simulator of spatial targets' dynamic optical properties is proposed. According to analysis the properties of spatial targets' simulator motion control system, using IPC as the main control layer, TurboPMAC2 as the control layer to meet coordinated motion control, data acquisition and analog output. A simulator using 5 servomotors which is connected with speed reducers to drive the output axis was implemented to simulate the motion of both the sun and the space target. Based on PMAC using PID and a notch filter algorithm, negative feedback, the speed and acceleration feed forward algorithm to satisfy the axis' requirements of the good stability and high precision at low speeds. In the actual system, it shows that the velocity precision is higher than 0.04 s ° and the precision of repetitive positioning is better than 0.006° when each axis is at a low-speed. Besides, the system achieves the control function of multi axis coordinated motion. The design provides an important technical support for detecting spatial targets, also promoting the theoretical research.

The common oncogenomic program of NOTCH1 and NOTCH3 signaling in T-cell acute lymphoblastic leukemia.

PubMed

Choi, Sung Hee; Severson, Eric; Pear, Warren S; Liu, Xiaole S; Aster, Jon C; Blacklow, Stephen C

2017-01-01

Notch is a major oncogenic driver in T cell acute lymphoblastic leukemia (T-ALL), in part because it binds to an enhancer that increases expression of MYC. Here, we exploit the capacity of activated NOTCH1 and NOTCH3 to induce T-ALL, despite substantial divergence in their intracellular regions, as a means to elucidate a broad, common Notch-dependent oncogenomic program through systematic comparison of the transcriptomes and Notch-bound genomic regulatory elements of NOTCH1- and NOTCH3-dependent T-ALL cells. ChIP-seq studies show a high concordance of functional NOTCH1 and NOTCH3 genomic binding sites that are enriched in binding motifs for RBPJ, the transcription factor that recruits activated Notch to DNA. The interchangeability of NOTCH1 and NOTCH3 was confirmed by rescue of NOTCH1-dependent T-ALL cells with activated NOTCH3 and vice versa. Despite remarkable overall similarity, there are nuanced differences in chromatin landscapes near critical common Notch target genes, most notably at a Notch-dependent enhancer that regulates MYC, which correlates with responsiveness to Notch pathway inhibitors. Overall, a common oncogenomic program driven by binding of either Notch is sufficient to maintain T-ALL cell growth, whereas cell-context specific differences appear to influence the response of T-ALL cells to Notch inhibition.

The common oncogenomic program of NOTCH1 and NOTCH3 signaling in T-cell acute lymphoblastic leukemia

PubMed Central

Pear, Warren S.; Liu, Xiaole S.; Aster, Jon C.

2017-01-01

Notch is a major oncogenic driver in T cell acute lymphoblastic leukemia (T-ALL), in part because it binds to an enhancer that increases expression of MYC. Here, we exploit the capacity of activated NOTCH1 and NOTCH3 to induce T-ALL, despite substantial divergence in their intracellular regions, as a means to elucidate a broad, common Notch-dependent oncogenomic program through systematic comparison of the transcriptomes and Notch-bound genomic regulatory elements of NOTCH1- and NOTCH3-dependent T-ALL cells. ChIP-seq studies show a high concordance of functional NOTCH1 and NOTCH3 genomic binding sites that are enriched in binding motifs for RBPJ, the transcription factor that recruits activated Notch to DNA. The interchangeability of NOTCH1 and NOTCH3 was confirmed by rescue of NOTCH1-dependent T-ALL cells with activated NOTCH3 and vice versa. Despite remarkable overall similarity, there are nuanced differences in chromatin landscapes near critical common Notch target genes, most notably at a Notch-dependent enhancer that regulates MYC, which correlates with responsiveness to Notch pathway inhibitors. Overall, a common oncogenomic program driven by binding of either Notch is sufficient to maintain T-ALL cell growth, whereas cell-context specific differences appear to influence the response of T-ALL cells to Notch inhibition. PMID:29023469

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

A Dynamic Attitude Measurement System Based on LINS

PubMed Central

Li, Hanzhou; Pan, Quan; Wang, Xiaoxu; Zhang, Juanni; Li, Jiang; Jiang, Xiangjun

2014-01-01

A dynamic attitude measurement system (DAMS) is developed based on a laser inertial navigation system (LINS). Three factors of the dynamic attitude measurement error using LINS are analyzed: dynamic error, time synchronization and phase lag. An optimal coning errors compensation algorithm is used to reduce coning errors, and two-axis wobbling verification experiments are presented in the paper. The tests indicate that the attitude accuracy is improved 2-fold by the algorithm. In order to decrease coning errors further, the attitude updating frequency is improved from 200 Hz to 2000 Hz. At the same time, a novel finite impulse response (FIR) filter with three notches is designed to filter the dither frequency of the ring laser gyro (RLG). The comparison tests suggest that the new filter is five times more effective than the old one. The paper indicates that phase-frequency characteristics of FIR filter and first-order holder of navigation computer constitute the main sources of phase lag in LINS. A formula to calculate the LINS attitude phase lag is introduced in the paper. The expressions of dynamic attitude errors induced by phase lag are derived. The paper proposes a novel synchronization mechanism that is able to simultaneously solve the problems of dynamic test synchronization and phase compensation. A single-axis turntable and a laser interferometer are applied to verify the synchronization mechanism. The experiments results show that the theoretically calculated values of phase lag and attitude error induced by phase lag can both match perfectly with testing data. The block diagram of DAMS and physical photos are presented in the paper. The final experiments demonstrate that the real-time attitude measurement accuracy of DAMS can reach up to 20″ (1σ) and the synchronization error is less than 0.2 ms on the condition of three axes wobbling for 10 min. PMID:25177802

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.

An Energy-Efficient Algorithm for Wearable Electrocardiogram Signal Processing in Ubiquitous Healthcare Applications

PubMed Central

Sodhro, Ali Hassan; Sodhro, Gul Hassan; Lohano, Sonia; Pirbhulal, Sandeep

2018-01-01

Rapid progress and emerging trends in miniaturized medical devices have enabled the un-obtrusive monitoring of physiological signals and daily activities of everyone’s life in a prominent and pervasive manner. Due to the power-constrained nature of conventional wearable sensor devices during ubiquitous sensing (US), energy-efficiency has become one of the highly demanding and debatable issues in healthcare. This paper develops a single chip-based wearable wireless electrocardiogram (ECG) monitoring system by adopting analog front end (AFE) chip model ADS1292R from Texas Instruments. The developed chip collects real-time ECG data with two adopted channels for continuous monitoring of human heart activity. Then, these two channels and the AFE are built into a right leg drive right leg drive (RLD) driver circuit with lead-off detection and medical graded test signal. Human ECG data was collected at 60 beats per minute (BPM) to 120 BPM with 60 Hz noise and considered throughout the experimental set-up. Moreover, notch filter (cutoff frequency 60 Hz), high-pass filter (cutoff frequency 0.67 Hz), and low-pass filter (cutoff frequency 100 Hz) with cut-off frequencies of 60 Hz, 0.67 Hz, and 100 Hz, respectively, were designed with bilinear transformation for rectifying the power-line noise and artifacts while extracting real-time ECG signals. Finally, a transmission power control-based energy-efficient (ETPC) algorithm is proposed, implemented on the hardware and then compared with the several conventional TPC methods. Experimental results reveal that our developed chip collects real-time ECG data efficiently, and the proposed ETPC algorithm achieves higher energy savings of 35.5% with a slightly larger packet loss ratio (PLR) as compared to conventional TPC (e.g., constant TPC, Gao’s, and Xiao’s methods). PMID:29558433

An Energy-Efficient Algorithm for Wearable Electrocardiogram Signal Processing in Ubiquitous Healthcare Applications.

PubMed

Sodhro, Ali Hassan; Sangaiah, Arun Kumar; Sodhro, Gul Hassan; Lohano, Sonia; Pirbhulal, Sandeep

2018-03-20

Rapid progress and emerging trends in miniaturized medical devices have enabled the un-obtrusive monitoring of physiological signals and daily activities of everyone's life in a prominent and pervasive manner. Due to the power-constrained nature of conventional wearable sensor devices during ubiquitous sensing (US), energy-efficiency has become one of the highly demanding and debatable issues in healthcare. This paper develops a single chip-based wearable wireless electrocardiogram (ECG) monitoring system by adopting analog front end (AFE) chip model ADS1292R from Texas Instruments. The developed chip collects real-time ECG data with two adopted channels for continuous monitoring of human heart activity. Then, these two channels and the AFE are built into a right leg drive right leg drive (RLD) driver circuit with lead-off detection and medical graded test signal. Human ECG data was collected at 60 beats per minute (BPM) to 120 BPM with 60 Hz noise and considered throughout the experimental set-up. Moreover, notch filter (cutoff frequency 60 Hz), high-pass filter (cutoff frequency 0.67 Hz), and low-pass filter (cutoff frequency 100 Hz) with cut-off frequencies of 60 Hz, 0.67 Hz, and 100 Hz, respectively, were designed with bilinear transformation for rectifying the power-line noise and artifacts while extracting real-time ECG signals. Finally, a transmission power control-based energy-efficient (ETPC) algorithm is proposed, implemented on the hardware and then compared with the several conventional TPC methods. Experimental results reveal that our developed chip collects real-time ECG data efficiently, and the proposed ETPC algorithm achieves higher energy savings of 35.5% with a slightly larger packet loss ratio (PLR) as compared to conventional TPC (e.g., constant TPC, Gao's, and Xiao's methods).

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

A complex multi-notch astronomical filter to suppress the bright infrared sky.

PubMed

Bland-Hawthorn, J; Ellis, S C; Leon-Saval, S G; Haynes, R; Roth, M M; Löhmannsröben, H-G; Horton, A J; Cuby, J-G; Birks, T A; Lawrence, J S; Gillingham, P; Ryder, S D; Trinh, C

2011-12-06

A long-standing and profound problem in astronomy is the difficulty in obtaining deep near-infrared observations due to the extreme brightness and variability of the night sky at these wavelengths. A solution to this problem is crucial if we are to obtain the deepest possible observations of the early Universe, as redshifted starlight from distant galaxies appears at these wavelengths. The atmospheric emission between 1,000 and 1,800 nm arises almost entirely from a forest of extremely bright, very narrow hydroxyl emission lines that varies on timescales of minutes. The astronomical community has long envisaged the prospect of selectively removing these lines, while retaining high throughput between them. Here we demonstrate such a filter for the first time, presenting results from the first on-sky tests. Its use on current 8 m telescopes and future 30 m telescopes will open up many new research avenues in the years to come.

Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation.

PubMed

Huang, Yin-Cheng; Lin, Sheng-Jia; Shih, Hung-Yu; Chou, Chung-Han; Chu, Hsiao-Han; Chiu, Ching-Chi; Yuh, Chiou-Hwa; Yeh, Tu-Hsueh; Cheng, Yi-Chuan

2017-09-08

Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased the DNA methylation of NOTCH1 and NOTCH3 and reduced the expression of NOTCH1 and NOTCH3 . NOTCH1 or NOTCH3 activation inhibited U-87 MG cell proliferation, whereas NOTCH1 and NOTCH3 inhibition by shRNAs induced cell proliferation, thus demonstrating the tumor-suppressive ability of NOTCH1 and NOTCH3 in U-87 MG cells. The induced cell proliferation caused by KMT2A knockdown could be nullified by using either constitutively active NOTCH1 or constitutively active NOTCH3. This result demonstrates that KMT2A positively regulates NOTCH1 and NOTCH3 and that this mechanism is essential for inhibiting the U-87 MG cell proliferation. The role of KMT2A knockdown in promoting tumor growth was further confirmed in vivo by transplanting U-87 MG cells into the brains of zebrafish larvae. In conclusion, we identified KMT2A-NOTCH as a negative regulatory cascade for glioblastoma cell proliferation, and this result provides important information for KMT2A- or NOTCH-targeted therapeutic strategies for brain tumors.

Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis

PubMed Central

Shi, Jianjun; Fallahi, Mohammad; Luo, Jun-Li

2011-01-01

Notch1 signaling is absolutely essential for steady-state thymic lymphopoiesis, but the role of other Notch receptors, and their potential overlap with the function of Notch1, remains unclear. Here we show that like Notch1, Notch3 is differentially expressed by progenitor thymocytes, peaking at the DN3 progenitor stage. Using mice carrying a gene-trapped allele, we show that thymic cellularity is slightly reduced in the absence of Notch3, although progression through the defined sequence of TCR-αβ development is normal, as are NKT and TCRγδ cell production. The absence of a profound effect from Notch3 deletion is not explained by residual function of the gene-trapped allele because insertion mapping suggests that the targeted allele would not encode functional signaling domains. We also show that although Notch1 and Notch3 are coexpressed on some early intrathymic progenitors, the relatively mild phenotype seen after Notch3 deletion does not result from the compensatory function of Notch1, nor does Notch3 function explain the likewise mild phenotype seen after conditional (intrathymic) deletion of Notch1. Our studies indicate that Notch1 and Notch3 carry out nonoverlapping functions during thymocyte differentiation, and that while Notch1 is absolutely required early in the lymphopoietic process, neither receptor is essential at later stages. PMID:21768299

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

PubMed

Baeten, Jeremy T; Lilly, Brenda

2015-06-26

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. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Design of a Compact Tuning Fork-Shaped Notched Ultrawideband Antenna for Wireless Communication Application

PubMed Central

Shakib, M. N.; Moghavvemi, M.; Mahadi, W. N. L.

2014-01-01

A new compact planar notched ultrawideband (UWB) antenna is designed for wireless communication application. The proposed antenna has a compact size of 0.182λ × 0.228λ × 0.018λ where λ is the wavelength of the lowest operating frequency. The antenna is comprised of rectangular radiating patch, ground plane, and an arc-shaped strip in between radiating patch and feed line. By introducing a new Tuning Fork-shaped notch in the radiating plane, a stopband is obtained. The antenna is tested and measured. The measured result indicated that fabricated antenna has achieved a wide bandwidth of 4.33–13.8 GHz (at −10 dB return loss) with a rejection frequency band of 5.28–6.97 GHz (WiMAX, WLAN, and C-band). The effects of the parameters of the antenna are discussed. The experiment results demonstrate that the proposed antenna can well meet the requirement for the UWB communication in spite of its compactness and small size. PMID:24723835

Rational design of gold nanocarrier for the delivery of JAG-1 peptide.

PubMed

Matea, Cristian T; Mocan, Teodora; Tabaran, Flaviu; Iancu, Cornel; Mocan, Lucian-Constantin

2015-06-16

Unique properties exhibited by nanoparticles makes them great candidates for applications in physics, chemistry, biology, material science and medicine. The biological applications of water-soluble gold nanoparticles range from contrast agents, delivery vehicles to therapeutics. Notch signaling is a complex network that orchestrates cell fate decisions, which involves proliferation, migration, differentiation and cell death in organisms ranging from insects to humans. Studies have showed that a correct orientation of the Jag-1 signalling protein on the substrates proves to be of great importance when promoting Jagged-1 Notch interactions, also the availability of the ligands, super cedes the importance of their concentration. The aim of the present study was to synthetize a Jag-1 functionalized nanocarrier, which would promote an efficient interaction between the Jag-1 peptide and the Notch receptor. To this end, two routes for gold nanoparticle-peptide assembly were investigated, and the synthetized bio-nanostructures were characterized and compared by means of UV-Vis, FT-IR, DLS and AFM techniques. We have obtained a stable, monodisperse, hetero-functionalized GNP-PEG-JAG-1 bio-nanostructure for Notch pathway activation applications.

Compensation based on linearized analysis for a six degree of freedom motion simulator

NASA Technical Reports Server (NTRS)

Parrish, R. V.; Dieudonne, J. E.; Martin, D. J., Jr.; Copeland, J. L.

1973-01-01

The inertial response characteristics of a synergistic, six-degree-of-freedom motion base are presented in terms of amplitude ratio and phase lag as functions of frequency data for the frequency range of interest (0 to 2 Hz) in real time, digital, flight simulators. The notch filters which smooth the digital-drive signals to continuous drive signals are presented, and appropriate compensation, based on the inertial response data, is suggested. The existence of an inverse transformation that converts actuator extensions into inertial positions makes it possible to gather the response data in the inertial axis system.

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

Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region.

PubMed

Xu, Xiang; Choi, Sung Hee; Hu, Tiancen; Tiyanont, Kittichoat; Habets, Roger; Groot, Arjan J; Vooijs, Marc; Aster, Jon C; Chopra, Rajiv; Fryer, Christy; Blacklow, Stephen C

2015-07-07

Notch receptors are transmembrane proteins that undergo activating proteolysis in response to ligand stimulation. A negative regulatory region (NRR) maintains receptor quiescence by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of autoinhibited human Notch3, and compare it with the Notch1 and Notch2 NRRs. The overall architecture of the autoinhibited conformation, in which three LIN12-Notch repeat (LNR) modules wrap around a heterodimerization domain, is preserved in Notch3, but the autoinhibited conformation of the Notch3 NRR is less stable. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the crystal. Similar homotypic interfaces exist in Notch1 and Notch2. Together, these studies reveal distinguishing structural features associated with increased basal activity of Notch3, demonstrate increased ligand-independent signaling for disease-associated mutations that map to the Notch3 NRR, and identify a conserved dimerization interface present in multiple Notch receptors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Loss of Notch2 and Notch3 in vascular smooth muscle causes patent ductus arteriosus.

PubMed

Baeten, Jeremy T; Jackson, Ashley R; McHugh, Kirk M; Lilly, Brenda

2015-12-01

The overlapping roles of the predominant Notch receptors in vascular smooth muscle cells, Notch2 and Notch3, have not been clearly defined in vivo. In this study, we use a smooth muscle-specific deletion of Notch2 together with a global Notch3 deletion to produce mice with combinations of mutant and wild-type Notch2/3 alleles in vascular smooth muscle cells. Mice with complete loss of Notch3 and smooth muscle-expressed Notch2 display late embryonic lethality and subcutaneous hemorrhage. Mice without smooth muscle-Notch2 and only one wild-type copy of Notch3 die within one day of birth and present with vascular defects, most notably patent ductus arteriosus (DA) and aortic dilation. These defects were associated with decreased expression of contractile markers in both the DA and aorta. These results demonstrate that Notch2 and Notch3 have overlapping roles in promoting development of vascular smooth muscle cells, and together contribute to functional closure of the DA. © 2015 Wiley Periodicals, Inc.

Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma.

PubMed

Natsuizaka, Mitsuteru; Whelan, Kelly A; Kagawa, Shingo; Tanaka, Koji; Giroux, Veronique; Chandramouleeswaran, Prasanna M; Long, Apple; Sahu, Varun; Darling, Douglas S; Que, Jianwen; Yang, Yizeng; Katz, Jonathan P; Wileyto, E Paul; Basu, Devraj; Kita, Yoshiaki; Natsugoe, Shoji; Naganuma, Seiji; Klein-Szanto, Andres J; Diehl, J Alan; Bass, Adam J; Wong, Kwok-Kin; Rustgi, Anil K; Nakagawa, Hiroshi

2017-11-24

Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial-mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.

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

PubMed Central

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

2009-01-01

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

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

PubMed Central

HAYASHI, YOSHIHIRO; OSANAI, MAKOTO; LEE, GANG-HONG

2015-01-01

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. PMID:26252838

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.

Discrete Notch signaling requirements in the specification of hematopoietic stem cells

PubMed Central

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

2014-01-01

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

Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions

PubMed Central

Intskirveli, Irakli

2017-01-01

Abstract Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral “notch” of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing. PMID:28660244

The Challenge of Targeting Notch in Hematologic Malignancies

PubMed Central

Hernandez Tejada, Fiorela N.; Galvez Silva, Jorge R.; Zweidler-McKay, Patrick A.

2014-01-01

Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic malignancies encompass a wide range of transformed cells, and consequently the roles of Notch are diverse in these diseases. For example Notch is a potent T-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carry activating mutations in the Notch1 receptor. Targeting Notch signaling in T-ALL with gamma-secretase inhibitors, which prevent Notch receptor activation, has shown pre-clinical activity, and is under evaluation clinically. In contrast, Notch signaling inhibits acute myeloblastic leukemia growth and survival, and although targeting Notch signaling in AML with Notch activators appears to have pre-clinical activity, no Notch agonists are clinically available at this time. As such, despite accumulating evidence about the biology of Notch signaling in different hematologic cancers, which provide compelling clinical promise, we are only beginning to target this pathway clinically, either on or off. In this review, we will summarize the evidence for oncogenic and tumor suppressor roles of Notch in a wide range of leukemias and lymphomas, and describe therapeutic opportunities for now and the future. PMID:24959528

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.

An Antibody to Notch2 Reverses the Osteopenic Phenotype of Hajdu-Cheney Mutant Male Mice

PubMed Central

Sanjay, Archana; Yu, Jungeun; Zanotti, Stefano

2017-01-01

Notch receptors play a central role in skeletal development and bone remodeling. Hajdu-Cheney syndrome (HCS), a disease characterized by osteoporosis and fractures, is associated with gain-of-NOTCH2 function mutations. To study HCS, we created a mouse model harboring a point 6955C>T mutation in the Notch2 locus upstream of the proline, glutamic acid, serine, and threonine domain, leading to a Q2319X change at the amino acid level. Notch2Q2319X heterozygous mutants exhibited cancellous and cortical bone osteopenia. Microcomputed tomography demonstrated that the cancellous and cortical osteopenic phenotype was reversed by the administration of antibodies generated against the negative regulatory region (NRR) of Notch2, previously shown to neutralize Notch2 activity. Bone histomorphometry revealed that anti-Notch2 NRR antibodies decreased the osteoclast number and eroded surface in cancellous bone of Notch2Q2319X mice. An increase in osteoclasts on the endocortical surface of Notch2Q2319X mice was not observed in the presence of anti-Notch2 NRR antibodies. The anti-Notch2 NRR antibody decreased the induction of Notch target genes and Tnfsf11 messenger RNA levels in bone extracts and osteoblasts from Notch2Q2319X mice. In vitro experiments demonstrated increased osteoclastogenesis in Notch2Q2319X mutants in response to macrophage colony-stimulating factor and receptor activator of nuclear factor–κB ligand, and these effects were suppressed by the anti-Notch2 NRR. In conclusion, Notch2Q2319X mice exhibit cancellous and cortical bone osteopenia that can be corrected by the administration of anti-Notch2 NRR antibodies. PMID:28323963

CONNECTIVE TISSUE GROWTH FACTOR IS A TARGET OF NOTCH SIGNALING IN CELLS OF THE OSTEOBLASTIC LINEAGE

PubMed Central

Canalis, Ernesto; Zanotti, Stefano; Smerdel-Ramoya, Anna

2014-01-01

Connective tissue growth factor (Ctgf) or CCN2 is a protein synthesized by osteoblasts necessary for skeletal homeostasis, although its overexpression inhibits osteogenic signals and bone formation. Ctgf is induced by bone morphogenetic proteins, transforming growth factor β and Wnt; and in the present studies, we explored whether Notch regulated Ctgf expression in osteoblasts. We employed RosaNotch mice, where the Notch intracellular domain (NICD) is expressed following the excision of a STOP cassette, placed between the Rosa26 promoter and NICD. Notch was activated by transduction of adenoviral vectors expressing Cre recombinase (Ad-CMV-Cre). Notch induced Ctgf mRNA levels in a time dependent manner and increased Ctgf heterogeneous nuclear RNA. Notch also destabilized Ctgf mRNA shortening its half-life from 13 h to 3 h. The effect of Notch on Ctgf expression was lost following Rbpjκ downregulation, demonstrating that it was mediated by Notch canonical signaling. However, downregulation of the classic Notch target genes Hes1, Hey1 and Hey2 did not modify the effect of Notch on Ctgf expression. Wild type osteoblasts exposed to immobilized Delta-like 1 displayed enhanced Notch signaling and increased Ctgf expression. In addition to the effects of Notch in vitro, Notch induced Ctgf in vivo, and calvariae and femurs from RosaNotch mice mated with transgenics expressing the Cre recombinase in cells of the osteoblastic lineage exhibited increased expression of Ctgf. In conclusion, Ctgf is a target of Notch canonical signaling in osteoblasts, and may act in concert with Notch to regulate skeletal homeostasis. PMID:24792956

O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals.

PubMed

Sawaguchi, Shogo; Varshney, Shweta; Ogawa, Mitsutaka; Sakaidani, Yuta; Yagi, Hirokazu; Takeshita, Kyosuke; Murohara, Toyoaki; Kato, Koichi; Sundaram, Subha; Stanley, Pamela; Okajima, Tetsuya

2017-04-11

The glycosyltransferase EOGT transfers O-GlcNAc to a consensus site in epidermal growth factor-like (EGF) repeats of a limited number of secreted and membrane proteins, including Notch receptors. In EOGT-deficient cells, the binding of DLL1 and DLL4, but not JAG1, canonical Notch ligands was reduced, and ligand-induced Notch signaling was impaired. Mutagenesis of O-GlcNAc sites on NOTCH1 also resulted in decreased binding of DLL4. EOGT functions were investigated in retinal angiogenesis that depends on Notch signaling. Global or endothelial cell-specific deletion of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt -/- retina, and Notch target gene expression was decreased in Eogt -/- endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development.

Notch2 blockade enhances hematopoietic stem cell mobilization and homing.

PubMed

Wang, Weihuan; Yu, Shuiliang; Myers, Jay; Wang, Yiwei; Xin, William W; Albakri, Marwah; Xin, Alison W; Li, Ming; Huang, Alex Y; Xin, Wei; Siebel, Christian W; Lazarus, Hillard M; Zhou, Lan

2017-10-01

Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation (HCT) may only mobilize limited numbers of hematopoietic progenitor cells (HPCs) into blood, precluding use of the procedure, or being placed at increased risk of complications due to slow hematopoietic reconstitution. Developing more efficacious HPC mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is not essential for homeostasis of adult hematopoietic stem cells (HSCs), Notch-ligand adhesive interaction maintains HSC quiescence and niche retention. Using Notch receptor blocking antibodies, we report that Notch2 blockade, but not Notch1 blockade, sensitizes hematopoietic stem cells and progenitors (HSPCs) to mobilization stimuli and leads to enhanced egress from marrow to the periphery. Notch2 blockade leads to transient myeloid progenitor expansion without affecting HSC homeostasis and self-renewal. We show that transient Notch2 blockade or Notch2-loss in mice lacking Notch2 receptor lead to decreased CXCR4 expression by HSC but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. In addition, we found that Notch2-blocked or Notch2-deficient marrow HSPCs show an increased homing to the marrow, while mobilized Notch2-blocked, but not Notch2-deficient stem cells and progenitors, displayed a competitive repopulating advantage and enhanced hematopoietic reconstitution. These findings suggest that blocking Notch2 combined with the current clinical regimen may further enhance HPC mobilization and improve engraftment during HCT. Copyright© 2017 Ferrata Storti Foundation.

Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies.

PubMed

Bernasconi-Elias, P; Hu, T; Jenkins, D; Firestone, B; Gans, S; Kurth, E; Capodieci, P; Deplazes-Lauber, J; Petropoulos, K; Thiel, P; Ponsel, D; Hee Choi, S; LeMotte, P; London, A; Goetcshkes, M; Nolin, E; Jones, M D; Slocum, K; Kluk, M J; Weinstock, D M; Christodoulou, A; Weinberg, O; Jaehrling, J; Ettenberg, S A; Buckler, A; Blacklow, S C; Aster, J C; Fryer, C J

2016-11-24

Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST (proline, glutamate, serine, threonine) domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that 2 of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, 2 of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies.

Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies

PubMed Central

Bernasconi-Elias, Paula; Hu, Tiancen; Jenkins, David; Firestone, Brant; Gans, Sara; Kurth, Esther; Capodieci, Paola; Deplazes-Lauber, Joelle; Petropoulos, Konstantin; Thiel, Phillip; Ponsel, Dirk; Choi, Sung Hee; LeMotte, Peter; London, Anne; Goetcshkes, Margaret; Nolin, Erin; Jones, Michael D.; Slocum, Kelly; Kluk, Michael J.; Weinstock, David M.; Christodoulou, Alexandra; Weinberg, Olga; Jaehrling, Jan; Ettenberg, Seth A.; Buckler, Alan; Blacklow, Stephen C.; Aster, Jon C.; Fryer, Christy J.

2016-01-01

Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that two of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, two of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies. PMID:27157619

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

PubMed

Cheng, Zhenshun; Tan, Qiuyue; Tan, Weijun; Zhang, L I

2015-08-01

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

A Robust Dynamic Heart-Rate Detection Algorithm Framework During Intense Physical Activities Using Photoplethysmographic Signals

PubMed Central

Song, Jiajia; Li, Dan; Ma, Xiaoyuan; Teng, Guowei; Wei, Jianming

2017-01-01

Dynamic accurate heart-rate (HR) estimation using a photoplethysmogram (PPG) during intense physical activities is always challenging due to corruption by motion artifacts (MAs). It is difficult to reconstruct a clean signal and extract HR from contaminated PPG. This paper proposes a robust HR-estimation algorithm framework that uses one-channel PPG and tri-axis acceleration data to reconstruct the PPG and calculate the HR based on features of the PPG and spectral analysis. Firstly, the signal is judged by the presence of MAs. Then, the spectral peaks corresponding to acceleration data are filtered from the periodogram of the PPG when MAs exist. Different signal-processing methods are applied based on the amount of remaining PPG spectral peaks. The main MA-removal algorithm (NFEEMD) includes the repeated single-notch filter and ensemble empirical mode decomposition. Finally, HR calibration is designed to ensure the accuracy of HR tracking. The NFEEMD algorithm was performed on the 23 datasets from the 2015 IEEE Signal Processing Cup Database. The average estimation errors were 1.12 BPM (12 training datasets), 2.63 BPM (10 testing datasets) and 1.87 BPM (all 23 datasets), respectively. The Pearson correlation was 0.992. The experiment results illustrate that the proposed algorithm is not only suitable for HR estimation during continuous activities, like slow running (13 training datasets), but also for intense physical activities with acceleration, like arm exercise (10 testing datasets). PMID:29068403

Effects of innovative virtual reality game and EMG biofeedback on neuromotor control in cerebral palsy.

PubMed

Yoo, Ji Won; Lee, Dong Ryul; Sim, Yon Ju; You, Joshua H; Kim, Cheol J

2014-01-01

Sensorimotor control dysfunction or dyskinesia is a hallmark of neuromuscular impairment in children with cerebral palsy (CP), and is often implicated in reaching and grasping deficiencies due to a neuromuscular imbalance between the triceps and biceps. To mitigate such muscle imbalances, an innovative electromyography (EMG)-virtual reality (VR) biofeedback system were designed to provide accurate information about muscle activation and motivation. However, the clinical efficacy of this approach has not yet been determined in children with CP. The purpose of this study was to investigate the effectiveness of a combined EMG biofeedback and VR (EMG-VR biofeedback) intervention system to improve muscle imbalance between triceps and biceps during reaching movements in children with spastic CP. Raw EMG signals were recorded at a sampling rate of 1,000 Hz, band-pass filtered between 20-450 Hz, and notch-filtered at 60 Hz during elbow flexion and extension movements. EMG data were then processed using MyoResearch Master Edition 1.08 XP software. All participants underwent both interventions consisting of the EMG-VR biofeedback combination and EMG biofeedback alone. EMG analysis resulted in improved muscle activation in the underactive triceps while decreasing overactive or hypertonic biceps in the EMG-VR biofeedback compared with EMG biofeedback. The muscle imbalance ratio between the triceps and biceps was consistently improved. The present study is the first clinical trial to provide evidence for the additive benefits of VR intervention for enhancing the upper limb function of children with spastic CP.

Notch Inhibitors for Cancer Treatment

PubMed Central

Espinoza, Ingrid; Miele, Lucio

2013-01-01

Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been developed. Most of these inhibitors had shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical drugs still under study in different clinical trials. In this review, we describe the basics of Notch signaling and the role of Notch in normal and cancer stem cells as a logic way to develop different Notch inhibitors and their current stage of progress for cancer patient’s treatment. PMID:23458608

Epithelial transformation by KLF4 requires Notch1 but not canonical Notch1 signaling

PubMed Central

Liu, Zhaoli; Teng, Lihong; Bailey, Sarah K.; Frost, Andra R.; Bland, Kirby I.; LoBuglio, Albert F.; Ruppert, J. Michael; Lobo-Ruppert, Susan M.

2009-01-01

The transcription factors Notch1 and KLF4 specify epithelial cell fates and confer stem cell properties. suggesting a functional relationship, each gene can act to promote or suppress tumorigenesis in a context-dependent manner, and alteration of KLF4 or Notch pathway genes in mice gives rise to similar phenotypes. Activation of a conditional allele of KLF4 in RK3E epithelial cells rapidly induces expression of Notch1 mRNA and the active, intracellular form of Notch1. KLF4-induced transformation was suppressed by knockdown of endogenous Notch1 using siRNA or an inhibitor of γ-secretase. Chromatin immunoprecipitation assay shows that KLF4 binds to the proximal Notch1 promoter in human mammary epithelial cells, and siRNA-mediated suppression of KLF4 in human mammary cancer cells results in reduced expression of Notch1. Furthermore, KLF4 and Notch1 expression are correlated in primary human breast tumors (N = 89; pearson analysis, r > 0.5, p < 0.0001). Like KLF4, Notch1 was previously shown to induce transformation of rat cells immortalized with adenovirus E1A, similar to RK3E cells. We therefore compared the signaling requirements for Notch1- or KLF4-induced malignant transformation of RK3E. As expected, transformation by Notch1 was suppressed by dominant-negative CSL or MaML1, inhibitors of canonical Notch1 signaling. However, these inhibitors did not suppress transformation by KLF4. Therefore, while KLF4-induced transformation requires Notch1, canonical Notch1 signaling is not required, and Notch1 may signal through a distinct pathway in cells with increased KLF4 activity. These results suggest that KLF4 could contribute to breast tumor progression by activating synthesis of Notch1 and by promoting signaling through a non-canonical Notch1 pathway. PMID:19717984

Histone deacetylase 6 controls Notch3 trafficking and degradation in T-cell acute lymphoblastic leukemia cells.

PubMed

Pinazza, Marica; Ghisi, Margherita; Minuzzo, Sonia; Agnusdei, Valentina; Fossati, Gianluca; Ciminale, Vincenzo; Pezzè, Laura; Ciribilli, Yari; Pilotto, Giorgia; Venturoli, Carolina; Amadori, Alberto; Indraccolo, Stefano

2018-04-12

Several studies have revealed that endosomal sorting controls the steady-state levels of Notch at the cell surface in normal cells and prevents its inappropriate activation in the absence of ligands. However, whether this highly dynamic physiologic process can be exploited to counteract dysregulated Notch signaling in cancer cells remains unknown. T-ALL is a malignancy characterized by aberrant Notch signaling, sustained by activating mutations in Notch1 as well as overexpression of Notch3, a Notch paralog physiologically subjected to lysosome-dependent degradation in human cancer cells. Here we show that treatment with the pan-HDAC inhibitor Trichostatin A (TSA) strongly decreases Notch3 full-length protein levels in T-ALL cell lines and primary human T-ALL cells xenografted in mice without substantially reducing NOTCH3 mRNA levels. Moreover, TSA markedly reduced the levels of Notch target genes, including pTα, CR2, and DTX-1, and induced apoptosis of T-ALL cells. We further observed that Notch3 was post-translationally regulated following TSA treatment, with reduced Notch3 surface levels and increased accumulation of Notch3 protein in the lysosomal compartment. Surface Notch3 levels were rescued by inhibition of dynein with ciliobrevin D. Pharmacologic studies with HDAC1, 6, and 8-specific inhibitors disclosed that these effects were largely due to inhibition of HDAC6 in T-ALL cells. HDAC6 silencing by specific shRNA was followed by reduced Notch3 expression and increased apoptosis of T-ALL cells. Finally, HDAC6 silencing impaired leukemia outgrowth in mice, associated with reduction of Notch3 full-length protein in vivo. These results connect HDAC6 activity to regulation of total and surface Notch3 levels and suggest HDAC6 as a potential novel therapeutic target to lower Notch signaling in T-ALL and other Notch3-addicted tumors.

A New Reassigned Spectrogram Method in Interference Detection for GNSS Receivers.

PubMed

Sun, Kewen; Jin, Tian; Yang, Dongkai

2015-09-02

Interference detection is very important for Global Navigation Satellite System (GNSS) receivers. Current work on interference detection in GNSS receivers has mainly focused on time-frequency (TF) analysis techniques, such as spectrogram and Wigner-Ville distribution (WVD), where the spectrogram approach presents the TF resolution trade-off problem, since the analysis window is used, and the WVD method suffers from the very serious cross-term problem, due to its quadratic TF distribution nature. In order to solve the cross-term problem and to preserve good TF resolution in the TF plane at the same time, in this paper, a new TF distribution by using a reassigned spectrogram has been proposed in interference detection for GNSS receivers. This proposed reassigned spectrogram method efficiently combines the elimination of the cross-term provided by the spectrogram itself according to its inherent nature and the improvement of the TF aggregation property achieved by the reassignment method. Moreover, a notch filter has been adopted in interference mitigation for GNSS receivers, where receiver operating characteristics (ROCs) are used as metrics for the characterization of interference mitigation performance. The proposed interference detection method by using a reassigned spectrogram is evaluated by experiments on GPS L1 signals in the disturbing scenarios in comparison to the state-of-the-art TF analysis approaches. The analysis results show that the proposed interference detection technique effectively overcomes the cross-term problem and also keeps good TF localization properties, which has been proven to be valid and effective to enhance the interference Sensors 2015, 15 22168 detection performance; in addition, the adoption of the notch filter in interference mitigation has shown a significant acquisition performance improvement in terms of ROC curves for GNSS receivers in jamming environments.

