WorldWideScience

Sample records for fatigue notch factor

  1. Factors Influencing Dwell Fatigue Cracking in Notches of Powder Metallurgy Superalloys

    Science.gov (United States)

    Gabb, T. P.; Telesman, J.; Ghosn, L.; Garg, A.; Gayda, J.

    2011-01-01

    The influences of heat treatment and cyclic dwells on the notch fatigue resistance of powder metallurgy disk superalloys were investigated for low solvus high refractory (LSHR) and ME3 disk alloys. Disks were processed to produce material conditions with varied microstructures and associated mechanical properties. Notched specimens were first subjected to baseline dwell fatigue cycles having a dwell at maximum load, as well as tensile, stress relaxation, creep rupture, and dwell fatigue crack growth tests at 704 C. Several material heat treatments displayed a bimodal distribution of fatigue life with the lives varying by two orders-of-magnitude, while others had more consistent fatigue lives. This response was compared to other mechanical properties, in search of correlations. The wide scatter in baseline dwell fatigue life was observed only for material conditions resistant to stress relaxation. For selected materials and conditions, additional tests were then performed with the dwells shifted in part or in total to minimum tensile load. The tests performed with dwells at minimum load exhibited lower fatigue lives than max dwell tests, and also exhibited early crack initiation and a substantial increase in the number of initiation sites. These results could be explained in part by modeling evolution of peak stresses in the notch with continued dwell fatigue cycling. Fatigue-environment interactions were determined to limit life for the fatigue cycles with dwells.

  2. Notch Fatigue Strength of a PM Disk Superalloy

    Science.gov (United States)

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

    2007-01-01

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

  3. On the Notch Effect in Low Temperature Carburized Stainless Steel under Fatigue

    Directory of Open Access Journals (Sweden)

    Minak G.

    2010-06-01

    Full Text Available The present paper describes the fatigue behaviour of carburized notched AISI 316 austenitic stainless steel specimens. Rotary four point bending fatigue tests have been performed using carburized smooth specimens with two different values of surface rugosity and notched specimen with two different stress concentration factors Kt, of 3.55 and 6.50 and the effects of carburizing on fatigue strength and notch sensitivity were discussed. Results show a general improvement of the fatigue life due to the treatment for all the series with an apparent notch sensitivity lower than one in the case of blunt notches due to secondary effects that were singled out.

  4. On the Notch Effect in Low Temperature Carburized Stainless Steel under Fatigue

    Science.gov (United States)

    Minak, G.

    2010-06-01

    The present paper describes the fatigue behaviour of carburized notched AISI 316 austenitic stainless steel specimens. Rotary four point bending fatigue tests have been performed using carburized smooth specimens with two different values of surface rugosity and notched specimen with two different stress concentration factors Kt, of 3.55 and 6.50 and the effects of carburizing on fatigue strength and notch sensitivity were discussed. Results show a general improvement of the fatigue life due to the treatment for all the series with an apparent notch sensitivity lower than one in the case of blunt notches due to secondary effects that were singled out.

  5. 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.

  6. Fatigue life estimation for different notched specimens based on the volumetric approach

    Directory of Open Access Journals (Sweden)

    Esmaeili F.

    2010-06-01

    Full Text Available In this paper, the effects of notch radius for different notched specimens has been studied on the values of stress concentration factor, notch strength reduction factor, and fatigue life duration of the specimens. The material which has been selected for this investigation is Al 2024T3 . Volumetric approach has been applied to obtain the values of notch strength reduction factor and results have been compared with those obtained from the Neuber and Peterson methods. Load controlled fatigue tests of mentioned specimens have been conducted on the 250kN servo-hydraulic Zwick/Amsler fatigue testing machine with the frequency of 10Hz. The fatigue lives of the specimens have also been predicted based on the available smooth S-N curve of Al2024-T3 and also the amounts of notch strength reduction factor which have been obtained from volumetric, Neuber and Peterson methods. The values of stress and strain around the notch roots are required to predict the fatigue life of notched specimens, so Ansys finite element code has been used and non-linear analyses have been performed to obtain the stress and strain distributions around the notches. The plastic deformations of the material have been simulated using multi-linear kinematic hardening and cyclic stress-strain relation. The work here shows that the volumetric approach does a very good job for predicting the fatigue life of the notched specimens.

  7. Biaxial Fatigue Cracking from Notch

    Science.gov (United States)

    2013-03-04

    Leevers (reference 11) noticed that the variation in  from 0 to 2 has little effect on the da/dN in PVC ( polyvinyl - chloride ), but reduces the da/dN...under biaxial rotating and bending. Ahmad (reference 2) formulated a model for the biaxial fatigue crack growth in aggressive environment, outlined by...1962, Vol. 90, pp. 238-239. 20. ASM Handbook , Vol. 12 Fractography: 1992, p. 430, 438. 21. Metals Handbook , Vol. 9 Fractography and Atlas of

  8. Influence of laser treatment on the fatigue of notched bar

    Institute of Scientific and Technical Information of China (English)

    ZhangHui; LingWeiye; JiangShouwei

    2003-01-01

    Fatigue cutting is a new approach for separating material. Man-made fatigue can be realized by applying a rotating bending load to a notched bar. To better utilize the new method, laser treatment is adopted in this study. After laser radiation at the notch root, the fatigue cycle of the bar drops dramatically. Based on the experimental result, we draw the conclusion that the fatigue of the bar is influenced by the shape of the hardened area. A hardened area that has a small axial dimension and a relatively large radial dimension facilitates the fatigue. The desirable hardened area can be obtained by controlling the laser treatment parameters.

