Progress Report on Alloy 617 Notched Specimen Testing

Energy Technology Data Exchange (ETDEWEB)

McMurtrey, Michael David [Idaho National Lab. (INL), Idaho Falls, ID (United States); Wright, Richard Neil [Idaho National Lab. (INL), Idaho Falls, ID (United States); Lillo, Thomas Martin [Idaho National Lab. (INL), Idaho Falls, ID (United States)

2016-08-01

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

Influence of Thread Root Radius on Maximum Local Stresses at Large Diameter Bolts under Axial Loading

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Cojocaru Vasile

2014-06-01

Full Text Available In the thread root area of the threaded bolts submitted to axial loading occur local stresses, higher that nominal stresses calculated for the bolts. These local stresses can generate failure and can reduce the fatigue life of the parts. The paper is focused on the study of the influence of the thread root radius on the maximum local stresses. A large diameter trapezoidal bolt was subjected to a static analysis (axial loading using finite element simulation.

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

Science.gov (United States)

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.

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

International Nuclear Information System (INIS)

Chan, Kwai S.

2015-01-01

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. (paper)

Effects of Notch Misalignment and Tip Radius on Displacement Field in V-Notch Rail Shear Test as Determined by Photogrammetry

Science.gov (United States)

Hill, Charles S.; Oliveras, Ovidio M.

2011-01-01

Evolution of the 3D strain field during ASTM-D-7078 v-notch rail shear tests on 8-ply quasi-isotropic carbon fiber/epoxy laminates was determined by optical photogrammetry using an ARAMIS system. Specimens having non-optimal geometry and minor discrepancies in dimensional tolerances were shown to display non-symmetry and/or stress concentration in the vicinity of the notch relative to a specimen meeting the requirements of the standard, but resulting shear strength and modulus values remained within acceptable bounds of standard deviation. Based on these results, and reported difficulty machining specimens to the required tolerances using available methods, it is suggested that a parametric study combining analytical methods and experiment may provide rationale to increase the tolerances on some specimen dimensions, reducing machining costs, increasing the proportion of acceptable results, and enabling a wider adoption of the test method.

Crack initiation life in notched Ti-6Al-4V titanium bars under uniaxial and multiaxial fatigue: synthesis based on the averaged strain energy density approach

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Giovanni Meneghetti

2017-07-01

Full Text Available The fatigue behaviour of circumferentially notched specimens made of titanium alloy, Ti-6Al-4V, has been analysed. To investigate the notch effect on the fatigue strength, pure bending, pure torsion and multiaxial bending-torsion fatigue tests have been carried out on specimens characterized by two different root radii, namely 0.1 and 4 mm. Crack nucleation and subsequent propagation have been accurately monitored by using the direct current potential drop (DCPD technique. Based on the results obtained from the potential drop technique, the crack initiation life has been defined in correspondence of a relative potential drop increase V/V0 equal to 1%, and it has been used as failure criterion. Doing so, the effect of extrinsic mechanisms operating during crack propagation phase, such as sliding contact, friction and meshing between fracture surfaces, is expected to be reduced. The experimental fatigue test results have been re-analysed by using the local strain energy density (SED averaged over a structural volume having radius R0 and surrounding the notch tip. Finally, the use of the local strain energy density parameter allowed us to properly correlate the crack initiation life of Ti-6Al-4V notched specimens, despite the different notch geometries and loading conditions involved in the tests

Fatigue crack growth from blunt notches

International Nuclear Information System (INIS)

Rhodes, D.

1982-01-01

A number of methods have been proposed, by which the formation and early growth of fatigue cracks at blunt notches may be predicted. In this report, four methods are compared - i.e. analysis of the crack tip plastic deformation, the cyclic contour integral, δJ, the strain in a critical volume of material, and the notch root plastic strain range. It is shown that these approaches have fundamental elements in common, and that all are compatable with linear elastic fracture mechanics. Early results from a continuing experimental programme are reported. (orig.) [de

Effect of Notches on Creep-Fatigue Behavior of a P/M Nickel-Based Superalloy

Science.gov (United States)

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.

Dwell Notch Low Cycle Fatigue Behavior of a Powder Metallurgy Nickel Disk Alloy

Science.gov (United States)

Telesman, J.; Gabb, T. P.; Yamada, Y.; Ghosn, L. J.; Jayaraman, N.

2012-01-01

A study was conducted to determine the processes which govern dwell notch low cycle fatigue (NLCF) behavior of a powder metallurgy (P/M) ME3 disk superalloy. The emphasis was placed on the environmentally driven mechanisms which may embrittle the highly stressed notch surface regions and reduce NLCF life. In conjunction with the environmentally driven notch surface degradation processes, the visco-plastic driven mechanisms which can significantly change the notch root stresses were also considered. Dwell notch low cycle fatigue testing was performed in air and vacuum on a ME3 P/M disk alloy specimens heat treated using either a fast or a slow cooling rate from the solutioning treatment. It was shown that dwells at the minimum stress typically produced a greater life debit than the dwells applied at the maximum stress, especially for the slow cooled heat treatment. Two different environmentally driven failure mechanisms were identified as the root cause of early crack initiation in the min dwell tests. Both of these failure mechanisms produced mostly a transgranular crack initiation failure mode and yet still resulted in low NLCF fatigue lives. The lack of stress relaxation during the min dwell tests produced higher notch root stresses which caused early crack initiation and premature failure when combined with the environmentally driven surface degradation mechanisms. The importance of environmental degradation mechanisms was further highlighted by vacuum dwell NLCF tests which resulted in considerably longer NLCF lives, especially for the min dwell tests.

Study on deformation behavior and life evaluation method for SUS304 notched plate under bending creep fatigue loading

International Nuclear Information System (INIS)

Fukuda, Yoshio; Satoh, Yoshimi; Nakamura, Kazuhiro; Takahashi, Yukio; Kuwabara, Kazuo.

1990-01-01

Creep-fatigue tests were carried out on notched plates under cyclic bending loads out of plane at 550degC, and the local strain at the notch-root and micro crack propagation behavior were measured. Then, inelastic analysis was performed for the experiment by using three kinds of constitutive models, such as kinematic hardening, ORNL and Ohno models. From the comparison of the experiment with the results of analysis, the following conclusions were obtained. (1) Creep strain caused at the notch-root during load holding was negligibly small compared with plastic strain, so that the neighborhood of the notch-root is subjected to constrained strain type damage. (2) The strain range at the notch-root can be calculated from the results of elastic-plastic analysis for monotonic loading independent of the constitutive models used, where the cyclic stress-strain relationship was used as the material monotonic deformation property. (3) The mean strain calculated was consistent with the experimental value in case of kinematic hardening or ORNL model, while not in case of Ohno model. (4) A method for predicting the crack initiation life of a notched plate has been proposed on the basis of micro-crack propagation behavior obtained by a fundamental creep-fatigue test. (author)

Thermally induced high frequency random amplitude fatigue damage at sharp notches

International Nuclear Information System (INIS)

Lewis, M.W.J.

1992-01-01

Experiments have been performed using the SUPERSOMITE facility to investigate the initiation and growth of fatigue cracks at the tips of sharp surface notches subjected to random thermally-induced stress. The experimental situation is complex involving plasticity, random amplitude loading and heat transfer medium/surface coupling. Crack initiation and growth prediction have been considered using the Creager and Neuber methods to compute the strain ranges in the vicinity of the notch root. Good agreement has been obtained between the experimental results and theoretical predictions. The paper reports the results of the analysis of the notch behavior

Notching of samples for fracture toughness' measurements via SEVNB Method of brittle ceramics

International Nuclear Information System (INIS)

Ribeiro, S.; Atilio, I.; Oliveira, M.R.; Garcia, G.C.R.; Rodrigues, J.A.

2012-01-01

The goal of this work is to present a notching machine to produce notches in ceramic bodies as well the choice and how to make the notches, using SiC produced by liquid phase sintering as experimental material. For the liquid sintering a mixture of Al 2 O 3 and Yb 2 O 3 as additive was applied. It was developed and built by an enterprise sited in Sao Carlos-SP an equipment, which permits to obtain polished notches in ceramic specimens to be fractured afterwards. That is to facilitate the measurement of K IC via the SEVNB method. Specimens of 10% of (Al 2 O 3 +Yb 2 O 3 ) containing SiC were sintered at 1950 deg C. Those specimens were machined and notched using razor blades and diamond pastes of 15, 9, 6, 3, 1 and 0.25 μm of particle size. The built machine to notch specimens is installed at DEMAR-EEL-USP, and it is said to be the first of that type in Brazil. The results showed that depending on the thickness of the razor blade and the size of the diamond particles, it can be curried out notches with distinct tip radius and notch depth values. (author)

Notch size effects on high cycle fatigue limit stress of Udimet 720

International Nuclear Information System (INIS)

Ren Weiju; Nicholas, Theodore

2003-01-01

Notch size effects on the high cycle fatigue (HCF) limit stress of Ni-base superalloy Udimet 720 were investigated on cylindrical specimens with three notch sizes of the same stress concentration factor K t =2.74. The HCF limit stress corresponding to a life of 10 6 cycles was experimentally determined at a stress ratio of 0.1 and a frequency of 25 Hz at room temperature. The stresses were calculated using finite element analysis (FEA) and the specimens analyzed using scanning electron microscopy (SEM). Test results show that at the same K t value, notch size can slightly affect the HCF limit stress of U720 when notch root plasticity occurs. FEA and SEM results reveal that the notch size effects are influenced by a complicated combination of the stress and plastic strain fields at the notch tip, the nominal stress, and the effects of prior plastic deformation on fatigue crack initiation

In-situ tensile testing of notched poly- and oligocrystalline 316L wires

Energy Technology Data Exchange (ETDEWEB)

Mitevski, Bojan [Materials Science and Engineering (ITM), Duisburg (Germany); Weiss, Sabine [Brandenburg Technical Univ., Cottbus-Senftenberg (Germany). Chair of Physical Metallurgy and Materials Science.; Fischer, Alfons [Duisburg-Essen Univ. (Germany). Materials Science and Engineering; Rush Univ. Medical Center, Chicago, IL (United States). Dept. of Orthopedics

2017-03-01

In-situ testing inside a scanning electron microscope is a helpful tool for detailed analyses of small sized specimens with respect to their mechanical properties and the correlated microstructural alterations. Thus, this test method is used to analyze the tensional properties of thin 316L (1.4441) wires used for microscale components, e.g., like coronary artery stents. Tensile tests were conducted on unnotched and circularly notched 316L wires (oe 0.95 mm) with a special focus on the number of grains within the cross section as well as the notch geometry. Four combinations of notch width (2 and 4 mm) and notch depth (diameter at notch root: 0.5 and 0.75 mm) were chosen. Notch depth and notch shape were adjusted by means of electrochemical polishing. Previous investigations showed, that oligocrystalline structures exhibit a different mechanical behavior compared to polycrystalline ones or single crystals. There are only a few data available on mechanical testing of oligocrystalline structures with respect to varying notch geometries. Depending on the notch geometry, grain size and, therefore, the number of grains within the notch cross section widely scattering yield- and tensile strength as well as failure elongation values were measured. However, the transition criterion between poly- and oligocrystalline behavior could be quantified to be 6 to 7 grains within the cross section.

Notching on cancer’s door: Notch signaling in brain tumors

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Marcin eTeodorczyk

2015-01-01

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

Self-collimation-based photonic crystal notch filters

International Nuclear Information System (INIS)

Lee, Sun-Goo; Kim, Seong-Han; Kee, Chul-Sik; Kim, Kap-Joong

2017-01-01

We introduce a design concept of an optical notch filter (NF) utilizing two perfectly reflecting mirrors and a beam splitter. Based on the new design concept, a photonic crystal (PC)-NF based on the self-collimation phenomenon in a two-dimensional PC is proposed and studied through finite-difference time-domain simulations and experimental measurements in a microwave region. The transmission properties of the self-collimation-based PC-NF were demonstrated to be controlled by adjusting the values of parameters such as the radius of rods in the line-defect beam splitter, distance between the two perfectly reflecting mirrors, and radius of rods on the outermost surface of the perfectly reflecting mirrors. Our results indicate that the proposed design concept could provide a new approach to manipulate light propagation, and the PC-NF could increase the applicability of the self-collimation phenomenon in a PC. (paper)

Crack initiation life analysis in notched pipe under cyclic bending loads

International Nuclear Information System (INIS)

Goak, S. R.; Kim, Y. J.; Lee, J. S.; Park, Y. W.

2000-01-01

In order to improve LBB(Leak-Before-Break) methodology, more precisely the crack growth evaluation, a benchmark problem was proposed by the CEA Saclay. The aim of this benchmark analysis was to evaluate the crack growth in a notched pipe under cyclic bending loads. The proposed benchmark analysis is composed of three main topic; fatigue crack initiation, crack propagation and crack penetration. This paper deals with the first topic, crack initiation in a notched pipe under four point bending. Both elastic-plastic finite element analysis and Neuber's rule were used to estimate the crack initiation life and the finite element models were verified by mesh-refinement, stress distribution and global deflection. In elastic-plastic finite element analysis, crack initiation life was determined by strain amplitude at the notch tip and strain-life curve of the material. In the analytical method, Neuber's rule with the consideration of load history and mean stress effect, was used for the life estimation. The effect of notch tip radius, strain range, cyclic hardening rule were examined in this study. When these results were compared with the experimental ones, the global deformation was a good agreement but the crack initiation cycle was higher than the experimental result

Stress Concentration Factor and Stress Intensity Factor with U-notch and Crack in the Beam

Energy Technology Data Exchange (ETDEWEB)

Seo, Bo Seong; Lee, Kwang Ho [Kyungpook National Univ., Daegu (Korea, Republic of)

2016-05-15

The stress concentration factors and stress intensity factors for a simple beam and a cantilever are analyzed by using finite element method and photoelasticity. Using the analyzed results, the estimated graphs on stress concentration factors and stress intensity factors are obtained. To analyze stress concentration factors of notch, the dimensionless notch length H(height of specimen)/h=1.1-2 and dimensionless gap space r(radius at the notch tip)/h=0.1~0.5 are used, where h=H-c and c is the notch length. As the notch gap length increases and the gap decreases, the stress concentration factors increase. Stress concentration factors of a simple beam are greater than those of a cantilever beam. However, actually, the maximum stress values under a load, a notch length and a gap occur more greatly in the cantilever beam than in the simple beam. To analyze stress intensity factors, the normalized crack length α(crack length)/H=0.2~0.5 is used. As the length of the crack increases, the normalized stress intensity factors increase. The stress intensity factors under a constant load and a crack length occur more greatly in the cantilever beam than in the simple beam.

Experimental determination of the micro-scale strength and stress-strain relation of an epoxy resin

DEFF Research Database (Denmark)

Zike, Sanita; Sørensen, Bent F.; Mikkelsen, Lars Pilgaard

2016-01-01

An approach is developed for determining the stress-strain law and a failure stress appropriate for micro-mechanical models of polymer materials. Double cantilever beam test specimens, made of an epoxy polymer with notches having finite root radius, were subjected to pure bending moments in an en......An approach is developed for determining the stress-strain law and a failure stress appropriate for micro-mechanical models of polymer materials. Double cantilever beam test specimens, made of an epoxy polymer with notches having finite root radius, were subjected to pure bending moments......-scale (5–6%). The hardening exponent of a power law hardening material was obtained by the use of the J-integral, estimating the strain energy density around the notch. The hardening exponent was found to be within the range of 5–6 and the corresponding micro-scale failure stress was in the range of 220...

[APPLICATION OF BUTTERFLY SHAPED LOCKING COMPRESSION PLATE IN COMPLEX DISTAL RADIUS FRACTURES].

Science.gov (United States)

Jiang, Zongyuan; Ma, Tao; Xia, Jiang; Hu, Caizhi; Xu, Lei

2014-06-01

To investigate the effectiveness of butterfly shaped locking compression plate for the treatment of complex distal radius fractures. Between June 2011 and January 2013, 20 cases of complex distal radius fractures were treated with butterfly shaped locking compression plate fixation. There were 11 males and 9 females with an average age of 54 years (range, 25-75 years). Injury was caused by falling in 10 cases, by traffic accident in 7 cases, and by falling from height in 3 cases. All of fractures were closed. According to AO classification system, there were 8 cases of type C1, 8 cases of type C2, and 4 cases of type C3. Of them, 9 cases had radial styloid process fracture, 4 cases had sigmoid notch fracture, and 7 cases had both radial styloid process fracture and sigmoid notch fracture. The mean interval between injury and operation was 5.2 days (range, 3-15 days). All incisions healed by first intention; no complications of infection and necrosis occurred. All cases were followed up 14 months on average (range, 10-22 months). All factures healed after 9.3 weeks on average (range, 6-11 weeks). No complications such as displacement of fracture, joint surface subsidence, shortening of the radius, and carpal tunnel syndrome were found during follow-up. At last follow-up, the mean palmar tilt angle was 10.2° (range, 7-15°), and the mean ulnar deviation angle was 21.8° (range, 17-24°). The mean range of motion of the wrist was 45.3° (range, 35-68°) in dorsal extension, 53.5° (range, 40-78°) in palmar flexion, 19.8° (range, 12-27°) in radial inclination, 26.6° (range, 18-31°) in ulnar inclination, 70.2° (range, 45-90°) in pronation, and 68.4° (range, 25-88°) in supination. According to the Dienst scoring system, the results were excellent in 8 cases, good in 10 cases, and fair in 2 cases, and the excellent and good rate was 90%. Treatment of complex distal radius fractures with butterfly shaped locking compression plate can reconstruct normal anatomic

Plastic deformation and failure mechanisms in nano-scale notched metallic glass specimens under tensile loading

Science.gov (United States)

Dutta, Tanmay; Chauniyal, Ashish; Singh, I.; Narasimhan, R.; Thamburaja, P.; Ramamurty, U.

2018-02-01

In this work, numerical simulations using molecular dynamics and non-local plasticity based finite element analysis are carried out on tensile loading of nano-scale double edge notched metallic glass specimens. The effect of acuteness of notches as well as the metallic glass chemical composition or internal material length scale on the plastic deformation response of the specimens are studied. Both MD and FE simulations, in spite of the fundamental differences in their nature, indicate near-identical deformation features. Results show two distinct transitions in the notch tip deformation behavior as the acuity is increased, first from single shear band dominant plastic flow localization to ligament necking, and then to double shear banding in notches that are very sharp. Specimens with moderately blunt notches and composition showing wider shear bands or higher material length scale characterizing the interaction stress associated with flow defects display profuse plastic deformation and failure by ligament necking. These results are rationalized from the role of the interaction stress and development of the notch root plastic zones.

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

Science.gov (United States)

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.

Effect of notch dimension on the fatigue life of V-notched structure

International Nuclear Information System (INIS)

Cheng Changzheng; Naman, Recho; Niu Zhongrong; Zhou Huanlin

2011-01-01

Highlights: → A novel method is proposed to calculate the SIFs of crack at notch tip. → Effect of notch opening angle on the crack extension and propagation is studied. → Influence of notch depth on the crack extension and propagation is analyzed. → The fatigue life of a welded joint is analyzed by the present method. - Abstract: The stress singularity degree associated to a V-notch has a great influence on the fatigue life of V-notched structure. The growth rate of the crack initiated at the tip of a V-notch depends on the stress singularity of the V-notch. The fatigue life accompanying with this small crack will represent a large amount of the total fatigue life. In this work, boundary element method (BEM) is used to study the propagation of the crack emanating from a V-notch tip under fatigue loading. A comparison of the fatigue life between the crack initiated from V-notch tip and a lateral crack is done by a crack propagation law until these two cracks have the same stress intensity factors (SIFs). The effect of initial crack length, notch opening angle and notch depth on the crack extension and propagation is analyzed. As an example of engineering application, the fatigue life of a welded joint is investigated by the present method. The influence of weld toe angle and initial crack length on the fatigue life of the welded structure is studied. Some suggestions are given as an attempt to improve the fatigue life of welded structures at the end.

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

Directory of Open Access Journals (Sweden)

Sung Hee Choi

Full Text Available 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.

Crack initiation life analysis in notched pipe under cyclic bending loads

International Nuclear Information System (INIS)

Lee, Joon Seong; Kwak, Sang Log; Kim, Young Jin; Park, Youn Won

2001-01-01

In order to improve leak-before-break methodology, more precisely the crack growth evaluation, a round robin analysis was proposed by the CEA Saclay. The aim of this analysis was to evaluate the crack initiation life, penetration life and shape of through wall crack under cyclic bending loads. The proposed round robin analysis is composed of three main topic; fatigue crack initiation, crack propagation and crack penetration. This paper deals with the first topic, crack initiation in a notched pipe under four point bending. Both elastic-plastic finite element analysis and Neuber's rule were used to estimate the crack initiation life and the finite element models were verified by mesh-refinement, stress distribution and global deflection. In elastic-plastic finite element analysis, crack initiation life was determined by strain amplitude at the notch tip and strain-life curve of the material. In the analytical method, Neuber's rule with the consideration of load history and mean stress effect, was used for the life estimation. The effect of notch tip radius, strain range, cyclic hardening rule were examined in this study. When these results were compared with the experimental ones, the global deformation was a good agreement but crack initiation cycle was higher than the experimental result

Fatigue assessment of laserbeam welded PM steel components by the notch stress approach

Energy Technology Data Exchange (ETDEWEB)

Waterkotte, R. [Schaeffler Technologies GmbH and Co. KG, Herzogenaurach (Germany); Sonsino, C.M. [Fraunhofer Institute for Structural Durability and System Reliability LBF, Darmstadt (Germany); Baumgartner, J.

2011-10-15

The local fatigue strength of a laserbeam weld of a complex engine component, which joins a PM with a formed sheet component, was assessed by the notch stress concept with the fictitious reference radius of r{sub ref}= 0.05 mm. First, simplified specimens, following the main geometric dimensions of the parts, were manufactured. On these specimens the fatigue strength was identified by tests and the notch stresses calculated by finite element analysis. Based on these results a design SN-curve was derived to assess the fatigue strength of the engine component. The numerical assessment of the welded joint was verified by proof tests with the component. The assessment could be improved by considering statistical and stress gradient dependent size effects according to the concept of the highly stressed volume. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

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

NARCIS (Netherlands)

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

2015-01-01

Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the

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

OpenAIRE

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

2004-01-01

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 ...

Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors.

Directory of Open Access Journals (Sweden)

Miguel Aste-Amézaga

2010-02-01

Full Text Available Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target.Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD, and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR. The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50 values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL. In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell

Fatigue-creep life prediction for a notched specimen of 2[1]/[4]Cr-1Mo steel at 600 C

International Nuclear Information System (INIS)

Inoue, Tatsuo; Sakane, Masao; Fukuda, Yoshio; Igari, Toshihide; Miyahara, Mitsuo; Okazaki, Masakazu

1994-01-01

This paper presents the life prediction of 2[1]/[4]Cr-1Mo notched specimens subjected to fast-fast, slow-slow and hold-time loadings at 600 C. The crack initiation lives of notched specimens were estimated based on the local stress-strain calculated by inelastic finite element analyses. For the life prediction, combinations of seven different constitutive models and five fatigue-creep damage laws were used. The applicability of the constitutive model and damage law is discussed. The constitutive models predict similar stress-strain relations at the notch root, leading to similar predicted lives. The damage model, however, has a much larger influence on the life prediction. ((orig.))

Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling.

Science.gov (United States)

Altmann, Christine; Vasic, Verica; Hardt, Stefanie; Heidler, Juliana; Häussler, Annett; Wittig, Ilka; Schmidt, Mirko H H; Tegeder, Irmgard

2016-10-22

Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues. Using newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve. Oppositely, progranulin deficient mice have long-lasting deficits in motor function tests after nerve injury due to enhanced losses of motor neurons and stronger microglia activation in the ventral horn of the spinal cord. Deep proteome and gene ontology (GO) enrichment analysis revealed that the proteins upregulated in progranulin overexpressing mice were involved in 'regulation of transcription' and 'response to insulin' (GO terms). Transcription factor prediction pointed to activation of Notch signaling and indeed, co-immunoprecipitation studies revealed that progranulin bound to the extracellular domain of Notch receptors, and this was functionally associated with higher expression of Notch target genes in the dorsal root ganglia of transgenic mice with neuronal progranulin overexpression. Functionally, these transgenic mice recovered normal gait and running, which was not achieved by controls and was stronger impaired in progranulin deficient mice. We infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery.

Assessment of correlation between knee notch width index and the three-dimensional notch volume

NARCIS (Netherlands)

van Eck, C.F.; Martins, C.A.Q.; Lorenz, S.G.F.; Fu, F.H.; Smolinski, P.

2010-01-01

This study was done to determine whether there is a correlation between the notch volume and the notch width index (NWI) as measured on the three most frequently used radiographic views: the Holmblad 45A degrees, Holmblad 70A degrees, and Rosenberg view. The notch volume of 20 cadaveric knees was

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

Science.gov (United States)

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.

Band-notched spiral antenna

Science.gov (United States)

Jeon, Jae; Chang, John

2018-03-13

A band-notched spiral antenna having one or more spiral arms extending from a radially inner end to a radially outer end for transmitting or receiving electromagnetic radiation over a frequency range, and one or more resonance structures positioned adjacent one or more segments of the spiral arm associated with a notch frequency band or bands of the frequency range so as to resonate and suppress the transmission or reception of electromagnetic radiation over said notch frequency band or bands.

Elasto-plastic stress/strain at notches, comparison of test and approximative computations

International Nuclear Information System (INIS)

Beste, A.; Seeger, T.

1979-01-01

The lifetime of cyclically loaded components is decisively determined by the value of the local load in the notch root. The determination of the elasto-plastic notch-stress and-strain is therefore an important element of recent methods of lifetime determination. These local loads are normally calculated with the help of approximation formulas. Yet there are no details about their accuracy. The basic construction of the approximation formulas is presented, along with some particulars. The use of approximations within the fully plastic range and for material laws which show a non-linear stress-strain (sigma-epsilon-)-behaviour from the beginning is explained. The use of approximation for cyclic loads is particularly discussed. Finally, the approximations are evaluated in terms of their exactness. The test results are compared with the results of the approximation calculations. (orig.) 891 RW/orig. 892 RKD [de

Notch Inhibits Osteoblast Differentiation and Causes Osteopenia

Science.gov (United States)

Zanotti, Stefano; Smerdel-Ramoya, Anna; Stadmeyer, Lisa; Durant, Deena; Radtke, Freddy; Canalis, Ernesto

2008-01-01

Notch receptors are determinants of cell fate decisions. To define the role of Notch in the adult skeleton, we created transgenic mice overexpressing the Notch intracellular domain (NICD) under the control of the type I collagen promoter. First-generation transgenics were small and osteopenic. Bone histomorphometry revealed that NICD caused a decrease in bone volume, secondary to a reduction in trabecular number; osteoblast and osteoclast number were decreased. Low fertility of founder mice and lethality of young pups did not allow the complete establishment of transgenic lines. To characterize the effect of Notch overexpression in vitro, NICD was induced in osteoblasts and stromal cells from Rosanotch mice, in which a STOP cassette flanked by loxP sites is upstream of NICD, by transduction with an adenoviral vector expressing Cre recombinase (Cre) under the control of the cytomegalovirus (CMV) promoter (Ad-CMV-Cre). NICD impaired osteoblastogenesis and inhibited Wnt/β-catenin signaling. To determine the effects of notch1 deletion in vivo, mice in which notch1 was flanked by loxP sequences (notch1loxP/loxP) were mated with mice expressing Cre recombinase under the control of the osteocalcin promoter. Conditional null notch1 mice had no obvious skeletal phenotype, possibly because of rescue by notch2; however, 1-month-old females exhibited a modest increase in osteoclast surface and eroded surface. Osteoblasts from notch1loxP/loxP mice, transduced with Ad-CMV-Cre and transfected with Notch2 small interfering RNA, displayed increased alkaline phosphatase activity. In conclusion, Notch signaling in osteoblasts causes osteopenia and impairs osteo-blastogenesis by inhibiting the Wnt/β-catenin pathway. PMID:18420737

Notch-strengthening in two-dimensional foams

NARCIS (Netherlands)

Onck, P.R.

Metallic foams show notch-strengthening behavior when analyzing double-edge notched specimen in compression and tension. A discrete microstructural model has been used to simulate the effect of notch depth and specimen size on the net-section-strength. The non-uniform deformation behavior is

Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy.

Science.gov (United States)

Chen, Tianhua; Li, Hao; Yin, Yiting; Zhang, Yuanpin; Liu, Zhen; Liu, Huaxiang

2017-11-02

Understanding the interactions between Notch1 and toll-like receptor 4 (TLR4) signaling pathways in the development of diabetic peripheral neuropathy may lead to interpretation of the mechanisms and novel approaches for preventing diabetic neuropathic pain. In the present study, the interactions between Notch1 and TLR4 signaling pathways were investigated by using dorsal root ganglion (DRG) from diabetic neuropathic pain rats and cultured DRG neurons under high glucose challenge. The results showed that high glucose induced not only Notch1 mRNA, HES1 mRNA, and TLR4 mRNA expression, but also Notch1 intracellular domain (NICD1) and TLR4 protein expression in DRG neurons. The proportion of NICD1-immunoreactive (IR) and TLR4-IR neurons in DRG cultures was also increased after high glucose challenge. The above alterations could be partially reversed by inhibition of either Notch1 or TLR4 signaling pathway. Inhibition of either Notch1 or TLR4 signaling pathway could improve mechanical allodynia and thermal hyperalgesia thresholds. Inhibition of Notch1 or TLR4 signaling also decreased tumor necrosis factor-α (TNF-α) levels in DRG from diabetic neuropathic rats. These data imply that the interaction between Notch1 and TLR4 signaling pathways is one of the important mechanisms in the development or progression of diabetic neuropathy.

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

NARCIS (Netherlands)

Sjöqvist, M.; Antfolk, D.; Ferraris, S.; Rraklli, V.; Haga, C.; Antila, C.; Mutvei, A.; Imanishi, S.Y.; Holmberg, J.; Jin, S.; Eriksson, J.E.; Lendahl, U.; Sahlgren, C.M.

Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick

Notch filters for port-Hamiltonian systems

NARCIS (Netherlands)

Dirksz, D.A.; Scherpen, J.M.A.; van der Schaft, A.J.; Steinbuch, M.

2012-01-01

In this paper a standard notch filter is modeled in the port-Hamiltonian framework. By having such a port-Hamiltonian description it is proven that the notch filter is a passive system. The notch filter can then be interconnected with another (nonlinear) port-Hamiltonian system, while preserving the

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

International Nuclear Information System (INIS)

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

2012-01-01

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

Eddy current standards - Cracks versus notches

Science.gov (United States)

Hagemaier, D. J.; Collingwood, M. R.; Nguyen, K. H.

1992-10-01

Eddy current tests aimed at evaluating cracks and electron-discharge machined (EDM) notches in 7075-T6 aluminum specimens are described. A comparison of the shape and amplitude of recordings made from both transverse and longitudinal scans of small EDM notches and fatigue cracks showd almost identical results. The signal amplitude and phase angle increased with an increase of EDM notch and crak size. It is concluded that equivalent eddy current results obtained from similar-size surface cracks and notches in aluminum can be used to establish a desired sensitivity level for inspection.

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

Science.gov (United States)

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.

Effects of Range of Stress and of Special Notches on Fatigue Properties of Aluminum Alloys Suitable for Airplane Propellers

Science.gov (United States)

Dolan, Thomas J

1942-01-01

Laboratory tests were made to obtain information on the load-resisting properties of X76S-T aluminum alloy when subjected to static, impact, and repeated loads. Results are presented from static-load test of unnotched specimens in tension and in torsion and of notched specimens in tension. Charpy impact values obtained from bend tests on notched specimens and tension impact values for both notched and unnotched specimens tested at several different temperatures are included. The endurance limits obtained from repeated bending fatigue tests made on three different types of testing machine are given for unnotched polished specimens, and the endurance limits of notched specimens subjected to six different ranges of bending stress are also reported. The results indicated that: (a) polished rectangular specimens had an endurance limit about 30 percent less than that obtained for round specimens; (b) a comparison of endurance limits obtained from tests on three different types of machine indicated that there was no apparent effect of speed of testing on the endurance limit for the range of speeds used (1,750 to 13,000 rpm). (c) the fatigue strength (endurance limit) of the X76S-T alloy was greatly decreased by the presence of a notch in the specimens; (d) no complete fractures of the entire specimens occurred in notched fatigue specimens when subjected to stress cycles for which the mean stress at the notch during the cycle was a compressive stress; for this test condition a microscopic cracking occurred near the root of the notch and was used as a criterion of failure of the specimen. (e) as the mean stress at the notch was decreased from a tensile (+) stress to a compressive (-) stress, it was found that the alternating stress that could be superimposed on the mean stress in the cycle without causing failure of the specimens was increased.

Effect of vibration loading on the fatigue life of part-through notched pipe

International Nuclear Information System (INIS)

Mittal, Rahul; Singh, P.K.; Pukazhendi, D.M.; Bhasin, V.; Vaze, K.K.; Ghosh, A.K.

2011-01-01

A systematic experimental and analytical study has been carried out to investigate the effect of vibration loading on the fatigue life of the piping components. Three Point bend (TPB) specimens machined from the actual pipe have been used for the evaluation of Paris constants by carrying out the experiments under vibration + cyclic and cyclic loading as per the ASTM Standard E647. These constants have been used for the prediction of the fatigue life of the pipe having part-through notch of a/t = 0.25 and aspect ratio (2c/a) of 10. Predicted results have shown the reduction in fatigue life of the notched pipe subjected to vibration + cyclic loading by 50% compared to that of cyclic loading. Predicted results have been validated by carrying out the full-scale pipe (with part-through notch) tests. Notched pipes were subjected to loading conditions such that the initial stress-intensity factor remains same as that of TPB specimen. Experimental results of the full-scale pipe tests under vibration + cyclic loading has shown the reduction in fatigue life by 70% compared to that of cyclic loading. Fractographic examination of the fracture surface of the tested specimens subjected to vibration + cyclic loading have shown higher presence of brittle phases such as martensite (in the form of isolated planar facets) and secondary micro cracks. This could be the reason for the reduction of fatigue life in pipe subjected to vibration + cyclic loading. - Highlights: → Vibration loading affects fatigue crack growth rate. → Crack initiation life depends on crack tip radius. → Crack initiation life depends on the characteristic distance. → Characteristic distance depends on the loading conditions. → Vibration + cyclic load gives lower fatigue life.

DOL behaviour of end-notched beams

DEFF Research Database (Denmark)

Gustafsson, P.J.; Hoffmeyer, Preben; Valentin, G.

1998-01-01

The long-term loading strength of end-notched beams made of glulam and LVL was tested. The beams were of various sizes, with and without a moisture sealing at the notch. Tests were conducted in open shelter climates, and at constant and cyclic relative humidity. The short-term strength was tested...... beams with a moisture sealing at the notch...

Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3.

Directory of Open Access Journals (Sweden)

He Meng

Full Text Available 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.

Analysis list: NOTCH1 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available NOTCH1 Blood + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/NOTCH1.1....tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/NOTCH1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/NOTC...H1.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/NOTCH1.Blood.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/Blood.gml ...

Loss of PTB or negative regulation of Notch mRNA reveals distinct zones of Notch and actin protein accumulation in Drosophila embryo.

Directory of Open Access Journals (Sweden)

Cedric S Wesley

Full Text Available 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.

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

Science.gov (United States)

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

Notch Signaling: Piercing a Harness of Simplicity

NARCIS (Netherlands)

Helbig, Christina; Amsen, Derk

2015-01-01

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

Notch3 signalling promotes tumour growth in colorectal cancer.

Science.gov (United States)

Serafin, Valentina; Persano, Luca; Moserle, Lidia; Esposito, Giovanni; Ghisi, Margherita; Curtarello, Matteo; Bonanno, Laura; Masiero, Massimo; Ribatti, Domenico; Stürzl, Michael; Naschberger, Elisabeth; Croner, Roland S; Jubb, Adrian M; Harris, Adrian L; Koeppen, Hartmut; Amadori, Alberto; Indraccolo, Stefano

2011-08-01

Increased Notch1 activity has been observed in intestinal tumours, partially accomplished by β-catenin-mediated up-regulation of the Notch ligand Jagged-1. Whether further mechanisms of Notch activation exist and other Notch receptors might be involved is unclear. Microarray data indicated that Notch3 transcript levels are significantly up-regulated in primary and metastatic CRC samples compared to normal mucosa. Moreover, Notch3 protein was expressed at strong/moderate levels by 19.7% of 158 CRC samples analysed, and at weak levels by 51.2% of the samples. Intrigued by these findings, we sought to investigate whether Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumourigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including Notch3, Delta-like 4 (DLL4), and Jagged-1 ligands. Stimulation with immobilized recombinant DLL4 or transduction with DLL4-expressing vectors dramatically increased Notch3 expression in CRC cells, associated with accelerated tumour growth. Forced expression of an active form of Notch3 mirrored the effects of DLL4 stimulation and increased tumour formation. Conversely, attenuation of Notch3 levels by shRNA resulted in perturbation of the cell cycle followed by reduction in cell proliferation, clonogenic capacity, and inhibition of tumour growth. Altogether, these findings indicate that Notch3 can modulate the tumourigenic properties of CRC cells and contributes to sustained Notch activity in DLL4-expressing tumours. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Notch signaling and progenitor/ductular reaction in steatohepatitis.

Directory of Open Access Journals (Sweden)

Carola M Morell

Full Text Available Persistent hepatic progenitor cells (HPC activation resulting in ductular reaction (DR is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis.Steatohepatitis was generated using methionine-choline deficient (MCD diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre.MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-β1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-β1 treatment in primary hepatic stellate cells (HSC induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-β1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression.Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.

Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders.

Science.gov (United States)

Chiang, Mark Y; Radojcic, Vedran; Maillard, Ivan

2016-07-01

This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses the therapeutic potential of Notch inhibition. NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B-cell malignancies truncate the C-terminal proline (P), glutamic acid (E), serine (S), threonine (T)-rich (PEST) domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent superenhancers that underlie oncogenic Notch functions. Notch signaling is a recurrent oncogenic pathway in multiple T- and B-cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.

Influence of side-groove root radius on the ductile fracture toughness of miniature C(T) specimens

Energy Technology Data Exchange (ETDEWEB)

Lucon, E.; Scibetta, M.

2009-05-15

The use of miniature C(T) specimens, MC(T), for fracture toughness measurements in the upper shelf regime has been investigated at SCK-CEN since 2004, in the framework of the Electrabel/Tractebel SCK-CEN Convention (now General Framework Agreement SUEZ-SCK-CEN). This geometry has been used and validated on both unirradiated (2004-05) and irradiated (2006) materials, mainly reactor pressure vessel (RPV) steels. While side-grooved MC(T) specimens have shown in all conditions a systematically lower tearing resistance and ductile crack initiation toughness as compared to standard-size 1TC(T) samples, the only plain-sided MC(T) specimen tested in 2005 exhibited very high ductile fracture toughness, thus pointing at a strong influence of side-grooving on the upper shelf properties of MC(T) specimens. This study investigates the influence of side-grooving on the initiation toughness and tearing resistance of MC(T) specimens, as a function of the root radius of the side-groove (ranging from 0.1 to 1 mm) and in comparison with plain-sided MC(T) and reference 1TC(T) samples. The material used is the well characterized DIN 22NiMoCr37 RPV steel, which had been used in the European project which generated the famous EURO fracture toughness data set.

Role of Notch signaling in the mammalian heart

Energy Technology Data Exchange (ETDEWEB)

Zhou, X.L.; Liu, J.C. [Department of Cardiac Surgery, The First Affiliated Hospital, Nanchang University, Donghu District, Nanchang, Jiangxi (China)

2013-12-12

Notch signaling is an evolutionarily ancient, highly conserved pathway important for deciding cell fate, cellular development, differentiation, proliferation, apoptosis, adhesion, and epithelial-to-mesenchymal transition. Notch signaling is also critical in mammalian cardiogenesis, as mutations in this signaling pathway are linked to human congenital heart disease. Furthermore, Notch signaling can repair myocardial injury by promoting myocardial regeneration, protecting ischemic myocardium, inducing angiogenesis, and negatively regulating cardiac fibroblast-myofibroblast transformation. This review provides an update on the known roles of Notch signaling in the mammalian heart. The goal is to assist in developing strategies to influence Notch signaling and optimize myocardial injury repair.

The effect of notches and pits on corrosion fatigue strength

Science.gov (United States)

Tatner, Ian

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.

Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia.

Science.gov (United States)

Fabbri, Giulia; Holmes, Antony B; Viganotti, Mara; Scuoppo, Claudio; Belver, Laura; Herranz, Daniel; Yan, Xiao-Jie; Kieso, Yasmine; Rossi, Davide; Gaidano, Gianluca; Chiorazzi, Nicholas; Ferrando, Adolfo A; Dalla-Favera, Riccardo

2017-04-04

Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4-13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a "NOTCH1 gene-expression signature" in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell-specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting.

Essential Role of Endothelial Notch1 in Angiogenesis

Science.gov (United States)

Limbourg, Florian P.; Takeshita, Kyosuke; Radtke, Freddy; Bronson, Roderick T.; Chin, Michael T.; Liao, James K.

2009-01-01

Background Notch signaling influences binary cell fate decisions in a variety of tissues. The Notch1 receptor is widely expressed during embryogenesis and is essential for embryonic development. Loss of global Notch1 function results in early embryonic lethality, but the cell type responsible for this defect is not known. Here, we identify the endothelium as the primary target tissue affected by Notch1 signaling. Methods and Results We generated an endothelium-specific deletion of Notch1 using Tie2Cre and conditional Notch1flox/flox mice. Mutant embryos lacking endothelial Notch1 died at approximately embryonic day 10.5 with profound vascular defects in placenta, yolk sac, and embryo proper, whereas heterozygous deletion had no effect. In yolk sacs of mutant embryos, endothelial cells formed a primary vascular plexus indicative of intact vasculogenesis but failed to induce the secondary vascular remodeling required to form a mature network of well-organized large and small blood vessels, which demonstrates a defect in angiogenesis. These vascular defects were also evident in the placenta, where blood vessels failed to invade the placental labyrinth, and in the embryo proper, where defective blood vessel maturation led to pericardial and intersomitic hemorrhage. Enhanced activation of caspase-3 was detected in endothelial and neural cells of mutant mice, which resulted in enhanced apoptotic degeneration of somites and the neural tube. Conclusions These findings recapitulate the vascular phenotype of global Notch1-/- mutants and indicate an essential cell-autonomous role of Notch1 signaling in the endothelium during vascular development. These results may have important clinical implications with regard to Notch1 signaling in adult angiogenesis. PMID:15809373

Void coalescence and fracture behavior of notched and un-notched tensile tested specimens in fine grain dual phase steel

Energy Technology Data Exchange (ETDEWEB)

Saeidi, N., E-mail: navidsae@gmail.com [Department of Materials Engineering, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Ashrafizadeh, F.; Niroumand, B. [Department of Materials Engineering, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Forouzan, M.R.; Mohseni mofidi, S. [Department of Mechanical Engineering, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Barlat, F. [Materials Mechanics Laboratory (MML), Graduate Institute of Ferrous Technology (GIFT), Pohang University of Science and Technology POSTECH, San 31 Hyoja-dong, Nam-gu, Pohang, Gyeongbuk 790-784 (Korea, Republic of)

2015-09-17

Due to growing global concern about the environmental issues, steel developers have been forced by automobile makers to produce more efficient steel grades with high strength to weight ratios along with high crashworthiness performance. In order to find deficiencies of the existing steels and develop superior steel products, detailed understanding of deformation and damage behavior in the existing steels is needed. In the present research, deformation and damage evolution during room temperature uniaxial tensile test of a modern high strength Dual Phase Steel, i.e. DP780, were studied. Detailed scanning electron microscopy (SEM) examination of the microstructures of notched and un-notched tensile fractured specimens revealed that in notched specimen, plastic deformation was concentrated more within the notched region. Therefore, much higher reduction in thickness with a high reduction gradient occurred in this region, In the un-notched specimen, however, plastic deformation was more uniformly distributed in larger parts of the gauge length, and therefore, thickness reduction happened with a lower gradient. Although geometric notch on the specimen did not change the void nucleation and growth mechanisms, the kinetics of these phenomena was influenced. On the other hand, voids linkage mechanism tended to change from void coalescence in the un-notched specimen to void sheeting in the notched specimen. Moreover, three different models developed by Brown & Embury (BM), Thomason and Pardoen were employed to predict the final fracture strain. It was revealed that, BM model showed much more accurate predictions for the studied DP steel in comparison with those of Thomason and Pardoens’ models.