A New Reassigned Spectrogram Method in Interference Detection for GNSS Receivers

PubMed Central

Sun, Kewen; Jin, Tian; Yang, Dongkai

2015-01-01

Interference detection is very important for Global Navigation Satellite System (GNSS) receivers. Current work on interference detection in GNSS receivers has mainly focused on time-frequency (TF) analysis techniques, such as spectrogram and Wigner–Ville distribution (WVD), where the spectrogram approach presents the TF resolution trade-off problem, since the analysis window is used, and the WVD method suffers from the very serious cross-term problem, due to its quadratic TF distribution nature. In order to solve the cross-term problem and to preserve good TF resolution in the TF plane at the same time, in this paper, a new TF distribution by using a reassigned spectrogram has been proposed in interference detection for GNSS receivers. This proposed reassigned spectrogram method efficiently combines the elimination of the cross-term provided by the spectrogram itself according to its inherent nature and the improvement of the TF aggregation property achieved by the reassignment method. Moreover, a notch filter has been adopted in interference mitigation for GNSS receivers, where receiver operating characteristics (ROCs) are used as metrics for the characterization of interference mitigation performance. The proposed interference detection method by using a reassigned spectrogram is evaluated by experiments on GPS L1 signals in the disturbing scenarios in comparison to the state-of-the-art TF analysis approaches. The analysis results show that the proposed interference detection technique effectively overcomes the cross-term problem and also keeps good TF localization properties, which has been proven to be valid and effective to enhance the interference detection performance; in addition, the adoption of the notch filter in interference mitigation has shown a significant acquisition performance improvement in terms of ROC curves for GNSS receivers in jamming environments. PMID:26364637

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

Therapeutic antibody targeting of individual Notch receptors.

PubMed

Wu, Yan; Cain-Hom, Carol; Choy, Lisa; Hagenbeek, Thijs J; de Leon, Gladys P; Chen, Yongmei; Finkle, David; Venook, Rayna; Wu, Xiumin; Ridgway, John; Schahin-Reed, Dorreyah; Dow, Graham J; Shelton, Amy; Stawicki, Scott; Watts, Ryan J; Zhang, Jeff; Choy, Robert; Howard, Peter; Kadyk, Lisa; Yan, Minhong; Zha, Jiping; Callahan, Christopher A; Hymowitz, Sarah G; Siebel, Christian W

2010-04-15

The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.

The Role of Notch3 in Cancer.

PubMed

Aburjania, Zviadi; Jang, Samuel; Whitt, Jason; Jaskula-Stzul, Renata; Chen, Herbert; Rose, J Bart

2018-04-05

The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review article focuses on the third Notch family subtype, Notch3. Regulation via Notch3 signaling was first implicated in vasculogenesis. However, more recent findings suggest that Notch3 signaling may play an important role in oncogenesis, tumor maintenance, and resistance to chemotherapy. Its role is mainly oncogenic, although in some cancers it appears to be tumor suppressive. Despite the wealth of published literature, it remains relatively underexplored and requires further research to shed more light on its role in cancer development, determine its tissue-specific function, and elaborate novel treatment strategies. Herein we summarize the role of Notch3 in cancer, possible mechanisms of its action, and current cancer treatment strategies targeting Notch3 signaling. The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review summarizes the existing data on the third subtype of the Notch family, Notch3. The role of Notch3 in different types of cancers is discussed, as well as implications of its modification and new strategies to affect Notch3 signaling activity. © AlphaMed Press 2018.

Notch Decoys that Selectively Block Dll/Notch or Jagged/Notch Disrupt Angiogenesis by Unique Mechanisms to Inhibit Tumor Growth

PubMed Central

Kangsamaksin, Thaned; Murtomaki, Aino; Kofler, Natalie M.; Cuervo, Henar; Chaudhri, Reyhaan A.; Tattersall, Ian W.; Rosenstiel, Paul E.; Shawber, Carrie J.; Kitajewski, Jan

2015-01-01

A pro-angiogenic role for Jagged-dependent activation of Notch signaling in the endothelium has yet to be described. Using proteins that encoded different NOTCH1 EGF-like repeats, we identified unique regions of DLL-class and JAG-class ligand/receptor interactions, and developed Notch decoys that function as ligand-specific Notch inhibitors. N110-24 decoy blocked JAG1/JAG2-mediated NOTCH1 signaling, angiogenic sprouting in vitro and retinal angiogenesis, demonstrating JAG-dependent Notch signal activation promotes angiogenesis. In tumors, N110-24 decoy reduced angiogenic sprouting, vessel perfusion, pericyte coverage, and tumor growth. JAG/NOTCH signaling uniquely inhibited expression of anti-angiogenic sVEFGFR-1/sFlt-1. N11-13 decoy interfered with DLL1/DLL4-mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis and in tumors. Thus, blockade of JAG- or DLL-mediated Notch signaling inhibits angiogenesis by distinct mechanisms. JAG/Notch signaling positively regulates angiogenesis by suppressing sVEGFR-1/sFlt-1 and promoting mural/endothelial cell interactions. Blockade of JAG-class ligands represents a novel, viable therapeutic approach to block tumor angiogenesis and growth. PMID:25387766

The adhesion force of Notch with Delta and the rate of Notch signaling.

PubMed

Ahimou, Francois; Mok, Lee-Peng; Bardot, Boris; Wesley, Cedric

2004-12-20

Notch signaling is repeatedly used during animal development to specify cell fates. Using atomic force microscopy on live cells, chemical inhibitors, and conventional analyses, we show that the rate of Notch signaling is linked to the adhesion force between cells expressing Notch receptors and Delta ligand. Both the Notch extracellular and intracellular domains are required for the high adhesion force with Delta. This high adhesion force is lost within minutes, primarily due to the action of Presenilin on Notch. Reduced turnover or Delta pulling accelerate this loss. These data suggest that strong adhesion between Notch and Delta might serve as a booster for initiating Notch signaling at a high rate.

NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951.

PubMed

Clappier, E; Collette, S; Grardel, N; Girard, S; Suarez, L; Brunie, G; Kaltenbach, S; Yakouben, K; Mazingue, F; Robert, A; Boutard, P; Plantaz, D; Rohrlich, P; van Vlierberghe, P; Preudhomme, C; Otten, J; Speleman, F; Dastugue, N; Suciu, S; Benoit, Y; Bertrand, Y; Cavé, H

2010-12-01

Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH+ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH+ patients showed a better early response to chemotherapy as compared with NOTCH- patients, according to the rate of poor pre-phase 'responders' (25% versus 44%; P=0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P=0.01) at completion of induction. However, the outcome of NOTCH+ patients was similar to that of NOTCH- patients, with a 5-year event-free survival (EFS) of 73% and 70% (P=0.82), and 5-year overall survival of 82% and 79% (P=0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH+) versus 42% (NOTCH-), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH+) versus 78% (NOTCH-). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1+ patients (8.3%), which could be related to a higher propensity of NOTCH+ leukemic blasts to target the CNS.

Correlation of ALDH1 and Notch3 Expression: Clinical implication in Ovarian Carcinomas.

PubMed

Kim, Mi Joung; Kim, A-Ram; Jeong, Ju-Yeon; Kim, Kwang-Il; Kim, Tae-Heon; Lee, Chan; Chung, Kwanghoe; Ko, Young-Hyeh; An, Hee-Jung

2017-01-01

Purpose : ALDH1 is a putative cancer stem cell marker, while the Notch signaling pathway is involved in regulation of cancer stem cell (CSC)s. This study aims to determine the expression of Notch signaling genes in ovarian CSCs, and to assess the clinical impact of expression of ALDH1 and Notch signaling genes in ovarian cancers. Methods : We examined expression of Notch signaling genes in FACS-sorted ALDH1(+) putative ovarian CSCs and expression of ALDH1 and Notch signaling genes in 86 ovarian epithelial tumors and various ovarian cancer cell lines by real-time RT-PCR, including Notch receptors ( Notch1-4 ), Notch ligands ( Jagged1 and Jagged2 ), and the downstream molecule, Hes1 . Furthermore, we correlated their expression with clinicopathological parameters and patient's survival in ovarian serous carcinoma (OSC)s, the most prevalent type of ovarian cancer. Results : The higher expression levels of ALDH1 and Notch related genes, especially Notch3 were associated with CSCs and with chemoresistant OSCs and paclitaxel-resistant SKpac ovarian cancer cells. Among the Notch signaling genes, high Notch3 expression was significantly associated with all the parameters of poor prognosis, i.e., advanced stage, lymph node and distant metastases, and chemoresistance, whereas other genes were less correlated with these parameters. A combined upregulation of ALDH1 and Notch3 was an independent poor prognostic factor in OSCs. Conclusions : ALDH1 correlates with Notch3 expression in ovarian carcinomas. ALDH1 and Notch3 overexpression is an independent poor prognostic indicator for worse patient's survival in this subset of OSCs.

Toward smart aerospace structures: design of a piezoelectric sensor and its analog interface for flaw detection.

PubMed

Boukabache, Hamza; Escriba, Christophe; Fourniols, Jean-Yves

2014-10-31

Structural health monitoring using noninvasive methods is one of the major challenges that aerospace manufacturers face in this decade. Our work in this field focuses on the development and the system integration of millimetric piezoelectric sensors/ actuators to generate and measure specific guided waves. The aim of the application is to detect mechanical flaws on complex composite and alloy structures to quantify efficiently the global structures' reliability. The study begins by a physical and analytical analysis of a piezoelectric patch. To preserve the structure's integrity, the transducers are directly pasted onto the surface which leads to a critical issue concerning the interfacing layer. In order to improve the reliability and mitigate the influence of the interfacing layer, the global equations of piezoelectricity are coupled with a load transfer model. Thus we can determine precisely the shear strain developed on the surface of the structure. To exploit the generated signal, a high precision analog charge amplifier coupled to a double T notch filter were designed and scaled. Finally, a novel joined time-frequency analysis based on a wavelet decomposition algorithm is used to extract relevant structures signatures. Finally, this paper provides examples of application on aircraft structure specimens and the feasibility of the system is thus demonstrated.

Toward Smart Aerospace Structures: Design of a Piezoelectric Sensor and Its Analog Interface for Flaw Detection

PubMed Central

Boukabache, Hamza; Escriba, Christophe; Fourniols, Jean-Yves

2014-01-01

Structural health monitoring using noninvasive methods is one of the major challenges that aerospace manufacturers face in this decade. Our work in this field focuses on the development and the system integration of millimetric piezoelectric sensors/ actuators to generate and measure specific guided waves. The aim of the application is to detect mechanical flaws on complex composite and alloy structures to quantify efficiently the global structures' reliability. The study begins by a physical and analytical analysis of a piezoelectric patch. To preserve the structure's integrity, the transducers are directly pasted onto the surface which leads to a critical issue concerning the interfacing layer. In order to improve the reliability and mitigate the influence of the interfacing layer, the global equations of piezoelectricity are coupled with a load transfer model. Thus we can determine precisely the shear strain developed on the surface of the structure. To exploit the generated signal, a high precision analog charge amplifier coupled to a double T notch filter were designed and scaled. Finally, a novel joined time-frequency analysis based on a wavelet decomposition algorithm is used to extract relevant structures signatures. Finally, this paper provides examples of application on aircraft structure specimens and the feasibility of the system is thus demonstrated. PMID:25365457

Induction of the Hajdu-Cheney Syndrome Mutation in CD19 B Cells in Mice Alters B-Cell Allocation but Not Skeletal Homeostasis.

PubMed

Yu, Jungeun; Zanotti, Stefano; Schilling, Lauren; Schoenherr, Chris; Economides, Aris N; Sanjay, Archana; Canalis, Ernesto

2018-06-01

Mice harboring Notch2 mutations replicating Hajdu-Cheney syndrome (Notch2 tm1.1ECan ) have osteopenia and exhibit an increase in splenic marginal zone B cells with a decrease in follicular B cells. Whether the altered B-cell allocation is responsible for the osteopenia of Notch2 tm1.1ECan mutants is unknown. To determine the effect of NOTCH2 activation in B cells on splenic B-cell allocation and skeletal phenotype, a conditional-by-inversion (COIN) Hajdu-Cheney syndrome allele of Notch2 (Notch2 [ΔPEST]COIN ) was used. Cre recombination generates a permanent Notch2 ΔPEST allele expressing a transcript for which sequences coding for the proline, glutamic acid, serine, and threonine-rich (PEST) domain are replaced by a stop codon. CD19-Cre drivers were backcrossed into Notch2 [ΔPEST]COIN/[ΔPEST]COIN to generate CD19-specific Notch2 ΔPEST/ΔPEST mutants and control Notch2 [ΔPEST]COIN/[ΔPEST]COIN littermates. There was an increase in marginal zone B cells and a decrease in follicular B cells in the spleen of CD19 Cre/WT ;Notch2 ΔPEST/ΔPEST mice, recapitulating the splenic phenotype of Notch2 tm1.1ECan mice. The effect was reproduced when the NOTCH1 intracellular domain was induced in CD19-expressing cells (CD19 Cre/WT ;Rosa Notch1/WT mice). However, neither CD19 Cre/WT ;Notch2 ΔPEST/ΔPEST nor CD19 Cre/WT ;Rosa Notch1/WT mice had a skeletal phenotype. Moreover, splenectomies in Notch2 tm1.1ECan mice did not reverse their osteopenic phenotype. In conclusion, Notch2 activation in CD19-expressing cells determines B-cell allocation in the spleen but has no skeletal consequences. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in Drosophila axon guidance.

PubMed

Kannan, Ramakrishnan; Cox, Eric; Wang, Lei; Kuzina, Irina; Gu, Qun; Giniger, Edward

2018-01-17

Notch signaling is required for the development and physiology of nearly every tissue in metazoans. Much of Notch signaling is mediated by transcriptional regulation of downstream target genes, but Notch controls axon patterning in Drosophila by local modulation of Abl tyrosine kinase signaling, via direct interactions with the Abl co-factors Disabled and Trio. Here, we show that Notch-Abl axonal signaling requires both of the proteolytic cleavage events that initiate canonical Notch signaling. We further show that some Notch protein is tyrosine phosphorylated in Drosophila , that this form of the protein is selectively associated with Disabled and Trio, and that relevant tyrosines are essential for Notch-dependent axon patterning but not for canonical Notch-dependent regulation of cell fate. Based on these data, we propose a model for the molecular mechanism by which Notch controls Abl signaling in Drosophila axons. © 2018. Published by The Company of Biologists Ltd.

Notch3 overexpression enhances progression and chemoresistance of urothelial carcinoma.

PubMed

Zhang, Heng; Liu, Limei; Liu, Chungang; Pan, Jinhong; Lu, Gensheng; Zhou, Zhansong; Chen, Zhiwen; Qian, Cheng

2017-05-23

Abnormal activation of Notch signaling is involved in the etiology of various diseases, including cancer, but the association between Notch3 expression in urothelial cancer and clinical outcome remains unclear, and the molecular mechanisms underlying Notch3 signaling activation are not well defined. In this study we examined 59 urothelial cancer patients and found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression being associated with poor clinical outcome. Notch3 knockdown resulted in decreased proliferation of urothelial cancer cells in vitro and decreased xenograft tumor growth in vivo. In addition, Notch3 knockdown rendered urothelial cancer cells more sensitive to cisplatin. Furthermore, suberoylanilide hydroxamic acid (SAHA, a histone deacetylase [HDAC] inhibitor) induced acetylation of NOTCH3, downregulated Notch 3, prevented urothelial cancer cell proliferation, and induced cell cycle arrest. Taken together, these data suggested that Notch 3 overexpression promotes growth and chemoresistance in urothelial cancer.

Notch3 overexpression enhances progression and chemoresistance of urothelial carcinoma

PubMed Central

Zhang, Heng; Liu, Limei; Liu, Chungang; Pan, Jinhong; Lu, Gensheng; Zhou, Zhansong; Chen, Zhiwen; Qian, Cheng

2017-01-01

Abnormal activation of Notch signaling is involved in the etiology of various diseases, including cancer, but the association between Notch3 expression in urothelial cancer and clinical outcome remains unclear, and the molecular mechanisms underlying Notch3 signaling activation are not well defined. In this study we examined 59 urothelial cancer patients and found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression being associated with poor clinical outcome. Notch3 knockdown resulted in decreased proliferation of urothelial cancer cells in vitro and decreased xenograft tumor growth in vivo. In addition, Notch3 knockdown rendered urothelial cancer cells more sensitive to cisplatin. Furthermore, suberoylanilide hydroxamic acid (SAHA, a histone deacetylase [HDAC] inhibitor) induced acetylation of NOTCH3, downregulated Notch 3, prevented urothelial cancer cell proliferation, and induced cell cycle arrest. Taken together, these data suggested that Notch 3 overexpression promotes growth and chemoresistance in urothelial cancer. PMID:28416766

Inhibition of Delta-induced Notch signaling using fucose analogs

PubMed Central

Schneider, Michael; Kumar, Vivek; Nordstrøm, Lars Ulrik; Feng, Lei; Takeuchi, Hideyuki; Hao, Huilin; Luca, Vincent C.; Garcia, K. Christopher; Stanley, Pamela; Wu, Peng; Haltiwanger, Robert S.

2017-01-01

Notch is a cell-surface receptor that controls cell fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools for inhibiting Notch activity are being developed as cancer therapeutics. Towards this end, we screened L-fucose analogs for their effects on Notch signaling. Two analogs, 6-alkynyl and 6-alkenyl fucose, were substrates of Pofut1 and were incorporated directly into Notch EGF repeats in cells. Both analogs were potent inhibitors of binding to and activation of Notch1 by Notch ligands Dll1 and Dll4, but not by Jag1. Mutagenesis and modeling studies suggest that incorporation of the analogs into EGF8 of Notch1 markedly reduces the ability of Delta ligands to bind and activate Notch1. PMID:29176671

N-acetylcysteine negatively regulates Notch3 and its malignant signaling

PubMed Central

Zhu, Juan-Juan; Liu, Xue-Xia; You, Hui; Gong, Mei-Ying; Zou, Ming; Cheng, Wen-Hsing; Zhu, Jian-Hong

2016-01-01

Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors. PMID:27102435

N-acetylcysteine negatively regulates Notch3 and its malignant signaling.

PubMed

Zhang, Xiong; Wang, Ya-Nan; Zhu, Juan-Juan; Liu, Xue-Xia; You, Hui; Gong, Mei-Ying; Zou, Ming; Cheng, Wen-Hsing; Zhu, Jian-Hong

2016-05-24

Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.

PubMed

Di Ianni, Mauro; Baldoni, Stefano; Del Papa, Beatrice; Aureli, Patrizia; Dorillo, Erica; De Falco, Filomena; Albi, Elisa; Varasano, Emanuela; Di Tommaso, Ambra; Giancola, Raffaella; Accorsi, Patrizia; Rotta, Gianluca; Rompietti, Chiara; Silva Barcelos, Estevão Carlos; Campese, Antonio Francesco; Di Bartolomeo, Paolo; Screpanti, Isabella; Rosati, Emanuela; Falzetti, Franca; Sportoletti, Paolo

2018-01-01

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1- mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

Approaching Terahertz Range with 3-color Broadband Coherent Raman Micro Spectroscopy

NASA Astrophysics Data System (ADS)

Ujj, Laszlo; Olson, Trevor; Amos, James

The presentation reports the recent progress made on reliable signal recording and processing using 3-color broadband coherent Raman scattering (3C-BCRS). Signals are generated either from nanoparticle structures on surfaces or from bulk samples in transmission and in epi-detected mode. Spectra are recorded with a narrowband (at 532 nm) and a broadband radiation produced by a newly optimized optical parametric oscillator using the signal or idler beams. Vibrational and librational bands are measured over the 0.15-15 THz spectral range from solution and crystalline samples. Volumetric Brag-filter approach is introduced for recording 3C-BCRS spectra at the first time. The technical limitations and advantages of the narrowband filtering relative to the Notch-filter technic is clarified. The signal is proportional to the spectral autocorrelation of the broadband radiation therefore the present scheme gives a better signal-to-noise ratio relative to the traditional multiplex CRS methods. This makes the automation of non-model dependent signal processing more reliable to extract vibrational information which is very crucial in coherent Raman microscopy. Financial support from the Hal Marcus College of Science and Engineering is greatly appreciated.

Development of frequency modulation reflectometer for Korea Superconducting Tokamak Advanced Research tokamak

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seo, Seong-Heon; Wi, H. M.; Lee, W. R.

2013-08-15

Frequency modulation reflectometer has been developed to measure the plasma density profile of the Korea Superconducting Tokamak Advanced Research tokamak. Three reflectometers are operating in extraordinary polarization mode in the frequency range of Q band (33.6–54 GHz), V band (48–72 GHz), and W band (72–108 GHz) to measure the density up to 7 × 10{sup 19} m{sup −3} when the toroidal magnetic field is 2 T on axis. The antenna is installed inside of the vacuum vessel. A new vacuum window is developed by using 50 μm thick mica film and 0.1 mm thick gold gasket. The filter bank ofmore » low pass filter, notch filter, and Faraday isolator is used to reject the electron cyclotron heating high power at attenuation of 60 dB. The full frequency band is swept in 20 μs. The mixer output is directly digitized with sampling rate of 100 MSamples/s. The phase is obtained by using wavelet transform. The whole hardware and software system is described in detail and the measured density profile is presented as a result.« less

New instantaneous frequency estimation method based on the use of image processing techniques

NASA Astrophysics Data System (ADS)

Borda, Monica; Nafornita, Ioan; Isar, Alexandru

2003-05-01

The aim of this paper is to present a new method for the estimation of the instantaneous frequency of a frequency modulated signal, corrupted by additive noise. This method represents an example of fusion of two theories: the time-frequency representations and the mathematical morphology. Any time-frequency representation of a useful signal is concentrated around its instantaneous frequency law and realizes the diffusion of the noise that perturbs the useful signal in the time - frequency plane. In this paper a new time-frequency representation, useful for the estimation of the instantaneous frequency, is proposed. This time-frequency representation is the product of two others time-frequency representations: the Wigner - Ville time-frequency representation and a new one obtained by filtering with a hard thresholding filter the Gabor representation of the signal to be processed. Using the image of this new time-frequency representation the instantaneous frequency of the useful signal can be extracted with the aid of some mathematical morphology operators: the conversion in binary form, the dilation and the skeleton. The simulations of the proposed method have proved its qualities. It is better than other estimation methods, like those based on the use of adaptive notch filters.

Evaluation of role of Notch3 signaling pathway in human lung cancer cells.

PubMed

Hassan, Wael Abdo; Yoshida, Ryoji; Kudoh, Shinji; Motooka, Yamato; Ito, Takaaki

2016-05-01

There is still a debate on the extent to which Notch3 signaling is involved in lung carcinogenesis and whether such function is dependent on cancer type or not. To evaluate Notch3 expression in different types of human lung cancer cells. Notch3 was detected in human lung cancer cell lines and in tissues. Then, small interfering RNA (siRNA) was used to down-regulate the expression of Notch3 in H69AR small cell lung carcinoma (SCLC) cells; two non-small cell lung carcinoma (NSCLC) cells; A549 adenocarcinoma (ADC); and H2170 squamous cell carcinoma (SCC). In addition, Notch3 intracellular domain (N3ICD) plasmid was transfected into H1688 human SCLC cells. We observed the effect of deregulating Notch3 signaling on the following cell properties: Notch-related proteins, cell morphology, adhesion, epithelial-mesenchymal transition (EMT), motility, proliferation and neuroendocrine (NE) features of SCLC. Notch3 is mainly expressed in NSCLC, and the expression of Notch1, Hes1 and Jagged1 is affected by Notch3. Notch3 has opposite functions in SCLC and NSCLC, being a tumor suppressor in the former and tumor promoting in the latter, in the context of cell adhesion, EMT and motility. Regarding cell proliferation, we found that inhibiting Notch3 in NSCLC decreases cell proliferation and induces apoptosis in NSCLC. Notch3 has no effect on cell proliferation or NE features of SCLC. Notch3 signaling in lung carcinoma is dependent on cell type. In SCLC, Notch3 behaves as a tumor suppressor pathway, while in NSCLC it acts as a tumor-promoting pathway.

The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.

PubMed

Rutten, Julie W; Klever, Roselin R; Hegeman, Ingrid M; Poole, Dana S; Dauwerse, Hans G; Broos, Ludo A M; Breukel, Cor; Aartsma-Rus, Annemieke M; Verbeek, J Sjef; van der Weerd, Louise; van Duinen, Sjoerd G; van den Maagdenberg, Arn M J M; Lesnik Oberstein, Saskia A J

2015-12-29

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.

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.

Stabilite thermique de filtres optiques interferentiels quart d'onde et a gradient d'indice pour l'astronomie

NASA Astrophysics Data System (ADS)

de Denus-Baillargeon, Marie-Maude

2007-05-01

Light coming from far-away astronomical objects carries a variety of information ranging from chemical composition to distance and kinematics. Amongst these astronomical bodies, galaxies are widely studied objects: they are slowly rotating entities made of gas, stars and dark matter, and their properties are broadly distributed. Rotation velocities of galaxies yield very important information, namely the mass enclosed in the rotation radius, and thus the respective distribution of luminous and dark matter. To determine the rotation velocity, the Doppler effect is a convenient tool. As an emission or absorption line shifts from its reference position, it is possible to calculate the approaching or receding velocity. The maximal rotation velocity difference between the approaching and receding sides is at most a few hundreds of km/s, which translates in a few nm shift from the rest wavelength at most, thus calling for very precise spectral information.Due to their distance, the objects observed with astronomical instrumentation are very faint. Optical instruments for astronomy thus require high throughput optical film systems, particularly those based on notch/bandpass filters with low/high in-band transmission and high/low out-of-band blocking power. This calls for very high film uniformity and high precision of film monitoring and process control. Such filters must also survive extreme environmental conditions ranging from fresh and humid climate to cryogenic temperatures.In the present work, we describe all steps leading from filter design to filter fabrication, process monitoring, and characterization. In particular, we focus on the comparison of the performance of graded-index (rugate) filters and quarter-wave stack narrowband filters deposited by plasma enhanced chemical vapor deposition and dual ion beam sputtering using SiO 2 , TiO 2 and Ta 2 O 5.Optical and mechanical properties of the individual films have been evaluated and are consistent with those found in the litterature reporting on the same tech niques. Namely, we find values of compressive stress of 160 and 410 MPa for layers of Ta 2 O 5 and SiO 2 deposited by DIBS and of 150 and 60 MPa for PECVD- deposited SiO 2 /TiO 2 mixtures rich in SiO 2 and TiO 2 respectively. Young's modulus of 109, 73, 55 and 94 GPa and refraction index of 2,13, 1,49, 1,59 and 2,09 have also been measured for those same materials. Properties of materials mixtures behave qualitatively as the ones reported in references on the subject.Attention is paid to the effect of temperature on the variation of the central wavelength and bandpass width. The results are discussed in terms of film material and filter design. We report variations of ~ =0,04°C for multilayers DIBS-produced filters and -0,0041/°C and 0,19°C for PECVD-deposited quarter- wave stacks and rugate filters respectively. These results match the predictions made by Takashashi's formulae. The bandwidth varies as well with temperature, and the extent of the variation seems related to the number of cavities in the filter. Further work is still needed in order to clearly establish the relation between the number of cavities and the bandpass' narrowing/widening with temperature.

Stabilite thermique de filtres optiques interferentiels quart d'onde et a gradient d'indice pour l'astronomie

NASA Astrophysics Data System (ADS)

de Denus-Baillargeon, Marie-Maude

Light coming from far-away astronomical objects carries a variety of information ranging from chemical composition to distance and kinematics. Amongst these astronomical bodies, galaxies are widely studied objects: they are slowly rotating entities made of gas, stars and dark matter, and their properties are broadly distributed. Rotation velocities of galaxies yield very important information, namely the mass enclosed in the rotation radius, and thus the respective distribution of luminous and dark matter. To determine the rotation velocity, the Doppler effect is a convenient tool. As an emission or absorption line shifts from its reference position, it is possible to calculate the approaching or receding velocity. The maximal rotation velocity difference between the approaching and receding sides is at most a few hundreds of km/s, which translates in a few nm shift from the rest wavelength at most, thus calling for very precise spectral information. Due to their distance, the objects observed with astronomical instrumentation are very faint. Optical instruments for astronomy thus require high throughput optical film systems, particularly those based on notch/bandpass filters with low/high in-band transmission and high/low out-of-band blocking power. This calls for very high film uniformity and high precision of film monitoring and process control. Such filters must also survive extreme environmental conditions ranging from fresh and humid climate to cryogenic temperatures. In the present work, we describe all steps leading from filter design to filter fabrication, process monitoring, and characterization. In particular, we focus on the comparison of the performance of graded-index (rugate) filters and quarter-wave stack narrowband filters deposited by plasma enhanced chemical vapor deposition and dual ion beam sputtering using SiO 2 , TiO 2 and Ta 2 O 5. Optical and mechanical properties of the individual films have been evaluated and are consistent with those found in the litterature reporting on the same techniques. Namely, we find values of compressive stress of 160 and 410 MPa for layers of Ta 2 O 5 and SiO 2 deposited by DIBS and of 150 and 60 MPa for PECVD- deposited SiO 2 /TiO 2 mixtures rich in SiO 2 and TiO 2 respectively. Young's modulus of 109, 73, 55 and 94 GPa and refraction index of 2,13, 1,49, 1,59 and 2,09 have also been measured for those same materials. Properties of materials mixtures behave qualitatively as the ones reported in references on the subject. Attention is paid to the effect of temperature on the variation of the central wavelength and bandpass width. The results are discussed in terms of film material and filter design. We report variations of ~ =0,04Å/°C for multilayers DIBS-produced filters and -0,0041/°C and 0,19Å/°C for PECVD-deposited quarter- wave stacks and rugate filters respectively. These results match the predictions made by Takashashi's formulae. The bandwidth varies as well with temperature, and the extent of the variation seems related to the number of cavities in the filter. Further work is still needed in order to clearly establish the relation between the number of cavities and the bandpass' narrowing/widening with temperature.

Loss of PTB or Negative Regulation of Notch mRNA Reveals Distinct Zones of Notch and Actin Protein Accumulation in Drosophila Embryo

PubMed Central

Wesley, Cedric S.; Guo, Heng; Chaudhry, Kanita A.; Thali, Markus J.; Yin, Jerry C.; Clason, Todd; Wesley, Umadevi V.

2011-01-01

Polypyrimidine Tract Binding (PTB) protein is a regulator of mRNA processing and translation. Genetic screens and studies of wing and bristle development during the post-embryonic stages of Drosophila suggest that it is a negative regulator of the Notch pathway. How PTB regulates the Notch pathway is unknown. Our studies of Drosophila embryogenesis indicate that (1) the Notch mRNA is a potential target of PTB, (2) PTB and Notch functions in the dorso-lateral regions of the Drosophila embryo are linked to actin regulation but not their functions in the ventral region, and (3) the actin-related Notch activity in the dorso-lateral regions might require a Notch activity at or near the cell surface that is different from the nuclear Notch activity involved in cell fate specification in the ventral region. These data raise the possibility that the Drosophila embryo is divided into zones of different PTB and Notch activities based on whether or not they are linked to actin regulation. They also provide clues to the almost forgotten role of Notch in cell adhesion and reveal a role for the Notch pathway in cell fusions. PMID:21750738

Prognostic Subcellular Notch2, Notch3 and Jagged1 Localization Patterns in Early Triple-negative Breast Cancer.

PubMed

Strati, Titika-Marina; Kotoula, Vassiliki; Kostopoulos, Ioannis; Manousou, Kyriaki; Papadimitriou, Christos; Lazaridis, Georgios; Lakis, Sotiris; Pentheroudakis, George; Pectasides, Dimitrios; Pazarli, Elissavet; Christodoulou, Christos; Razis, Evangelia; Pavlakis, Kitty; Magkou, Christina; Chrisafi, Sofia; Aravantinos, Gerasimos; Bafaloukos, Dimitrios; Papakostas, Pavlos; Gogas, Helen; Kalogeras, Konstantine T; Fountzilas, George

2017-05-01

The Notch pathway has been implicated in triple-negative breast cancer (TNBC). Herein, we studied the subcellular localization of the less investigated Notch2 and Notch3 and that of the Jagged1 (Jag1) ligand in patients with operable TNBC. We applied immunohistochemistry for Notch2, Notch3 and Jag1 in 333 tumors from TNBC patients treated with adjuvant anthracycline-based chemotherapy. We evaluated cytoplasmic (c), membranous (m) and nuclear (n) protein localization. c-Notch2 (35% positive tumors), c-Notch3 (63%), c-Jag1 (43%), m-Notch3 (23%) and n-Jag1 (17%) were analyzed individually and by using hierarchical clustering for prognostic evaluation. Upon multivariate analysis, compared to high m-Notch3 in the absence of n-Jag1 (cluster 4), all other marker combinations (clusters 1, 2, 3) conferred significantly higher risk for relapse (p<0.05). Specific Notch3 and Jag1 subcellular localization patterns may provide clues for the behavior of the tumors and potentially for Jag1 targeting in TNBC patients. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord

PubMed Central

Rusanescu, Gabriel; Mao, Jianren

2014-01-01

Notch receptors are key regulators of nervous system development and promoters of neural stem cells renewal and proliferation. Defects in the expression of Notch genes result in severe, often lethal developmental abnormalities. Notch3 is generally thought to have a similar proliferative, anti-differentiation and gliogenic role to Notch1. However, in some cases, Notch3 has an opposite, pro-differentiation effect. Here, we show that Notch3 segregates from Notch1 and is transiently expressed in adult rat and mouse spinal cord neuron precursors and immature neurons. This suggests that during the differentiation of adult neural progenitor cells, Notch signalling may follow a modified version of the classical lateral inhibition model, involving the segregation of individual Notch receptors. Notch3 knockout mice, otherwise neurologically normal, are characterized by a reduced number of mature inhibitory interneurons and an increased number of highly excitable immature neurons in spinal cord laminae I–II. As a result, these mice have permanently lower nociceptive thresholds, similar to chronic pain. These results suggest that defective neuronal differentiation, for example as a result of reduced Notch3 expression or activation, may underlie human cases of intractable chronic pain, such as fibromyalgia and neuropathic pain. PMID:25164209

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. PMID:25356737

Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice.

PubMed

Shan, Lin; Aster, Jon C; Sklar, Jeffrey; Sunday, Mary E

2007-02-01

The notch gene family encodes transmembrane receptors that regulate cell differentiation by interacting with surface ligands on adjacent cells. Previously, we demonstrated that tumor necrosis factor-alpha (TNF) induces neuroendocrine (NE) cell differentiation in H82, but not H526, undifferentiated small cell lung carcinoma lines. We now test the hypothesis that TNF mediates NE cell differentiation in part by altering Notch gene expression. First, using RT-PCR, we determined that TNF treatment of H82, but not H526, transiently decreases notch-1 mRNA in parallel with induction of gene expression for the NE-specific marker DOPA decarboxylase (DDC). Second, we treated H82 and H526 with notch-1 antisense vs. sense oligodeoxynucleotides. Using quantitative RT-PCR and Western analyses we demonstrate that DDC mRNA and protein are increased in H82 by notch-1 antisense, whereas notch-1 mRNA and activated Notch-1 protein are decreased. mRNA for Hes1, a transcription factor downstream from activated Notch, is also decreased by Notch-1 antisense in H82 but not H526. After 7 days of Notch-1 antisense treatment, neural cell adhesion molecule (NCAM) immunoreactivity is induced in H82 but not H526. Third, we generated transgenic mice bearing notch-1 driven by the neural/NE-specific calcitonin promoter, which express activated Notch-1 in developing lung epithelium. Newborn NotchCal mouse lungs have high levels of hes1 mRNA, reflecting increased activated Notch, compared with wild-type. NotchCal lungs have decreased CGRP-positive NE cells, decreased protein gene product 9.5 (PGP9.5)-positive NE cells, and decreased gastrin-releasing peptide (GRP), CGRP, and DDC mRNA levels compared with normal littermates. Cumulatively, these observations provide further support for a role for Notch-1 signaling in regulating pulmonary NE cell differentiation.