  9. Notch Corrosion Fatigue Behavior of Ti-6Al-4V

    Directory of Open Access Journals (Sweden)

    Sergio Baragetti

    2014-06-01

    Full Text Available The aim of this paper is to map the corrosion fatigue characteristics of Ti-6Al-4V alloy through the evaluation of the corrosion fatigue initiation and failure mechanisms. The study included the effect of the stress concentration factor at very high Kt values and the role of different inert or corrosive environments. This alloy is widely used in naval-structures and aero-engine communities and the outcomes of the work will have direct relevance to industrial service operations. Axial fatigue tests (R = 0.1; 2 × 105 cycles; f = 10 Hz were carried out on smooth and high notched (Ktmax = 18.65 flat specimens in laboratory air, paraffin oil, laboratory air + beeswax coating, recirculated 3.5% NaCl solution. The step loading procedure was used to perform the fatigue tests and the surface replica method and crack propagation gages were used to check crack nucleation and propagation until failure. Log-Log plots of σmax vs. Kt showed a bilinear behavior and enabled the demonstration of the presence of a threshold stress intensity factor (Kt = 8–9, after which the environment has no effect on the fatigue damage for all the tested environments.

  10. Notch Corrosion Fatigue Behavior of Ti-6Al-4V.

    Science.gov (United States)

    Baragetti, Sergio

    2014-06-11

    The aim of this paper is to map the corrosion fatigue characteristics of Ti-6Al-4V alloy through the evaluation of the corrosion fatigue initiation and failure mechanisms. The study included the effect of the stress concentration factor at very high Kt values and the role of different inert or corrosive environments. This alloy is widely used in naval-structures and aero-engine communities and the outcomes of the work will have direct relevance to industrial service operations. Axial fatigue tests (R = 0.1; 2 × 10⁵ cycles; f = 10 Hz) were carried out on smooth and high notched (Ktmax = 18.65) flat specimens in laboratory air, paraffin oil, laboratory air + beeswax coating, recirculated 3.5% NaCl solution. The step loading procedure was used to perform the fatigue tests and the surface replica method and crack propagation gages were used to check crack nucleation and propagation until failure. Log-Log plots of σmaxvs.Kt showed a bilinear behavior and enabled the demonstration of the presence of a threshold stress intensity factor (Kt = 8-9), after which the environment has no effect on the fatigue damage for all the tested environments.

  11. Corrosion Fatigue Crack Growth Behavior at Notched Hole in 7075-T6 Under Biaxial and Uniaxial Fatigue with Different Phases

    Science.gov (United States)

    2015-09-17

    CORROSION FATIGUE CRACK GROWTH BEHAVIOR AT NOTCHED HOLE IN 7075-T6 UNDER BIAXIAL AND UNIAXIAL FATIGUE WITH DIFFERENT PHASES... CORROSION FATIGUE CRACK GROWTH BEHAVIOR AT NOTCHED HOLE IN 7075-T6 UNDER BIAXIAL AND UNIAXIAL FATIGUE WITH DIFFERENT PHASES THESIS...UNLIMITED AFIT-ENY-MS-15-S-065 CORROSION FATIGUE CRACK GROWTH BEHAVIOR AT NOTCHED HOLE IN 7075-T6 UNDER BIAXIAL AND UNIAXIAL FATIGUE WITH

  12. Multiaxial fatigue strength of severely notched titanium grade 5 alloy

    Directory of Open Access Journals (Sweden)

    F. Berto

    2015-07-01

    Full Text Available The multiaxial fatigue strength of severely notched titanium grade 5 alloy (Ti-6Al-4V is investigated. Experimental tests under combined tension and torsion loading, both in-phase and out-of-phase, have been carried out on axisymmetric V-notched specimens considering different nominal load ratios (R = -1, 0. All specimens are characterized by a notch tip radius less than 0.1 mm, a notch depth of 6 mm and a notch opening angle equal to 90 degrees. The experimental data from multiaxial tests are compared with those from pure tension and pure torsion tests on un-notched and notched specimens, carried out at load ratio ranging from R = -3 to R = 0.5. In total, more than 160 new fatigue data are examined, first in terms of nominal stress amplitudes referred to the net area and then in terms of the local strain energy density averaged over a control volume surrounding the V-notch tip. The dependence of the control radius on the loading mode is analysed showing a very different notch sensitivity for tension and torsion. For the titanium alloy Ti-6Al-4V, the control volume is found to be strongly dependent on the loading mode

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

    Science.gov (United States)

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

    2016-07-01

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

  14. Fatigue strength of Al7075 notched plates based on the local SED averaged over a control volume

    Science.gov (United States)

    Berto, Filippo; Lazzarin, Paolo

    2014-01-01

    When pointed V-notches weaken structural components, local stresses are singular and their intensities are expressed in terms of the notch stress intensity factors (NSIFs). These parameters have been widely used for fatigue assessments of welded structures under high cycle fatigue and sharp notches in plates made of brittle materials subjected to static loading. Fine meshes are required to capture the asymptotic stress distributions ahead of the notch tip and evaluate the relevant NSIFs. On the other hand, when the aim is to determine the local Strain Energy Density (SED) averaged in a control volume embracing the point of stress singularity, refined meshes are, not at all, necessary. The SED can be evaluated from nodal displacements and regular coarse meshes provide accurate values for the averaged local SED. In the present contribution, the link between the SED and the NSIFs is discussed by considering some typical welded joints and sharp V-notches. The procedure based on the SED has been also proofed to be useful for determining theoretical stress concentration factors of blunt notches and holes. In the second part of this work an application of the strain energy density to the fatigue assessment of Al7075 notched plates is presented. The experimental data are taken from the recent literature and refer to notched specimens subjected to different shot peening treatments aimed to increase the notch fatigue strength with respect to the parent material.