Void coalescence and fracture behavior of notched and un-notched tensile tested specimens in fine grain dual phase steel

International Nuclear Information System (INIS)

Saeidi, N.; Ashrafizadeh, F.; Niroumand, B.; Forouzan, M.R.; Mohseni mofidi, S.; Barlat, F.

2015-01-01

Due to growing global concern about the environmental issues, steel developers have been forced by automobile makers to produce more efficient steel grades with high strength to weight ratios along with high crashworthiness performance. In order to find deficiencies of the existing steels and develop superior steel products, detailed understanding of deformation and damage behavior in the existing steels is needed. In the present research, deformation and damage evolution during room temperature uniaxial tensile test of a modern high strength Dual Phase Steel, i.e. DP780, were studied. Detailed scanning electron microscopy (SEM) examination of the microstructures of notched and un-notched tensile fractured specimens revealed that in notched specimen, plastic deformation was concentrated more within the notched region. Therefore, much higher reduction in thickness with a high reduction gradient occurred in this region, In the un-notched specimen, however, plastic deformation was more uniformly distributed in larger parts of the gauge length, and therefore, thickness reduction happened with a lower gradient. Although geometric notch on the specimen did not change the void nucleation and growth mechanisms, the kinetics of these phenomena was influenced. On the other hand, voids linkage mechanism tended to change from void coalescence in the un-notched specimen to void sheeting in the notched specimen. Moreover, three different models developed by Brown & Embury (BM), Thomason and Pardoen were employed to predict the final fracture strain. It was revealed that, BM model showed much more accurate predictions for the studied DP steel in comparison with those of Thomason and Pardoens’ models

Notch effects in uniaxial tension specimens

International Nuclear Information System (INIS)

Delph, T.J.

1979-03-01

Results of a literature survey on the effect of notches on the time-dependent failure of uniaxial tension specimens at elevated temperatures are presented. Particular attention is paid to the failure of notched specimens containing weldments

Stress concentration at notches

CERN Document Server

Savruk, Mykhaylo P

2017-01-01

This book compiles solutions of linear theory of elasticity problems for isotropic and anisotropic bodies with sharp and rounded notches. It contains an overview of established and recent achievements, and presents the authors’ original solutions in the field considered with extensive discussion. The volume demonstrates through numerous, useful examples the effectiveness of singular integral equations for obtaining exact solutions of boundary problems of the theory of elasticity for bodies with cracks and notches. Incorporating analytical and numerical solutions of the problems of stress concentrations in solid bodies with crack-like defects, this volume is ideal for scientists and PhD students dealing with the problems of theory of elasticity and fracture mechanics. Stands as a modern and extensive compendium of solutions to the problems of linear theory of elasticity of isotropic and anisotropic bodies with sharp and rounded notches; Adopts a highly reader-friendly layout of tables, charts, approximation ...

Deep lateral notch sign and double notch sign in complete tears of the anterior cruciate ligament: MR imaging evaluation

Energy Technology Data Exchange (ETDEWEB)

Grimberg, Alexandre [University of California, San Diego School of Medicine, Division of Musculoskeletal Radiology, Department of Radiology, San Diego, CA (United States); Universidade Federal de Sao Paulo, Department of Diagnostic Imaging, Sao Paulo, SP (Brazil); Shirazian, Hoda; Torshizy, Hamid; Smitaman, Edward; Resnick, Donald L. [University of California, San Diego School of Medicine, Division of Musculoskeletal Radiology, Department of Radiology, San Diego, CA (United States); Chang, Eric Y. [Veterans Administrations San Diego Healthcare Systems, Osteoradiology Section, Department of Radiology, San Diego, CA (United States); University of California, San Diego School of Medicine, Division of Musculoskeletal Radiology, Department of Radiology, San Diego, CA (United States)

2014-11-20

To systematically compare the notches of the lateral femoral condyle (LFC) in patients with and without complete tears of the anterior cruciate ligament (ACL) in MR studies by (1) evaluating the dimensions of the lateral condylopatellar sulcus; (2) evaluating the presence and appearance of an extra or a double notch and its association with such tears. This retrospective study was approved by our institutional review board, and informed written patient consent was waived. In 58 cases of complete ACL tears and 37 control cases with intact ACL, the number of notches on the LFC was determined, and the depth and anteroposterior (AP) length of each notch were measured in each third of the LFC. The chi-square test, t-test, and logistic regression model were used to analyze demographic data and image findings, as appropriate. Presence of more than one notch demonstrated a sensitivity of 17.2 %, specificity of 100 %, positive predictive value of 100 %, and negative predictive value of 43.5 % for detecting a complete ACL tear. Lateral third depth measurement (p = 0.028) was a significant associated finding with a complete ACL tear. A deep notch in the lateral third of the LFC is a significant associated finding with a complete ACL tear when compared with an ACL-intact control group, and the presence of more than one notch is a specific but insensitive sign of such a tear. (orig.)

Magnetoresistance effect in permalloy nanowires with various types of notches

Science.gov (United States)

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.

Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry.

Directory of Open Access Journals (Sweden)

Michael J Kluk

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

Simplified elastoplastic methods of analysing fatigue in notches

International Nuclear Information System (INIS)

Autrusson, B.

1993-01-01

The aim of this study is to show the state of the art concerning methods of mechanical analysis available in the literature for evaluating notch root elastoplastic strain. The components of fast breeder reactors are subjected to numerous thermal transients, which can cause fatigue failure. To prevent this from happening, it is necessary to know the local strain range and to use it to estimate the number of cycles to crack initiation. Practical methods have been developed for the calculation of the local strain range, and have led to the drafting of design rules. Direct methods of determining the local strain range of the 'inelastic analysis' type have also been described. In conclusion a series of recommendations is made on the applicability and the conservatism of these methods

Fatigue limit prediction of ferritic-pearlitic ductile cast iron considering stress ratio and notch size

Science.gov (United States)

Deguchi, T.; Kim, H. J.; Ikeda, T.

2017-05-01

The mechanical behavior of ductile cast iron is governed by graphite particles and casting defects in the microstructures, which can significantly decrease the fatigue strength. In our previous study, the fatigue limit of ferritic-pearlitic ductile cast iron specimens with small defects ((\\sqrt{{area}}=80˜ 1500{{μ }}{{m}})) could successfully be predicted based on the \\sqrt{{area}} parameter model by using \\sqrt{{area}} as a geometrical parameter of defect as well as the tensile strength as a material parameter. In addition, the fatigue limit for larger defects could be predicted based on the conventional fracture mechanics approach. In this study, rotating bending and tension-compression fatigue tests with ferritic-pearlitic ductile cast iron containing circumferential sharp notches as well as smooth specimens were performed to investigate quantitatively the effects of defect. The notch depths ranged 10 ˜ 2500 μm and the notch root radii were 5 and 50 μm. The stress ratios were R = -1 and 0.1. The microscopic observation of crack propagation near fatigue limit revealed that the fatigue limit was determined by the threshold condition for propagation of a small crack emanating from graphite particles. The fatigue limit could be successfully predicted as a function of R using a method proposed in this study.

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

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Vanessa de Oliveira-Carlos

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

Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in murine Kras(G12D-induced skin carcinogenesis in vivo.

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Pawel K Mazur

Full Text Available BACKGROUND: The Ras and Notch signaling pathways are frequently activated during development to control many diverse cellular processes and are often dysregulated during tumorigenesis. To study the role of Notch and oncogenic Kras signaling in a progenitor cell population, Pdx1-Cre mice were utilized to generate conditional oncogenic Kras(G12D mice with ablation of Notch1 and/or Notch2. METHODOLOGY/PRINCIPAL FINDINGS: Surprisingly, mice with activated Kras(G12D and Notch1 but not Notch2 ablation developed skin papillomas progressing to squamous cell carcinoma providing evidence for Pdx1 expression in the skin. Immunostaining and lineage tracing experiments indicate that PDX1 is present predominantly in the suprabasal layers of the epidermis and rarely in the basal layer. Further analysis of keratinocytes in vitro revealed differentiation-dependent expression of PDX1 in terminally differentiated keratinocytes. PDX1 expression was also increased during wound healing. Further analysis revealed that loss of Notch1 but not Notch2 is critical for skin tumor development. Reasons for this include distinct Notch expression with Notch1 in all layers and Notch2 in the suprabasal layer as well as distinctive p21 and β-catenin signaling inhibition capabilities. CONCLUSIONS/SIGNIFICANCE: Our results provide strong evidence for epidermal expression of Pdx1 as of yet not identified function. In addition, this finding may be relevant for research using Pdx1-Cre transgenic strains. Additionally, our study confirms distinctive expression and functions of Notch1 and Notch2 in the skin supporting the importance of careful dissection of the contribution of individual Notch receptors.

High levels of Notch signaling down-regulate Numb and Numblike

NARCIS (Netherlands)

Chapman, G.; Liu, L.; Sahlgren, C.; Dahlqvist, C.; Lendahl, U.

2006-01-01

Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch,

Magnetoresistance effect in permalloy nanowires with various types of notches

Directory of Open Access Journals (Sweden)

Y. Gao

2018-05-01

Full Text Available 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.

Inhibitory role of Notch1 in calcific aortic valve disease.

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Asha Acharya

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

The pathological significance of Notch1 in oral squamous cell carcinoma.

Science.gov (United States)

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.

The influence of finite Larmor radius effects on the radial interchange motions of plasma filaments

DEFF Research Database (Denmark)

Madsen, Jens; Garcia, Odd E.; Larsen, Jeppe Stærk

2011-01-01

The influence of finite Larmor radius (FLR) effects on the perpendicular convection of isolated particle density filaments driven by interchange motions in magnetized plasmas is investigated using a two-moment gyrofluid model. By means of numerical simulations on a two-dimensional, bi-periodic do......The influence of finite Larmor radius (FLR) effects on the perpendicular convection of isolated particle density filaments driven by interchange motions in magnetized plasmas is investigated using a two-moment gyrofluid model. By means of numerical simulations on a two-dimensional, bi......-periodic domain perpendicular to the magnetic field, it is demonstrated that the radial velocities of the blob-like filaments are roughly described by the inertial scaling, which prescribes a velocity proportional to the square root of the summed electron and ion pressures times the square root of the blob width...

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

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Galina Dvoriantchikova

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

Stress analysis and optimization of Nd:YAG pulsed laser processing of notches for fracture splitting of a C70S6 connecting rod

International Nuclear Information System (INIS)

Kou, Shuqing; Gao, Yan; Zhao, Yong; Lin, Baojun

2017-01-01

The pulsed laser pre-processing of a notch as the fracture initiation source for the splitting process is the key mechanism of an advanced fracture splitting technology for C70S6 connecting rods. This study investigated the stress field of Nd:YAG pulsed laser grooving, which affects the rapid fracture initiation at the notch root and the controlled crack extension in the critical fracture splitting quality, to improve manufacturing quality. Thermal elastic-plastic incremental theory was applied to build the finite element analysis model of the stress field of pulsed laser grooving for fracture splitting based on the Rotary-Gauss body heat source. The corresponding numerical simulation of the stress field was conducted. The changes and distributions of the stress during pulsed laser grooving were examined, the influence rule of the primary technological parameters on the residual stress was analyzed, and the analysis results were validated by the corresponding cutting experiment. Results showed that the residual stress distribution was concentrated in the Heat-affected zone (HAZ) near the fracture splitting notch, which would cause micro-cracks in the HAZ. The stress state of the notch root in the fracture initiation direction was tensile stress, which was beneficial to the fracture initiation and the crack rapid extension in the subsequent fracture splitting process. However, the uneven distribution of the stress could lead to fracture splitting defects, and thus the residual stress should be lowered to a reasonable range. Decreasing the laser pulse power, increasing the processing speed, and lowering the pulse width can lower the residual stress. Along with the actual production, the reasonable main technological parameters were obtained.

Stress analysis and optimization of Nd:YAG pulsed laser processing of notches for fracture splitting of a C70S6 connecting rod

Energy Technology Data Exchange (ETDEWEB)

Kou, Shuqing; Gao, Yan; Zhao, Yong; Lin, Baojun [Jilin University, Changchun (China)

2017-05-15

The pulsed laser pre-processing of a notch as the fracture initiation source for the splitting process is the key mechanism of an advanced fracture splitting technology for C70S6 connecting rods. This study investigated the stress field of Nd:YAG pulsed laser grooving, which affects the rapid fracture initiation at the notch root and the controlled crack extension in the critical fracture splitting quality, to improve manufacturing quality. Thermal elastic-plastic incremental theory was applied to build the finite element analysis model of the stress field of pulsed laser grooving for fracture splitting based on the Rotary-Gauss body heat source. The corresponding numerical simulation of the stress field was conducted. The changes and distributions of the stress during pulsed laser grooving were examined, the influence rule of the primary technological parameters on the residual stress was analyzed, and the analysis results were validated by the corresponding cutting experiment. Results showed that the residual stress distribution was concentrated in the Heat-affected zone (HAZ) near the fracture splitting notch, which would cause micro-cracks in the HAZ. The stress state of the notch root in the fracture initiation direction was tensile stress, which was beneficial to the fracture initiation and the crack rapid extension in the subsequent fracture splitting process. However, the uneven distribution of the stress could lead to fracture splitting defects, and thus the residual stress should be lowered to a reasonable range. Decreasing the laser pulse power, increasing the processing speed, and lowering the pulse width can lower the residual stress. Along with the actual production, the reasonable main technological parameters were obtained.

Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis.

Science.gov (United States)

Gao, Wei; Sweeney, Catherine; Connolly, Mary; Kennedy, Aisling; Ng, Chin Teck; McCormick, Jennifer; Veale, Douglas J; Fearon, Ursula

2012-07-01

To examine the effect of hypoxia on Notch-1 signaling pathway components and angiogenesis in inflammatory arthritis. The expression and regulation of Notch-1, its ligand delta-like protein 4 (DLL-4) and downstream signaling components (hairy-related transcription factor 1 [HRT-1], HRT-2), and hypoxia-inducible factor 1α (HIF-1α) under normoxic and hypoxic conditions (1-3%) were assessed in synovial tissue specimens from patients with inflammatory arthritis and controls and in human dermal microvascular endothelial cells (HDMECs) by immunohistology, dual immunofluorescence staining (Notch-1/factor VIII), Western blotting, and real-time polymerase chain reaction. In vivo synovial tissue oxygen levels (tissue PO2) were measured under direct visualization at arthroscopy. HDMEC activation under hypoxic conditions in the presence of Notch-1 small interfering RNA (siRNA), the γ-secretase inhibitor DAPT, or dimethyloxalylglycine (DMOG) was assessed by Matrigel tube formation assay, migration assay, invasion assay, and matrix metalloproteinase 2 (MMP-2)/MMP-9 zymography. Expression of Notch-1, its ligand DLL-4, and HRT-1 was demonstrated in synovial tissue, with the strongest expression localized to perivascular/vascular regions. Localization of Notch-1 to synovial endothelium was confirmed by dual immunofluorescence staining. Notch-1 intracellular domain (NICD) expression was significantly higher in synovial tissue from patients with tissue PO2 of PO2 of >20 mm Hg (>3% O2). Exposure of HDMECs to 3% hypoxia induced HIF-1α and NICD protein expression and DLL-4, HRT-1, and HRT-2 messenger RNA expression. DMOG directly induced NICD expression, while Notch-1 siRNA inhibited hypoxia-induced HIF-1α expression, suggesting that Notch-1/HIF-1α signaling is bidirectional. Finally, 3% hypoxia-induced angiogenesis, endothelial cell migration, endothelial cell invasion, and proMMP-2 and proMMP-9 activities were inhibited by Notch-1 siRNA and/or the γ-secretase inhibitor DAPT. Our

Evidence of non-canonical NOTCH signaling

DEFF Research Database (Denmark)

Traustadóttir, Gunnhildur Ásta; Jensen, Charlotte H; Thomassen, Mads

2016-01-01

Dlk1(+/+) and Dlk1(-/-) mouse tissues at E16.5, we demonstrated that several NOTCH signaling pathways indeed are affected by DLK1 during tissue development, and this was supported by a lower activation of NOTCH1 protein in Dlk1(+/+) embryos. Likewise, but using a distinct Dlk1-manipulated (si...

Notch and the awesome power of genetics.

Science.gov (United States)

Greenwald, Iva

2012-07-01

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

Plane-stress fields for sharp notches in pressure-sensitive materials

International Nuclear Information System (INIS)

Al-Abduljabbar, Abdulhamid

2003-01-01

The effect of pressure sensitive yield on materials toughness can be determined by investigating stress fields around cracks and notches. In this work, fully-developed plastic stress fields around sharp wedge-shaped notches of perfectly-plastic pressure-sensitive materials are investigated for plane-stress case and Mode 1 loading condition. The pressure-sensitive yielding behavior is represented using the Drucker-Prager criterion. Using equilibrium equations, boundary conditions, and the yield criterion, closed-form expressions for stress fields are derived. The analysis covers the gradual change in the notch angle and compares it with the limiting case of a pure horizontal crack. Effects of notch geometry and pressure sensitivity on stress fields are examined by considering different specimen geometries, as well as different levels of pressure sensitivity. Results indicate that while the stress values directly ahead of the notch-tip are not affected, the extent of stress sector at notch front is reduced, thereby causing increase in the radial stress value around the notch. As the pressure sensitivity increases the reduction of the stress sector directly ahead of the notch tip is more evident. Also, for high pressure sensitivity values, introduction of the notch angle reduces the variation of the stress levels. Results are useful for design of structural components. (author)

Modifiers of notch transcriptional activity identified by genome-wide RNAi

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Firnhaber Christopher B

2010-10-01

Full Text Available Abstract Background The Notch signaling pathway regulates a diverse array of developmental processes, and aberrant Notch signaling can lead to diseases, including cancer. To obtain a more comprehensive understanding of the genetic network that integrates into Notch signaling, we performed a genome-wide RNAi screen in Drosophila cell culture to identify genes that modify Notch-dependent transcription. Results Employing complementary data analyses, we found 399 putative modifiers: 189 promoting and 210 antagonizing Notch activated transcription. These modifiers included several known Notch interactors, validating the robustness of the assay. Many novel modifiers were also identified, covering a range of cellular localizations from the extracellular matrix to the nucleus, as well as a large number of proteins with unknown function. Chromatin-modifying proteins represent a major class of genes identified, including histone deacetylase and demethylase complex components and other chromatin modifying, remodeling and replacement factors. A protein-protein interaction map of the Notch-dependent transcription modifiers revealed that a large number of the identified proteins interact physically with these core chromatin components. Conclusions The genome-wide RNAi screen identified many genes that can modulate Notch transcriptional output. A protein interaction map of the identified genes highlighted a network of chromatin-modifying enzymes and remodelers that regulate Notch transcription. Our results open new avenues to explore the mechanisms of Notch signal regulation and the integration of this pathway into diverse cellular processes.

On short cracks that depart from elastoplastic notch tips

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Verônica Miquelin Machado

2017-07-01

Full Text Available The behavior of short cracks that depart from elastoplastic notch tips is modeled to estimate the stresses required to initiate and to propagate cracks in notched structural components, and to evaluate the size of tolerable crack-like defects under general loading conditions. This analysis can model both fatigue and environmentally assisted cracking problems; can evaluate notch sensitivity in both cases; and can as well be used to establish design or acceptance criteria for tolerable non-propagating crack-like defects in such cases. The growth of short cracks is assumed driven by the applied stresses and by the stress gradient ahead the notch tip, and supported by the material resistances to crack initiation and to long crack propagation by fatigue or EAC. In the elastoplastic case, the stress gradient ahead of the notch tip is quantified by a J-field to consider the short crack behavior. The tolerable short crack predictions made by this model are evaluated by suitable fatigue and EAC tests of notched specimens specially designed to start nonpropagating cracks from the notch tips, both under elastic and elastoplastic conditions.

Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease.

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Idowu, Jessica; Home, Trisha; Patel, Nisha; Magenheimer, Brenda; Tran, Pamela V; Maser, Robin L; Ward, Christopher J; Calvet, James P; Wallace, Darren P; Sharma, Madhulika

2018-02-20

Polycystic kidney disease (PKD) is a genetic disorder characterized by fluid-filled cysts in the kidney and liver that ultimately leads to end-stage renal disease. Currently there is no globally approved therapy for PKD. The Notch signaling pathway regulates cellular processes such as proliferation and de-differentiation, which are cellular hallmarks of PKD. Thus we hypothesized that the Notch pathway plays a critical role in PKD. Evaluation of protein expression of Notch signaling components in kidneys of Autosomal Recessive PKD (ARPKD) and Autosomal Dominant PKD (ADPKD) mouse models and of ADPKD patients revealed that Notch pathway members, particularly Notch3, were consistently upregulated or activated in cyst-lining epithelial cells. Notch3 expression correlated with rapidly growing cysts and co-localized with the proliferation marker, PCNA. Importantly, Notch inhibition significantly decreased forskolin-induced Notch3 activation and proliferation of primary human ADPKD cells, and significantly reduced cyst formation and growth of human ADPKD cells cultured in collagen gels. Thus our data indicate that Notch3 is aberrantly activated and facilitates epithelial cell proliferation in PKD, and that inhibition of Notch signaling may prevent cyst formation and growth.

Proteolytic regulation of Notch1 receptor activity in cancer

NARCIS (Netherlands)

van Tetering, Geert

2011-01-01

The Notch receptor is part of a highly conserved signaling pathway essential in development and disease in embryos and adults. Notch proteins coordinate cell-cell communication through receptor-ligand interactions between adjacent cells. First Notch is cleaved in the Golgi by furin at Site-1 (S1)

Significance of a notch in the otoacoustic emission stimulus spectrum.

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Grenner, J

2012-09-01

To explain a clinical observation: a notch in the stimulus spectrum during transient evoked otoacoustic emission measurement in ears with secretory otitis media. The effects of tympanic under-pressure were investigated using a pressure chamber. A model of the ear canal was also studied. Tympanic membrane reflectance increased as a consequence of increased stiffness, causing a notch in the stimulus spectrum. In an adult, the notch could be clearly distinguished at an under-pressure of approximately -185 daPa. The sound frequency of the notch corresponded to a wavelength four times the ear canal length. The ear canal of infants was too short to cause a notch within the displayed frequency range. The notch was demonstrated using both Otodynamics and Madsen equipment. A notch in the otoacoustic emission stimulus spectrum can be caused by increased stiffness of the tympanic membrane, raising suspicion of low middle-ear pressure or secretory otitis media. This finding is not applicable to infants.

Notch3 marks clonogenic mammary luminal progenitor cells in vivo.

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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.

Frequency and distribution of Notch mutations in tumor cell lines

International Nuclear Information System (INIS)

Mutvei, Anders Peter; Fredlund, Erik; Lendahl, Urban

2015-01-01

Deregulated Notch signaling is linked to a variety of tumors and it is therefore important to learn more about the frequency and distribution of Notch mutations in a tumor context. In this report, we use data from the recently developed Cancer Cell Line Encyclopedia to assess the frequency and distribution of Notch mutations in a large panel of cancer cell lines in silico. Our results show that the mutation frequency of Notch receptor and ligand genes is at par with that for established oncogenes and higher than for a set of house-keeping genes. Mutations were found across all four Notch receptor genes, but with notable differences between protein domains, mutations were for example more prevalent in the regions encoding the LNR and PEST domains in the Notch intracellular domain. Furthermore, an in silico estimation of functional impact showed that deleterious mutations cluster to the ligand-binding and the intracellular domains of NOTCH1. For most cell line groups, the mutation frequency of Notch genes is higher than in associated primary tumors. Our results shed new light on the spectrum of Notch mutations after in vitro culturing of tumor cells. The higher mutation frequency in tumor cell lines indicates that Notch mutations are associated with a growth advantage in vitro, and thus may be considered to be driver mutations in a tumor cell line context. The online version of this article (doi:10.1186/s12885-015-1278-x) contains supplementary material, which is available to authorized users

The importance of Notch signaling in peripheral T-cell lymphomas

DEFF Research Database (Denmark)

Kamstrup, Maria Rørbæk; Biskup, Edyta; Gjerdrum, Lise Mette Rahbek

2014-01-01

Peripheral T-cell lymphomas (PTLs) represent an area of high medical need. Previously, we demonstrated high expression of Notch, a known oncogene, in primary cutaneous anaplastic large cell lymphoma (ALCL). In this study, we performed immunohistochemical staining for Notch1 in lymph nodes from PTL...... cases) (p > 0.05). In the ALK+ ALCL cell line, Karpas-299, pharmacological inhibition of Notch with γ-secretase inhibitor (GSI) I was far more potent than with GSI IX, XX and XXI with regard to cell viability and apoptosis. In conclusion, PTL tumor cells have prominent Notch1 expression and treatment...... with Notch inhibitors has cytotoxic effects....

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

International Nuclear Information System (INIS)

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

2013-01-01

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

Notched audiograms and noise exposure history in older adults.

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Nondahl, David M; Shi, Xiaoyu; Cruickshanks, Karen J; Dalton, Dayna S; Tweed, Ted S; Wiley, Terry L; Carmichael, Lakeesha L

2009-12-01

Using data from a population-based cohort study, we compared four published algorithms for identifying notched audiograms and compared their resulting classifications with noise exposure history. Four algorithms: (1) , (2) , (3) , and (4) were used to identify notched audiograms. Audiometric evaluations were collected as a part of the 10-yr follow-up examinations of the Epidemiology of Hearing Loss Study, in Beaver Dam, WI (2003-2005, N = 2395). Detailed noise exposure histories were collected by interview at the baseline examination (1993-1995) and updated at subsequent visits. An extensive history of occupational noise exposure, participation in noisy hobbies, and firearm usage was used to evaluate consistency of the notch classifications with the history of noise exposure. 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, and 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 in women than in men. These results suggest that there is a 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.

Inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer

Institute of Scientific and Technical Information of China (English)

Zhao Li; Ma Yongjie; Gu Feng; Fu Li

2014-01-01

Background Paclitaxel (PAC) is the first-line chemotherapy drug for most breast cancer patients,but clinical studies showed that some breast cancer patients were insensitive to PAC,which led to chemotherapy failure.It was reported that Notch1 signaling participated in drug resistance of breast cancer.Here,we show whether Notch1 expression is related to PAC sensitivity of breast cancer.Methods We employed Notch1 siRNA and Notch1 inhibitor,N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT),to down regulate Notch1 expression in human breast cancer cells MDA-MB-231,and detected the inhibition effect by Western blotting and reverse trans cription-polymerase chain reaction,respectively.After 24 hours exposure to different concentration of PAC (0,1,5,10,15,20,and 25 μg/ml),the viability of the control group and experimental group cells was tested by MTT.We also examined the expression of Notch1 in PAC sensitive and nonsensitive breast cancer patients,respectively by immunohistochemistry (IHC).The PAC sensitivity of breast cancer patients were identified by collagen gel droplet embedded culture-drug sensitivity test (CD-DST).Results Down regulation of Notch1 expression by Notch1siRNA interference or Notch1 inhibitor increased the PAC sensitivity in MDA-MB-231 cells (P ＜0.05).Also,the expression of Notch1 in PAC sensitive patients was much lower than that of PAC non-sensitive patients (P ＜0.01).Conclusion Notch1 expression has an effect on PAC sensitivity in breast cancer patients,and the inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer.

NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells

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Mauro Di Ianni

2018-04-01

Full Text Available 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.

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

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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.

Static and Fatigue Behavior Investigation of Artificial Notched Steel Reinforcement

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Yafei Ma

2017-05-01

Full Text Available Pitting corrosion is one of the most common forms of localized corrosion. Corrosion pit results in a stress concentration and fatigue cracks usually initiate and propagate from these corrosion pits. Aging structures may fracture when the fatigue crack reaches a critical size. This paper experimentally simulates the effects of pitting morphologies on the static and fatigue behavior of steel bars. Four artificial notch shapes are considered: radial ellipse, axial ellipse, triangle and length-variable triangle. Each shape notch includes six sizes to simulate a variety of pitting corrosion morphologies. The stress-strain curves of steel bars with different notch shape and depth are obtained based on static tensile testing, and the stress concentration coefficients for various conditions are determined. It was determined that the triangular notch has the highest stress concentration coefficient, followed by length-variable triangle, radial ellipse and axial ellipse shaped notches. Subsequently, the effects of notch depth and notch aspect ratios on the fatigue life under three stress levels are investigated by fatigue testing, and the equations for stress range-fatigue life-notch depth are obtained. Several conclusions are drawn based on the proposed study. The established relationships provide an experimental reference for evaluating the fatigue life of concrete bridges.

Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

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Matthew R. Broadus

2016-05-01

Full Text Available Upon Notch pathway activation, the receptor is cleaved to release the Notch intracellular domain (NICD, which translocates to the nucleus to activate gene transcription. Using Xenopus egg extracts, we have identified a Notch1-specific destruction signal (N1-Box. We show that mutations in the N1-Box inhibit NICD1 degradation and that the N1-Box is transferable for the promotion of degradation of heterologous proteins in Xenopus egg extracts and in cultured human cells. Mutation of the N1-Box enhances Notch1 activity in cultured human cells and zebrafish embryos. Human cancer mutations within the N1-Box enhance Notch1 signaling in transgenic zebrafish, highlighting the physiological relevance of this destruction signal. We find that binding of the Notch nuclear factor, CSL, to the N1-Box blocks NICD1 turnover. Our studies reveal a mechanism by which degradation of NICD1 is regulated by the N1-Box to minimize stochastic flux and to establish a threshold for Notch1 pathway activation.

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

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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.

In vivo analysis of the Notch receptor S1 cleavage.

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Robert J Lake

2009-08-01

Full Text Available A ligand-independent cleavage (S1 in the extracellular domain of the mammalian Notch receptor results in what is considered to be the canonical heterodimeric form of Notch on the cell surface. The in vivo consequences and significance of this cleavage on Drosophila Notch signaling remain unclear and contradictory. We determined the cleavage site in Drosophila and examined its in vivo function by a transgenic analysis of receptors that cannot be cleaved. Our results demonstrate a correlation between loss of cleavage and loss of in vivo function of the Notch receptor, supporting the notion that S1 cleavage is an in vivo mechanism of Notch signal control.

The functional role of Notch signaling in human gliomas

DEFF Research Database (Denmark)

Stockhausen, Marie-Thérése; Kristoffersen, Karina; Poulsen, Hans Skovgaard

2010-01-01

have been referred to as brain cancer stem cells (bCSC), as they share similarities to normal neural stem cells in the brain. The Notch signaling pathway is involved in cell fate decisions throughout normal development and in stem cell proliferation and maintenance. The role of Notch in cancer is now...... firmly established, and recent data implicate a role for Notch signaling also in gliomas and bCSC. In this review, we explore the role of the Notch signaling pathway in gliomas with emphasis on its role in normal brain development and its interplay with pathways and processes that are characteristic...

Hyper-activation of Notch3 amplifies the proliferative potential of rhabdomyosarcoma cells.

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Maria De Salvo

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

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

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Dominguez, Maria

2014-04-01

The inappropriate Notch signalling can influence virtually all aspect of cancer, including tumour-cell growth, survival, apoptosis, angiogenesis, invasion and metastasis, although it does not do this alone. Hence, elucidating the partners of Notch that are active in cancer is now the focus of much intense research activity. The genetic toolkits available, coupled to the small size and short life of the fruit fly Drosophila melanogaster, makes this an inexpensive and effective animal model, suited to large-scale cancer gene discovery studies. The fly eye is not only a non-vital organ but its stereotyped size and disposition also means it is easy to screen for mutations that cause tumours and metastases and provides ample opportunities to test cancer theories and to unravel unanticipated nexus between Notch and other cancer genes, or to discover unforeseen Notch's partners in cancer. These studies suggest that Notch's oncogenic capacity is brought about not simply by increasing signal strength but through partnerships, whereby oncogenes gain more by cooperating than acting individually, as in a ring 'organized crime'. Copyright © 2014 Elsevier Ltd. All rights reserved.

PI3K/AKT signaling inhibits NOTCH1 lysosome-mediated degradation.

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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.

Automated Root Tracking with "Root System Analyzer"

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Schnepf, Andrea; Jin, Meina; Ockert, Charlotte; Bol, Roland; Leitner, Daniel

2015-04-01

identification number, the distance between branching point to the parent root base, the root length, the root radius and the nodes that belong to each individual root path. This information is relevant for the analysis of dynamic root system development as well as the parameterisation of root architecture models. Here, we show results of Root System Analyzer applied to analyse the root systems of wheat plants grown in rhizotrons. Different treatments with respect to soil moisture and apatite concentrations were used to test the effects of those conditions on root system development. Photographs of the root systems were taken at high spatial and temporal resolution and root systems are automatically tracked.

The histone deacetylase HDAC1 positively regulates Notch signaling during Drosophila wing development

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Zehua Wang

2018-02-01

Full Text Available The Notch signaling pathway is highly conserved across different animal species and plays crucial roles in development and physiology. Regulation of Notch signaling occurs at multiple levels in different tissues and cell types. Here, we show that the histone deacetylase HDAC1 acts as a positive regulator of Notch signaling during Drosophila wing development. Depletion of HDAC1 causes wing notches on the margin of adult wing. Consistently, the expression of Notch target genes is reduced in the absence of HDAC1 during wing margin formation. We further provide evidence that HDAC1 acts upstream of Notch activation. Mechanistically, we show that HDAC1 regulates Notch protein levels by promoting Notch transcription. Consistent with this, the HDAC1-associated transcriptional co-repressor Atrophin (Atro is also required for transcriptional activation of Notch in the wing disc. In summary, our results demonstrate that HDAC1 positively regulates Notch signaling and reveal a previously unidentified function of HDAC1 in Notch signaling.

Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone

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Anna Engler

2018-01-01

Full Text Available Neurogenesis continues in the ventricular-subventricular zone (V-SVZ of the adult forebrain from quiescent neural stem cells (NSCs. V-SVZ NSCs are a reservoir for new olfactory bulb (OB neurons that migrate through the rostral migratory stream (RMS. To generate neurons, V-SVZ NSCs need to activate and enter the cell cycle. The mechanisms underlying NSC transition from quiescence to activity are poorly understood. We show that Notch2, but not Notch1, signaling conveys quiescence to V-SVZ NSCs by repressing cell-cycle-related genes and neurogenesis. Loss of Notch2 activates quiescent NSCs, which proliferate and generate new neurons of the OB lineage. Notch2 deficiency results in accelerated V-SVZ NSC exhaustion and an aging-like phenotype. Simultaneous loss of Notch1 and Notch2 resembled the total loss of Rbpj-mediated canonical Notch signaling; thus, Notch2 functions are not compensated in NSCs, and Notch2 is indispensable for the maintenance of NSC quiescence in the adult V-SVZ.

Far infrared promotes wound healing through activation of Notch1 signaling.

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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.

Mandibular Ramus Notching As a Tool for Sexual Dimorphism

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Bibhuti Bhusana Panda

2016-02-01

Full Text Available Sex determination from a single or a part of bone is always difficult in absence of other bones of the same individual. The current study is an attempt to know the sex of an individual from the study of posterior ramus of mandible. The study was done from December, 2014 to August, 2015 in various Medical Colleges of the state of Odisha, India with the use of morbid anatomical specimen of mandibles and simple measuring instruments. The posterior ramus of adult mandibles were studied for presence or absence of any notching and if present its position in relation to occlusal plane. The study resulted, that there was a role of notch position in sex determination. The presence or absence of the notch though was not a consistent finding of all the mandibles. Males had frequent notching at the level of occlusal plane (P< 0.01 and females had frequent notching above the occlusal plane (P < 0.01. Notch present below the occlusal plane had no relation with sex. Accuracy of sexing mandible from the posterior ramus notch position was 61%, which was more for males (68.57% as compared to females (43.33%. So the posterior ramus of mandible could be considered for determination of sex of mandible but this should not be the sole criteria and should be correlated with the other standard criteria.

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

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Robert Wunderlich

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

Notch signaling inhibitor DAPT provides protection against acute craniocerebral injury.

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Hong-Mei Zhang

Full Text Available Notch signaling pathway is involved in many physiological and pathological processes. The γ-secretase inhibitor DAPT inhibits Notch signaling pathway and promotes nerve regeneration after cerebral ischemia. However, neuroprotective effects of DAPT against acute craniocerebral injury remain unclear. In this study, we established rat model of acute craniocerebral injury, and found that with the increase of damage grade, the expression of Notch and downstream protein Hes1 and Hes5 expression gradually increased. After the administration of DAPT, the expression of Notch, Hes1 and Hes5 was inhibited, apoptosis and oxidative stress decreased, neurological function and cognitive function improved. These results suggest that Notch signaling can be used as an indicator to assess the severity of post-traumatic brain injury. Notch inhibitor DAPT can reduce oxidative stress and apoptosis after acute craniocerebral injury, and is a potential drug for the treatment of acute craniocerebral injury.

Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major.

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Floriane Auderset

Full Text Available The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4(+ T helper (Th 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4(+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1 and Notch2 (N2 are expressed on activated CD4(+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2(ΔCD4Cre were infected with the protozoan parasite Leishmania major. N1N2(ΔCD4Cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4(+ T cells and increased secretion of the IL-5 and IL-13 Th2 cytokines. Mice with single inactivation of N1 or N2 in their T cells were resistant to infection and developed a protective Th1 immune response, showing that CD4(+ T cell expression of N1 or N2 is redundant in driving Th1 differentiation. Furthermore, we show that Notch signaling is required for the secretion of IFNγ by Th1 cells. This effect is independent of CSL/RBP-Jκ, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jκ deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. Collectively, we demonstrate here a crucial role for RBP-Jκ-independent Notch signaling in the differentiation of a functional Th1 immune response following L. major infection.

Complete Absence of Suprascapular Notch: A Case Report

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Rohini Mohan Pawar

2015-10-01

Full Text Available Suprascapular Nerve Entrapment (SSNE is an acquired neuropathy secondary to compression of suprascapular nerve in the Suprascapular Notch (SSN. Complete ossification of superior transverse scapular ligament may be a cause for suprascapular nerve entrapment. The absence of suprascapular notch is not very common condition, though its prevalence was quoted by Indian authors to be varying from 1.36% to 32.46% in different parts of the country. It is considered to be a predisposing factor for suprascapular nerve entrapment neuropathy. We noticed a male scapula without suprascapular notch in osteology section of Forensic Medicine department. In this case we observed costal and dorsal surfaces of the left scapula of a male without suprascapular notch at its superior border. The details of the said scapula are discussed in this report.

Femoral intercondylar notch shape and dimensions in ACL-injured patients

NARCIS (Netherlands)

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

2010-01-01

The femoral intercondylar notch has been an anatomic site of interest as it houses the anterior cruciate ligament (ACL). The objective of this study was to arthroscopically evaluate the femoral notch in patients with known ACL injury. This evaluation included establishing a classification for notch

Radius crossover sign: an indication of malreduced radius shaft greenstick fractures.

Science.gov (United States)

Wright, Patrick B; Crepeau, Allison E; Herrera-Soto, José A; Price, Charles T

2012-06-01

Radius shaft greenstick fractures in children can be a challenging injury to treat because angulation and rotational alignment are difficult to assess. In this report, we describe a simple method for analyzing the deformity and identifying rotational and angular malalignment. This technique involves analyzing the forearm radiographs as 2 segments, proximal and distal, and assuring that the rotational position of each matches the other. We present 3 cases of proximal radius greenstick fractures in malalignment to demonstrate the radius crossover sign. Identifying the radius crossover sign, and proceeding with further closed reduction may prevent deformity that could otherwise result in a significant loss of forearm motion. Level V.

On impact testing of subsize Charpy V-notch type specimens

International Nuclear Information System (INIS)

Mikhail, A.S.; Nanstad, R.K.

1994-01-01

The potential for using subsize specimens to determine the actual properties of reactor pressure vessel steels is receiving increasing attention for improved vessel condition monitoring that could be beneficial for light-water reactor plant-life extension. This potential is made conditional upon, on the one hand, by the possibility of cutting samples of small volume from the internal surface of the pressure vessel for determination of actual properties of the operating pressure vessel. The plant-life extension will require supplemental surveillance data that cannot be provided by the existing surveillance programs. Testing of subsize specimens manufactured from broken halves of previously tested surveillance Charpy V-notch (CVN) specimens offers an attractive means of extending existing surveillance programs. Using subsize CVN type specimens requires the establishment of a specimen geometry that is adequate to obtain a ductile-to-brittle transition curve similar to that obtained from full-size specimens. This requires the development of a correlation of transition temperature and upper-shelf toughness between subsize and full-size specimens. The present study was conducted under the Heavy-Section Steel Irradiation Program. Different published approaches to the use of subsize specimens were analyzed and five different geometries of subsize specimens were selected for testing and evaluation. The specimens were made from several types of pressure vessel steels with a wide range of yield strengths, transition temperatures, and upper-shelf energies (USEs). Effects of specimen dimensions, including depth, angle, and radius of notch have been studied. The correlation of transition temperature determined from different types of subsize specimens and the full-size specimen is presented. A new procedure for transforming data from subsize specimens was developed and is presented

Expression of Notch1 Correlates with Breast Cancer Progression and Prognosis.

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Xun Yuan

Full Text Available Various studies have evaluated the significance of Notch1 expression in breast cancer, but the results have ever been disputed. By using 21 studies involving 3867 patients, this meta-analysis revealed that the expression of Notch1 was significantly higher in breast cancer than in normal tissues (OR=7.21; 95%CI, 4.7-11.07 and that higher Notch1 expression was associated with transition from ductal carcinoma in situ (DCIS to invasive cancer (OR=3.75; 95% CI, 1.8-7.78. Higher Notch1 activity was observed in the basal subtype of breast cancer (OR=2.53; 95% CI, 1.18-5.43. Moreover, patients with Notch1 overexpression exhibited significantly worse overall and recurrence-free survival. Our meta-analysis suggests that Notch inhibitors may be useful in blocking the early progression of DCIS and that the outcomes of clinical trials for Notch1-targeting therapeutics could be improved by the molecular stratification of breast cancer patients.

Functional studies on the role of Notch signaling in Hydractinia development.

Science.gov (United States)

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.

A Compact Printed Quadruple Band-Notched UWB Antenna

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Xiaoyin Li

2013-01-01

Full Text Available A novel compact coplanar waveguide- (CPW- fed ultrawideband (UWB printed planar volcano-smoke antenna (PVSA with four band-notches for various wireless applications is proposed and demonstrated. The low-profile antenna consists of a C-shaped parasitic strip to generate a notched band at 8.01~8.55 GHz for the ITU band, two C-shaped slots, and an inverted U-shaped slot etched in the radiator patch to create three notched bands at 5.15~5.35 GHz, 5.75~5.85 GHz, and 7.25~7.75 GHz for filtering the WLAN and X-band satellite signals. Simulated and measured results both confirm that the proposed antenna has a broad bandwidth of 3.1~12 GHz with VSWR < 2 and good omnidirectional radiation patterns with four notched-bands.

Cell proliferation control by Notch signalling during imaginal discs development in Drosophila

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Carlos Estella

2015-02-01

Full Text Available The Notch signalling pathway is evolutionary conserved and participates in numerous developmental processes, including the control of cell proliferation. However, Notch signalling can promote or restrain cell division depending on the developmental context, as has been observed in human cancer where Notch can function as a tumor suppressor or an oncogene. Thus, the outcome of Notch signalling can be influenced by the cross-talk between Notch and other signalling pathways. The use of model organisms such as Drosophila has been proven to be very valuable to understand the developmental role of the Notch pathway in different tissues and its relationship with other signalling pathways during cell proliferation control. Here we review recent studies in Drosophila that shed light in the developmental control of cell proliferation by the Notch pathway in different contexts such as the eye, wing and leg imaginal discs. We also discuss the autonomous and non-autonomous effects of the Notch pathway on cell proliferation and its interactions with different signalling pathways.

Optical stress investigations of notched bars with superimposed types of loads

International Nuclear Information System (INIS)

Richard, H.A.; Theis, W.