Notch signaling in lung diseases: focus on Notch1 and Notch3

PubMed Central

Zong, Dandan; Ouyang, Ruoyun; Li, Jinhua; Chen, Yan; Chen, Ping

2016-01-01

Notch signaling is an evolutionarily conserved cell–cell communication mechanism that plays a key role in lung homeostasis, injury and repair. The loss of regulation of Notch signaling, especially Notch1 and Notch3, has recently been linked to the pathogenesis of important lung diseases, in particular, chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, pulmonary arterial hypertension (PAH), lung cancer and lung lesions in some congenital diseases. This review focuses on recent advances related to the mechanisms and the consequences of aberrant or absent Notch1/3 activity in the initiation and progression of lung diseases. Our increasing understanding of this signaling pathway offers great hope that manipulating Notch signaling may represent a promising alternative complementary therapeutic strategy in the future. PMID:27378579

Current views on the role of Notch signaling and the pathogenesis of human leukemia

PubMed Central

2011-01-01

The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis. Constitutive activation of Notch signaling has been shown to result in excessive cellular proliferation and a wide range of malignancies, including leukemia, glioblastoma and lung and breast cancers. Notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. This minireview focuses on recent advances related to the mechanisms and roles of activated Notch1, Notch2, Notch3 and Notch4 signaling in human lymphocytic leukemia, myeloid leukemia and B cell lymphoma, as well as their significance, and recent advances in Notch-targeted therapies. PMID:22128846

Continuous cardiac output measurement - Aspects of Doppler frequency analysis

NASA Technical Reports Server (NTRS)

Mackay, R. S.; Hechtman, H. B.

1975-01-01

From the suprasternal notch blood flow velocity in the aorta can be measured non-invasively by a Doppler probe. Integration over systole after frequency analysis gives a measure of stroke volume if a separate diameter observation is incorporated. Frequency analysis by a zero crossing counter or by a set of parallel phaselock loops was less effective than a set of bandpass filters. Observations on dogs, baboons and humans before and after exercise or surgery suggest the indications to be useful. Application to judging heart failure by the effect of introducing a volume load is indicated. Changes in output also are measured in freely moving subjects.

A simulation method for combining hydrodynamic data and acoustic tag tracks to predict the entrainment of juvenile salmonids onto the Yolo Bypass under future engineering scenarios

USGS Publications Warehouse

Blake, Aaron R.; Stumpner, Paul; Burau, Jon R.

2017-01-01

During water year 2016 the U.S. Geological Survey California Water Science Center (USGS) collaborated with the California Department of Water Resources (DWR) to conduct a joint hydrodynamic and fisheries study to acquire data that could be used to evaluate the effects of proposed modifications to the Fremont Weir on outmigrating juvenile Chinook salmon. During this study the USGS surgically implanted acoustic tags in juvenile late fall run Chinook salmon from the Coleman National Fish Hatchery, released the acoustically tagged juvenile salmon into the Sacramento River upstream of the Fremont Weir, and tracked their movements as they emigrated past the western end of the Fremont Weir.The USGS analyzed tracking data from the acoustically tagged juvenile salmon along with detailed hydrodynamic data collected in the Sacramento River during the winter/spring of water year 2016 in the vicinity of the western end of the Fremont Weir to assess the potential for enhancing the entrainment of Sacramento River Chinook salmon onto the Yolo Bypass under six different Fremont Weir modification scenarios. Each modification scenario consists of a notch or multiple notches in the Fremont Weir which are designed to divert a portion of the Sacramento River onto the Yolo Bypass when the Sacramento River is below the crest of the Fremont Weir. The primary goal of this entrainment analysis was to investigate how the location of the notch or notches in each scenario affected the entrainment of juvenile Chinook salmon onto the Yolo Bypass, and to predict the notch location or locations that would result in maximum entrainment under each modification scenario. Stumpner et al.’s (in review) analysis of hydraulic data collected during the 2016 study period showed that backwater effects in the Sacramento River created significant variability in the relationship between Sacramento River stage and the proportion of the Sacramento River flow that we expect to be diverted onto the Yolo Bypass under the modification scenarios. Because of this variability, accurately evaluating the entrainment potential of possible notch locations for each scenario required combining historic abundance data for juvenile Sacramento River Chinook salmon with historic hydraulic data for the Sacramento River in the vicinity of the Fremont Weir, so that the entrainment estimates would reflect the covariance between Sacramento River stage, Sacramento River discharge, and juvenile salmon abundance within the historic record.We used a Monte Carlo simulation framework to combine the high resolution hydrodynamic data and acoustic tag track data collected in 2016 with historic juvenile salmon abundance, Sacramento River stage, and Sacramento River discharge data from a period spanning water years 1996-2010 to assess the entrainment potential of different weir modification scenarios under historic conditions. The scenarios we simulated consisted of four single notch configurations, and two multiple notch configurations in the vicinity of the western end of the Fremont Weir. For each notch configuration the 15-water-year entrainment simulation was repeated for 63 possible notch locations in the vicinity of the western end of the Fremont Weir. This approach allowed us to assess the effect of notch location on the entrainment of juvenile salmonids onto the Yolo Bypass for each of the six notch configurations that we evaluated.The entrainment simulations showed that the location of each notch configuration had a major impact on the entrainment for each scenario; the predicted entrainment of some scenarios varied by as much as 400% based on where the notch (or notches) was (were) located in the study area. All of the single notch scenarios performed best when they were located within a 330 ft (100 meter) long section of the Sacramento River bank adjacent to the western terminus of the Fremont Weir (Table 1). Both of the multiple notch scenarios performed best when their upstream notches were located about 660 ft (200 meters) upstream of the western terminus of the Fremont Weir (Table 1). The results of the entrainment simulations indicated that for each notch configuration the same notch location produced near-maximum entrainment regardless of run abundance timing; this result suggests that there are areas within the study are where a notch (or notches) can be sited to achieve maximum entrainment for all runs (barring significant behavioral or physiological differences between runs). In addition, the simulation results indicate that for each notch configuration the same location is expected to produce nearmaximum entrainment for both wet water years and dry water years.Based on the results of the entrainment simulation we make three general recommendations for strategies to improve the entrainment potential of a notch in the Fremont Weir:1) Comparisons between the maximum entrainment potential for each scenario suggested that total entrainment of winter run, spring run, and fall run salmon onto the Yolo Bypass can be increased by increasing the amount of water entering a notch when the Sacramento River stage is between 19 ft and 22 ft NAVD88; this could be accomplished by lowering notch invert elevations or by adding a control section to the Sacramento River to raise stage for a given discharge.2) The relationship between Sacramento River stage and entrainment for each scenario indicated that entrainment efficiency for each scenario declined significantly once Sacramento River stage exceeded bankfull (approximately 28.5 ft NAVD88). This effect was likely due to inundation of the floodplain between the Sacramento River and the Fremont Weir; Stumpner et. al (In Review) have documented a reduction in the strength of the secondary circulation and centralization of the downwelling zone in the Sacramento River when this floodplain is inundated. Therefore, increasing the height of the river right bank of the Sacramento River to coincide with the height of the Fremont Weir is recommended to increase entrainment at higher stages. 3) Bathymetric features upstream of notch openings appeared to have a major impact on the entrainment potential of the simulated notches. For this reason we recommend taking care to avoid siting notches immediately downstream of bank features that alter the sidewall boundary layer, and we expect that smoothing the bank bathymetry upstream of a notch will enhance entrainment. Finally, we caution that the entrainment simulation was based on the behavior of large hatchery smolts, so it is likely that our results will be sensitive to any differences in behavior and physiology between these hatchery surrogates and naturally migrating juvenile salmon.

Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis.

PubMed

Fiddes, Ian T; Lodewijk, Gerrald A; Mooring, Meghan; Bosworth, Colleen M; Ewing, Adam D; Mantalas, Gary L; Novak, Adam M; van den Bout, Anouk; Bishara, Alex; Rosenkrantz, Jimi L; Lorig-Roach, Ryan; Field, Andrew R; Haeussler, Maximilian; Russo, Lotte; Bhaduri, Aparna; Nowakowski, Tomasz J; Pollen, Alex A; Dougherty, Max L; Nuttle, Xander; Addor, Marie-Claude; Zwolinski, Simon; Katzman, Sol; Kriegstein, Arnold; Eichler, Evan E; Salama, Sofie R; Jacobs, Frank M J; Haussler, David

2018-05-31

Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and is a determinant of neuronal number in the mammalian cortex. We find that three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals that different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation into cortical neurons. Furthermore, NOTCH2NL genes provide the breakpoints in 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism and deletions with microcephaly and schizophrenia. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

An optimization of the FPGA/NIOS adaptive FIR filter using linear prediction to reduce narrow band RFI for the next generation ground-based ultra-high energy cosmic-ray experiment

NASA Astrophysics Data System (ADS)

Szadkowski, Zbigniew; Fraenkel, E. D.; Glas, Dariusz; Legumina, Remigiusz

2013-12-01

The electromagnetic part of an extensive air shower developing in the atmosphere provides significant information complementary to that obtained by water Cherenkov detectors which are predominantly sensitive to the muonic content of an air shower at ground. The emissions can be observed in the frequency band between 10 and 100 MHz. However, this frequency range is significantly contaminated by narrow-band RFI and other human-made distortions. The Auger Engineering Radio Array currently suppresses the RFI by multiple time-to-frequency domain conversions using an FFT procedure as well as by a set of manually chosen IIR notch filters in the time-domain. An alternative approach developed in this paper is an adaptive FIR filter based on linear prediction (LP). The coefficients for the linear predictor are dynamically refreshed and calculated in the virtual NIOS processor. The radio detector is an autonomous system installed on the Argentinean pampas and supplied from a solar panel. Powerful calculation capacity inside the FPGA is a factor. Power consumption versus the degree of effectiveness of the calculation inside the FPGA is a figure of merit to be minimized. Results show that the RFI contamination can be significantly suppressed by the LP FIR filter for 64 or less stages.

AKAP200 promotes Notch stability by protecting it from Cbl/lysosome-mediated degradation in Drosophila melanogaster.

PubMed

Bala Tannan, Neeta; Collu, Giovanna; Humphries, Ashley C; Serysheva, Ekatherina; Weber, Ursula; Mlodzik, Marek

2018-01-01

AKAP200 is a Drosophila melanogaster member of the "A Kinase Associated Protein" family of scaffolding proteins, known for their role in the spatial and temporal regulation of Protein Kinase A (PKA) in multiple signaling contexts. Here, we demonstrate an unexpected function of AKAP200 in promoting Notch protein stability. In Drosophila, AKAP200 loss-of-function (LOF) mutants show phenotypes that resemble Notch LOF defects, including eye patterning and sensory organ specification defects. Through genetic interactions, we demonstrate that AKAP200 interacts positively with Notch in both the eye and the thorax. We further show that AKAP200 is part of a physical complex with Notch. Biochemical studies reveal that AKAP200 stabilizes endogenous Notch protein, and that it limits ubiquitination of Notch. Specifically, our genetic and biochemical evidence indicates that AKAP200 protects Notch from the E3-ubiquitin ligase Cbl, which targets Notch to the lysosomal pathway. Indeed, we demonstrate that the effect of AKAP200 on Notch levels depends on the lysosome. Interestingly, this function of AKAP200 is fully independent of its role in PKA signaling and independent of its ability to bind PKA. Taken together, our data indicate that AKAP200 is a novel tissue specific posttranslational regulator of Notch, maintaining high Notch protein levels and thus promoting Notch signaling.

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.

Notch3 and Mef2c Proteins Are Mutually Antagonistic via Mkp1 Protein and miR-1/206 MicroRNAs in Differentiating Myoblasts*

PubMed Central

Gagan, Jeffrey; Dey, Bijan K.; Layer, Ryan; Yan, Zhen; Dutta, Anindya

2012-01-01

The Notch signaling pathway is a well known regulator of skeletal muscle stem cells known as satellite cells. Loss of Notch1 signaling leads to spontaneous myogenic differentiation. Notch1, normally expressed in satellite cells, is targeted for proteasomal degradation by Numb during differentiation. A homolog of Notch1, Notch3, is also expressed in these cells but is not inhibited by Numb. We find that Notch3 is paradoxically up-regulated during the early stages of differentiation by an enhancer that requires both MyoD and activated Notch1. Notch3 itself strongly inhibits the myogenic transcription factor Mef2c, most likely by increasing the p38 phosphatase Mkp1, which inhibits the Mef2c activator p38 MAP kinase. Active Notch3 decreases differentiation. Mef2c, however, induces microRNAs miR-1 and miR-206, which directly down-regulate Notch3 and allow differentiation to proceed. Thus, the myogenic differentiation-induced microRNAs miR-1 and -206 are important for differentiation at least partly because they turn off Notch3. We suggest that the transient expression of Notch3 early in differentiation generates a temporal lag between myoblast activation by MyoD and terminal differentiation into myotubes directed by Mef2c. PMID:23055528

Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies

PubMed Central

Zweidler-McKay, Patrick A.; He, Yiping; Xu, Lanwei; Rodriguez, Carlos G.; Karnell, Fredrick G.; Carpenter, Andrea C.; Aster, Jon C.; Allman, David; Pear, Warren S.

2005-01-01

Although Notch receptor expression on malignant B cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively active, truncated forms of the 4 mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All 4 truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (Hes1) recapitulated the Notch effects, suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies, including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)–translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies. PMID:16118316

CADASIL mutant NOTCH3(R90C) decreases the viability of HS683 oligodendrocytes via apoptosis.

PubMed

Tang, Mibo; Shi, Changhe; Song, Bo; Yang, Jing; Yang, Ting; Mao, Chengyuan; Li, Yusheng; Liu, Xinjing; Zhang, Shuyu; Wang, Hui; Luo, Haiyang; Xu, Yuming

2017-07-01

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease caused by mutations in NOTCH3. Prevailing models suggest that demyelination occurs secondary to vascular pathology. However, in zebrafish, NOTCH3 is also expressed in mature oligodendrocytes. Thus, we hypothesized that in addition to vascular defects, mutant NOTCH3 may alter glial function in individuals with CADASIL. The aim of this study was to characterize the direct effects of a mutant NOTCH3 protein in HS683 oligodendrocytes. HS683 oligodendrocytes transfected with wild-type NOTCH3, mutant NOTCH3(R90C), and empty control vector were used to study the impact of the NOTCH3(R90C) mutant on its protein hydrolytic processing, cell viability, apoptosis, autophagy, oxidative stress, and the related upstream events using immunoblotting, immunofluorescence, RT-PCR, and flow cytometry. We determined that HS683 oligodendrocytes transfected with mutant NOTCH3(R90C), which is the hotspot mutation site-associated with CADASIL, exhibited aberrant NOTCH3 proteolytic processing. Compared to cells overexpressing wild-type NOTCH3, cells overexpressing NOTCH3(R90C) were less viable and had a higher rate of apoptosis. Immunoblotting revealed that cells transfected with NOTCH3(R90C) had higher levels of intrinsic mitochondrial apoptosis, extrinsic death receptor path-related apoptosis, and autophagy compared with cells transfected with wild-type NOTCH3. This study suggests that in patients with CADASIL, early defects in glia influenced by NOTCH3(R90C) may directly contribute to white matter pathology in addition to secondary vascular defects. This study provides a potential therapeutic target for the future treatment of CADASIL.

Notch3 Ameliorates Cardiac Fibrosis After Myocardial Infarction by Inhibiting the TGF-β1/Smad3 Pathway.

PubMed

Zhang, Mingming; Pan, Xietian; Zou, Qian; Xia, Yuesheng; Chen, Jiangwei; Hao, Qimeng; Wang, Haichang; Sun, Dongdong

2016-10-01

Notch3 and TGF-β1 signaling play a key role in the pathogenesis and progression of chronic cardiovascular disease. However, whether Notch3 protects against myocardial infarction (MI) and the underlying mechanisms remains unknown. C57BL/6 mice were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) before coronary artery ligation. Four weeks after constructing MI model, cardiac function and fibrosis were compared between groups. The cardiac fibroblast cells (CFs) were isolated from newborn C57BL/6 mice (1-3 days old) and transfected with lentivirus carrying Notch3 cDNA. TGF-β1 (5 ng/ml), a well-known pro-fibrotic factor, was administered 72 h after Notch3 cDNA administration in CFs. The related proteins of fibrosis such as a-smooth muscle actin (a-SMA), Type I collagen, metalloprotease (MMP)-9 and the tissue inhibitor of metalloproteinases (TIMP)-2 were examined by western blot analysis. Notch3 cDNA treatment attenuated cardiac damage and inhibited fibrosis in mice with MI. Meanwhile, Notch3 siRNA administration aggravated cardiac function damage and markedly enhanced cardiac fibrosis in mice with MI. Overexpression of Notch3 inhibited TGF-β1-induced fibroblast-myofibroblast transition of mouse cardiac fibroblast cells, as evidenced by down-regulating a-SMA and Type I collagen expression. Notch3 cDNA treatment also increased MMP-9 expression and decreased TIMP-2 expression in the TGF-β1-stimulated cells. This study indicates that Notch3 is an important protective factor for cardiac fibrosis in a MI model, and the protective effect of Notch3 is attributable to its action on TGF-β1/Smad3 signaling.

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

Non-canonical NOTCH3 signalling limits tumour angiogenesis.

PubMed

Lin, Shuheng; Negulescu, Ana; Bulusu, Sirisha; Gibert, Benjamin; Delcros, Jean-Guy; Ducarouge, Benjamin; Rama, Nicolas; Gadot, Nicolas; Treilleux, Isabelle; Saintigny, Pierre; Meurette, Olivier; Mehlen, Patrick

2017-07-18

Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells.

Non-canonical NOTCH3 signalling limits tumour angiogenesis

PubMed Central

Lin, Shuheng; Negulescu, Ana; Bulusu, Sirisha; Gibert, Benjamin; Delcros, Jean-Guy; Ducarouge, Benjamin; Rama, Nicolas; Gadot, Nicolas; Treilleux, Isabelle; Saintigny, Pierre; Meurette, Olivier; Mehlen, Patrick

2017-01-01

Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells. PMID:28719575

A novel cost-effective parallel narrowband ANC system with local secondary-path estimation

NASA Astrophysics Data System (ADS)

Delegà, Riccardo; Bernasconi, Giancarlo; Piroddi, Luigi

2017-08-01

Many noise reduction applications are targeted at multi-tonal disturbances. Active noise control (ANC) solutions for such problems are generally based on the combination of multiple adaptive notch filters. Both the performance and the computational cost are negatively affected by an increase in the number of controlled frequencies. In this work we study a different modeling approach for the secondary path, based on the estimation of various small local models in adjacent frequency subbands, that greatly reduces the impact of reference-filtering operations in the ANC algorithm. Furthermore, in combination with a frequency-specific step size tuning method it provides a balanced attenuation performance over the whole controlled frequency range (and particularly in the high end of the range). Finally, the use of small local models is greatly beneficial for the reactivity of the online secondary path modeling algorithm when the characteristics of the acoustic channels are time-varying. Several simulations are provided to illustrate the positive features of the proposed method compared to other well-known techniques.

Electronically controlled rejections of spoof surface plasmons polaritons

NASA Astrophysics Data System (ADS)

Zhou, Yong Jin; Xiao, Qian Xun

2017-03-01

We have proposed and experimentally demonstrated a band-notched surface plasmonic filter, which is composed of an ultra-wide passband plasmonic filter with a simple C-shaped ring on the back of the substrate. Enhanced narrowband or broadband rejections of spoof surface plasmon polaritons (SPPs) can be achieved with double C-shaped rings in the propagation or transverse direction. By mounting active components across the slit cut in the C-shaped ring, dynamic control of rejection of spoof SPPs can be accomplished. Both the rejection of spoof SPPs and the rejection bandwidth can be controlled when the Schottky barrier diode is forward-biased or reverse-biased. The frequency spectrum of the rejection band can be electronically adjusted by tuning the applied bias voltage across the varactor diode. Both simulated and measured results agree well and demonstrate dynamic control of propagation of spoof SPPs at the microwave frequencies. Such electronically controllable devices could find more applications in advanced plasmonic integrated functional circuits in microwave and terahertz frequencies.

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

Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL

PubMed Central

De Falco, Filomena; Sabatini, Rita; Del Papa, Beatrice; Falzetti, Franca; Di Ianni, Mauro; Sportoletti, Paolo; Baldoni, Stefano; Screpanti, Isabella; Marconi, Pierfrancesco; Rosati, Emanuela

2015-01-01

In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4. Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells. Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL. PMID:26041884

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xin-Hua; Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029; Yao, Shen

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 signalingmore » 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.« less

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

Latent NOTCH3 epitopes unmasked in CADASIL and regulated by protein redox state.

PubMed

Zhang, Xiaojie; Lee, Soo Jung; Young, Kelly Z; Josephson, David A; Geschwind, Michael D; Wang, Michael M

2014-10-02

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL is caused by more than a hundred NOTCH3 mutations. Virtually all encoded mutant proteins contain an odd number of cysteines. As such, structural changes in NOTCH3 may be the primary molecular abnormality in CADASIL. Thus, we sought evidence for structurally altered NOTCH3 protein in CADASIL tissue. Four antibodies were raised in rabbits against two non-overlapping N-terminal NOTCH3 sequences. These reagents were used in immunohistochemical experiments to detect epitopes in post-mortem CADASIL brains (n=8), control brains, and cells overexpressing NOTCH3. To determine the biochemical nature of NOTCH3 epitopes, we used these antibodies to probe pure NOTCH3-Fc fusion proteins treated with acid, urea, guanidinium, ionic detergents, acrylamide, and thiol- and phosphorus-based reductants. All antibodies avidly stained arteries in 8 of 8 CADASIL brain samples. The most prominent staining was in degenerating media of leptomeningeal arteries and sclerotic penetrating vessels. Normal appearing vessels from control brains were not reactive. Antibodies did not react with cultured cells overexpressing NOTCH3 or with purified NOTCH3-Fc protein. Furthermore, treatment of pure protein with acid, chaotropic denaturants, alkylators, and detergents failed to unmask N-terminal NOTCH3 epitopes. Antibodies, however, recognized novel N-terminal epitopes in purified NOTCH3-Fc protein treated with three different reductants (DTT, beta-mercaptoethanol, and TCEP). We conclude that CADASIL arteries feature latent N-terminal NOTCH3 epitopes, suggesting the first evidence in vivo of NOTCH3 structural alterations. Published by Elsevier B.V.

Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis.

PubMed

Lin, Neng-Yu; Distler, Alfiya; Beyer, Christian; Philipi-Schöbinger, Ariella; Breda, Silvia; Dees, Clara; Stock, Michael; Tomcik, Michal; Niemeier, Andreas; Dell'Accio, Francesco; Gelse, Kolja; Mattson, Mark P; Schett, Georg; Distler, Jörg Hw

2016-11-01

Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice. Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments. Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1. Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA. 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/.

Assessment of Creep Deformation, Damage, and Rupture Life of 304HCu Austenitic Stainless Steel Under Multiaxial State of Stress

NASA Astrophysics Data System (ADS)

Sahoo, K. C.; Goyal, Sunil; Parameswaran, P.; Ravi, S.; Laha, K.

2018-03-01

The role of the multiaxial state of stress on creep deformation and rupture behavior of 304HCu austenitic stainless steel was assessed by performing creep rupture tests on both smooth and notched specimens of the steel. The multiaxial state of stress was introduced by incorporating circumferential U-notches of different root radii ranging from 0.25 to 5.00 mm on the smooth specimens of the steel. Creep tests were carried out at 973 K over the stress range of 140 to 220 MPa. In the presence of notch, the creep rupture strength of the steel was found to increase with the associated decrease in rupture ductility. Over the investigated stress range and notch sharpness, the strengthening was found to increase drastically with notch sharpness and tended toward saturation. The fractographic studies revealed the mixed mode of failure consisting of transgranular dimples and intergranular creep cavitation for shallow notches, whereas the failure was predominantly intergranular for relatively sharper notches. Detailed finite element analysis of stress distribution across the notch throat plane on creep exposure was carried out to assess the creep failure of the material in the presence of notch. The reduction in von-Mises stress across the notch throat plane, which was greater for sharper notches, increased the creep rupture strength of the material. The variation in fracture behavior of the material in the presence of notch was elucidated based on the von-Mises, maximum principal, and hydrostatic stresses. Electron backscatter diffraction analysis of creep strain distribution across the notch revealed localized creep straining at the notch root for sharper notches. A master curve for predicting creep rupture life under the multiaxial state of stress was generated considering the representative stress having contributions from both the von-Mises and principal stress components of the stress field in the notch throat plane. Rupture ductility was also predicted based on the multiaxial state of stress.

Screening of whole genome sequences identified high-impact variants for stallion fertility.

PubMed

Schrimpf, Rahel; Gottschalk, Maren; Metzger, Julia; Martinsson, Gunilla; Sieme, Harald; Distl, Ottmar

2016-04-14

Stallion fertility is an economically important trait due to the increase of artificial insemination in horses. The availability of whole genome sequence data facilitates identification of rare high-impact variants contributing to stallion fertility. The aim of our study was to genotype rare high-impact variants retrieved from next-generation sequencing (NGS)-data of 11 horses in order to unravel harmful genetic variants in large samples of stallions. Gene ontology (GO) terms and search results from public databases were used to obtain a comprehensive list of human und mice genes predicted to participate in the regulation of male reproduction. The corresponding equine orthologous genes were searched in whole genome sequence data of seven stallions and four mares and filtered for high-impact genetic variants using SnpEFF, SIFT and Polyphen 2 software. All genetic variants with the missing homozygous mutant genotype were genotyped on 337 fertile stallions of 19 breeds using KASP genotyping assays or PCR-RFLP. Mixed linear model analysis was employed for an association analysis with de-regressed estimated breeding values of the paternal component of the pregnancy rate per estrus (EBV-PAT). We screened next generation sequenced data of whole genomes from 11 horses for equine genetic variants in 1194 human and mice genes involved in male fertility and linked through common gene ontology (GO) with male reproductive processes. Variants were filtered for high-impact on protein structure and validated through SIFT and Polyphen 2. Only those genetic variants were followed up when the homozygote mutant genotype was missing in the detection sample comprising 11 horses. After this filtering process, 17 single nucleotide polymorphism (SNPs) were left. These SNPs were genotyped in 337 fertile stallions of 19 breeds using KASP genotyping assays or PCR-RFLP. An association analysis in 216 Hanoverian stallions revealed a significant association of the splice-site disruption variant g.37455302G>A in NOTCH1 with the de-regressed estimated breeding values of the paternal component of the pregnancy rate per estrus (EBV-PAT). For 9 high-impact variants within the genes CFTR, OVGP1, FBXO43, TSSK6, PKD1, FOXP1, TCP11, SPATA31E1 and NOTCH1 (g.37453246G>C) absence of the homozygous mutant genotype in the validation sample of all 337 fertile stallions was obvious. Therefore, these variants were considered as potentially deleterious factors for stallion fertility. In conclusion, this study revealed 17 genetic variants with a predicted high damaging effect on protein structure and missing homozygous mutant genotype. The g.37455302G>A NOTCH1 variant was identified as a significant stallion fertility locus in Hanoverian stallions and further 9 candidate fertility loci with missing homozygous mutant genotypes were validated in a panel including 19 horse breeds. To our knowledge this is the first study in horses using next generation sequencing data to uncover strong candidate factors for stallion fertility.

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

Notch3 negatively regulates chemoresistance in breast cancers.

PubMed

Gu, Xiaoting; Lu, Chunxiao; He, Dongxu; Lu, Yangfan; Jin, Jian; Liu, Dequan; Ma, Xin

2016-10-14

To define the role of the NOTCH signaling pathway in the development of chemoresistance and the associated epithelial-mesenchymal transition (EMT), we investigated the effect of Notch3 on adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM cells). We found that Notch3 was downregulated and involved in the chemoresistance of MCF-7/ADM cells, while forced expression of Notch3 reversed the chemoresistance. Furthermore, fos-related antigen 1 (Fra1) was negatively regulated by Notch3 and was highly expressed in MCF-7/ADM cells. Increased Fra1 activated the EMT process. Finally, Notch3 expression was confirmed in clinically chemoresistant samples of breast cancers from patients receiving anthracycline-based chemotherapy. Low expression of Notch3 was an unfavorable predictor of distant relapse-free survival in ER positive breast cancers. Taken together, our findings demonstrate that the Notch3-Fra1 signaling pathway mediates chemoresistance via the EMT.

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

Targeting the Notch signaling pathway in autoimmune diseases.

PubMed

Ma, Daoxin; Zhu, Yuanchao; Ji, Chunyan; Hou, Ming

2010-05-01

The Notch signaling pathway regulates a variety of processes and has been linked to diverse effects. Aberrant Notch function is important in several disorders. Pre-clinical studies have suggested that inhibition of Notch is an attractive approach to treat hematologic and solid malignancies. Many patients with refractory autoimmune diseases respond poorly to therapy and have significant morbidity and the treatment is highly toxic, so more effective therapies for autoimmune diseases are being examined. The role of the Notch pathway and therapeutic strategies targeting it in many illnesses, especially autoimmune diseases. The Notch pathway has unique and attractive advantages for targeting. Targeting it has already been trialed in many experiments, which may show better efficacy and fewer side effects compared with classical drugs for the treatment. Targeting Notch might provide etiological rather than symptomatic treatment. Various methods targeting the Notch pathway have been under investigation. Rational targeting of the Notch signaling pathway in cancer and some autoimmune diseases has proven to be successful. Classical drugs for the treatment of autoimmune diseases are inefficient and toxic to some extent, and targeting the Notch pathway is a promising therapeutic concept. However, there are still many questions about targeting Notch in autoimmune diseases, and further investigation will be needed.

The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals.

PubMed

Wu, Nan; Nguyen, Quy; Wan, Ying; Zhou, Tiaohao; Venter, Julie; Frampton, Gabriel A; DeMorrow, Sharon; Pan, Duojia; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco; Bai, Haibo

2017-07-01

The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development.

The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals

PubMed Central

Wu, Nan; Nguyen, Quy; Wan, Ying; Zhou, Tiaohao; Venter, Julie; Frampton, Gabriel A; DeMorrow, Sharon; Pan, Duojia; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco; Bai, Haibo

2018-01-01

The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development. PMID:28581486

IL6 blockade potentiates the anti-tumor effects of γ-secretase inhibitors in Notch3-expressing breast cancer.

PubMed

Wang, Dong; Xu, Jiahui; Liu, Bingjie; He, Xueyan; Zhou, Lei; Hu, Xin; Qiao, Feng; Zhang, Anli; Xu, Xiaojun; Zhang, Huafeng; Wicha, Max S; Zhang, Lixing; Shao, Zhi-Ming; Liu, Suling

2018-02-01

Notch pathways have important roles in carcinogenesis including pathways involving the Notch1 and Notch2 oncogenes. Pan-Notch inhibitors, such as gamma secretase inhibitors (GSIs), have been used in the clinical trials, but the outcomes of these trials have been insufficient and have yielded unclear. In the present study, we demonstrated that GSIs, such as MK-0752 and RO4929097, inhibit breast tumor growth, but increase the breast cancer stem cell (BCSC) population in Notch3-expressing breast cancer cells, in a process that is coupled with IL6 induction and is blocked by the IL6R antagonist Tocilizumab (TCZ). IL6 induction results from inhibition of Notch3-Hey2 signaling through MK-0752. Furthermore, HIF1α upregulates Notch3 expression via direct binding to the Notch3 promoter and subsequently downregulates BCSCs by decreasing the IL6 levels in Notch3-expressing breast cancer cells. Utilizing both breast cancer cell line xenografts and patient-derived xenografts (PDX), we showed that the combination of MK-0752 and Tocilizumab significantly decreases BCSCs and inhibits tumor growth and thus might serve as a novel therapeutic strategy for treating women with Notch3-expressing breast cancers.

Notch signaling mediates granulocyte-macrophage colony-stimulating factor priming-induced transendothelial migration of human eosinophils.

PubMed

Liu, L Y; Wang, H; Xenakis, J J; Spencer, L A

2015-07-01

Priming with cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances eosinophil migration and exacerbates the excessive accumulation of eosinophils within the bronchial mucosa of asthmatics. However, mechanisms that drive GM-CSF priming are incompletely understood. Notch signaling is an evolutionarily conserved pathway that regulates cellular processes, including migration, by integrating exogenous and cell-intrinsic cues. This study investigates the hypothesis that the priming-induced enhanced migration of human eosinophils requires the Notch signaling pathway. Using pan Notch inhibitors and newly developed human antibodies that specifically neutralize Notch receptor 1 activation, we investigated a role for Notch signaling in GM-CSF-primed transmigration of human blood eosinophils in vitro and in the airway accumulation of mouse eosinophils in vivo. Notch receptor 1 was constitutively active in freshly isolated human blood eosinophils, and inhibition of Notch signaling or specific blockade of Notch receptor 1 activation during GM-CSF priming impaired priming-enhanced eosinophil transendothelial migration in vitro. Inclusion of Notch signaling inhibitors during priming was associated with diminished ERK phosphorylation, and ERK-MAPK activation was required for GM-CSF priming-induced transmigration. In vivo in mice, eosinophil accumulation within allergic airways was impaired following systemic treatment with Notch inhibitor, or adoptive transfer of eosinophils treated ex vivo with Notch inhibitor. These data identify Notch signaling as an intrinsic pathway central to GM-CSF priming-induced eosinophil tissue migration. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Design and Calibration of a Raman Spectrometer for use in a Laser Spectroscopy Instrument Intended to Analyze Martian Surface and Atmospheric Characteristics for NASA

NASA Technical Reports Server (NTRS)

Lucas, John F.; Hornef, James

2016-01-01

This project's goal is the design of a Raman spectroscopy instrument to be utilized by NASA in an integrated spectroscopy strategy that will include Laser-Induced Breakdown Spectroscopy (LIBS) and Laser-Induced Florescence Spectroscopy (LIFS) for molecule and element identification on Mars Europa, and various asteroids. The instrument is to be down scaled from a dedicated rover mounted instrument into a compact unit with the same capabilities and accuracy as the larger instrument. The focus for this design is a spectrometer that utilizes Raman spectroscopy. The spectrometer has a calculated range of 218 nm wavelength spectrum with a resolution of 1.23 nm. To filter out the laser source wavelength of 532 nm the spectrometer design utilizes a 532 nm wavelength dichroic mirror and a 532 nm wavelength notch filter. The remaining scatter signal is concentrated by a 20 x microscopic objective through a 25-micron vertical slit into a 5mm diameter, 1cm focal length double concave focusing lens. The light is then diffracted by a 1600 Lines per Millimeter (L/mm) dual holographic transmission grating. This spectrum signal is captured by a 1-inch diameter double convex 3 cm focal length capture lens. An Intensified Charge Couple Device (ICCD) is placed within the initial focal cone of the capture lens and the Raman signal captured is to be analyzed through spectroscopy imaging software. This combination allows for accurate Raman spectroscopy to be achieved. The components for the spectrometer have been bench tested in a series of prototype developments based on theoretical calculations, alignment, and scaling strategies. The mounting platform is 2.5 cm wide by 8.8 cm long by 7 cm height. This platform has been tested and calibrated with various sources such as a neon light source and ruby crystal. This platform is intended to be enclosed in a ruggedized enclosure for mounting on a rover platform. The size and functionality of the Raman spectrometer allows for the rover to carry other mission critical devices. This project will be continued at NASA until the requirements are met for the expected initial 2020 launch date.

The effect of notches and pits on corrosion fatigue strength

NASA Astrophysics Data System (ADS)

Tatner, Ian

An investigation has been undertaken to examine the fatigue behaviour of two martensitic steels in air and aggressive environments. The steels studied are, 18% Ni marageing steel and FV520B, the later being a stainless steel turbine blade material and the former being a marageing steel that suffers general corrosion in mild environments. Both steels were heat treated to give similar tensile strength.The design and manufacture of an autoclave allowed push-pull fatigue tests to be conducted in aggressive environments at elevated temperatures.Corrosion potential was monitored using a three electrode cell and was controlled during testing. Base-line fatigue tests were conducted with a range of constant corrosion potentials, using both notched and plain FV520B specimens. In addition fatigue tests with pulsed corrosion potential were performed to asses the effect of transient corrosion conditions on the corrosion fatigue strength. The pulsed tests were designed to simulate service transients in the oxygen content and general chemical hostility in the condensing steam environment during start-up and shut down of the steam turbine.Post test examination of fractured samples was performed using Scanning Electron Microscopy (SEM) and optical microscope techniques. The fractography results were used to quantify microstructural and fracture features of the steels.A model based on the size and geometry of the initial corrosion pitting has been proposed to asses the fatigue life of FV520B in an aggressive environment.The effect of pitting on the corrosion fatigue strength of FV520B has been modelled using linear elastic fracture mechanics (LEFM) type approach. The model has shown a good correlation between predicted fatigue lives with experimental results.The results suggest that the fatigue life is governed by the mechanical stress concentrating effect of the pits rather than the electrochemical damage caused by the environment.Finite Element Analysis (FEA) of the notch allowed calculation of the elastic stress intensity factor (K[t]) for the specimen geometry used. The experimental results together with numerical results of FEA were used to calculate of the notch strength reduction factor (K[f]) for the material. This has been used to derive the notch sensitivity factors (q) for both materials.The results of fatigue tests in air showed that although both materials have similar tensile strength their plain fatigue strengths are different. The sensitivity of the fatigue strength to notches was also found to be significantly different. The marageing steel showed a higher sensitivity to a notch than the FV520B.An empirical model has been proposed to quantify the notch sensitivity and the effects of various microstructural features on the fatigue strength. A model has been developed to predict the serviceable life of a peak hardened FV520B turbine blade subjected to aggressive low load conditions during start-up and non-aggressive high load conditions during continual running. The model is based on the conclusions suggested in the work of a threshold stress intensity factor being reached where a fatigue crack will grow from a corrosion pit at the root of a notch. The model is then used to highlight the life reduction caused to steam turbine blades due to increased numbers of start-up cycles.

Temporal Ordering of Dynamic Expression Data from Detailed Spatial Expression Maps.