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

    Energy Technology Data Exchange (ETDEWEB)

    Mittal, Rahul [Nuclear Power Corporation of India Limited, Mumbai (India); Singh, P.K., E-mail: singh_pawank@yahoo.com [Bhabha Atomic Research Centre, Mumbai (India); Pukazhendi, D.M. [Structural Engineering research Centre, Chennai (India); Bhasin, V.; Vaze, K.K.; Ghosh, A.K. [Bhabha Atomic Research Centre, Mumbai (India)

    2011-10-15

    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.

  16. 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....

  17. Notch sensitivity jeopardizes titanium locking plate fatigue strength.

    Science.gov (United States)

    Tseng, Wo-Jan; Chao, Ching-Kong; Wang, Chun-Chin; Lin, Jinn

    2016-12-01

    Notch sensitivity may compromise titanium-alloy plate fatigue strength. However, no studies providing head-to-head comparisons of stainless-steel or titanium-alloy locking plates exist. Custom-designed identically structured locking plates were made from stainless steel (F138 and F1314) or titanium alloy. Three screw-hole designs were compared: threaded screw-holes with angle edges (type I); threaded screw-holes with chamfered edges (type II); and non-threaded screw-holes with chamfered edges (type III). The plates' bending stiffness, bending strength, and fatigue life, were investigated. The stress concentration at the screw threads was assessed using finite element analyses (FEA). The titanium plates had higher bending strength than the F1314 and F138 plates (2.95:1.56:1) in static loading tests. For all metals, the type-III plate fatigue life was highest, followed by type-II and type-I. The type-III titanium plates had longer fatigue lives than their F138 counterparts, but the type-I and type-II titanium plates had significantly shorter fatigue lives. All F1314 plate types had longer fatigue lives than the type-III titanium plates. The FEA showed minimal stress difference (0.4%) between types II and III, but the stress for types II and III was lower (11.9% and 12.4%) than that for type I. The screw threads did not cause stress concentration in the locking plates in FEA, but may have jeopardized the fatigue strength, especially in the notch-sensitive titanium plates. Improvement to the locking plate design is necessary. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. A unifying approach to fatigue design in presence of defects and notches subject to uniaxial loading

    Directory of Open Access Journals (Sweden)

    Atzori Bruno

    2014-06-01

    Full Text Available In the recent past, Atzori and Lazzarin proposed a diagram able to include the geometrical effects on the fatigue limit of defects, short cracks, long cracks and U-shaped notches of whatever severity. The diagram shows that defect sensitivity and notch sensitivity can be considered as two sides of the same medal, thus creating a bridging between Linear Elastic Fracture Mechanics and Notch Mechanics. The fundamental material parameter, dependent on the load ratio, necessary to define the diagram is the El Haddad-Smith-Topper length parameter a0 defined by the plain material fatigue limit and the threshold value of the mode I stress intensity factor for long cracks. It is worth noting that a0 does not contain any geometry-related parameter. The diagram has been validated in the past against a number of experimental results and has been subsequently extended to sharp and blunt V-shaped notches, dependent on their absolute dimensions. After summarising the theory supporting the approach, some application examples relevant to both defect and notch sensitivity will be given

  19. Fatigue Analysis of Notched Laminates: A Time-Efficient Macro-Mechanical Approach

    Science.gov (United States)

    Naghipour, P.; Pineda, E. J.; Bednarcyk, B. A.; Arnold, S. M.; Waas, A. M.

    2016-01-01

    A coupled transversely isotropic deformation and damage fatigue model is implemented within the finite element method and was utilized along with a static progressive damage model to predict the fatigue life, stiffness degradation as a function of number of cycles, and post-fatigue tension and compression response of notched, multidirectional laminates. Initially, the material parameters for the fatigue model were obtained utilizing micromechanics simulations and the provided [0], [90] and [plus or minus 45] experimental composite laminate S-N (stress-cycle) data. Within the fatigue damage model, the transverse and shear properties of the plies were degraded with an isotropic scalar damage variable. The damage in the longitudinal (fiber) ply direction was suppressed, and only the strength of the fiber was degraded as a function of fatigue cycles. A maximum strain criterion was used to capture the failure in each element, and once this criterion was satisfied, the longitudinal stiffness of the element was decreased by a factor of 10 (sup 4). The resulting, degraded properties were then used to calculate the new stress state. This procedure was repeated until final failure of the composite laminate was achieved or a specified number of cycles reached. For post-fatigue tension and compression behavior, four internal state variables were used to control the damage and failure. The predictive capability of the above-mentioned approach was assessed by performing blind predictions of the notched multidirectional IM7/977-3 composite laminates response under fatigue and post-fatigue tensile and compressive loading, followed by a recalibration phase. Although three different multidirectional laminates were analyzed in the course of this study, only detailed results (i.e., stiffness degradation and post-fatigue stress-train curves as well as damage evolution states for a single laminate ([30/60/90/minus 30/minus 60] (sub 2s)) are discussed in detail here.