1982-01-01

Starting from the notch effect for various types of load, notch stresses are determined by optical methods for superimposed tensile and shearing stress and for superimposed tensile and bending stress. The superimposed stresses are induced by a device developed at the Technical Mechanics Department of Kaiserslautern University; only tensile stress needs to be applied to this testing device. The investigations have shown that in notched bars subject to superimposed tensile and shearing stress, stress increases will be higher than the maximum values of the two types of stress. For superimposed tensile and bending stress, notches on the outer side of the test piece and eccentric notches on the inner side may lead to a considerable stress increase. However, the stress distribution can be improved by an optimum arrangement of notches. (orig.) [de

Notched K-wire for low thermal damage bone drilling.

Science.gov (United States)

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.

Role of Notch Signaling in Human Breast Cancer Pathogenesis

Science.gov (United States)

2006-11-01

transform HMLE cells. Similarly, overexpression of ErbB2, a receptor tyrosine kinase upstream of Ras normally found overexpressed in many breast cancers ...Assess Notch-Ras cooperation in breast cancers in vivo: Since the major observation in this project has been the cooperation of Notch and Ras in HMLE ...metastasis. The in vitro cooperation between Notch and Ras in HMLE cells is mimicked in naturally arising breast cancers in vivo. Further dissection of the

Notch signaling and ghost cell fate in the calcifying cystig odontogenic tumor

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Siar CH

2011-11-01

Full Text Available Abstract Notch signaling is an evolutionarily conserved mechanism that enables adjacent cells to adopt different fates. Ghost cells (GCs are anucleate cells with homogeneous pale eosinophilic cytoplasm and very pale to clear central areas (previous nucleus sites. Although GCs are present in a variety of odontogenic lesions notably the calcifying cystic odontogenic tumor (GCOT, their nature and process of formation remains elusive. The aim of this study was to investigate the role of Notch signaling in the cell fate specification of GCs in CCOT. Immunohistochemical staining for four Notch receptors (Notch1, Notch2, Notch3 and Notch4 and three ligands (Jagged1, Jagged2 and Delta1 was performed on archival tissues of five CCOT cases. Level of positivity was quantified as negative (0, mild (+, moderate (2+ and strong (3+. Results revealed that GCs demonstrated overexpression for Notch1 and Jagged1 suggesting that Notch1Jagged1 signaling might serve as the main transduction mechanism in cell fate decision for GCs in CCOT. Protein localizations were largely membranous and/or cytoplasmic. Mineralized GCs also stained positive implicating that the calcification process might be associated with upregulation of these molecules. The other Notch receptors and ligands were weak to absent in GCs and tumoral epithelium. Stromal endothelium and fibroblasts were stained variably positive.

Computer simulation of the Charpy V-notch toughness test

International Nuclear Information System (INIS)

Norris, D.M. Jr.

1977-01-01

The dynamic Charpy V-notch test was simulated on a computer. The calculational models (for A-533 Grade B class 1 steel) used both a rounded and a flat-tipped striker. The notch stress/strain state was found to be independent of the three-point loading type and was most strongly correlated with notch-opening displacement. The dynamic stress/strain state at the time of fracture initiation was obtained by comparing the calculated deformed shape with that obtained in interrupted Charpy V-notch tests where cracking had started. The calculation was also compared with stress/strain states calculated in other geometries at failure. The distribution and partition of specimen energy was calculated and adiabatic heating and strain rate are discussed

Coastal dune dynamics in response to excavated foredune notches

Science.gov (United States)

Ruessink, B. G.; Arens, S. M.; Kuipers, M.; Donker, J. J. A.

2018-04-01

Dune management along developed coasts has traditionally focussed on the suppression of the geomorphic dynamics of the foredune to improve its role in sea defence. Because a stabilized foredune acts as an almost total barrier to aeolian transport from the beach, the habitat diversity in the more landward dunes has degraded. With the overarching objective to mitigate this undesirable loss in biodiversity, dune management projects nowadays increasingly intend to restore aeolian dynamics by reconnecting the beach-dune system with notches excavated through the foredune. Here, we use repeat topographic survey data to examine the geomorphic response of a coastal dune system in the Dutch National Park Zuid-Kennemerland to five notches excavated in 2012-2013 within an 850-m stretch of the 20-m high established foredune. The notches were dug in a V-shape (viewed onshore), with a width between approximately 50 and 100 m at the top, a (cross-dune) length between 100 and 200 m, and excavation depths between 9 and 12.5 m. The 1 × 1 m digital terrain models, acquired with airborne Lidar and UAV photogrammetry, illustrate that during the 3-year survey period the notches developed into a U-shape because of wall deflation, and that up to 8-m thick and 150-m long depositional lobes formed landward of the notches. Sand budget computations showed that the sand volume of the entire study area increased by about 22,750 m3/year, which, given the 850-m width of the study area, corresponds to an aeolian input from the beach of approximately 26.5 m3/m/year. Between 2006 and 2012 all wind-blown beach sand deposited on the seaward side of the foredune; since 2013, the notches have caused 75% of the sand to be deposited landward of the foredune. This highlights that the notches are highly effective conduits for aeolian transport into the back dunes. Future monitoring is required to determine for how long the notches will stimulate aeolian dynamics and if (and when) vegetation eventually

Water movement through plant roots - exact solutions of the water flow equation in roots with linear or exponential piecewise hydraulic properties

Science.gov (United States)

Meunier, Félicien; Couvreur, Valentin; Draye, Xavier; Zarebanadkouki, Mohsen; Vanderborght, Jan; Javaux, Mathieu

2017-12-01

In 1978, Landsberg and Fowkes presented a solution of the water flow equation inside a root with uniform hydraulic properties. These properties are root radial conductivity and axial conductance, which control, respectively, the radial water flow between the root surface and xylem and the axial flow within the xylem. From the solution for the xylem water potential, functions that describe the radial and axial flow along the root axis were derived. These solutions can also be used to derive root macroscopic parameters that are potential input parameters of hydrological and crop models. In this paper, novel analytical solutions of the water flow equation are developed for roots whose hydraulic properties vary along their axis, which is the case for most plants. We derived solutions for single roots with linear or exponential variations of hydraulic properties with distance to root tip. These solutions were subsequently combined to construct single roots with complex hydraulic property profiles. The analytical solutions allow one to verify numerical solutions and to get a generalization of the hydric behaviour with the main influencing parameters of the solutions. The resulting flow distributions in heterogeneous roots differed from those in uniform roots and simulations led to more regular, less abrupt variations of xylem suction or radial flux along root axes. The model could successfully be applied to maize effective root conductance measurements to derive radial and axial hydraulic properties. We also show that very contrasted root water uptake patterns arise when using either uniform or heterogeneous root hydraulic properties in a soil-root model. The optimal root radius that maximizes water uptake under a carbon cost constraint was also studied. The optimal radius was shown to be highly dependent on the root hydraulic properties and close to observed properties in maize roots. We finally used the obtained functions for evaluating the impact of root maturation

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

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Xiaodong Mu

2016-01-01

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

Notch inhibition counteracts Paneth cell death in absence of caspase-8.

Science.gov (United States)

Jeon, M K; Kaemmerer, E; Schneider, U; Schiffer, M; Klaus, C; Hennings, J; Clahsen, T; Ackerstaff, T; Niggemann, M; Schippers, A; Longerich, T; Sellge, G; Trautwein, C; Wagner, N; Liedtke, C; Gassler, N

2018-05-16

Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8 ∆int ) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8 ∆int mice. The secretory cell metaplasia in DBZ-treated casp8 ∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8 ∆int background. Our data suggest that casp8 acts in the intestinal Notch network.

Notch 1 as a potential therapeutic target in cutaneous T-cell lymphoma

DEFF Research Database (Denmark)

Kamstrup, Maria Rørbæk; Gjerdrum, Lise Mette Rahbek; Biskup, Edyta Urszula

2010-01-01

Deregulation of Notch signaling has been linked to the development of T-cell leukemias and several solid malignancies. Yet, it is unknown whether Notch signalling is involved in the pathogenesis of mycosis fungoides and Sezary syndrome, the most common subtypes of cutaneous T cell lymphoma....... By immunohistochemistry of 40 biopsies taken from skin lesions of mycosis fungoides and Sezary syndrome we demonstrated prominent expression of Notch1 on tumor cells, especially in the more advanced stages. The gamma-secretase inhibitor I blocked Notch signaling and potently induced apoptosis in cell lines derived from...... mycosis fungoides (MyLa) and Sezary syndrome (SeAx, HuT-78)and in primary leukemic Sézary cells. Specific downregulation of Notch1 (but not Notch2 and Notch3) by siRNA induced apoptosis in SeAx. The mechanism of apoptosis involved the inhibition of NF-kappaB, which is the most important prosurvival...

A conceptual approach to approximate tree root architecture in infinite slope models

Science.gov (United States)

Schmaltz, Elmar; Glade, Thomas

2016-04-01

Vegetation-related properties - particularly tree root distribution and coherent hydrologic and mechanical effects on the underlying soil mantle - are commonly not considered in infinite slope models. Indeed, from a geotechnical point of view, these effects appear to be difficult to be reproduced reliably in a physically-based modelling approach. The growth of a tree and the expansion of its root architecture are directly connected with both intrinsic properties such as species and age, and extrinsic factors like topography, availability of nutrients, climate and soil type. These parameters control four main issues of the tree root architecture: 1) Type of rooting; 2) maximum growing distance to the tree stem (radius r); 3) maximum growing depth (height h); and 4) potential deformation of the root system. Geometric solids are able to approximate the distribution of a tree root system. The objective of this paper is to investigate whether it is possible to implement root systems and the connected hydrological and mechanical attributes sufficiently in a 3-dimensional slope stability model. Hereby, a spatio-dynamic vegetation module should cope with the demands of performance, computation time and significance. However, in this presentation, we focus only on the distribution of roots. The assumption is that the horizontal root distribution around a tree stem on a 2-dimensional plane can be described by a circle with the stem located at the centroid and a distinct radius r that is dependent on age and species. We classified three main types of tree root systems and reproduced the species-age-related root distribution with three respective mathematical solids in a synthetic 3-dimensional hillslope ambience. Thus, two solids in an Euclidian space were distinguished to represent the three root systems: i) cylinders with radius r and height h, whilst the dimension of latter defines the shape of a taproot-system or a shallow-root-system respectively; ii) elliptic

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

Science.gov (United States)

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

2017-03-13

During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of notch and alloying on steel properties during extension

International Nuclear Information System (INIS)

Vinokur, B.B.; Pilyushenko, U.L.; Kasatkin, O.G.

1985-01-01

A study was made on change of strength and plastic characteristics during extension of notched steel samples of 15 compositions containing often-used alloying elements in various amounts and combinations. The notch causes increase of strength and decrease of plastic properties of structural steels during extension. The most pronounced change of properties takes place for the notched sample with expansion angle close to 180 deg. Reduction of notch expansion angle below 150 deg causes slower decrease of the rate of property change. Nickel alloying and vanadium, titanium microalloying assist the improvement of steel plasticity despite the increase of strength properties. Introduction of these elements in steel compensate partially for the negative notch effect. Alloying by silicon, molybdenum and tungsten results in steel strengthening and chromium alloying causes some loss of strength. Manse, chromium, silicon, molybdenum and tungsten cause decrease of plasticity, which intensifies the negative notch effect. When determining concentration ranges of carbon and alloying elements within the limits of quality composition it is necessary to consider both technology and possibility of sufficient change of properties especially in the case of stress concentrator presence in structures

Insensible is a novel nuclear inhibitor of Notch activity in Drosophila.

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Franck Coumailleau

Full Text Available Notch signalling regulates a wide range of developmental processes. In the Drosophila peripheral nervous system, Notch regulates a series of binary fate decisions that lead to the formation of regularly spaced sensory organs. Each sensory organ is generated by single sensory organ precursor cell (SOP via a series of asymmetric cell divisions. Starting from a SOP-specific Cis-Regulatory Module (CRM, we identified insensible (insb, a.k.a CG6520, as a SOP/neuron-specific gene encoding a nuclear factor that inhibits Notch signalling activity. First, over-expression of Insb led to the transcriptional repression of a Notch reporter and to phenotypes associated with the inhibition of Notch. Second, while the complete loss of insb activity had no significant phenotype, it enhanced the bristle phenotype associated with reduced levels of Hairless, a nuclear protein acting as a co-repressor for Suppressor of Hairless. In conclusion, our work identified Insb as a novel SOP/neuron-specific nuclear inhibitor of Notch activity in Drosophila.

Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

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Eileen M Redmond

Full Text Available To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling.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.These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA.

Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung cancer.

Science.gov (United States)

Yi, Fuming; Amarasinghe, Baru; Dang, Thao P

2013-01-01

Notch signaling plays an essential role in development as well as cancer. We have previously shown that Notch3 is important for lung cancer growth and survival. Notch receptors are activated through the interaction with their ligands, resulting in proteolytic cleavage of the receptors. This interaction is modulated by Fringe, a family of fucose-specific β1,3 N-acetylglucosaminyltransferases that modify the extracellular subunit of Notch receptors. Studies in developmental models showed that Fringe enhances Notch's response to Delta ligands at the expense of Jagged ligands. We observed that Manic Fringe expression is down-regulated in lung cancer. Since Jagged1, a known ligand for Notch3, is often over-expressed in lung cancer, we hypothesized that Fringe negatively regulates Notch3 activation. In this study, we show that re-expression of Manic Fringe down-regulates Notch3 target genes HES1 and HeyL and reduces tumor phenotype in vitro and in vivo. The mechanism for this phenomenon appears to be related to modulation of Notch3 protein stability. Proteasome inhibition reverses Manic Fringe-induced protein turnover. Taken together, our data provide the first evidence that Manic Fringe functions as a tumor suppressor in the lung and that the mechanism of its anti-tumor activity is mediated by inhibition of Notch3 activation.

Water movement through plant roots – exact solutions of the water flow equation in roots with linear or exponential piecewise hydraulic properties

Directory of Open Access Journals (Sweden)

F. Meunier

2017-12-01

Full Text Available In 1978, Landsberg and Fowkes presented a solution of the water flow equation inside a root with uniform hydraulic properties. These properties are root radial conductivity and axial conductance, which control, respectively, the radial water flow between the root surface and xylem and the axial flow within the xylem. From the solution for the xylem water potential, functions that describe the radial and axial flow along the root axis were derived. These solutions can also be used to derive root macroscopic parameters that are potential input parameters of hydrological and crop models. In this paper, novel analytical solutions of the water flow equation are developed for roots whose hydraulic properties vary along their axis, which is the case for most plants. We derived solutions for single roots with linear or exponential variations of hydraulic properties with distance to root tip. These solutions were subsequently combined to construct single roots with complex hydraulic property profiles. The analytical solutions allow one to verify numerical solutions and to get a generalization of the hydric behaviour with the main influencing parameters of the solutions. The resulting flow distributions in heterogeneous roots differed from those in uniform roots and simulations led to more regular, less abrupt variations of xylem suction or radial flux along root axes. The model could successfully be applied to maize effective root conductance measurements to derive radial and axial hydraulic properties. We also show that very contrasted root water uptake patterns arise when using either uniform or heterogeneous root hydraulic properties in a soil–root model. The optimal root radius that maximizes water uptake under a carbon cost constraint was also studied. The optimal radius was shown to be highly dependent on the root hydraulic properties and close to observed properties in maize roots. We finally used the obtained functions for evaluating the impact

hCLP46 regulates U937 cell proliferation via Notch signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Ma, Wenzhan; Du, Jie; Chu, Qiaoyun [College of Life Science, Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); Wang, Youxin [School of Public Health and Family Medicine, Capital Medical University, Beijing 100069 (China); Liu, Lixin [College of Life Science, Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); Song, Manshu [School of Public Health and Family Medicine, Capital Medical University, Beijing 100069 (China); Wang, Wei, E-mail: wei6014@yahoo.com [College of Life Science, Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); School of Public Health and Family Medicine, Capital Medical University, Beijing 100069 (China)

2011-04-29

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

Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states.

Science.gov (United States)

LeBon, Lauren; Lee, Tom V; Sprinzak, David; Jafar-Nejad, Hamed; Elowitz, Michael B

2014-09-25

The Notch signaling pathway consists of multiple types of receptors and ligands, whose interactions can be tuned by Fringe glycosyltransferases. A major challenge is to determine how these components control the specificity and directionality of Notch signaling in developmental contexts. Here, we analyzed same-cell (cis) Notch-ligand interactions for Notch1, Dll1, and Jag1, and their dependence on Fringe protein expression in mammalian cells. We found that Dll1 and Jag1 can cis-inhibit Notch1, and Fringe proteins modulate these interactions in a way that parallels their effects on trans interactions. Fringe similarly modulated Notch-ligand cis interactions during Drosophila development. Based on these and previously identified interactions, we show how the design of the Notch signaling pathway leads to a restricted repertoire of signaling states that promote heterotypic signaling between distinct cell types, providing insight into the design principles of the Notch signaling system, and the specific developmental process of Drosophila dorsal-ventral boundary formation.

Why does necking ignore notches in dynamic tension?

Directory of Open Access Journals (Sweden)

Rotbaum Y.

2015-01-01

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

TLX1 and NOTCH coregulate transcription in T cell acute lymphoblastic leukemia cells

Directory of Open Access Journals (Sweden)

Lee Norman H

2010-07-01

Full Text Available Abstract Background The homeobox gene TLX1 (for T-cell leukemia homeobox 1, previously known as HOX11 is inappropriately expressed in a major subgroup of T cell acute lymphoblastic leukemia (T-ALL where it is strongly associated with activating NOTCH1 mutations. Despite the recognition that these genetic lesions cooperate in leukemogenesis, there have been no mechanistic studies addressing how TLX1 and NOTCH1 functionally interact to promote the leukemic phenotype. Results Global gene expression profiling after downregulation of TLX1 and inhibition of the NOTCH pathway in ALL-SIL cells revealed that TLX1 synergistically regulated more than 60% of the NOTCH-responsive genes. Structure-function analysis demonstrated that TLX1 binding to Groucho-related TLE corepressors was necessary for maximal transcriptional regulation of the NOTCH-responsive genes tested, implicating TLX1 modulation of the NOTCH-TLE regulatory network. Comparison of the dataset to publicly available biological databases indicated that the TLX1/NOTCH-coregulated genes are frequently targeted by MYC. Gain- and loss-of-function experiments confirmed that MYC was an essential mediator of TLX1/NOTCH transcriptional output and growth promotion in ALL-SIL cells, with TLX1 contributing to the NOTCH-MYC regulatory axis by posttranscriptional enhancement of MYC protein levels. Functional classification of the TLX1/NOTCH-coregulated targets also showed enrichment for genes associated with other human cancers as well as those involved in developmental processes. In particular, we found that TLX1, NOTCH and MYC coregulate CD1B and RAG1, characteristic markers of early cortical thymocytes, and that concerted downregulation of the TLX1 and NOTCH pathways resulted in their irreversible repression. Conclusions We found that TLX1 and NOTCH synergistically regulate transcription in T-ALL, at least in part via the sharing of a TLE corepressor and by augmenting expression of MYC. We conclude that

The Role of Notch Signaling Pathway in Breast Cancer Pathogenesis

Science.gov (United States)

2005-07-01

breast cancer cells, I tested whether ErbB2 overexpression will cooperate with Notch in HMLE cells. While overexpression of activated Notch1 failed to...tyrosine kinase upstream of Ras normally found overexpressed in many breast cancers , also failed to transform HMLE cells. These observations suggested...cooperation between Notch1IC and ErbB2 signaling in transforming HMLE cells. Breast cancers typically do not harbor oncogenic Ras mutations; nevertheless

Notch Signaling Pathway Is Activated in Motoneurons of Spinal Muscular Atrophy

Directory of Open Access Journals (Sweden)

Gabriel Olmos

2013-05-01

Full Text Available Spinal muscular atrophy (SMA is a neurodegenerative disease produced by low levels of Survival Motor Neuron (SMN protein that affects alpha motoneurons in the spinal cord. Notch signaling is a cell-cell communication system well known as a master regulator of neural development, but also with important roles in the adult central nervous system. Aberrant Notch function is associated with several developmental neurological disorders; however, the potential implication of the Notch pathway in SMA pathogenesis has not been studied yet. We report here that SMN deficiency, induced in the astroglioma cell line U87MG after lentiviral transduction with a shSMN construct, was associated with an increase in the expression of the main components of Notch signaling pathway, namely its ligands, Jagged1 and Delta1, the Notch receptor and its active intracellular form (NICD. In the SMNΔ7 mouse model of SMA we also found increased astrocyte processes positive for Jagged1 and Delta1 in intimate contact with lumbar spinal cord motoneurons. In these motoneurons an increased Notch signaling was found, as denoted by increased NICD levels and reduced expression of the proneural gene neurogenin 3, whose transcription is negatively regulated by Notch. Together, these findings may be relevant to understand some pathologic attributes of SMA motoneurons.

Down-regulation of Notch-1 by γ-secretase inhibitor suppress the ...

African Journals Online (AJOL)

Notch-1 signaling is crucial for stem cell maintenance and in a variety of tissues. Previous research has demonstrated that Notch-1 activity plays a key role in prostate tumorigenesis. However, the function of Notch-1 signaling in tumorigenesis can be either oncogene or suppressor gene. In our paper, γ- secretase inhibitor ...

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

International Nuclear Information System (INIS)

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.

2011-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

Liu, Xin-Hua [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Yao, Shen; Qiao, Rui-Fang; Levine, Alice C. [Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Kirschenbaum, Alexander [Department of Urology, Mount Sinai School of Medicine, New York, NY 10029 (United States); Pan, Jiangping; Wu, Yong [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Qin, Weiping [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Bauman, William A. [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Rehabilitation Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Cardozo, Christopher P., E-mail: chris.cardozo@mssm.edu [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Rehabilitation Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States)

2011-10-14

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

Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells

International Nuclear Information System (INIS)

Dontu, Gabriela; Jackson, Kyle W; McNicholas, Erin; Kawamura, Mari J; Abdallah, Wissam M; Wicha, Max S

2004-01-01

Notch signaling has been implicated in the regulation of cell-fate decisions such as self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. Moreover, depending on the cellular and developmental context, the Notch pathway acts as a regulator of cell survival and cell proliferation. Abnormal expression of Notch receptors has been found in different types of epithelial metaplastic lesions and neoplastic lesions, suggesting that Notch may act as a proto-oncogene. The vertebrate Notch1 and Notch4 homologs are involved in normal development of the mammary gland, and mutated forms of these genes are associated with development of mouse mammary tumors. In order to determine the role of Notch signaling in mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent 'mammospheres'. Notch signaling was activated using exogenous ligands, or was inhibited using previously characterized Notch signaling antagonists. Utilizing this system, we demonstrate that Notch signaling can act on mammary stem cells to promote self-renewal and on early progenitor cells to promote their proliferation, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch-activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, mammary epithelial cells. These studies

Droplet digital PCR analysis of NOTCH1 gene mutations in chronic lymphocytic leukemia.

Science.gov (United States)

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.

Vía de señalización Notch y nuevas estrategias para el tratamiento de cáncer Notch signaling pathway and new strategies in cancer treatment

Directory of Open Access Journals (Sweden)

Leticia Santos

2006-04-01

Full Text Available La vía de señalización Notch desempeña un papel fundamental en las diferentes etapas del desarrollo celular como la proliferación, crecimiento, diferenciación y apoptosis. Estudios recientes han demostrado que, dependiendo del nivel de expresión y del contexto celular, los receptores de membrana Notch contribuyen en la resistencia a apoptosis en células tumorales. Estos descubrimientos sugieren que componentes de la vía de señalización Notch son un blanco potencial para el desarrollo de terapias más efectivas contra el cáncer. Esta revisión describe la función de la vía Notch y nuevas estrategias utilizadas en la modulación de su señal.The Notch signaling pathway plays a crucial role at different stages of cell development, such as proliferation, growth, differentiation, and apoptosis. Recent studies demonstrate that depending on the expression level and cellular context, the Notch receptors play a role in apoptosis resistance in malignant cells. These findings suggest that Notch signaling components may be a potential target in the development of new cancer therapies. This review describes the function of the Notch pathway and new strategies in the modulation of its signal.

Compact microstrip bandpass filter with tunable notch

DEFF Research Database (Denmark)

Christensen, Silas; Zhurbenko, Vitaliy; Johansen, Tom Keinicke

2014-01-01

Two different designs combining a bandpass and a notch filter are developed to operate in the receiving band from 350–470 MHz. The bandpass filter is designed from a simple structure, by use of only four short circuited stubs and a half wavelength transmission line connecting the stubs. The tunable...... notch filter ensures an attenuation level of 19.3 dB to 27.3 dB in the frequency range from 360–480 MHz. The measured passband ripple of the combined filter is less than 0.5 dB, while the insertion loss for the simplest design is less than 1.7 dB only 10 MHz from the notch frequency. Even though...... the wavelength on the selected substrate (εr = 3.55) is approximately 45 cm, the outer dimensions of the final filter only measure 10×10 cm2....

ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway.

Science.gov (United States)

Larrivée, Bruno; Prahst, Claudia; Gordon, Emma; del Toro, Raquel; Mathivet, Thomas; Duarte, Antonio; Simons, Michael; Eichmann, Anne

2012-03-13

Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions. Copyright © 2012 Elsevier Inc. All rights reserved.

Passive notch circuit for pulsed-off compression fields

International Nuclear Information System (INIS)

Nunnally, W.C.

1976-06-01

The operation and simulated results of a passive notch circuit used to pulse off the field in a multiturn, fusion-power system, compression coil are presented. The notch circuit permits initial plasma preparation at field zero, adiabatic compression as the field returns to its initial value, and long field decay time for plasma confinement. The major advantages and disadvantages of the notch circuit are compared with those of a standard capacitor power supply system. The major advantages are that: (1) slow-rising fields can be used for adiabatic compression, (2) solid-state switches can be used because of the inherent current and voltage waveforms, and (3) long field decay times are easier to attain than with single-turn coils

The Notch Signaling Pathway Is Balancing Type 1 Innate Lymphoid Cell Immune Functions

Directory of Open Access Journals (Sweden)

Thibaut Perchet

2018-06-01

Full Text Available The Notch pathway is one of the canonical signaling pathways implicated in the development of various solid tumors. During carcinogenesis, the Notch pathway dysregulation induces tumor expression of Notch receptor ligands participating to escape the immune surveillance. The Notch pathway conditions both the development and the functional regulation of lymphoid subsets. Its importance on T cell subset polarization has been documented contrary to its action on innate lymphoid cells (ILC. We aim to analyze the effect of the Notch pathway on type 1 ILC polarization and functions after disruption of the RBPJk-dependent Notch signaling cascade. Indeed, type 1 ILC comprises conventional NK (cNK cells and type 1 helper innate lymphoid cells (ILC1 that share Notch-related functional characteristics such as the IFNg secretion downstream of T-bet expression. cNK cells have strong antitumor properties. However, data are controversial concerning ILC1 functions during carcinogenesis with models showing antitumoral capacities and others reporting ILC1 inability to control tumor growth. Using various mouse models of Notch signaling pathway depletion, we analyze the effects of its absence on type 1 ILC differentiation and cytotoxic functions. We also provide clues into its role in the maintenance of immune homeostasis in tissues. We show that modulating the Notch pathway is not only acting on tumor-specific T cell activity but also on ILC immune subset functions. Hence, our study uncovers the intrinsic Notch signaling pathway in ILC1/cNK populations and their response in case of abnormal Notch ligand expression. This study help evaluating the possible side effects mediated by immune cells different from T cells, in case of multivalent forms of the Notch receptor ligand delta 1 treatments. In definitive, it should help determining the best novel combination of therapeutic strategies in case of solid tumors.

Charge Radius Measurement of the Halo Nucleus $^{11}$Li

CERN Multimedia

Kluge, H-J; Kuehl, T; Simon, H; Wang, Haiming; Zimmermann, C; Onishi, T; Tanihata, I; Wakasugi, M

2002-01-01

%IS385 %title\\\\ \\\\The root-mean-square charge radius of $^{11}$Li will be determined by measuring the isotope shift of a suitable atomic transition in a laser spectroscopic experiment. Comparing the charge radii of the lithium isotopes obtained by this nuclear-model-independent method with the relevant mass radii obtained before will help to answer the question whether the proton distribution in halo nuclei at the neutron drip-line is decoupled to the first order from their neutron distribution. The necessary experimental sensitivity requires the maximum possible rate of $^{11}$Li nuclei in a beam of low emittance which can only be provided by ISOLDE.

The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality

DEFF Research Database (Denmark)

Boskovski, Marko T; Yuan, Shiaulou; Pedersen, Nis Borbye

2013-01-01

to such determination. We previously identified GALNT11 as a candidate disease gene in a patient with heterotaxy, and now demonstrate, in Xenopus tropicalis, that galnt11 activates Notch signalling. GALNT11 O-glycosylates human NOTCH1 peptides in vitro, thereby supporting a mechanism of Notch activation either...... by increasing ADAM17-mediated ectodomain shedding of the Notch receptor or by modification of specific EGF repeats. We further developed a quantitative live imaging technique for Xenopus left-right organizer cilia and show that Galnt11-mediated Notch1 signalling modulates the spatial distribution and ratio...... of motile and immotile cilia at the left-right organizer. galnt11 or notch1 depletion increases the ratio of motile cilia at the expense of immotile cilia and produces a laterality defect reminiscent of loss of the ciliary sensor Pkd2. By contrast, Notch overexpression decreases this ratio, mimicking...

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

Science.gov (United States)

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.

Meniscal root entrapment of an osteochondritis dissecans loose body.

Science.gov (United States)

Jones, Christopher R; McMonagle, Joseph S; Garrett, William E

2014-09-01

Loose bodies are relatively common in the knee. On radiographs they can often be seen in the medial and lateral gutters, intercondylar notch, and the posterior compartment. At times an apparent loose body is not free to move in the knee because it has been covered by synovium and is no longer mobile. It is uncommon for an osteochondral loose body to become incorporated into meniscal tissue. We report a case of an apparent loose body becoming incorporated into the posterior horn and root of the medial meniscus. We are not aware that this condition has been previously reported. Because removing the entire loose body would have destabilized the posterior root of the medial meniscus, it is important to be aware of this potential occurrence.

Broadband notch filter design for millimeter-wave plasma diagnostics

DEFF Research Database (Denmark)

Furtula, Vedran; Michelsen, Poul; Leipold, Frank

2010-01-01

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

Notch pathway signaling in the skin antagonizes Merkel cell development.

Science.gov (United States)

Logan, Gregory J; Wright, Margaret C; Kubicki, Adam C; Maricich, Stephen M

2018-02-15

Merkel cells are mechanosensitive skin cells derived from the epidermal lineage whose development requires expression of the basic helix-loop-helix transcription factor Atoh1. The genes and pathways involved in regulating Merkel cell development during embryogenesis are poorly understood. Notch pathway signaling antagonizes Atoh1 expression in many developing body regions, so we hypothesized that Notch signaling might inhibit Merkel cell development. We found that conditional, constitutive overexpression of the Notch intracellular domain (NICD) in mouse epidermis significantly decreased Merkel cell numbers in whisker follicles and touch domes of hairy skin. Conversely, conditional deletion of the obligate NICD binding partner RBPj in the epidermis significantly increased Merkel cell numbers in whisker follicles, led to the development of ectopic Merkel cells outside of touch domes in hairy skin epidermis, and altered the distribution of Merkel cells in touch domes. Deletion of the downstream Notch effector gene Hes1 also significantly increased Merkel cell numbers in whisker follicles. Together, these data demonstrate that Notch signaling regulates Merkel cell production and patterning. Copyright © 2018 Elsevier Inc. All rights reserved.

Dangerous Liaisons: Deviant Endothelium NOTCHes toward Tumor Metastasis.

Science.gov (United States)

Guo, Peipei; Rafii, Shahin

2017-03-13

In this issue of Cancer Cell, Wieland et al. uncover a feedback loop in which tumor cells, by augmenting Notch signaling, provoke a senescent and pro-inflammatory state in endothelial cells, promoting neutrophil infiltration, tumor cell adhesion, and metastasis. Interfering with this Notch-dependent crosstalk may be a therapeutic approach to block metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Experimental analysis of compressive notch strengthening in closed-cell aluminum alloy foam

NARCIS (Netherlands)

Antoniou, A; Onck, PR; Bastawros, Ashraf F.

2004-01-01

The notch strengthening effect is studied experimentally in closed cell aluminum foams. The limit loads, net section strength were found for a set of double-edge-notched (DEN) and single-edge-notched (SEN) specimens loaded in compression. In addition, the evolution of the deformation is monitored

An Evolutionary-Conserved Function of Mammalian Notch Family Members as Cell Adhesion Molecules

Science.gov (United States)

Murata, Akihiko; Yoshino, Miya; Hikosaka, Mari; Okuyama, Kazuki; Zhou, Lan; Sakano, Seiji; Yagita, Hideo; Hayashi, Shin-Ichi

2014-01-01

Notch family members were first identified as cell adhesion molecules by cell aggregation assays in Drosophila studies. However, they are generally recognized as signaling molecules, and it was unclear if their adhesion function was restricted to Drosophila. We previously demonstrated that a mouse Notch ligand, Delta-like 1 (Dll1) functioned as a cell adhesion molecule. We here investigated whether this adhesion function was conserved in the diversified mammalian Notch ligands consisted of two families, Delta-like (Dll1, Dll3 and Dll4) and Jagged (Jag1 and Jag2). The forced expression of mouse Dll1, Dll4, Jag1, and Jag2, but not Dll3, on stromal cells induced the rapid and enhanced adhesion of cultured mast cells (MCs). This was attributed to the binding of Notch1 and Notch2 on MCs to each Notch ligand on the stromal cells themselves, and not the activation of Notch signaling. Notch receptor-ligand binding strongly supported the tethering of MCs to stromal cells, the first step of cell adhesion. However, the Jag2-mediated adhesion of MCs was weaker and unlike other ligands appeared to require additional factor(s) in addition to the receptor-ligand binding. Taken together, these results demonstrated that the function of cell adhesion was conserved in mammalian as well as Drosophila Notch family members. Since Notch receptor-ligand interaction plays important roles in a broad spectrum of biological processes ranging from embryogenesis to disorders, our finding will provide a new perspective on these issues from the aspect of cell adhesion. PMID:25255288

A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation

DEFF Research Database (Denmark)

Shih, Hung Ping; Kopp, Janel L; Sandhu, Manbir

2012-01-01

necessitates subsequent Sox9 downregulation and evasion from Notch activity via cell-autonomous repression of Sox9 by Ngn3. If high Notch levels are maintained, endocrine progenitors retain Sox9 and undergo ductal fate conversion. Taken together, our findings establish a novel role for Notch in initiating both...

Spoof surface plasmon polaritons based notch filter for ultra-wideband microwave waveguide

DEFF Research Database (Denmark)

Xiao, Binggang; Li, Sheng-Hua; Xiao, Sanshui

2016-01-01

Spoof surface plasmon polaritons based notch filter for ultra-wideband microwave waveguide is proposed. Owing to subwavelength confinement, such a filter has advantage in the structure size without sacrificing the performance. The spoof SPP based notch is introduced to suppress the WLAN and satel......Spoof surface plasmon polaritons based notch filter for ultra-wideband microwave waveguide is proposed. Owing to subwavelength confinement, such a filter has advantage in the structure size without sacrificing the performance. The spoof SPP based notch is introduced to suppress the WLAN...

Lunatic fringe-mediated Notch signaling regulates adult hippocampal neural stem cell maintenance.

Science.gov (United States)

Semerci, Fatih; Choi, William Tin-Shing; Bajic, Aleksandar; Thakkar, Aarohi; Encinas, Juan Manuel; Depreux, Frederic; Segil, Neil; Groves, Andrew K; Maletic-Savatic, Mirjana

2017-07-12

Hippocampal neural stem cells (NSCs) integrate inputs from multiple sources to balance quiescence and activation. Notch signaling plays a key role during this process. Here, we report that Lunatic fringe ( Lfng), a key modifier of the Notch receptor, is selectively expressed in NSCs. Further, Lfng in NSCs and Notch ligands Delta1 and Jagged1, expressed by their progeny, together influence NSC recruitment, cell cycle duration, and terminal fate. We propose a new model in which Lfng-mediated Notch signaling enables direct communication between a NSC and its descendants, so that progeny can send feedback signals to the 'mother' cell to modify its cell cycle status. Lfng-mediated Notch signaling appears to be a key factor governing NSC quiescence, division, and fate.

Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma.

Science.gov (United States)

Eberl, Markus; Mangelberger, Doris; Swanson, Jacob B; Verhaegen, Monique E; Harms, Paul W; Frohm, Marcus L; Dlugosz, Andrzej A; Wong, Sunny Y

2018-02-12

Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh + /Notch + suprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh +++ /Notch - basal cells survive throughout treatment. Inhibiting Notch specifically promotes tumor persistence without causing drug resistance, while activating Notch is sufficient to regress already established lesions. Altogether, these findings suggest that the three-dimensional architecture of BCCs establishes a natural hierarchy of drug response in the tumor and that this hierarchy can be overcome, for better or worse, by modulating Notch. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Science.gov (United States)

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.

Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

OpenAIRE

Broadus, Matthew R.; Chen, Tony W.; Neitzel, Leif R.; Ng, Victoria H.; Jodoin, Jeanne; Lee, Laura A.; Salic, Adrian; Robbins, David J.; Capobianco, Anthony J.; Patton, James G.; Huppert, Stacey S.; Lee, Ethan

2016-01-01

Upon Notch pathway activation, the receptor is cleaved to release the Notch intracellular domain (NICD), which translocates to the nucleus to activate gene transcription. Using Xenopus egg extracts, we have identified a Notch1-specific destruction signal (N1-Box). We show that mutations in the N1-Box inhibit NICD1 degradation and that the N1-Box is transferable for the promotion of degradation of heterologous proteins in Xenopus egg extracts and in cultured human cells. Mutation of the N1-Box...

Evaluation of Notch and Hypoxia Signaling Pathways in Chemically ...

African Journals Online (AJOL)

Hepatocellular carcinoma (HCC) is a common worldwide malignancy. Notch signaling pathway contributes to the genesis of diverse cancers, however, its role in HCC is unclear. Hypoxia is a common feature of HCC. Signal integration between Notch and hypoxia may be involved in HCC. The aim of this study was to ...

Notch sensitivity of ductile metallic foams : A computational study

NARCIS (Netherlands)

Mangipudi, K. R.; Onck, P. R.

2011-01-01

The role of notches in the fracture strength of metal foams has been studied using a multiscale model based on a two-dimensional Voronoi representation of the cellular architecture. The effect of the crack length to the specimen width ratio on the net section strength of double edge notch (DEN)

Failure of a porous solid from a deep notch

DEFF Research Database (Denmark)

Redanz, Pia; Fleck, Norman A.; McMeeking, Robert M.

1997-01-01

A finite strain finite element method is used to examine the stress state near the tip of a deep notch in an elastic-plastic porous solid. The notch is loaded in mode I plane strain tension and small scale yielding is assumed. Two rate independent strain hardening material models are used...

Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development.

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Yidong Wang

Full Text Available Endocardial to mesenchymal transformation (EMT is a fundamental cellular process required for heart valve formation. Notch, Wnt and Bmp pathways are known to regulate this process. To further address how these pathways coordinate in the process, we specifically disrupted Notch1 or Jagged1 in the endocardium of mouse embryonic hearts and showed that Jagged1-Notch1 signaling in the endocardium is essential for EMT and early valvular cushion formation. qPCR and RNA in situ hybridization assays reveal that endocardial Jagged1-Notch1 signaling regulates Wnt4 expression in the atrioventricular canal (AVC endocardium and Bmp2 in the AVC myocardium. Whole embryo cultures treated with Wnt4 or Wnt inhibitory factor 1 (Wif1 show that Bmp2 expression in the AVC myocardium is dependent on Wnt activity; Wnt4 also reinstates Bmp2 expression in the AVC myocardium of endocardial Notch1 null embryos. Furthermore, while both Wnt4 and Bmp2 rescue the defective EMT resulting from Notch inhibition, Wnt4 requires Bmp for its action. These results demonstrate that Jagged1-Notch1 signaling in endocardial cells induces the expression of Wnt4, which subsequently acts as a paracrine factor to upregulate Bmp2 expression in the adjacent AVC myocardium to signal EMT.

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

Science.gov (United States)

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.

An expanded Notch-Delta model exhibiting long-range patterning and incorporating MicroRNA regulation.

Directory of Open Access Journals (Sweden)

Jerry S Chen

2014-06-01

Full Text Available Notch-Delta signaling is a fundamental cell-cell communication mechanism that governs the differentiation of many cell types. Most existing mathematical models of Notch-Delta signaling are based on a feedback loop between Notch and Delta leading to lateral inhibition of neighboring cells. These models result in a checkerboard spatial pattern whereby adjacent cells express opposing levels of Notch and Delta, leading to alternate cell fates. However, a growing body of biological evidence suggests that Notch-Delta signaling produces other patterns that are not checkerboard, and therefore a new model is needed. Here, we present an expanded Notch-Delta model that builds upon previous models, adding a local Notch activity gradient, which affects long-range patterning, and the activity of a regulatory microRNA. This model is motivated by our experiments in the ascidian Ciona intestinalis showing that the peripheral sensory neurons, whose specification is in part regulated by the coordinate activity of Notch-Delta signaling and the microRNA miR-124, exhibit a sparse spatial pattern whereby consecutive neurons may be spaced over a dozen cells apart. We perform rigorous stability and bifurcation analyses, and demonstrate that our model is able to accurately explain and reproduce the neuronal pattern in Ciona. Using Monte Carlo simulations of our model along with miR-124 transgene over-expression assays, we demonstrate that the activity of miR-124 can be incorporated into the Notch decay rate parameter of our model. Finally, we motivate the general applicability of our model to Notch-Delta signaling in other animals by providing evidence that microRNAs regulate Notch-Delta signaling in analogous cell types in other organisms, and by discussing evidence in other organisms of sparse spatial patterns in tissues where Notch-Delta signaling is active.

Immunolocalization of notch signaling protein molecules in a maxillary chondrosarcoma and its recurrent tumor

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Siar CH

2010-10-01

Full Text Available Abstract Background Notch receptors are critical determinants of cell fate in a variety of organisms. Notch signaling is involved in the chondrogenic specification of neural crest cells. Aberrant Notch activity has been implicated in numerous human diseases including cancers; however its role in chondrogenic tumors has not been clarified. Method Tissue samples from a case of primary chondrosarcoma of the maxilla and its recurrent tumor were examined immunohistochemically for Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1 expression. Results Both primary and recurrent tumors were histopathologically diagnosed as conventional hyaline chondrosarcoma (WHO Grade I. Hypercellular tumor areas strongly expressed Notch3 and Jagged1 in spindle and pleomorphic cells suggesting up-regulation of these protein molecules at sites of tumor proliferation. Expression patterns were distinct with some overlap. Differentiated malignant and atypical chondrocytes demonstrated variable expression levels of Jagged1, and weak to absent staining for Notch1, 4 and Delta1. Protein immunolocalization was largely membranous and cytoplasmic, sometimes outlining the lacunae of malignant chondrocytes. Hyaline cartilage demonstrated a diffuse or granular precipitation of Jagged1 suggesting presence of soluble Jagged1 activity at sites of abnormal chondrogenesis. No immunoreactivity for the other Notch members was observed. Calcified cartilage was consistently Notch-negative indicating down-regulation of Notch with cartilage maturation. Stromal components namely endothelial cells and fibroblasts variably expressed Notch1, 3 and Jagged1 but were mildly or non-reactive for the other members. Conclusions Results indicate that Notch signaling pathway may participate in cellular differentiation and proliferation in chondrosarcoma. Findings implicate Notch3 and Jagged1 as key molecules that influence the differentiation and maturation of cells of chondrogenic lineage.

Mastermind-Like 1 Is Ubiquitinated: Functional Consequences for Notch Signaling.