PubMed

Bailey, Charlotte S L; Bone, Robert A; Murray, Philip J; Dale, J Kim

2017-02-09

During somitogenesis, pairs of epithelial somites form in a progressive manner, budding off from the anterior end of the pre-somitic mesoderm (PSM) with a strict species-specific periodicity. The periodicity of the process is regulated by a molecular oscillator, known as the "segmentation clock," acting in the PSM cells. This clock drives the oscillatory patterns of gene expression across the PSM in a posterior-anterior direction. These so-called clock genes are key components of three signaling pathways: Wnt, Notch, and fibroblast growth factor (FGF). In addition, Notch signaling is essential for synchronizing intracellular oscillations in neighboring cells. We recently gained insight into how this may be mechanistically regulated. Upon ligand activation, the Notch receptor is cleaved, releasing the intracellular domain (NICD), which moves to the nucleus and regulates gene expression. NICD is highly labile, and its phosphorylation-dependent turnover acts to restrict Notch signaling. The profile of NICD production (and degradation) in the PSM is known to be oscillatory and to resemble that of a clock gene. We recently reported that both the Notch receptor and the Delta ligand, which mediate intercellular coupling, themselves exhibit dynamic expression at both the mRNA and protein levels. In this article, we describe the sensitive detection methods and detailed image analysis tools that we used, in combination with the computational modeling that we designed, to extract and overlay expression data from distinct points in the expression cycle. This allowed us to construct a spatio-temporal picture of the dynamic expression profile for the receptor, the ligand, and the Notch target clock genes throughout an oscillation cycle. Here, we describe the protocols used to generate and culture the PSM explants, as well as the procedure to stain for the mRNA or protein. We also explain how the confocal images were subsequently analyzed and temporally ordered computationally to generate ordered sequences of clock expression snapshots, hereafter defined as "kymographs," for the visualization of the spatiotemporal expression of Delta-like1 (Dll1) and Notch1 throughout the PSM.

Notch signaling pathways in human thoracic ossification of the ligamentum flavum.

PubMed

Qu, Xiaochen; Chen, Zhongqiang; Fan, Dongwei; Sun, Chuiguo; Zeng, Yan; Hou, Xiaofei; Ning, Shanglong

2016-08-01

This study investigated the pathological process of Notch signaling in the osteogenesis of ligamentum flavum tissues and cells, and the associated regulatory mechanisms. Notch receptors, ligands, and target genes were identified by quantitative polymerase chain reaction (qPCR) in ligamentum flavum cells and immunohistochemistry in ligamentum flavum sections from ossification of the ligamentum flavum (OLF) patients and controls. The temporospatial expression patterns of JAG1/Notch2/HES1 in human ligamentum flavum cells during osteogenic differentiation were determined by qPCR. Lentiviral vectors for Notch2 overexpression and knockdown were constructed and transfected into ligamentum flavum cells before osteogenic differentiation to examine the function of Notch signaling pathways in the osteogenic differentiation of ligamentum flavum cells. Alkaline phosphatase, Runx2, Osterix, osteocalcin, and osteopontin mRNA levels, alkaline phosphatase activity, and Alizarin Red staining were used as indicators of osteogenic differentiation. JAG1/Notch2/HES1 mRNA levels were up-regulated in ligamentum flavum cells from OLF patients, which increased during osteogenic differentiation. Immunohistochemical analysis suggested positive Notch2 expression at the ossification front. Down-regulation of Notch2 expression decelerated osteogenic differentiation of ligamentum flavum cells, and Notch2 overexpression promoted osteogenic differentiation of ligamentum flavum cells. Expression of Runx2 and Osterix increased in a manner similar to that of Notch2 during osteogenic differentiation of ligamentum flavum cells, and Notch2 knockdown and overexpression influenced their expression levels. Notch signaling plays an important role in OLF, and Notch may affect the osteogenic differentiation of ligamentum flavum cells via interactions with Runx2 and Osterix.© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1481-1491, 2016. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Notch Signaling Modulates MUC16 Biosynthesis in an In Vitro Model of Human Corneal and Conjunctival Epithelial Cell Differentiation

PubMed Central

Xiong, Linjie; Woodward, Ashley M.

2011-01-01

Purpose. Notch proteins are a family of transmembrane receptors that coordinate binary cell fate decisions and differentiation in wet-surfaced epithelia. We sought to determine whether Notch signaling contributes to maintaining mucosal homeostasis by modulating the biosynthesis of cell surface-associated mucins in an in vitro model of human corneal (HCLE) and conjunctival (HCjE) epithelial cell differentiation. Methods. HCLE and HCjE cells were grown at different stages of differentiation, representing nondifferentiated (preconfluent and confluent) and differentiated (stratified) epithelial cultures. Notch signaling was blocked with the γ-secretase inhibitor dibenzazepine (DBZ). The presence of Notch intracellular domains (Notch1 to Notch3) and mucin protein (MUC1, -4, -16) was evaluated by electrophoresis and Western blot analysis. Mucin gene expression was determined by TaqMan real-time polymerase chain reaction. Results. Here we demonstrate that Notch3 is highly expressed in undifferentiated and differentiated HCLE and HCjE cells, and that Notch1 and Notch2 biosynthesis is enhanced by induction of differentiation with serum-containing media. Inhibition of Notch signaling with DBZ impaired MUC16 biosynthesis in a concentration-dependent manner in undifferentiated cells at both preconfluent and confluent stages, but not in postmitotic stratified cells. In contrast to protein levels, the amount of MUC16 transcripts were not significantly reduced after DBZ treatment, suggesting that Notch regulates MUC16 posttranscriptionally. Immunoblots of DBZ-treated epithelial cells grown at different stages of differentiation revealed no differences in the levels of MUC1 and MUC4. Conclusions. These results indicate that MUC16 biosynthesis is posttranscriptionally regulated by Notch signaling at early stages of epithelial cell differentiation, and suggest that Notch activation contributes to maintaining a mucosal phenotype at the ocular surface. PMID:21508102

Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development.

PubMed

Pedrosa, Ana-Rita; Graça, José L; Carvalho, Sandra; Peleteiro, Maria C; Duarte, António; Trindade, Alexandre

2016-01-01

The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1-4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis. Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence. We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector. Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease. © 2015 Wiley Periodicals, Inc.

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

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.

Investigation of the Effects of Notch Width on Eddy Current Response and Comparison of Signals from Notches and Cracks

NASA Astrophysics Data System (ADS)

Larson, B. F.; Lo, C. C. H.; Nakagawa, N.

2010-02-01

This paper reports on work conducted to investigate the effect that electrical discharge machining (EDM) notch width has on the eddy current (EC) signal as a function of coil drive frequency. The notch results are also compared to EC signals from laboratory-grown fatigue cracks. This study builds upon previous work with titanium, Inconel and aluminum materials where the signal amplitude was shown to decrease, as expected, as the notch width decreases. The trend was captured well by numerical results and this allowed estimates to be made about the signals from idealized "zero-width" notches. The results indicated that the signal reduction factor from a 0.127 mm (0.005 inch) wide, rectangular notch to a theoretical zero-width semi-elliptical notch of the same size ranged from 25 to 42% for low conductivity materials when data was collected at 2 MHz. For aluminum, the difference between signals from 0.127 mm wide notches and estimated signals for zero-width notches was approximately 50%. However, 2 MHz is an uncommonly high frequency for inspecting aluminum alloys so additional work was necessary to investigate the notch width effect at lower frequencies. This study sought to determine how the notch-width effect changed as a function of frequency for high conductivity materials such as aluminum.

Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord.

PubMed

Rusanescu, Gabriel; Mao, Jianren

2014-10-01

Notch receptors are key regulators of nervous system development and promoters of neural stem cells renewal and proliferation. Defects in the expression of Notch genes result in severe, often lethal developmental abnormalities. Notch3 is generally thought to have a similar proliferative, anti-differentiation and gliogenic role to Notch1. However, in some cases, Notch3 has an opposite, pro-differentiation effect. Here, we show that Notch3 segregates from Notch1 and is transiently expressed in adult rat and mouse spinal cord neuron precursors and immature neurons. This suggests that during the differentiation of adult neural progenitor cells, Notch signalling may follow a modified version of the classical lateral inhibition model, involving the segregation of individual Notch receptors. Notch3 knockout mice, otherwise neurologically normal, are characterized by a reduced number of mature inhibitory interneurons and an increased number of highly excitable immature neurons in spinal cord laminae I-II. As a result, these mice have permanently lower nociceptive thresholds, similar to chronic pain. These results suggest that defective neuronal differentiation, for example as a result of reduced Notch3 expression or activation, may underlie human cases of intractable chronic pain, such as fibromyalgia and neuropathic pain. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

NOTCH3 Is Induced in Cancer-Associated Fibroblasts and Promotes Angiogenesis in Oral Squamous Cell Carcinoma.

PubMed

Kayamori, Kou; Katsube, Ken-Ichi; Sakamoto, Kei; Ohyama, Yoshio; Hirai, Hideaki; Yukimori, Akane; Ohata, Yae; Akashi, Takumi; Saitoh, Masao; Harada, Kiyoshi; Harada, Hiroyuki; Yamaguchi, Akira

2016-01-01

Recent studies have shown that Notch signaling is involved in many types of cancers, including oral squamous cell carcinomas (OSCCs). However, the role of Notch signaling in the tumor microenvironment is not yet fully understood. In this study, we investigated the roles of NOTCH3 signaling in cancer associated fibroblasts (CAFs) in OSCCs. Immunohistochemical study of 93 human tongue OSCC cases indicated that about one third of OSCCs showed NOTCH3 expression in CAFs, and that this expression significantly correlated with tumor-size. In vitro study showed that OSCC cell lines, especially HO1-N-1 cells stimulated NOTCH3 expression in normal human dermal fibroblasts (NHDFs) through direct cell-to-cell contact. Immunohistochemical and morphometric analysis using human OSCC samples demonstrated that NOTCH3 expression in CAFs significantly correlated with micro-vessel density in cancer stroma. In vitro angiogenesis assays involving co-culture of NHDFs with HO1-N-1 and human umbilical endothelial cells (HUVECs), and NOTCH3 knockdown in NHDFs using siRNA, demonstrated that HO1-N-1 cells significantly promoted tube formation dependent on NOTCH3-expression in NHDFs. Moreover, NOTCH3 expression in CAFs was related to poor prognosis of the OSCC patients. This work provides a new insight into the role of Notch signaling in CAFs associated with tumor angiogenesis and the possibility of NOTCH3-targeted molecular therapy in OSCCs.

NOTCH3 Is Induced in Cancer-Associated Fibroblasts and Promotes Angiogenesis in Oral Squamous Cell Carcinoma

PubMed Central

Kayamori, Kou; Katsube, Ken-ichi; Sakamoto, Kei; Ohyama, Yoshio; Hirai, Hideaki; Yukimori, Akane; Ohata, Yae; Akashi, Takumi; Saitoh, Masao; Harada, Kiyoshi; Harada, Hiroyuki; Yamaguchi, Akira

2016-01-01

Recent studies have shown that Notch signaling is involved in many types of cancers, including oral squamous cell carcinomas (OSCCs). However, the role of Notch signaling in the tumor microenvironment is not yet fully understood. In this study, we investigated the roles of NOTCH3 signaling in cancer associated fibroblasts (CAFs) in OSCCs. Immunohistochemical study of 93 human tongue OSCC cases indicated that about one third of OSCCs showed NOTCH3 expression in CAFs, and that this expression significantly correlated with tumor-size. In vitro study showed that OSCC cell lines, especially HO1-N-1 cells stimulated NOTCH3 expression in normal human dermal fibroblasts (NHDFs) through direct cell-to-cell contact. Immunohistochemical and morphometric analysis using human OSCC samples demonstrated that NOTCH3 expression in CAFs significantly correlated with micro-vessel density in cancer stroma. In vitro angiogenesis assays involving co-culture of NHDFs with HO1-N-1 and human umbilical endothelial cells (HUVECs), and NOTCH3 knockdown in NHDFs using siRNA, demonstrated that HO1-N-1 cells significantly promoted tube formation dependent on NOTCH3-expression in NHDFs. Moreover, NOTCH3 expression in CAFs was related to poor prognosis of the OSCC patients. This work provides a new insight into the role of Notch signaling in CAFs associated with tumor angiogenesis and the possibility of NOTCH3-targeted molecular therapy in OSCCs. PMID:27124156

Some observations on the nature of the audiometric 4000 hz notch: data from 3430 veterans.

PubMed

Wilson, Richard H

2011-01-01

Pure-tone, air-conduction audiograms notched at 4000 Hz have long been considered the signature configuration for noise-induced hearing loss even though there is an extensive literature that does not mesh with this simple explanation. There are many reports of notched audiograms from individuals with no history of noise exposure and, conversely, reports of audiograms with no notches from individuals with a history of noise exposure. Recent reports increasingly suggest that unilateral 4000 Hz notches are common. The prevalence of notched audiograms at 4000 Hz is dependent on the definition of the notch and the population under study. To examine the prevalence and characteristics of audiograms that are notched at 4000 Hz. Retrospective, descriptive. The participants were 3430 veterans evaluated in the Audiology Clinic at the VA Medical Center, Mountain Home, Tennessee. The mean age was 62.3 yr. Data Collection and Analyses: The data were collected in the course of a 60 min, routine audiological evaluation. In addition to pure-tone audiometry, a history, otoscopy, speech audiometry in quiet and in noise, and aural-acoustic immittance measures were included in the clinic protocol but were not evaluated in this report. A notch was defined when the 4000 Hz threshold minus the 2000 Hz threshold and the 4000 Hz threshold minus the 8000 Hz threshold both were ≥10 dB. Overall the mean LE (left ear) thresholds at 2000, 3000, and 4000 Hz were at hearing levels 2-3 dB higher than the hearing levels for the corresponding mean RE (right ear) thresholds; the differences were significant. A notched audiogram was observed in 40.6% of the participants in at least one ear with 15.4% having bilateral notches, 28.8% LE notches, and 27.1% RE notches. Unilateral 4000 Hz notches were almost twice as prevalent as bilateral 4000 Hz notches. Viewed as a function of age, notched audiograms were most common (∼35% of the participants) in the 40 and 50 yr groups with a diminishing prevalence in the 60-80 yr groups. The mean notch depth at 4000 Hz was consistently 20-26 dB across the seven age groups. In comparison to the thresholds of the audiograms that were not notched, the thresholds of the audiograms with 4000 Hz notches (1) at 250-2000 Hz were at hearing levels 2-3 dB lower, (2) at 3000 and 4000 Hz were at hearing levels 8-17 dB higher, and (3) at 8000 Hz were at hearing levels 3-4 dB lower; the threshold differences were significant at all frequencies for both ears. The data suggest that unilateral, 4000 Hz notched audiograms are as common or more common than bilateral notched audiograms and that unilateral notched audiograms are equally common for the LE and RE. The prevalence and characteristics of 4000 Hz notched audiograms in this veteran sample are similar to those observed in the population as a whole. American Academy of Audiology.

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-22

... Railway, LLC--Acquisition and Operation Exemption-- Three Notch Railroad Co., Inc. Three Notch Railway... from Three Notch Railroad Co., Inc. (TNHR) and to operate approximately 34 miles of rail line \\1... assigned TNHR's agreement with Andalusia & Conecuh Railroad Company, which was assigned to TNHR by the...

Space-time windowing of angle-beam wavefield data to characterize scattering from defects

NASA Astrophysics Data System (ADS)

Weng, Yu; Michaels, Jennifer E.

2018-04-01

The primary focus of ultrasonic nondestructive evaluation is defect detection and characterization. In particular, fatigue cracks emanating from fastener holes are commonly found in aerospace structures. Therefore, scattering of ultrasonic waves from crack-like notches is of practical interest. Here, angle-beam shear waves are used to interrogate notches in aluminum plates. In prior work, notch-scattering was characterized and quantified in the frequency-wavenumber domain, which has the undesirable effect of lumping all scattered shear wave energy from notches into a single energy curve. This present work focuses on developing space-time windowing methods to quantify notch-scattered energy directly in the time-space domain. Two strategies are developed. The first is to indirectly characterize notch-scattering via the change in scattering as compared to the undamaged through-hole. The second strategy is to directly track notch-scattered waves in the time-space domain and then quantify scattered energy by constructing energy-versus-direction curves. Both strategies provide a group of energy difference curves, which show how notch-scattering evolves as time progresses. Notch-scattering quantification results for different notch lengths are shown and discussed.

RNA interference-mediated NOTCH3 knockdown induces phenotype switching of vascular smooth muscle cells in vitro

PubMed Central

Liu, Nan; Li, Ying; Chen, Hui; Wei, Wei; An, Yulin; Zhu, Guangming

2015-01-01

Notch3 plays an important role in differentiation, migration and signal transduction of vascular smooth muscle cells (VSMCs). In this study, we used RNA interference (RNAi) technique to investigate the effect of knocking down the expression of the NOTCH3 gene in VSMCs on the phenotype determination under pathologic status. Real-time PCR and Western Blot experiments verified the expression levels of Notch3 mRNA and protein were reduced more than 40% and 50% in the NOTCH3 siRNA group. When the expression of Notch3 was decreased, the proliferation, apoptosis and immigration of VSMCs were enhanced compared to control groups (P < 0.01). NOTCH3 siRNA VSMCs observed using confocal microscopy showed abnormal nuclear configuration, a disorganized actin filament system, polygonal cell shapes, and decreasing cell sizes. Additionally, knocking down the expression of NOTCH3 may evoke the CASR and FAK expression. In Conclusion, interfering with the expression of NOTCH3 causes VSMCs to exhibit an intermediate phenotype. CaSR and FAK may be involved in the Notch3 signaling pathway. PMID:26550181

NOTCH3 is expressed in human apical papilla and in subpopulations of stem cells isolated from the tissue.

PubMed

Jamal, Mohamed; Chogle, Sami M; Karam, Sherif M; Huang, George T-J

2015-09-01

NOTCH plays a role in regulating stem cell function and fate decision. It is involved in tooth development and injury repair. Information regarding NOTCH expression in human dental root apical papilla (AP) and its residing stem cells (SCAP) is limited. Here we investigated the expression of NOTCH3, its ligand JAG1, and mesenchymal stem cell markers CD146 and STRO-1 in the AP or in the primary cultures of SCAP isolated from AP. Our in situ immunostaining showed that in the AP NOTCH3 and CD146 were co-expressed and associated with blood vessels having NOTCH3 located more peripherally. In cultured SCAP, NOTCH3 and JAG1 were co-expressed. Flow cytometry analysis showed that 7%, 16% and 98% of the isolated SCAP were positive for NOTCH3, STRO-1 and CD146, respectively with a rare 1.5% subpopulation of SCAP co-expressing all three markers. The expression level of NOTCH3 reduced when SCAP underwent osteogenic differentiation. Our findings are the first step towards defining the regulatory role of NOTCH3 in SCAP fate decision.

RNA interference-mediated NOTCH3 knockdown induces phenotype switching of vascular smooth muscle cells in vitro.

PubMed

Liu, Nan; Li, Ying; Chen, Hui; Wei, Wei; An, Yulin; Zhu, Guangming

2015-01-01

Notch3 plays an important role in differentiation, migration and signal transduction of vascular smooth muscle cells (VSMCs). In this study, we used RNA interference (RNAi) technique to investigate the effect of knocking down the expression of the NOTCH3 gene in VSMCs on the phenotype determination under pathologic status. Real-time PCR and Western Blot experiments verified the expression levels of Notch3 mRNA and protein were reduced more than 40% and 50% in the NOTCH3 siRNA group. When the expression of Notch3 was decreased, the proliferation, apoptosis and immigration of VSMCs were enhanced compared to control groups (P < 0.01). NOTCH3 siRNA VSMCs observed using confocal microscopy showed abnormal nuclear configuration, a disorganized actin filament system, polygonal cell shapes, and decreasing cell sizes. Additionally, knocking down the expression of NOTCH3 may evoke the CASR and FAK expression. In Conclusion, interfering with the expression of NOTCH3 causes VSMCs to exhibit an intermediate phenotype. CaSR and FAK may be involved in the Notch3 signaling pathway.

Solar Rejection Filter for Large Telescopes

NASA Technical Reports Server (NTRS)

Hemmati, Hamid; Lesh, James

2009-01-01

To reject solar radiation photons at the front aperture for large telescopes, a mosaic of large transmission mode filters is placed in front of the telescope or at the aperture of the dome. Filtering options for effective rejection of sunlight include a smaller filter down-path near the focus of the telescope, and a large-diameter filter located in the front of the main aperture. Two types of large filters are viable: reflectance mode and transmittance mode. In the case of reflectance mode, a dielectric coating on a suitable substrate (e.g. a low-thermal-expansion glass) is arranged to reflect only a single, narrow wavelength and to efficiently transmit all other wavelengths. These coatings are commonly referred to as notch filter. In this case, the large mirror located in front of the telescope aperture reflects the received (signal and background) light into the telescope. In the case of transmittance mode, a dielectric coating on a suitable substrate (glass, sapphire, clear plastic, membrane, and the like) is arranged to transmit only a single wavelength and to reject all other wavelengths (visible and near IR) of light. The substrate of the large filter will determine its mass. At first glance, a large optical filter with a diameter of up to 10 m, located in front of the main aperture, would require a significant thickness to avoid sagging. However, a segmented filter supported by a structurally rugged grid can support smaller filters. The obscuration introduced by the grid is minimal because the total area can be made insignificant. This configuration can be detrimental to a diffraction- limited telescope due to diffraction effects at the edges of each sub-panel. However, no discernable degradation would result for a 20 diffraction-limit telescope (a photon bucket). Even the small amount of sagging in each subpanel should have minimal effect in the performance of a non-diffraction limited telescope because the part has no appreciable optical power. If the front aperture filter is integrated with the telescope dome, it will reject heat from the dome and will significantly reduce dome temperature regulation requirements and costs. Also, the filter will protect the telescope optics from dust and other contaminants in the atmosphere. It will be simpler to clean or replace this filter than the telescope primary mirror. It may be necessary to paint the support grid with a highly reflective material to avoid overheating.

Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.

PubMed

Ali, Syed A; Justilien, Verline; Jamieson, Lee; Murray, Nicole R; Fields, Alan P

2016-03-14

We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC. Copyright © 2016 Elsevier Inc. All rights reserved.

notch3 is essential for oligodendrocyte development and vascular integrity in zebrafish

PubMed Central

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

2013-01-01

SUMMARY Mutations in the human NOTCH3 gene cause CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL is an inherited small vessel disease characterized by diverse clinical manifestations including vasculopathy, neurodegeneration and dementia. Here we report two mutations in the zebrafish notch3 gene, one identified in a previous screen for mutations with reduced expression of myelin basic protein (mbp) and another caused by a retroviral insertion. Reduced mbp expression in notch3 mutant embryos is associated with fewer oligodendrocyte precursor cells (OPCs). Despite an early neurogenic phenotype, mbp expression recovered at later developmental stages and some notch3 homozygous mutants survived to adulthood. These mutants, as well as adult zebrafish carrying both mutant alleles together, displayed a striking stress-associated accumulation of blood in the head and fins. Histological analysis of mutant vessels revealed vasculopathy, including: an enlargement (dilation) of vessels in the telencephalon and fin, disorganization of the normal stereotyped arrangement of vessels in the fin, and an apparent loss of arterial morphological structure. Expression of hey1, a well-known transcriptional target of Notch signaling, was greatly reduced in notch3 mutant fins, suggesting that Notch3 acts via a canonical Notch signaling pathway to promote normal vessel structure. Ultrastructural analysis confirmed the presence of dilated vessels in notch3 mutant fins and revealed that the vessel walls of presumed arteries showed signs of deterioration. Gaps in the arterial wall and the presence of blood cells outside of vessels in mutants indicated that compromised vessel structure led to hemorrhage. In notch3 heterozygotes, we found elevated expression of both notch3 itself and target genes, indicating that specific alterations in gene expression due to partial loss of Notch3 function might contribute to the abnormalities observed in heterozygous larvae and adults. Our analysis of zebrafish notch3 mutants indicates that Notch3 regulates OPC development and mbp gene expression in larvae, and maintains vascular integrity in adults. PMID:23720232

Increased Notch3 Activity Mediates pathological Changes in Structure of Cerebral arteries

PubMed Central

Baron-Menguy, Celine; Domenga-Denier, Valérie; Ghezali, Lamia; Faraci, Frank; Joutel, Anne

2016-01-01

CADASIL, the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3R169C mouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone. In this study, we investigated the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3R169C mice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred prior to myogenic tone deficits. This defect was not prevented by genetic reduction of TIMP3 in TgNotch3R169C mice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3R170C/R170C) exhibited similar reductions in arterial lumen, and both TgNotch3R169C and Notch3R170C/R170C mice showed increased cerebral artery expression of Notch3 target genes. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3R169C mice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure-independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow. PMID:27821617

Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries.

PubMed

Baron-Menguy, Celine; Domenga-Denier, Valérie; Ghezali, Lamia; Faraci, Frank M; Joutel, Anne

2017-01-01

CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), the most frequent genetic cause of stroke and vascular dementia, is caused by highly stereotyped mutations in the NOTCH3 receptor, which is predominantly expressed in vascular smooth muscle. The well-established TgNotch3 R169C mouse model develops characteristic features of the human disease, with deposition of NOTCH3 and other proteins, including TIMP3 (tissue inhibitor of metalloproteinase 3), on brain vessels, as well as reduced maximal dilation, and attenuated myogenic tone of cerebral arteries, but without elevated blood pressure. Increased TIMP3 levels were recently shown to be a major determinant of altered myogenic tone. In this study, we investigated the contribution of TIMP3 and Notch3 signaling to the impairment of maximal vasodilator capacity caused by the archetypal R169C mutation. Maximally dilated cerebral arteries in TgNotch3 R169C mice exhibited a decrease in lumen diameter over a range of physiological pressures that occurred before myogenic tone deficits. This defect was not prevented by genetic reduction of TIMP3 in TgNotch3 R169C mice and was not observed in mice overexpressing TIMP3. Knock-in mice with the R169C mutation (Notch3 R170C/R170C ) exhibited similar reductions in arterial lumen, and both TgNotch3 R169C and Notch3 R170C/R170C mice showed increased cerebral artery expression of Notch3 target genes. Reduced maximal vasodilation was prevented by conditional reduction of Notch activity in smooth muscle of TgNotch3 R169C mice and mimicked by conditional activation of Notch3 in smooth muscle, an effect that was blood pressure-independent. We conclude that increased Notch3 activity mediates reduction in maximal dilator capacity of cerebral arteries in CADASIL and may contribute to reductions in cerebral blood flow. © 2016 American Heart Association, Inc.

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.

Epidermal Notch signalling: differentiation, cancer and adhesion.

PubMed

Watt, Fiona M; Estrach, Soline; Ambler, Carrie A

2008-04-01

The Notch pathway plays an important role in regulating epidermal differentiation. Notch ligands, receptors and effectors are expressed in a complex and dynamic pattern in embryonic and adult skin. Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages and that Notch acts as an epidermal tumour suppressor. Notch signalling interacts with a range of other pathways to fulfil these functions and acts via RBP-Jkappa dependent and independent mechanisms. The effects on differentiation can be cell autonomous and non-autonomous, and Notch contributes to stem cell clustering via modulation of cell adhesion.

The fracture behavior of filament wound cylinders with surface flaws

NASA Technical Reports Server (NTRS)

Harris, C. E.; Morris, D. H.; Poe, C. C., Jr.

1985-01-01

The behavior of tensile coupons with surface notches of various semielliptical shapes has been evaluated for specimens obtained from a thick filament wound graphite/epoxy cylinder. Specimens with very shallow notches were observed to be notch insensitive and the unnotched strength from these specimens was determined to be 54.97 Ksi with an associated failure strain of 1.328 percent. Specimens with deeper notches were sensitive to notch depth and notch aspect ratio. Isotropic linear elastic fracture mechanics with an estimated fracture toughness of 27.2 Ksi-in.-to the 1/2 correctly predicted the influence of notch depth, aspect ratio and specimen finite width.

Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway

PubMed Central

Reizis, Boris; Leder, Philip

2002-01-01

The Notch signaling pathway regulates the commitment and early development of T lymphocytes. We studied Notch-mediated induction of the pre-T cell receptor α (pTa) gene, a T-cell-specific transcriptional target of Notch. The pTa enhancer was activated by Notch signaling and contained binding sites for its nuclear effector, CSL. Mutation of the CSL-binding sites abolished enhancer induction by Notch and delayed the up-regulation of pTa transgene expression during T cell lineage commitment. These results show a direct mechanism of stage- and tissue-specific gene induction by the mammalian Notch/CSL signaling pathway. PMID:11825871

Non-ARC solution to metal reflective notching: its evaluation and selection

NASA Astrophysics Data System (ADS)

Buffat, Stephen J.

1997-07-01

Patterning photoresists on reflective topography such as aluminum is one of the more difficult problems in device manufacturing. Interference effects caused by reflected light from the substrate/photoresist interface and surface topography result in coupling of additional energy into the film. This leads to linewidth variation known as reflective notching which severely impacts process latitude and increases critical dimension variation. For many years, suppliers approached the problem by adding dyes that absorb in the actinic region to create a larger non-bleachable absorption. In recent years, strongly absorbing intermediate layers or ARC's, both organic and inorganic, have seen widespread implementation to control reflective notching. However, if a fab is not equipped to accommodate the required ARC process, the processing can be very time consuming, cumbersome and costly. This study was undertaken to determine if a non-ARC, i-line photoresist process could be developed to reduce or eliminate aluminum reflective notching and accompanying critical dimension variation. This study was designed to screen, identify, and characterize various resist chemistries. Based on the screening characterization, a final, cost effective resist chemistry without ARC was selected, fully characterized and transferred into production. The selected material is currently being used in a high volume 0.60 micrometers CMOS, 200 mm wafer manufacturing process.

The Varied Roles of Notch in Cancer

PubMed Central

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

2018-01-01

Notch receptors influence cellular behavior by participating in a seemingly simple signaling pathway, but outcomes produced by Notch signaling are remarkably varied depending on signal dose and cell context. Here, after briefly reviewing new insights into physiologic mechanisms of Notch signaling in healthy tissues and defects in Notch signaling that contribute to congenital disorders and viral infection, we discuss the varied roles of Notch in cancer, focusing on cell autonomous activities that may be either oncogenic or tumor suppressive. PMID:27959635

Discrete shear-transformation-zone plasticity modeling of notched bars

NASA Astrophysics Data System (ADS)

Kondori, Babak; Amine Benzerga, A.; Needleman, Alan

2018-02-01

Plane strain tension analyses of un-notched and notched bars are carried out using discrete shear transformation zone plasticity. In this framework, the carriers of plastic deformation are shear transformation zones (STZs) which are modeled as Eshelby inclusions. Superposition is used to represent a boundary value problem solution in terms of discretely modeled Eshelby inclusions, given analytically for an infinite elastic medium, and an image solution that enforces the prescribed boundary conditions. The image problem is a standard linear elastic boundary value problem that is solved by the finite element method. Potential STZ activation sites are randomly distributed in the bars and constitutive relations are specified for their evolution. Results are presented for un-notched bars, for bars with blunt notches and for bars with sharp notches. The computed stress-strain curves are serrated with the magnitude of the associated stress-drops depending on bar size, notch acuity and STZ evolution. Cooperative deformation bands (shear bands) emerge upon straining and, in some cases, high stress levels occur within the bands. Effects of specimen geometry and size on the stress-strain curves are explored. Depending on STZ kinetics, notch strengthening, notch insensitivity or notch weakening are obtained. The analyses provide a rationale for some conflicting findings regarding notch effects on the mechanical response of metallic glasses.

Expression of Notch1 and Numb in small cell lung cancer.

PubMed

Kikuchi, Hajime; Sakakibara-Konishi, Jun; Furuta, Megumi; Yokouchi, Hiroshi; Nishihara, Hiroshi; Yamazaki, Shigeo; Uramoto, Hidetaka; Tanaka, Fumihiro; Harada, Masao; Akie, Kenji; Sugaya, Fumiko; Fujita, Yuka; Takamura, Kei; Kojima, Tetsuya; Harada, Toshiyuki; Higuchi, Mitsunori; Honjo, Osamu; Minami, Yoshinori; Watanabe, Naomi; Oizumi, Satoshi; Suzuki, Hiroyuki; Ishida, Takashi; Dosaka-Akita, Hirotoshi; Isobe, Hiroshi; Munakata, Mitsuru; Nishimura, Masaharu

2017-02-07

Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

Notch-Induced Expression of FZD7 Requires Noncanonical NOTCH3 Signaling in Human Breast Epithelial Cells.

PubMed

Bhat, Vasudeva; Sun, Yu Jia; Weger, Steve; Raouf, Afshin

2016-04-01

The evolutionarily conserved Notch and Wnt signaling pathways have demonstrated roles in normal mammary gland development and in breast carcinogenesis. We previously reported that in human mammary gland, signaling through NOTCH3 alone regulates the commitment of the undifferentiated bipotential progenitors to the luminal cell fate, indicating that NOTCH3 may regulate the expression of unique genes apart from the other Notch receptors. In this study, we used gain of function and loss of function experiments and found that a Wnt signaling receptor, Frizzled7 (FZD7), is a unique and nonredundant target of NOTCH3 in human breast epithelial cells. Interestingly, neither the constitutively active forms of NOTCH1-2, 4 nor loss of expression of these receptors were able to alter expression of FZD7 in human breast epithelial cells. We further show that FZD7-expressing cells are found more frequently in the luminal progenitor-enriched subpopulation of cells obtained from breast reduction samples compared with the undifferentiated bipotent progenitors. Also, we show that NOTCH3-induced expression of FZD7 occurs in the absence of CSL (CBF1-Suppressor of Hairless-Lag-1). Our data suggest that noncanonical Notch signaling through NOTCH3 could modulate Wnt signaling via FZD7 and in this way, might be involved in luminal cell differentiation.

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

PubMed

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

2015-06-01

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. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

Acetylation-Dependent Regulation of Notch Signaling in Macrophages by SIRT1 Affects Sepsis Development

PubMed Central

Bai, Xiaozhi; He, Ting; Liu, Yang; Zhang, Julei; Li, Xiaoqiang; Shi, Jihong; Wang, Kejia; Han, Fu; Zhang, Wei; Zhang, Yijie; Cai, Weixia; Hu, Dahai

2018-01-01

SIRT1 is reported to participate in macrophage differentiation and affect sepsis, and Notch signaling is widely reported to influence inflammation and macrophage activation. However, the specific mechanisms through which SIRT1 regulates sepsis and the relationship between SIRT1 and Notch signaling remain poorly elucidated. In this study, we found that SIRT1 levels were decreased in sepsis both in vitro and in vivo and that SIRT1 regulation of Notch signaling affected inflammation. In lipopolysaccharide (LPS)-induced sepsis, the levels of Notch signaling molecules, including Notch1, Notch2, Hes1, and intracellular domain of Notch (NICD), were increased. However, NICD could be deacetylated by SIRT1, and this led to the suppression of Notch signaling. Notably, in macrophages from myeloid-specific RBP-J−/− mice, in which Notch signaling is inhibited, pro-inflammatory cytokines were expressed at lower levels than in macrophages from wild-type littermates and in RBP-J−/− macrophages, and the NF-κB pathway was also inhibited. Accordingly, in the case of RBP-J−/− mice, LPS-induced inflammation and mortality were lower than in wild-type mice. Our results indicate that SIRT1 inhibits Notch signaling through NICD deacetylation and thus ultimately alleviates sepsis. PMID:29867921

BCL6 antagonizes NOTCH2 to maintain survival of human follicular lymphoma cells

PubMed Central

Valls, Ester; Lobry, Camille; Geng, Huimin; Wang, Ling; Cardenas, Mariano; Rivas, Martín; Cerchietti, Leandro; Oh, Philmo; Yang, Shao Ning; Oswald, Erin; Graham, Camille W.; Jiang, Yanwen; Hatzi, Katerina; Agirre, Xabier; Perkey, Eric; Li, Zhuoning; Tam, Wayne; Bhatt, Kamala; Leonard, John P.; Zweidler-McKay, Patrick A.; Maillard, Ivan; Elemento, Olivier; Ci, Weimin; Aifantis, Iannis; Melnick, Ari

2017-01-01

Summary Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and Notch pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably BCL6 up-regulation is associated with repression of Notch2 and its target genes in primary human and murine germinal center cells. Repression of Notch2 is an essential function of BCL6 in FL and GC B-cells since inducible expression of Notch2 abrogated GC formation in mice and kills FL cells. Indeed BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo. These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2. PMID:28232365

Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahrenhoerster, Lori S.; Leuthner, Tess C.; Tate, Everett R.