  20. Notch fatigue behavior: Metallic glass versus ultra-high strength steel

    Science.gov (United States)

    Wang, X. D.; Qu, R. T.; Wu, S. J.; Duan, Q. Q.; Liu, Z. Q.; Zhu, Z. W.; Zhang, H. F.; Zhang, Z. F.

    2016-01-01

    Studying the effect of notch on the fatigue behavior of structural materials is of significance for the reliability and safety designing of engineering structural components. In this work, we conducted notch fatigue experiments of two high-strength materials, i.e. a Ti32.8Zr30.2Ni5.3Cu9Be22.7 metallic glass (MG) and a 00Ni18Co15Mo8Ti ultra-high strength steel (CM400 UHSS), and compared their notch fatigue behavior. Experimental results showed that although both the strength and plasticity of the MG were much lower than those of the UHSS, the fatigue endurance limit of the notched MG approached to that of the notched UHSS, and the fatigue ratio of the notched MG was even higher. This interesting finding can be attributed to the unique shear banding mechanism of MG. It was found that during fatigue process abundant shear bands formed ahead of the notch root and in the vicinity of the crack in the notched MG, while limited plastic deformation was observed in the notched UHSS. The present results may improve the understanding on the fatigue mechanisms of high-strength materials and offer new strategies for structural design and engineering application of MG components with geometrical discontinuities. PMID:27752136

  1. Notch fatigue behavior: Metallic glass versus ultra-high strength steel

    Science.gov (United States)

    Wang, X. D.; Qu, R. T.; Wu, S. J.; Duan, Q. Q.; Liu, Z. Q.; Zhu, Z. W.; Zhang, H. F.; Zhang, Z. F.

    2016-10-01

    Studying the effect of notch on the fatigue behavior of structural materials is of significance for the reliability and safety designing of engineering structural components. In this work, we conducted notch fatigue experiments of two high-strength materials, i.e. a Ti32.8Zr30.2Ni5.3Cu9Be22.7 metallic glass (MG) and a 00Ni18Co15Mo8Ti ultra-high strength steel (CM400 UHSS), and compared their notch fatigue behavior. Experimental results showed that although both the strength and plasticity of the MG were much lower than those of the UHSS, the fatigue endurance limit of the notched MG approached to that of the notched UHSS, and the fatigue ratio of the notched MG was even higher. This interesting finding can be attributed to the unique shear banding mechanism of MG. It was found that during fatigue process abundant shear bands formed ahead of the notch root and in the vicinity of the crack in the notched MG, while limited plastic deformation was observed in the notched UHSS. The present results may improve the understanding on the fatigue mechanisms of high-strength materials and offer new strategies for structural design and engineering application of MG components with geometrical discontinuities.

  2. Matrix fatigue crack development in a notched continuous fiber SCS-6/Ti-15-3 composite

    Science.gov (United States)

    Hillberry, B. M.; Johnson, W. S.

    1990-01-01

    In this study the extensive matrix fatigue cracking that has been observed in notched SCS-6/Ti-15-3 composites is investigated. Away from the notch a uniform spacing of the fatigue cracks develops. Closer to the notch, fiber-matrix debonding which occurs increases the crack spacing. Crack spacing and debond length determined from shear-lag cylinder models compare favorably with experimental observations. Scanning electron microscope (SEM) fractography showed that the principal fatigue crack initiation occurred around the zero degree fibers. Interface failure in the 90 degree plies does not lead to the development of the primary fatigue cracking.

  3. Averaged strain energy density-based synthesis of crack initiation life in notched steel bars under torsional fatigue

    Directory of Open Access Journals (Sweden)

    Filippo Berto

    2016-10-01

    Full Text Available The torsional fatigue behaviour of circumferentially notched specimens made of austenitic stainless steel, SUS316L, and carbon steel, SGV410, characterized by different notch root radii has been recently investigated by Tanaka. In that contribution, it was observed that the total fatigue life of the austenitic stainless steel increases with increasing stress concentration factor for a given applied nominal shear stress amplitude. By using the electrical potential drop method, Tanaka observed that the crack nucleation life was reduced with increasing stress concentration, on the other hand the crack propagation life increased. The experimental fatigue results, originally expressed in terms of nominal shear stress amplitude, have been reanalysed by means of the local strain energy density (SED averaged over a control volume having radius R0 surrounding the notch tip. To exclude all extrinsic effects acting during the fatigue crack propagation phase, such as sliding contact and/or friction between fracture surfaces, crack initiation life has been considered in the present work. In the original paper, initiation life was defined in correspondence of a 0.1÷0.4-mm-deep crack. The control radius R0 for fatigue strength assessment of notched components, thought of as a material property, has been estimated by imposing the constancy of the averaged SED for both smooth and cracked specimens at NA = 2 million loading cycles

  4. The Variability of Fatigue in Notched Bars of IN100 (Preprint)

    Science.gov (United States)