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Mozhgan Farshbaf

Full Text Available Early studies demonstrated the involvement of ubiquitination of the Notch intracellular domain for rapid turnover of the transcriptional complex at Notch target genes. It was shown that this ubiquitination was promoted by the co-activator Mastermind like 1 (MAML1. MAML1 also contains numerous lysine residues that may also be ubiquitinated and necessary for protein regulation. In this study, we show that over-expressed MAML1 is ubiquitinated and identify eight conserved lysine residues which are required for ubiquitination. We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination. Furthermore, we show that a mutant MAML1 that has decreased ubiquitination shows increased output from a HES1 reporter gene assay. Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation. In summary, this study identifies that MAML1 is ubiquitinated in the absence of Notch signaling to maintain low levels of MAML1 in the cell. Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway.

A Novel Notch-YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma.

Science.gov (United States)

Slemmons, Katherine K; Crose, Lisa E S; Riedel, Stefan; Sushnitha, Manuela; Belyea, Brian; Linardic, Corinne M

2017-12-01

Rhabdomyosarcoma (RMS), a cancer characterized by skeletal muscle features, is the most common soft-tissue sarcoma of childhood. While low- and intermediate-risk groups have seen improved outcomes, high-risk patients still face a 5-year survival rate of statistic that has not changed in over 40 years. Understanding the biologic underpinnings of RMS is critical. The developmental pathways of Notch and YAP have been identified as potent but independent oncogenic signals that support the embryonal variant of RMS (eRMS). Here, the cross-talk between these pathways and the impact on eRMS tumorigenesis is reported. Using human eRMS cells grown as three-dimensional (3D) rhabdospheres, which enriches in stem cells, it was found that Notch signaling transcriptionally upregulates YAP1 gene expression and YAP activity. Reciprocally, YAP transcriptionally upregulates the Notch ligand genes JAG1 and DLL1 and the core Notch transcription factor RBPJ This bidirectional circuit boosts expression of key stem cell genes, including SOX2 , which is functionally required for eRMS spheres. Silencing this circuit for therapeutic purposes may be challenging, because the inhibition of one node (e.g., pharmacologic Notch blockade) can be rescued by upregulation of another (constitutive YAP expression). Instead, dual inhibition of Notch and YAP is necessary. Finally, supporting the existence of this circuit beyond a model system, nuclear Notch and YAP protein expression are correlated in human eRMS tumors, and YAP suppression in vivo decreases Notch signaling and SOX2 expression. Implications: This study identifies a novel oncogenic signaling circuit driving eRMS stemness and tumorigenesis, and provides evidence and rationale for combination therapies co-targeting Notch and YAP. Mol Cancer Res; 15(12); 1777-91. ©2017 AACR . ©2017 American Association for Cancer Research.

Immunohistochemical expression of Notch signaling in the lining epithelium of periapical cysts.

Science.gov (United States)

Meliou, Eleni; Kerezoudis, Nikolaos; Tosios, Konstantinos; Lafkas, Daniel; Kiaris, Hippokratis

2011-02-01

In this study we evaluated the immunohistochemical expression of the receptors Notch 1 and Notch 2, the ligand Delta 1, and the transcription factors HES 1 and HES 5 in the epithelium of well-defined periapical cysts. Immunohistochemistry was carried out on 55 formalin-fixed and paraffin-embedded, well-defined periapical cysts with minimum inflammation, obtained from the archival tissue database of the Department of Oral Pathology and Surgery. Western blotting was performed to evaluate the specificity of the anti-Notch antibody and the expression of Notch signaling in 5 fresh-frozen periapical cysts. The levels of staining intensity were estimated by the performance of a semiautomated image analysis system. Descriptive statistic of mean values obtained by computerized image analysis method was performed. Immunostaining reaction of all Notch signaling components was observed in the cytoplasm and/or the cytoplasmic membrane in the majority of epithelial cells of periapical cysts. Nuclear staining was observed occasionally in all cases. Notch 2 showed strong staining in 52.83% of the cases, followed by Notch 1 (35.85%), HES 1 and HES 5 moderate staining in 72.73% and 57.69% of the cases, respectively, and Delta 1 weak staining in 58.33% of the cases. No statistical correlation was found between the antibodies and the sex or the age of the study group. Notch is an evolutionarily conserved signaling mechanism that regulates cell fate decisions during development and postnatal life in organisms as diverse as worms, flies, and humans. The present observations indicate that Notch pathway is active downstream in the lining epithelium of periapical cysts, suggesting an involvement of this pathway in periapical cyst growth and expansion. Copyright © 2011 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Geometry of polynomials and root-finding via path-lifting

Science.gov (United States)

Kim, Myong-Hi; Martens, Marco; Sutherland, Scott

2018-02-01

Using the interplay between topological, combinatorial, and geometric properties of polynomials and analytic results (primarily the covering structure and distortion estimates), we analyze a path-lifting method for finding approximate zeros, similar to those studied by Smale, Shub, Kim, and others. Given any polynomial, this simple algorithm always converges to a root, except on a finite set of initial points lying on a circle of a given radius. Specifically, the algorithm we analyze consists of iterating where the t k form a decreasing sequence of real numbers and z 0 is chosen on a circle containing all the roots. We show that the number of iterates required to locate an approximate zero of a polynomial f depends only on log\\vert f(z_0)/ρ_\\zeta\\vert (where ρ_\\zeta is the radius of convergence of the branch of f-1 taking 0 to a root ζ) and the logarithm of the angle between f(z_0) and certain critical values. Previous complexity results for related algorithms depend linearly on the reciprocals of these angles. Note that the complexity of the algorithm does not depend directly on the degree of f, but only on the geometry of the critical values. Furthermore, for any polynomial f with distinct roots, the average number of steps required over all starting points taken on a circle containing all the roots is bounded by a constant times the average of log(1/ρ_\\zeta) . The average of log(1/ρ_\\zeta) over all polynomials f with d roots in the unit disk is \

Asymmetric cell division and Notch signaling specify dopaminergic neurons in Drosophila.

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Murni Tio

Full Text Available In Drosophila, dopaminergic (DA neurons can be found from mid embryonic stages of development till adulthood. Despite their functional involvement in learning and memory, not much is known about the developmental as well as molecular mechanisms involved in the events of DA neuronal specification, differentiation and maturation. In this report we demonstrate that most larval DA neurons are generated during embryonic development. Furthermore, we show that loss of function (l-o-f mutations of genes of the apical complex proteins in the asymmetric cell division (ACD machinery, such as inscuteable and bazooka result in supernumerary DA neurons, whereas l-o-f mutations of genes of the basal complex proteins such as numb result in loss or reduction of DA neurons. In addition, when Notch signaling is reduced or abolished, additional DA neurons are formed and conversely, when Notch signaling is activated, less DA neurons are generated. Our data demonstrate that both ACD and Notch signaling are crucial mechanisms for DA neuronal specification. We propose a model in which ACD results in differential Notch activation in direct siblings and in this context Notch acts as a repressor for DA neuronal specification in the sibling that receives active Notch signaling. Our study provides the first link of ACD and Notch signaling in the specification of a neurotransmitter phenotype in Drosophila. Given the high degree of conservation between Drosophila and vertebrate systems, this study could be of significance to mechanisms of DA neuronal differentiation not limited to flies.

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch*

Science.gov (United States)

Harvey, Beth M.; Rana, Nadia A.; Moss, Hillary; Leonardi, Jessica; Jafar-Nejad, Hamed; Haltiwanger, Robert S.

2016-01-01

Glycosylation of the Notch receptor is essential for its activity and serves as an important modulator of signaling. Three major forms of O-glycosylation are predicted to occur at consensus sites within the epidermal growth factor-like repeats in the extracellular domain of the receptor: O-fucosylation, O-glucosylation, and O-GlcNAcylation. We have performed comprehensive mass spectral analyses of these three types of O-glycosylation on Drosophila Notch produced in S2 cells and identified peptides containing all 22 predicted O-fucose sites, all 18 predicted O-glucose sites, and all 18 putative O-GlcNAc sites. Using semiquantitative mass spectral methods, we have evaluated the occupancy and relative amounts of glycans at each site. The majority of the O-fucose sites were modified to high stoichiometries. Upon expression of the β3-N-acetylglucosaminyltransferase Fringe with Notch, we observed varying degrees of elongation beyond O-fucose monosaccharide, indicating that Fringe preferentially modifies certain sites more than others. Rumi modified O-glucose sites to high stoichiometries, although elongation of the O-glucose was site-specific. Although the current putative consensus sequence for O-GlcNAcylation predicts 18 O-GlcNAc sites on Notch, we only observed apparent O-GlcNAc modification at five sites. In addition, we performed mass spectral analysis on endogenous Notch purified from Drosophila embryos and found that the glycosylation states were similar to those found on Notch from S2 cells. These data provide foundational information for future studies investigating the mechanisms of how O-glycosylation regulates Notch activity. PMID:27268051

The influence of temperature dynamics and dynamic finite ion Larmor radius effects on seeded high amplitude plasma blobs

DEFF Research Database (Denmark)

Held, Magnus; Wiesenberger, M.; Madsen, Jens

2016-01-01

Thermal effects on the perpendicular convection of seeded pressure blobs in the scrape-off layer of magnetised fusion plasmas are investigated. Our numerical study is based on a four field full-F gyrofluid model, which entails the consistent description of high fluctuation amplitudes and dynamic...... finite Larmor radius effects. We find that the maximal radial blob velocity increases with the square root of the initial pressure perturbation and that a finite Larmor radius contributes to highly compact blob structures that propagate in the poloidal direction. An extensive parameter study reveals...... that a smooth transition to this compact blob regime occurs when the finite Larmor radius effect strength, defined by the ratio of the magnetic field aligned component of the ion diamagnetic to the E × B vorticity, exceeds unity. The maximal radial blob velocities agree excellently with the inertial velocity...

Notch signalling mediates reproductive constraint in the adult worker honeybee

Science.gov (United States)

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

2016-01-01

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

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

DEFF Research Database (Denmark)

Kristoffersen, Karina; Nedergaard, Mette Kjølhede; Villingshøj, Mette

2014-01-01

BACKGROUND: 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. METHODS: Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing...

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.

Directory of Open Access Journals (Sweden)

Richa Tripathi

Full Text Available 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.

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

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Neeta Bala Tannan

2018-01-01

Full Text Available 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.

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

Science.gov (United States)

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.

Application and validation of the notch master curve in medium and high strength structural steels

Energy Technology Data Exchange (ETDEWEB)

Cicero, Sergio; Garcia, Tiberio [Universidad de Cantabria, Santander (Spain); Madrazo, Virginia [PCTCAN, Santander (Spain)

2015-10-15

This paper applies and validates the Notch master curve in two ferritic steels with medium (steel S460M) and high (steel S690Q) strength. The Notch master curve is an engineering tool that allows the fracture resistance of notched ferritic steels operating within their corresponding ductile-to-brittle transition zone to be estimated. It combines the Master curve and the Theory of critical distances in order to take into account the temperature and the notch effect respectively, assuming that both effects are independent. The results, derived from 168 fracture tests on notched specimens, demonstrate the capability of the Notch master curve for the prediction of the fracture resistance of medium and high strength ferritic steels operating within their ductile-to-brittle transition zone and containing notches.

Theoretical and experimental study of Chen chaotic system with notch filter feedback control

International Nuclear Information System (INIS)

Ming, Zhang Xiao; Jian-Hua, Peng; Ju-Fang, Chen

2010-01-01

Since the past two decades, the time delay feedback control method has attracted more and more attention in chaos control studies because of its simplicity and efficiency compared with other chaos control schemes. Recently, it has been proposed to suppress low-dimensional chaos with the notch filter feedback control method, which can be implemented in a laser system. In this work, we have analytically determined the controllable conditions for notch filter feedback controlling of Chen chaotic system in terms of the Hopf bifurcation theory. The conditions for notch filter feedback controlled Chen chaoitc system having a stable limit cycle solution are given. Meanwhile, we also analysed the Hopf bifurcation direction, which is very important for parameter settings in notch filter feedback control applications. Finally, we apply the notch filter feedback control methods to the electronic circuit experiments and numerical simulations based on the theoretical analysis. The controlling results of notch filter feedback control method well prove the feasibility and reliability of the theoretical analysis. (general)

Genetic screens to identify new Notch pathway mutants in Drosophila.

Science.gov (United States)

Giagtzoglou, Nikolaos

2014-01-01

Notch signaling controls a wide range of developmental processes, including proliferation, apoptosis, and cell fate specification during both development and adult tissue homeostasis. The functional versatility of the Notch signaling pathway is tightly linked with the complexity of its regulation in different cellular contexts. To unravel the complexity of Notch signaling, it is important to identify the different components of the Notch signaling pathway. A powerful strategy to accomplish this task is based on genetic screens. Given that the developmental context of signaling is important, these screens should be customized to specific cell populations or tissues. Here, I describe how to perform F1 clonal forward genetic screens in Drosophila to identify novel components of the Notch signaling pathway. These screens combine a classical EMS (ethyl methanesulfonate) chemical mutagenesis protocol along with clonal analysis via FRT-mediated mitotic recombination. These F1 clonal screens allow rapid phenotypic screening within clones of mutant cells induced at specific developmental stages and in tissues of interest, bypassing the pleiotropic effects of isolated mutations. More importantly, since EMS mutations have been notoriously difficult to map to specific genes in the past, I briefly discuss mapping methods that allow rapid identification of the causative mutations.

Root activity pattern of banana under irrigated and rain conditions

International Nuclear Information System (INIS)

Sobhana, A.; Aravindakshan, M.; Wahid, P.A.

1989-01-01

Root morphology by excavation method and root activity pattern by 32 P soil-injection technique have been studied in banana var., Nendran under rainfed/irrigated conditions. The number of roots, length and diameter of roots and dry weight of roots were found to be more for the rainfed banana crop compared to the irrigated. The results of the radiotracer studies indicated that about 60 per cent of the active roots of irrigated banana lie within 20 cm distance and about 90 per cent of the total root activity is found within 40 cm distance from the plant. In the case of rainfed crop about 85 per cent of the active roots were found within a radius of 40 cm around the plant. Active roots were found to be more concentrated at 15 to 30 cm depth under rainfed conditions while the density of active roots was more or less uniform along the profile upto a dpeth of 60 cm in irrigated banana. (author). 4 refs., 3 figs

Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.

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Zhao-Jun Liu

Full Text Available Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM. They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1(Flox/Flox embryonic fibroblasts (MEFs. Notch1-deficient (Notch1(-/- MEFs displayed faster growth and motility rate compared to Notch1(Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1 in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441, which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1. Functionally, "Notch-activated" stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4 in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.

Effect of delaminations on improvement of notch toughness at low temperatures

International Nuclear Information System (INIS)

Zhou, W.; Loh, N.L.

1996-01-01

The notched-bar impact test is often used to assess the notch toughness of engineering materials. The principle of the test is that a material absorbs a certain amount of energy when it breaks; the energy thus absorbed is an indication of the material's resistance to impact fracture. If the material is brittle, it breaks easily with a small amount of absorbed energy. If it is tough, it will absorb more energy to fracture. It has been well recognized that most engineering materials undergo a transition from notch tough to notch brittle behavior when the temperature is reduced. In the present study, however, an abnormal trend in the transition behavior was found for an austenitic stainless steel. V-notched specimens of the steel were tested under impact loading in a wide temperature range from -196 C to room temperature. Contrary to expectation, the impact energy values obtained at low temperatures were found to be much higher than those obtained at room temperature, indicating that the steel became tougher rather than more brittle when the test temperature was lowered. This intriguing phenomenon cannot be explained simply according to the tensile stress fracture criterion. Strong evidence has been obtained in the present study to show that the improvement of notch toughness at low temperatures is caused by delaminations

Volar plating for distal radius fractures--do not trust the image intensifier when judging distal subchondral screw length.

Science.gov (United States)

Park, Derek H; Goldie, Boyd S

2012-09-01

The use of the volar plate to treat distal radius fractures is increasing but despite the theoretical advantages of a volar approach there have been reports of extensor tendon ruptures due to prominent screw tips protruding past the dorsal cortex. The valley in the intermediate column between Lister tubercle and the sigmoid notch of the distal radius makes it difficult to rely on fluoroscopy to judge screw length. Our aim was to quantify the dimensions of this valley and to demonstrate the danger of relying on intraoperative image intensification fluoroscopy to determine lengths of distal screws. We measured the depth of this valley in the intermediate column of the distal radius in 33 patients with computed tomographic (9 patients) or magnetic resonance image (24 patients) scans of the wrist. There was a consistent valley in all images examined [average 1.8 mm (95% confidence interval, 1.6-2.0 mm)]. Thirty-nine percent of wrists had a valley depth of at least 2 mm. Standard lateral views or rotation of the forearm to obtain oblique views does not identify prominent screw tips; and whatever the rotation of the forearm, screw tips protruding beyond dorsal cortex may look as if it is within the bone when in fact it is out. When drilling we suggest noting the depth at which the drill bit just penetrates dorsal cortex and routinely downsize the distal screw length by 2 mm. We caution against relying on flourosocopy when judging the length of the distal subchondral screws.

Notch2 transduction by feline leukemia virus in a naturally infected cat.

Science.gov (United States)

Watanabe, Shinya; Ito, Jumpei; Baba, Takuya; Hiratsuka, Takahiro; Kuse, Kyohei; Ochi, Haruyo; Anai, Yukari; Hisasue, Masaharu; Tsujimoto, Hajime; Nishigaki, Kazuo

2014-04-01

Feline leukemia virus (FeLV) induces neoplastic and nonneoplastic diseases in cats. The transduction of cellular genes by FeLV is sometimes observed and associated with neoplastic diseases including lymphoma and sarcoma. Here, we report the first natural case of feline Notch2 transduction by FeLV in an infected cat with multicentric lymphoma and hypercalcemia. We cloned recombinant FeLVs harboring Notch2 in the env gene. Notch2 was able to activate expression of a reporter gene, similar to what was previously reported in cats with experimental FeLV-induced thymic lymphoma. Our findings suggest that the transduction of Notch2 strongly correlates with FeLV-induced lymphoma.

The Evolution of the Maine Lobster V-Notch Practice: Cooperation in a Prisoner's Dilemma Game

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James Acheson

2011-03-01

Full Text Available The Maine lobster industry is experiencing record high catches because, in all probability, of an effective management program. One of the most important conservation measures is the V-notch program that allows fishermen to conserve proven breeding females by notching the tails of egg-bearing lobsters. Such marked lobsters may never be taken. Although thousands of lobster fishermen participate, it is a voluntary practice. The genesis of this practice is not easily explained, because V-notching poses a prisoner's dilemma problem that gives fishermen an incentive to avoid the practice. The most common explanations for ways to overcome prisoner's dilemma problems will not work in the case of the V-notch. An unusual combination of factors explains the V-notch program: (1 a strong belief among those in the industry that the V-notch is effective in conserving the lobster stock; (2 a low discount rate because the long-term gains from V-notching are higher than the one-time gain from defection; (3 a gain in reputation for those who V-notch. At the start of the 20th century, fishermen did not V-notch; by the end of the century, V-notching was common. We explain the change in strategies using a three-parameter evolutionary model that emphasizes the importance of culture change.

Identification of 11-amino acid peptides that disrupt Notch-mediated processes in Drosophila

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Yeh Hsiao-Fong

2011-06-01

Full Text Available Abstract Background The conserved Notch signaling pathway regulates cell fate decisions and maintains stem cells in multicellular organisms. Up-regulation of Notch signaling is observed in several types of cancer and is causally involved in proliferation and survival of cancer cells. Thus, it is of great interest to look for anti-Notch reagents for therapeutic purposes. In model animal Drosophila, Notch signaling restricts selection of sensory organ precursors (SOPs during external sensory (ES organ development. To look for novel genes that can suppress Notch signaling, we performed a gain-of-function modifier screen to look for genes that enhance the phenotype of ectopic ES organs induced by overexpression of phyllopod, a gene required for SOP specification. Results From the gain-of-function screen, we discovered that overexpression of polished rice/tarsal-less (pri/tal increases the numbers of ES organs as well as SOPs. pri/tal is a polycistronic gene that contains four short open reading frames encoding three 11-amino acid and one 32-amino acid peptides. Ectopic expression of the 11 amino-acid peptides recapitulates the pri/tal misexpression phenotype in ectopic ES organ formation. In situ hybridization experiment reveals that pri/tal mRNA is expressed in the SOPs of the chemosensory organs and the stretch-sensing chordotonal organs. In Drosophila wing development, the Notch signaling pathway mediates the formation of the dorsal-ventral (DV compartmental boundary and the restriction of the vein width from the primordial veins, the proveins. We also found that pri/tal mRNA is expressed in the DV boundary and the longitudinal proveins, and overexpression of Pri/Tal peptides disrupts the DV boundary formation and helps to expand the width of the wing vein. Genetic analyses further show that a Notch loss-of-function allele strongly enhances these two phenotypes. Cut and E(splmβ are target genes of the Notch pathway in DV boundary formation and

Tensile behavior of unnotched and notched tungsten--copper laminar composites

International Nuclear Information System (INIS)

Hoffman, C.A.

1976-06-01

Relations were studied between the tensile strengths of unnotched and of notched, and elastic moduli of unnotched laminar sheet or foil composites and the amounts of reinforcement. Tungsten was used as the reinforcement and copper as the matrix, and the tests were run at room temperature. Three thicknesses of tungsten (i.e., 0.00254, 0.0127, and 0.0254 cm (0.001, 0.005, and 0.010 in) were used, and the nominal volume fraction of tungsten was varied from about 0.05 to 0.95. It was found that the tensile strength of the unnotched specimens could be related to the amount of reinforcement, as could the elastic moduli, and that these values could be predicted by use of the rule of mixtures. The tensile strengths of the notched laminar composites could be predicted by use of the rule of mixtures using strengths for notched constituents, provided notch effects did not predominate. (Author)

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

Science.gov (United States)

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

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

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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

Planar Ultrawideband Antenna with Photonically Controlled Notched Bands

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Drasko Draskovic

2013-01-01

Full Text Available A design of a planar microstrip-fed ultrawideband (UWB printed circular monopole antenna with optically controlled notched bands is presented. The proposed antenna is composed of a circular ultrawideband patch, with an etched T-shaped slot controlled by an integrated silicon switch. The slot modifies the frequency response of the antenna suppressing 3.5–5 GHz band when the switch is in open state. The optical switch is controlled by a low-power near-infrared (808 nm laser diode, which causes the change in the frequency response of the antenna generating a frequency notch. This solution could be expanded to include several notches in the antenna frequency response achieving a fully reconfigurable UWB antenna. The antenna could be remotely controlled at large distances using optical fiber. The prototype antenna has been fully characterized to verify these design concepts.

RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice.

Science.gov (United States)

Schouwey, K; Aydin, I T; Radtke, F; Beermann, F

2011-01-20

The Notch signaling pathway is an ubiquitous cell-cell interaction mechanism, which is essential in controlling processes like cell proliferation, cell fate decision, differentiation or stem cell maintenance. Recent data have shown that Notch signaling is RBP-Jκ-dependent in melanocytes, being required for survival of these pigment cells that are responsible for coloration of the skin and hairs in mammals. In addition, Notch is believed to function as an oncogene in melanoma, whereas it is a tumor suppressor in mouse epidermis. In this study, we addressed the implication of the Notch signaling in the development of another population of pigment cells forming the retinal pigment epithelium (RPE) in mammalian eyes. The constitutive activity of Notch in Tyrp1::NotchIC/° transgenic mice enhanced RPE cell proliferation, and the resulting RPE-derived pigmented tumor severely affected the overall eye structure. This RPE cell proliferation is dependent on the presence of the transcription factor RBP-Jκ, as it is rescued in mice lacking RBP-Jκ in the RPE. In conclusion, Notch signaling in the RPE uses the canonical pathway, which is dependent on the transcription factor RBP-Jκ. In addition, it is of importance for RPE development, and constitutive Notch activity leads to hyperproliferation and benign tumors of these pigment cells.

Electroacupuncture pretreatment induces tolerance against focal cerebral ischemia through activation of canonical Notch pathway

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Zhao Yu

2012-09-01

Full Text Available Abstract Background Electroacupuncture (EA pretreatment can induce the tolerance against focal cerebral ischemia. However, the underlying mechanisms have not been fully understood. Emerging evidences suggest that canonical Notch signaling may be involved in ischemic brain injury. In the present study, we tested the hypothesis that EA pretreatment-induced tolerance against focal cerebral ischemia is mediated by Notch signaling. Results EA pretreatment significantly enhanced Notch1, Notch4 and Jag1 gene transcriptions in the striatum, except Notch1 intracellular domain level, which could be increased evidently by ischemia. After ischemia and reperfusion, Hes1 mRNA and Notch1 intracellular domain level in ischemic striatum in EA pretreatment group were increased and reached the peak at 2 h and 24 h, respectively, which were both earlier than the peak achieved in control group. Intraventricular injection with the γ-secretase inhibitor MW167 attenuated the neuroprotective effect of EA pretreatment. Conclusions EA pretreatment induces the tolerance against focal cerebral ischemia through activation of canonical Notch pathway.

Notch activation is dispensable for D, L-sulforaphane-mediated inhibition of human prostate cancer cell migration.

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Eun-Ryeong Hahm

Full Text Available D, L-Sulforaphane (SFN, a synthetic racemic analog of broccoli constituent L-sulforaphane, is a highly promising cancer chemopreventive agent with in vivo efficacy against chemically-induced as well as oncogene-driven cancer in preclinical rodent models. Cancer chemopreventive effect of SFN is characterized by G(2/M phase cell cycle arrest, apoptosis induction, and inhibition of cell migration and invasion. Moreover, SFN inhibits multiple oncogenic signaling pathways often hyperactive in human cancers, including nuclear factor-κB, Akt, signal transducer and activator of transcription 3, and androgen receptor. The present study was designed to determine the role of Notch signaling, which is constitutively active in many human cancers, in anticancer effects of SFN using prostate cancer cells as a model. Exposure of human prostate cancer cells (PC-3, LNCaP, and/or LNCaP-C4-2B to SFN as well as its naturally-occurring thio-, sulfinyl-, and sulfonyl-analogs resulted in cleavage (activation of Notch1, Notch2, and Notch4, which was accompanied by a decrease in levels of full-length Notch forms especially at the 16- and 24-hour time points. The SFN-mediated cleavage of Notch isoforms was associated with its transcriptional activation as evidenced by RBP-Jk-, HES-1A/B- and HEY-1 luciferase reporter assays. Migration of PC-3 and LNCaP cells was decreased significantly by RNA interference of Notch1 and Notch2, but not Notch4. Furthermore, SFN-mediated inhibition of PC-3 and LNCaP cell migration was only marginally affected by knockdown of Notch1 and Notch2. Strikingly, SFN administration to Transgenic Adenocarcinoma of Mouse Prostate transgenic mice failed to increase levels of cleaved Notch1, cleaved Notch2, and HES-1 proteins in vivo in prostatic intraepithelial neoplasia, well-differentiated carcinoma or poorly-differentiated prostate cancer lesions. These results indicate that Notch activation is largely dispensable for SFN-mediated inhibition of cell

Critical applied stresses for a crack initiation from a sharp V-notch

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L. Náhlík

2014-10-01

Full Text Available The aim of the paper is to estimate a value of the critical applied stress for a crack initiation from a sharp V-notch tip. The classical approach of the linear elastic fracture mechanics (LELM was generalized, because the stress singularity exponent differs from 0.5 in the studied case. The value of the stress singularity exponent depends on the V-notch opening angle. The finite element method was used for a determination of stress distribution in the vicinity of the sharp V-notch tip and for the estimation of the generalized stress intensity factor depending on the V-notch opening angle. Critical value of the generalized stress intensity factor was obtained using stability criteria based on the opening stress component averaged over a critical distance d from the V-notch tip and generalized strain energy density factor. Calculated values of the critical applied stresses were compared with experimental data from the literature and applicability of the LEFM concept is discussed.

Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice.

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Silvia Fre

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

Experience with the Notch Stress Approach for Fatigue Assessment of Welded Joints

DEFF Research Database (Denmark)

Pedersen, Mikkel Melters; Mouritsen, Ole Ø.; Hansen, Michael Rygaard

2010-01-01

In this paper, fatigue assessment using the notch stress approach is discussed based on re-analysis of many fatigue test results and experience from practical application. Three topics are treated; evaluation of the fatigue strength for as-welded details (FAT225) in the notch stress system......, problems regarding assessment of mild-SCF details and a novel proposal for extension of the notch stress approach for use with post-weld treated details....

Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium.

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Elmadhun, Nassrene Y; Sabe, Ashraf A; Lassaletta, Antonio D; Chu, Louis M; Kondra, Katelyn; Sturek, Michael; Sellke, Frank W

2014-09-01

Impaired angiogenesis is a known consequence of metabolic syndrome (MetS); however, the mechanism is not fully understood. Recent studies have shown that the notch signaling pathway is an integral component of cardiac angiogenesis. We tested, in a clinically relevant swine model, the effects of MetS on notch and apoptosis signaling in chronically ischemic myocardium. Ossabaw swine were fed either a regular diet (control [CTL], n = 8) or a high-cholesterol diet (MetS, n = 8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, the wine underwent cardiac harvest of the ischemic myocardium. Downregulation of pro-angiogenesis proteins notch2, notch4, jagged2, angiopoietin 1, and endothelial nitric oxide synthase were found in the MetS group compared with the CTL group. Also, upregulation of pro-apoptosis protein caspase 8 and downregulation of anti-angiogenesis protein phosphorylated forkhead box transcription factor 03 and pro-survival proteins phosphorylated P38 and heat shock protein 90 were present in the MetS group. Cell death was increased in the MetS group compared with the CTL group. Both CTL and MetS groups had a similar arteriolar count and capillary density, and notch3 and jagged1 were both similarly concentrated in the smooth muscle wall. MetS in chronic myocardial ischemia significantly impairs notch signaling by downregulating notch receptors, ligands, and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling, and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, suggesting that inhibition of notch signaling might underlie the decreased angiogenesis in later stages of MetS. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Prognostic value of Notch-1 expression in hepatocellular carcinoma: a meta-analysis

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Wu T

2015-10-01

Full Text Available Tao Wu,1 Min Jiao,1 Li Jing,1 Min-Cong Wang,1 Hai-Feng Sun,2 Qing Li,1 Yi-Yang Bai,1 Yong-Chang Wei,1 Ke-Jun Nan,1 Hui Guo1 1Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, 2Department of Oncology, Shaanxi Cancer Hospital, Xi’an, People’s Republic of China Abstract: Association of Notch-1 expression with prognosis of patients with hepatocellular carcinoma (HCC remains controversial. We conducted a meta-analysis to reevaluate the association of Notch-1 expression with clinicopathological characteristics and prognosis of HCC. PubMed, Embase, Web of Science, and China National Knowledge Infrastructure were searched to look for relevant studies. The association between Notch-1 expression and clinicopathological parameters and overall survival (OS was then reassessed using the meta-analysis for odds ratio (OR or hazard ratio (HR and 95% confidence interval (CI. A total of seven studies, including 810 HCC patients, were eligible for the meta-analysis. Our data showed that high Notch-1 expression was able to predict poor OS (HR 1.50, 95% CI 1.17–1.83, P=0.0001. The pooled OR showed that high Notch-1 expression was significantly associated with tumor metastasis (OR 0.37, 95% CI 0.16–0.86, P=0.02 and tumor size >5 cm (OR 0.48, 95% CI 0.26–0.88, P=0.02. In contrast, there was no association between high Notch-1 expression and tumor differentiation, late TNM stage, tumor number, and portal vein invasion of HCC. In conclusion, Notch-1 overexpression might predict poorer survival and more aggressive behavior in patients with HCC. Keywords: hepatocellular carcinoma, Notch-1, prognosis, clinicopathological features, meta-analysis

Damage Study in Notched Particulate Composie Specimens Under Nonuniform Strain Loading

National Research Council Canada - National Science Library

Kwon, Y

1999-01-01

.... The numerical specimen considered had a semi-circular notch with a linearly varying length. The initial crack size occurring at the notch tip was modeled and predicted using a micro/macro-approach along with a damage model...

Spoof surface plasmon polaritons based notch filter for ultra-wideband microwave waveguide

DEFF Research Database (Denmark)

Xiao, Binggang; Li, Sheng-Hua; Xiao, Sanshui

2016-01-01

Spoof surface plasmon polaritons based notch filter for ultra-wideband microwave waveguide is proposed. Owing to subwavelength confinement, such a filter has advantage in the structure size without sacrificing the performance. The spoof SPP based notch is introduced to suppress the WLAN and satel...... and satellite communication signals. Due to planar structures proposed here, it is easy to integrate in the microwave integrated systems, which can play an important role in the microwave communication circuit and system.......Spoof surface plasmon polaritons based notch filter for ultra-wideband microwave waveguide is proposed. Owing to subwavelength confinement, such a filter has advantage in the structure size without sacrificing the performance. The spoof SPP based notch is introduced to suppress the WLAN...

Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway.

Science.gov (United States)

Gao, Feng; Yao, Min; Cao, Yanping; Liu, Shuxia; Liu, Qingjuan; Duan, Huijun

2016-05-01

The Notch pathway is known to be linked to diabetic nephropathy (DN); however, its underlying mechanism was poorly understood. In the present study, we examined the effect of Valsartan, an angiotensin II type 1 receptor antagonist, on the Notch pathway and podocyte loss in DN. Diabetes was induced in mice by an intraperitoneal injection of streptozotocin and and this was followed by treatment with Valsartan. Levels of blood glucose, kidney weight and body weight, as well as proteinuria were measured. Samples of the kidneys were also histologically examined. The relative levels of Jagged1, Notch1, Notch intracellular domain 1 (NICD1), Hes family BHLH transcription factor 1 (Hes1) and Hes-related family BHLH transcription factor with YRPW motif 1 expression (Hey1) in the glomeruli were determined by immunohistochemical analysis, western blot analysis and RT-qPCR. The B-Cell CLL/Lymphoma 2 (Bcl-2) and p53 pathways were examined by western blot analysis. Apoptosis and detachment of podocytes from the glomerular basement membrane were examined using a TUNEL assay, flow cytometric analysis and ELISA. The number of podocytes was quantified by measuring Wilms tumor-1 (WT-1) staining. We noted that the expression of Jagged1, Notch1, NICD1, Hes1 and Hey1 was increased in a time-dependent manner in the glomeruli of mice with streptozotocin (STZ)-induced diabetes. Moreover, in diabetic mice, Valsartan significantly reduced kidney weight and proteinuria, and mitigated the pathogenic processes in the kidneys. Valsartan also inhibited the activation of Notch, Bcl-2 and p53 pathways and ameliorated podocyte loss in the glomeruli of mice with STZ-induced diabetes. Taken together, these findings indicated that Valsartan exerted a beneficial effect on reducing podocyte loss, which is associated with inhibition of Notch pathway activation in the glomeruli of diabetic mice.

Role of Notch signalling pathway in cancer and its association with ...

Indian Academy of Sciences (India)

The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organ- ... Abnormal Notch signalling is seen in many cancers like T-cell acute ...... Morgan T. H. 1917 The theory of the gene.

Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages.

Science.gov (United States)

Palaga, Tanapat; Ratanabunyong, Siriluk; Pattarakankul, Thitiporn; Sangphech, Naunpun; Wongchana, Wipawee; Hadae, Yukihiro; Kueanjinda, Patipark

2013-09-01

Macrophages are cellular targets for infection by bacteria and viruses. The fate of infected macrophages plays a key role in determining the outcome of the host immune response. Apoptotic cell death of macrophages is considered to be a protective host defense that eliminates pathogens and infected cells. In this study, we investigated the involvement of Notch signaling in regulating apoptosis in macrophages treated with tuberculin purified protein derivative (PPD). Murine bone marrow-derived macrophages (BMMs) treated with PPD or infected with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) induced upregulation of Notch1. This upregulation correlated well with the upregulation of the anti-apoptotic gene mcl-1 both at the transcriptional and translational levels. Decreased levels of Notch1 and Mcl-1 were observed in BMM treated with PPD when a gamma secretase inhibitor (GSI), which inhibits the processing of Notch receptors, was used. Moreover, silencing Notch1 in the macrophage-like cell line RAW264.7 decreased Mcl-1 protein expression, suggesting that Notch1 is critical for Mcl-1 expression in macrophages. A significant increase in apoptotic cells was observed upon treatment of BMM with PPD in the presence of GSI compared to the vehicle-control treated cells. Finally, analysis of the mcl-1 promoter in humans and mice revealed a conserved potential CSL/RBP-Jκ binding site. The association of Notch1 with the mcl-1 promoter was confirmed by chromatin immunoprecipitation. Taken together, these results indicate that Notch1 inhibits apoptosis of macrophages stimulated with PPD by directly controlling the mcl-1 promoter.

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.

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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; pcervix tissue (0.95±0.20, 0.70±0.20; pcancer 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.

Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production.

Science.gov (United States)

Wanngren, Johanna; Ottervald, Jan; Parpal, Santiago; Portelius, Erik; Strömberg, Kia; Borgegård, Tomas; Klintenberg, Rebecka; Juréus, Anders; Blomqvist, Jenny; Blennow, Kaj; Zetterberg, Henrik; Lundkvist, Johan; Rosqvist, Susanne; Karlström, Helena

2012-09-21

The γ-secretase complex is an appealing drug target when the therapeutic strategy is to alter amyloid-β peptide (Aβ) aggregation in Alzheimer disease. γ-Secretase is directly involved in Aβ formation and determines the pathogenic potential of Aβ by generating the aggregation-prone Aβ42 peptide. Because γ-secretase mediates cleavage of many substrates involved in cell signaling, such as the Notch receptor, it is crucial to sustain these pathways while altering the Aβ secretion. A way of avoiding interference with the physiological function of γ-secretase is to use γ-secretase modulators (GSMs) instead of inhibitors of the enzyme. GSMs modify the Aβ formation from producing the amyloid-prone Aβ42 variant to shorter and less amyloidogenic Aβ species. The modes of action of GSMs are not fully understood, and even though the pharmacology of GSMs has been thoroughly studied regarding Aβ generation, knowledge is lacking about their effects on other substrates, such as Notch. Here, using immunoprecipitation followed by MALDI-TOF MS analysis, we found that two novel, second generation GSMs modulate both Notch β and Aβ production. Moreover, by correlating S3-specific Val-1744 cleavage of Notch intracellular domain (Notch intracellular domain) to total Notch intracellular domain levels using immunocytochemistry, we also demonstrated that Notch intracellular domain is not modulated by the compounds. Interestingly, two well characterized, nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drug), R-flurbiprofen and sulindac sulfide, affect only Aβ and not Notch β formation, indicating that second generation GSMs and nonsteroidal anti-inflammatory drug-based GSMs have different modes of action regarding Notch processing.

Prediction of multiaxial fatigue life for notched specimens of titanium alloy TC4

Energy Technology Data Exchange (ETDEWEB)

Wu, Z. R.; Li, Z. X. [Southeast University, Nanjing (China); Hu, X. T.; Song, Y. D. [Nanjing University, Nanjing (China)

2016-05-15

Both the proportional and nonproportional multiaxial fatigue tests were conducted on two kinds of notched specimens of titanium alloy TC4. The multiaxial fatigue critical area of notched specimen is considered as the location experiencing the maximum damage. It is unsatisfactory to predict the multiaxial fatigue life with the local stress and strain in the fatigue critical area. The critical distance concepts are employed in the multiaxial life prediction method for notched specimens. The proposed method was checked by the test data of TC4 notched specimens. The prediction results are almost within a factor of three scatter band of the test results.

Ultra-Wideband Notched Characteristic Fed by Coplanar Waveguide

Directory of Open Access Journals (Sweden)

Rastanto Hadinegoro

2015-02-01

Full Text Available In this paper, a novel Ultra-Wide Band (UWB notch patch antenna with co-planar waveguide (CPW fed is presented. This antenna only used one layer and the patch antenna is constructed on the first layer and back to back with CPW fed and bottom part is ground plane. The width notch is used to achieve the UWB characteristic. The results shown that the impedance bandwidth is 1130 MHz (1.662–2.792 GHz or about 50.7% for VSWR <2.

Estimations of creep behavior and failure life for a circumferentially notched specimen

International Nuclear Information System (INIS)

Kobayashi, Ken-ichi; Yokobori, Toshimitsu; Kikuchi, Kenji.

1997-01-01

No method with which to characterize and/or illustrate total creep behavior for specimens with notches, holes or cracks has been proposed. In this paper it is proposed that most creep curves can be drawn with a master curve for each creep test whenever test conditions and failure modes are similar to each other, and the lifetime ratio normalized by the rupture time is introduced. Using smooth and circumferentially notched specimens of 2.25 Cr-1 Mo steel, creep tests were performed at 600degC for examination of this concept. Furthermore, a θ projection method was used to describe creep curves for notched specimens and to extrapolate longer creep lives. Then, the whole creep curve shape for notched specimens could be easily drawn, except for that in the vicinity of the rupture point. However, longer creep lives of notched specimens were underestimated in comparison with a simple extrapolation of the experimental data. This resulted from the negative dependence of the parameter of θ 3 on the applied stress. (author)

Notch Signaling and Brain Tumors

DEFF Research Database (Denmark)

Stockhausen, Marie; Kristoffersen, Karina; Poulsen, Hans Skovgaard

2011-01-01

Human brain tumors are a heterogenous group of neoplasms occurring inside the cranium and the central spinal cord. In adults and children, astrocytic glioma and medulloblastoma are the most common subtypes of primary brain tumors. These tumor types are thought to arise from cells in which Notch...

Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros.

Science.gov (United States)

Naylor, Richard W; Jones, Elizabeth A

2009-11-01

Previous studies have highlighted a role for the Notch signalling pathway during pronephrogenesis in the amphibian Xenopus laevis, and in nephron development in the mammalian metanephros, yet a mechanism for this function remains elusive. Here, we further the understanding of how Notch signalling patterns the early X. laevis pronephros anlagen, a function that might be conserved in mammalian nephron segmentation. Our results indicate that early phase pronephric Notch signalling patterns the medio-lateral axis of the dorso-anterior pronephros anlagen, permitting the glomus and tubules to develop in isolation. We show that this novel function acts through the Notch effector gene hrt1 by upregulating expression of wnt4. Wnt-4 then patterns the proximal pronephric anlagen to establish the specific compartments that span the medio-lateral axis. We also identified pronephric expression of lunatic fringe and radical fringe that is temporally and spatially appropriate for a role in regulating Notch signalling in the dorso-anterior region of the pronephros anlagen. On the basis of these results, along with data from previous publications, we propose a mechanism by which the Notch signalling pathway regulates a Wnt-4 function that patterns the proximal pronephric anlagen.

Digital notch filter based active damping for LCL filters

DEFF Research Database (Denmark)

Yao, Wenli; Yang, Yongheng; Zhang, Xiaobin

2015-01-01

. In contrast, the active damping does not require any dissipation elements, and thus has become of increasing interest. As a result, a vast of active damping solutions have been reported, among which multi-loop control systems and additional sensors are necessary, leading to increased cost and complexity....... In this paper, a notch filter based active damping without the requirement of additional sensors is proposed, where the inverter current is employed as the feedback variable. Firstly, a design method of the notch filter for active damping is presented. The entire system stability has then been investigated...... in the z-domain. Simulations and experiments are carried out to verify the proposed active damping method. Both results have confirmed that the notch filter based active damping can ensure the entire system stability in the case of resonances with a good system performance....

Three-dimensional vibrations of cylindrical elastic solids with V-notches and sharp radial cracks

Science.gov (United States)

McGee, O. G.; Kim, J. W.

2010-02-01

This paper provides free vibration data for cylindrical elastic solids, specifically thick circular plates and cylinders with V-notches and sharp radial cracks, for which no extensive previously published database is known to exist. Bending moment and shear force singularities are known to exist at the sharp reentrant corner of a thick V-notched plate under transverse vibratory motion, and three-dimensional (3-D) normal and transverse shear stresses are known to exist at the sharp reentrant terminus edge of a V-notched cylindrical elastic solid under 3-D free vibration. A theoretical analysis is done in this work utilizing a variational Ritz procedure including these essential singularity effects. The procedure incorporates a complete set of admissible algebraic-trigonometric polynomials in conjunction with an admissible set of " edge functions" that explicitly model the 3-D stress singularities which exist along a reentrant terminus edge (i.e., α>180°) of the V-notch. The first set of polynomials guarantees convergence to exact frequencies, as sufficient terms are retained. The second set of edge functions—in addition to representing the corner stress singularities—substantially accelerates the convergence of frequency solutions. This is demonstrated through extensive convergence studies that have been carried out by the investigators. Numerical analysis has been carried out and the results have been given for cylindrical elastic solids with various V-notch angles and depths. The relative depth of the V-notch is defined as (1- c/ a), and the notch angle is defined as (360°- α). For a very small notch angle (1° or less), the notch may be regarded as a "sharp radial crack." Accurate (four significant figure) frequencies are presented for a wide spectrum of notch angles (360°- α), depths (1- c/ a), and thickness ratios ( a/ h for plates and h/ a for cylinders). An extended database of frequencies for completely free thick sectorial, semi-circular, and

Notch and hydrogen effects on sensitized 21-6-9 stainless steel

International Nuclear Information System (INIS)

Caskey, C.R. Jr.