2015-03-01

Over half of T cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively activemore » Notch1 transgene (Notch{sup ICN-TG}). Following exposure of adult Notch{sup ICN-TG} mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3 μg/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed Notch{sup ICN-TG} offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed Notch{sup ICN-TG} offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and B to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression. - Highlights: • Adult mice exposed to 30 μg/kg TCDD have higher efficiency of CD8 thymocyte generation. • Mice carrying a constitutively active Notch transgene were exposed to 3 μg/kg TCDD throughout development. • Progression of Notch-induced thymoma was different in offspring exposed to TCDD developmentally. • Developmental AHR activation attenuates later-life Notch1-dependent impacts on T cell differentiation.« less

A Minimized MIMO-UWB Antenna with High Isolation and Triple Band-Notched Functions

NASA Astrophysics Data System (ADS)

Kong, Yuanyuan; Li, Yingsong; Yu, Kai

2016-11-01

A compact high isolation MIMO-UWB antenna with triple frequency rejection bands is proposed for UWB communication applications. The proposed MIMO-UWB antenna consists of two identical UWB antennas and each antenna element has a semicircle ring shaped radiation patch fed by a bend microstrip feeding line for covering the UWB band, which operates from 2.85 GHz to 11.79 GHz with an impedance bandwidth of 122.1 %. By etching a L-shaped slot on the ground plane, and embedding an "anchor" shaped stub into the patch and integrating an open ring under the semicircle shaped radiation patch, three notch bands are realized to suppress WiMAX (3.3-3.6 GHz), WLAN(5.725-5.825 GHz) and uplink of X-band satellite (7.9-8.4 GHz) signals. The high isolation with S21<-20 dB in most UWB band is obtained by adding a protruded decoupling structure. The design procedure of the MIMO-UWB antenna is given in detail. The proposed MIMO-UWB antenna is simulated, fabricated and measured. Experimental results demonstrate that the proposed MIMO-UWB antenna has a stable gain, good impedance match, high isolation, low envelope correlation coefficient and good radiation pattern at the UWB operating band and it can provide three designated notch bands.

Notch Promotes Dynamin-Dependent Endocytosis of Nephrin

PubMed Central

Waters, Aoife M.; Wu, Megan Yi Jun; Huang, Yi-Wei; Liu, Guang Ying; Holmyard, Doug; Onay, Tuncer; Jones, Nina; Egan, Sean E.; Robinson, Lisa A.

2012-01-01

Notch signaling in podocytes causes proteinuria and glomerulosclerosis in humans and rodents, but the underlying mechanism remains unknown. Here, we analyzed morphologic, molecular, and cellular events before the onset of proteinuria in newborn transgenic mice that express activated Notch in podocytes. Immunohistochemistry revealed a loss of the slit diaphragm protein nephrin exclusively in podocytes expressing activated Notch. Podocyte-specific deletion of Rbpj, which is essential for canonical Notch signaling, prevented this loss of nephrin. Overexpression of activated Notch decreased cell surface nephrin and increased cytoplasmic nephrin in transfected HEK293T cells; pharmacologic inhibition of dynamin, but not depletion of cholesterol, blocked these effects on nephrin, suggesting that Notch promotes dynamin-dependent, raft-independent endocytosis of nephrin. Supporting an association between Notch signaling and nephrin trafficking, electron microscopy revealed shortened podocyte foot processes and fewer slit diaphragms among the transgenic mice compared with controls. These data suggest that Notch signaling induces endocytosis of nephrin, thereby triggering the onset of proteinuria. PMID:22052054

Structural basis for Notch1 engagement of Delta-like 4

DOE PAGES

Luca, Vincent C.; Jude, Kevin M.; Pierce, Nathan W.; ...

2015-02-20

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

Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity

DOE PAGES

Luca, Vincent C.; Kim, Byoung Choul; Ge, Chenghao; ...

2017-03-02

Notch receptor activation initiates cell fate decisions and is distinctive in its reliance on mechanical force and protein glycosylation. The 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 complexed with an engineered, high-affinity variant of Jagged1 (Jag1) reveals a binding interface that extends ~120 angstroms along five consecutive domains of each protein. O-Linked fucose modifications on Notch1 epidermal growth factor–like (EGF) domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Delta-like 4 ligand. Jag1 undergoes conformational changes uponmore » Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. In conclusion, this mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling.« less

Effect of strain rate and notch geometry on tensile properties and fracture mechanism of creep strength enhanced ferritic P91 steel

NASA Astrophysics Data System (ADS)

Pandey, Chandan; Mahapatra, M. M.; Kumar, Pradeep; Saini, N.

2018-01-01

Creep strength enhanced ferritic (CSEF) P91 steel were subjected to room temperature tensile test for quasi-static (less than 10-1/s) strain rate by using the Instron Vertical Tensile Testing Machine. Effect of different type of notch geometry, notch depth and angle on mechanical properties were also considered for different strain rate. In quasi-static rates, the P91 steel showed a positive strain rate sensitivity. On the basis of tensile data, fracture toughness of P91 steel was also calculated numerically. For 1 mm notch depth (constant strain rate), notch strength and fracture toughness were found to be increased with increase in notch angle from 45° to 60° while the maximum value attained in U-type notch. Notch angle and notch depth has found a minute effect on P91 steel strength and fracture toughness. The fracture surface morphology was studied by field emission scanning electron microscopy (FESEM).

Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luca, Vincent C.; Kim, Byoung Choul; Ge, Chenghao

Notch receptor activation initiates cell fate decisions and is distinctive in its reliance on mechanical force and protein glycosylation. The 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 complexed with an engineered, high-affinity variant of Jagged1 (Jag1) reveals a binding interface that extends ~120 angstroms along five consecutive domains of each protein. O-Linked fucose modifications on Notch1 epidermal growth factor–like (EGF) domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Delta-like 4 ligand. Jag1 undergoes conformational changes uponmore » Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. In conclusion, this mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling.« less

Structural basis for Notch1 engagement of Delta-like 4

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luca, Vincent C.; Jude, Kevin M.; Pierce, Nathan W.

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

Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL

PubMed Central

Machuca-Parra, Arturo I.; Bigger-Allen, Alexander A.; Sanchez, Angie V.; Saint-Geniez, Magali

2017-01-01

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3. No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling. PMID:28698285

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

NOTCH pathway inactivation promotes bladder cancer progression

PubMed Central

Maraver, Antonio; Fernandez-Marcos, Pablo J.; Cash, Timothy P.; Mendez-Pertuz, Marinela; Dueñas, Marta; Maietta, Paolo; Martinelli, Paola; Muñoz-Martin, Maribel; Martínez-Fernández, Mónica; Cañamero, Marta; Roncador, Giovanna; Martinez-Torrecuadrada, Jorge L.; Grivas, Dimitrios; de la Pompa, Jose Luis; Valencia, Alfonso; Paramio, Jesús M.; Real, Francisco X.; Serrano, Manuel

2015-01-01

NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features. PMID:25574842

A Novel High-Throughput 1536-well Notch1 γ-Secretase AlphaLISA Assay

PubMed Central

Chau, De-ming; Shum, David; Radu, Constantin; Bhinder, Bhavneet; Gin, David; Gilchrist, M. Lane; Djaballah, Hakim; Li, Yue-Ming

2013-01-01

The Notch pathway plays a crucial role in cell fate decisions through controlling various cellular processes. Overactive Notch signal contributes to cancer development from leukemias to solid tumors. γ-Secretase is an intramembrane protease responsible for the final proteolytic step of Notch that releases the membrane-tethered Notch fragment for signaling. Therefore, γ-secretase is an attractive drug target in treating Notch-mediated cancers. However, the absence of high-throughput γ-secretase assay using Notch substrate has limited the identification and development of γ-secretase inhibitors that specifically target the Notch signaling pathway. Here, we report on the development of a 1536-well γ-secretase assay using a biotinylated recombinant Notch1 substrate. We effectively assimilated and miniaturized this newly developed Notch1 substrate with the AlphaLISA detection technology and demonstrated its robustness with a calculated Z’ score of 0.66. We further validated this optimized assay by performing a pilot screening against a chemical library consisting of ~5,600 chemicals and identified known γ-secretase inhibitors e.g. DAPT, and Calpeptin; as well as a novel γ-secretase inhibitor referred to as KD-I-085. This assay is the first reported 1536-well AlphaLISA format and represents a novel high-throughput Notch1-γ-secretase assay, which provides an unprecedented opportunity to discover Notch-selective γ-secretase inhibitors that can be potentially used for the treatment of cancer and other human disorders. PMID:23448293

Effect of open hole on tensile failure properties of 2D triaxial braided textile composites and tape equivalents

NASA Technical Reports Server (NTRS)

Norman, Timothy L.; Anglin, Colin; Gaskin, David; Patrick, Mike

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 triaxial braided textile composite materials. Four fiber architectures were considered with different combinations of braid angle, longitudinal and braider yam size, and percentage of longitudinal yarns. 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 yams 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. Longitudinal yarn splitting occurred in three of four architectures that were longitudinally fiber dominated. Damage initiation stress decreased with increasing braid angle. No significant differences in prediction of near notch stress between measured and predicted stress 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.

PI3K/AKT signaling inhibits NOTCH1 lysosome-mediated degradation.

PubMed

Platonova, Natalia; Manzo, Teresa; Mirandola, Leonardo; Colombo, Michela; Calzavara, Elisabetta; Vigolo, Emilia; Cermisoni, Greta Chiara; De Simone, Daria; Garavelli, Silvia; Cecchinato, Valentina; Lazzari, Elisa; Neri, Antonino; Chiaramonte, Raffaella

2015-06-06

The pathways of NOTCH and PI3K/AKT are dysregulated in about 60% and 48% of T-cell acute lymphoblastic leukemia (T-ALL) patients, respectively. In this context, they interact and cooperate in controlling tumor cell biology. Here, we propose a novel mechanism by which the PI3K/AKT pathway regulates NOTCH1 in T-ALL, starting from the evidence that the inhibition of PI3K/AKT signaling induced by treatment with LY294002 or transient transfection with a dominant negative AKT mutant downregulates NOTCH1 protein levels and activity, without affecting NOTCH1 transcription. We showed that the withdrawal of PI3K/AKT signaling was associated to NOTCH1 phosphorylation in tyrosine residues and monoubiquitination of NOTCH1 detected by Ubiquitin capture assay. Co-immunoprecipitation assay and colocalization analysis further showed that the E3 ubiquitin ligase c-Cbl interacts and monoubiquitinates NOTCH1, activating its lysosomal degradation. These results suggest that the degradation of NOTCH1 could represent a mechanism of control by which NOTCH1 receptors are actively removed from the cell surface. This mechanism is finely regulated by the PI3K/AKT pathway in physiological conditions. In pathological conditions characterized by PI3K/AKT hyperactivation, such as T-ALL, the excessive AKT signaling could lead to NOTCH1 signaling dysregulation. Therefore, a therapeutic strategy directed to PI3K/AKT in T-ALL could contemporaneously inhibit the dysregulated NOTCH1 signaling. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

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

PubMed

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

2016-09-08

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.

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

Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma

PubMed Central

Baglioni, Michele; Fornari, Francesca; Giannone, Ferdinando; Ravaioli, Matteo; Cescon, Matteo; Chieco, Pasquale; Bolondi, Luigi; Gramantieri, Laura

2014-01-01

To successfully target Notch receptors as part of a multidrug anticancer strategy, it will be essential to fully characterize the factors that are modulated by Notch signaling. We recently reported that Notch3 silencing in HCC results in p53 up-regulation in vitro and, therefore, we focused on the mechanisms that associate Notch3 to p53 protein expression. We explored the regulation of p53 by Notch3 signalling in three HCC cell lines HepG2, SNU398 and Hep3B.We found that Notch3 regulates p53 at post-transcriptional level controlling both Cyclin G1 expression and the feed-forward circuit involving p53, miR-221 and MDM2. Moreover, our results were validated in human HCCs and in a rat model of HCC treated with Notch3 siRNAs. Our findings are becoming an exciting area for further in-depth research toward targeted inactivation of Notch3 receptor as a novel therapeutic approach for increasing the drug-sensitivity, and thereby improving the treatment outcome of patients affected by HCC. Indeed, we proved that Notch3 silencing strongly increases the effects of Nutilin-3. With regard to therapeutic implications, Notch3-specific drugs could represent a valuable strategy to limit Notch signaling in the context of hepatocellular carcinoma over-expressing this receptor. PMID:25431954

The Smallest Form Factor UWB Antenna with Quintuple Rejection Bands for IoT Applications Utilizing RSRR and RCSRR.

PubMed

Rahman, MuhibUr; Park, Jung-Dong

2018-03-19

In this paper, we present the smallest form factor microstrip-fed ultra-wideband antenna with quintuple rejection bands for use in wireless sensor networks, mobile handsets, and Internet of things (IoT). Five rejection bands have been achieved at the frequencies of 3.5, 4.5, 5.25, 5.7, and 8.2 GHz, inseminating four rectangular complementary split ring resonators (RCSRRs) on the radiating patch and placing two rectangular split-ring resonators (RSRR) near the feedline-patch junction of the conventional ultra-wideband (UWB) antenna. The design guidelines of the implemented notched bands are provided at the desired frequency bands and analyzed. The measured results demonstrate that the proposed antenna delivers a wide impedance bandwidth from 3 to 11 GHz with a nearly omnidirectional radiation pattern, high rejection in the multiple notched-bands, and good radiation efficiency over the entire frequency band except at the notched frequencies. Simulated and measured response match well specifically at the stop-bands.

Layup Configuration Effect on Notch Residual Strength in Composite Laminates

PubMed Central

Santhanakrishnan Balakrishnan, Venkateswaran; Seidlitz, Holger

2018-01-01

The current trend shows an increasing demand for composites due to their high stiffness to weight ratio and the recent progress in manufacturing and cost reduction of composites. To combine high strength and stiffness in a cost-effective way, composites are often joined with steel or aluminum. However, joining of thermoset composite materials is challenging because circular holes are often used to join them with their metal counterparts. These design based circular holes induce high stress concentration around the hole. The purpose of this paper is to focus on layup configuration and its impact on notch stress distribution. To ensure high quality and uniformity, the holes were machined by a 5 kW continuous wave (cw) CO2 laser. The stress distribution was evaluated and compared by using finite element analysis and Lekhnitskii’s equations. For further understanding, the notch strength of the laminates was compared and strain distributions were analyzed using the digital image correlation technique. PMID:29461492

The Smallest Form Factor UWB Antenna with Quintuple Rejection Bands for IoT Applications Utilizing RSRR and RCSRR

PubMed Central

2018-01-01

In this paper, we present the smallest form factor microstrip-fed ultra-wideband antenna with quintuple rejection bands for use in wireless sensor networks, mobile handsets, and Internet of things (IoT). Five rejection bands have been achieved at the frequencies of 3.5, 4.5, 5.25, 5.7, and 8.2 GHz, inseminating four rectangular complementary split ring resonators (RCSRRs) on the radiating patch and placing two rectangular split-ring resonators (RSRR) near the feedline-patch junction of the conventional ultra-wideband (UWB) antenna. The design guidelines of the implemented notched bands are provided at the desired frequency bands and analyzed. The measured results demonstrate that the proposed antenna delivers a wide impedance bandwidth from 3 to 11 GHz with a nearly omnidirectional radiation pattern, high rejection in the multiple notched-bands, and good radiation efficiency over the entire frequency band except at the notched frequencies. Simulated and measured response match well specifically at the stop-bands. PMID:29562714

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.

EFFECTS OF MINERAL CONTENT ON THE FRACTURE PROPERTIES OF EQUINE CORTICAL BONE IN DOUBLE-NOTCHED BEAMS

PubMed Central

McCormack, Jordan; Stover, Susan M.; Gibeling, Jeffery C.; Fyhrie, David P.

2012-01-01

We recently developed a method to measure cortical bone fracture initiation toughness using a double-notched beam in four-point bending. This method was used to test the hypothesis that mineralization around the two notch roots is correlated with fracture toughness and crack extension (physical damage). Total energy absorbed to failure negatively correlated with average mineralization of the beam (r2=0.62), but not with notch root mineralization. Fracture initiation toughness was positively correlated to mineralization at the broken notch root (r2=0.34). Crack length extension at the unbroken notch was strongly negatively correlated with the average mineralization of the notch roots (r2=0.81) whereas crack length extension at the broken notch did not correlate with any of the mineralization measurements. Mineralization at the notch roots and the average mineralization contributed independently to the mechanical and damage properties. The data are consistent with an hypothesis that a) high notch root mineralization results in less stable crack length extension but high force to initiate unstable crack propagation while b) higher average mineralization leads to low post-yield (and total) energy absorption to failure. PMID:22394589

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

PubMed Central

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

2006-01-01

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

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

Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment.

PubMed

Feng, Shufang; Shi, Tianyao; Qiu, Jiangxia; Yang, Haihong; Wu, Yan; Zhou, Wenxia; Wang, Wei; Wu, Haitao

2017-10-01

It is well known that Notch1 signaling plays a crucial role in embryonic neural development and adult neurogenesis. The latest evidence shows that Notch1 also plays a critical role in synaptic plasticity in mature hippocampal neurons. So far, deeper insights into the function of Notch1 signaling during the different steps of adult neurogenesis are still lacking, and the mechanisms by which Notch1 dysfunction is associated with brain disorders are also poorly understood. In the current study, we found that Notch1 was highly expressed in the adult-born immature neurons in the hippocampal dentate gyrus. Using a genetic approach to selectively ablate Notch1 signaling in late immature precursors in the postnatal hippocampus by cross-breeding doublecortin (DCX) + neuron-specific proopiomelanocortin (POMC)-α Cre mice with floxed Notch1 mice, we demonstrated a previously unreported pivotal role of Notch1 signaling in survival and function of adult newborn neurons in the dentate gyrus. Moreover, behavioral and functional studies demonstrated that POMC-Notch1 -/- mutant mice showed anxiety and depressive-like behavior with impaired synaptic transmission properties in the dentate gyrus. Finally, our mechanistic study showed significantly compromised phosphorylation of cAMP response element-binding protein (CREB) in Notch1 mutants, suggesting that the dysfunction of Notch1 mutants is associated with the disrupted pCREB signaling in postnatally generated immature neurons in the dentate gyrus.-Feng, S., Shi, T., Qiu, J., Yang, H., Wu, Y., Zhou, W., Wang, W., Wu, H. Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment. © FASEB.

PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor.

PubMed

Wang, Kai; Zhang, Qin; Li, Danan; Ching, Keith; Zhang, Cathy; Zheng, Xianxian; Ozeck, Mark; Shi, Stephanie; Li, Xiaorong; Wang, Hui; Rejto, Paul; Christensen, James; Olson, Peter

2015-03-15

To identify and characterize novel, activating mutations in Notch receptors in breast cancer and to determine response to the gamma secretase inhibitor (GSI) PF-03084014. We used several computational approaches, including novel algorithms, to analyze next-generation sequencing data and related omic datasets from The Cancer Genome Atlas (TCGA) breast cancer cohort. Patient-derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with PF-03084014. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by PF-03084014. We identified mutations within and upstream of the PEST domains of NOTCH1, NOTCH2, and NOTCH3 in the TCGA dataset. Mutations occurred via several genetic mechanisms and compromised the function of the PEST domain, a negative regulatory domain commonly mutated in other cancers. Focal amplifications of NOTCH2 and NOTCH3 were also observed, as were heterodimerization or extracellular domain mutations at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple-negative breast cancer subtype (TNBC). PDX models were also identified that harbored PEST domain mutations, and these models were highly sensitive to PF-03084014. This work suggests that Notch-altered breast cancer constitutes a bona fide oncogenic driver segment with the most common alteration being PEST domain mutations present in multiple Notch receptors. Importantly, functional studies suggest that this newly identified class can be targeted with Notch inhibitors, including GSIs. ©2015 American Association for Cancer Research.

Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis.

PubMed

MacGrogan, Donal; D'Amato, Gaetano; Travisano, Stanislao; Martinez-Poveda, Beatriz; Luxán, Guillermo; Del Monte-Nieto, Gonzalo; Papoutsi, Tania; Sbroggio, Mauro; Bou, Vanesa; Gomez-Del Arco, Pablo; Gómez, Manuel Jose; Zhou, Bin; Redondo, Juan Miguel; Jiménez-Borreguero, Luis J; de la Pompa, José Luis

2016-05-13

The Notch signaling pathway is crucial for primitive cardiac valve formation by epithelial-mesenchymal transition, and NOTCH1 mutations cause bicuspid aortic valve; however, the temporal requirement for the various Notch ligands and receptors during valve ontogeny is poorly understood. The aim of this study is to determine the functional specificity of Notch in valve development. Using cardiac-specific conditional targeted mutant mice, we find that endothelial/endocardial deletion of Mib1-Dll4-Notch1 signaling, possibly favored by Manic-Fringe, is specifically required for cardiac epithelial-mesenchymal transition. Mice lacking endocardial Jag1, Notch1, or RBPJ displayed enlarged valve cusps, bicuspid aortic valve, and septal defects, indicating that endocardial Jag1 to Notch1 signaling is required for post-epithelial-mesenchymal transition valvulogenesis. Valve dysmorphology was associated with increased mesenchyme proliferation, indicating that Jag1-Notch1 signaling restricts mesenchyme cell proliferation non-cell autonomously. Gene profiling revealed upregulated Bmp signaling in Jag1-mutant valves, providing a molecular basis for the hyperproliferative phenotype. Significantly, the negative regulator of mesenchyme proliferation, Hbegf, was markedly reduced in Jag1-mutant valves. Hbegf expression in embryonic endocardial cells could be readily activated through a RBPJ-binding site, identifying Hbegf as an endocardial Notch target. Accordingly, addition of soluble heparin-binding EGF-like growth factor to Jag1-mutant outflow tract explant cultures rescued the hyperproliferative phenotype. During cardiac valve formation, Dll4-Notch1 signaling leads to epithelial-mesenchymal transition and cushion formation. Jag1-Notch1 signaling subsequently restrains Bmp-mediated valve mesenchyme proliferation by sustaining Hbegf-EGF receptor signaling. Our studies identify a mechanism of signaling cross talk during valve morphogenesis involved in the origin of congenital heart defects associated with reduced NOTCH function. © 2016 American Heart Association, Inc.

The Hajdu Cheney Mutation Is a Determinant of B-Cell Allocation of the Splenic Marginal Zone.

PubMed

Yu, Jungeun; Zanotti, Stefano; Walia, Bhavita; Jellison, Evan; Sanjay, Archana; Canalis, Ernesto

2018-01-01

The neurogenic locus notch homolog protein (Notch)-2 receptor is a determinant of B-cell allocation, and gain-of-NOTCH2-function mutations are associated with Hajdu-Cheney syndrome (HCS), a disease presenting with osteoporosis and acro-osteolysis. We generated a mouse model reproducing the HCS mutation (Notch2HCS), and heterozygous global mutant mice displayed gain-of-Notch2 function. In the mutant spleen, the characteristic perifollicular rim marking the marginal zone (MZ), which is the interface between the nonlymphoid red pulp and the lymphoid white pulp, merged with components of the white pulp. As a consequence, the MZ of Notch2HCS mice occupied most of the splenic structure. To explore the mechanisms involved, lymphocyte populations from the bone marrow and spleen were harvested from heterozygous Notch2HCS mice and sex-matched control littermates and analyzed by flow cytometry. Notch2HCS mice had an increase in CD21/35 high CD23 - splenic MZ B cells of approximately fivefold and a proportional decrease in splenic follicular B cells (CD21/35 int CD23 + ) at 1, 2, and 12 months of age. Western blot analysis revealed that Notch2HCS mutant splenocytes had increased phospho-Akt and phospho-Jun N-terminal kinase, and gene expression analysis of splenic CD19 + B cells demonstrated induction of Hes1 and Hes5 in Notch2HCS mutants. Anti-Notch2 antibodies decreased MZ B cells in control and Notch2HCS mice. In conclusion, Notch2HCS mutant mice have increased mature B cells in the MZ of the spleen. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.

PubMed

Poe, Jonathan C; Jia, Wei; Su, Hsuan; Anand, Sarah; Rose, Jeremy J; Tata, Prasanthi V; Suthers, Amy N; Jones, Corbin D; Kuan, Pei Fen; Vincent, Benjamin G; Serody, Jonathan S; Horwitz, Mitchell E; Ho, Vincent T; Pavletic, Steven Z; Hakim, Frances T; Owzar, Kouros; Zhang, Dadong; Blazar, Bruce R; Siebel, Christian W; Chao, Nelson J; Maillard, Ivan; Sarantopoulos, Stefanie

2017-11-09

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8 , each critical to B-cell differentiation and fate. All- trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4 -to- IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5 , but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.

The Human Papillomavirus Type 8 E6 Protein Interferes with NOTCH Activation during Keratinocyte Differentiation

PubMed Central

Meyers, Jordan M.; Spangle, Jennifer M.

2013-01-01

Cutaneous β-human papillomavirus (β-HPV) E6 proteins inhibit NOTCH signaling by associating with the transcriptional coactivator MAML1. NOTCH has tumor suppressor activities in epithelial cells and is activated during keratinocyte differentiation. Here we report that HPV type 8 (HPV8) E6 subverts NOTCH activation during keratinocyte differentiation by inhibiting RBPJ/MAML1 transcriptional activator complexes at NOTCH target DNA. NOTCH inhibition impairs epithelial differentiation and may thus contribute to β-HPV replication and viral oncogenesis. PMID:23365452

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

Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression*

PubMed Central

Wang, Chunmei; Qi, Runzi; Li, Nan; Wang, Zhengxin; An, Huazhang; Zhang, Qinghua; Yu, Yizhi; Cao, Xuetao

2009-01-01

Notch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting the cell cycle and inducing apoptosis. HCC cells are resistant to apoptotic induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), so new therapeutic approaches have been explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced apoptosis, whereas Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent upon p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together, Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to improve the therapeutic efficacy of TRAIL-resistant HCC. PMID:19376776

A decorated raven bone from the Zaskalnaya VI (Kolosovskaya) Neanderthal site, Crimea

PubMed Central

Evans, Sarah; Stepanchuk, Vadim; Tsvelykh, Alexander; d’Errico, Francesco

2017-01-01

We analyze a radius bone fragment of a raven (Corvus corax) from Zaskalnaya VI rock shelter, Crimea. The object bears seven notches and comes from an archaeological level attributed to a Micoquian industry dated to between 38 and 43 cal kyr BP. Our study aims to examine the degree of regularity and intentionality of this set of notches through their technological and morphometric analysis, complemented by comparative experimental work. Microscopic analysis of the notches indicate that they were produced by the to-and-fro movement of a lithic cutting edge and that two notches were added to fill in the gap left between previously cut notches, probably to increase the visual consistency of the pattern. Multivariate analysis of morphometric data recorded on the archaeological notches and sets of notches cut by nine modern experimenters on radii of domestic turkeys shows that the variations recorded on the Zaskalnaya set are comparable to experimental sets made with the aim of producing similar, parallel, equidistant notches. Identification of the Weber Fraction, the constant that accounts for error in human perception, for equidistant notches cut on bone rods and its application to the Zaskalnaya set of notches and thirty-six sets of notches incised on seventeen Upper Palaeolithic bone objects from seven sites indicate that the Zaskalnaya set falls within the range of variation of regularly spaced experimental and Upper Palaeolithic sets of notches. This suggests that even if the production of the notches may have had a utilitarian reason the notches were made with the goal of producing a visually consistent pattern. This object represents the first instance of a bird bone from a Neanderthal site bearing modifications that cannot be explained as the result of butchery activities and for which a symbolic argument can be built on direct rather than circumstantial evidence. PMID:28355292

HEY1 is expressed independent of NOTCH1 and is associated with poor prognosis in head and neck squamous cell carcinoma.

PubMed

Rettig, Eleni M; Bishop, Justin A; Agrawal, Nishant; Chung, Christine H; Sharma, Rajni; Zamuner, Fernando; Li, Ryan J; Koch, Wayne M; Califano, Joseph A; Guo, Theresa; Gaykalova, Daria A; Fakhry, Carole

2018-07-01

Notch signaling is frequently altered in head and neck squamous cell carcinoma (HNSCC). However, the nature and clinical implications of this dysregulation are not well understood. We previously described an association of transcriptionally active NOTCH1 Intracellular Domain (NICD1) immunohistochemical (IHC) expression pattern with high-risk pathologic characteristics. Here we further characterize Notch signaling in HNSCC. IHC expression patterns and clinicopathologic associations of Notch pathway molecules were evaluated among 78 tumors with known NOTCH1 mutation status. IHC was performed for JAG1, a NOTCH1 activating ligand, and HEY1, an NICD1 transcriptional target and Notch pathway activation marker. IHC pattern and H-score (% staining × intensity) were recorded and compared to clinicopathologic characteristics and survival. Survival was analyzed using Kaplan Meier method and Cox proportional hazards models (HR). JAG1 and NICD1 expression patterns were highly concordant among tumors without truncating NOTCH1 mutations (p < 0.001), but were dissimilar among tumors with truncating NOTCH1 mutations (p = 0.24). There was evidence for JAG1-independent NOTCH1 activation among seven tumors, all with wild-type NOTCH1. HEY1 expression was associated with neither JAG1 nor NICD1 expression, but was associated with NOTCH1 mutation status (p = 0.03). Twelve (16%) tumors expressed HEY1 but not NICD1. Higher HEY1 H-score was significantly associated with worse overall (adjusted hazard ratio [aHR] 2.0, 95% CI = 1.0-4.2) and disease-specific (aHR = 3.3, 95% CI = 1.4-7.9) survival, whereas JAG1 and NICD1 expression were not associated with survival. These findings suggest both NOTCH1-dependent and -independent HEY1 regulation, and imply a previously unrecognized prognostic role for HEY1 in HNSCC. Copyright © 2018 Elsevier Ltd. All rights reserved.

Notch Signaling and Alloreactivity.

PubMed

Radojcic, Vedran; Maillard, Ivan

2016-12-01

Solid organ and allogeneic hematopoietic cell transplantation have become standard therapeutic interventions that save patient lives and improve quality of life. Our enhanced understanding of transplantation immunobiology has refined clinical management and improved outcomes. However, organ rejection and graft-versus-host disease remain major obstacles to the broader successful application of these therapeutic procedures. Notch signaling regulates multiple aspects of adaptive and innate immunity. Preclinical studies identified Notch signaling as a promising target in autoimmune diseases, as well as after allogeneic hematopoietic cell and solid organ transplantation. Notch was found to be a central regulator of alloreactivity across clinically relevant models of transplantation. Notch inhibition in T cells prevented graft-versus-host disease and organ rejection, establishing organ tolerance by skewing CD4 T helper polarization away from a proinflammatory response toward suppressive regulatory T cells. Notch ligand blockade also dampened alloantibody deposition and prevented chronic rejection through humoral mechanisms. Toxicities of systemic Notch blockade were observed with γ-secretase inhibitors in preclinical and early clinical trials across different indications, but they did not arise upon preclinical targeting of Delta-like Notch ligands, a strategy sufficient to confer full benefits of Notch ablation in T cell alloimmunity. Because multiple clinical grade reagents have been developed to target individual Notch ligands and receptors, the benefits of Notch blockade in transplantation are calling for translation of preclinical findings into human transplantation medicine.

Notch3 orchestrates epithelial and inflammatory responses to promote acute kidney injury.

PubMed

Kavvadas, Panagiotis; Keuylian, Zela; Prakoura, Niki; Placier, Sandrine; Dorison, Aude; Chadjichristos, Christos E; Dussaule, Jean-Claude; Chatziantoniou, Christos

2018-07-01

Acute kidney injury is a major risk factor for subsequent chronic renal and/or cardiovascular complications. Previous studies have shown that Notch3 was de novo expressed in the injured renal epithelium in the early phases of chronic kidney disease. Here we examined whether Notch3 is involved in the inflammatory response and the epithelial cell damage that typifies ischemic kidneys using Notch3 knockout mice and mice with short-term activated Notch3 signaling (N3ICD) in renal epithelial cells. After ischemia/reperfusion, N3ICD mice showed exacerbated infiltration of inflammatory cells and severe tubular damage compared to control mice. Inversely, Notch3 knockout mice were protected against ischemia/reperfusion injury. Renal macrophages derived from Notch3 knockout mice failed to activate proinflammatory cytokines. Chromatin immunoprecipitation analysis of the Notch3 promoter identified NF-κB as the principal inducer of Notch3 in ischemia/reperfusion. Thus, Notch3 induced by NF-κB in the injured epithelium sustains a proinflammatory environment attracting activated macrophages to the site of injury leading to a rapid deterioration of renal function and structure. Hence, targeting Notch3 may provide a novel therapeutic strategy against ischemia/reperfusion and acute kidney injury by preservation of epithelial structure and disruption of proinflammatory signaling. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

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

PubMed Central

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

2010-01-01

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

Structure and Function of the Mind bomb E3 ligase in the context of Notch Signal Transduction

PubMed Central

Guo, Bingqian; McMillan, Brian J.; Blacklow, Stephen C.

2016-01-01

The Notch signaling pathway has a critical role in cell fate determination and tissue homeostasis in a variety of different lineages. In the context of normal Notch signaling, the Notch receptor of the “signal-receiving” cell is activated in trans by a Notch ligand from a neighboring “signal-sending” cell. Genetic studies in several model organisms have established that ubiquitination of the Notch ligand, and its regulated endocytosis, is essential for transmission of this activation signal. In mammals, this ubiquitination step is dependent on the protein Mind bomb 1 (Mib1), a large multi-domain RING-type E3 ligase, and its direct interaction with the intracellular tails of Notch ligand molecules. Here, we discuss our current understanding of Mind bomb structure and mechanism in the context of Notch signaling and beyond. PMID:27285058

The emerging roles of Notch signaling in leukemia and stem cells

PubMed Central

2013-01-01

The Notch signaling pathway plays a critical role in maintaining the balance between cell proliferation, differentiation and apoptosis, and is a highly conserved signaling pathway that regulates normal development in a context- and dose-dependent manner. Dysregulation of Notch signaling has been suggested to be key events in a variety of hematological malignancies. Notch1 signaling appears to be the central oncogenic trigger in T cell acute lymphoblastic leukemia (T-ALL), in which the majority of human malignancies have acquired mutations that lead to constitutive activation of Notch1 signaling. However, emerging evidence unexpectedly demonstrates that Notch signaling can function as a potent tumor suppressor in other forms of leukemia. This minireview will summarize recent advances related to the roles of activated Notch signaling in human lymphocytic leukemia, myeloid leukemia, stem cells and stromal microenvironment, and we will discuss the perspectives of Notch signaling as a potential therapeutic target as well. PMID:24252593

Spectral manipulation and complementary spectra with birefringence polarization control

NASA Astrophysics Data System (ADS)

Ding, Pan-Feng; Han, Pin

2017-03-01

A polarization control method using crystal birefringence is suggested to manipulate polychromatic light. This scheme can be used with narrower bandwidth to produce various spectral effects, such as a notch filter, a flat top, and triangle-type, nipple-type, and central-frequency-dominant distributions. A modulated spectrum with greater bandwidth can be used as an optical frequency ruler, and phenomena called complementary spectra are also proposed, where the two spectral distributions, produced by rotating the polarizer, complement each other in the sense that the peaks and valleys in one spectrum are the reverse in the other. These results benefit the controlling of the spectral shape and the measurement of an unknown optical frequency.

Regulation of pancreatic stellate cell activation by Notch3.

PubMed

Song, Haiyan; Zhang, Yuxiang

2018-01-05

Activated pancreatic stellate cells (PaSCs) are the key cellular source of cancer-associated fibroblasts in the pancreatic stroma of patients with pancreatic ductal adenocarcinoma (PDAC), however, the activation mechanism of PaSCs is not yet known. The Notch signaling pathway, components of which are expressed in stromal cells, is involved in the fibrosis of several organs, including the lung and liver. In the current study, we investigated whether Notch signal transduction is involved in PaSC activation in PDAC. The expression of Notch signaling pathway components in human PDAC was examined via immunohistochemical staining and assessed in mouse PaSCs using RT-qPCR and western blotting. Notch3 expression in both PDAC stromal cells and activated mouse PaSCs was evaluated using immunofluorescence, RT-qPCR and western blotting. The impact of siRNA-mediated Notch3 knockdown on PaSC activation was detected with RT-qPCR and western blotting, and the impact on PaSC proliferation and migration was detected using CCK-8 assays and scratch experiments. The effect of conditioned medium from PaSCs activated with Notch3 siRNA on pancreatic cancer (LTPA) cells was also detected with CCK-8 assays and scratch experiments. The data were analyzed for statistical significance using Student's t-test. Notch3 was overexpressed in both human PDAC stromal cells and activated mouse PaSCs, and Notch3 knockdown with Notch3 siRNA decreased the proliferation and migration of mouse PaSCs. The levels of markers related to PaSC activation, such as α-smooth muscle actin (α-SMA), collagen I and fibronectin, decreased in response to Notch3 knockdown, indicating that Notch3 plays an important role in PaSC activation. Furthermore, we confirmed that inhibition of PaSC activation via Notch3 siRNA reduced the proliferation and migration of PaSC-induced mouse pancreatic cancer (LTPA) cells. Notch3 inhibition in PaSCs can inhibit the activation, proliferation and migration of PaSCs and reduce the PaSC-induced pro-tumorigenic effect. Therefore, Notch3 silencing in PaSCs is a potential novel therapeutic option for patients with PDAC.

Electro-optic electrodes based on Lithium Niobate Mach Zhender Interferometer Modulators for wearable bioelectric activity recording

NASA Astrophysics Data System (ADS)

Fernandes, Mariana S.; Correia, José H.; Mendes, Paulo M.