    2012-08-01

    conducted having nominally 40 m micro-notches machined using focused ion beam ( FIB ) in the geometric center of the two notches. These micro-notches... FIB crack starters in the notch and replicated to measure the small crack growth rates. This also allows a comparison of the small crack growth...ID JAI19045. 8) M. Aratani and J.F. Knott , “The Growth of Short Fatigue Cracks Ahead of a Notch in High Strength Steel,” Eng. Failure. Anal., 17

  5. Microstructure-Sensitive Fatigue Design of Notched Components

    Science.gov (United States)

    2015-01-26

    Materials , World journal of mechanics (05 2013) TOTAL: 2 Books Number of Manuscripts: Patents Submitted Patents Awarded Awards Graduate Students...Received Book TOTAL: Received Book Chapter TOTAL: PERCENT_SUPPORTEDNAME FTE Equivalent: Total Number: Discipline Oluwamayowa Okeyoyin 1.00 Li Shi 1.00...complexity of realistic microstructures. Notch size effects and notch root inelastic behavior are combined with probability distributions of

  6. 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.

  7. Multiaxial fatigue assessment of welded joints using the notch stress approach

    DEFF Research Database (Denmark)

    Pedersen, Mikkel Melters

    2016-01-01

    This paper presents an evaluation of the safety involved when performing fatigue assessment of multiaxially loaded welded joints. The notch stress approach according to the IIW is used together with 8 different multiaxial criteria, including equivalent stress-, interaction equation- and critical...

  8. Biaxial fatigue tests of notched specimens for AISI 304L stainless steel

    Directory of Open Access Journals (Sweden)

    G. Beretta

    2016-07-01

    Full Text Available High cycle fatigue tests were conducted for stainless steel AISI 304L. The geometry was a thin walled tube with a passing through hole. The tests were axial, torsional and in-phase axial-torsional, all of them under load control with R = −1. The S-N curves were constructed following the ASTM E739 standard and the fatigues limits were calculated following the method of maximum likelihood proposed by Bettinelli. The crack direction along the surface was analysed, with especial attention to the crack initiation zones. The notch fatigue limits for different hole diameters were compared with the predictions done with a microstructural fracture mechanics model.

  9. Factors associated with intern fatigue.

    Science.gov (United States)

    Friesen, Lindsay D; Vidyarthi, Arpana R; Baron, Robert B; Katz, Patricia P

    2008-12-01

    Prior data suggest that fatigue adversely affects patient safety and resident well-being. ACGME duty hour limitations were intended, in part, to reduce resident fatigue, but the factors that affect intern fatigue are unknown. To identify factors associated with intern fatigue following implementation of duty hour limitations. Cross-sectional confidential survey of validated questions related to fatigue, sleep, and stress, as well as author-developed teamwork questions. Interns in cognitive specialties at the University of California, San Francisco. Univariate statistics characterized the distribution of responses. Pearson correlations elucidated bivariate relationships between fatigue and other variables. Multivariate linear regression models identified factors independently associated with fatigue, sleep, and stress. Of 111 eligible interns, 66 responded (59%). In a regression analysis including gender, hours worked in the previous week, sleep quality, perceived stress, and teamwork, only poorer quality of sleep and greater perceived stress were significantly associated with fatigue (p 80 h was not significantly associated with perceived stress, quality of sleep, or fatigue. Simply decreasing the number of duty hours may be insufficient to reduce intern fatigue. Residency programs may need to incorporate programmatic changes to reduce stress, improve sleep quality, and foster teamwork in order to decrease intern fatigue and its deleterious consequences.

  10. Effect of V Notch Shape on Fatigue Life in Steel Beam Made of AISI 1037

    Directory of Open Access Journals (Sweden)

    Qasim Bader

    2014-04-01

    Full Text Available The present work encompasses effect of V notch shape with various geometries and dimensions on fatigue life behavior in steel beam made of Medium Carbon Steel AISI 1037 which has a wide application in industry. Fatigue life of notched specimens is calculated using the fatigue life obtained from the experiments for smooth specimens (reference and by use Numerical method (FEA.The fatigue experiments were carried out at room temperature, applying a fully reversed cyclic load with the frequency of (50Hz and mean stress equal to zero (R= -1, on a cantilever rotating-bending fatigue testing machine. The stress ratio was kept constant throughout the experiment. Different instruments have been used in this investigation like Chemical composition analyzer type (Spectromax ,Tensile universal testing machine type (WDW-100E ,Hardness tester type (HSV- 1000 , Fatigue testing machine model Gunt WP 140, Optical Light Microscope (OLM and Scanning Electron Microscope (SEM were employed to examine the fracture features . The results show that there is acceptable error between experimental and numerical works .