1979-01-01

Type 21-6-9 stainless steel alloy is slightly notch sensitive in the solution annealed condition, a behavior that is aggravated by sensitization anneal at 920 0 K. The lower toughness of the sensitized alloy is a measure of microstructural embrittlement associated with carbide precipitation in grain boundaries. The tendency toward grain boundary fracture in the sensitized alloy is accentuated by stress concentration at the notch. Also, there is an increase in notch sensitivity when the alloy is tested in a high pressure (69 MPa) hydrogen environment, due to susceptibility of the grain boundaries to hydrogen embrittlement

Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad

Directory of Open Access Journals (Sweden)

Angelo Sparaneo

2016-01-01

Full Text Available The transcription factor Nrf2 (NF-E2 related factor 2 is a master regulator of the cell antioxidant response associated with tumor growth and resistance to cytotoxic treatments. In particular, Nrf2 induces upregulation of cytoprotective genes by interacting with the closely situated AREs (Antioxidant Response Elements in response to endogenous or exogenous stress stimuli and takes part to several oncogenic signaling pathways. Among these, the crosstalk with Notch pathway has been shown to enhance cytoprotection and maintenance of cellular homeostasis, tissue organization by modulating cell proliferation kinetics, and stem cell self-renewal in several organs. The role of Notch and Nrf2 related pathways in tumorigenesis is highly variable and when they are both abnormally activated they can synergistically cause neoplastic proliferation by promoting cell survival, differentiation, invasion, and metastases. NFE2L2, KEAP1, and NOTCH genes family appear in the list of significantly mutated genes in tumors in both combined and individual sets, supporting the crucial role that the aberrant Nrf2-Notch crosstalk might have in cancerogenesis. In this review, we summarize current knowledge about the alterations of Nrf2 and Notch pathways and their reciprocal transcriptional regulation throughout tumorigenesis and progression of lung tumors, supporting the potentiality of putative biomarkers and therapeutic targets.

Mechano sorptive behaviour of notched beams in bending

DEFF Research Database (Denmark)

Jensen, Signe Kamp; Hoffmeyer, Preben

1996-01-01

Short term bending tests with end-notched beams at constant or varying moisture content have shown an apparent contradictory dependency between moisture content and strength. The higher the moisture content the higher the strength. Varying moisture results in particularly significant differences...... and by neglecting deformation due to shear. Compression stresses perpendicular to grain in excess of 6 MPa were found in the vicinity of the notch following a period of adsorption. Similarly, small tension stresses of the order 1 MPa were registered in this area when the specimens were at their most dry condition...

Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

International Nuclear Information System (INIS)

Ma, Lijie; Dong, Pingping; Liu, Longzi; Gao, Qiang; Duan, Meng; Zhang, Si; Chen, She; Xue, Ruyi; Wang, Xiaoying

2016-01-01

Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.

Overexpression of protein O-fucosyltransferase 1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Ma, Lijie [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China); Dong, Pingping [Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai (China); Liu, Longzi; Gao, Qiang; Duan, Meng [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China); Zhang, Si; Chen, She [Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Xue, Ruyi, E-mail: xue.ruyi@zs-hospital.sh.cn [Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai (China); Wang, Xiaoying, E-mail: xiaoyingwang@fudan.edu.cn [Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai (China)

2016-04-29

Aberrant activation of Notch signaling frequently occurs in liver cancer, and is associated with liver malignancies. However, the mechanisms regulating pathologic Notch activation in hepatocellular carcinoma (HCC) remain unclear. Protein O-fucosyltransferase 1 (Pofut1) catalyzes the addition of O-linked fucose to the epidermal growth factor-like repeats of Notch. In the present study, we detected the expression of Pofut1 in 8 HCC cell lines and 253 human HCC tissues. We reported that Pofut1 was overexpressed in HCC cell lines and clinical HCC tissues, and Pofut1 overexpression clinically correlated with the unfavorable survival and high disease recurrence in HCC. The in vitro assay demonstrated that Pofut1 overexpression accelerated the cell proliferation and migration in HCC cells. Furthermore, Pofut1 overexpression promoted the binding of Notch ligand Dll1 to Notch receptor, and hence activated Notch signaling pathway in HCC cells, indicating that Pofut1 overexpression could be a reason for the aberrant activation of Notch signaling in HCC. Taken together, our findings indicated that an aberrant activated Pofut1-Notch pathway was involved in HCC progression, and blockage of this pathway could be a promising strategy for the therapy of HCC. - Highlights: • Pofut1 overexpression in HCC was correlated with aggressive tumor behaviors. • Pofut1 overexpression in HCC was associated with poor prognosis. • Pofut1 promoted cell proliferation, migration and invasion in hepatoma cells. • Pofut1 activated Notch signaling pathway in hepatoma cells.

Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways

International Nuclear Information System (INIS)

Talora, Claudio; Cialfi, Samantha; Segatto, Oreste; Morrone, Stefania; Kim Choi, John; Frati, Luigi; Paolo Dotto, Gian; Gulino, Alberto; Screpanti, Isabella

2005-01-01

Notch signaling plays a key role in cell-fate determination and differentiation in different organisms and cell types. Several reports suggest that Notch signaling may be involved in neoplastic transformation. However, in primary keratinocytes, Notch1 can function as a tumor suppressor. Similarly, in HPV-positive cervical cancer cells, constitutively active Notch1 signaling was found to cause growth suppression. Activated Notch1 in these cells represses viral E6/E7 expression through AP-1 down-modulation, resulting in increased p53 expression and a block of pRb hyperphosphorylation. Here we show that in cervical cancer cell lines in which Notch1 ability to repress AP-1 activity is impaired, Notch1-enforced expression elicits an alternative pathway leading to growth arrest. Indeed, activated Notch1 signaling suppresses activity of the helix-loop-helix transcription factor E47, via ERK1/2 activation, resulting in inhibition of cell cycle progression. Moreover, we found that RBP-Jκ-dependent Notch signaling is specifically repressed in cervical cancer cells and this repression could provide one such mechanism that needs to be activated for cervical carcinogenesis. Finally, we show that inhibition of endogenous Notch1 signaling, although results in a proliferative advantage, sensitizes cervical cancer cell lines to drug-induced apoptosis. Together, our results provide novel molecular insights into Notch1-dependent growth inhibitory effects, counteracting the transforming potential of HPV

Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background

Directory of Open Access Journals (Sweden)

Sara N. Koenig

2015-03-01

Full Text Available Thoracic aortic aneurysms (TAA are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/−; Nos3−/− mice. Echocardiographic analysis of Notch1+/−; Nos3−/− mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/−; Nos3−/− mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.

Acoustic emission during tensile deformation and fracture of nuclear grade AISI type 304 stainless steel specimens with notches

International Nuclear Information System (INIS)

Mukhopadhyay, C.K.; Jayakumar, T.; Baldev Raj

1996-01-01

Acoustic emission generated during tensile deformation and fracture of nuclear grade AISI type 304 stainless steel specimens with notches has been studied. The extent of acoustic activity generated depends on notch tip severity, notch tip blunting and tearing of the notches. The equation N=AK m applied to the acoustic emission data of the notched specimens has shown good correlation. Acoustic emission technique can be used to estimate the size of an unknown notch. (author)

Constitutively active Notch1 converts cranial neural crest-derived frontonasal mesenchyme to perivascular cells in vivo

Directory of Open Access Journals (Sweden)

Sophie R. Miller

2017-03-01

Full Text Available Perivascular/mural cells originate from either the mesoderm or the cranial neural crest. Regardless of their origin, Notch signalling is necessary for their formation. Furthermore, in both chicken and mouse, constitutive Notch1 activation (via expression of the Notch1 intracellular domain is sufficient in vivo to convert trunk mesoderm-derived somite cells to perivascular cells, at the expense of skeletal muscle. In experiments originally designed to investigate the effect of premature Notch1 activation on the development of neural crest-derived olfactory ensheathing glial cells (OECs, we used in ovo electroporation to insert a tetracycline-inducible NotchΔE construct (encoding a constitutively active mutant of mouse Notch1 into the genome of chicken cranial neural crest cell precursors, and activated NotchΔE expression by doxycycline injection at embryonic day 4. NotchΔE-targeted cells formed perivascular cells within the frontonasal mesenchyme, and expressed a perivascular marker on the olfactory nerve. Hence, constitutively activating Notch1 is sufficient in vivo to drive not only somite cells, but also neural crest-derived frontonasal mesenchyme and perhaps developing OECs, to a perivascular cell fate. These results also highlight the plasticity of neural crest-derived mesenchyme and glia.

The role of the transcription factor Rbpj in the development of dorsal root ganglia

Directory of Open Access Journals (Sweden)

Chen Jia-Yin

2011-04-01

Full Text Available Abstract Background The dorsal root ganglion (DRG is composed of well-characterized populations of sensory neurons and glia derived from a common pool of neural crest stem cells (NCCs, and is a good system to study the mechanisms of neurogenesis and gliogenesis. Notch signaling is known to play important roles in DRG development, but the full scope of Notch functions in mammalian DRG development remains poorly understood. Results In the present study, we used Wnt1-Cre to conditionally inactivate the transcription factor Rbpj, a critical integrator of activation signals from all Notch receptors, in NCCs and their derived cells. Deletion of Rbpj caused the up-regulation of NeuroD1 and precocious neurogenesis in DRG early development but led to an eventual deficit of sensory neurons at later stages, due to reduced cell proliferation and abnormal cell death. In addition, gliogenesis was delayed initially, but a near-complete loss of glia was observed finally in Rbpj-deficient DRG. Furthermore, we found P75 and Sox10, which are normally expressed exclusively in neuronal and glial progenitors of the DRG after the NCCs have completed their migration, were co-expressed in many cells of the DRG of Rbpj conditional knock-out mice. Conclusions Our data indicate that Rbpj-mediated canonical Notch signaling inhibits DRG neuronal differentiation, possibly by regulating NeuroD1 expression, and is required for DRG gliogenesis in vivo.

Fibre Optic Notch Filter For The Antiproton Decelerator Stochastic Cooling System

CERN Document Server

Simmonds, Max Vincent John

2016-01-01

The project scope included reverse engineering, upgrading, and recovering the operational conditions of an existing fibre optic notch filter. Once operational, tests were to be preformed to confirm the performance of the temperature stabilisation. The end goal is to use said notch filter in the Antiproton Decelerator (AD) facility at CERN to help aid antimatter research. The notch filter was successfully reverse engineered and then documented. Changes were made in order to increase performance and reliability, and also allow easy integration into the AD. An additional phase was added whereby the notch filter was to be controller via a touchscreen computer, situated next to the filter, allowing engineers to set-up each of the electronic devices used. While one of the devices (Motorised Delay Line) can be controlled by the touchscreen computer, the other two cannot.Due to time constraints and difficulties with the Beckhoff TwincatII programming language, the USB devices were not able to be controlled via the To...

Notch signaling in embryology and cancer

National Research Council Canada - National Science Library

Reichrath, J; Reichrath, Sandra

2012-01-01

"The goal of this volume is to comprehensively cover a highly readable overview on our present knowledge of the role of Notch signalling for embryology and cancer, with a focus on new findings in molecular biology...

Conditions for crack initiation in an orthotropic bi-material notch

Czech Academy of Sciences Publication Activity Database

Klusák, Jan; Profant, T.; Kotoul, M.

2012-01-01

Roč. 19, č. 4 (2012), s. 302-307 ISSN 1537-6494 R&D Projects: GA ČR GA101/08/0994; GA ČR GAP108/10/2049 Institutional support: RVO:68081723 Keywords : General singular stress concentrators * Fracture mechanics * Notch es * Bi-material notch es * Fracture mechanics Subject RIV: JL - Materials Fatigue, Friction Mechanics Impact factor: 0.701, year: 2012

On the notch ductility of a magnesium-rare earth alloy

Energy Technology Data Exchange (ETDEWEB)

Kondori, B., E-mail: bkondori.13034@tamu.edu [Department of Materials Science & Engineering, Texas A& M University, College Station, TX 77843 (United States); Benzerga, A.A. [Department of Materials Science & Engineering, Texas A& M University, College Station, TX 77843 (United States); Department of Aerospace Engineering, Texas A& M University, College Station, TX 77843 (United States)

2015-10-28

The room-temperature notch ductility of magnesium-rare earth alloy WE43 is investigated for two loading orientations. This material is endowed with quasi-isotropic plastic flow properties, higher strength and similar uniaxial ductility in comparison with other commercially available Mg alloys. The authors have recently shown that the notch ductility of a Mg–Al–Zn alloy is greater than its uniaxial ductility over a wide range of notch geometries. This paper investigates whether the same trends hold for WE43, discusses the orientation dependence of ductility and the propensity for intergranular fracture at high levels of hydrostatic tension. The latter mode of fracture is analyzed by means of detailed fractography in order to elucidate the role of grain-boundary particles and precipitates in the fracture process.

Notch Sensitivity of Fatigue Behavior of a Hi-Nicalon™/SiC-B4C Composite at 1,200 °C in Air and in Steam

Science.gov (United States)

Ruggles-Wrenn, M. B.; Kurtz, G.

2013-10-01

The effect of holes on the fatigue life of a non-oxide ceramic composite processed via chemical vapor infiltration (CVI) was examined at 1,200 °C in laboratory air and in steam. The effect of holes on tensile strength at 1,200 °C was also evaluated. The composite comprised laminated woven Hi-Nicalon™ fibers in an oxidation inhibited matrix, which consisted of alternating layers of silicon carbide and boron carbide. Fiber preforms had pyrolytic carbon fiber coating with boron carbon overlay applied. Unnotched specimens and specimens with a center hole having a radius to width ratio of 0.24 were tested in tension-tension fatigue at 0.1 Hz and at 1.0 Hz. The fatigue stresses ranged from 100 to 140 MPa in air and in steam. Fatigue run-out was defined as 105 cycles at 0.1 Hz and as 2 × 105 cycles at 1.0 Hz. The net-section strength was less than the unnotched ultimate tensile strength. Comparison of notched and unnotched data also revealed that the fatigue performance was notch insensitive in both air and steam environments. Composite microstructure, as well as damage and failure mechanisms were investigated.

Experimental and Numerical Analysis of Notched Composites Under Tension Loading

Science.gov (United States)

Aidi, Bilel; Case, Scott W.

2015-12-01

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

The Advanced Glaucoma Intervention Study (AGIS): 10. Variability among academic glaucoma subspecialists in assessing optic disc notching.

Science.gov (United States)

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

Notch signaling regulates platelet-derived growth factor receptor-β expression in vascular smooth muscle cells

NARCIS (Netherlands)

Jin, S.; Hansson, E.M.; Tikka, S.; Lanner, F.; Sahlgren, C.; Farnebo, F.; Baumann, M.; Kalimo, H.; Lendahl, U.

2008-01-01

Notch signaling is critically important for proper architecture of the vascular system, and mutations in NOTCH3 are associated with CADASIL, a stroke and dementia syndrome with vascular smooth muscle cell (VSMC) dysfunction. In this report, we link Notch signaling to platelet-derived growth factor

Minocycline attenuates the development of diabetic neuropathy by inhibiting spinal cord Notch signaling in rat.

Science.gov (United States)

Yang, Cheng; Gao, Jie; Wu, Banglin; Yan, Nuo; Li, Hui; Ren, Yiqing; Kan, Yufei; Liang, Jiamin; Jiao, Yang; Yu, Yonghao

2017-10-01

We studied the effects of minocycline (an inhibitor of microglial activation) on the expression and activity of Notch-1 receptor, and explored the therapeutic efficacy of minocycline combined with Notch inhibitor DAPT in the treatment of diabetic neuropathic pain (DNP). Diabetic rat model was established by intraperitoneal injection (ip) of Streptozotocin (STZ). Expression and activity of Notch-1 and expression of macrophage/microglia marker Iba-1 were detected by WB. Diabetes induction significantly attenuated sciatic nerve conduction velocity, and dramatically augmented the expression and the activity of Notch-1 in the lumbar enlargement of the spinal cord. Minocycline treatment, however, accelerated the decreased conduction velocity of sciatic nerve and suppressed Notch-1expression and activity in diabetic rats. Similar to DAPT treatment, minocycline administration also prolonged thermal withdrawal latency (TWL) and increase mechanical withdrawal threshold (MWT) in diabetic rats in response to heat or mechanical stimulation via inhibition the expression and the activity of Notch-1 in spinal cord. Combination of DAPT and minocycline further inhibited Notch-1 receptor signaling and reduce neuropathic pain exhibited as improved TWL and MWT. Our study revealed a novel mechanism of Notch-1 receptor inhibition in spinal cord induced by minocycline administration, and suggested that the combination of minocycline and DAPT has the potential to treat DNP. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche.

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Chen-Yuan Tseng

2014-12-01

Full Text Available Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs, and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age-dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self-renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion.

Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

Science.gov (United States)

Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

2016-01-01

Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

Design of UWB Filter with WLAN Notch

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Harish Kumar

2012-01-01

Full Text Available UWB technology- (operating in broad frequency range of 3.1–10.6 GHz based filter with WLAN notch has shown great achievement for high-speed wireless communications. To satisfy the UWB system requirements, a band pass filter with a broad pass band width, low insertion loss, and high stop-band suppression are needed. UWB filter with wireless local area network (WLAN notch at 5.6 GHz and 3 dB fractional bandwidth of 109.5% using a microstrip structure is presented. Initially a two-transmission-pole UWB band pass filter in the frequency range 3.1–10.6 GHz is achieved by designing a parallel-coupled microstrip line with defective ground plane structure using GML 1000 substrate with specifications: dielectric constant 3.2 and thickness 0.762 mm at centre frequency 6.85 GHz. In this structure a λ/4 open-circuited stub is introduced to achieve the notch at 5.6 GHz to avoid the interference with WLAN frequency which lies in the desired UWB band. The design structure was simulated on electromagnetic circuit simulation software and fabricated by microwave integrated circuit technique. The measured VNA results show the close agreement with simulated results.

Glioma cell fate decisions mediated by Dll1-Jag1-Fringe in Notch1 signaling pathway.

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Shi, Xiaofei; Wang, Ruiqi

2017-09-21

The Notch family of proteins plays a vital role in determining cell fates, such as proliferation, differentiation, and apoptosis. It has been shown that Notch1 and its ligands, Dll1 and Jag1, are overexpressed in many glioma cell lines and primary human gliomas. The roles of Notch1 in some cancers have been firmly established, and recent data implicate that it plays important roles in glioma cell fate decisions. This paper focuses on devising a specific theoretical framework that incorporates Dll1, Jag1, and Fringe in Notch1 signaling pathway to explore their functional roles of these proteins in glioma cells in the tumorigenesis and progression of human gliomas, and to study how glioma cell fate decisions are modulated by both trans-activation and cis-inhibition. This paper presents a computational model for Notch1 signaling pathway in glioma cells. Based on the bifurcation analysis of the model, we show that how the glioma cell fate decisions are modulated by both trans-activation and cis-inhibition mediated by the Fringe protein, providing insight into the design and control principles of the Notch signaling system and the gliomas. This paper presents a computational model for Notch1 signaling pathway in glioma cells based on intertwined dynamics with cis-inhibition and trans-activation involving the proteins Notch1, Dll1, Jag1, and Fringe. The results show that how the glioma cell fate transitions are performed by the Notch1 signaling. Transition from grade III ∼ IV with significantly high Notch1 to grade I ∼ II with high Notch1, and then to normal cells by repressing the Fringe levels or decreasing the strength of enhancement induced by Fringe.

Dll1- and Dll4-mediated Notch signaling is required for homeostasis of intestinal stem cells

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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

Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.

Science.gov (United States)

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.

Ever-changing proton radius?

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Mihovilovic, Miha [Institut fuer Kernphysik, Johannes-Gutenberg-Universitaet, Mainz (Germany)

2016-07-01

The discrepancy between the proton charge radius extracted from the muonic hydrogen Lamb shift measurement and the presently best value obtained from elastic scattering experiments remains unexplained and represents a burning problem of today's nuclear physics. Therefore, several new experiments are underway, committed to provide new insight into the problem. High-precision electron scattering experiments are in progress at the Jefferson Lab and the Mainz Microtron. As a counterpart to these measurements, a muon-proton scattering experiment is envisioned at the Paul Scherrer Institute. Together with the nuclear scattering experiments, new atomic measurements are underway at the Max Planck Institute in Garching, which aim to further improve also the spectroscopic results on electronic hydrogen. These experiments are complemented by extensive theoretical efforts focused on studying various processes contributing to the atomic Lamb shift measurements that could explain the difference, as well as on pursuing different ways to interpret nuclear form-factor measurements, which could lead to a consistent value of the radius. In this presentation the currently best proton radius measurements are summarized, and the importance of the observed inconsistency between the hydrogen and the muonic-hydrogen data is discussed. Selected new experiments dedicated to remeasuring the radius are described, and the results of the MAMI experiment are presented.

Puzzling out the proton radius puzzle

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Mihovilovič Miha

2014-01-01

Full Text Available The discrepancy between the proton charge radius extracted from the muonic hydrogen Lamb shift measurement and the best present value obtained from the elastic scattering experiments, remains unexplained and represents a burning problem of today’s nuclear physics: after more than 50 years of research the radius of a basic constituent of matter is still not understood. This paper presents a summary of the best existing proton radius measurements, followed by an overview of the possible explanations for the observed inconsistency between the hydrogen and the muonic-hydrogen data. In the last part the upcoming experiments, dedicated to remeasuring the proton radius, are described.

Puzzling out the proton radius puzzle

Energy Technology Data Exchange (ETDEWEB)

Mihovilovič, M.; Merkel, H.; Weber, A. [Institut für Kernphysik, Johannes Gutenberg-Universität Mainz, Johann-Joachim-Becher-Weg 45, 55128 Mainz (Germany)

2016-01-22

The discrepancy between the proton charge radius extracted from the muonic hydrogen Lamb shift measurement and the best present value obtained from the elastic scattering experiments, remains unexplained and represents a burning problem of today’s nuclear physics: after more than 50 years of research the radius of a basic constituent of matter is still not understood. This paper presents a summary of the best existing proton radius measurements, followed by an overview of the possible explanations for the observed inconsistency between the hydrogen and the muonic-hydrogen data. In the last part the upcoming experiments, dedicated to remeasuring the proton radius, are described.

Nuclear charge radius of $^{12}$Be

CERN Document Server

Krieger, Andreas; Bissell, Mark L; Frömmgen, Nadja; Geppert, Christopher; Hammen, Michael; Kreim, Kim; Kowalska, Magdalena; Krämer, Jörg; Neff, Thomas; Neugart, Rainer; Neyens, Gerda; Nörtershäuser, Wilfried; Novotny, Christian; Sanchez, Rodolfo; Yordanov, Deyan T

2012-01-01

The nuclear charge radius of $^{12}$Be was precisely determined using the technique of collinear laser spectroscopy on the $2s_{1/2}\\rightarrow 2p_{1/2, 3/2}$ transition in the Be$^{+}$ ion. The mean square charge radius increases from $^{10}$Be to $^{12}$Be by $\\delta ^{10,12} = 0.69(5)$ fm$^{2}$ compared to $\\delta ^{10,11} = 0.49(5)$ fm$^{2}$ for the one-neutron halo isotope $^{11}$Be. Calculations in the fermionic molecular dynamics approach show a strong sensitivity of the charge radius to the structure of $^{12}$Be. The experimental charge radius is consistent with a breakdown of the N=8 shell closure.

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

Energy Technology Data Exchange (ETDEWEB)

Lai, Peng-Yeh [Institute of Molecular Biology and Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan, ROC (China); Tsai, Chong-Bin [Institute of Molecular Biology and Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan, ROC (China); Department of Ophthalmology, Chiayi Christian Hospital, Chiayi 600, Taiwan, ROC (China); Tseng, Min-Jen, E-mail: biomjt@ccu.edu.tw [Institute of Molecular Biology and Department of Life Science, National Chung Cheng University, Chiayi 621, Taiwan, ROC (China)

2013-01-18

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

The significance of the neurovascular structures passing through the spinoglenoid notch

International Nuclear Information System (INIS)

Atekin, Mustafa; Demiryiirek, Deniz; Bayramoglu, Alp; Tuccar, Eray

2003-01-01

To define the detailed anatomy of the neurovascular bundle at the spinoglenoid notch and to report the dimensions of these structures in cadavers. In the present study, the external diameters of suprascapular artery, vein and nerve were measured at the spinoglenoid region in 18 formalin fixed cadavers (36 soulders) by using a caliper. The study was carried out in the dissection laboratory of Anatomy Department of Hacettepe University ,Ankara University, Ankara and Mersin University ,Mersin,Turkey, between2002 and 2003.The average external diameter for suprascapular vein was 2.6 mmand nerve was 2.2 mm. The spinoglenoid notch was roofed by the spinoglenoid ligament and appeared as a fibroosseous foramen in all cadavers. We found that vascular structures (suprascapular artery and vein )occupied 68.5% and the suprascapular nerve occupied 31.5% of this foramen. Although the diameters of the vascular structures at the spinoglenoid notch measured by magnetic resonance imaging have been reported,to our knowledge, external diameters of these structures at the spinoglenoid notch have not been described in cadavers. We believe that detailed anatomy of suprascapular neurovascular bundle at the spinoglenoid notch should be appreciated for better understanding of risk factors possibly causing the sprascapular nerve entrapment syndrome specially for those who are involved in voilent ovehead sports activities such as volleyball and baseball. (author)

Ehrlichia chaffeensis TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival

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Taslima T. Lina

2016-07-01

Full Text Available Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40% were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activation of the Notch pathway causes inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2 and p38 mitogen-activated protein kinase (MAPK pathways required for PU.1 and subsequent Toll-like receptor 2/4 (TLR2/4 expression. This investigation reveals a novel mechanism whereby E. chaffeensis exploits the Notch pathway to evade the host innate immune response for intracellular survival.

Epidermal Notch1 recruits RORγ + group 3 innate lymphoid cells to orchestrate normal skin repair

NARCIS (Netherlands)

Z. Li (Zhi); T. Hodgkinson (Tom); E.J. Gothard (Elizabeth J.); S. Boroumand (Soulmaz); R. Lamb (Rebecca); I. Cummins (Ian); P. Narang (Priyanka); A. Sawtell (Amy); J. Coles (Jenny); G. Leonov (German); A. Reboldi (Andrea); C.D. Buckley; T. Cupedo (Tom); C. Siebel (Christian); A. Bayat (Ardeshir); M. Coles (Mark); C.A. Ambler (Carrie A.)

2016-01-01

textabstractNotch 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.

Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits.

Science.gov (United States)

Kast, Jessica; Hanecker, Patrizia; Beaufort, Nathalie; Giese, Armin; Joutel, Anne; Dichgans, Martin; Opherk, Christian; Haffner, Christof

2014-08-13

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) represents the most common hereditary form of cerebral small vessel disease characterized by early-onset stroke and premature dementia. It is caused by mutations in the transmembrane receptor Notch3, which promote the aggregation and accumulation of the Notch3 extracellular domain (Notch3-ECD) within blood vessel walls. This process is believed to mediate the abnormal recruitment and dysregulation of additional factors including extracellular matrix (ECM) proteins resulting in brain vessel dysfunction. Based on recent evidence indicating a role for the transforming growth factor-β (TGF-β) pathway in sporadic and familial small vessel disease we studied fibronectin, fibrillin-1 and latent TGF-β binding protein 1 (LTBP-1), three ECM constituents involved in the regulation of TGF-β bioavailability, in post-mortem brain tissue from CADASIL patients and control subjects. Fibronectin and fibrillin-1 were found to be enriched in CADASIL vessels without co-localizing with Notch3-ECD deposits, likely as a result of fibrotic processes secondary to aggregate formation. In contrast, LTBP-1 showed both an accumulation and a striking co-localization with Notch3-ECD deposits suggesting specific recruitment into aggregates. We also detected increased levels of the TGF-β prodomain (also known as latency-associated peptide, LAP) indicating dysregulation of the TGF-β pathway in CADASIL development. In vitro analyses revealed a direct interaction between LTBP-1 and Notch3-ECD and demonstrated a specific co-aggregation of LTBP-1 with mutant Notch3. We propose LTBP-1 as a novel component of Notch3-ECD deposits and suggest its involvement in pathological processes triggered by Notch3-ECD aggregation.

Notch1 is a 5-fluorouracil resistant and poor survival marker in human esophagus squamous cell carcinomas.

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Jian Liu

Full Text Available Notch signaling involves the processes that govern cell proliferation, cell fate decision, cell differentiation and stem cell maintenance. Due to its fundamental role in stem cells, it has been speculated during the recent years that Notch family may have critical functions in cancer stem cells or cancer cells with a stem cell phenotype, therefore playing an important role in the process of oncogenesis. In this study, expression of Notch family in KYSE70, KYSE140 and KYSE450 squamous esophageal cancer cell lines and virus transformed squamous esophageal epithelial cell line Het-1A was examined by quantitative RT-PCR. Compared to the Het-1A cells, higher levels of Nocth1 and Notch3 expression in the cancer cell lines were identified. Due to the finding that NOTCH3 mainly mediates squamous cell differentiation, NOTCH1 expression was further studied in these cell lines. By Western blot analyses, the KYSE70 cell line which derived from a poorly differentiated tumor highly expressed Notch1, and the Notch1 expression in this cell line was hypoxia inducible, while the KYSE450 cell line which derived from a well differentiated tumor was always negative for Notch1, even in hypoxia. Additional studies demonstrated that the KYSE70 cell line was more 5-FU resistant than the KYSE450 cell line and such 5-FU resistance is correlated to Notch1 expression verified by Notch1 knockdown experiments. In clinical samples, Notch1 protein expression was detected in the basal cells of human esophagus epithelia, and its expression in squamous cell carcinomas was significantly associated with higher pathological grade and shorter overall survival. We conclude that Notch1 expression is associated with cell aggressiveness and 5-FU drug resistance in human esophageal squamous cell carcinoma cell lines in vitro and is significantly associated with a poor survival in human esophageal squamous cell carcinomas.

Evolutionary anatomy of the Neandertal ulna and radius in the light of the new El Sidrón sample.

Science.gov (United States)

Pérez-Criado, Laura; Rosas, Antonio

2017-05-01

This paper aims to improve our understanding of the phylogenetic trait polarity related to hominin forearm evolution, in particular those traits traditionally defined as "Neandertal features." To this aim, twelve adult and adolescent fragmented forelimb elements (including ulnae and radii) of Homo neanderthalensis recovered from the site of El Sidrón (Asturias, Spain) were examined comparatively using three-dimensional geometric and traditional morphometrics. Mean centroid size and shape comparisons, principal components analysis, and phylogenetic signal analysis were undertaken. Our investigations revealed that the proximal region of the ulna discriminated best between Neandertals and modern humans, with fewer taxonomically-informative features in the distal ulna and radius. Compared to modern humans, the divergent features in the Neandertal ulna are an increase in olecranon breadth (a derived trait), lower coronoid length (primitive), and anterior orientation of the trochlear notch (primitive). In the Neandertal radius, we observe a larger neck length (primitive), medial orientation of the radial tubercle (secondarily primitive), and a curved diaphysis (secondarily primitive). Anatomically, we identified three units of evolutionary change: 1) the olecranon and its fossa, 2) the coronoid-radius neck complex, and 3) the tubercle and radial diaphysis. Based on our data, forearm evolution followed a mosaic pattern in which some features were inherited from a pre-Homo ancestor, others originated in some post-ergaster and pre-antecessor populations, and other characters emerged in the specific Homo sapiens and H. neanderthalensis lineages, sometimes appearing as secondarily primitive. Future investigations might consider the diverse phylogenetic origin of apomorphies while at the same time seeking to elucidate their functional meaning. Copyright © 2017 Elsevier Ltd. All rights reserved.

ADAM10 regulates Notch function in intestinal stem cells of mice.

Science.gov (United States)

Tsai, Yu-Hwai; VanDussen, Kelli L; Sawey, Eric T; Wade, Alex W; Kasper, Chelsea; Rakshit, Sabita; Bhatt, Riha G; Stoeck, Alex; Maillard, Ivan; Crawford, Howard C; Samuelson, Linda C; Dempsey, Peter J

2014-10-01

A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a cell surface sheddase that regulates physiologic processes, including Notch signaling. ADAM10 is expressed in all intestinal epithelial cell types, but the requirement for ADAM10 signaling in crypt homeostasis is not well defined. We analyzed intestinal tissues from mice with constitutive (Vil-Cre;Adam10(f/f) mice) and conditional (Vil-CreER;Adam10(f/f) and Leucine-rich repeat-containing GPCR5 [Lgr5]-CreER;Adam10(f/f) mice) deletion of ADAM10. We performed cell lineage-tracing experiments in mice that expressed a gain-of-function allele of Notch in the intestine (Rosa26(NICD)), or mice with intestine-specific disruption of Notch (Rosa26(DN-MAML)), to examine the effects of ADAM10 deletion on cell fate specification and intestinal stem cell maintenance. Loss of ADAM10 from developing and adult intestine caused lethality associated with altered intestinal morphology, reduced progenitor cell proliferation, and increased secretory cell differentiation. ADAM10 deletion led to the replacement of intestinal cell progenitors with 2 distinct, post-mitotic, secretory cell lineages: intermediate-like (Paneth/goblet) and enteroendocrine cells. Based on analysis of Rosa26(NICD) and Rosa26(DN-MAML) mice, we determined that ADAM10 controls these cell fate decisions by regulating Notch signaling. Cell lineage-tracing experiments showed that ADAM10 is required for survival of Lgr5(+) crypt-based columnar cells. Our findings indicate that Notch-activated stem cells have a competitive advantage for occupation of the stem cell niche. ADAM10 acts in a cell autonomous manner within the intestinal crypt compartment to regulate Notch signaling. This process is required for progenitor cell lineage specification and crypt-based columnar cell maintenance. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J.

Science.gov (United States)

Wacker, Stephan Armin; Alvarado, Cristobal; von Wichert, Götz; Knippschild, Uwe; Wiedenmann, Jörg; Clauss, Karen; Nienhaus, Gerd Ulrich; Hameister, Horst; Baumann, Bernd; Borggrefe, Tilman; Knöchel, Walter; Oswald, Franz

2011-01-05

The evolutionarily conserved Notch signal transduction pathway regulates fundamental cellular processes during embryonic development and in the adult. Ligand binding induces presenilin-dependent cleavage of the receptor and a subsequent nuclear translocation of the Notch intracellular domain (NICD). In the nucleus, NICD binds to the recombination signal sequence-binding protein J (RBP-J)/CBF-1 transcription factor to induce expression of Notch target genes. Here, we report the identification and functional characterization of RBP-J interacting and tubulin associated (RITA) (C12ORF52) as a novel RBP-J/CBF-1-interacting protein. RITA is a highly conserved 36 kDa protein that, most interestingly, binds to tubulin in the cytoplasm and shuttles rapidly between cytoplasm and nucleus. This shuttling RITA exports RBP-J/CBF-1 from the nucleus. Functionally, we show that RITA can reverse a Notch-induced loss of primary neurogenesis in Xenopus laevis. Furthermore, RITA is able to downregulate Notch-mediated transcription. Thus, we propose that RITA acts as a negative modulator of the Notch signalling pathway, controlling the level of nuclear RBP-J/CBF-1, where its amounts are limiting.

The role of uric acid in the pathogenesis of diabetic retinopathy based on notch pathway.

Science.gov (United States)

Zhu, Dan-Dan; Wang, Yun-Zhi; Zou, Chen; She, Xin-Ping; Zheng, Zhi

2018-06-19

Uric acid has been proposed as an independent risk factor of diabetic retinopathy. Although Notch signaling was reported to be affected in the presence of high concentrations of uric acid or glucose, the underlying mechanisms of hyperuricemia through the Notch signaling pathway to promote the development of diabetic retinopathy remain unknown. We incubated human retinal endothelial cells (HRECs) with high glucose, high uric acid and high glucose plus high glucose respectively and evaluated the apoptosis rate in different treated cells by Tunel staining. We induced diabetic model by intraperitoneally streptozotocin. Then healthy rats and diabetic rats were given with adenine and oteracil potassium by gavage. Using automatic biochemical analyzer to detect blood glucose, uric acid, urea nitrogen, creatinine levels, to verify the success of modeling. The expression and mRNA levels of ICAM-1, IL-6, MCP-1, TNF-a, receptors Notch 1, ligands Dll 1, Dll 4, Jagged 1, Jagged 2 were detected by RT-PCR and Western-Blot. Notch1 siRNA was used to interfere Notch signaling pathway, the expression and mRNA levels of ICAM-1, IL-6, MCP-1 and TNF-α was detected by RT-PCR and Western blot respectively. In vitro models, the apoptosis of HRECs cells in high uric acid plus high glucose group was the most significant. In vitro and vivo models, detection of inflammatory cytokines revealed that the expression of inflammatory cytokines increased most significantly in high uric acid plus high glucose group. Notch signaling pathway activity was also increased most significantly in high uric acid plus high glucose group. After Notch 1 siRNA transfection in high glucose and high glucose plus uric acid group, the activity of Notch signaling pathway was successfully down-regulated. We found that the apoptosis of HRECs was significantly decreased in cells transfected with Notch 1 siRNA compared to the blank vector group, and the expression of inflammatory cytokines in cells was also significantly

An obligatory role of mind bomb-1 in notch signaling of mammalian development.

Directory of Open Access Journals (Sweden)

Bon-Kyoung Koo

2007-11-01

Full Text Available The Notch signaling pathway is an evolutionarily conserved intercellular signaling module essential for cell fate specification that requires endocytosis of Notch ligands. Structurally distinct E3 ubiquitin ligases, Neuralized (Neur and Mind bomb (Mib, cooperatively regulate the endocytosis of Notch ligands in Drosophila. However, the respective roles of the mammalian E3 ubiquitin ligases, Neur1, Neur2, Mib1, and Mib2, in mammalian development are poorly understood.Through extensive use of mammalian genetics, here we show that Neur1 and Neur2 double mutants and Mib2(-/- mice were viable and grossly normal. In contrast, conditional inactivation of Mib1 in various tissues revealed the representative Notch phenotypes: defects of arterial specification as deltalike4 mutants, abnormal cerebellum and skin development as jagged1 conditional mutants, and syndactylism as jagged2 mutants.Our data provide the first evidence that Mib1 is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable.

Keratin-6 driven ODC expression to hair follicle keratinocytes enhances stemness and tumorigenesis by negatively regulating Notch

Energy Technology Data Exchange (ETDEWEB)

Arumugam, Aadithya; Weng, Zhiping; Chaudhary, Sandeep C.; Afaq, Farrukh [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Elmets, Craig A. [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294-0019 (United States); Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

2014-08-29

Highlights: • Targeting ODC to hair follicle augments skin carcinogenesis and invasive SCCs. • Hair follicle ODC expands stem cell compartment carrying CD34{sup +}/K15{sup +}/p63{sup +} keratinocytes. • Negatively regulated Notch1 is associated with expansion of stem cell compartment. - Abstract: Over-expression of ornithine decarboxylase (ODC) is known to be involved in the epidermal carcinogenesis. However, the mechanism by which it enhances skin carcinogenesis remains undefined. Recently, role of stem cells localized in various epidermal compartments has been shown in the pathogenesis of skin cancer. To direct ODC expression in distinct epidermal compartments, we have developed keratin 6 (K6)-ODC/SKH-1 and keratin 14 (K14)-ODC/SKH-1 mice and employed them to investigate the role of ODC directed to these epidermal compartments on UVB-induced carcinogenesis. K6-driven ODC over-expression directed to outer root sheath (ORS) of hair follicle was more effective in augmenting tumorigenesis as compared to mice where K14-driven ODC expression was directed to inter-follicular epidermal keratinocytes. Chronically UVB-irradiated K6-ODC/SKH-1 developed 15 ± 2.5 tumors/mouse whereas K14-ODC/SKH-1 developed only 6.8 ± 1.5 tumors/mouse. K6-ODC/SKH-1 showed augmented UVB-induced proliferation and much higher pro-inflammatory responses than K14-ODC/SKH-1 mice. Tumors induced in K6-ODC/SKH-1 were rapidly growing, invasive and ulcerative squamous cell carcinoma (SCC) showing decreased expression of epidermal polarity marker E-cadherin and enhanced mesenchymal marker, fibronectin. Interestingly, the number of CD34/CK15/p63 positive stem-like cells was significantly higher in chronically UVB-irradiated K6-ODC/SKH-1 as compared to K14-ODC/SKH-1 mice. Reduced Notch1 expression was correlated with the expansion of stem cell compartment in these animals. However, other signaling pathways such as DNA damage response or mTOR signaling pathways were not significantly different in

Keratin-6 driven ODC expression to hair follicle keratinocytes enhances stemness and tumorigenesis by negatively regulating Notch

International Nuclear Information System (INIS)

Arumugam, Aadithya; Weng, Zhiping; Chaudhary, Sandeep C.; Afaq, Farrukh; Elmets, Craig A.; Athar, Mohammad

2014-01-01

Highlights: • Targeting ODC to hair follicle augments skin carcinogenesis and invasive SCCs. • Hair follicle ODC expands stem cell compartment carrying CD34 + /K15 + /p63 + keratinocytes. • Negatively regulated Notch1 is associated with expansion of stem cell compartment. - Abstract: Over-expression of ornithine decarboxylase (ODC) is known to be involved in the epidermal carcinogenesis. However, the mechanism by which it enhances skin carcinogenesis remains undefined. Recently, role of stem cells localized in various epidermal compartments has been shown in the pathogenesis of skin cancer. To direct ODC expression in distinct epidermal compartments, we have developed keratin 6 (K6)-ODC/SKH-1 and keratin 14 (K14)-ODC/SKH-1 mice and employed them to investigate the role of ODC directed to these epidermal compartments on UVB-induced carcinogenesis. K6-driven ODC over-expression directed to outer root sheath (ORS) of hair follicle was more effective in augmenting tumorigenesis as compared to mice where K14-driven ODC expression was directed to inter-follicular epidermal keratinocytes. Chronically UVB-irradiated K6-ODC/SKH-1 developed 15 ± 2.5 tumors/mouse whereas K14-ODC/SKH-1 developed only 6.8 ± 1.5 tumors/mouse. K6-ODC/SKH-1 showed augmented UVB-induced proliferation and much higher pro-inflammatory responses than K14-ODC/SKH-1 mice. Tumors induced in K6-ODC/SKH-1 were rapidly growing, invasive and ulcerative squamous cell carcinoma (SCC) showing decreased expression of epidermal polarity marker E-cadherin and enhanced mesenchymal marker, fibronectin. Interestingly, the number of CD34/CK15/p63 positive stem-like cells was significantly higher in chronically UVB-irradiated K6-ODC/SKH-1 as compared to K14-ODC/SKH-1 mice. Reduced Notch1 expression was correlated with the expansion of stem cell compartment in these animals. However, other signaling pathways such as DNA damage response or mTOR signaling pathways were not significantly different in tumors induced

Notch Filter Analysis and Its Application in Passive Coherent Location Radar (in English

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Li Ji-chuan

2015-01-01

Full Text Available The Normalized Least-Mean-Squares (NLMS algorithm is widely used to cancel the direct and multiple path interferences in Passive Coherent Location (PCL radar systems. This study proposes that the interference cancelation using the NLMS algorithm and the calculation of the radar Cross Ambiguity Function (CAF can be modeled as a notch filter, with the notch located at zero Doppler frequency in the surface of the radar CAF. The analysis shows that the notch’s width and depth are closely related to the step size of the NLMS algorithm. Subsequently, the effect of the notch in PCL radar target detection is analyzed. The results suggest that the detection performance of the PCL radar deteriorates because of the wide notch. Furthermore, the Nonuniform NLMS (NNLMS algorithm is proposed for removing the clutter with the Doppler frequency by using notch filtering. A step-size matrix is adopted to mitigate the low Doppler frequency clutter and lower the floor of the radar CAF. With the step-size matrix, can be obtained notches of different depths and widths in different range units of the CAF, which can filter the low Doppler frequency clutter. In addition, the convergence rate of the NNLMS algorithm is better than that of the traditional NLMS algorithm. The validity of the NNLMS algorithm is verified by experimental results.