2011-05-01

Wearable devices are used to record several physiological signals, providing unobtrusive and continuous monitoring. A main challenge in these systems is to develop new recording sensors, specially envisioning bioelectric activity detection. Available devices are difficult to integrate, mainly due to the amount of electrical wires and components needed. This work proposes a fiber-optic based device, which basis of operation relies on the electro-optic effect. A Lithium Niobate (LiBnO3) Mach-Zehnder Interferometer (MZI) modulator is used as the core sensing component, followed by a signal conversion and processing stage. Tests were performed in order to validate the proposed acquisition system in terms of signal amplification and quality, stability and frequency response. A light source with a wavelength operation of 1530- 1565 nm was used. The modulated intensity is amplified and converted to an output voltage with a high transimpedance gain. The filtering and electric amplification included a 50Hz notch filter, a bandpass filter with a -3 dB bandwidth from 0.50 to 35 Hz. The obtained system performance on key elements such as sensitivity, frequency content, and signal quality, have shown that the proposed acquisition system allows the development of new wearable bioelectric monitoring solutions based on optical technologies.

Intra-lineage Fate Decisions Involve Activation of Notch Receptors Basal to the Midbody in Drosophila Sensory Organ Precursor Cells.

PubMed

Trylinski, Mateusz; Mazouni, Khalil; Schweisguth, François

2017-08-07

Notch receptors regulate cell fate decisions during embryogenesis and throughout adult life. In many cell lineages, binary fate decisions are mediated by directional Notch signaling between the two sister cells produced by cell division. How Notch signaling is restricted to sister cells after division to regulate intra-lineage decision is poorly understood. More generally, where ligand-dependent activation of Notch occurs at the cell surface is not known, as methods to detect receptor activation in vivo are lacking. In Drosophila pupae, Notch signals during cytokinesis to regulate the intra-lineage pIIa/pIIb decision in the sensory organ lineage. Here, we identify two pools of Notch along the pIIa-pIIb interface, apical and basal to the midbody. Analysis of the dynamics of Notch, Delta, and Neuralized distribution in living pupae suggests that ligand endocytosis and receptor activation occur basal to the midbody. Using selective photo-bleaching of GFP-tagged Notch and photo-tracking of photo-convertible Notch, we show that nuclear Notch is indeed produced by receptors located basal to the midbody. Thus, only a specific subset of receptors, located basal to the midbody, contributes to signaling in pIIa. This is the first in vivo characterization of the pool of Notch contributing to signaling. We propose a simple mechanism of cell fate decision based on intra-lineage signaling: ligands and receptors localize during cytokinesis to the new cell-cell interface, thereby ensuring signaling between sister cells, hence intra-lineage fate decision. Copyright © 2017 Elsevier Ltd. All rights reserved.

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia.

PubMed

Minervini, Angela; Francesco Minervini, Crescenzio; Anelli, Luisa; Zagaria, Antonella; Casieri, Paola; Coccaro, Nicoletta; Cumbo, Cosimo; Tota, Giuseppina; Impera, Luciana; Orsini, Paola; Brunetti, Claudia; Giordano, Annamaria; Specchia, Giorgina; Albano, Francesco

2016-12-27

In chronic lymphocytic leukemia (CLL), NOTCH1 gene mutations (NOTCH1mut) have been associated with adverse prognostic features but the independence of these as a prognostic factor is still controversial. In our study we validated a c.7541-7542delCT NOTCH1 mutation assay based on droplet digital PCR (ddPCR); we also analyzed the NOTCH1mut allelic burden, expressed as fractional abundance (FA), in 88 CLL patients at diagnosis to assess its prognostic role and made a longitudinal ddPCR analysis in 10 cases harboring NOTCH1mut to verify the FA variation over time. Our data revealed that with the ddPCR approach the incidence of NOTCH1mut in CLL was much higher (53.4%) than expected. However, longitudinal ddPCR analysis of CLL cases showed a statistically significant reduction of the NOTCH1mut FA detected at diagnosis after treatment (median FA 11.67 % vs 0.09 %, respectively, p = 0.01); the same difference, in terms of NOTCH1mut FA, was observed in the relapsed cases compared to the NOTCH1mut allelic fraction observed in patients in complete or partial remission (median FA 4.75% vs 0.43%, respectively, p = 0.007). Our study demonstrated a much higher incidence of NOTCH1mut in CLL than has previously been reported, and showed that the NOTCH1mut allelic burden evaluation by ddPCR might identify patients in need of a closer clinical follow-up during the "watch and wait" interval and after standard chemotherapy.

Characteristics of Notch2(+) pancreatic cancer stem-like cells and the relationship with centroacinar cells.

PubMed

Zhou, Zhu-Chao; Dong, Qiang-Gang; Fu, De-Liang; Gong, Yi-Yi; Ni, Quan-Xing

2013-08-01

Notch2, a surface marker in cell lines, is used to isolate, identify and localise pancreatic cancer stem-like cells and is a target for therapy of these cells. Sphere formation was induced in Panc-1 and Bxpc-3 pancreatic cancer cell lines, and Notch2(+) cells were separated from Bxpc-3 and Panc-1 cell lines by magnetic activated cell sorting (MACS). Expression of stem cell-related markers, OCT4, Nanog and PDX1, were measured by immunofluorescent (IF) staining. Expression of Notch2 was also determined immunohistochemically in pancreatic tissues. Notch2(+) cells were transplanted in subcutaneous of mice. AQP1 and AQP5 were also measured by IF in Bxpc-3 cells. The Notch signal pathway inhibitor, Compound E (CE), was used to treat Notch2(+) Bxpc-3 cells, and their vitalities were subsequently measured by the CCK-8 method. Positive expression of OCT4, Nanog and PDX1 was observed in Notch2(+) cells. Notch2(+) cells at centroacinar cell (CAC) and terminal ductal locations expressed AQP1 and AQP5. They were strongly tumourigenic in mice, and CE inhibited proliferation of Notch2(+) Bxpc-3 cells to some degree. OCT4 and Nanog can be used as markers of self-renewal in pancreatic cancer stem cells. Notch2(+) cells in human pancreatic cancer Bxpc-3 and Panc-1 cell lines had the properties of cancer stem cells. The results suggest that Notch2(+) pancreatic cancer stem-like cells had a close relationship with CAC. © 2013 International Federation for Cell Biology.

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

PubMed Central

El Machhour, Fala; Keuylian, Zela; Kavvadas, Panagiotis; Dussaule, Jean-Claude

2015-01-01

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN. PMID:25421557

Estrogen improves the proliferation and differentiation of hBMSCs derived from postmenopausal osteoporosis through notch signaling pathway.

PubMed

Fan, Jin-Zhu; Yang, Liu; Meng, Guo-Lin; Lin, Yan-shui; Wei, Bo-Yuan; Fan, Jing; Hu, Hui-Min; Liu, Yan-Wu; Chen, Shi; Zhang, Jin-Kang; He, Qi-Zhen; Luo, Zhuo-Jing; Liu, Jian

2014-07-01

Estrogen deficiency is the main reason of bone loss, leading to postmenopausal osteoporosis, and estrogen replacement therapy (ERT) has been demonstrated to protect bone loss efficiently. Notch signaling controls proliferation and differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Moreover, imperfect estrogen-responsive elements (EREs) were found in the 5'-untranslated region of Notch1 and Jagged1. Thus, we examined the molecular and biological links between estrogen and the Notch signaling in postmenopausal osteoporosis in vitro. hBMSCs were obtained from healthy women and patients with postmenopausal osteoporosis. Notch signaling molecules were quantified using real-time polymerase chain reaction (real-time PCR) and Western Blot. Luciferase reporter constructs with putative EREs were transfected into hBMSCs and analyzed. hBMSCs were transduced with lentiviral vectors containing human Notch1 intracellular domain (NICD1). We also used N-[N-(3, 5-diflurophenylacetate)-l-alanyl]-(S)-phenylglycine t-butyl ester, a γ-secretase inhibitor, to suppress the Notch signaling. We found that estrogen enhanced the Notch signaling in hBMSCs by promoting the expression of Jagged1. hBMSCs cultured with estrogen resulted in the up-regulation of Notch signaling and increased proliferation and differentiation. Enhanced Notch signaling could enhance the proliferation and differentiation of hBMSCs from patients with postmenopausal osteoporosis (OP-hBMSCs). Our results demonstrated that estrogen preserved bone mass partly by activating the Notch signaling. Because long-term ERT has been associated with several side effects, the Notch signaling could be a potential target for treating postmenopausal osteoporosis.

Damage Tolerant Design for Cold-Section Turbine Engine Disks

DTIC Science & Technology

1981-06-01

Ti-6Al-4V Disks ......... .. 59 28. FIOO 2nd-Stage Fan Disk Designs ........ ................ .. 61 29. Fan Disk Tangential Stress Profile... 61 30. Life-Limiting Features of Damage-Tolerant Disk .......... ... 62 31. Disk Life Limits .... ...................... 62 32. Life Test...Stress Rati• Model ..... .......... .. 113 61 . Thick-Section Center-Notched Specimen ....... ............. .. 116 62. Bolthole Specimen

Imaging the Cemento-Enamel Junction Using a 20-MHz Ultrasonic Transducer.

PubMed

Nguyen, Kim-Cuong T; Le, Lawrence H; Kaipatur, Neelambar R; Major, Paul W

2016-01-01

The cemento-enamel junction (CEJ), which is the intersection between enamel and cementum, is an important landmark in the diagnosis of periodontal disease. Pulse-echo ultrasound was used to image the CEJs of six porcine lower central incisors with a single 20-MHz transducer. A notch was longitudinally created on the enamel as a stable marker, from which the CEJ was measured. Data were acquired along the tooth's axis at 0.4-mm intervals. Time-distance data were bandpass-filtered to enhance signal-to-noise ratio and record density was increased fourfold to 0.1-mm spacing by a frequency-distance interpolation scheme. Reflections from the CEJ were unambiguously identified along with those from enamel, dentin and cementum. The notch-CEJ distances measured by the ultrasound and micro-computed tomography methods correlated strongly (r = 0.996, p < 0.05) and were in good agreement with the 95% lines of agreement between -0.49 and 0.17 mm, as statistically determined by Bland-Altman analysis. The results indicate the potential of ultrasound to be a reliable and non-ionizing technique to image the CEJ. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

The Advanced Glaucoma Intervention Study (AGIS): 10. Variability among academic glaucoma subspecialists in assessing optic disc notching.

PubMed

Gaasterland, D E; Blackwell, B; Dally, L G; Caprioli, J; Katz, L J; Ederer, F

2001-01-01

An analysis of data from the Advanced Glaucoma Intervention Study (AGIS) has found eyes reported to have partial optic disc rim notching (not to the edge) at baseline to have less risk of subsequent visual field loss than eyes with no notching. Because this is counterintuitive and because classification of notching had not been defined in the AGIS protocol, we have assessed AGIS ophthalmologists interobserver and intraobserver agreement on notching. Fourteen glaucoma subspecialists classified notching in 26 pairs of stereoscopic disc photographs of eyes with mild to severe glaucomatous optic neuropathy. They classified images as showing either no notching, notching not to the edge, or notching to the edge. Several hours later, 10 of them classified the same images a second time. In an analysis of interobserver agreement, of 26 stereoscopic images, a plurality of ophthalmologists classified notching as absent in 9 (35%), as present but not to the edge in 7 (27%), and as present and not to the edge in 10 (38%). All 14 ophthalmologists (100%) agreed on the classification of 7 (27%) of the images, and 13 of the 14 ophthalmologists (93%) agreed on the classification of 4 additional images (15%). Of these 11 images with at least 93% agreement, notching was reported as absent in 3 (27%) and to the edge in 8 (73%). In the remaining 15 images, there was substantial disagreement about whether notching was present and, if so, whether it was to the edge. In an analysis of intraobserver agreement, none of the 10 ophthalmologists who completed the viewing a second time classified all eyes exactly the same as the first time, though 5 ophthalmologists made 4 or fewer reclassifications. Overall, 80% of the original classifications were reproduced on second reading. Of the initial classifications that were not reproduced, slightly more than half were first classified as having notching not to the edge. Without definitions or examples of optic disc rim notching, the glaucoma subspecialists had relatively high intraobserver agreement but were likely to disagree with each other in characterizing the degree of disc rim notching. We recommend development of a standard photographic classification of disc rim notching. The classification should be tested for inter- and intra-observer agreement.

The Advanced Glaucoma Intervention Study (AGIS): 10. Variability among academic glaucoma subspecialists in assessing optic disc notching.

PubMed Central

Gaasterland, D E; Blackwell, B; Dally, L G; Caprioli, J; Katz, L J; Ederer, F

2001-01-01

PURPOSE: An analysis of data from the Advanced Glaucoma Intervention Study (AGIS) has found eyes reported to have partial optic disc rim notching (not to the edge) at baseline to have less risk of subsequent visual field loss than eyes with no notching. Because this is counterintuitive and because classification of notching had not been defined in the AGIS protocol, we have assessed AGIS ophthalmologists interobserver and intraobserver agreement on notching. METHODS: Fourteen glaucoma subspecialists classified notching in 26 pairs of stereoscopic disc photographs of eyes with mild to severe glaucomatous optic neuropathy. They classified images as showing either no notching, notching not to the edge, or notching to the edge. Several hours later, 10 of them classified the same images a second time. RESULTS: In an analysis of interobserver agreement, of 26 stereoscopic images, a plurality of ophthalmologists classified notching as absent in 9 (35%), as present but not to the edge in 7 (27%), and as present and not to the edge in 10 (38%). All 14 ophthalmologists (100%) agreed on the classification of 7 (27%) of the images, and 13 of the 14 ophthalmologists (93%) agreed on the classification of 4 additional images (15%). Of these 11 images with at least 93% agreement, notching was reported as absent in 3 (27%) and to the edge in 8 (73%). In the remaining 15 images, there was substantial disagreement about whether notching was present and, if so, whether it was to the edge. In an analysis of intraobserver agreement, none of the 10 ophthalmologists who completed the viewing a second time classified all eyes exactly the same as the first time, though 5 ophthalmologists made 4 or fewer reclassifications. Overall, 80% of the original classifications were reproduced on second reading. Of the initial classifications that were not reproduced, slightly more than half were first classified as having notching not to the edge. CONCLUSION: Without definitions or examples of optic disc rim notching, the glaucoma subspecialists had relatively high intraobserver agreement but were likely to disagree with each other in characterizing the degree of disc rim notching. We recommend development of a standard photographic classification of disc rim notching. The classification should be tested for inter- and intra-observer agreement. PMID:11797305

[Expression of Notch Gene and Its Role of Anti-apoptosis and Drug-resistance of Cells in Chronic Lymphocytic Leukemia].

PubMed

Zhang, Jin-Yan; Zhang, Ju-Shun; Xu, Zhen-Shu

2015-08-01

To investigate the expression of Notch gene in chronic lymphocytic leukemia cells and to explore the change of Notch protein after the therapy with cytosine arabinoside or dexmethasone, and the mechanism of Notch mediated anti-apoptosis and drug-resistance in chronic lymphocytic leukemia cells. The mononuclear cells from bone marrow or peripheral blood of chronic lymphocytic leukemia patients (24 cases) and healthy donors (14 cases) were collected, then the expression of Notch gene, BCL-2, as well as NF-κB gene were detected by real-time fluorescent quantitative PCR (qRT-PCR) at the level of transcription. The change of Notch protein in L1210 cell lines after therapy with cytosine arabinoside and dexmethasone was determined by Western blot. mRNA expression levels of Notch1, Notch2, BCL-2 and NF-κB gene in CLL group were significantly higher than those in healthy control group (0.8556 ± 0.8726 vs 0.6731 ± 0.5334, P = 0.0182; 1.2273 ± 0.8207 vs 0.6577 ± 0.6424, P < 0.0001; 8.0960 ± 7.5661 vs 0.5969 ± 0.4976, P < 0.0001; 1.0966 ± 0.6925 vs 0.5373 ± 0.7180, P < 0.0001, respectively), but no significant difference was found between Notch3 and Notch4 gene (1.1914 ± 2.4219 vs 0.8713 ± 0.7937, P = 0.3427; 0.8174 ± 1.0869 vs 0.9752 ± 1.3446, P = 0.2402, respectively). Notch1 protein expression in L1210 cells were significantly decreased after treating with cytosine arabinoside of low and middle concentrations, but increased after treating with cytosine arabinoside of high concentration or prolonging time of cytosine arabinoside of middle con-centration. Notch1 protein expression in L1210 cells dereased after treating with dexamethasone, but did not be changed with the different concentrations and different times of dexmethason. The transcription level of Notch gene in CLL patients significantly higher than that in normal controls. The Notch1 protein expression is down-regulated in process of inhibiting L1210 cell proliferation by Ara-C and dexmethason. Notch signaling pathway may mediated anti-apoptosis and drug resistance of CLL cells. Notch molecule possibly plays an important role in the anti-apoptosis and drug-resistance of CLL cells.

Associations between polymorphisms in the NICD domain of bovine NOTCH1 gene and growth traits in Chinese Qinchuan cattle.

PubMed

Liu, Mei; Zhang, Chenge; Lai, Xinsheng; Xue, Jing; Lan, Xianyong; Lei, Chuzhao; Jia, Yutang; Chen, Hong

2017-05-01

NOTCH1 is one of the four mammalian Notch receptors, which is involved in the Notch signaling pathway. Specifically, NOTCH1 promotes the proliferation of myogenic precursor cells, and the NICD domain of NOTCH1 can impair regeneration of skeletal muscles. However, similar research on the bovine NOTCH1 gene is lacking. In this study, we detected the polymorphisms of the bovine NOTCH1 gene in a total of 448 individuals from Chinese Qinchuan cattle with DNA pooling, forced PCR-RFLP, and DNA sequencing methods. Five novel SNPs were identified within the NICD domain, and eight haplotypes comprising combinations of these five SNPs were studied as well. The association analysis of SNPs' effects with growth traits revealed that g.A48250G was significantly associated with body height, body weight, and height at hip cross, and that g.A49239C only showed significant associations with body height. This suggests that the NOTCH1 gene is a strong candidate gene that could be utilized as a promising marker in beef cattle breeding programs.

Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms.

PubMed

Feyerabend, Thorsten B; Terszowski, Grzegorz; Tietz, Annette; Blum, Carmen; Luche, Hervé; Gossler, Achim; Gale, Nicholas W; Radtke, Freddy; Fehling, Hans Jörg; Rodewald, Hans-Reimer

2009-01-16

Notch1 signaling is required for T cell development and has been implicated in fate decisions in the thymus. We showed that Notch1 deletion in progenitor T cells (pro-T cells) revealed their latent developmental potential toward becoming conventional and plasmacytoid dendritic cells. In addition, Notch1 deletion in pro-T cells resulted in large numbers of thymic B cells, previously explained by T-to-B cell fate conversion. Single-cell genotyping showed, however, that the majority of these thymic B cells arose from Notch1-sufficient cells by a cell-extrinsic pathway. Fate switching nevertheless exists for a subset of thymic B cells originating from Notch1-deleted pro-T cells. Chimeric mice lacking the Notch ligand delta-like 4 (Dll4) in thymus epithelium revealed an essential role for Dll4 in T cell development. Thus, Notch1-Dll4 signaling fortifies T cell commitment by suppressing non-T cell lineage potential in pro-T cells, and normal Notch1-driven T cell development repels excessive B cells in the thymus.

Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL.

PubMed

Machuca-Parra, Arturo I; Bigger-Allen, Alexander A; Sanchez, Angie V; Boutabla, Anissa; Cardona-Vélez, Jonathan; Amarnani, Dhanesh; Saint-Geniez, Magali; Siebel, Christian W; Kim, Leo A; D'Amore, Patricia A; Arboleda-Velasquez, Joseph F

2017-08-07

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling. © 2017 Machuca-Parra et al.

NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma.

PubMed

Edwards, Andrew K; Glithero, Kyle; Grzesik, Peter; Kitajewski, Alison A; Munabi, Naikhoba Co; Hardy, Krista; Tan, Qian Kun; Schonning, Michael; Kangsamaksin, Thaned; Kitajewski, Jan K; Shawber, Carrie J; Wu, June K

2017-11-02

Infantile hemangioma (IH) is a vascular tumor that begins with rapid vascular proliferation shortly after birth, followed by vascular involution in early childhood. We have found that NOTCH3, a critical regulator of mural cell differentiation and maturation, is expressed in hemangioma stem cells (HemSCs), suggesting that NOTCH3 may function in HemSC-to-mural cell differentiation and pathological vessel stabilization. Here, we demonstrate that NOTCH3 is expressed in NG2+PDGFRβ+ perivascular HemSCs and CD31+GLUT1+ hemangioma endothelial cells (HemECs) in proliferating IHs and becomes mostly restricted to the αSMA+NG2loPDGFRβlo mural cells in involuting IHs. NOTCH3 knockdown in HemSCs inhibited in vitro mural cell differentiation and perturbed αSMA expression. In a mouse model of IH, NOTCH3 knockdown or systemic expression of the NOTCH3 inhibitor, NOTCH3 Decoy, significantly decreased IH blood flow, vessel caliber, and αSMA+ perivascular cell coverage. Thus, NOTCH3 is necessary for HemSC-to-mural cell differentiation, and adequate perivascular cell coverage of IH vessels is required for IH vessel stability.

Molecular Pathways: Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer

PubMed Central

Previs, Rebecca A.; Coleman, Robert L.; Harris, Adrian L.; Sood, Anil K.

2014-01-01

Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and crosstalk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3–4, Jagged 1–2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Since the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway. PMID:25388163

(−)-Epigallocatechin Gallate Targets Notch to Attenuate the Inflammatory Response in the Immediate Early Stage in Human Macrophages

PubMed Central

Wang, Tengfei; Xiang, Zemin; Wang, Ya; Li, Xi; Fang, Chongye; Song, Shuang; Li, Chunlei; Yu, Haishuang; Wang, Han; Yan, Liang; Hao, Shumei; Wang, Xuanjun; Sheng, Jun

2017-01-01

Inflammation plays important roles at different stages of diabetes mellitus, tumorigenesis, and cardiovascular diseases. (−)-Epigallocatechin gallate (EGCG) can attenuate inflammatory responses effectively. However, the immediate early mechanism of EGCG in inflammation remains unclear. Here, we showed that EGCG attenuated the inflammatory response in the immediate early stage of EGCG treatment by shutting off Notch signaling and that the effect did not involve the 67-kDa laminin receptor, the common receptor for EGCG. EGCG eliminated mature Notch from the cell membrane and the nuclear Notch intercellular domain, the active form of Notch, within 2 min by rapid degradation via the proteasome pathway. Transcription of the Notch target gene was downregulated simultaneously. Knockdown of Notch 1/2 expression by RNA interference impaired the downregulation of the inflammatory response elicited by EGCG. Further study showed that EGCG inhibited lipopolysaccharide-induced inflammation and turned off Notch signaling in human primary macrophages. Taken together, our results show that EGCG targets Notch to regulate the inflammatory response in the immediate early stage. PMID:28443100

Notch Signaling in Postnatal Pituitary Expansion: Proliferation, Progenitors, and Cell Specification

PubMed Central

Nantie, Leah B.; Himes, Ashley D.; Getz, Dan R.

2014-01-01

Mutations in PROP1 account for up to half of the cases of combined pituitary hormone deficiency that result from known causes. Despite this, few signaling molecules and pathways that influence PROP1 expression have been identified. Notch signaling has been linked to Prop1 expression, but the developmental periods during which Notch signaling influences Prop1 and overall pituitary development remain unclear. To test the requirement for Notch signaling in establishing the normal pituitary hormone milieu, we generated mice with early embryonic conditional loss of Notch2 (conditional knockout) and examined the consequences of chemical Notch inhibition during early postnatal pituitary maturation. We show that loss of Notch2 has little influence on early embryonic pituitary proliferation but is crucial for postnatal progenitor maintenance and proliferation. In addition, we show that Notch signaling is necessary embryonically and postnatally for Prop1 expression and robust Pit1 lineage hormone cell expansion, as well as repression of the corticotrope lineage. Taken together, our studies identify temporal and cell type–specific roles for Notch signaling and highlight the importance of this pathway throughout pituitary development. PMID:24673559

Design of intelligent mesoscale periodic array structures utilizing smart hydrogel

NASA Technical Reports Server (NTRS)

Sunkara, H. B.; Penn, B. G.; Frazier, D. O.; Weissman, J. M.; Asher, S. A.

1996-01-01

Mesoscale Periodic Array Structures (MPAS, also known as crystalline colloidal arrays), composed of aqueous or nonaqueous dispersions of self-assembled submicron colloidal spheres are emerging toward the development of advanced optical devices for technological applications. This is because of their unique optical diffraction properties and the ease with which these intriguing properties can be modulated experimentally. Moreover our recent advancements in this area which include 'locking' the liquid MPAS into solid or semisolid polymer matrices for greater stability with longer life span, and incorporation of CdS quantum dots and laser dyes into colloidal spheres to obtain nonlinear optical (NLO) responses further corroborate the use of MPAS in optical technology. Our long term goal is fabrication of all-optical and electro-optical devices such as spatial light modulators for optical signal processing and flat panel display devices by utilizing intelligent nonlinear periodic array structural materials. Here we show further progress in the design of novel linear MPAS which have the ability to sense and respond to an external source such as temperature. This is achieved by combining the self-assembly properties of polymer colloidal spheres and thermoshrinking properties of smart polymer gels. At selected temperatures the periodic array efficiently Bragg diffracts light and transmits most of the light at other temperatures. Hence these intelligent systems are of potential use as fixed notch filters optical switches or limiters to protect delicate optical sensors from high intensity laser radiation.

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

Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9

PubMed Central

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

2015-01-01

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

Conditional ablation of the Notch2 receptor in the ocular lens

PubMed Central

Saravanamuthu, Senthil S.; Le, Tien T.; Gao, Chun Y.; Cojocaru, Radu I.; Pandiyan, Pushpa; Liu, Chunqiao; Zhang, Jun; Zelenka, Peggy S.; Brown, Nadean L.

2011-01-01

Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation. PMID:22173065

Fragment analysis represents a suitable approach for the detection of hotspot c.7541_7542delCT NOTCH1 mutation in chronic lymphocytic leukemia.

PubMed

Vavrova, Eva; Kantorova, Barbara; Vonkova, Barbara; Kabathova, Jitka; Skuhrova-Francova, Hana; Diviskova, Eva; Letocha, Ondrej; Kotaskova, Jana; Brychtova, Yvona; Doubek, Michael; Mayer, Jiri; Pospisilova, Sarka

2017-09-01

The hotspot c.7541_7542delCT NOTCH1 mutation has been proven to have a negative clinical impact in chronic lymphocytic leukemia (CLL). However, an optimal method for its detection has not yet been specified. The aim of our study was to examine the presence of the NOTCH1 mutation in CLL using three commonly used molecular methods. Sanger sequencing, fragment analysis and allele-specific PCR were compared in the detection of the c.7541_7542delCT NOTCH1 mutation in 201 CLL patients. In 7 patients with inconclusive mutational analysis results, the presence of the NOTCH1 mutation was also confirmed using ultra-deep next generation sequencing. The NOTCH1 mutation was detected in 15% (30/201) of examined patients. Only fragment analysis was able to identify all 30 NOTCH1-mutated patients. Sanger sequencing and allele-specific PCR showed a lower detection efficiency, determining 93% (28/30) and 80% (24/30) of the present NOTCH1 mutations, respectively. Considering these three most commonly used methodologies for c.7541_7542delCT NOTCH1 mutation screening in CLL, we defined fragment analysis as the most suitable approach for detecting the hotspot NOTCH1 mutation. Copyright © 2017 Elsevier Ltd. All rights reserved.

The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development

PubMed Central

Maillard, Ivan; Nakamura, Makoto; Pear, Warren S.; Griffin, James D.

2007-01-01

Signaling mediated by various Notch receptors and their ligands regulates diverse biological processes, including lymphoid cell fate decisions. Notch1 is required during T-cell development, while Notch2 and the Notch ligand Delta-like1 control marginal zone B (MZB) cell development. We previously determined that Mastermind-like (MAML) transcriptional coactivators are required for Notchinduced transcription by forming ternary nuclear complexes with Notch and the transcription factor CSL. The 3 MAML family members (MAML1-MAML3) are collectively essential for Notch activity in vivo, but whether individual MAMLs contribute to the specificity of Notch functions is unknown. Here, we addressed this question by studying lymphopoiesis in the absence of the Maml1 gene. Since Maml1−/− mice suffered perinatal lethality, hematopoietic chimeras were generated with Maml1−/−, Maml1+/−, or wild-type fetal liver progenitors. Maml1 deficiency minimally affected T-cell development, but was required for the development of MZB cells, similar to the phenotype of Notch2 deficiency. Moreover, the number of MZB cells correlated with Maml1 gene dosage. Since all 3 Maml genes were expressed in MZB cells and their precursors, these results suggest that Maml1 is specifically required for Notch2 signaling in MZB cells. PMID:17699740

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers.

PubMed

Choy, Lisa; Hagenbeek, Thijs J; Solon, Margaret; French, Dorothy; Finkle, David; Shelton, Amy; Venook, Rayna; Brauer, Matthew J; Siebel, Christian W

2017-03-15

Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc , and the mammary stem cell regulator Id4 This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers. Cancer Res; 77(6); 1439-52. ©2017 AACR . ©2017 American Association for Cancer Research.

The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia

PubMed Central

Palomero, Teresa; Dominguez, Maria; Ferrando, Adolfo A.

2008-01-01

Activating mutations in NOTCH1 are the most prominent genetic abnormality in T-cell acute Lymphoblastic Leukemia (T-ALL) and inhibition of NOTCH1 signaling with γ-secretase inhibitors (GSIs) has been proposed as targeted therapy in this disease. However, most T-ALL cell lines with mutations in NOTCH1 fail to respond to GSI therapy. Using gene expression profiling and mutation analysis we showed that mutational loss of PTEN is a common event in T-ALL and is associated with resistance to NOTCH inhibition. Furthermore, our studies revealed that NOTCH1 induces upregulation of the PI3K-AKT pathway via HES1, which negatively controls the expression of PTEN. This regulatory circuitry is evolutionary conserved from Drosophila to humans as demonstrated by the interaction of overexpression of Delta and Akt in a model of Notch-induced transformation in the fly eye. Loss of PTEN and constitutive activation of AKT in T-ALL induce increased glucose metabolism and bypass the requirement of NOTCH1 signaling to sustain cell growth. Importantly, PTEN-null/GSI resistant T-ALL cells switch their oncogene addiction from NOTCH1 to AKT and are highly sensitive to AKT inhibitors. These results should facilitate the development of molecular therapies targeting NOTCH1 and AKT for the treatment of T-ALL. PMID:18414037

Effect of Notches on Creep-Fatigue Behavior of a P/M Nickel-Based Superalloy

NASA Technical Reports Server (NTRS)

Telesman, Jack; Gabb, Timothy P.; Ghosn, Louis J.; Gayda, John, Jr.

2015-01-01

A study was performed to determine and model the effect of high temperature dwells on notched low cycle fatigue (NLCF) and notch stress rupture behavior of a fine grain LSHR powder metallurgy (PM) nickel-based superalloy. It was shown that a 90 second dwell applied at the minimum stress (min dwell) was considerably more detrimental to the NLCF lives than similar dwell applied at the maximum stress (max dwell). The short min dwell NLCF lives were shown to be caused by growth of small oxide blisters which caused preferential cracking when coupled with high concentrated notch root stresses. The cyclic max dwell notch tests failed mostly by a creep accumulation, not by fatigue, with the crack origin shifting internally to a substantial distance away from the notch root. The classical von Mises plastic flow model was unable to match the experimental results while the hydrostatic stress profile generated using the Drucker-Prager plasticity flow model was consistent with the experimental findings. The max dwell NLCF and notch stress rupture tests exhibited substantial creep notch strengthening. The triaxial Bridgman effective stress parameter was able to account for the notch strengthening by collapsing the notched and uniform gage geometry test data into a singular grouping.

A New Method to Cancel RFI---The Adaptive Filter

NASA Astrophysics Data System (ADS)

Bradley, R.; Barnbaum, C.

1996-12-01

An increasing amount of precious radio frequency spectrum in the VHF, UHF, and microwave bands is being utilized each year to support new commercial and military ventures, and all have the potential to interfere with radio astronomy observations. Some radio spectral lines of astronomical interest occur outside the protected radio astronomy bands and are unobservable due to heavy interference. Conventional approaches to deal with RFI include legislation, notch filters, RF shielding, and post-processing techniques. Although these techniques are somewhat successful, each suffers from insufficient interference cancellation. One concept of interference excision that has not been used before in radio astronomy is adaptive interference cancellation. The concept of adaptive interference canceling was first introduced in the mid-1970s as a way to reduce unwanted noise in low frequency (audio) systems. Examples of such systems include the canceling of maternal ECG in fetal electrocardiography and the reduction of engine noise in the passenger compartment of automobiles. Only recently have high-speed digital filter chips made adaptive filtering possible in a bandwidth as large a few megahertz, finally opening the door to astronomical uses. The system consists of two receivers: the main beam of the radio telescope receives the desired signal corrupted by RFI coming in the sidelobes, and the reference antenna receives only the RFI. The reference antenna is processed using a digital adaptive filter and then subtracted from the signal in the main beam, thus producing the system output. The weights of the digital filter are adjusted by way of an algorithm that minimizes, in a least-squares sense, the power output of the system. Through an adaptive-iterative process, the interference canceler will lock onto the RFI and the filter will adjust itself to minimize the effect of the RFI at the system output. We are building a prototype 100 MHz receiver and will measure the cancellation effectiveness of the system on the 140 ft telescope at Green Bank Observatory.

FPGA/NIOS Implementation of an Adaptive FIR Filter Using Linear Prediction to Reduce Narrow-Band RFI for Radio Detection of Cosmic Rays

NASA Astrophysics Data System (ADS)

Szadkowski, Zbigniew; Fraenkel, E. D.; van den Berg, Ad M.

2013-10-01

We present the FPGA/NIOS implementation of an adaptive finite impulse response (FIR) filter based on linear prediction to suppress radio frequency interference (RFI). This technique will be used for experiments that observe coherent radio emission from extensive air showers induced by ultra-high-energy cosmic rays. These experiments are designed to make a detailed study of the development of the electromagnetic part of air showers. Therefore, these radio signals provide information that is complementary to that obtained by water-Cherenkov detectors which are predominantly sensitive to the particle content of an air shower at ground. The radio signals from air showers are caused by the coherent emission due to geomagnetic and charge-excess processes. These emissions can be observed in the frequency band between 10-100 MHz. However, this frequency range is significantly contaminated by narrow-band RFI and other human-made distortions. A FIR filter implemented in the FPGA logic segment of the front-end electronics of a radio sensor significantly improves the signal-to-noise ratio. In this paper we discuss an adaptive filter which is based on linear prediction. The coefficients for the linear predictor (LP) are dynamically refreshed and calculated in the embedded NIOS processor, which is implemented in the same FPGA chip. The Levinson recursion, used to obtain the filter coefficients, is also implemented in the NIOS and is partially supported by direct multiplication in the DSP blocks of the logic FPGA segment. Tests confirm that the LP can be an alternative to other methods involving multiple time-to-frequency domain conversions using an FFT procedure. These multiple conversions draw heavily on the power consumption of the FPGA and are avoided by the linear prediction approach. Minimization of the power consumption is an important issue because the final system will be powered by solar panels. The FIR filter has been successfully tested in the Altera development kits with the EP4CE115F29C7 from the Cyclone IV family and the EP3C120F780C7 from the Cyclone III family at a 170 MHz sampling rate, a 12-bit I/O resolution, and an internal 30-bit dynamic range. Most of the slow floating-point NIOS calculations have been moved to the FPGA logic segments as extended fixed-point operations, which significantly reduced the refreshing time of the coefficients used in the LP. We conclude that the LP is a viable alternative to other methods such as non-adaptive methods involving digital notch filters or multiple time-to-frequency domain conversions using an FFT procedure.

Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival.

PubMed

Baker, Andrew; Wyatt, Debra; Bocchetta, Maurizio; Li, Jun; Filipovic, Aleksandra; Green, Andrew; Peiffer, Daniel S; Fuqua, Suzanne; Miele, Lucio; Albain, Kathy S; Osipo, Clodia

2018-05-10

Trastuzumab targets the HER2 receptor on breast cancer cells to attenuate HER2-driven tumor growth. However, resistance to trastuzumab-based therapy remains a major clinical problem for women with HER2+ breast cancer. Breast cancer stem cells (BCSCs) are suggested to be responsible for drug resistance and tumor recurrence. Notch signaling has been shown to promote BCSC survival and self-renewal. Trastuzumab-resistant cells have increased Notch-1 expression. Notch signaling drives cell proliferation in vitro and is required for tumor recurrence in vivo. We demonstrate herein a mechanism by which Notch-1 is required for trastuzumab resistance by repressing PTEN expression to contribute to activation of ERK1/2 signaling. Furthermore, Notch-1-mediated inhibition of PTEN is necessary for BCSC survival in vitro and in vivo. Inhibition of MEK1/2-ERK1/2 signaling in trastuzumab-resistant breast cancer cells mimics effects of Notch-1 knockdown on bulk cell proliferation and BCSC survival. These findings suggest that Notch-1 contributes to trastuzumab resistance by repressing PTEN and this may lead to hyperactivation of ERK1/2 signaling. Furthermore, high Notch-1 and low PTEN mRNA expression may predict poorer overall survival in women with breast cancer. Notch-1 protein expression predicts poorer survival in women with HER2+ breast cancer. These results support a potential future clinical trial combining anti-Notch-1 and anti-MEK/ERK therapy for trastuzumab-resistant breast cancer.

Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner

PubMed Central

Coutaz, Manuel; Hurrell, Benjamin P.; Auderset, Floriane; Wang, Haiping; Siegert, Stefanie; Eberl, Gerard; Ho, Ping-Chih; Radtke, Freddy; Tacchini-Cottier, Fabienne

2016-01-01

Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed. Intracellular IL-17 co-localized with the CD71 iron transporter in the draining lymph node of both control and Notch-deficient Th17 cells. Immunization induced CD71 surface expression in control, but not in Notch-deficient Th17 cells, revealing defective CD71 intracellular transport in absence of Notch signaling. Moreover, Notch receptor deficient Th17 cells had impaired mTORC2 activity. These data reveal a context-dependent impact of Notch on vesicular transport during high metabolic demand suggesting a role for Notch signaling in the bridging of T cell metabolic demands and effector functions. Collectively, our findings indicate a prominent regulatory role for Notch signaling in the fine-tuning of Th17 cell differentiation and effector function. PMID:27974744

Enhanced osteogenic differentiation of rat bone marrow mesenchymal stem cells on titanium substrates by inhibiting Notch3.

PubMed

Wang, Huiming; Jiang, Zhiwei; Zhang, Jing; Xie, Zhijian; Wang, Ying; Yang, Guoli

2017-08-01

The role of the Notch pathway has already been identified as a crucial regulator of bone development. However, the Notch signaling pathway has gone largely unexplored during osseointegration. This study aims to investigate the role of Notch signaling on osteogenic differentiation of rat derived bone marrow mesenchymal stem cells (BMSCs) on sandblasted, large-grit, acid-etched (SLA) treated Ti disks. The involved target genes in Notch pathways were identified by in vitro microarray and bioinformatics analyses with or without osteogenic induction. Adhesion, proliferation, and osteogenic related assay were subsequently conducted with target gene shRNA treatment. We found that 11 genes in the Notch signaling pathway were differentially expressed after osteogenic induction on SLA-treated Ti disks, which included up-regulated genes (Notch2, Dll1, Dll3, Ncstn, Ncor2, and Hes5) and down-regulated genes (Notch3, Lfng, Mfng, Jag2 and Maml2). With Notch3 shRNA treatment, the adhesion and proliferation of BMSCs on SLA-treated Ti disks were inhibited. Moreover, the expression levels of alkaline phosphatase (ALP), osteocalcin (OCN), calcium deposition, BMP2 and Runx2 increased significantly compared with that observed in control groups, suggesting that the function of Notch3 was inhibitory in the osteogenic differentiation of BMSCs on SLA-treated titanium. Inhibition Notch3 can enhance osteogenic differentiation of BMSCs on SLA-treated Ti disks, which potentially provides a gene target for improving osseointegration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

PubMed Central

Kamga, Paul Takam; Bassi, Giulio; Cassaro, Adriana; Midolo, Martina; Di Trapani, Mariano; Gatti, Alessandro; Carusone, Roberta; Resci, Federica; Perbellini, Omar; Gottardi, Michele; Bonifacio, Massimiliano; Kamdje, Armel Hervé Nwabo; Ambrosetti, Achille; Krampera, Mauro

2016-01-01

Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB. These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML. PMID:26967055

Activation of the Notch-1 signaling pathway may be involved in intracerebral hemorrhage-induced reactive astrogliosis in rats.

PubMed

Zhong, Jian-Hua; Zhou, Hua-Jun; Tang, Tao; Cui, Han-Jin; Yang, A-Li; Zhang, Qi-Mei; Zhou, Jing-Hua; Zhang, Qiang; Gong, Xun; Zhang, Zhao-Hui; Mei, Zhi-Gang

2017-10-27

OBJECTIVE Reactive astrogliosis, a key feature that is characterized by glial proliferation, has been observed in rat brains after intracerebral hemorrhage (ICH). However, the mechanisms that control reactive astrogliosis formation remain unknown. Notch-1 signaling plays a critical role in modulating reactive astrogliosis. The purpose of this paper was to establish whether Notch-1 signaling is involved in reactive astrogliosis after ICH. METHODS ICH was induced in adult male Sprague-Dawley rats via stereotactic injection of autologous blood into the right globus pallidus. N-[ N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT) was injected into the lateral ventricle to block Notch-1 signaling. The rats' brains were perfused to identify proliferating cell nuclear antigen (PCNA)-positive/GFAP-positive nuclei. The expression of GFAP, Notch-1, and the activated form of Notch-1 (Notch intracellular domain [NICD]) and its ligand Jagged-1 was assessed using immunohistochemical and Western blot analyses, respectively. RESULTS Notch-1 signaling was upregulated and activated after ICH as confirmed by an increase in the expression of Notch-1 and NICD and its ligand Jagged-1. Remarkably, blockade of Notch-1 signaling with the specific inhibitor DAPT suppressed astrocytic proliferation and GFAP levels caused by ICH. In addition, DAPT improved neurological outcome after ICH. CONCLUSIONS Notch-1 signaling is a critical regulator of ICH-induced reactive astrogliosis, and its blockage may be a potential therapeutic strategy for hemorrhagic injury.

A central role for Notch in effector CD8+ T cell differentiation

PubMed Central

Backer, Ronald A.; Helbig, Christina; Gentek, Rebecca; Kent, Andrew; Laidlaw, Brian J.; Dominguez, Claudia X.; de Souza, Yevan S.; van Trierum, Stella E.; van Beek, Ruud; Rimmelzwaan, Guus F.; ten Brinke, Anja; Willemsen, A. Marcel; van Kampen, Antoine H. C.; Kaech, Susan M.; Blander, J. Magarian; van Gisbergen, Klaas; Amsen, Derk

2014-01-01

Activated CD8+ T cells choose between terminal effector cell (TEC) or memory precursor cell (MPC) fates. We show that Notch controls this choice. Notch promoted differentiation of immediately protective TECs and was correspondingly required for clearance of an acute influenza virus infection. Notch activated a major portion of the TEC-specific gene expression program and suppressed the MPC-specific program. Expression of Notch receptors was induced on naïve CD8+ T cells by inflammatory mediators and interleukin 2 (IL-2) via mTOR and T-bet dependent pathways. These pathways were subsequently amplified downstream of Notch, creating a positive feedback loop. Notch thus functions as a central hub where information from different sources converges to match effector T cell differentiation to the demands of the infection. PMID:25344724

Effect of verteporfin-PDT on the Notch signaling pathway in cholangiocarcinoma (CCA) cell lines

NASA Astrophysics Data System (ADS)

Cerec, Virginie; Andreola, Fausto; Pereira, Stephen P.

2009-06-01

Accumulating preclinical and clinical evidence supports a pro-oncogenic function for Notch signaling in several solid tumors. Therefore, Notch inhibitory agents, such as gamma-secretase inhibitors (GSI), are being investigated as cancer therapeutic agents and a potential adjuvant to conventional chemo/radiotherapy. To date, no in vitro data are available on the cellular response and effect of either photodynamic therapy (PDT) or GSI on human cholangiocarcinoma (CCA). Consequently, we aimed to study the: (i) constitutive expression of Notch signaling pathway in CCA cell lines; (ii) response to Verteporfin-PDT and to GSI, as single agents on CCA cell lines; (iii) effect of Verteporfin-PDT on Notch signaling pathway expression. Expression of Notch signaling components was studied in two cholangiocarcinoma cell lines, HuCCT1 and TFK-1 (intra- and extrahepatic, respectively). No difference in basal expression of Notch1, 2 and Jagged1 was observed in either cell line. In contrast, Notch3 was found to be weakly and highly expressed in HuCCT1 and TFK-1 cells, respectively - supporting our recent microarray data which showed Notch3 overexpression in biliary brushings from patients with extrahepatic CCA. HuCCT1 and TFK-1 differentially responded to Verteporfin-PDT treatment; preliminary data showed no clear effect of GSI on proliferation/apoptosis in either cell line following short exposure (6 and 24h). Following Verteporfin-PDT, Notch1, 2 and Jagged-1 expression was down-regulated in both cell lines, while Notch3 expression was unaffected in HuCCT1 cells and down-regulated in TFK-1 cells. The Notch signaling pathway could represent a potential target for combination therapy in CCA treatment.

Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy

PubMed Central

Vázquez-Ulloa, Elenaé; Ramos-Cruz, Ana Clara; Prada, Diddier; Avilés-Salas, Alejandro; Chávez-Blanco, Alma Delia; Herrera, Luis A.; Lizano, Marcela; Contreras-Paredes, Adriana

2018-01-01

The participation of NOTCH signaling in invasive cervical cancer (ICC) remains controversial since both tumor suppressive and oncogenic properties have been described. Additionally, the role of NUMB, a negative regulator of NOTCH, remains unclear in ICC. We aimed to investigate the role of NOTCH1 and NUMB expression and their localization in cervical intraepithelial neoplasia (CIN) and ICC samples. A total of 144 biopsies were obtained from the Instituto Nacional de Cancerología, México from 2004 to 2017, and were subjected to immunohistochemistry for NOTCH1 and NUMB. We found that nuclear NOTCH1 expression was more frequently found in CIN samples compared with ICC (77.55% vs. 15.79%, p = 0.001). NUMB was almost exclusively found in the nucleus of CIN samples (32.65% vs. 6.32%, p = 0.001). Cytoplasmic expression of NOTCH1 (44.21%) and NUMB (35.79%) was the most frequent localization in ICC. Multivariable-adjusted analysis showed that the loss of nuclear NOTCH1 expression was an independent predictor of malignancy (β = –3.428, 95% confidence interval [95% CI] = –5.127, –1.728, p = 0.001). In contrast, the association between cytoplasmic NUMB expression and cervical cancer was lost after adjusting for nuclear NOTCH1 expression (β = 2.074, 95% [CI] = –0.358, 4.506, P = 0.094). Additionally, patients with cytoplasmic NOTCH1 expression showed a borderline association with longer overall survival (OS) than those with nuclear NOTCH1 expression (P = 0.08). Our data suggest that the loss of nuclear NOTCH1 but not NUMB might be an independent predictor of malignancy in cervical cancer. PMID:29721172

Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.

PubMed

Pellegrinet, Luca; Rodilla, Veronica; Liu, Zhenyi; Chen, Shuang; Koch, Ute; Espinosa, Lluis; Kaestner, Klaus H; Kopan, Raphael; Lewis, Julian; Radtke, Freddy

2011-04-01

Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors due to their conversion into postmitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SCs), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiologic ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Transgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ER(T2)). Notch1 signaling was found to be activated in intestinal SCs. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into postmitotic goblet cells, concomitant with loss of SCs (Olfm4(+), Lgr5(+), and Ascl2(+)). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut. Notch signaling in SCs and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SCs. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Dll1- and Dll4-mediated Notch signaling is required for homeostasis of intestinal stem cells

PubMed Central

Pellegrinet, Luca; Rodilla, Veronica; Liu, Zhenyi; Chen, Shuang; Koch, Ute; Espinosa, Lluis; Kaestner, Klaus H.; Kopan, Raphael; Lewis, Julian; Radtke, Freddy

2011-01-01

Background & Aims Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors, due to their conversion into post-mitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SC), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiological ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Methods Trasgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ERT2). Results Notch1 signaling was found to be activated in intestinal SC. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into post-mitotic goblet cells, concomitant with loss of SC (Olfm4+, Lgr5+ and Ascl2+). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut. Conclusions Notch signaling in SC and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SC. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice. PMID:21238454

Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity.

PubMed

Liu, Baohui; Lin, Xi; Yang, Xiangsheng; Dong, Huimin; Yue, Xiaojing; Andrade, Kelsey C; Guo, Zhentao; Yang, Jian; Wu, Liquan; Zhu, Xiaonan; Zhang, Shenqi; Tian, Daofeng; Wang, Junmin; Cai, Qiang; Chen, Qizuan; Mao, Shanping; Chen, Qianxue; Chang, Jiang

2015-09-01

Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity

PubMed Central

Liu, Baohui; Lin, Xi; Yang, Xiangsheng; Dong, Huimin; Yue, Xiaojing; Andrade, Kelsey C; Guo, Zhentao; Yang, Jian; Wu, Liquan; Zhu, Xiaonan; Zhang, Shenqi; Tian, Daofeng; Wang, Junmin; Cai, Qiang; Chen, Qizuan; Mao, Shanping; Chen, Qianxue; Chang, Jiang

2015-01-01

Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis. PMID:26108681

Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy.

PubMed

Vázquez-Ulloa, Elenaé; Ramos-Cruz, Ana Clara; Prada, Diddier; Avilés-Salas, Alejandro; Chávez-Blanco, Alma Delia; Herrera, Luis A; Lizano, Marcela; Contreras-Paredes, Adriana

2018-04-10

The participation of NOTCH signaling in invasive cervical cancer (ICC) remains controversial since both tumor suppressive and oncogenic properties have been described. Additionally, the role of NUMB, a negative regulator of NOTCH, remains unclear in ICC. We aimed to investigate the role of NOTCH1 and NUMB expression and their localization in cervical intraepithelial neoplasia (CIN) and ICC samples. A total of 144 biopsies were obtained from the Instituto Nacional de Cancerología, México from 2004 to 2017, and were subjected to immunohistochemistry for NOTCH1 and NUMB. We found that nuclear NOTCH1 expression was more frequently found in CIN samples compared with ICC (77.55% vs. 15.79%, p = 0.001). NUMB was almost exclusively found in the nucleus of CIN samples (32.65% vs. 6.32%, p = 0.001). Cytoplasmic expression of NOTCH1 (44.21%) and NUMB (35.79%) was the most frequent localization in ICC. Multivariable-adjusted analysis showed that the loss of nuclear NOTCH1 expression was an independent predictor of malignancy (β = -3.428, 95% confidence interval [95% CI] = -5.127, -1.728, p = 0.001). In contrast, the association between cytoplasmic NUMB expression and cervical cancer was lost after adjusting for nuclear NOTCH1 expression (β = 2.074, 95% [CI] = -0.358, 4.506, P = 0.094). Additionally, patients with cytoplasmic NOTCH1 expression showed a borderline association with longer overall survival (OS) than those with nuclear NOTCH1 expression ( P = 0.08). Our data suggest that the loss of nuclear NOTCH1 but not NUMB might be an independent predictor of malignancy in cervical cancer.

Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-α.

PubMed

Dou, Xiao-Wei; Liang, Yuan-Ke; Lin, Hao-Yu; Wei, Xiao-Long; Zhang, Yong-Qu; Bai, Jing-Wen; Chen, Chun-Fa; Chen, Min; Du, Cai-Wen; Li, Yao-Chen; Tian, Jie; Man, Kwan; Zhang, Guo-Jun

2017-01-01

The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor α expression (ERα). Identification of the key regulator that governs the luminal phenotype of breast cancer will clarify the pathogenic mechanism and provide novel therapeutic strategies for this subtype of cancer. ERα signaling pathway sustains the epithelial phenotype and inhibits the epithelial-mesenchymal transition (EMT) of breast cancer. In this study, we demonstrate that Notch3 positively associates with ERα in both breast cancer cell lines and human breast cancer tissues. We found that overexpression of Notch3 intra-cellular domain, a Notch3 active form (N3ICD), in ERα negative breast cancer cells re-activated ERα, while knock-down of Notch3 reduced ERα transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ERα. Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ERα promoter and activates ERα expression. Moreover, Notch3 suppressed EMT, while suppression of Notch3 promoted EMT in cellular assay. Overexpressing N3ICD in triple-negative breast cancer suppressed tumorigenesis and metastasis in vivo . Conversely, depletion of Notch3 in luminal breast cancer promoted metastasis in vivo . Furthermore, Notch3 transcripts were significantly associated with prolonged relapse-free survival in breast cancer, in particular in ERα positive breast cancer patients. Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ERα expression in breast cancer. These findings delineate the role of a Notch3/ERα axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ERα negative or low-expressing breast cancers to hormone therapy.

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease.

PubMed

El Machhour, Fala; Keuylian, Zela; Kavvadas, Panagiotis; Dussaule, Jean-Claude; Chatziantoniou, Christos

2015-07-01

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN. Copyright © 2015 by the American Society of Nephrology.

Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia.

PubMed

Tao, Yong-Kang; Zeng, Heng; Zhang, Guo-Qiang; Chen, Sean T; Xie, Xue-Jiao; He, Xiaochen; Wang, Shuo; Wen, Hongyan; Chen, Jian-Xiong

2017-06-01

Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development. This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI. Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2 + /Sca1 + and NG2 + /c-kit + progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b + macrophage infiltration into ischemic areas compared to that of WT mice. Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the pre-existing coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation. Copyright © 2016. Published by Elsevier B.V.

Notch3 Maintains Luminal Phenotype and Suppresses Tumorigenesis and Metastasis of Breast Cancer via Trans-Activating Estrogen Receptor-α

PubMed Central

Dou, Xiao-Wei; Liang, Yuan-Ke; Lin, Hao-Yu; Wei, Xiao-Long; Zhang, Yong-Qu; Bai, Jing-Wen; Chen, Chun-Fa; Chen, Min; Du, Cai-Wen; Li, Yao-Chen; Tian, Jie; Man, Kwan; Zhang, Guo-Jun

2017-01-01

The luminal A phenotype is the most common breast cancer subtype and is characterized by estrogen receptor α expression (ERα). Identification of the key regulator that governs the luminal phenotype of breast cancer will clarify the pathogenic mechanism and provide novel therapeutic strategies for this subtype of cancer. ERα signaling pathway sustains the epithelial phenotype and inhibits the epithelial-mesenchymal transition (EMT) of breast cancer. In this study, we demonstrate that Notch3 positively associates with ERα in both breast cancer cell lines and human breast cancer tissues. We found that overexpression of Notch3 intra-cellular domain, a Notch3 active form (N3ICD), in ERα negative breast cancer cells re-activated ERα, while knock-down of Notch3 reduced ERα transcript and proteins, with alteration of down-stream genes, suggesting its ability to regulate ERα. Mechanistically, our results show that Notch3 specifically binds to the CSL binding element of the ERα promoter and activates ERα expression. Moreover, Notch3 suppressed EMT, while suppression of Notch3 promoted EMT in cellular assay. Overexpressing N3ICD in triple-negative breast cancer suppressed tumorigenesis and metastasis in vivo. Conversely, depletion of Notch3 in luminal breast cancer promoted metastasis in vivo. Furthermore, Notch3 transcripts were significantly associated with prolonged relapse-free survival in breast cancer, in particular in ERα positive breast cancer patients. Our observations demonstrate that Notch3 governs the luminal phenotype via trans-activating ERα expression in breast cancer. These findings delineate the role of a Notch3/ERα axis in maintaining the luminal phenotype and inhibiting tumorigenesis and metastasis in breast cancer, providing a novel strategy to re-sensitize ERα negative or low-expressing breast cancers to hormone therapy. PMID:29109797

Modulation of notch signaling pathway to prevent H2O2/menadione-induced SK-N-MC cells death by EUK134.

PubMed

Kamarehei, Maryam; Yazdanparast, Razieh

2014-10-01

The brain in Alzheimer's disease is under increased oxidative stress, and this may have a role in the pathogenesis and neural death in this disorder. It has been verified that numerous signaling pathways involved in neurodegenerative disorders are activated in response to reactive oxygen species (ROS). EUK134, a synthetic salen-manganese antioxidant complex, has been found to possess many interesting pharmacological activities awaiting exploration. The present study is to characterize the role of Notch signaling in apoptotic cell death of SK-N-MC cells. The cells were treated with hydrogen peroxide (H2O2) or menadione to induce oxidative stress. The free-radical scavenging capabilities of EUK134 were studied through the MTT assay, glutathione peroxidase (GPx) enzyme activity assay, and glutathione (GSH) Levels. The extents of lipid peroxidation, protein carbonyl formation, and intracellular ROS levels, as markers of oxidative stress, were also studied. Our results showed that H2O2/menadione reduced GSH levels and GPx activity. However, EUK134 protected cells against ROS-induced cell death by down-regulation of lipid peroxidation and protein carbonyl formation as well as restoration of antioxidant enzymes activity. ROS induced apoptosis and increased NICD and HES1 expression. Inhibition of NICD production proved that Notch signaling is involved in apoptosis through p53 activation. Moreover, H2O2/menadione led to Numb protein down-regulation which upon EUK134 pretreatment, its level increased and subsequently prevented Notch pathway activation. We indicated that EUK134 can be a promising candidate in designing natural-based drugs for ROS-induced neurodegenerative diseases. Collectively, ROS activated Notch signaling in SK-N-MC cells leading to cell apoptosis.

40 CFR 1033.530 - Duty cycles and calculations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... with two idle settings, eight propulsion notches, and at least one dynamic brake notch and tested using... dynamic brake) Switch weighting factors Low Idle A 0.190 0.190 0.299 Normal Idle B 0.190 0.315 0.299 Dynamic Brake C 0.125 (1) 0.000 Notch 1 1 0.065 0.065 0.124 Notch 2 2 0.065 0.065 0.123 Notch 3 3 0.052 0...

Flexible ultra-wideband antenna incorporated with metamaterial structures: multiple notches for chipless RFID application

NASA Astrophysics Data System (ADS)

Jalil, M. E.; Rahim, M. K. A.; Samsuri, N. A.; Dewan, R.; Kamardin, K.

2017-01-01

A coplanar waveguide (CPW) ultra-wideband (UWB) antenna incorporated with metamaterial—split ring resonator structure—that operates from 3.0 to 12.0 GHz is proposed for chipless RFID tag. The 30 mm × 40 mm flexible chipless RFID tag is designed on the fleece substrate ( ɛ r = 1.35, thickness = 1 mm and tan δ = 0.025). A six-slotted modified complementary split ring resonator (MCSRR) is introduced into the ultra-wideband antenna to produce multiple band notches at 3.0, 4.0, 5.0, 6.0 and 7.0 GHz. The frequency shifting technique is introduced for designing a high-capacity chipless RFID tag with compact size. Each MCSRR is able to code in four different allocations (00, 01, 10 and 11). To achieve encoding of 10-bits data (10,234 number), six MCSRRs are proposed with three-slotted MCSRR in the radiator and three-slotted MCSRR in the ground plane.

Refractive Index Sensor Based on a Metal-Insulator-Metal Waveguide Coupled with a Symmetric Structure.

PubMed

Yan, Shubin; Zhang, Meng; Zhao, Xuefeng; Zhang, Yanjun; Wang, Jicheng; Jin, Wen

2017-12-11

In this study, a new refractive index sensor based on a metal-insulator-metal waveguide coupled with a notched ring resonator and stub is designed. The finite element method is used to study the propagation characteristics of the sensor. According to the calculation results, the transmission spectrum exhibits a typical Fano resonance shape. The phenomenon of Fano resonance is caused by the coupling between the broadband spectrum and narrowband spectrum. In the design, the broadband spectrum signal is generated by the stub, while the narrowband spectrum signal is generated by the notched ring resonator. In addition, the structural parameters of the resonators and the structure filled with media of different refractive indices are varied to study the sensing properties. The maximum achieved sensitivity of the sensor reached 1071.4 nm/RIU. The results reveal potential applications of the coupled system in the field of sensors.

Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature.

PubMed

Kristoffersen, Karina; Nedergaard, Mette Kjølhede; Villingshøj, Mette; Borup, Rehannah; Broholm, Helle; Kjær, Andreas; Poulsen, Hans Skovgaard; Stockhausen, Marie-Thérése

2014-07-01

Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC. Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice. By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control. Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

2013-01-18

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

Induced pluripotent stem cells with NOTCH1 gene mutation show impaired differentiation into smooth muscle and endothelial cells: Implications for bicuspid aortic valve-related aortopathy.

PubMed

Jiao, Jiao; Tian, Weihua; Qiu, Ping; Norton, Elizabeth L; Wang, Michael M; Chen, Y Eugene; Yang, Bo

2018-03-12

The NOTCH1 gene mutation has been identified in bicuspid aortic valve patients. We developed an in vitro model with human induced pluripotent stem cells (iPSCs) to evaluate the role of NOTCH1 in smooth muscle and endothelial cell (EC) differentiation. The iPSCs were derived from a patient with a normal tricuspid aortic valve and aorta. The NOTCH1 gene was targeted in iPSCs with the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 nuclease (Cas9) system. The NOTCH1 -/- (NOTCH1 homozygous knockout) and isogenic control iPSCs (wild type) were differentiated into neural crest stem cells (NCSCs) and into cardiovascular progenitor cells (CVPCs). The NCSCs were differentiated into smooth muscle cells (SMCs). The CVPCs were differentiated into ECs. The differentiations of SMCs and ECs were compared between NOTCH1 -/- and wild type cells. The expression of NCSC markers (SRY-related HMG-box 10 and transcription factor AP-2 alpha) was significantly lower in NOTCH1 -/- NCSCs than in wild type NCSCs. The SMCs derived from NOTCH1 -/- NCSCs showed immature morphology with smaller size and decreased expression of all SMC-specific contractile proteins. In NOTCH1 -/- CVPCs, the expression of ISL1, NKX2.5, and MYOCD was significantly lower than that in isogenic control CVPCs, indicating impaired differentiation from iPSCs to CVPCs. The NOTCH1 -/- ECs derived from CVPCs showed significantly lower expression of cluster of differentiation 105 and cluster of differentiation 31 mRNA and protein, indicating a defective differentiation process. NOTCH1 is critical in SMC and EC differentiation of iPSCs through NCSCs and CVPCs, respectively. NOTCH1 gene mutations might potentially contribute to the development of thoracic aortic aneurysms by affecting SMC differentiation in some patients with bicuspid aortic valve. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Far infrared promotes wound healing through activation of Notch1 signaling.

PubMed

Hsu, Yung-Ho; Lin, Yuan-Feng; Chen, Cheng-Hsien; Chiu, Yu-Jhe; Chiu, Hui-Wen

2017-11-01

The Notch signaling pathway is critically involved in cell proliferation, differentiation, development, and homeostasis. Far infrared (FIR) has an effect that promotes wound healing. However, the underlying molecular mechanisms are unclear. In the present study, we employed in vivo and HaCaT (a human skin keratinocyte cell line) models to elucidate the role of Notch1 signaling in FIR-promoted wound healing. We found that FIR enhanced keratinocyte migration and proliferation. FIR induced the Notch1 signaling pathway in HaCaT cells and in a microarray dataset from the Gene Expression Omnibus database. We next determined the mRNA levels of NOTCH1 in paired normal and wound skin tissues derived from clinical patients using the microarray dataset and Ingenuity Pathway Analysis software. The result indicated that the Notch1/Twist1 axis plays important roles in wound healing and tissue repair. In addition, inhibiting Notch1 signaling decreased the FIR-enhanced proliferation and migration. In a full-thickness wound model in rats, the wounds healed more rapidly and the scar size was smaller in the FIR group than in the light group. Moreover, FIR could increase Notch1 and Delta1 in skin tissues. The activation of Notch1 signaling may be considered as a possible mechanism for the promoting effect of FIR on wound healing. FIR stimulates keratinocyte migration and proliferation. Notch1 in keratinocytes has an essential role in FIR-induced migration and proliferation. NOTCH1 promotes TWIST1-mediated gene expression to assist wound healing. FIR might promote skin wound healing in a rat model. FIR stimulates keratinocyte migration and proliferation. Notch1 in keratinocytes has an essential role in FIR-induced migration and proliferation. NOTCH1 promotes TWIST1-mediated gene expression to assist wound healing. FIR might promote skin wound healing in a rat model.

NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence.

PubMed

Parry, Aled J; Hoare, Matthew; Bihary, Dóra; Hänsel-Hertsch, Robert; Smith, Stephen; Tomimatsu, Kosuke; Mannion, Elizabeth; Smith, Amy; D'Santos, Paula; Russell, I Alasdair; Balasubramanian, Shankar; Kimura, Hiroshi; Samarajiwa, Shamith A; Narita, Masashi

2018-05-09

Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. We have recently identified that NOTCH1 can drive 'lateral induction' of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell-cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.

Endothelial Notch signalling limits angiogenesis via control of artery formation

PubMed Central

Hasan, Sana S.; Tsaryk, Roman; Lange, Martin; Wisniewski, Laura; Moore, John C.; Lawson, Nathan D.; Wojciechowska, Karolina; Schnittler, Hans; Siekmann, Arndt F.

2017-01-01

Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial-venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation. PMID:28714969

Could Notch signaling pathway be a potential therapeutic option in renal diseases?

PubMed

Marquez-Exposito, Laura; Cantero-Navarro, Elena; Lavoz, Carolina; Fierro-Fernández, Marta; Poveda, Jonay; Rayego-Mateos, Sandra; Rodrigues-Diez, Raúl R; Morgado-Pascual, José Luis; Orejudo, Macarena; Mezzano, Sergio; Ruiz-Ortega, Marta

2018-02-10

Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by γ-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells. Recent studies suggest an interaction between Notch and NF-κB pathway involved in the regulation of renal inflammatory process. On the other hand, there are some miRNAs that could regulate Notch components and down-stream responses. All these data suggest that Notch blockade could be a novel therapeutic option for renal diseases. Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Characterization of a new B-ALL cell line with constitutional defect of the Notch signaling pathway

PubMed Central

Kamga, Paul Takam; Dal Collo, Giada; Bassi, Giulio; Midolo, Martina; Delledonne, Massimo; Chilosi, Marco; Bonifacio, Massimiliano; Krampera, Mauro

2018-01-01

Notch signaling contribution to B-cell acute lymphoblastic leukemia (B-ALL) development is still under investigation. The serendipitous onset of B-ALL in a patient affected by the germinal Notch mutation-dependent Alagille syndrome allowed us to establish a B-ALL cell line (VR-ALL) bearing a genetic loss of function in components of Notch signaling. VR-ALL is a common-type B-ALL cell line, grows in conventional culture medium supplemented with 10% serum, and gives rise, once injected into immunodeficient NOG mice, to a mouse xenograft model of B-ALL. Exome sequencing revealed deleterious mutations in some components of Notch signaling, including Jagged1, Notch1, and Notch2. In addition, VR-ALL is sensitive both in vitro and in vivo to γ-secretase inhibitors (GSIs) as well as conventional anti-leukemic drugs. For all these reasons, VR-ALL may help to gain more insights into the role of Notch signaling in B-ALL. PMID:29719609

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.

Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy.

PubMed

Nwabo Kamdje, A H; Bassi, G; Pacelli, L; Malpeli, G; Amati, E; Nichele, I; Pizzolo, G; Krampera, M

2012-05-01

Stromal cells are essential components of the bone marrow (BM) microenvironment that regulate and support the survival of different tumors, including chronic lymphocytic leukemia (CLL). In this study, we investigated the role of Notch signaling in the promotion of survival and chemoresistance of human CLL cells in coculture with human BM-mesenchymal stromal cells (hBM-MSCs) of both autologous and allogeneic origin. The presence of BM-MSCs rescued CLL cells from apoptosis both spontaneously and following induction with various drugs, including Fludarabine, Cyclophosphamide, Bendamustine, Prednisone and Hydrocortisone. The treatment with a combination of anti-Notch-1, Notch-2 and Notch-4 antibodies or γ-secretase inhibitor XII (GSI XII) reverted this protective effect by day 3, even in presence of the above-mentioned drugs. Overall, our findings show that stromal cell-mediated Notch-1, Notch-2 and Notch-4 signaling has a role in CLL survival and resistance to chemotherapy. Therefore, its blocking could be an additional tool to overcome drug resistance and improve the therapeutic strategies for CLL.

Preliminary report on tests of tensile specimens with a part-through surface notch for a filament wound graphite/epoxy material

NASA Technical Reports Server (NTRS)

Harris, C. E.; Morris, D. H.

1985-01-01

The behavior of tensile coupons with surface notches of various semi-elliptical shapes were evaluated for specimens obtained from a filament wound graphite/epoxy cylinder. The quasi-static test results, in some instances, are inadequate for defining complete trend curves and the interpretive analysis is considered to be preliminary. Specimens with very shallow notches were observed to be notch insensitive and the unnotched strength from these specimens was determined to be 54.97 Ksi. The failure strain of the laminate was found to be 1.328%. Specimens with deeper notches were sensitive to notch depth, notch aspect ratio, and specimen width. Using the unnotched strength of 54.97 Ksi and Poe's general toughness parameter, the fracture toughness was estimated to be 27.2 Ksi square root of In. Isotropic linear elastic fracture mechanics together with the estimated fracture toughness correctly predicted the influence of notch depth, aspect ratio, and specimen finitewidth.

Drosophila melanogaster auxilin regulates the internalization of Delta to control activity of the Notch signaling pathway

PubMed Central

Hagedorn, Elliott J.; Bayraktar, Jennifer L.; Kandachar, Vasundhara R.; Bai, Ting; Englert, Dane M.; Chang, Henry C.

2006-01-01

We have isolated mutations in the Drosophila melanogaster homologue of auxilin, a J-domain–containing protein known to cooperate with Hsc70 in the disassembly of clathrin coats from clathrin-coated vesicles in vitro. Consistent with this biochemical role, animals with reduced auxilin function exhibit genetic interactions with Hsc70 and clathrin. Interestingly, the auxilin mutations interact specifically with Notch and disrupt several Notch-mediated processes. Genetic evidence places auxilin function in the signal-sending cells, upstream of Notch receptor activation, suggesting that the relevant cargo for this auxilin-mediated endocytosis is the Notch ligand Delta. Indeed, the localization of Delta protein is disrupted in auxilin mutant tissues. Thus, our data suggest that auxilin is an integral component of the Notch signaling pathway, participating in the ubiquitin-dependent endocytosis of Delta. Furthermore, the fact that auxilin is required for Notch signaling suggests that ligand endocytosis in the signal-sending cells needs to proceed past coat disassembly to activate Notch. PMID:16682530

Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair.

PubMed

Li, Zhi; Hodgkinson, Tom; Gothard, Elizabeth J; Boroumand, Soulmaz; Lamb, Rebecca; Cummins, Ian; Narang, Priyanka; Sawtell, Amy; Coles, Jenny; Leonov, German; Reboldi, Andrea; Buckley, Christopher D; Cupedo, Tom; Siebel, Christian; Bayat, Ardeshir; Coles, Mark C; Ambler, Carrie A

2016-04-21

Notch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal. Epidermal Notch induces recruitment of immune cell subsets including RORγ(+) ILC3s into wounded dermis; RORγ(+) ILC3s are potent sources of IL17F in wounds and control immunological and epidermal cell responses. Mice deficient for RORγ(+) ILC3s heal wounds poorly resulting from delayed epidermal proliferation and macrophage recruitment in a CCL3-dependent process. Notch1 upregulates TNFα and the ILC3 recruitment chemokines CCL20 and CXCL13. TNFα, as a Notch1 effector, directs ILC3 localization and rates of wound healing. Altogether these findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair.

Notch-mediated lateral inhibition regulates proneural wave propagation when combined with EGF-mediated reaction diffusion

PubMed Central

Sato, Makoto; Yasugi, Tetsuo; Minami, Yoshiaki; Miura, Takashi; Nagayama, Masaharu

2016-01-01

Notch-mediated lateral inhibition regulates binary cell fate choice, resulting in salt and pepper patterns during various developmental processes. However, how Notch signaling behaves in combination with other signaling systems remains elusive. The wave of differentiation in the Drosophila visual center or “proneural wave” accompanies Notch activity that is propagated without the formation of a salt and pepper pattern, implying that Notch does not form a feedback loop of lateral inhibition during this process. However, mathematical modeling and genetic analysis clearly showed that Notch-mediated lateral inhibition is implemented within the proneural wave. Because partial reduction in EGF signaling causes the formation of the salt and pepper pattern, it is most likely that EGF diffusion cancels salt and pepper pattern formation in silico and in vivo. Moreover, the combination of Notch-mediated lateral inhibition and EGF-mediated reaction diffusion enables a function of Notch signaling that regulates propagation of the wave of differentiation. PMID:27535937

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

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

PubMed

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

2011-10-14

Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy. Copyright © 2011. Published by Elsevier Inc.

Viscoplastic crack initiation and propagation in crosslinked UHMWPE from clinically relevant notches up to 0.5mm radius.

PubMed

Sirimamilla, P Abhiram; Rimnac, Clare M; Furmanski, Jevan

2018-01-01

Highly crosslinked UHMWPE is now the material of choice for hard-on-soft bearing couples in total joint replacements. However, the fracture resistance of the polymer remains a design concern for increased longevity of the components in vivo. Fracture research utilizing the traditional linear elastic fracture mechanics (LEFM) or elastic plastic fracture mechanics (EPFM) approach has not yielded a definite failure criterion for UHMWPE. Therefore, an advanced viscous fracture model has been applied to various notched compact tension specimen geometries to estimate the fracture resistance of the polymer. Two generic crosslinked UHMWPE formulations (remelted 65kGy and remelted 100kGy) were analyzed in this study using notched test specimens with three different notch radii under static loading conditions. The results suggest that the viscous fracture model can be applied to crosslinked UHMWPE and a single value of critical energy governs crack initiation and propagation in the material. To our knowledge, this is one of the first studies to implement a mechanistic approach to study crack initiation and propagation in UHMWPE for a range of clinically relevant stress-concentration geometries. It is believed that a combination of structural analysis of components and material parameter quantification is a path to effective failure prediction in UHMWPE total joint replacement components, though additional testing is needed to verify the rigor of this approach. Copyright © 2017 Elsevier Ltd. All rights reserved.