  11. The effects of pack carburizing using charcoal of unused mahogany on fatigue characteristic of v-notch shaft steel specimens

    Science.gov (United States)

    Supriyono, Jamasri

    2017-04-01

    The aim of this research is to study the fatigue characteristic of v-notch shaft steel specimens before and after pack carburizing. The carbon source is taken from charcoal of unused mahogany. The fatigue test is conducted on rotary bending machine. The specimens are made of low carbon steel of 0.17% carbon content. Pack carburizing is conducted to the specimens at 930°C. V-notch is made to present the stress concentration factor on the specimens. To see the effects of the carburizing in changing the material properties, micro-structures before and after carburizingare looked and micro hardness measurements along the cross sectional area are carried out. The results show that the carburizing process increases fatigue strength of the material. The micro-structures of the raw material are ferrite and pearlite. The carburized material is divided into two zones i.e. surface zone and core zone. The surface zone consists of hypereutectoid, eutectoid, and hypoeutectoid sub-zone. The core zone is the same as raw material

  12. Holding time effect of pack carburizing on fatigue characteristic of v-notch shaft steel specimens

    Science.gov (United States)

    Supriyono, Jamasri

    2017-06-01

    The objective of this research is to study the effect of the holding times of pack carburizing process on fatigue characteristic of v-notch shaft steel specimens. The carbon source was taken from charcoal of unused mahogany. The holding times were 2, 3 and 4 hours. The fatigue tests were conducted on rotary bending machine. The specimens were made of low carbon steel of 0.17% carbon content. Pack carburizing was conducted to the specimens at 930°C. V-notch was made to present the stress concentration on the specimens. To see the effects of the carburizing in changing the material properties, the micro-structures and hardness tests along the cross sectional area of the specimens were carried out. The results showed that the holding time of the carburizing process influences the fatigue strength of the material. The longer the holding time will be the higher the fatigue strength. The increase of the fatigue strength is due to the carbon content on the surface. It was confirmed by the micro-structures and the hardness tests results. The cross sectional area of carburized material is divided into two zones i.e. surface zone and core zone. The surface zone consists of hypereutectoid, eutectoid, and hypo eutectoid sub-zone. The core zone is the same as raw material. The longer the holding time will be the deeper the surface zone.

  13. Re-analysis of fatigue data for welded joints using the notch stress approach

    DEFF Research Database (Denmark)

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

    2010-01-01

    Experimental fatigue data for welded joints have been collected and subjected to re-analysis using the notch stress approach according to IIW recommendations. This leads to an overview regarding the reliability of the approach, based on a large number of results (767 specimens). Evidently......-welded joints agree quite well with the FAT 225 curve; however a reduction to FAT 200 is suggested in order to achieve approximately the same safety as observed in the nominal stress approach....

  14. An elasto-plastic approach to estimate lifetime of notched components under variable amplitude fatigue loading: a preliminary investigation

    Directory of Open Access Journals (Sweden)

    N. Zuhair Faruq

    2016-07-01

    Full Text Available The present paper is concerned with the formulation of an elasto-plastic strain based approach suitable for assessing fatigue strength of notched components subjected to in-service variable amplitude cyclic loading. The hypothesis is formed that the crack initiation plane is closely aligned with the plane of maximum shear strain amplitude, its orientation and the associated stress/strain quantities being determined using the Maximum Variance Method. Fatigue damage is estimated by applying the Modified Manson-Coffin Curve Method (MMCCM along with the Point Method (PM. In the proposed approach, the required critical distance is treated as a material property whose value is not affected either by the sharpness of the notch being assessed or by the profile of the load spectrum being applied. The detrimental effect of non-zero mean stresses and degree of multiaxiality of the local stress/strain histories is also considered. The accuracy and reliability of the proposed design methodology was checked against several experimental data taken from the literature and generated under different uniaxial variable amplitude load histories. In order to determine the required local stress/strain states, refined elasto-plastic finite element models were solved using commercial software ANSYS®. This preliminary validation exercise allowed us to prove that the proposed approach is capable of estimates laying within an error factor of about 2. These preliminary results are certainly promising, strongly supporting the idea that the proposed design strategy can successfully be used to assess the fatigue lifetime of notched metallic components subjected to in-service multiaxial variable amplitude loading sequences.

  15. Metabolic Factors in Fatigue

    Institute of Scientific and Technical Information of China (English)

    Mark Hargreaves

    2006-01-01

    Increased non-oxidative and oxidative ATP production via metabolic pathways in skeletal muscle is essential for the maintenance of force and power production during exercise. However, substrate depletion and accumulation of metabolic byproducts are potential causes of fatigue. Reduced PCr availability can limit power production during sprint exercise, whereas carbohydrate depletion is a major limitation to endurance performance. During sprint exercise increased Pi and H+ may contribute to fatigue, and during prolonged strenuous exercise, the accumulation of NH3, reactive oxygen species, and heat can limit performance. Appropriate training programs and nutritional interventions are potential strategies to enhance fatigue resistance and exercise performance.

  16. 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.

  17. Experimental Evaluation of Fatigue Crack Initiation from Corroded Hemispherical Notches in Aerospace Structural Materials

    Science.gov (United States)

    Garcia, Daniel B.; Forman, Royce; Shindo, David

    2010-01-01

    A test program was developed and executed to evaluate the influence of corroded hemispherical notches on the fatigue crack initiation and propagation in aluminum 7075-T7351, 4340 steel, and D6AC steel. Surface enhancements such as shot peening and laser shock peening were also incorporated as part of the test effort with the intent of improving fatigue performance. In addition to the testing, fracture mechanics and endurance limit based analysis methods were evaluated to characterize the results with the objective of challenging typical assumptions used in modeling fatigue cracks from corrosion pits. The results specifically demonstrate that the aluminum and steel alloys behave differently with respect to fatigue crack initiation from hemispherical corrosion pits. The aluminum test results were bounded by the fracture mechanics and endurance limit models while exhibiting a general insensitivity to the residual stress field generated by shot peening. The steel specimens were better characterized by the endurance limit fatigue properties and did exhibit sensitivities to residual stresses from the shot peening and laser shock peening