Disrupting Jagged1-Notch signaling impairs spatial memory formation in adult mice.

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Sargin, Derya; Botly, Leigh C P; Higgs, Gemma; Marsolais, Alexander; Frankland, Paul W; Egan, Sean E; Josselyn, Sheena A

2013-07-01

It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1(+/-)) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1-Notch signaling is critical for memory formation in the adult brain. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

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

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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/.

Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia.

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Kuang, Shao-Qing; Fang, Zhihong; Zweidler-McKay, Patrick A; Yang, Hui; Wei, Yue; Gonzalez-Cervantes, Emilio A; Boumber, Yanis; Garcia-Manero, Guillermo

2013-01-01

The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA)/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL). We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2'-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.

The Dmp1-SOST Transgene Interacts With and Downregulates the Dmp1-Cre Transgene and the Rosa(Notch) Allele.

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Zanotti, Stefano; Canalis, Ernesto

2016-05-01

Activation of Notch1 in osteocytes of Rosa(Notch) mice, where a loxP-flanked STOP cassette and the Nicd coding sequence were targeted to the reverse orientation splice acceptor (Rosa)26 locus, causes osteopetrosis associated with suppressed Sost expression and enhanced Wnt signaling. To determine whether Sost downregulation mediates the effects of Notch activation in osteocytes, Rosa(Notch) mice were crossed with transgenics expressing Cre recombinase or SOST under the control of the dentin matrix protein (Dmp)1 promoter. Dmp1-SOST transgenics displayed vertebral osteopenia and a modest femoral cancellous and cortical bone phenotype, whereas hemizygous Dmp1-Cre transgenics heterozygous for the Rosa(Notch) allele (Dmp1-Cre;Rosa(Notch)) exhibited osteopetrosis. The phenotype of Notch activation in osteocytes was prevented in Dmp1-Cre;Rosa(Notch) mice hemizygous for the Dmp1-SOST transgene. The effect was associated with downregulated Notch signaling and suppressed Dmp1 and Rosa26 expression. To test whether SOST regulates Notch expression in osteocytes, cortical bone cultures from Dmp1-Cre;Rosa(Notch) mice or from Rosa(Notch) control littermates were exposed to recombinant human SOST. The addition of SOST had only modest effects on Notch target gene mRNA levels and suppressed Dmp1, but not Cre or Rosa26, expression. These findings suggest that prevention of the Dmp1-Cre;Rosa(Notch) skeletal phenotype by Dmp1-SOST is not secondary to SOST expression but to interactions among the Dmp1-SOST and Dmp1-Cre transgenes and the Rosa26 locus. In conclusion, the Dmp1-SOST transgene suppresses the expression of the Dmp1-Cre transgene and of Rosa26. © 2015 Wiley Periodicals, Inc.

Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors.

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Xinzhu Deng

Full Text Available Mammalian NOTCH1-4 receptors are all associated with human malignancy, although exact roles remain enigmatic. Here we employ glp-1(ar202, a temperature-sensitive gain-of-function C. elegans NOTCH mutant, to delineate NOTCH-driven tumor responses to radiotherapy. At ≤20°C, glp-1(ar202 is wild-type, whereas at 25°C it forms a germline stem cell⁄progenitor cell tumor reminiscent of human cancer. We identify a NOTCH tumor phenotype in which all tumor cells traffic rapidly to G2⁄M post-irradiation, attempt to repair DNA strand breaks exclusively via homology-driven repair, and when this fails die by mitotic death. Homology-driven repair inactivation is dramatically radiosensitizing. We show that these concepts translate directly to human cancer models.

A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies.

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Ortega, M; Bhatnagar, H; Lin, A-P; Wang, L; Aster, J C; Sill, H; Aguiar, R C T

2015-04-01

Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC.

Notch and VEGF Interactions in Breast Cancer

National Research Council Canada - National Science Library

Shawber, Carrie J

2006-01-01

The proposal objective is to define Notch and VEGFR-3 in breast cancer. We investigated this relationship in primary endothelial cell cultures, mouse embryos, human breast tumors, and mouse mammary tumor xenografts...

Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion

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Fabienne Billiard

2018-01-01

Full Text Available Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of β-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic β-islet cell progenitors, as well as the proliferation of insulin-secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action.

Engineered Biomaterials Control Differentiation and Proliferation of Human-Embryonic-Stem-Cell-Derived Cardiomyocytes via Timed Notch Activation

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Jason C. Tung

2014-03-01

Full Text Available For cell-based treatments of myocardial infarction, a better understanding of key developmental signaling pathways and more robust techniques for producing cardiomyocytes are required. Manipulation of Notch signaling has promise as it plays an important role during cardiovascular development, but previous studies presented conflicting results that Notch activation both positively and negatively regulates cardiogenesis. We developed surface- and microparticle-based Notch-signaling biomaterials that function in a time-specific activation-tunable manner, enabling precise investigation of Notch activation at specific developmental stages. Using our technologies, a biphasic effect of Notch activation on cardiac differentiation was found: early activation in undifferentiated human embryonic stem cells (hESCs promotes ectodermal differentiation, activation in specified cardiovascular progenitor cells increases cardiac differentiation. Signaling also induces cardiomyocyte proliferation, and repeated doses of Notch-signaling microparticles further enhance cardiomyocyte population size. These results highlight the diverse effects of Notch activation during cardiac development and provide approaches for generating large quantities of cardiomyocytes.

The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt.

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Sophie K Kay

2017-02-01

Full Text Available The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch's interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant

Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

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Song Zhang

Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

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

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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.

Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment.

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Katsushima, Keisuke; Natsume, Atsushi; Ohka, Fumiharu; Shinjo, Keiko; Hatanaka, Akira; Ichimura, Norihisa; Sato, Shinya; Takahashi, Satoru; Kimura, Hiroshi; Totoki, Yasushi; Shibata, Tatsuhiro; Naito, Mitsuru; Kim, Hyun Jin; Miyata, Kanjiro; Kataoka, Kazunori; Kondo, Yutaka

2016-12-06

Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.

Linear intra-bone geometry dependencies of the radius: Radius length determination by maximum distal width

International Nuclear Information System (INIS)

Baumbach, S.F.; Krusche-Mandl, I.; Huf, W.; Mall, G.; Fialka, C.

2012-01-01

Purpose: The aim of the study was to investigate possible linear intra-bone geometry dependencies by determining the relation between the maximum radius length and maximum distal width in two independent populations and test for possible gender or age effects. A strong correlation can help develop more representative fracture models and osteosynthetic devices as well as aid gender and height estimation in anthropologic/forensic cases. Methods: First, maximum radius length and distal width of 100 consecutive patients, aged 20–70 years, were digitally measured on standard lower arm radiographs by two independent investigators. Second, the same measurements were performed ex vivo on a second cohort, 135 isolated, formalin fixed radii. Standard descriptive statistics as well as correlations were calculated and possible gender age influences tested for both populations separately. Results: The radiographic dataset resulted in a correlation of radius length and width of r = 0.753 (adj. R 2 = 0.563, p 2 = 0.592) and side no influence on the correlation. Radius length–width correlation for the isolated radii was r = 0.621 (adj. R 2 = 0.381, p 2 = 0.598). Conclusion: A relatively strong radius length–distal width correlation was found in two different populations, indicating that linear body proportions might not only apply to body height and axial length measurements of long bones but also to proportional dependency of bone shapes in general.

Notch Signaling Is Associated With ALDH Activity And An Aggressive Metastatic Phenotype In Murine Osteosarcoma Cells

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Xiaodong eMu

2013-06-01

Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone, and pulmonary metastatic disease accounts for nearly all mortality. However, little is known about the biochemical signaling alterations that drive the progression of metastatic disease. Two murine OS cell populations, K7M2 and K12, are clonally related but differ significantly in their metastatic phenotypes and therefore represent excellent tools for studying metastatic OS molecular biology. K7M2 cells are highly metastatic, whereas K12 cells display limited metastatic potential. Here we report that the expression of Notch genes (Notch1, 2, 4 are up-regulated, including downstream targets Hes1 and Stat3, in the highly metastatic K7M2 cells compared to the less metastatic K12 cells, indicating that the Notch signaling pathway is more active in K7M2 cells. We have previously described that K7M2 cells exhibit higher levels of aldehyde dehydrogenase (ALDH activity. Here we report that K7M2 cell ALDH activity is reduced with Notch inhibition, suggesting that ALDH activity may be regulated in part by the Notch pathway. Notch signaling is also associated with increased resistance to oxidative stress, migration, invasion, and VEGF expression in vitro. However, Notch inhibition did not significantly alter K7M2 cell proliferation. In conclusion, we provide evidence that Notch signaling is associated with ALDH activity and increased metastatic behavior in OS cells. Both Notch and ALDH are putative molecular targets for the treatment and prevention of OS metastasis.

Mind bomb-1 in dendritic cells is specifically required for Notch-mediated T helper type 2 differentiation.

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Hyun-Woo Jeong

Full Text Available In dendritic cell (DC-CD4(+ T cell interaction, Notch signaling has been implicated in the CD4(+ T cell activation, proliferation, and subset differentiation. However, there has been a lot of debate on the exact role of Notch signaling. Here, we observed that expression of Mind bomb-1 (Mib1, a critical regulator of Notch ligands for the activation of Notch signaling, increases gradually as precursor cells differentiate into DCs in mice. To clarify the role of Mib1 in DC-CD4(+ T cell interactions, we generated Mib1-null bone marrow-derived DCs. These cells readily expressed Notch ligands but failed to initiate Notch activation in the adjacent cells. Nevertheless, Mib1-null DCs were able to prime the activation and proliferation of CD4(+ T cells, suggesting that Notch activation in CD4(+ T cells is not required for these processes. Intriguingly, stimulation of CD4(+ T cells with Mib1-null DCs resulted in dramatically diminished Th2 cell populations, while preserving Th1 cell populations, both in vitro and in vivo. Our results demonstrate that Mib1 in DCs is critical for the activation of Notch signaling in CD4(+ T cells, and Notch signaling reinforces Th2 differentiation, but is not required for the activation or proliferation of the CD4(+ T cells.

Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

Energy Technology Data Exchange (ETDEWEB)

Frampton, Gabriel; Coufal, Monique [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Li, Huang [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Ramirez, Jonathan [Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States); DeMorrow, Sharon, E-mail: demorrow@medicine.tamhsc.edu [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States)

2010-05-15

The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the {gamma}-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-{gamma}-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the {gamma}-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

International Nuclear Information System (INIS)

Frampton, Gabriel; Coufal, Monique; Li, Huang; Ramirez, Jonathan; DeMorrow, Sharon

2010-01-01

The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the γ-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-γ-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the γ-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

Notch1 regulates hippocampal plasticity through interaction with the Reelin pathway, glutamatergic transmission and CREB signaling

Directory of Open Access Journals (Sweden)

Emanuele eBrai

2015-11-01

Full Text Available Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, ApoER2, and the ionotropic receptor, NMDAR. Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced CREB signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia.

Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia.

Directory of Open Access Journals (Sweden)

Shao-Qing Kuang

Full Text Available The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL. We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B-ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2'-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL.

Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity

International Nuclear Information System (INIS)

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

Notch signalling in primary cutaneous CD30+ lymphoproliferative disorders: a new therapeutic approach?

DEFF Research Database (Denmark)

Kamstrup, M R; Biskup, E; Gniadecki, R

2010-01-01

The oncogenic potential of deregulated Notch signalling has been described in several haematopoietic malignancies. We have previously reported an increased expression of Notch1 in primary cutaneous CD30+ lymphoproliferative disorders, lymphomatoid papulosis and primary cutaneous anaplastic large...

Genome-wide identification and characterization of Notch transcription complex-binding sequence paired sites in leukemia cells

Science.gov (United States)

Severson, Eric; Arnett, Kelly L.; Wang, Hongfang; Zang, Chongzhi; Taing, Len; Liu, Hudan; Pear, Warren S.; Liu, X. Shirley; Blacklow, Stephen C.; Aster, Jon C.

2018-01-01

Notch transcription complexes (NTCs) drive target gene expression by binding to two distinct types of genomic response elements, NTC monomer-binding sites and sequence-paired sites (SPSs) that bind NTC dimers. SPSs are conserved and are linked to the Notch-responsiveness of a few genes, but their overall contribution to Notch-dependent gene regulation is unknown. To address this issue, we determined the DNA sequence requirements for NTC dimerization using a fluorescence resonance energy transfer (FRET) assay, and applied insights from these in vitro studies to Notch-“addicted” leukemia cells. We find that SPSs contribute to the regulation of approximately a third of direct Notch target genes. While originally described in promoters, SPSs are present mainly in long-range enhancers, including an enhancer containing a newly described SPS that regulates HES5. Our work provides a general method for identifying sequence-paired sites in genome-wide data sets and highlights the widespread role of NTC dimerization in Notch-transformed leukemia cells. PMID:28465412

Reduced Notch signalling leads to postnatal skeletal muscle hypertrophy in Pofut1cax/cax mice.

Science.gov (United States)

Al Jaam, Bilal; Heu, Katy; Pennarubia, Florian; Segelle, Alexandre; Magnol, Laetitia; Germot, Agnès; Legardinier, Sébastien; Blanquet, Véronique; Maftah, Abderrahman

2016-09-01

Postnatal skeletal muscle growth results from the activation of satellite cells and/or an increase in protein synthesis. The Notch signalling pathway maintains satellite cells in a quiescent state, and once activated, sustains their proliferation and commitment towards differentiation. In mammals, POFUT1-mediated O-fucosylation regulates the interactions between NOTCH receptors and ligands of the DELTA/JAGGED family, thus initiating the activation of canonical Notch signalling. Here, we analysed the consequences of downregulated expression of the Pofut1 gene on postnatal muscle growth in mutant Pofut1(cax/cax) (cax, compact axial skeleton) mice and differentiation of their satellite cell-derived myoblasts (SCDMs). Pofut1(cax/cax) mice exhibited muscle hypertrophy, no hyperplasia and a decrease in satellite cell numbers compared with wild-type C3H mice. In agreement with these observations, Pofut1(cax/cax) SCDMs differentiated earlier concomitant with reduced Pax7 expression and decrease in PAX7(+)/MYOD(-) progenitor cells. In vitro binding assays showed a reduced interaction of DELTA-LIKE 1 ligand (DLL1) with NOTCH receptors expressed at the cell surface of SCDMs, leading to a decreased Notch signalling as seen by the quantification of cleaved NICD and Notch target genes. These results demonstrated that POFUT1-mediated O-fucosylation of NOTCH receptors regulates myogenic cell differentiation and affects postnatal muscle growth in mice. © 2016 The Authors.

Effects of Notch Introduction on 3-Point Bending Cutting Characteristics of Frozen Fish

OpenAIRE

Hagura, Yoshio; Suzuki, Kanichi

2002-01-01

We have proposed a freeze cutting method in which a three point bending load is applied on a frozen fish body to cut in round slices. Lowering the three-point bending load can facilitate the freeze cutting processing. Based on the idea that a notch in the fish body may lower the cutting load, the effect of introducing a notch was examined with respect to cutting stress and smoothness of cut surface in model fish meat and in saury. It was found that the introduced notch effectively lowered the...

Spectral radius of graphs

CERN Document Server

Stevanovic, Dragan

2015-01-01

Spectral Radius of Graphs provides a thorough overview of important results on the spectral radius of adjacency matrix of graphs that have appeared in the literature in the preceding ten years, most of them with proofs, and including some previously unpublished results of the author. The primer begins with a brief classical review, in order to provide the reader with a foundation for the subsequent chapters. Topics covered include spectral decomposition, the Perron-Frobenius theorem, the Rayleigh quotient, the Weyl inequalities, and the Interlacing theorem. From this introduction, the

Estimation of runoff mitigation by morphologically different cover crop root systems

Science.gov (United States)

Yu, Yang; Loiskandl, Willibald; Kaul, Hans-Peter; Himmelbauer, Margarita; Wei, Wei; Chen, Liding; Bodner, Gernot

2016-07-01

Hydrology is a major driver of biogeochemical processes underlying the distinct productivity of different biomes, including agricultural plantations. Understanding factors governing water fluxes in soil is therefore a key target for hydrological management. Our aim was to investigate changes in soil hydraulic conductivity driven by morphologically different root systems of cover crops and their impact on surface runoff. Root systems of twelve cover crop species were characterized and the corresponding hydraulic conductivity was measured by tension infiltrometry. Relations of root traits to Gardner's hydraulic conductivity function were determined and the impact on surface runoff was estimated using HYDRUS 2D. The species differed in both rooting density and root axes thickness, with legumes distinguished by coarser axes. Soil hydraulic conductivity was changed particularly in the plant row where roots are concentrated. Specific root length and median root radius were the best predictors for hydraulic conductivity changes. For an intensive rainfall simulation scenario up to 17% less rainfall was lost by surface runoff in case of the coarsely rooted legumes Melilotus officinalis and Lathyrus sativus, and the densely rooted Linum usitatissimum. Cover crops with coarse root axes and high rooting density enhance soil hydraulic conductivity and effectively reduce surface runoff. An appropriate functional root description can contribute to targeted cover crop selection for efficient runoff mitigation.

Effects of consolidation temperature, strength and microstructure on fracture toughness of nanostructured ferritic alloys

International Nuclear Information System (INIS)

Miao, P.; Odette, G.R.; Yamamoto, T.; Alinger, M.; Hoelzer, D.; Gragg, D.

2007-01-01

Fully consolidated nanostructured ferritic alloys (NFAs) were prepared by attritor milling pre-alloyed Fe-14Cr-3W-0.4Ti and 0.3 wt% Y 2 O 3 powders, followed by hot isostatic pressing (HIPing) at 1000 o C or 1150 o C at 200 MPa for 4 h. Transmission electron microscopy (TEM) revealed similar bimodal distributions of fine and coarse ferrite grains in both cases. However, as expected, the alloy microhardness decreased with increasing in HIPing temperature. Three point bend tests on single edge notched specimens, with a nominal root radius ρ = 0.15 mm, were used to measure the notch fracture toughness, K ρ , as a function of test temperature. The K ρ curves were found to be similar for both processing conditions. It appears that the coarser ferrite grains control cleavage fracture, in a way that is independent of alloy strength and HIPing temperature

The Research Progress of SiRNA Targeting Notch1 on Tumor Cells: A Mini Review of the State of the Art

Directory of Open Access Journals (Sweden)

Lanfen Huo

2016-09-01

Full Text Available Notch signaling is a highly conserved signaling pathway, playing an important role in a variety of cell differentiation, development and regulation. Notch signaling includes Notch1-4; Notch1 gene encodes Notch1 signaling that can shorten cell cycle, enhance cell proliferation, inhibit cell differentiation, and promote apoptosis. Mutation and overexpression of the Notch1 gene may induce tumorigenesis, which plays an important role in the development of tumors across a variety of signaling pathways. Currently, using RNA interference technology (RNAi synthesizing small interference RNA (siRNA targeting Notch1 gene（siNotch1）has become a hot topic, and clinical application of gene silencing has also obtained a certain therapeutic effect. In this paper, the application of Notch1 gene silencing in tumor progress was reviewed.

A potentiometric biosensor for the detection of notch 3 using functionalized ZnO nanorods.

Science.gov (United States)

Ibupoto, Z H; Khun, K; Liu, X; Willander, M

2014-09-01

The notch signalling plays a vital and radical role for the activity of cellular proliferation, differentiation and apoptosis. In this study, for the first time a particular biosensor is developed for the detection of notch 3. ZnO nanorods were fabricated on the gold coated glass substrate by hydrothermal method and afterwards were decorated with the gold nanoparticles by electrodepositing technique. Scanning electron microscopy (SEM) has shown the perpendicular to the substrate growth pattern of ZnO nanorods. X-ray diffraction (XRD) studies showed the c-axis oriented growth direction with wurtzite crystal structure of ZnO nanorods. X-ray Photoelectron Spectroscopy (XPS) and energy dispersive X-ray (EDX) techniques have shown the presence of Zn, O and Au atoms in the prepared functional material. Furthermore, the anti-notch 3 was physically adsorbed on the gold nanoparticles functionalized ZnO nanorods. The developed potentiometric immunosensor has shown response to the wide range of notch 3 molecules. The detected range included 1.00 x 10(-5)-1.50 x 10(0 ) μg/mL with a sensitivity of 23.15 ± 0.31 mV/decade. The analytical parameters including reproducibility, stability, and selectivity were also investigated and the observed results indicate the acceptable performance of the notch 3 biosensor. Moreover, the proposed notch 3 biosensor exhibited a fast response time of 10 s.

Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling.

LENUS (Irish Health Repository)

Pradeep, C-R

2012-02-16

A large fraction of ductal carcinoma in situ (DCIS), a non-invasive precursor lesion of invasive breast cancer, overexpresses the HER2\\/neu oncogene. The ducts of DCIS are abnormally filled with cells that evade apoptosis, but the underlying mechanisms remain incompletely understood. We overexpressed HER2 in mammary epithelial cells and observed growth factor-independent proliferation. When grown in extracellular matrix as three-dimensional spheroids, control cells developed a hollow lumen, but HER2-overexpressing cells populated the lumen by evading apoptosis. We demonstrate that HER2 overexpression in this cellular model of DCIS drives transcriptional upregulation of multiple components of the Notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising Notch3, its cleaved intracellular domain and the transcriptional regulator HES1, resulting in elevated levels of c-MYC and cyclin D1. In line with HER2-Notch3 collaboration, drugs intercepting either arm reverted the DCIS-like phenotype. In addition, we report upregulation of Notch3 in hyperplastic lesions of HER2 transgenic animals, as well as an association between HER2 levels and expression levels of components of the Notch pathway in tumor specimens of breast cancer patients. Therefore, it is conceivable that the integration of the Notch and HER2 signaling pathways contributes to the pathophysiology of DCIS.

Gamma-glutamylcyclotransferase promotes the growth of human glioma cells by activating Notch-Akt signaling

Energy Technology Data Exchange (ETDEWEB)

Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao; Tan, Guo-Wei; Wang, Zhan-Xiang, E-mail: md_wzx7189@163.com

2016-03-18

Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects. GGCT overexpression promotes the expression of Notch receptors and activates Akt signaling in glioma cells, and Notch-Akt signaling is activated in glioma tissues with high expression of GGCT. Finally, we show that inhibition of Notch-Akt signaling with Notch inhibitor MK-0752 blocks the effects of GGCT on glioma proliferation and colony formation. In conclusion, GGCT plays a critical role in glioma cell proliferation and may be a potential cancer therapeutic target. - Highlights: • GGCT expression is up-regulated in human glioma tissues and cell lines. • GGCT promotes glioma cell growth and colony formation. • GGCT promotes the activation of Notch-Akt signaling in glioma cells and tissues. • Notch inhibition blocks the role of GGCT in human glioma cells.

The proton radius puzzle

Science.gov (United States)

Bonesini, Maurizio

2017-12-01

The FAMU (Fisica degli Atomi Muonici) experiment has the goal to measure precisely the proton Zemach radius, thus contributing to the solution of the so-called proton radius "puzzle". To this aim, it makes use of a high-intensity pulsed muon beam at RIKEN-RAL impinging on a cryogenic hydrogen target with an high-Z gas admixture and a tunable mid-IR high power laser, to measure the hyperfine (HFS) splitting of the 1S state of the muonic hydrogen. From the value of the exciting laser frequency, the energy of the HFS transition may be derived with high precision ( 10-5) and thus, via QED calculations, the Zemach radius of the proton. The experimental apparatus includes a precise fiber-SiPMT beam hodoscope and a crown of eight LaBr3 crystals and a few HPGe detectors for detection of the emitted characteristic X-rays. Preliminary runs to optimize the gas target filling and its operating conditions have been taken in 2014 and 2015-2016. The final run, with the pump laser to drive the HFS transition, is expected in 2018.

Relationship between mucoid hypertrophy of the anterior cruciate ligament (ACL) and morphologic change of the intercondylar notch: MRI and arthroscopy correlation

International Nuclear Information System (INIS)

Cha, Ji Hyeon; Shin, Myung Jin; Choi, Byeong Kyoo; Lee, Sang Hoon; Bin, Sung Il

2008-01-01

The purpose of this study was to evaluate the relationship between mucoid hypertrophy of the anterior cruciate ligament (ACL) and morphologic change of the intercondylar notch. We retrospectively reviewed the 105 patients with knee magnetic resonance imaging (MRI) with or without knee arthroscopy [group 1: patients with arthroscopic notchplasty (N = 47), group 2: knee arthroscopy demonstrating intact ACL (N = 33), and group 3: patients with normal knee MRI but no arthroscopy (N = 25)]. Groups 2 and 3 served as an arthroscopic and MR control group, respectively. Two musculoskeletal radiologists reviewed all MR examinations. The intercondylar notch width, notch index (width of intercondylar notch/width of femoral condyle), transverse notch angle (TNA), sagittal notch angle (SNA), and notch area were recorded on axial and sagittal MR images at the midpoint of Blumensaat's line which was identified on sagittal images. The diameter of the ACL was recorded on coronal MR images at the posterior end of Blumensaat's line. The mean values of the intercondylar notch width, notch index, TNA, SNA, notch area, and ACL diameter for the three groups were 16.0 mm/0.2/50.3 /36.5 /249.0 mm 2 /7.7 mm (group 1); 19.3 mm/0.3/52.9 /40.2 /323.4 mm 2 /4.8 mm (group 2); and 20.3 mm/0.3/51.4 /39.1 /350.8 mm 2 /4.5 mm (group 3). The intercondylar notch width, notch index, SNA, and notch area were smaller, and ACL diameter was thicker in group 1 compared with the other groups (p < 0.05). Patients with mucoid ACL hypertrophy show a narrower notch, a steeper notch angle, and a smaller notch area than control groups. (orig.)

Oridonin inhibits breast cancer growth and metastasis through blocking the Notch signaling

Directory of Open Access Journals (Sweden)

Shixin Xia

2017-05-01

Full Text Available Background: Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to inhibit growth and metastasis of human breast cancer cells. Methods: The effect of oridonin on proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in human breast cancer cells. The inhibitive effect of oridonin in vivo was determined by using xenografted nude mice. In addition, the expression of Notch receptors (Notch 1–4 was detected by western blot. Results: Oridonin inhibited human breast cancer cells in vitro and in vivo. In addition, oridonin significantly induced human breast cancer cells apoptosis. Furthermore, the oridonin treatment not only inhibited cancer cell migration and invasion, but more significantly, decreased the expression of Notch 1-4 protein. Conclusion: Our results suggest that the inhibitive effect of oridonin is likely to be driven by the inhibition of Notch signaling pathway and the resulting increased apoptosis.

The Early Entry of Al into Cells of Intact Soybean Roots (A Comparison of Three Developmental Root Regions Using Secondary Ion Mass Spectrometry Imaging).

Science.gov (United States)

Lazof, D. B.; Goldsmith, J. G.; Rufty, T. W.; Linton, R. W.

1996-11-01

Al localization was compared in three developmental regions of primary root of an Al-sensitive soybean (Glycine max) genotype using secondary ion mass spectrometry. In cryosections obtained after a 4-h exposure to 38 [mu]M [Al3+], Al had penetrated across the root and into the stele in all three regions. Although the greatest localized Al concentration was consistently at the root periphery, the majority of the Al in each region had accumulated in cortical cells. It was apparent that the secondary ion mass spectrometry 27Al+ mass signal was spread throughout the intracellular area and was not particularly intense in the cell wall. Inclusion of some cell wall in determinations of the Al levels across the root radius necessitated that these serve as minimal estimates for intracellular Al. Total accumulation of intracellular Al for each region was 60, 73, and 210 nmol g-1 fresh weight after 4 h, increasing with root development. Early metabolic responses to external Al, including those that have been reported deep inside the root and in mature regions, might result directly from intracellular Al. These responses might include ion transport events at the endodermis of mature roots or events associated with lateral root emergence, as well as events within the root tip.

The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt

KAUST Repository

Kay, Sophie K.

2017-03-01

The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch’s interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain

The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt

KAUST Repository

Kay, Sophie K.; Harrington, Heather A.; Shepherd, Sarah; Brennan, Keith; Dale, Trevor; Osborne, James M.; Gavaghan, David J.; Byrne, Helen M.

2017-01-01

The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch’s interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain

UWB Filtering Power Divider with Two Narrow Notch-bands and Wide Stop-band

Science.gov (United States)

Wei, Feng; Wang, Xin-Yi; Zou, Xin Tong; Shi, Xiao Wei

2017-12-01

A compact filtering ultra-wideband (UWB) microstrip power divider (PD) with two sharply rejected notch-bands and wide stopband is analyzed and designed in this paper. The proposed UWB PD is based on a conventional Wilkinson power divider, while two stub loaded resonators (SLRs) are coupled into two symmetrical output ports to achieve a bandpass filtering response. The simplified composite right/left-handed (SCRLH) resonators are employed to generate the dual notched bands. Defected ground structure (DGS) is introduced to improve the passband performance. Good insertion/return losses, isolation and notch-band rejection are achieved as demonstrated in both simulation and experiment.

Mechanism of Notch Pathway Activation and Its Role in the Regulation of Olfactory Plasticity in Drosophila melanogaster.

Directory of Open Access Journals (Sweden)

Simon Kidd

Full Text Available The neural plasticity of sensory systems is being increasingly recognized as playing a role in learning and memory. We have previously shown that Notch, part of an evolutionarily conserved intercellular signaling pathway, is required in adult Drosophila melanogaster olfactory receptor neurons (ORNs for the structural and functional plasticity of olfactory glomeruli that is induced by chronic odor exposure. In this paper we address how long-term exposure to odor activates Notch and how Notch in conjunction with chronic odor mediates olfactory plasticity. We show that upon chronic odor exposure a non-canonical Notch pathway mediates an increase in the volume of glomeruli by a mechanism that is autonomous to ORNs. In addition to activating a pathway that is autonomous to ORNs, chronic odor exposure also activates the Notch ligand Delta in second order projection neurons (PNs, but this does not appear to require acetylcholine receptor activation in PNs. Delta on PNs then feeds back to activate canonical Notch signaling in ORNs, which restricts the extent of the odor induced increase in glomerular volume. Surprisingly, even though the pathway that mediates the increase in glomerular volume is autonomous to ORNs, nonproductive transsynaptic Delta/Notch interactions that do not activate the canonical pathway can block the increase in volume. In conjunction with chronic odor, the canonical Notch pathway also enhances cholinergic activation of PNs. We present evidence suggesting that this is due to increased acetylcholine release from ORNs. In regulating physiological plasticity, Notch functions solely by the canonical pathway, suggesting that there is no direct connection between morphological and physiological plasticity.

The Effect of Numerical 2D and 3D Fem Element Modelling on Strain and Stress Distributions at Laser Weld Notches in Steel Sandwich Type Panels

Directory of Open Access Journals (Sweden)

Niklas Karol

2018-03-01

Full Text Available Like other means of transport, merchant ships face the problem of increasing requirements concerning the environment protection, which, among other issues, implies the reduction of fuel consumption by the ship. Here, the conventional approach which consists in making use of higher strength steels to decrease the mass of the ship hull can be complemented by the use of new steel structures of sandwich panel type. However, the lack of knowledge and experience concerning, among other issues, fatigue strength assessment of thin-walled sandwich structures makes their use limited. Untypical welds imply the need for individual approach to the fatigue analysis. The article presents the effect of numerical FEM modelling with the aid of two-dimensional (2D and three-dimensional (3D elements on the results of strain and stress distributions in the areas of toe and root notches of the analysed laser weld. The presented results of computer simulation reveal that modelling of strain and stress states in 2D (instead of full 3D affects only the results in close vicinity of the notch, and the observed differences rapidly disappear at a distance of 0.05 mm from the bottom of the notch. The obtained results confirm the possibility of use of numerically effective 2D strain and stress state models for analysing the fatigue strength of laser weld according to local approach.

Critical cladding radius for hybrid cladding modes

Science.gov (United States)

Guyard, Romain; Leduc, Dominique; Lupi, Cyril; Lecieux, Yann

2018-05-01

In this article we explore some properties of the cladding modes guided by a step-index optical fiber. We show that the hybrid modes can be grouped by pairs and that it exists a critical cladding radius for which the modes of a pair share the same electromagnetic structure. We propose a robust method to determine the critical cladding radius and use it to perform a statistical study on the influence of the characteristics of the fiber on the critical cladding radius. Finally we show the importance of the critical cladding radius with respect to the coupling coefficient between the core mode and the cladding modes inside a long period grating.

miR-935 suppresses gastric signet ring cell carcinoma tumorigenesis by targeting Notch1 expression

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Yan, Chao [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Yu, Jianchun, E-mail: yu_jchpumch@163.com [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Kang, Weiming [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Liu, Yuqin [Cell Culture Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005 (China); Ma, Zhiqiang; Zhou, Li [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China)

2016-01-29

Gastric signet ring cell carcinoma (GSRCC) is a unique pathological type of gastric carcinoma that is extremely invasive and has a poor prognosis. Expression of microRNAs (miRNAs) has been closely linked to the carcinogenesis of gastric cancer and has been considered as a powerful prognostic marker. The function of miR-935 has never been reported in cancer before. We found, using microRNA array, that expression of miR-935 in GSRCC cell lines is lower than in non-GSRCC cell lines, and enhanced expression of miR-935 in GSRCC cell-lines inhibit cell proliferation, migration and invasion. We also identified Notch1 as a direct target of miR-935. Knockdown of Notch1 reduced proliferation, migration/invasion of GSRCC cells, and overexpression Notch1's activated form (Notch intracellular domain) could rescue miR-935's tumor suppressive effect on GSRCC. Expression of miR-935 was lower in gastric carcinoma tissue than in paired normal tissue samples, and lower in GSRCC than in non-GSRCC. Our results demonstrate the inverse correlation between the expression of miR-935 and Notch1 in gastric tissues. We conclude that miR-935 inhibits gastric carcinoma cell proliferation, migration and invasion by targeting Notch1, suggesting potential applications of the miR-935-Notch1 pathway in gastric cancer clinical diagnosis and therapeutics, especially in gastric signet ring cell carcinoma. - Highlights: • The expression of miR-935 is lower in GC tissue than in paired normal tissue. • The expression of miR-935 is lower in GSRCC tissue than in non-GSRCC. • Enhanced expression of miR-935 suppresses tumorigenesis of GSRCC. • Notch1 is a direct target of miR-935.

FOXP3 expression is modulated by TGF-β1/NOTCH1 pathway in human melanoma

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Skarmoutsou, Eva; Bevelacqua, Valentina; D'Amico, Fabio; Russo, Angela; Spandidos, Demetrios A.; Scalisi, Aurora

2018-01-01

Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability. PMID:29620159

Estimation of Low Cycle Fatigue Response of 316 LN Stainless Steel in the Presence of Notch

Science.gov (United States)

Agrawal, Richa; Veerababu, J.; Goyal, Sunil; Sandhya, R.; Uddanwadiker, Rashmi; Padole, Pramod

2018-02-01

Notches introduced in the plain specimen result in the multiaxial state of stress that exists in the actual components due to the presence of flaws and defects. In the present work, low cycle fatigue life estimation of plain and notched specimens of 316 LN stainless steel is carried out at room temperature and 823 K. The plain and notched specimens with different notch radii were subjected to varying strain amplitudes ranging from ± 0.25 to ± 1.0% at a strain rate of 3 × 10-3 s-1. The fatigue life decreased in the presence of notch for all strain amplitudes at both the temperatures. The decrease in fatigue life was found to be more at room temperature than at 823 K. The fatigue life of the notched specimen decreased by approximately 94.2% compared to plain specimen at room temperature. However, at 823 K the decrease in fatigue life for notched specimen was approximately 84.6%. Low cycle fatigue life of the plain and notched specimens was estimated by Neuber's rule and finite element analysis approach. Neuber's rule overestimated the fatigue life by maximum factor of 2.6 for specimens at room temperature and by maximum factor of 5 for specimens at 823 K. However, it gives closer approximation at higher strain amplitudes at 823 K. Life estimation by finite element analysis at room temperature was within a factor of 1.5 as compared to experimental life, whereas it underestimated the fatigue life within a factor of 6 at high temperature.

Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity

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David P. Sparling

2016-02-01

Full Text Available Objective: As the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs, which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk (A-Rbpj and the obligate γ-secretase component Nicastrin (A-Nicastrin. Methods: Glucose homeostasis and both local adipose and systemic insulin sensitivity were examined in GSI-treated, A-Rbpj and A-Nicastrin mice, as well as vehicle-treated or control littermates, with complementary in vitro studies in primary hepatocytes and 3T3-L1 adipocytes. Results: GSI-treatment increases hepatic insulin sensitivity in obese mice but leads to reciprocal lowering of adipose glucose disposal. While A-Rbpj mice show normal body weight, adipose development and mass and unchanged adipose insulin sensitivity as control littermates, A-Nicastrin mice are relatively insulin-resistant, mirroring the GSI effect on adipose insulin action. Conclusions: Notch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D. Keywords: Notch, γ-secretase complex, Insulin resistance

An iterative algorithm for calculating stylus radius unambiguously

International Nuclear Information System (INIS)

Vorburger, T V; Zheng, A; Renegar, T B; Song, J-F; Ma, L

2011-01-01

The stylus radius is an important specification for stylus instruments and is commonly provided by instrument manufacturers. However, it is difficult to measure the stylus radius unambiguously. Accurate profiles of the stylus tip may be obtained by profiling over an object sharper than itself, such as a razor blade. However, the stylus profile thus obtained is a partial arc, and unless the shape of the stylus tip is a perfect sphere or circle, the effective value of the radius depends on the length of the tip profile over which the radius is determined. We have developed an iterative, least squares algorithm aimed to determine the effective least squares stylus radius unambiguously. So far, the algorithm converges to reasonable results for the least squares stylus radius. We suggest that the algorithm be considered for adoption in documentary standards describing the properties of stylus instruments.

Notched Strength of Woven Fabric Kenaf Composite Plates with Different Stacking Sequences and Hole Sizes

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Hans Romayne Anders

2016-01-01

Full Text Available Advantages of using kenaf fibres over synthetic fibres in composites manufacturing are relatively cheap, less abrasive and hazardous during handling, and renewable materials. Current work investigates parametric effects on notched strength of woven fabric kenaf polymer composites plates with variation of lay-up types, notch sizes and plate thickness. Testing coupons are prepared using hand lay-up technique and circular notch were drilled prior to mechanical testing. Stress concentration at the notch edge promotes micro-damage event as tensile loading was applied leading to crack initiation and propagations across the plate width. It is suggested that woven fabric kenaf polymer composites are potentially used in low and medium load bearing applications.

Notch signaling activation in human embryonic stem cells is required for embryonic but not trophoblastic lineage commitment

OpenAIRE

Yu, Xiaobing; Zou, Jizhong; Ye, Zhaohui; Hammond, Holly; Chen, Guibin; Tokunaga, Akinori; Mali, Prashant; Li, Yue-Ming; Civin, Curt; Gaiano, Nicholas; Cheng, Linzhao

2008-01-01

The Notch signaling pathway plays important roles in cell fate determination during embryonic development and adult life. In this study, we focus on the role of Notch signaling in governing cell fate choices in human embryonic stem (hES) cells. Using genetic and pharmacological approaches, we achieved both blockade and conditional activation of Notch signaling in several hES cell lines. We report here that activation of Notch signaling is required for undifferentiated hES cells to form the pr...

2S-4S spectroscopy in hydrogen atom: The new value for the Rydberg constant and the proton charge radius

Science.gov (United States)

Kolachevsky, N.; Beyer, A.; Maisenbacher, L.; Matveev, A.; Pohl, R.; Khabarova, K.; Grinin, A.; Lamour, T.; Yost, D. C.; Haensch, T. W.; Udem, Th.

2018-02-01

The core of the "proton radius puzzle" is the discrepancy of four standard deviations between the proton root mean square charge radii (rp) determined from regular hydrogen (H), and the muonic hydrogen atom (μp). We have measured the 2S-4P transition frequency in H, utilizing a cryogenic beam of H and directly demonstrate that quantum interference of neighboring atomic resonances can lead to line shifts much larger than the proton radius discrepancy. Using an asymmetric fit function we obtain rp = 0.8335(95) fm and the Rydberg constant R∞ = 10 973 731.568 076 (96) m-1. The new value for rp is 3.3 combined standard deviations smaller than the latest CODATA value, but in good agreement with the value from μp.

Implementation and investigation of circular slot UWB antenna with dual-band-notched characteristics

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DadashZadeh Gholamreza

2011-01-01

Full Text Available Abstract The design and analysis of an ultra wideband aperture antenna with dual-band-notched characteristics are presented. The proposed antenna consists of a circular ring exciting stub on the front side and a circular slot on the back ground plane. By utilizing a parasitic strip and a T-shaped stub on the antenna structure, two notched bands of 850 MHz (3.5-4.35 GHz and 900 MHz (5.05-5.95 GHz are achieved. The proposed antenna is fabricated and measured. Measured results show that this antenna operates from 2.3 GHz to upper 11 GHz for voltage standing wave ratio less than 2, except two frequency notched bands of 3.5-4.35 and 5.05-5.95 GHz. Moreover, the experimental results show that proposed antenna has stable radiation patterns and constant gain. A conceptual circuit model, which is based on the measured impedance of the proposed antenna, is also shown to investigate the dual-band-notched characteristics.

Occupational noise exposure, hearing loss, and notched audiograms in the HUNT Nord-Trøndelag hearing loss study, 1996-1998.

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Lie, Arve; Engdahl, Bo; Hoffman, Howard J; Li, Chuan-Ming; Tambs, Kristian

2017-06-01

To study the prevalence and usefulness of audiometric notches in the diagnosis of noise-induced hearing loss (NIHL). Audiograms and data on noise exposure from 23,297 men and 26,477 women, aged 20 to 101 years, from the Nord-Trøndelag Hearing Loss Study, 1996-1998. The prevalence of four types of audiometric notches (Coles, Hoffman, Wilson) and 4 kHz notch were computed in relation to occupational noise exposure, age, sex, and report of recurrent ear infections. The prevalence of notches in the 3 to 6 kHz range (Wilson, Hoffman, and Coles) ranged from 50% to 60% in subjects without occupational noise exposure, and 60% to 70% in the most occupationally noise-exposed men. The differences were statistically significant only for bilateral notches. For 4 kHz notches, the prevalence varied from 25% in occupationally nonexposed to 35% in the most occupationally exposed men, and the differences were statistically significant for both bilateral and unilateral notches. For women, the prevalence of notches was lower than in men, especially for 4 kHz notches, and the differences between occupationally noise exposed and nonexposed were smaller. Recreational exposure to high music was not associated with notched audiograms. The detection of bilateral notches and unilateral 4 kHz notches is of some value in diagnosing NIHL, especially in men. 4 Laryngoscope, 127:1442-1450, 2017. © 2016 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of American Laryngological, Rhinological and Otological Society Inc, “The Triological Society” and American Laryngological Association (ALA).

Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas.

Science.gov (United States)

Jen, Kuang-Yu; Song, Ihn Young; Banta, Karl Luke; Wu, Di; Mao, Jian-Hua; Balmain, Allan

2012-01-19

T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.

Rapid measurement of auditory filter shape in mice using the auditory brainstem response and notched noise.