Functional studies on the role of Notch signaling in Hydractinia development.

PubMed

Gahan, James M; Schnitzler, Christine E; DuBuc, Timothy Q; Doonan, Liam B; Kanska, Justyna; Gornik, Sebastian G; Barreira, Sofia; Thompson, Kerry; Schiffer, Philipp; Baxevanis, Andreas D; Frank, Uri

2017-08-01

The function of Notch signaling was previously studied in two cnidarians, Hydra and Nematostella, representing the lineages Hydrozoa and Anthozoa, respectively. Using pharmacological inhibition in Hydra and a combination of pharmacological and genetic approaches in Nematostella, it was shown in both animals that Notch is required for tentacle morphogenesis and for late stages of stinging cell maturation. Surprisingly, a role for Notch in neural development, which is well documented in bilaterians, was evident in embryonic Nematostella but not in adult Hydra. Adult neurogenesis in the latter seemed to be unaffected by DAPT, a drug that inhibits Notch signaling. To address this apparent discrepancy, we studied the role of Notch in Hydractinia echinata, an additional hydrozoan, in all life stages. Using CRISPR-Cas9 mediated mutagenesis, transgenesis, and pharmacological interference we show that Notch is dispensable for Hydractinia normal neurogenesis in all life stages but is required for the maturation of stinging cells and for tentacle morphogenesis. Our results are consistent with a conserved role for Notch in morphogenesis and nematogenesis across Cnidaria, and a lineage-specific loss of Notch dependence in neurogenesis in hydrozoans. Copyright © 2017 Elsevier Inc. All rights reserved.

[The effect of notch's angle and depth on crack propagation of zirconia ceramics].

PubMed

Chen, Qingya; Chen, Xinmin

2012-10-01

This paper is aimed to study the effect of notch's angle and depth on crack propagation of zirconia ceramics. We fabricated cuboid-shaped zirconia ceramics samples with the standard sizes of 4. 4 mm x 2. 2 mm x 18 mm for the experiments, divided the samples into 6 groups, and prepared notches on these samples with different angles and depth. We placed the samples with loads until they were broke, and observe the fracture curve of each sample. We then drew coordinates and described the points of the fracture curve under a microscope, and made curve fitting by the software-Origin. When the notch angle beta = 90 degrees, the crack propagation is pure type I; when beta = 60 degrees, the crack propagation is mainly type I; and when beta = 30 degrees, the crack propagation is a compound of type I and type III. With the increasing of the notch depth, the effect of notch angles on crack propagation increases. In addition, Notch angle is a very important fracture mechanics parameter for crack propagation of zirconia ceramics. With the increasing of notch depth, the impact of notch angle increases.

Perivascular Delivery of Notch 1 siRNA Inhibits Injury-Induced Arterial Remodeling

PubMed Central

Redmond, Eileen M.; Liu, Weimin; Hamm, Katie; Hatch, Ekaterina; Cahill, Paul A.; Morrow, David

2014-01-01

Objectives To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling. Methods and Results Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown. Conclusion These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA. PMID:24416200

NOTCH3 variants in patients with subcortical vascular cognitive impairment: a comparison with typical CADASIL patients.

PubMed

Yoon, Cindy W; Kim, Young-Eun; Seo, Sang Won; Ki, Chang-Seok; Choi, Seong Hye; Kim, Jong-Won; Na, Duk L

2015-08-01

Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is thought to be a common form of hereditary subcortical vascular cognitive impairment (SVCI), there is little data on the frequency of NOTCH3 variants in SVCI patients. We prospectively screened for NOTCH3 variants in consecutive SVCI patients who underwent brain magnetic resonance imaging and amyloid positron emission tomography as well as sequence analysis for mutational hotspots in the NOTCH3 gene. Among 117 patients with SVCI, 16 patients had either known mutations or variants of unknown significance in the NOTCH3 gene. There were no differences in clinical and neuroimaging features between SVCI patients with and without NOTCH3 variants, only except for a higher number of deep microbleeds in SVCI patients with NOTCH3 variants. Our findings suggest that there is a phenotypic entity of NOTCH3 variant that is similar to that of sporadic SVCI but not of typical CADASIL. Notably, 2 SVCI patients with NOTCH3 mutations showed significant amyloid burden, which challenges the prevailing concept that CADASIL represents the genetic model of pure small vessel disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

PubMed

Church, Jarrod E; Trieu, Jennifer; Chee, Annabel; Naim, Timur; Gehrig, Stefan M; Lamon, Séverine; Angelini, Corrado; Russell, Aaron P; Lynch, Gordon S

2014-04-01

New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the frequency-force relationship in regenerating muscles of C57BL/10 and mdx mice after injury, indicating reduced force at each stimulation frequency, but enhanced the frequency-force relationship in muscles from dko mice. We conclude that while Notch inhibition produces slight functional defects in dystrophic muscle, Notch activation does not significantly improve muscle regeneration in murine models of muscular dystrophy. Furthermore, the inconsistent expression of Notch targets between murine models and DMD patients suggests caution when making interspecies comparisons.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuncharin, Yanin; Sangphech, Naunpun; Kueanjinda, Patipark

The Notch signaling pathway plays important roles in tumorigenesis in a context-dependent manner. In human cervical cancer, alterations in Notch signaling have been reported, and both tumor-suppressing and tumor-promoting roles of Notch signaling have been proposed; however, the precise molecular mechanisms governing these roles in cervical cancer remain controversial. MAML is a transcriptional co-activator originally identified by its role in Notch signaling. Recent evidence suggests that it also plays a role in other signaling pathways, such as the p53 and {beta}-catenin pathways. MAML is required for stable formation of Notch transcriptional complexes at the promoters of Notch target genes. Chromosomalmore » translocations affecting MAML have been shown to promote tumorigenesis. In this study, we used a truncated dominant-negative MAML1 (DN-MAML) to investigate the role of MAML in HPV-positive cervical cancer cell lines. Three human cervical cancer cell lines (HeLa, SiHa and CaSki) expressed all Notch receptors and the Notch target genes Hes1 and MAML1. Among these 3 cell lines, constitutive appearance of cleaved Notch1 was found only in CaSki cells, which suggests that Notch1 is constitutively activated in this cell line. Gamma secretase inhibitor (GSI) treatment, which suppresses Notch receptor activation, completely abrogated this form of Notch1 but had no effect on cell viability. Overexpression of DN-MAML by retroviral transduction in CaSki cells resulted in significant decreases in the mRNA levels of Hes1 and Notch1 but had no effects on the levels of MAML1, p53 or HPV E6/E7. DN-MAML expression induced increased viability of CaSki cells without any effect on cell cycle progression or cell proliferation. In addition, clonogenic assay experiments revealed that overexpression of DN-MAML resulted in increased colony formation compared to the overexpression of the control vector. When the status of the NF-{kappa}B pathway was investigated, CaSki cells overexpressing DN-MAML exhibited loss of phospho-I{kappa}B{alpha}, decreased total I{kappa}B{alpha} and nuclear localization of NF-{kappa}B p65, which suggests that the NF-{kappa}B pathway is hyperactivated. Furthermore, increased level of cleaved Notch1 was detected when DN-MAML was expressed. When DN-MAML-overexpressing cells were treated with GSI, significantly decreased cell viability was observed, indicating that inhibition of Notch signaling using GSI treatment and DN-MAML expression negatively affects cell viability. Taken together, targeting Notch signaling using DN-MAML and GSI treatment may present a novel method to control cell viability in cervical cancer cells.« less

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

NASA Astrophysics Data System (ADS)

Chan, Kwai S.

2015-12-01

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

C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence

PubMed Central

Singh, Komudi; Chao, Michael Y.; Somers, Gerard A.; Komatsu, Hidetoshi; Corkins, Mark E.; Larkins-Ford, Jonah; Tucey, Tim; Dionne, Heather M.; Walsh, Melissa B.; Beaumont, Emma K.; Hart, Douglas P.; Lockery, Shawn; Hart, Anne C.

2011-01-01

Summary Background The conserved DOS motif proteins OSM-7 and OSM-11 function as co-ligands with canonical DSL ligands to activate C. elegans Notch receptors during development. We report herein that Notch ligands, co-ligands and the receptors LIN-12 and GLP-1 regulate two C. elegans behaviors: chemosensory avoidance of octanol and quiescence during molting lethargus. Results C. elegans lacking osm-7 or osm-11 are defective in their response to octanol. We find that OSM-11 is secreted from hypodermal seam cells into the pseudocoelomic body cavity and acts non-cell autonomously as a diffusible factor. OSM-11 acts with the DSL ligand LAG-2 to activate LIN-12 and GLP-1 Notch receptors in the neurons of adult animals,- thereby regulating octanol avoidance response. In adult animals, over-expression of osm-11 and consequent Notch receptor activation induces anachronistic sleep-like quiescence. Perturbation of Notch signaling altered basal activity in adults as well as arousal thresholds and quiescence during molting lethargus. Genetic epistasis studies revealed that Notch signaling regulates quiescence via previously identified circuits and genetic pathways including the egl-4 cGMP-dependent kinase. Conclusions Our findings indicate that the conserved Notch pathway modulates behavior in adult C. elegans in response to environmental stress. Additionally, Notch signaling regulates sleep-like quiescence in C. elegans suggesting Notch may regulate sleep in other species. PMID:21549604

Endodermal Hedgehog signals modulate Notch pathway activity in the developing digestive tract mesenchyme

PubMed Central

Kim, Tae-Hee; Kim, Byeong-Moo; Mao, Junhao; Rowan, Sheldon; Shivdasani, Ramesh A.

2011-01-01

The digestive tract epithelium and its adjoining mesenchyme undergo coordinated patterning and growth during development. The signals they exchange in the process are not fully characterized but include ligands of the Hedgehog (Hh) family, which originate in the epithelium and are necessary for mesenchymal cells to expand in number and drive elongation of the developing gut tube. The Notch signaling pathway has known requirements in fetal and adult intestinal epithelial progenitors. We detected Notch pathway activity in the embryonic gut mesenchyme and used conditional knockout mice to study its function. Selective disruption of the Notch effector gene RBP-Jκ (Rbpj) in the mesenchyme caused progressive loss of subepithelial fibroblasts and abbreviated gut length, revealing an unexpected requirement in this compartment. Surprisingly, constitutive Notch activity also induced rapid mesenchymal cell loss and impaired organogenesis, probably resulting from increased cell death and suggesting the need for a delicate balance in Notch signaling. Because digestive tract anomalies in mouse embryos with excess Notch activity phenocopy the absence of Hh signaling, we postulated that endodermal Hh restrains mesenchymal Notch pathway activity. Indeed, Hh-deficient embryos showed Notch overactivity in their defective gut mesenchyme and exposure to recombinant sonic hedgehog could override Notch-induced death of cultured fetal gut mesenchymal cells. These results reveal unexpected interactions between prominent signals in gastrointestinal development and provide a coherent explanation for Hh requirements in mesenchymal cell survival and organ growth. PMID:21750033

Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells.

PubMed

Hubmann, Rainer; Hilgarth, Martin; Schnabl, Susanne; Ponath, Elena; Reiter, Marlies; Demirtas, Dita; Sieghart, Wolfgang; Valent, Peter; Zielinski, Christoph; Jäger, Ulrich; Shehata, Medhat

2013-03-01

Chronic lymphocytic leukaemia (CLL) cells express constitutively activated NOTCH2 in a protein kinase C (PKC)- dependent manner. The transcriptional activity of NOTCH2 correlates not only with the expression of its target gene FCER2 (CD23) but is also functionally linked with CLL cell viability. In the majority of CLL cases, DNA-bound NOTCH2 complexes are less sensitive to the γ-secretase inhibitor (GSI) DAPT. Therefore, we searched for compounds that interfere with NOTCH2 signalling at the transcription factor level. Using electrophoretic mobility shift assays (EMSA), we identified the Aspergillum-derived secondary metabolite gliotoxin as a potent NOTCH2 transactivation inhibitor. Gliotoxin completely blocked the formation of DNA-bound NOTCH2 complexes in CLL cells independent of their sensitivity to DAPT. The inhibition of NOTCH2 signalling by gliotoxin was associated with down regulation of CD23 (FCER) expression and induction of apoptosis. Short time exposure of CLL cells indicated that the early apoptotic effect of gliotoxin is independent of proteasome regulated nuclear factor κB activity, and is associated with up regulation of NOTCH3 and NR4A1 expression. Gliotoxin could overcome the supportive effect of primary bone marrow stromal cells in an ex vivo CLL microenvironment model. In conclusion, we identified gliotoxin as a potent NOTCH2 inhibitor with a promising therapeutic potential in CLL. © 2012 Blackwell Publishing Ltd.

γ-Secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer

PubMed Central

Mizugaki, H; Sakakibara-Konishi, J; Ikezawa, Y; Kikuchi, J; Kikuchi, E; Oizumi, S; Dang, T P; Nishimura, M

2012-01-01

Background: Notch receptor has an important role in both development and cancer. We previously reported that inhibition of the Notch3 by γ-secretase inhibitor (GSI) induces apoptosis and suppresses tumour proliferation in non-small-cell lung cancer. Although radiation is reported to induce Notch activation, little is known about the relationship between radiation and Notch pathway. Methods: We examined the effect of combining GSI and radiation at different dosing in three Notch expressing lung cancer cell lines. The cytotoxic effect of GSI and radiation was evaluated using MTT assay and clonogenic assay in vitro and xenograft models. Expressions of Notch pathway, mitogen-activated protein kinase (MAPK) pathway and Bcl-2 family proteins were investigated using western blot analysis. Results: We discovered that the antitumour effect of combining GSI and radiation was dependent on treatment schedule. γ-Secretase inhibitor administration after radiation had the greatest growth inhibition of lung cancer in vitro and in vivo. We showed that the combination induced apoptosis of lung cancer cell lines through the regulation of MAPK and Bcl-2 family proteins. Furthermore, activation of Notch after radiation was ameliorated by GSI administration, suggesting that treatment with GSI prevents Notch-induced radiation resistance. Conclusion: Notch has an important role in lung cancer. Treatment with GSI after radiation can significantly enhance radiation-mediated tumour cytotoxicity. PMID:22596234

Effects of geometric factors and shear band patterns on notch sensitivity in bulk metallic glasses

DOE PAGES

Li, Weidong; Bei, Hongbin; Gao, Yanfei

2016-09-21

Our recent experiments in notched bulk metallic glasses have found reduced, or insensitive, or improved strengths, while in many of these cases the ductile strain prior to final failure is enhanced. First, although the inverse notch effect is explained by a shift from shear localization to cavitation failure, it is suggested in this work that the synergistic effect between cohesive fracture at the notched area and shear bands emanating from the notch roots may extend the parametric space for the notch insensitive behavior. Second, the dependence of shear band patterns on notch geometric factors is determined by the Rudnicki-Rice theorymore » and the free-volume-based finite element simulations. Our results suggest conditions for shear band multiplication to take place and for the shear-localization-induced failure to be delayed.« less

Effects of geometric factors and shear band patterns on notch sensitivity in bulk metallic glasses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Weidong; Bei, Hongbin; Gao, Yanfei

Our recent experiments in notched bulk metallic glasses have found reduced, or insensitive, or improved strengths, while in many of these cases the ductile strain prior to final failure is enhanced. First, although the inverse notch effect is explained by a shift from shear localization to cavitation failure, it is suggested in this work that the synergistic effect between cohesive fracture at the notched area and shear bands emanating from the notch roots may extend the parametric space for the notch insensitive behavior. Second, the dependence of shear band patterns on notch geometric factors is determined by the Rudnicki-Rice theorymore » and the free-volume-based finite element simulations. Our results suggest conditions for shear band multiplication to take place and for the shear-localization-induced failure to be delayed.« less

Cartilage-specific RBPjκ-dependent and -independent Notch signals regulate cartilage and bone development

PubMed Central

Kohn, Anat; Dong, Yufeng; Mirando, Anthony J.; Jesse, Alana M.; Honjo, Tasuku; Zuscik, Michael J.; O’Keefe, Regis J.; Hilton, Matthew J.

2012-01-01

The Notch signaling pathway has emerged as an important regulator of endochondral bone formation. Although recent studies have examined the role of Notch in mesenchymal and chondro-osteo progenitor cell populations, there has yet to be a true examination of Notch signaling specifically within developing and committed chondrocytes, or a determination of whether cartilage and bone formation are regulated via RBPjκ-dependent or -independent Notch signaling mechanisms. To develop a complete understanding of Notch signaling during cartilage and bone development we generated and compared general Notch gain-of-function (Rosa-NICDf/+), RBPjκ-deficient (Rbpjκf/f), and RBPjκ-deficient Notch gain-of-function (Rosa-NICDf/+;Rbpjκf/f) conditional mutant mice, where activation or deletion of floxed alleles were specifically targeted to mesenchymal progenitors (Prx1Cre) or committed chondrocytes (inducible Col2CreERT2). These data demonstrate, for the first time, that Notch regulation of chondrocyte maturation is solely mediated via the RBPjκ-dependent pathway, and that the perichodrium or osteogenic lineage probably influences chondrocyte terminal maturation and turnover of the cartilage matrix. Our study further identifies the cartilage-specific RBPjκ-independent pathway as crucial for the proper regulation of chondrocyte proliferation, survival and columnar chondrocyte organization. Unexpectedly, the RBPjκ-independent Notch pathway was also identified as an important long-range cell non-autonomous regulator of perichondral bone formation and an important cartilage-derived signal required for coordinating chondrocyte and osteoblast differentiation during endochondral bone development. Finally, cartilage-specific RBPjκ-independent Notch signaling likely regulates Ihh responsiveness during cartilage and bone development. PMID:22354840

Cisplatin selects for stem-like cells in osteosarcoma by activating Notch signaling

PubMed Central

Yang, Jian; Gao, Tian; Simões, Bruno M.; Eyre, Rachel; Guo, Weichun; Clarke, Robert B.

2016-01-01

Notch signaling regulates normal stem cells and is also thought to regulate cancer stem cells (CSCs). Recent data indicate that Notch signaling plays a role in the development and progression of osteosarcoma, however the regulation of Notch in chemo-resistant stem-like cells has not yet been fully elucidated. In this study we generated cisplatin-resistant osteosarcoma cells by treating them with sub-lethal dose of cisplatin, sufficient to induce DNA damage responses. Cisplatin-resistant osteosarcoma cells exhibited lower proliferation, enhanced spheroid formation and more mesenchymal characteristics than cisplatin-sensitive cells, were enriched for Stro-1+/CD117+ cells and showed increased expression of stem cell-related genes. A similar effect was observed in vivo, and in addition in vivo tumorigenicity was enhanced during serial transplantation. Using several publicly available datasets, we identified that Notch expression was closely associated with osteosarcoma stem cells and chemotherapy resistance. We confirmed that cisplatin-induced enrichment of osteosarcoma stem cells was mediated through Notch signaling in vitro, and immunohistochemistry showed that cleaved Notch1 (NICD1) positive cells were significantly increased in a relapsed xenograft which had received cisplatin treatment. Furthermore, pretreatment with a γ-secretase inhibitor (GSI) to prevent Notch signalling inhibited cisplatin-enriched osteosarcoma stem cell activity in vitro, including Stro-1+/CD117+ double positive cells and spheroid formation capacity. The Notch inhibitor DAPT also prevented tumor recurrence in resistant xenograft tumors. Overall, our results show that cisplatin induces the enrichment of osteosarcoma stem-like cells through Notch signaling, and targeted inactivation of Notch may be useful for the elimination of CSCs and overcoming drug resistance. PMID:27102300

Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma.

PubMed

Mann, Christopher D; Bastianpillai, Christopher; Neal, Christopher P; Masood, Muhammad M; Jones, Donald J L; Teichert, Friederike; Singh, Rajinder; Karpova, Elena; Berry, David P; Manson, Margaret M

2012-01-01

In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

Multiple Notch signaling events control Drosophila CNS midline neurogenesis, gliogenesis and neuronal identity

PubMed Central

Wheeler, Scott R.; Stagg, Stephanie B.; Crews, Stephen T.

2009-01-01

The study of how transcriptional control and cell signaling influence neurons and glia to acquire their differentiated properties is fundamental to understanding CNS development and function. The Drosophila CNS midline cells are an excellent system for studying these issues because they consist of a small population of diverse cells with well-defined gene expression profiles. In this paper, the origins and differentiation of midline neurons and glia were analyzed. Midline precursor (MP) cells each divide once giving rise to two neurons; here, we use a combination of single-cell gene expression mapping and time-lapse imaging to identify individual MPs, their locations, movements and stereotyped patterns of division. The role of Notch signaling was investigated by analyzing 37 midline-expressed genes in Notch pathway mutant and misexpression embryos. Notch signaling had opposing functions: it inhibited neurogenesis in MP1,3,4 and promoted neurogenesis in MP5,6. Notch signaling also promoted midline glial and median neuroblast cell fate. This latter result suggests that the median neuroblast resembles brain neuroblasts that require Notch signaling, rather than nerve cord neuroblasts, the formation of which is inhibited by Notch signaling. Asymmetric MP daughter cell fates also depend on Notch signaling. One member of each pair of MP3–6 daughter cells was responsive to Notch signaling. By contrast, the other daughter cell asymmetrically acquired Numb, which inhibited Notch signaling, leading to a different fate choice. In summary, this paper describes the formation and division of MPs and multiple roles for Notch signaling in midline cell development, providing a foundation for comprehensive molecular analyses. PMID:18701546

Heat shock protein 70 (Hsp70) interacts with the Notch1 intracellular domain and contributes to the activity of Notch signaling in myelin-reactive CD4 T cells.

PubMed

Juryńczyk, Maciej; Lewkowicz, Przemysław; Domowicz, Małgorzata; Mycko, Marcin P; Selmaj, Krzysztof W

2015-10-15

Notch receptors (Notch1-4) are involved in the differentiation of CD4 T cells and the development of autoimmunity. Mechanisms regulating Notch signaling in CD4 T cells are not fully elucidated. In this study we investigated potential crosstalk between Notch pathway molecules and heat shock protein 70 (Hsp70), the major intracellular chaperone involved in the protein transport during immune responses and other stress conditions. Using Hsp70(-/-) mice we found that Hsp70 is critical for up-regulation of NICD1 and induction of Notch target genes in Jagged1- and Delta-like1-stimulated CD4 T cells. Co-immunoprecipitation analysis of wild-type CD4 T cells stimulated with either Jagged1 or Delta-like1 showed a direct interaction between NICD1 and Hsp70. Both molecules co-localized within the nucleus of CD4 T cells stimulated with Notch ligands. Molecular interaction and nuclear colocalization of NICD1 and Hsp70 were also detected in CD4 T cells reactive against myelin oligodendrocyte glycoprotein (MOG)35-55, which showed Hsp70-dependent up-regulation of both NICD1 and Notch target genes. In conclusion, we demonstrate for the first time that Hsp70 interacts with NICD1 and contributes to the activity of Notch signaling in CD4 T cells. Interaction between Hsp70 and NICD1 may represent a novel mechanism regulating Notch signaling in activated CD4 T cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC.

PubMed

Frank, Sander B; Berger, Penny L; Ljungman, Mats; Miranti, Cindy K

2017-06-01

Many pathways dysregulated in prostate cancer are also involved in epithelial differentiation. To better understand prostate tumor initiation, we sought to investigate specific genes and mechanisms required for normal basal to luminal cell differentiation. Utilizing human prostate basal epithelial cells and an in vitro differentiation model, we tested the hypothesis that regulation of NOTCH3 by the p38 MAPK family (hereafter p38-MAPK), via MYC, is required for luminal differentiation. Inhibition (SB202190 and BIRB796) or knockdown of p38α (also known as MAPK14) and/or p38δ (also known as MAPK13) prevented proper differentiation. Additionally, treatment with a γ-secretase inhibitor (RO4929097) or knockdown of NOTCH1 and/or NOTCH3 greatly impaired differentiation and caused luminal cell death. Constitutive p38-MAPK activation through MKK6(CA) increased NOTCH3 (but not NOTCH1) mRNA and protein levels, which was diminished upon MYC inhibition (10058-F4 and JQ1) or knockdown. Furthermore, we validated two NOTCH3 enhancer elements through a combination of enhancer (e)RNA detection (BruUV-seq) and luciferase reporter assays. Finally, we found that the NOTCH3 mRNA half-life increased during differentiation or upon acute p38-MAPK activation. These results reveal a new connection between p38-MAPK, MYC and NOTCH signaling, demonstrate two mechanisms of NOTCH3 regulation and provide evidence for NOTCH3 involvement in prostate luminal cell differentiation. © 2017. Published by The Company of Biologists Ltd.

Notch3 as a novel therapeutic target in metastatic medullary thyroid cancer.

PubMed

Lou, Irene; Odorico, Scott; Yu, Xiao-Min; Harrison, April; Jaskula-Sztul, Renata; Chen, Herbert

2018-01-01

Medullary thyroid cancer portends poor survival once liver metastasis occurs. We hypothesize that Notch3 overexpression in medullary thyroid cancer liver metastasis will decrease proliferation and growth of the tumor. TT cells were modified genetically to overexpress Notch3 in the presence of doxycycline, creating the TT-Notch3 cell line. Mice were injected intrasplenically with either TT-Notch3 or control vector TT-TRE cells. Each cell line had 3 treatment groups: control with 12 weeks of standard chow, early DOX with doxycycline chow at day 0 and for 70 days thereafter, and late DOX with doxycycline chow at 8 weeks. Each animal underwent micro-computed tomography to evaluate for tumor formation and tumor quantification was performed. Animals were killed at 12 weeks, and the harvested liver was stained with Ki-67, hematoxylin and eosin, and Notch3. Induction of Notch3 did not prevent formation of medullary thyroid cancer liver metastases as all mice in the early DOX group developed tumors. However, induction of Notch after medullary thyroid cancer liver tumor formation decreased tumor size, as seen on micro-computed tomography scans (late DOX group). This translated to a 37-fold decrease in tumor volume (P = .001). Notch3 overexpression also resulted in decreased Ki-67 index (P = .038). Moreover, Notch3 induction led to increased areas of neutrophil infiltration and necrosis on hematoxylin and eosin staining of the tumors CONCLUSION: Notch3 overexpression demonstrates an antiproliferative effect on established metastatic medullary thyroid cancer liver tumors and is a potential therapeutic target in treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Notch3 expression correlates with thyroid cancer differentiation, induces apoptosis, and predicts disease prognosis.

PubMed

Somnay, Yash R; Yu, Xiao-Min; Lloyd, Ricardo V; Leverson, Glen; Aburjania, Zviadi; Jang, Samuel; Jaskula-Sztul, Renata; Chen, Herbert

2017-03-01

Thyroid tumorigenesis is characterized by a progressive loss of differentiation exhibited by a range of disease variants. The Notch receptor family (1-4) regulates developmental progression in both normal and cancerous tissues. This study sought to characterize the third Notch isoform (Notch3) across the various differentiated states of thyroid cancer, and determine its clinical impact. Notch3 expression was analyzed in a tissue microarray of normal and pathologic thyroid biopsies from 155 patients. The functional role of Notch3 was then investigated by upregulating its expression in a follicular thyroid cancer (FTC) cell line. Notch3 expression regressed across decreasingly differentiated, increasingly malignant thyroid specimens, correlated with clinicopathological attributes reflecting poor prognosis, and independently predicted survival following univariate and multivariate analyses. Overexpression of the active Notch3 intracellular domain (NICD3) in a gain-of-function FTC line led to functional activation of centromere-binding protein 1, while increasing thyroid-specific gene transcription. NICD3 induction also reduced tumor burden in vivo and initiated the intrinsic apoptotic cascade, alongside suppressing cyclin and B-cell lymphoma 2 family expression. Loss of Notch3 expression may be fundamental to the process of dedifferentiation that accompanies thyroid oncogenesis. Conversely, activation of Notch3 in thyroid cancer exerts an antiproliferative effect and restores elements of a differentiated phenotype. These findings provide preclinical rationale for evaluating Notch3 as a disease prognosticator and therapeutic target in advanced thyroid cancer. Cancer 2017;123:769-82. © 2016 American Cancer Society. © 2016 American Cancer Society.

Notch sensitivity jeopardizes titanium locking plate fatigue strength.

PubMed

Tseng, Wo-Jan; Chao, Ching-Kong; Wang, Chun-Chin; Lin, Jinn

2016-12-01

Notch sensitivity may compromise titanium-alloy plate fatigue strength. However, no studies providing head-to-head comparisons of stainless-steel or titanium-alloy locking plates exist. Custom-designed identically structured locking plates were made from stainless steel (F138 and F1314) or titanium alloy. Three screw-hole designs were compared: threaded screw-holes with angle edges (type I); threaded screw-holes with chamfered edges (type II); and non-threaded screw-holes with chamfered edges (type III). The plates' bending stiffness, bending strength, and fatigue life, were investigated. The stress concentration at the screw threads was assessed using finite element analyses (FEA). The titanium plates had higher bending strength than the F1314 and F138 plates (2.95:1.56:1) in static loading tests. For all metals, the type-III plate fatigue life was highest, followed by type-II and type-I. The type-III titanium plates had longer fatigue lives than their F138 counterparts, but the type-I and type-II titanium plates had significantly shorter fatigue lives. All F1314 plate types had longer fatigue lives than the type-III titanium plates. The FEA showed minimal stress difference (0.4%) between types II and III, but the stress for types II and III was lower (11.9% and 12.4%) than that for type I. The screw threads did not cause stress concentration in the locking plates in FEA, but may have jeopardized the fatigue strength, especially in the notch-sensitive titanium plates. Improvement to the locking plate design is necessary. Copyright © 2016 Elsevier Ltd. All rights reserved.

Low-cycle fatigue testing methods

NASA Technical Reports Server (NTRS)

Lieurade, H. P.

1978-01-01

The good design of highly stressed mechanical components requires accurate knowledge of the service behavior of materials. The main methods for solving the problems of designers are: determination of the mechanical properties of the material after cyclic stabilization; plotting of resistance to plastic deformation curves; effect of temperature on the life on low cycle fatigue; and simulation of notched parts behavior.

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.

Influence of notch depth on tearing morphology and tearing energy in carbon-black-loaded SBR (styrene butadiene rubber)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldberg, A.; LeMay, J.D.; Sanchez, R.J.

Tearing energies (T) have been evaluated for carbon-black-reinforced SBR tested in uniaxial tension. The influence of notch depth on T and fracture morphology have also been determined. The influence of notch depth on the stress-strain behavior and on the failure stress and failure strain is also illustrated. The ratio of recovered-to-input energy as a function of both stress and strain was determined for notched and notch-free samples.

Martian Surface & Pathfinder Airbags

NASA Technical Reports Server (NTRS)

1997-01-01

This image of the Martian surface was taken in the afternoon of Mars Pathfinder's first day on Mars. Taken by the Imager for Mars Pathfinder (IMP camera), the image shows a diversity of rocks strewn in the foreground. A hill is visible in the distance (the notch within the hill is an image artifact). Airbags are seen at the lower right.

The IMP is a stereo imaging system with color capability provided by 24 selectable filters -- twelve filters per 'eye.' It stands 1.8 meters above the Martian surface, and has a resolution of two millimeters at a range of two meters.

Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The Imager for Mars Pathfinder (IMP) was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal Investigator.

Microelectromechanical accelerometer with resonance-cancelling control circuit including an idle state

DOEpatents

Chu, Dahlon D.; Thelen, Jr., Donald C.; Campbell, David V.

2001-01-01

A digital feedback control circuit is disclosed for use in an accelerometer (e.g. a microelectromechanical accelerometer). The digital feedback control circuit, which periodically re-centers a proof mass in response to a sensed acceleration, is based on a sigma-delta (.SIGMA..DELTA.) configuration that includes a notch filter (e.g. a digital switched-capacitor filter) for rejecting signals due to mechanical resonances of the proof mass and further includes a comparator (e.g. a three-level comparator). The comparator generates one of three possible feedback states, with two of the feedback states acting to re-center the proof mass when that is needed, and with a third feedback state being an "idle" state which does not act to move the proof mass when no re-centering is needed. Additionally, the digital feedback control system includes an auto-zero trim capability for calibration of the accelerometer for accurate sensing of acceleration. The digital feedback control circuit can be fabricated using complementary metal-oxide semiconductor (CMOS) technology, bi-CMOS technology or bipolar technology and used in single- and dual-proof-mass accelerometers.

FILTSoft: A computational tool for microstrip planar filter design

NASA Astrophysics Data System (ADS)

Elsayed, M. H.; Abidin, Z. Z.; Dahlan, S. H.; Cholan N., A.; Ngu, Xavier T. I.; Majid, H. A.

2017-09-01

Filters are key component of any communication system to control spectrum and suppress interferences. Designing a filter involves long process as well as good understanding of the basic hardware technology. Hence this paper introduces an automated design tool based on Matlab-GUI, called the FILTSoft (acronym for Filter Design Software) to ease the process. FILTSoft is a user friendly filter design tool to aid, guide and expedite calculations from lumped elements level to microstrip structure. Users just have to provide the required filter specifications as well as the material description. FILTSoft will calculate and display the lumped element details, the planar filter structure, and the expected filter's response. An example of a lowpass filter design was calculated using FILTSoft and the results were validated through prototype measurement for comparison purposes.

Notch3 is required for arterial identity and maturation of vascular smooth muscle cells

PubMed Central

Domenga, Valérie; Fardoux, Peggy; Lacombe, Pierre; Monet, Marie; Maciazek, Jacqueline; Krebs, Luke T.; Klonjkowski, Bernard; Berrou, Eliane; Mericskay, Matthias; Li, Zhen; Tournier-Lasserve, Elisabeth; Gridley, Thomas; Joutel, Anne

2004-01-01

Formation of a fully functional artery proceeds through a multistep process. Here we show that Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC). In adult Notch3–/– mice distal arteries exhibit structural defects and arterial myogenic responses are defective. The postnatal maturation stage of vSMC is deficient in Notch3–/– mice. We further show that Notch3 is required for arterial specification of vSMC but not of endothelial cells. Our data reveal Notch3 to be the first cell-autonomous regulator of arterial differentiation and maturation of vSMC. PMID:15545631

Parkin mediates neuroprotection through activation of Notch1 signaling.

PubMed

Yoon, Ji-Hye; Ann, Eun-Jung; Kim, Mi-Yeon; Ahn, Ji-Seon; Jo, Eun-Hye; Lee, Hye-Jin; Lee, Hye-Won; Lee, Young Chul; Kim, Jeong-Sun; Park, Hee-Sae

2017-02-04

Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Inactivation of Parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins and ensuing neurodegeneration. In this study, we show that Parkin positively regulates the Notch1 signaling pathway. Overexpression of Parkin stabilized Notch1-IC protein levels, whereas knockdown of Parkin decreased Notch1-IC protein stability. Notably, overexpression of Parkin disrupted oxidative stress-induced apoptosis in neuronal cells. However, knockdown of Notch1 inhibited Parkin-induced neuronal cell survival. Together, these results indicate that Parkin is a novel regulator of the Notch1 signaling pathway, which promotes neuronal cell survival.

Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions.

PubMed

Heitzler, P; Simpson, P

1993-03-01

In Drosophila each neural precursor is chosen from a group of cells through cell interactions mediated by Notch and Delta which may function as receptor and ligand (signal), respectively, in a lateral signalling pathway. The cells of a group are equipotential and express both Notch and Delta. Hyperactive mutant Notch molecules, (Abruptex), probably have an enhanced affinity for the ligand. When adjacent to wild-type cells, cells bearing the Abruptex proteins are unable to produce the signal. It is suggested that in addition to the binding of Notch molecules on one cell to the Delta molecules of opposing cells, the Notch and Delta proteins on the surface of the same cell may interact. Binding between a cell's own Notch and Delta molecules would alter the availability of these proteins to interact with their counterparts on adjacent cells.

Waveform frequency notching

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doerry, Armin W.; Andrews, John

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 ROMmore » 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.« less

Notch signaling genes

PubMed Central

Terragni, Jolyon; Zhang, Guoqiang; Sun, Zhiyi; Pradhan, Sriharsa; Song, Lingyun; Crawford, Gregory E; Lacey, Michelle; Ehrlich, Melanie

2014-01-01

Notch intercellular signaling is critical for diverse developmental pathways and for homeostasis in various types of stem cells and progenitor cells. Because Notch gene products need to be precisely regulated spatially and temporally, epigenetics is likely to help control expression of Notch signaling genes. Reduced representation bisulfite sequencing (RRBS) indicated significant hypomethylation in myoblasts, myotubes, and skeletal muscle vs. many nonmuscle samples at intragenic or intergenic regions of the following Notch receptor or ligand genes: NOTCH1, NOTCH2, JAG2, and DLL1. An enzymatic assay of sites in or near these genes revealed unusually high enrichment of 5-hydroxymethylcytosine (up to 81%) in skeletal muscle, heart, and cerebellum. Epigenetics studies and gene expression profiles suggest that hypomethylation and/or hydroxymethylation help control expression of these genes in heart, brain, myoblasts, myotubes, and within skeletal muscle myofibers. Such regulation could promote cell renewal, cell maintenance, homeostasis, and a poised state for repair of tissue damage. PMID:24670287