  18. Effect of Notch Location on Fatigue Life Prediction of Strength Mismatched HSLA Steel Weldments

    Institute of Scientific and Technical Information of China (English)

    S. Ravi; V. Balasubramanian; S. Nemat Nasser

    2004-01-01

    Welding of high strength low alloy steels (HSLA) involves usage of Iow, even and high strength filler materials (electrodes) than the parent material depending on the application of the welded structures and the availability of the filler material. In the present investigation, the fatigue crack growth behaviour of weld metal (WM) and heat affected zone (HAZ) regions of under matched (UM), equal matched (EM) and over matched (OM)joints has been studied. The base material used in this investigation is HSLA-80 steel of weldable grade. Shielded metal arc welding (SMAW) process has been used to fabricate the butt joints. Centre cracked tension (CCT) specimen has been used to evaluate the fatigue crack growth behaviour of the welded joints. Fatigue crack growth experiments have been conducted using servo hydraulic controlled fatigue testing machine at constant amplitude loading (R=0). A method has been proposed to predict the fatigue life of HSLA steel welds using fracture mechanics approach by incorporating influences of mismatch ratio (MMR) and notch location.

  19. Notched multiaxial fatigue of Al7050-T7451: on the need for an equivalent process zone size

    Directory of Open Access Journals (Sweden)

    J.L.A Ferreira

    2017-07-01

    Full Text Available The aim of this work is to investigate stress gradient effects on the fatigue life estimation of notched Al 7050-T7451 specimens under combined torsion and push-pull loading conditions. Initially, simple push-pull and torsion fatigue tests in plain and notched specimens were independently conducted not only to obtain the material properties necessary to calibrate a standard multiaxial critical plane based model, but also to raise the critical distance versus life curves in tension (L  – Nf and in torsion (L  – Nf. This latter step also required a Finite Element Elastic Stress Analysis of the notched specimens tested in the medium high-cycle fatigue regime. Then, proportional multiaxial fatigue tests were carried out using this same notched geometry. The combination of a multiaxial model with the theory of critical distance (TCD was applied to estimate fatigue lives. For this aluminium alloy, neither the use of the L  – Nf nor L  – Nf combined with the predictive multiaxial model was able to estimate lives in an accurate way.

  20. A comparison of conventional local approach and the short crack approach to fatigue crack initiation at a notch

    Energy Technology Data Exchange (ETDEWEB)

    Ranganathan, Narayanaswami; Leroy, Rene; Tougui, Abdellah [Laboratoire de Mecanique et Rheologie, Universite Francois Rabelais de Tours, Polytech Tours, Departement Mecanique et Conception de Systemes, Tours (France)

    2009-09-15

    Methods to estimate fatigue crack initiation life at a notch tip are compared. The methods used determine the strain amplitudes at the notch tip using Neuber's or Glinka's approximation. In conventional approaches, equivalent-damage levels are determined, using appropriate strain-life relationships coupled with damage-summation models. In the short-crack approach, a crack-like defect is assumed to exist at the notch tip. It is shown that the short-crack concept can be successfully applied to predict crack-initiation behavior at a notch. Model predictions are compared with carefully designed experiments. It is shown that model predictions are very close to experimentally measured lives under an aircraft-wing loading spectrum. (Abstract Copyright [2009], Wiley Periodicals, Inc.)

  1. An Investigation on the Wear Resistance and Fatigue Behaviour of Ti-6Al-4V Notched Members Coated with Hydroxyapatite Coatings

    Directory of Open Access Journals (Sweden)

    Reza H Oskouei

    2016-02-01

    Full Text Available In this study, surface properties of Ti-6Al-4V alloy coated with hydroxyapatite coatings were investigated. Wear resistance and fatigue behaviour of samples with coating thicknesses of 10 and 50 µm as well as uncoated samples were examined. Wear experiments demonstrated that the friction factor of the uncoated titanium decreased from 0.31 to 0.06, through a fluctuating trend, after 50 cycles of wear tests. However, the friction factor of both the coated samples (10 and 50 µm gradually decreased from 0.20 to 0.12 after 50 cycles. At the end of the 50th cycle, the penetration depth of the 10 and 50 µm coated samples were 7.69 and 6.06 µm, respectively. Fatigue tests showed that hydroxyapatite coatings could improve fatigue life of a notched Ti-6Al-4V member in both low and high cycle fatigue zones. It was understood, from fractography of the fracture surfaces, that the fatigue zone of the uncoated specimens was generally smaller in comparison with that of the coated specimens. No significant difference was observed between the fatigue life of coated specimens with 10 and 50 µm thicknesses.

  2. Two-step phase shifting interferometry technique for evaluation of fatigue process zone parameters in notched specimens

    Science.gov (United States)

    Muravsky, Leonid I.; Picart, Pascal; Kmet', Arkady B.; Voronyak, Taras I.; Ostash, Orest P.; Stasyshyn, Ihor V.