Science.gov (United States)

Lina, Ioan A; Lauer, Amanda M

2013-04-01

The notched noise method is an effective procedure for measuring frequency resolution and auditory filter shapes in both human and animal models of hearing. Briefly, auditory filter shape and bandwidth estimates are derived from masked thresholds for tones presented in noise containing widening spectral notches. As the spectral notch widens, increasingly less of the noise falls within the auditory filter and the tone becomes more detectible until the notch width exceeds the filter bandwidth. Behavioral procedures have been used for the derivation of notched noise auditory filter shapes in mice; however, the time and effort needed to train and test animals on these tasks renders a constraint on the widespread application of this testing method. As an alternative procedure, we combined relatively non-invasive auditory brainstem response (ABR) measurements and the notched noise method to estimate auditory filters in normal-hearing mice at center frequencies of 8, 11.2, and 16 kHz. A complete set of simultaneous masked thresholds for a particular tone frequency were obtained in about an hour. ABR-derived filter bandwidths broadened with increasing frequency, consistent with previous studies. The ABR notched noise procedure provides a fast alternative to estimating frequency selectivity in mice that is well-suited to high through-put or time-sensitive screening. Copyright © 2013 Elsevier B.V. All rights reserved.

Notch4 Signaling Induces a Mesenchymal–Epithelial–like Transition in Melanoma Cells to Suppress Malignant Behaviors

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Rad, Ehsan Bonyadi; Hammerlindl, Heinz; Wels, Christian; Popper, Ulrich; Menon, Dinoop Ravindran; Breiteneder, Heimo; Kitzwoegerer, Melitta; Hafner, Christine; Herlyn, Meenhard; Bergler, Helmut; Schaider, Helmut

2016-01-01

The effects of Notch signaling are context-dependent and both oncogenic and tumor-suppressive functions have been described. Notch signaling in melanoma is considered oncogenic, but clinical trials testing Notch inhibition in this malignancy have not proved successful. Here, we report that expression of the constitutively active intracellular domain of Notch4 (N4ICD) in melanoma cells triggered a switch from a mesenchymal-like parental phenotype to an epithelial-like phenotype. The epithelial-like morphology was accompanied by strongly reduced invasive, migratory, and proliferative properties concomitant with the downregulation of epithelial–mesenchymal transition markers Snail2 (SNAI2), Twist1, vimentin (VIM), and MMP2 and the reexpression of E-cadherin (CDH1). The N4ICD-induced phenotypic switch also resulted in significantly reduced tumor growth in vivo. Immunohistochemical analysis of primary human melanomas and cutaneous metastases revealed a significant correlation between Notch4 and E-cadherin expression. Mechanistically, we demonstrate that N4ICD induced the expression of the transcription factors Hey1 and Hey2, which bound directly to the promoter regions of Snail2 and Twist1 and repressed gene transcription, as determined by EMSA and luciferase assays. Taken together, our findings indicate a role for Notch4 as a tumor suppressor in melanoma, uncovering a potential explanation for the poor clinical efficacy of Notch inhibitors observed in this setting. PMID:26801977

Prediction and measurement of the reflection of the fundamental anti-symmetric Lamb wave from cracks and notches

International Nuclear Information System (INIS)

Lowe, M.J.S.; Cawley, P.; Kao, J-Y; Diligent, O.

2000-01-01

The interaction of the fundamental antisymmetric Lamb wave (a o ) with cracks and with notches of different depth and width has been investigated both experimentally and by finite element analysis. Excellent agreement between the predictions and the measurements has been obtained. It has been shown that the reflection coefficient is a function of both the notch width to wavelength and notch depth to wavelength ratios. Both the relationship between the reflection coefficient and notch, depth, and the frequency dependence of the reflection coefficient, are very different for the a o mode compared to the s o mode which was studied earlier. Physical insight into the reasons for the different behavior is given by examination of the stress fields and opening displacements at the crack or notch

Specificity and autoregulation of Notch binding by tandem WW domains in suppressor of Deltex.

Science.gov (United States)

Jennings, Martin D; Blankley, Richard T; Baron, Martin; Golovanov, Alexander P; Avis, Johanna M

2007-09-28

WW domains target proline-tyrosine (PY) motifs and frequently function as tandem pairs. When studied in isolation, single WW domains are notably promiscuous and regulatory mechanisms are undoubtedly required to ensure selective interactions. Here, we show that the fourth WW domain (WW4) of Suppressor of Deltex, a modular Nedd4-like protein that down-regulates the Notch receptor, is the primary mediator of a direct interaction with a Notch-PY motif. A natural Trp to Phe substitution in WW4 reduces its affinity for general PY sequences and enhances selective interaction with the Notch-PY motif via compensatory specificity-determining interactions with PY-flanking residues. When WW4 is paired with WW3, domain-domain association, impeding proper folding, competes with Notch-PY binding to WW4. This novel mode of autoinhibition is relieved by binding of another ligand to WW3. Such cooperativity may facilitate the transient regulatory interactions observed in vivo between Su(dx) and Notch in the endocytic pathway. The highly conserved tandem arrangement of WW domains in Nedd4 proteins, and similar arrangements in more diverse proteins, suggests domain-domain communication may be integral to regulation of their associated cellular activities.

Design and Analysis of Robust Active Damping for LCL Filters using Digital Notch Filters

DEFF Research Database (Denmark)

Yao, Wenli; Yang, Yongheng; Zhang, Xiaobin

2017-01-01

Resonant poles of LCL filters may challenge the entire system stability especially in digital-controlled Pulse Width Modulation (PWM) inverters. In order to tackle the resonance issues, many active damping solutions have been reported. For instance, a notch filter can be employed to damp the reso......Resonant poles of LCL filters may challenge the entire system stability especially in digital-controlled Pulse Width Modulation (PWM) inverters. In order to tackle the resonance issues, many active damping solutions have been reported. For instance, a notch filter can be employed to damp...... the resonance, where the notch frequency should be aligned exactly to the resonant frequency of the LCL filter. However, parameter variations of the LCL filter as well as the time delay appearing in digital control systems will induce resonance drifting, and thus break this alignment, possibly deteriorating...... the original damping. In this paper, the effectiveness of the notch filter based active damping is firstly explored, considering the drifts of the resonant frequency. It is revealed that, when the resonant frequency drifts away from its nominal value, the phase lead or lag introduced by the notch filter may...

The transcriptional corepressor SMRTER influences both Notch and ecdysone signaling during Drosophila development

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Bryan W. Heck

2011-12-01

SMRTER (SMRT-related and ecdysone receptor interacting factor is the Drosophila homologue of the vertebrate proteins SMRT and N-CoR, and forms with them a well-conserved family of transcriptional corepressors. Molecular characterization of SMRT-family proteins in cultured cells has implicated them in a wide range of transcriptional regulatory pathways. However, little is currently known about how this conserved class of transcriptional corepressors regulates the development of particular tissues via specific pathways. In this study, through our characterization of multiple Smrter (Smr mutant lines, mosaic analysis of a loss-of-function Smr allele, and studies of two independent Smr RNAi fly lines, we report that SMRTER is required for the development of both ovarian follicle cells and the wing. In these two tissues, SMRTER inhibits not only the ecdysone pathway, but also the Notch pathway. We differentiate SMRTER's influence on these two signaling pathways by showing that SMRTER inhibits the Notch pathway, but not the ecdysone pathway, in a spatiotemporally restricted manner. We further confirm the likely involvement of SMRTER in the Notch pathway by demonstrating a direct interaction between SMRTER and Suppressor of Hairless [Su(H], a DNA-binding transcription factor pivotal in the Notch pathway, and the colocalization of both proteins at many chromosomal regions in salivary glands. Based on our results, we propose that SMRTER regulates the Notch pathway through its association with Su(H, and that overcoming a SMRTER-mediated transcriptional repression barrier may represent a key mechanism used by the Notch pathway to control the precise timing of events and the formation of sharp boundaries between cells in multiple tissues during development.

Persistent expression of activated notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure.

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Aujla, Paven K; Bogdanovic, Vedran; Naratadam, George T; Raetzman, Lori T

2015-08-01

As the pituitary gland develops, signals from the hypothalamus are necessary for pituitary induction and expansion. Little is known about the control of cues that regulate early signaling between the two structures. Ligands and receptors of the Notch signaling pathway are found in both the hypothalamus and Rathke's pouch. The downstream Notch effector gene Hes1 is required for proper pituitary formation; however, these effects could be due to the action of Hes1 in the hypothalamus, Rathke's pouch, or both. To determine the contribution of hypothalamic Notch signaling to pituitary organogenesis, we used mice with loss and gain of Notch function within the developing hypothalamus. We demonstrate that loss of Notch signaling by conditional deletion of Rbpj in the hypothalamus does not affect expression of Hes1 within the posterior hypothalamus or expression of Hes5. In contrast, expression of activated Notch within the hypothalamus results in ectopic Hes5 expression and increased Hes1 expression, which is sufficient to disrupt pituitary development and postnatal expansion. Taken together, our results indicate that Rbpj-dependent Notch signaling within the developing hypothalamus is not necessary for pituitary development, but persistent Notch signaling and ectopic Hes5 expression in hypothalamic progenitors affects pituitary induction and expansion. © 2015 Wiley Periodicals, Inc.

A U-Shaped Slot UWB Antenna with Flexible and Wide Tunable Dual Notch Band

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Zhang Zhongmin

2016-01-01

Full Text Available A coplanar waveguide (CPW fed ultra-wideband (UWB antenna with flexible and wide tunable dual bandnotched characteristics is proposed in this paper. The dual band-notched function is achieved by using an U-shaped slot inserted into the ellipse radiation patch and by using an elliptic parasitic slit placed near the ground plane. The wide tunable band-notched characteristic is implemented by adjusting the length of U-shaped slot and by adjusting the length of ellipse parasitic slit. The design aims to achieve wide reconfigurable band-notched features on the UWB antenna. The simulated results indicate that the proposed antenna has a wide bandwidth (VSWR under 2 from 2.9GHz to 12.6GHz with fractional bandwidth of 125%, and has a wide tunable notch band center frequency from 4.5GHz to 12.4GHz.

Study of the ultrasonic technique of elapsed time of notch

International Nuclear Information System (INIS)

Gomes, L.C.F.L.; Rebello, J.M.A.

1989-01-01

The study of the ultrasonic technique of elapsed time in the dimensionment of notch inclined of 15 and 30 degree and of depth of 5 and 10 mm using the superficial Rayleigh wave and the mode conversion, with a headstock transmitter and other receiver. The dimensionment of notch and of the binding of the piece were made with headstock in different positions. Between the various results obtained can be mentioned the increase of the dimensionment, by two techniques, with the increase of the angle and/or of the depth. (V.R.B.)

dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats

International Nuclear Information System (INIS)

Baladron, Victoriano; Ruiz-Hidalgo, Maria Jose; Nueda, Maria Luisa; Diaz-Guerra, Maria Jose M.; Garcia-Ramirez, Jose Javier; Bonvini, Ezio; Gubina, Elena; Laborda, Jorge

2005-01-01

The protein dlk, encoded by the Dlk1 gene, belongs to the Notch epidermal growth factor (EGF)-like family of receptors and ligands, which participate in cell fate decisions during development. The molecular mechanisms by which dlk regulates cell differentiation remain unknown. By using the yeast two-hybrid system, we found that dlk interacts with Notch1 in a specific manner. Moreover, by using luciferase as a reporter gene under the control of a CSL/RBP-Jk/CBF-1-dependent promoter in the dlk-negative, Notch1-positive Balb/c 14 cell line, we found that addition of synthetic dlk EGF-like peptides to the culture medium or forced expression of dlk decreases endogenous Notch activity. Furthermore, the expression of the gene Hes-1, a target for Notch1 activation, diminishes in confluent Balb/c14 cells transfected with an expression construct encoding for the extracellular EGF-like region of dlk. The expression of Dlk1 and Notch1 increases in 3T3-L1 cells maintained in a confluent state for several days, which is associated with a concomitant decrease in Hes-1 expression. On the other hand, the decrease of Dlk1 expression in 3T3-L1 cells by antisense cDNA transfection is associated with an increase in Hes-1 expression. These results suggest that dlk functionally interacts in vivo with Notch1, which may lead to the regulation of differentiation processes modulated by Notch1 activation and signaling, including adipogenesis

Chondromalacia of trochlear notch after healing of olecranon stress fracture: a case report.

Science.gov (United States)

Lu, Cheng-Chang; Chen, Shen-Kai; Wang, Chih-Wei; Chou, Pei-Hsi

2006-05-01

Chondromalacia of the trochlear notch and stress fracture of olecranon are uncommon injuries in the throwing athletes. We report an 18-year-old high school pitcher who had persistent postero-lateral elbow pain after a healed olecranon stress fracture of the right elbow. Diagnostic arthroscopy revealed chondromalacia of the trochlear notch. After treatment with arthroscopic drilling and abrasion chondroplasty, he returned to competitive pitching 1 year later postsurgery. This rare association between chondromalacia and stress fracture of the olecranon has not been reported previously in the literatures. Chondromalacia of the trochlear notch should be included as a differential diagnosis in evaluating athletes with persistent elbow pain after healed olecranon stress fractures.

Investigation on the Crack Initiation of V-Shaped Notch Tip in Precision Cropping

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Lijun Zhang

2014-01-01

Full Text Available The crack initiation of V-shaped notch tip has a very important influence on the cross-section quality and the cropping time for every segment of metal bar in course of low stress precision cropping. By the finite element method, the influence of machining precision of V-shaped notch bottom corner on the crack initiation location is analyzed and it is pointed out that the crack initiation point locates in the place at the maximal equivalent stress change rate on V-shaped notch surface. The judgment criterion of the crack initiation direction is presented and the corresponding crack initiation angle can be calculated by means of the displacement extrapolation method. The factual crack initiation angle of the metal bar has been measured by using the microscopic measurement system. The formula of the crack initiation life of V-shaped notch tip is built, which mainly includes the stress concentration factor of V-shaped notch, the tensile properties of metal material, and the cyclic loading conditions. The experimental results show that the obtained theoretical analyses about the crack initiation location, the crack initiation direction, and the crack initiation time in this paper are correct. It is also shown that the crack initiation time accounts for about 80% of the cropping time for every segment of the metal bar.

Time dependent voiding mechanisms in polyamide 6 submitted to high stress triaxiality: experimental characterisation and finite element modelling

Science.gov (United States)

Selles, Nathan; King, Andrew; Proudhon, Henry; Saintier, Nicolas; Laiarinandrasana, Lucien

2017-08-01

Double notched round bars made of semi-crystalline polymer polyamide 6 (PA6) were submitted to monotonic tensile and creep tests. The two notches had a root radius of 0.45 mm, which imposes a multiaxial stress state and a state of high triaxiality in the net (minimal) section of the specimens. Tests were carried out until the failure occurred from one of the notches. The other one, unbroken but deformed under steady strain rate or steady load, was inspected using the Synchrotron Radiation Computed Tomography (SRCT) technique. These 3D through thickness inspections allowed the study of microstructural evolution at the peak stress for the monotonic tensile test and at the beginning of the tertiary creep for the creep tests. Cavitation features were assessed with a micrometre resolution within the notched region. Spatial distributions of void volume fraction ( Vf) and void morphology were studied. Voiding mechanisms were similar under steady strain rates and steady loads. The maximum values of Vf were located between the axis of revolution of the specimens and the notch surface and voids were considered as flat cylinders with a circular basis perpendicular to the loading direction. A model, based on porous plasticity, was used to simulate the mechanical response of this PA6 material under high stress triaxiality. Both macroscopic behaviour (loading curves) and voiding micro-mechanisms (radial distributions of void volume fraction) were accurately predicted using finite element simulations.

Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity

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Bruno M. Simões

2015-09-01

Full Text Available Breast cancers (BCs typically express estrogen receptors (ERs but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.

Occupational noise exposure, hearing loss, and notched audiograms in the HUNT Nord‐Trøndelag hearing loss study, 1996–1998

Science.gov (United States)

Engdahl, Bo; Hoffman, Howard J.; Li, Chuan‐Ming; Tambs, Kristian

2016-01-01

Objectives/Hypothesis To study the prevalence and usefulness of audiometric notches in the diagnosis of noise‐induced hearing loss (NIHL). Study Design Audiograms and data on noise exposure from 23,297 men and 26,477 women, aged 20 to 101 years, from the Nord‐Trøndelag Hearing Loss Study, 1996–1998. Methods The prevalence of four types of audiometric notches (Coles, Hoffman, Wilson) and 4 kHz notch were computed in relation to occupational noise exposure, age, sex, and report of recurrent ear infections. Results The prevalence of notches in the 3 to 6 kHz range (Wilson, Hoffman, and Coles) ranged from 50% to 60% in subjects without occupational noise exposure, and 60% to 70% in the most occupationally noise‐exposed men. The differences were statistically significant only for bilateral notches. For 4 kHz notches, the prevalence varied from 25% in occupationally nonexposed to 35% in the most occupationally exposed men, and the differences were statistically significant for both bilateral and unilateral notches. For women, the prevalence of notches was lower than in men, especially for 4 kHz notches, and the differences between occupationally noise exposed and nonexposed were smaller. Recreational exposure to high music was not associated with notched audiograms. Conclusions The detection of bilateral notches and unilateral 4 kHz notches is of some value in diagnosing NIHL, especially in men. Level of Evidence 4 Laryngoscope, 127:1442–1450, 2017 PMID:27696439

Quantification of gamma-secretase modulation differentiates inhibitor compound selectivity between two substrates Notch and amyloid precursor protein

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Yang Ting

2008-11-01

Full Text Available Abstract Background Deposition of amyloid-β protein (Aβ is a major pathological hallmark of Alzheimer's disease (AD. Aβ is generated from γ-secretase cleavage of amyloid precursor protein (APP. In addition to APP, γ-secretase also cleaves other type I integral membrane proteins, including the Notch receptor, a key molecule involved in embryonic development. Results To explore selective γ-secretase inhibitors, a combination of five methods was used to systematically determine these inhibitors' profiles on the γ-secretase cleavage of APP and Notch. When two potent γ-secretase inhibitors, compound E (cpd E and DAPT, were used in a conventional in vitro γ-secretase activity assay, cpd E completely blocked Aβ generation from the cleavage of substrate APP C100, but only had a minor effect on Notch cleavage and NICD generation. Next, cpd E and DAPT were applied to HEK293 cells expressing a truncated Notch substrate NotchΔE. Both cpd E and DAPT were more potent in blocking Aβ generation than NICD generation. Third, a reporter construct was created that carried the NICD targeting promoter with three Su(H binding sequences followed by the luciferase gene. We found that the inhibition of NICD generation by cpd E and DAPT was consistent with the reduced expression of luciferase gene driven by this Notch targeting promoter. Fourth, levels of "Notch-Aβ-like" (Nβ* peptide derived from two previously reported chimeric APP with its transmembrane domain or the juxtamembrane portion replaced by the Notch sequence were quantified. Measurement of Nβ* peptides by ELISA confirmed that EC50's of cpd E were much higher for Nβ* than Aβ. Finally, the expression levels of Notch target gene her6 in cpd E or DAPT-treated zebrafish were correlated with the degree of tail curvature due to defective somitogenesis, a well characterized Notch phenotype in zebrafish. Conclusion Our ELISA-based quantification of Aβ and Nβ* in combination with the test in

Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells

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Zou Jie

2013-01-01

Full Text Available Abstract Background Notch1 is a potent regulator known to play an oncogenic role in many malignancies including T-cell acute lymphoblastic leukemia (T-ALL. Tumor hypoxia and increased hypoxia-inducible factor-1α (HIF-1α activity can act as major stimuli for tumor aggressiveness and progression. Although hypoxia-mediated activation of the Notch1 pathway plays an important role in tumor cell survival and invasiveness, the interaction between HIF-1α and Notch1 has not yet been identified in T-ALL. This study was designed to investigate whether hypoxia activates Notch1 signalling through HIF-1α stabilization and to determine the contribution of hypoxia and HIF-1α to proliferation, invasion and chemoresistance in T-ALL. Methods T-ALL cell lines (Jurkat, Sup-T1 transfected with HIF-1α or Notch1 small interference RNA (siRNA were incubated in normoxic or hypoxic conditions. Their potential for proliferation and invasion was measured by WST-8 and transwell assays. Flow cytometry was used to detect apoptosis and assess cell cycle regulation. Expression and regulation of components of the HIF-1α and Notch1 pathways and of genes related to proliferation, invasion and apoptosis were assessed by quantitative real-time PCR or Western blot. Results Hypoxia potentiated Notch1 signalling via stabilization and activation of the transcription factor HIF-1α. Hypoxia/HIF-1α-activated Notch1 signalling altered expression of cell cycle regulatory proteins and accelerated cell proliferation. Hypoxia-induced Notch1 activation increased the expression of matrix metalloproteinase-2 (MMP2 and MMP9, which increased invasiveness. Of greater clinical significance, knockdown of Notch1 prevented the protective effect of hypoxia/HIF-1α against dexamethasone-induced apoptosis. This sensitization correlated with losing the effect of hypoxia/HIF-1α on Bcl-2 and Bcl-xL expression. Conclusions Notch1 signalling is required for hypoxia/HIF-1α-induced proliferation

On the proton radius problem

OpenAIRE

Giannini, M. M.; Santopinto, E.

2013-01-01

The recent values of the proton charge radius obtained by means of muonic-hydrogen laser spectroscopy are about $4\\%$ different from the electron scattering data. It has been suggested that the proton radius is actually measured in different frames and that, starting from a non relativistic quark model calculation, the Lorentz transformation of the form factors accounts properly for the discepancy. We shall show that the relation between the charge radii measured in different frames can be de...

Understanding the mass-radius relation for sub-Neptunes: radius as a proxy for composition

Energy Technology Data Exchange (ETDEWEB)

Lopez, Eric D.; Fortney, Jonathan J. [Department of Astronomy and Astrophysics, University of California, Santa Cruz, CA 95064 (United States)

2014-09-01

Transiting planet surveys like Kepler have provided a wealth of information on the distribution of planetary radii, particularly for the new populations of super-Earth- and sub-Neptune-sized planets. In order to aid in the physical interpretation of these radii, we compute model radii for low-mass rocky planets with hydrogen-helium envelopes. We provide model radii for planets 1-20 M {sub ⊕}, with envelope fractions 0.01%-20%, levels of irradiation 0.1-1000 times Earth's, and ages from 100 Myr to 10 Gyr. In addition we provide simple analytic fits that summarize how radius depends on each of these parameters. Most importantly, we show that at fixed H/He envelope fraction, radii show little dependence on mass for planets with more than ∼1% of their mass in their envelope. Consequently, planetary radius is to a first order a proxy for planetary composition, i.e., H/He envelope fraction, for Neptune- and sub-Neptune-sized planets. We recast the observed mass-radius relationship as a mass-composition relationship and discuss it in light of traditional core accretion theory. We discuss the transition from rocky super-Earths to sub-Neptune planets with large volatile envelopes. We suggest ∼1.75 R {sub ⊕} as a physically motivated dividing line between these two populations of planets. Finally, we discuss these results in light of the observed radius occurrence distribution found by Kepler.

LPL gene expression is associated with poor prognosis in CLL and closely related to NOTCH1 mutations

DEFF Research Database (Denmark)

Kristensen, Louise; Kielsgaard Kristensen, Thomas; Abildgaard, Niels

2016-01-01

these markers. AIM: To evaluate LPL gene expression together with the well-established prognostic markers of CLL and investigate correlations with more recently identified prognostic markers, NOTCH1 and TP53 mutations. METHODS: On 149 patients LPL gene expression was analyzed by real-time RT-PCR. Exon 34...... of NOTCH1 was PCR amplified and directly sequenced. RESULTS: LPL gene expression could be measured as a categorical variable (LPL+/LPL-) and was associated with time to treatment (p... and new prognostic markers, 3 out of 4 patients, who received treatment within 24 months after diagnosis, were LPL+ (p=0.03). There was a strong correlation between NOTCH1 mutation and LPL+ (p=0.005). The unfavorable prognosis of LPL+ was maintained in CLL with wild-type NOTCH1. CONCLUSIONS: NOTCH1...

Intracellular-activated Notch1 can reactivate Kaposi's sarcoma-associated herpesvirus from latency

International Nuclear Information System (INIS)

Lan, Ke; Murakami, Masanao; Choudhuri, Tathagata; Kuppers, Daniel A.; Robertson, Erle S.

2006-01-01

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a predominantly latent infection in the infected host. Importantly, during latency, only a small number of viral encoded genes are expressed. This viral gene expression pattern contributes to the establishment of long-term infection as well as the ability of the virus to evade the immune system. Previous studies have been shown that the replication and transcription activator (RTA) encoded by ORF50 activates it downstream genes and initiates viral lytic reactivation through functional interaction with RBP-Jκ, the major downstream effector of the Notch signaling pathway. This indicates that RTA can usurp the conserved Notch signaling pathway and mimic the activities of intracellular Notch1 to modulate gene expression. In this report, we show that the activated intracellular domain of Notch1 (ICN) is aberrantly accumulated in KSHV latently infected pleural effusion lymphoma (PEL) cells. ICN activated the RTA promoter in a dose-dependent manner, and forced expression of ICN in latently infected KSHV-positive cells initiated full blown lytic replication with the production of infectious viral progeny. However, latency-associated nuclear antigen (LANA) which is predominantly expressed during latency can specifically down-modulate ICN-mediated transactivation of RTA and so control KSHV for lytic reactivation. These results demonstrate that LANA can inhibit viral lytic replication by antagonizing ICN function and suggest that LANA is a critical component of the regulatory control mechanism for switching between viral latent and lytic replication by directly interacting with effectors of the conserved cellular Notch1 pathway

Recombination radius of a Frenkel pair and capture radius of a self-interstitial atom by vacancy clusters in bcc Fe

International Nuclear Information System (INIS)

Nakashima, Kenichi; Stoller, Roger E; Xu, Haixuan

2015-01-01

The recombination radius of a Frenkel pair is a fundamental parameter for the object kinetic Monte Carlo (OKMC) and mean field rate theory (RT) methods that are used to investigate irradiation damage accumulation in irradiated materials. The recombination radius in bcc Fe has been studied both experimentally and numerically, however there is no general consensus about its value. The detailed atomistic processes of recombination also remain uncertain. Values from 1.0a 0 to 3.3a 0 have been employed as a recombination radius in previous studies using OKMC and RT. The recombination process of a Frenkel pair is investigated at the atomic level using the self-evolved atomistic kinetic Monte Carlo (SEAKMC) method in this paper. SEAKMC calculations reveal that a self-interstitial atom recombines with a vacancy in a spontaneous reaction from several nearby sites following characteristic pathways. The recombination radius of a Frenkel pair is estimated to be 2.26a 0 by taking the average of the recombination distances from 80 simulation cases. In addition, we apply these procedures to the capture radius of a self-interstitial atom by a vacancy cluster. The capture radius is found to gradually increase with the size of the vacancy cluster. The fitting curve for the capture radius is obtained as a function of the number of vacancies in the cluster. (paper)

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

International Nuclear Information System (INIS)

Ahrenhoerster, Lori S.; Leuthner, Tess C.; Tate, Everett R.; Lakatos, Peter A.; Laiosa, Michael D.

2015-01-01

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 active Notch1 transgene (Notch ICN-TG ). Following exposure of adult Notch 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 ICN-TG offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed Notch 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

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

Energy Technology Data Exchange (ETDEWEB)

Ahrenhoerster, Lori S.; Leuthner, Tess C.; Tate, Everett R.; Lakatos, Peter A.; Laiosa, Michael D., E-mail: laiosa@uwm.edu

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 active 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

Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling.

Science.gov (United States)

Troll, Joshua V; Hamilton, M Kristina; Abel, Melissa L; Ganz, Julia; Bates, Jennifer M; Stephens, W Zac; Melancon, Ellie; van der Vaart, Michiel; Meijer, Annemarie H; Distel, Martin; Eisen, Judith S; Guillemin, Karen

2018-02-23

Resident microbes promote many aspects of host development, although the mechanisms by which microbiota influence host tissues remain unclear. We showed previously that the microbiota is required for allocation of appropriate numbers of secretory cells in the zebrafish intestinal epithelium. Because Notch signaling is crucial for secretory fate determination, we conducted epistasis experiments to establish whether the microbiota modulates host Notch signaling. We also investigated whether innate immune signaling transduces microbiota cues via the Myd88 adaptor protein. We provide the first evidence that microbiota-induced, Myd88-dependent signaling inhibits host Notch signaling in the intestinal epithelium, thereby promoting secretory cell fate determination. These results connect microbiota activity via innate immune signaling to the Notch pathway, which also plays crucial roles in intestinal homeostasis throughout life and when impaired can result in chronic inflammation and cancer. © 2018. Published by The Company of Biologists Ltd.

lin-12 Notch functions in the adult nervous system of C. elegans

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Tucey Tim M

2005-07-01

Full Text Available Abstract Background Notch signaling pathways are conserved across species and traditionally have been implicated in cell fate determination during embryonic development. Notch signaling components are also expressed postdevelopmentally in the brains of adult mice and Drosophila. Recent studies suggest that Notch signaling may play a role in the physiological, rather than developmental, regulation of neurons. Here, we investigate a new non-developmental role for Caenorhabditis elegans lin-12 Notch signaling in neurons regulating the spontaneous reversal rate during locomotion. Results The spontaneous reversal rate of C. elegans during normal locomotion is constant. Both lin-12 gain and loss of function mutant animals had significantly increased reversal rates compared to wild type controls. These defects were caused by lin-12 activity, because the loss of function defect could be rescued by a wild type lin-12 transgene. Furthermore, overexpression of lin-12 recapitulated the gain-of-function defect. Increasing or decreasing lin-12 activity in the postdevelopmental adult animal was sufficient to rapidly and reversibly increase reversals, thereby excluding a developmental role for lin-12. Although lin-12 is expressed in the vulval and somatic gonad lineages, we find that these tissues play no role in regulating reversal rates. In contrast, altering lin-12 activity specifically in the nervous system was sufficient to increase reversals. These behavioral changes require components of the canonical lin-12 signaling cascade, including the ligand lag-2 and the transcriptional effector lag-1. Finally, the C. elegans AMPA/kainate glutamate receptor homolog glr-1 shows strong genetic interactions with lin-12, suggesting that glr-1 and/or other glutamate gated channels may be targets of lin-12 regulation. Conclusion Our results demonstrate a neuronal role for lin-12 Notch in C. elegans and suggest that lin-12 acutely regulates neuronal physiology to

The Notch ligand delta-like 3 promotes tumor growth and inhibits Notch signaling in lung cancer cells in mice

International Nuclear Information System (INIS)

Deng, San-Ming; Yan, Xian-Chun; Liang, Liang; Wang, Li; Liu, Yuan; Duan, Juan-Li; Yang, Zi-Yan; Chang, Tian-Fang; Ruan, Bai; Zheng, Qi-Jun; Han, Hua

2017-01-01

Although it has been suggested that Dll3, one of the Notch ligands, promotes the proliferation and inhibits the apoptosis of cancer cells, the role of Dll3 in cancers remains unclear. In this study, we found that in the murine Lewis lung carcinoma (LLC) cells, the level of Dll3 mRNA changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with tumor necrosis factor (TNF)-α. Dll3 was also expressed at higher level in human lung carcinoma tissues than in the para-carcinoma tissues. Overexpression of Dll3 in LLC cells promoted cell proliferation and reduced apoptosis in vitro, and enhanced tumor growth when inoculated in vivo in mice. The Dll3-mediated proliferation could be due to increased Akt phosphorylation in LLC cells, because an Akt inhibitor counteracted Dll3-induced proliferation. Moreover, Dll3 overexpression promoted PI3K/Akt signaling through inhibiting Notch signaling. - Highlights: • The level of Dll3 in Lewis lung carcinoma changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with TNF-α. • The Dll3 was rarely detectable in the para-carcinoma tissues, but positive in 82.1% of NSCLC tissues from 84 patients. • Overexpression of Dll3 in LLC cells promoted tumor growth but did not remarkably alter TME after inoculated in mice. • Overexpression of Dll3 in LLC cells promoted cell proliferation and reduced apoptosis in vitro in an Akt-dependent way. • Dll3 overexpression promoted PI3K/Akt signaling through inhibiting Notch signaling.

Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

Science.gov (United States)

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

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo.

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Kristina Preuße

2015-06-01

Full Text Available Notch signalling is a fundamental pathway that shapes the developing embryo and sustains adult tissues by direct communication between ligand and receptor molecules on adjacent cells. Among the ligands are two Delta paralogues, DLL1 and DLL4, that are conserved in mammals and share a similar structure and sequence. They activate the Notch receptor partly in overlapping expression domains where they fulfil redundant functions in some processes (e.g. maintenance of the crypt cell progenitor pool. In other processes, however, they appear to act differently (e.g. maintenance of foetal arterial identity raising the questions of how similar DLL1 and DLL4 really are and which mechanism causes the apparent context-dependent divergence. By analysing mice that conditionally overexpress DLL1 or DLL4 from the same genomic locus (Hprt and mice that express DLL4 instead of DLL1 from the endogenous Dll1 locus (Dll1Dll4ki, we found functional differences that are tissue-specific: while DLL1 and DLL4 act redundantly during the maintenance of retinal progenitors, their function varies in the presomitic mesoderm (PSM where somites form in a Notch-dependent process. In the anterior PSM, every cell expresses both Notch receptors and ligands, and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed. Transgenic DLL4 cannot replace DLL1 during somitogenesis and in heterozygous Dll1Dll4ki/+ mice, the Dll1Dll4ki allele causes a dominant segmentation phenotype. Testing several aspects of the complex Notch signalling system in vitro, we found that both ligands have a similar trans-activation potential but that only DLL4 is an efficient cis-inhibitor of Notch signalling, causing a reduced net activation of Notch. These differential cis-inhibitory properties are likely to contribute to the functional divergence of DLL1 and DLL4.

Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1

DEFF Research Database (Denmark)

Robert-Moreno, Àlex; Robert-Moreno, Àlex; Guiu, Jordi

2008-01-01

Specific deletion of Notch1 and RBPjκ in the mouse results in abrogation of definitive haematopoiesis concomitant with the loss of arterial identity at embryonic stage. As prior arterial determination is likely to be required for the generation of embryonic haematopoiesis, it is difficult...... to establish the specific haematopoietic role of Notch in these mutants. By analysing different Notch-ligand-null embryos, we now show that Jagged1 is not required for the establishment of the arterial fate but it is required for the correct execution of the definitive haematopoietic programme, including...... activation of Notch1 is responsible for regulating GATA2 expression in the AGM, which in turn is essential for definitive haematopoiesis in the mouse....

No evidence for induction of key components of the Notch signaling pathway (Notch-1, Jagged-1) by treatment with UV-B, 1,25(OH)(2)D(3), and/or epigenetic drugs (TSA, 5-Aza) in human keratinocytes in vitro.

Science.gov (United States)

Reichrath, Sandra; Reichrath, Jörg

2012-01-01

Notch signaling is of high importance for growth and survival of various cell types. We now analyzed the protein expression of two key components of the Notch signaling pathway (Notch-1, Jagged-1) in spontaneously immortalized (HaCaT) and in malignant (SCL-1) human keratinocytes, using western analysis. We found that Notch-1 and its corresponding ligand Jagged-1 are expressed in both cell lines, with no marked change following UV-B treatment. Moreover, treatment of both cell lines before or after UV-B irradiation with 1,25-dihydroxyvitamin D(3), the biologically active form of vitamin D, and/or epigenetic modulating drugs (TSA; 5-Aza) did not result in a marked modulation of the protein expression of Notch-1 or Jagged-1. Under the experimental conditions of this study, treatment with 1,25(OH)(2)D(3) protected human keratinocytes in part against the antiproliferative effects of UV-B-radiation. In conclusion, our findings do not point at a differential expression of these two key components of Notch signaling in non-malignant as compared to malignant human keratinocytes, indicating that alterations in their expression are not of importance for the photocarcinogenesis of human squamous cell carcinomas. Moreover, our findings do not support the hypothesis that modulation of Notch signaling may be involved in the photoprotective effect of 1,25-dihydroxyvitamin D(3), that we and others reported previously. Additionally, we demonstrate that epigenetic modulating drugs (TSA, 5-Aza) do not markedly modulate the expression Notch-1 or Jagged-1 in UV-B-treated human keratinocytes in vitro.

Notch1 and 4 Signaling Responds to an Increasing Vascular Wall Shear Stress in a Rat Model of Arteriovenous Malformations

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Jian Tu

2014-01-01

Full Text Available Notch signaling is suggested to promote the development and maintenance of cerebral arteriovenous malformations (AVMs, and an increasing wall shear stress (WSS contributes to AVM rupture. Little is known about whether WSS impacts Notch signaling, which is important for understanding the angiogenesis of AVMs. WSS was measured in arteriovenous fistulas (AVF surgically created in 96 rats at different time points over a period of 84 days. The expression of Notch receptors 1 and 4 and their ligands, Delta1 and 4, Jagged1, and Notch downstream gene target Hes1 was quantified in “nidus” vessels. The interaction events between Notch receptors and their ligands were quantified using proximity ligation assay. There was a positive correlation between WSS and time (r=0.97; P<0.001. The expression of Notch receptors and their ligands was upregulated following AVF formation. There was a positive correlation between time and the number of interactions between Notch receptors and their ligands aftre AVF formation (r=0.62, P<0.05 and a positive correlation between WSS and the number of interactions between Notch receptors and their ligands (r=0.87, P<0.005. In conclusion, an increasing WSS may contribute to the angiogenesis of AVMs by activation of Notch signaling.

Dynamic plastic behaviour of a notched free-free beam subjected to step-loading at one end

International Nuclear Information System (INIS)

Zhang, Y.; Yang, J.L.

2002-01-01

A rigid perfectly plastic model is developed to study the initial, small deflection response of a free-free beam with an initial notch along its span under a concentrated step-loading suddenly applied at one end of the beam. Complete solutions are obtained for various combinations of the magnitude of the load, the location of the notch and its defect-severity. The partitioning of the initial energy dissipation rates is discussed for some typical situations. It is concluded that: (i) the different initial deformation mechanisms and the initial energy dissipation rate of the beam depend not only on the magnitude of the load but also on the defect-severity and location of the notch; (ii) because of the influence of the notch, the structural response of the beam is far more complicated than that of the un-notched free-free beam; and (iii) for some cases the maximum rate of energy dissipation in plastic hinges will be more than 1/3 of the total input energy rate, while for an un-notched free-free beam, it has been demonstrated that the plastic dissipated energy is always less than 1/3 of the input energy [Int. J. Impact Engng 21 (1998) 165

160 Gb/s Raman-assisted notch-filtered XPM wavelength conversion and transmission

DEFF Research Database (Denmark)

Galili, Michael; Oxenløwe, Leif Katsuo; Mulvad, Hans Christian Hansen

2007-01-01

In-line wavelength conversion of 160 Gb/s data by Raman-assisted notch-filtered XPM is demonstrated for 130 km total transmission. The improvement in system performance from applying Raman gain during conversion is shown.......In-line wavelength conversion of 160 Gb/s data by Raman-assisted notch-filtered XPM is demonstrated for 130 km total transmission. The improvement in system performance from applying Raman gain during conversion is shown....

[Treatment of proximal humeral fractures by reverse shoulder arthroplasty: mid-term evaluation of functional results and Notching].

Science.gov (United States)

Hernández-Elena, J; de la Red-Gallego, M Á; Garcés-Zarzalejo, C; Pascual-Carra, M A; Pérez-Aguilar, M D; Rodríguez-López, T; Alfonso-Fernández, A; Pérez-Núñez, M I

2015-01-01

An analysis was made on relationship between Notching and functional and radiographic parameters after treatment of acute proximal humeral fractures with reverse total shoulder arthroplasty. A retrospective evaluation was performed on 37 patients with acute proximal humeral fracture treated by reversed shoulder arthroplasty. The mean follow-up was 24 months. Range of motion, intraoperative and postoperative complications were recorded. Nerot's classification was used to evaluate Notching. Patient satisfaction was evaluated with the Constant Score (CS). Statistical analysis was performed to evaluate the relationship between Notching and glenosphere position, or functional outcomes. Mean range of elevation, abduction, external and internal rotation were 106.22°, 104.46°, 46.08° and 40.27°, respectively. Mean CS was 63. Notching was present at 12 months in 29% of patients. Statistical analysis showed significance differences between age and CS, age and notching development, and tilt with notching. No statistical significance differences were found between elevation, abduction, internal and external rotation and CS either with scapular or glenosphere-neck angle. Reverse shoulder arthroplasty is a valuable option for acute humeral fractures in patients with osteoporosis and cuff-tear arthropathy. It leads to early pain relief and shoulder motion. Nevertheless, it is not exempt from complications, and long-term studies are needed to determine the importance of notching. Copyright © 2014 SECOT. Published by Elsevier Espana. All rights reserved.

Peripheral Osteoma of the Mandibular Notch: Report of a Case

International Nuclear Information System (INIS)

Iwai, Toshinori; Izumi, Toshiharu; Baba, Junichi; Maegawa, Jiro; Mitsudo, Kenji; Tohnai, Iwai

2013-01-01

Osteoma is a benign, slow-growing osteogenic tumor that sometimes arises from the craniomaxillofacial region, such as the sinus, temporal or jaw bones. Osteoma consists of compact or cancellous bone that may be peripheral, central or extraskeletal type. Peripheral osteoma arises from the periosteum and is commonly a unilateral, pedunculated mushroom-like mass. Peripheral osteoma of the mandible is relatively uncommon, and peripheral osteoma of the mandibular notch is extremely rare, although many cases arise from the mandibular body, angle, condyle, or coronoid process. We report here an unusual peripheral osteoma of the mandibular notch in a 78-year-old nonsyndromic female

Use of notched beams to establish fracture criteria for beryllium

International Nuclear Information System (INIS)

Mayville, R.A.

1980-01-01

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

Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.

Directory of Open Access Journals (Sweden)

Alexis Dumortier

2010-02-01

Full Text Available The Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth.To study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD, characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP, a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia.Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.

Notched Strength of Woven Fabric Kenaf Composites with Different Fiber Orientations

Directory of Open Access Journals (Sweden)

Ahmad Hilton

2017-01-01

Full Text Available The awareness of implementing sustainable materials in construction industry is gaining good attention among engineers worldwide. Kenaf fibers are local renewable materials to combine with epoxy polymers matrix in producing lightweight composite materials which may replace imported synthetic fiber composites especially in developing countries. Other benefits of using kenaf fiber composites are relatively cheap, less abrasive and less hazardous during fabrication handling. Current study investigates parametric study on notched strength of woven fabric kenaf composite plates with different fiber orientations and circular hole sizes. Stress concentration occurred at the notch edge promotes to micro-damage events such as matrix cracking and fiber fracture as remote tensile loading applied. Current study showed that 0° fiber orientation gives optimum notched strength, plates with larger fiber tilting than 0° are associated with further strength reduction. Kenaf fibers give an alternative to material designers to opt woven fabric kenaf composites in low and medium load bearing applications.

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

Science.gov (United States)

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).

Diagnosing CADASIL using MRI: evidence from families with known mutations of Notch 3 gene

International Nuclear Information System (INIS)

Chawda, S.J.; Lange, R.P.J. de; St-Clair, D.; Hourihan, M.D.; Halpin, S.F.S.

2000-01-01

Clinical data and MRI findings are presented on 18 subjects from two families with neuropathologically confirmed CADASIL. DNA analysis revealed mutations in exon 4 of Notch 3 gene in both families. All family members with mutations in Notch 3 gene had extensive abnormalities on MRI, principally lesions in the white matter of the frontal lobes and in the external capsules. Of several family members in whom a diagnosis of CADASIL was suspected on the basis of minor symptoms, one had MRI changes consistent with CADASIL; none of these cases carried a mutation in the Notch 3 gene. MRI and clinical features that may alert the radiologist to the diagnosis of CADASIL are reviewed. However, a wide differential diagnosis exists for the MRI appearances of CADASIL, including multiple sclerosis and small-vessel disease secondary to hypertension. The definitive diagnosis cannot be made on MRI alone and requires additional evidence, where available, from a positive family history and by screening DNA for mutations of Notch 3 gene. (orig.)

Scalable In-Band Optical Notch-Filter Labeling for Ultrahigh Bit Rate Optical Packet Switching

DEFF Research Database (Denmark)

Medhin, Ashenafi Kiros; Galili, Michael; Oxenløwe, Leif Katsuo

2014-01-01

We propose a scalable in-band optical notch-filter labeling scheme for optical packet switching of high-bit-rate data packets. A detailed characterization of the notch-filter labeling scheme and its effect on the quality of the data packet is carried out in simulation and verified by experimental...... demonstrations. The scheme is able to generate more than 91 different labels that can be applied to 640-Gb/s optical time division multiplexed packets causing an eye opening penalty of $1.2-dB. Experimental demonstration shows that up to 256 packets can be uniquely labeled by employing up to eight notch filters...... with only 0.9-dB power penalty to achieve BER of 1E-9. Using the proposed labeling scheme, optical packet switching of 640 Gb/s data packets is experimentally demonstrated in which two data packets are labeled by making none and one spectral hole using a notch filter and are switched using a LiNbO$_3...

Fringe Controls Naïve CD4+T Cells Differentiation through Modulating Notch Signaling in Asthmatic Rat Models

Science.gov (United States)

Gu, Wen; Xu, Weiguo; Ding, Tao; Guo, Xuejun

2012-01-01

The ability of Notch signaling to regulate T helper cell development and differentiation has been widely accepted. Fringe, O-fucose-β1,3-N-acetylglucosaminyltransferases modulate Notch receptor expression and promote the Notch signaling pathway through receptor-ligand binding. In this study, we assayed the expression levels of three Fringe homologs in naive CD4+T cells in asthmatic rats. We found that Radical Fringe (Rfng) was highly expressed, whereas both Lunatic Fringe (Lfng) and Manic Fringe (Mfng) were expressed at low levels. Down-regulation of Rfng using siRNA, and overexpression of Lfng or Mfng enhanced Th1 subset lineages and diminished Th2 subset lineages. Notch signaling was more activated in asthmatic naïve CD4+T cells than in control cells, and Lfng, but not Mfng or Rfng, partly inhibited Notch signaling in asthmatic naïve CD4+T lymphocytes. Lfng overexpression resulted in significantly decreased Th2 cytokine production in asthma, which was the same effect as the GSI (γ-secretase inhibitor) treatment alone, but had an increased effect on Th1 cytokines than GSI treatment. Collectively, these data identify the essential role of Fringe modulating naïve CD4+T cells differentiation through Notch signaling. Lfng regulated Th2 cells differentiation via a Notch-dependent manner and Th1 cells differentiation via a Notch-independent manner. Fringe could be a therapeutic strategy for the management and prevention of allergic asthma. PMID:23071776

Fringe controls naïve CD4(+)T cells differentiation through modulating notch signaling in asthmatic rat models.

Science.gov (United States)

Gu, Wen; Xu, Weiguo; Ding, Tao; Guo, Xuejun

2012-01-01

The ability of Notch signaling to regulate T helper cell development and differentiation has been widely accepted. Fringe, O-fucose-β1,3-N-acetylglucosaminyltransferases modulate Notch receptor expression and promote the Notch signaling pathway through receptor-ligand binding. In this study, we assayed the expression levels of three Fringe homologs in naive CD4(+)T cells in asthmatic rats. We found that Radical Fringe (Rfng) was highly expressed, whereas both Lunatic Fringe (Lfng) and Manic Fringe (Mfng) were expressed at low levels. Down-regulation of Rfng using siRNA, and overexpression of Lfng or Mfng enhanced Th1 subset lineages and diminished Th2 subset lineages. Notch signaling was more activated in asthmatic naïve CD4(+)T cells than in control cells, and Lfng, but not Mfng or Rfng, partly inhibited Notch signaling in asthmatic naïve CD4(+)T lymphocytes. Lfng overexpression resulted in significantly decreased Th2 cytokine production in asthma, which was the same effect as the GSI (γ-secretase inhibitor) treatment alone, but had an increased effect on Th1 cytokines than GSI treatment. Collectively, these data identify the essential role of Fringe modulating naïve CD4(+)T cells differentiation through Notch signaling. Lfng regulated Th2 cells differentiation via a Notch-dependent manner and Th1 cells differentiation via a Notch-independent manner. Fringe could be a therapeutic strategy for the management and prevention of allergic asthma.

Human papillomavirus 16E6 and NFX1-123 potentiate notch signaling and differentiation without activating cellular arrest

Energy Technology Data Exchange (ETDEWEB)

Vliet-Gregg, Portia A.; Hamilton, Jennifer R. [Center for Global Infectious Disease Research, Seattle Children' s Research Institute, 1900 Ninth Ave., Seattle, WA 98101 (United States); Katzenellenbogen, Rachel A., E-mail: rkatzen@uw.edu [Center for Global Infectious Disease Research, Seattle Children' s Research Institute, 1900 Ninth Ave., Seattle, WA 98101 (United States); Department of Pediatrics, Division of Adolescent Medicine, University of Washington, Seattle WA (United States)

2015-04-15

High-risk human papillomavirus (HR HPV) oncoproteins bind host cell proteins to dysregulate and uncouple apoptosis, senescence, differentiation, and growth. These pathways are important for both the viral life cycle and cancer development. HR HPV16 E6 (16E6) interacts with the cellular protein NFX1-123, and they collaboratively increase the growth and differentiation master regulator, Notch1. In 16E6 expressing keratinocytes (16E6 HFKs), the Notch canonical pathway genes Hes1 and Hes5 were increased with overexpression of NFX1-123, and their expression was directly linked to the activation or blockade of the Notch1 receptor. Keratinocyte differentiation genes Keratin 1 and Keratin 10 were also increased, but in contrast their upregulation was only indirectly associated with Notch1 receptor stimulation and was fully unlinked to growth arrest, increased p21{sup Waf1/CIP1}, or decreased proliferative factor Ki67. This leads to a model of 16E6, NFX1-123, and Notch1 differently regulating canonical and differentiation pathways and entirely uncoupling cellular arrest from increased differentiation. - Highlights: • 16E6 and NFX1-123 increased the Notch canonical pathway through Notch1. • 16E6 and NFX1-123 increased the differentiation pathway indirectly through Notch1. • 16E6 and NFX1-123 increased differentiation gene expression without growth arrest. • Increased NFX1-123 with 16E6 may create an ideal cellular phenotype for HPV.

The hippo pathway promotes Notch signaling in regulation of cell differentiation, proliferation, and oocyte polarity.

Directory of Open Access Journals (Sweden)

Jianzhong Yu

2008-03-01

Full Text Available Specification of the anterior-posterior axis in Drosophila oocytes requires proper communication between the germ-line cells and the somatically derived follicular epithelial cells. Multiple signaling pathways, including Notch, contribute to oocyte polarity formation by controlling the temporal and spatial pattern of follicle cell differentiation and proliferation. Here we show that the newly identified Hippo tumor-suppressor pathway plays a crucial role in the posterior follicle cells in the regulation of oocyte polarity. Disruption of the Hippo pathway, including major components Hippo, Salvador, and Warts, results in aberrant follicle-cell differentiation and proliferation and dramatic disruption of the oocyte anterior-posterior axis. These phenotypes are related to defective Notch signaling in follicle cells, because misexpression of a constitutively active form of Notch alleviates the oocyte polarity defects. We also find that follicle cells defective in Hippo signaling accumulate the Notch receptor and display defects in endocytosis markers. Our findings suggest that the interaction between Hippo and classic developmental pathways such as Notch is critical to spatial and temporal regulation of differentiation and proliferation and is essential for development of the body axes in Drosophila.

Atractylenolide I-mediated Notch pathway inhibition attenuates gastric cancer stem cell traits

Energy Technology Data Exchange (ETDEWEB)

Ma, Li; Mao, Rurong; Shen, Ke; Zheng, Yuanhong; Li, Yueqi [State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237 (China); Liu, Jianwen, E-mail: liujian@ecust.edu.cn [State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237 (China); Ni, Lei, E-mail: nilei625@yahoo.com [Department of Respiration, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Road II, Shanghai 200025 (China)

2014-07-18

Highlights: • This paper supports the anti-tumor effects of AT-I on gastric cancer in vitro. • AT-I attenuates gastric cancer stem cell traits. • It is the systematic study regarding AT-I suppression of Notch pathway in GC and GCSLCs. - Abstract: Atractylenolide I (AT-I), one of the main naturally occurring compounds of Rhizoma Atractylodis Macrocephalae, has remarkable anti-cancer effects on various cancers. However, its effects on the treatment of gastric cancer remain unclear. Via multiple cellular and molecular approaches, we demonstrated that AT-I could potently inhibit cancer cell proliferation and induce apoptosis through inactivating Notch pathway. AT-I treatment led to the reduction of expressions of Notch1, Jagged1, and its downstream Hes1/ Hey1. Our results showed that AT-I inhibited the self-renewal capacity of gastric stem-like cells (GCSLCs) by suppression of their sphere formation capacity and cell viability. AT-I attenuated gastric cancer stem cell (GCSC) traits partly through inactivating Notch1, leading to reducing the expressions of its downstream target Hes1, Hey1 and CD44 in vitro. Collectively, our results suggest that AT-I might develop as a potential therapeutic drug for the treatment of gastric cancer.

Atractylenolide I-mediated Notch pathway inhibition attenuates gastric cancer stem cell traits

International Nuclear Information System (INIS)

Ma, Li; Mao, Rurong; Shen, Ke; Zheng, Yuanhong; Li, Yueqi; Liu, Jianwen; Ni, Lei

2014-01-01

Highlights: • This paper supports the anti-tumor effects of AT-I on gastric cancer in vitro. • AT-I attenuates gastric cancer stem cell traits. • It is the systematic study regarding AT-I suppression of Notch pathway in GC and GCSLCs. - Abstract: Atractylenolide I (AT-I), one of the main naturally occurring compounds of Rhizoma Atractylodis Macrocephalae, has remarkable anti-cancer effects on various cancers. However, its effects on the treatment of gastric cancer remain unclear. Via multiple cellular and molecular approaches, we demonstrated that AT-I could potently inhibit cancer cell proliferation and induce apoptosis through inactivating Notch pathway. AT-I treatment led to the reduction of expressions of Notch1, Jagged1, and its downstream Hes1/ Hey1. Our results showed that AT-I inhibited the self-renewal capacity of gastric stem-like cells (GCSLCs) by suppression of their sphere formation capacity and cell viability. AT-I attenuated gastric cancer stem cell (GCSC) traits partly through inactivating Notch1, leading to reducing the expressions of its downstream target Hes1, Hey1 and CD44 in vitro. Collectively, our results suggest that AT-I might develop as a potential therapeutic drug for the treatment of gastric cancer

A Maximum Radius for Habitable Planets.

Science.gov (United States)

Alibert, Yann

2015-09-01

We compute the maximum radius a planet can have in order to fulfill two constraints that are likely necessary conditions for habitability: 1- surface temperature and pressure compatible with the existence of liquid water, and 2- no ice layer at the bottom of a putative global ocean, that would prevent the operation of the geologic carbon cycle to operate. We demonstrate that, above a given radius, these two constraints cannot be met: in the Super-Earth mass range (1-12 Mearth), the overall maximum that a planet can have varies between 1.8 and 2.3 Rearth. This radius is reduced when considering planets with higher Fe/Si ratios, and taking into account irradiation effects on the structure of the gas envelope.

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

Science.gov (United States)

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.

The notch and TGF-β signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma.

Directory of Open Access Journals (Sweden)

Jonas Sjölund

Full Text Available BACKGROUND: Despite recent progress, therapy for metastatic clear cell renal cell carcinoma (CCRCC is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We show that inhibition of endogenous Notch signaling modulates TGF-β dependent gene regulation in CCRCC cells. Analysis of gene expression data representing 176 CCRCCs showed that elevated TGF-β pathway activity correlated significantly with shortened disease specific survival (log-rank test, p = 0.006 and patients with metastatic disease showed a significantly elevated TGF-β signaling activity (two-sided Student's t-test, p = 0.044. Inhibition of Notch signaling led to attenuation of both basal and TGF-β1 induced TGF-β signaling in CCRCC cells, including an extensive set of genes known to be involved in migration and invasion. Functional analyses revealed that Notch inhibition decreased the migratory and invasive capacity of CCRCC cells. CONCLUSION: An extensive cross-talk between the Notch and TGF-β signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease.

Potential involvement of Notch1 signalling in the pathogenesis of primary cutaneous CD30-positive lymphoproliferative disorders

DEFF Research Database (Denmark)

Kamstrup, M.R.; Ralfkiaer, E.; Skovgaard, G.L.

2008-01-01

Background The central role of Notch signalling in T-cell development and oncogenesis raises the question of the importance of this pathway in cutaneous T-cell lymphomas. Objectives To investigate the pattern of expression of Notch and its ligands, Jagged and Delta, in skin samples of primary...... obtained from three patients with LyP and two patients with primary cutaneous ALCL. Results We identified single Notch1-positive cells or small clusters of atypical cells in LyP. Similarly, strongly positive Jagged1 cells tended to be localized in clusters. Primary cutaneous ALCL had higher expression...... of Notch1 and Jagged1 compared with LyP. Cells expressing Notch1 and Jagged1 were colocalized and a subset of cells expressed both the receptor and the ligand. The expression of the ligand Delta1 was low to undetectable in both types of lymphoproliferations. A subpopulation of lymphoma cells was found...

Myositis ossificans within the intercondylar notch treated arthroscopically

International Nuclear Information System (INIS)

Leung, Allen H.; Desai, Panna; Rybak, Leon D.; Rose, Donald J.

2010-01-01

We present a case of intraarticular myositis ossificans in the right knee of a child. Myositis ossificans (MO), though relatively rare in childhood and even more uncommon within a joint, should be included in the differential diagnosis of an intra-articular mass when indicated by the typical clinical, radiographic, and histologic findings. An 11-year-old male presented with a history of trauma to his right knee. Four weeks after the initial injury, an MRI demonstrated evidence of an ACL rupture with a ''cystic mass'' within the intercondylar notch along the anterior surface of the torn ligament. At subsequent arthroscopy, the mass noted on MRI was removed. The histology was consistent with MO. The authors believe this to be the first case of MO in the intercondylar notch detected by MRI, treated by arthroscopy, and confirmed by histology. (orig.)

Myositis ossificans within the intercondylar notch treated arthroscopically

Energy Technology Data Exchange (ETDEWEB)

Leung, Allen H.; Desai, Panna [Hospital for Joint Diseases/New York University, Department of Pathology, New York, NY (United States); Rybak, Leon D. [Hospital for Joint Diseases/New York University, Department of Radiology, New York, NY (United States); Rose, Donald J. [Hospital for Joint Diseases/New York University, Department of Orthopedic Surgery, New York, NY (United States)

2010-09-15

We present a case of intraarticular myositis ossificans in the right knee of a child. Myositis ossificans (MO), though relatively rare in childhood and even more uncommon within a joint, should be included in the differential diagnosis of an intra-articular mass when indicated by the typical clinical, radiographic, and histologic findings. An 11-year-old male presented with a history of trauma to his right knee. Four weeks after the initial injury, an MRI demonstrated evidence of an ACL rupture with a ''cystic mass'' within the intercondylar notch along the anterior surface of the torn ligament. At subsequent arthroscopy, the mass noted on MRI was removed. The histology was consistent with MO. The authors believe this to be the first case of MO in the intercondylar notch detected by MRI, treated by arthroscopy, and confirmed by histology. (orig.)

Gene expression profiling of the Notch-AhR-IL22 axis at homeostasis and in response to tissue injury.

Science.gov (United States)

Weidenbusch, Marc; Rodler, Severin; Song, Shangqing; Romoli, Simone; Marschner, Julian A; Kraft, Franziska; Holderied, Alexander; Kumar, Santosh; Mulay, Shrikant R; Honarpisheh, Mohsen; Kumar Devarapu, Satish; Lech, Maciej; Anders, Hans-Joachim

2017-12-22

Notch and interleukin-22 (IL-22) signaling are known to regulate tissue homeostasis and respond to injury in humans and mice, and the induction of endogenous aryl hydrocarbon receptor (Ahr) ligands through Notch links the two pathways in a hierarchical fashion. However in adults, the species-, organ- and injury-specific gene expression of the Notch-AhR-IL22 axis components is unknown. We therefore performed gene expression profiling of DLL1, DLL3, DLL4, DLK1, DLK2, JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, ADAM17/TNF-α ADAM metalloprotease converting enzyme (TACE), PSEN1, basigin (BSG)/CD147, RBP-J, HES1, HES5, HEY1, HEYL, AHR, ARNT, ARNT2, CYP1A1, CYP24A1, IL-22, IL22RA1, IL22RA2, IL10RB, and STAT3 under homeostatic conditions in ten mature murine and human organs. Additionally, the expression of these genes was assessed in murine models of acute sterile inflammation and progressive fibrosis. We show that there are organ-specific gene expression profiles of the Notch-AhR-IL22 axis in humans and mice. Although there is an overall interspecies congruency, specific differences between human and murine expression signatures do exist. In murine tissues with AHR/ARNT expression CYP1A1 and IL-22 were correlated with HES5 and HEYL expression, while in human tissues no such correlation was found. Notch and AhR signaling are involved in renal inflammation and fibrosis with specific gene expression changes in each model. Despite the presence of all Notch pathway molecules in the kidney and a model-specific induction of Notch ligands, IL-22 was only up-regulated in acute inflammation, but rapidly down-regulated during regeneration. This implies that for targeting injury responses, e.g. via IL-22, species-specific differences, injury type and time points have to be considered. © 2017 The Author(s).

Probabilistic fatigue life prediction methodology for notched components based on simple smooth fatigue tests

Energy Technology Data Exchange (ETDEWEB)

Wu, Z. R.; Li, Z. X. [Dept.of Engineering Mechanics, Jiangsu Key Laboratory of Engineering Mechanics, Southeast University, Nanjing (China); Hu, X. T.; Xin, P. P.; Song, Y. D. [State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing (China)

2017-01-15

The methodology of probabilistic fatigue life prediction for notched components based on smooth specimens is presented. Weakestlink theory incorporating Walker strain model has been utilized in this approach. The effects of stress ratio and stress gradient have been considered. Weibull distribution and median rank estimator are used to describe fatigue statistics. Fatigue tests under different stress ratios were conducted on smooth and notched specimens of titanium alloy TC-1-1. The proposed procedures were checked against the test data of TC-1-1 notched specimens. Prediction results of 50 % survival rate are all within a factor of two scatter band of the test results.

Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch

DEFF Research Database (Denmark)

López-Arribillaga, Erika; Rodilla, Verónica; Pellegrinet, Luca

2015-01-01

Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. T...

Effects of microstructures on hydrogen induced cracking of electrochemically hydrogenated double notched tensile sample of 4340 steel

Energy Technology Data Exchange (ETDEWEB)

Sk, Mobbassar Hassan, E-mail: Skmobba@qu.edu.qa [Center for Advanced Materials, Qatar University, Doha (Qatar); Overfelt, Ruel A. [Materials Research and Education Center, Materials Engineer, Auburn University, Auburn, AL (United States); Abdullah, Aboubakr M. [Center for Advanced Materials, Qatar University, Doha (Qatar)

2016-04-06

Quantitative fractographic characteristics of 4340 steel is demonstrated for a grain size range of 10−100 µm and hardness range of 41–52 HRC. Double-notched tensile samples were electrochemically charged in-situ with hydrogen in 0.5 m H{sub 2}SO{sub 4}+5 mg/l As{sub 2}O{sub 3} solution for 0–40 min charging time. Hydrogen induced fracture initiations were analyzed by novel metallographic investigation of the “unbroken” notch while the overall fractographic behaviors were examined by the scanning electron microscopic imaging of the fracture surfaces of the actually broken notch. Effect of hydrogen was predominantly manifested as intergranular fracture for the harder samples and quasi-cleavage fracture for the softer counterparts. 10–40 µm samples showed the maximum intensity of the hydrogen induced fracture features (intergranular and/or quasi-cleavage) close to the notch which gradually reduced with increasing distance from the notch. The largest grained samples (100 µm) however showed brittle behavior even in absence of hydrogen with similar intensity of percent fracture features at all distance from the notch, while presence of hydrogen intensified the overall percent brittle fractures with their intensities being highest close to the notch. Finally, the brittle fracture characteristics of the hydrogen embrittled samples were shown to be distinguishably different from that of the liquid nitrogen treated samples of same grain sizes and hardnesses.

Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway

International Nuclear Information System (INIS)

Gao, Rundi; Chen, Ruilin; Cao, Yu; Wang, Yuan; Song, Kang; Zhang, Ya; Yang, Junchao

2017-01-01

Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. - Highlights: • Emodin inhibits TGF-β1-induced EMT in alveolar epithelial cells. • Emodin regulates the expression patterns of the Notch signaling pathway-related factors. • Emodin inhibits TGF-β1-induced Notch-1 nucleus translocation and activation.

Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Gao, Rundi; Chen, Ruilin; Cao, Yu [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Wang, Yuan [Department of Pulmonary Function, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Song, Kang [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China); Zhang, Ya [Zhejiang Chinese Medicine University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang Province 310006 (China); Yang, Junchao, E-mail: yangjunchaozj@zcmu.edu.cn [Department of Respiration, The First Affiliated Hospital of Zhejiang Chinese Medicine University, NO. 56, Youdian Road, Shangcheng District, Hangzhou, Zhejiang Province 310006 (China)

2017-03-01

Pulmonary fibrosis is characterized by the destruction of lung tissue architecture and the formation of fibrous foci, currently has no satisfactory treatment. Emodin is a component of Chinese herb that has been reported to be medicament on pancreatic fibrosis and liver fibrosis. However, its role in pulmonary fibrosis has not been established yet. In the present study, we investigated the hypothesis that Emodin plays an inhibitory role in TGF-β1 induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cell, and Emodin exerts its effect through the Notch signaling pathway. Emodin inhibits the proliferation of Rat alveolar type II epithelial cells RLE-6TN in a concentration-dependent manner; reduces the expression of Collagen I, α-SMA and Vimentin, promotes the expression of E-cadherin. Moreover, Emodin could regulate the expression patterns of the Notch signaling pathway-related factors and reduce the Notch-1 nucleus translocation. Knockdown of Notch-1 enhances the inhibitory effect of Emodin on TGF-β1-induced EMT in RLE-6TN cells. In conclusion, the data of the present study suggests that Emodin suppresses TGF-β1-induced EMT in alveolar epithelial cells through Notch signaling pathway and shows the potential to be effective in the treatment of pulmonary fibrosis. - Highlights: • Emodin inhibits TGF-β1-induced EMT in alveolar epithelial cells. • Emodin regulates the expression patterns of the Notch signaling pathway-related factors. • Emodin inhibits TGF-β1-induced Notch-1 nucleus translocation and activation.

Folic Acid supplementation stimulates notch signaling and cell proliferation in embryonic neural stem cells.

Science.gov (United States)

Liu, Huan; Huang, Guo-Wei; Zhang, Xu-Mei; Ren, Da-Lin; X Wilson, John

2010-09-01

The present study investigated the effect of folic acid supplementation on the Notch signaling pathway and cell proliferation in rat embryonic neural stem cells (NSCs). The NSCs were isolated from E14-16 rat brain and grown as neurospheres in serum-free suspension culture. Individual cultures were assigned to one of 3 treatment groups that differed according to the concentration of folic acid in the medium: Control (baseline folic acid concentration of 4 mg/l), low folic acid supplementation (4 mg/l above baseline, Folate-L) and high folic acid supplementation (40 mg/l above baseline, Folate-H). NSCs were identified by their expression of immunoreactive nestin and proliferating cells by incorporation of 5'bromo-2'deoxyuridine. Cell proliferation was also assessed by methyl thiazolyl tetrazolium assay. Notch signaling was analyzed by real-time PCR and western blot analyses of the expression of Notch1 and hairy and enhancer of split 5 (Hes5). Supplementation of NSCs with folic acid increased the mRNA and protein expression levels of Notch1 and Hes5. Folic acid supplementation also stimulated NSC proliferation dose-dependently. Embryonic NSCs respond to folic acid supplementation with increased Notch signaling and cell proliferation. This mechanism may mediate the effects of folic acid supplementation on neurogenesis in the embryonic nervous system.

Correlation of eddy current responses between fatigue cracks and electrical-discharge-machining notches

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Seo, Sukho; Choi, Gyudong; Eom, Tae Jhoun; Lee, Bokwon; Lee, Soo Yeol

2017-07-01

The eddy current responses of Electrical Discharge Machining (EDM) notches and fatigue cracks are directly compared to verify the reliability of eddy current inspection. The fatigue crack growth tests using a constant load range control mode were conducted to obtain a variety of edge crack sizes, ranging from 0.9 to 6.6 mm for Al alloy and from 0.1 to 3 mm for Ti alloy. EDM notch specimens of Al and Ti alloys were accordingly prepared in lengths similar to that of the fatigued specimen. The crack length was determined by optical microscope and scanning electron microscope. The eddy current responses between the EDM and fatigued specimens with varying notch/crack length were examined using probe sensors at (100-500) kHz and (1-2) MHz for Al and Ti alloys, respectively. The results show a significant difference in the eddy current signal between the two specimens, based on the correlation between the eddy current response and notch/crack length. This suggests that eddy current inspection using the EDM reference specimen is inaccurate in determining the precise crack size, unless the eddy current response data base is obtained from a fatigue-cracked specimen.

Magnetic domain wall motion in notch patterned permalloy nanowire devices

Energy Technology Data Exchange (ETDEWEB)

Chen, Ting-Chieh; Kuo, Cheng-Yi; Mishra, Amit K.; Das, Bipul; Wu, Jong-Ching, E-mail: phjcwu@cc.ncue.edu.tw

2015-11-01

We report a study of magnetization reversal process of notch-patterned permalloy (Py) nanowires (NWs) by using an in-situ magnetic force microscopy (MFM). Three neighboring straight NWs and an individual straight NW with discs connected to the wires ends are fabricated by standard electron beam lithography through a lift-off technique. MFM images are taken in the presence of an in-plane magnetic field applied along the wires length. As a result, the nucleation, pinning and depinning of domain walls (DWs) along the NW are observed. The artificial constraints (notch) in such symmetrical geometry of NWs indeed serve as pinning sites to pin the DWs. The nature of magnetization reversal, pinning field and depinning field for the DWs that are observed in these permalloy NWs, indicate the key roles of notch depth, the terminal connection structure of NW end and the inter-wire interaction among the NWs. The in-situ MFM measurements are examined with the micromagnetic simulations. Consequently, good agreements are obtained for the DW structures and the effect of DWs pining/depinning, however a dissimilarity in experimental and simulation observations for the direction of propagation of DWs in NWs needs further investigation.

Material inertia and size effects in the Charpy V-notch test

DEFF Research Database (Denmark)

Desandre, D. A.; Benzerga, A. A.; Tvergaard, Viggo

2004-01-01

The effect of material inertia on the size dependence of the absorbed energy in the Charpy V-notch test is investigated. The material response is characterized by an elastic-viscoplastic constitutive relation for a porous plastic solid, with adiabatic heating due to plastic dissipation and the re......The effect of material inertia on the size dependence of the absorbed energy in the Charpy V-notch test is investigated. The material response is characterized by an elastic-viscoplastic constitutive relation for a porous plastic solid, with adiabatic heating due to plastic dissipation...

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

NARCIS (Netherlands)

Rutten, J.W.; Dauwerse, H.G.; Peters, D.J.; Goldfarb, A.; Venselaar, H.; Haffner, C.; Ommen, G.J. van; Aartsma-Rus, A.M.; Oberstein, S.A.

2016-01-01

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, is a hereditary cerebral small vessel disease caused by characteristic cysteine altering missense mutations in theNOTCH3gene.NOTCH3mutations in CADASIL result in an uneven number of cysteine

An amelogenin mutation leads to disruption of the odontogenic apparatus and aberrant expression of Notch I

Science.gov (United States)

Chen, Xu; Li, Yong; Alawi, Faizan; Bouchard, Jessica R.; Kulkarni, Ashok B.; Gibson, Carolyn W.

2012-01-01

BACKGROUND Amelogenins are highly conserved proteins secreted by ameloblasts in the dental organ of developing teeth. These proteins regulate dental enamel thickness and structure in humans and mice. Mice that express an amelogenin transgene with a P70T mutation (TgP70T) develop abnormal epithelial proliferation in an amelogenin null (KO) background. Some of these cellular masses have the appearance of proliferating stratum intermedium, which is the layer adjacent to the ameloblasts in unerupted teeth. As Notch proteins are thought to constitute the developmental switch that separates ameloblasts from stratum intermedium, these signaling proteins were evaluated in normal and proliferating tissues. METHODS Mandibles were dissected for histology and immunohistochemistry using Notch I antibodies. Molar teeth were dissected for western blotting and RT-PCR for evaluation of Notch levels through imaging and statistical analyses. RESULTS Notch I was immunolocalized to ameloblasts of TgP70TKO mice, KO ameloblasts stained, but less strongly, and wild-type teeth had minimal staining. Cells within the proliferating epithelial cell masses were positive for Notch I and had an appearance reminiscent of calcifying epithelial odontogenic tumor with amyloid-like deposits. Notch I protein and mRNA were elevated in molar teeth from TgP70TKO mice. CONCLUSION Expression of TgP70T leads to abnormal structures in mandibles and maxillae of mice with the KO genetic background and these mice have elevated levels of Notch I in developing molars. As cells within the masses also express transgenic amelogenins, development of the abnormal proliferations suggests communication between amelogenin producing cells and the proliferating cells, dependent on the presence of the mutated amelogenin protein. PMID:20923441

Roles of Notch1 Signaling in Regulating Satellite Cell Fates Choices and Postnatal Skeletal Myogenesis.

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Shan, Tizhong; Xu, Ziye; Wu, Weiche; Liu, Jiaqi; Wang, Yizhen

2017-11-01

Adult skeletal muscle stem cells, also called satellite cells, are indispensable for the growth, maintenance, and regeneration of the postnatal skeletal muscle. Satellite cells, predominantly quiescent in mature resting muscles, are activated after skeletal muscle injury or degeneration. Notch1 signaling is an evolutionarily conserved pathway that plays crucial roles in satellite cells homeostasis and postnatal skeletal myogenesis and regeneration. Activation of Notch1 signaling promotes the muscle satellite cells quiescence and proliferation, but inhibits differentiation of muscle satellite cells. Notably, the new roles of Notch1 signaling during late-stage of skeletal myogenesis including in post-differentiation myocytes and post-fusion myotubes have been recently reported. Here, we mainly review and discuss the regulatory roles of Notch1 in regulating satellite cell fates choices and skeletal myogenesis. J. Cell. Physiol. 232: 2964-2967, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately.

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Shi, Yan; Shu, Bin; Yang, Ronghua; Xu, Yingbin; Xing, Bangrong; Liu, Jian; Chen, Lei; Qi, Shaohai; Liu, Xusheng; Wang, Peng; Tang, Jinming; Xie, Julin

2015-06-16

Wnt and Notch signaling pathways are critically involved in relative cell fate decisions within the development of cutaneous tissues. Moreover, several studies identified the above two pathways as having a significant role during wound healing. However, their biological effects during cutaneous tissues repair are unclear. We employed a self-controlled model (Sprague-Dawley rats with full-thickness skin wounds) to observe the action and effect of Wnt/β-catenin and Notch signalings in vivo. The quality of wound repair relevant to the gain/loss-of-function Wnt/β-catenin and Notch activation was estimated by hematoxylin-and-eosin and Masson staining. Immunofluorescence analysis and Western blot analysis were used to elucidate the underlying mechanism of the regulation of Wnt and Notch signaling pathways in wound healing. Meanwhile, epidermal stem cells (ESCs) were cultured in keratinocyte serum-free medium with Jaggedl or in DAPT (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl) to investigate whether the interruption of Notch signaling contributes to the expression of Wnt/β-catenin signaling. The results showed that in vivo the gain-of-function Wnt/β-catenin and Notch activation extended the ability to promote wound closure. We further determined that activation or inhibition of Wnt signaling and Notch signaling can affect the proliferation of ESCs, the differentiation and migration of keratinocytes, and follicle regeneration by targeting c-Myc and Hes1, which ultimately lead to enhanced or delayed wound healing. Furthermore, Western blot analysis suggested that the two pathways might interact in vivo and in vitro. These results suggest that Wnt and Notch signalings play important roles in cutaneous repair by targeting c-Myc and Hes1 separately. What's more, interaction between the above two pathways might act as a vital role in regulation of wound healing.

Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation.

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Laura Asnaghi

Full Text Available The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway may be important even in well-oxygenated uveal melanoma cells. HIF-1α protein accumulation in normoxia was inhibited by rapamycin. As expected, hypoxia (1% pO2 further induced HIF-1α protein levels along with its target genes VEGF and LOX. Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1α mutant into Mel285 cells with low HIF-1α baseline levels. In contrast, HIF-1α knockdown using shRNA significantly decreased growth in hypoxia, and reduced by more than 50% tumor invasion in four lines with high HIF-1α baseline levels. Pharmacologic blockade of HIF-1α protein expression using digoxin dramatically suppressed cellular invasion both in normoxia and in hypoxia. We found that Notch pathway components, including Jag1-2 ligands, Hes1-Hey1 targets and the intracellular domain of Notch1, were increased in hypoxia, as well as the phosphorylation levels of Erk1-2 and Akt. Pharmacologic and genetic inhibition of Notch largely blocked the hypoxic induction of invasion as did the pharmacologic suppression of Erk1-2 activity. In addition, the increase in Erk1-2 and Akt phosphorylation by hypoxia was partially reduced by inhibiting Notch signaling. Our findings support the functional importance of HIF-1α signaling in promoting the invasive capacity of uveal melanoma cells in both hypoxia and normoxia, and suggest that pharmacologically targeting HIF-1α pathway directly or through blockade of Notch or Erk1-2 pathways can slow tumor spread.

Genetic deletion of Rnd3 in neural stem cells promotes proliferation via upregulation of Notch signaling.

Science.gov (United States)

Dong, Huimin; Lin, Xi; Li, Yuntao; Hu, Ronghua; Xu, Yang; Guo, Xiaojie; La, Qiong; Wang, Shun; Fang, Congcong; Guo, Junli; Li, Qi; Mao, Shanping; Liu, Baohui

2017-10-31

Rnd3, a Rho GTPase, is involved in the inhibition of actin cytoskeleton dynamics through the Rho kinase-dependent signaling pathway. We previously demonstrated that mice with genetic deletion of Rnd3 developed a markedly larger brain compared with wild-type mice. Here, we demonstrate that Rnd3 knockout mice developed an enlarged subventricular zone, and we identify a novel role for Rnd3 as an inhibitor of Notch signaling in neural stem cells. Rnd3 deficiency, both in vivo and in vitro , resulted in increased levels of Notch intracellular domain protein. This led to enhanced Notch signaling and promotion of aberrant neural stem cell growth, thereby resulting in a larger subventricular zone and a markedly larger brain. Inhibition of Notch activity abrogated this aberrant neural stem cell growth.

Epithelial-stromal interaction via Notch signaling is essential for the full maturation of gut-associated lymphoid tissues.

Science.gov (United States)

Obata, Yuuki; Kimura, Shunsuke; Nakato, Gaku; Iizuka, Keito; Miyagawa, Yurika; Nakamura, Yutaka; Furusawa, Yukihiro; Sugiyama, Machiko; Suzuki, Keiichiro; Ebisawa, Masashi; Fujimura, Yumiko; Yoshida, Hisahiro; Iwanaga, Toshihiko; Hase, Koji; Ohno, Hiroshi

2014-12-01

Intrinsic Notch signaling in intestinal epithelial cells restricts secretory cell differentiation. In gut-associated lymphoid tissue (GALT), stromal cells located beneath the follicle-associated epithelium (FAE) abundantly express the Notch ligand delta-like 1 (Dll1). Here, we show that mice lacking Rbpj-a gene encoding a transcription factor implicated in Notch signaling-in intestinal epithelial cells have defective GALT maturation. This defect can be attributed to the expansion of goblet cells, which leads to the down-regulation of CCL20 in FAE. These data demonstrate that epithelial Notch signaling maintained by stromal cells contributes to the full maturation of GALT by restricting secretory cell differentiation in FAE. © 2014 The Authors.

Epithelial–stromal interaction via Notch signaling is essential for the full maturation of gut-associated lymphoid tissues

Science.gov (United States)

Obata, Yuuki; Kimura, Shunsuke; Nakato, Gaku; Iizuka, Keito; Miyagawa, Yurika; Nakamura, Yutaka; Furusawa, Yukihiro; Sugiyama, Machiko; Suzuki, Keiichiro; Ebisawa, Masashi; Fujimura, Yumiko; Yoshida, Hisahiro; Iwanaga, Toshihiko; Hase, Koji; Ohno, Hiroshi

2014-01-01

Intrinsic Notch signaling in intestinal epithelial cells restricts secretory cell differentiation. In gut-associated lymphoid tissue (GALT), stromal cells located beneath the follicle-associated epithelium (FAE) abundantly express the Notch ligand delta-like 1 (Dll1). Here, we show that mice lacking Rbpj—a gene encoding a transcription factor implicated in Notch signaling—in intestinal epithelial cells have defective GALT maturation. This defect can be attributed to the expansion of goblet cells, which leads to the down-regulation of CCL20 in FAE. These data demonstrate that epithelial Notch signaling maintained by stromal cells contributes to the full maturation of GALT by restricting secretory cell differentiation in FAE. Subject Categories Development & Differentiation; Immunology; Signal Transduction PMID:25378482

[Valsartan inhibits angiotensin II-Notch signaling of mesangial cells induced by high glucose].

Science.gov (United States)

Yuan, Qin; Lyu, Chuan; Wu, Can; Lei, Sha; Shao, Ying; Wang, Qiuyue

2016-01-01

To explore the role of angiotensin II (Ang II)-Notch signaling in high glucose-induced secretion of extracellular matrix of rat mesangial cells (RMCs) and to further investigate the protective effect of valsartan (one of Ang II receptor blockers) on kidney. Subcultured RMCs were divided into groups as follows: normal glucose group (5.5 mmol/L glucose); high glucose group (30 mmol/L glucose); high concentration of mannitol as osmotic control group (5.5 mmol/L glucose and 24.5 mmol/L mannitol); normal glucose plus 1 μmol/L N-[N-(3, 5-difluorophenacetyl)-L-alanyl ]-S-phenylglycine t-butyl ester (DAPT) group; normal glucose plus (1, 5, 10) μmol/L valsartan group; high glucose plus 1 μmol/L DAPT group; high glucose plus (1, 5, 10) μmol/L valsartan group. Cells and supernatants were harvested after 12, 24 and 48 hours. Notch1 expression was examined by Western blotting. Secretion of transforming growth factor (TGF-β) and fibronectin (FN) were detected by ELISA. Compared to the normal glucose group, Notch1 expression was elevated in the high glucose group after 12 hours, and peaked at 24 hours. Besides, secretion of TGF-β and FN were much higher in the high glucose group than in the normal glucose group in a time-dependent manner. Compared to the untreated group, Notch1 expression decreased in a dose-dependent manner in the valsartan or DAPT treated group under high glucose after 24 hours. After pre-treatment by either valsartan or DAPT in the high glucose group, secretion of TGF-β and FN obviously decreased as compared to the untreated group. Hyperglycemia could stimulate activation of Notch signaling in cultured RMCs, which may increase secretion of downstream fibrotic factors such as TGF-β and FN. Valsartan may decrease the secretion of downstream FN in a dose-dependent manner via inhibiting AngII-Notch signaling.

Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch

NARCIS (Netherlands)

Amsen, Derk; Antov, Andrey; Jankovic, Dragana; Sher, Alan; Radtke, Freddy; Souabni, Abdallah; Busslinger, Meinrad; McCright, Brent; Gridley, Thomas; Flavell, Richard A.

2007-01-01

CD4(+) T helper cells differentiate into T helper 1 (Th1) or Th2 effector lineages, which orchestrate immunity to different types of microbes. Both Th1 and Th2 differentiation can be induced by Notch, but what dictates which of these programs is activated in response to Notch is not known. By using

Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions.

Science.gov (United States)

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.

Specification of Drosophila corpora cardiaca neuroendocrine cells from mesoderm is regulated by Notch signaling.

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Sangbin Park

2011-08-01

Full Text Available Drosophila neuroendocrine cells comprising the corpora cardiaca (CC are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism.

Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.

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Alon Peled

2016-10-01

Full Text Available Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs, the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Application of Notched Long-Period Fiber Grating Based Sensor for CO2 Gas Sensing

Science.gov (United States)

Wu, Chao-Wei; Chiang, Chia-Chin

2016-01-01

An inductively coupled plasma etching process to fabricate notched long-period fiber gratings for CO2 gas sensing is proposed in this article. In the gas sensing test, the 15% mixed CO2 gas was used for characterization of CO2 adsorption by the amine-modified nanoporous silica foams of the notched long-period fiber grating sensor. The results shows the spectra were changed with the CO2 gas flow within 13 min. During the absorption process, the transmission of the resonant dip was decreased by 2.884 dB. Therefore, the proposed notched long-period fiber grating gas sensor shows good performance and is suitable as a gas sensor for monitoring the CO2 adsorption process.

Finite-Larmor-radius stability theory of EBT plasmas

International Nuclear Information System (INIS)

Berk, H.L.; Cheng, C.Z.; Rosenbluth, M.N.; Van Dam, J.W.

1982-11-01

An eikonal ballooning-mode formalism is developed to describe curvature-driven modes of hot electron plasmas in bumpy tori. The formalism treats frequencies comparable to the ion-cyclotron frequency, as well as arbitrary finite Larmor radius and field polarization, although the detailed analysis is restricted to E/sub parallel/ = 0. Moderate hot-electron finite-Larmor-radius effects are found to lower the background beta core limit, whereas strong finite-Lamor-radius effects produce stabilization

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

Science.gov (United States)

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.

miR-342-5p Regulates Neural Stem Cell Proliferation and Differentiation Downstream to Notch Signaling in Mice

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Fang Gao

2017-04-01

Full Text Available Summary: Notch signaling is critically involved in neural development, but the downstream effectors remain incompletely understood. In this study, we cultured neurospheres from Nestin-Cre-mediated conditional Rbp-j knockout (Rbp-j cKO and control embryos and compared their miRNA expression profiles using microarray. Among differentially expressed miRNAs, miR-342-5p showed upregulated expression as Notch signaling was genetically or pharmaceutically interrupted. Consistently, the promoter of the miR-342-5p host gene, the Ena-vasodilator stimulated phosphoprotein-like (Evl, was negatively regulated by Notch signaling, probably through HES5. Transfection of miR-342-5p promoted the differentiation of neural stem cells (NSCs into intermediate neural progenitors (INPs in vitro and reduced the stemness of NSCs in vivo. Furthermore, miR-342-5p inhibited the differentiation of neural stem/intermediate progenitor cells into astrocytes, likely mediated by targeting GFAP directly. Our results indicated that miR-342-5p could function as a downstream effector of Notch signaling to regulate the differentiation of NSCs into INPs and astrocytes commitment. : In this article, Han and colleagues show that miR-342-5p acts as a downstream effector of Notch signaling in the mouse CNS. Notch signal inhibits miR-342-5p expression by regulating its host gene Evl. And with attenuated Notch signal in NSCs, miR-342-5p is upregulated to promote NSCs transition into INPs, and to inhibit astrocyte commitment by targeting GFAP. Keywords: neural stem cells, intermediate neural progenitors, Notch, RBP-J, neuron, glia, miR-342-5p

Effect of finite edge radius on ductile fracture ahead of the cutting tool edge in micro-cutting of Al2024-T3

International Nuclear Information System (INIS)

Subbiah, Sathyan; Melkote, Shreyes N.

2008-01-01

Evidence of ductile fracture leading to material separation has been reported recently in ductile metal cutting [S. Subbiah, S.N. Melkote, ASME J. Manuf. Sci. Eng. 28(3) (2006)]. This paper investigates the effect of finite edge radius on such ductile fracture. The basic question of whether such ductile fracture occurs in the presence of a finite edge radius is explored by performing a series of experiments with inserts of different edge radii at various uncut chip thickness values ranging from 15 to 105 μm. Chip-roots are obtained in these experiments using a quick-stop device and examined in a scanning electron microscope. Clear evidence of material separation is seen at the interface zone between the chip and machined surface even when the edge radius is large compared to the uncut chip thickness. Failure is seen to occur at the upper, middle, and/or the lower edges of the interface zone. Based on these observations, a hypothesis is presented for the events leading to the occurrence of this failure when cutting with an edge radius tool. Finite element simulations are performed to study the nature of stress state ahead of the tool edge with and without edge radius. Hydrostatic stress is seen to be tensile in front of the tool and hence favors the occurrence of ductile fracture leading to material separation. The stress components are, however lower than those seen with a sharp tool