    2016-08-01

    A new two-step phase shifting interferometry technique for evaluation of a fatigue process zone (FPZ) in notched metal and alloy specimens is proposed. In comparison with well-known destructive and nondestructive methods evaluating FPZ, this technique possesses higher accuracy and performance and allows defining the FPZ size for notched specimens made of metals and alloys with low, moderate or high plasticity. The technique is fulfilled by retrieval of a total surface relief of a studied notched specimen, extraction of surface roughness and waviness phase maps from the retrieved surface relief, calculation of a surface roughness parameter Ra spatial distribution and definition of the FPZ size by using an extracted surface roughness phase map. Obtained experimental results have confirmed assumption that the surface roughness of notched specimens after cyclic loading reaches its maximum values at the FPZ boundary. This boundary is produced as the narrow strip containing pixels possessing the maximum values on the spatial distribution of the roughness parameter Ra near a notch root. The basic distances d* defining the FPZ sizes were measured for notched specimens made of a low-carbon steel and aluminum alloys 2024-T6 and 7075-T3. Results of the distances d* measurement are very close to respective results obtained with the help of other methods for the FPZ evaluation.

  3. Fatigue Crack Propagation from Notched Specimens of 304 SS in elevated Temperature Aqueous Environment

    Energy Technology Data Exchange (ETDEWEB)

    Wire, G. L.; Mills, W. J.

    2002-08-01

    Fatigue crack propagation (FCP) rates for 304 stainless steel (304SS) were determined in 24 degree C and 288 degree C air and 288 degree C water using double-edged notch (DEN) specimens of 304 stainless steel (304 SS). Test performed at matched loading conditions in air and water at 288 degree C with 20-6- cc h[sub]2/kg h[sub]2O provided a direct comparison of the relative crack growth rates in air and water over a wide range of crack growth rates. The DEN crack extension ranged from short cracks (0.03-0.25 mm) to long cracks up to 4.06 mm, which are consistent with conventional deep crack tests. Crack growth rates of 304 SS in water were about 12 times the air rate. This 12X environmental enhancement persisted to crack extensions up to 4.06 mm, far outside the range associated with short crack effects. The large environmental degradation for 304 SS crack growth is consistent with the strong reduction of fatigue life in high hydrogen water. Further, very similar environmental effects w ere reported in fatigue crack growth tests in hydrogen water chemistry (HWC). Most literature data in high hydrogen water show only a mild environmental effect for 304 SS, of order 2.5 times air or less, but the tests were predominantly performed at high cyclic stress intensity or equivalently, high air rates. The environmental effect in low oxygen environments at low stress intensity depends strongly on both the stress ratio, R, and the load rise time, T[sub]r, as recently reported for austenitic stainless steel in BWR water. Fractography was performed for both tests in air and water. At 288 degree C in water, the fracture surfaces were crisply faceted with a crystallographic appearance, and showed striations under high magnification. The cleavage-like facets on the fracture surfaces suggest that hydrogen embrittlement is the primary cause of accelerated cracking.

  4. Crack growth behavior under creep-fatigue conditions using compact and double edge notch tension-compression specimens

    Science.gov (United States)

    Narasimha Chary, Santosh Balaji

    The American Society for Testing and Materials (ASTM) has recently developed a new standard for creep-fatigue crack growth testing, E 2760-10, that supports testing compact specimens, C(T), under load controlled conditions. C(T) specimens are commonly used for fatigue and creep-fatigue crack growth testing under constant-load-amplitude conditions. The use of these specimens is limited to positive load ratios. They are also limited in the amount of crack growth data that can be developed at high stress intensity values due to accumulation of plastic and/or creep strains leading to ratcheting in the specimen. Testing under displacement control can potentially address these shortcomings of the load-controlled tests for which the C(T) geometry is unsuitable. A double edge notch tension-compression, DEN(T-C), specimen to perform displacement controlled creep-fatigue crack growth testing is developed and optimized with the help of finite element and boundary element analyses. Accurate expressions for estimating the fracture mechanics crack tip parameters such as the stress intensity parameter, K, the crack mouth opening displacement (CMOD), and the load-line displacement (LLD) are developed over a wide range of crack sizes for the DEN(T-C) specimen. A new compliance relationship for use in experimental testing has been developed by using the compliance form available in ASTM E-647 standard. Experimentally determined compliance value compared well with the new relation for C15 steel (AISI 1015) and P91 steel tested at room and elevated temperature conditions respectively. Fatigue crack growth rate data generated using the DEN(T-C) specimens on the two metallic materials are in good agreement with the data generated using standard compact specimens; thus validating the stress-intensity factor and the compliance equation for the double edge notch tension-compression specimen. The testing has shown that the DEN(T-C) specimen is prone to crack asymmetry issues. Through

  5. Creep-Rupture and Fatigue Behavior of a Notched Oxide/Oxide Ceramic Matrix Composite at Elevated Temperature

    Science.gov (United States)

    2008-06-01

    ultrasonic bath of deionized water to remove any excess debris and then dried in an oven at 90°C for 30 minutes. 16 Figure 9. Specimen dimensions...Figure 107. 155 MPa Fatigue (right) 100 Bibliography 1. “3M Ceramic Fiber Typical Properties,” Nextel™ Ceramic Textiles Technical Notebook... ultrasonic C-scans,” Composites Science and Technology, 61[11], 1561-1570 (2001). 20. Kramb, Victoria A., Reji John and Larry P. Zawada. “Notched

  6. Effects of Changes in Test Temperature on Tensile Properties and Notched Vs Fatigue Precracked Toughness of a Zr-Based BMG Composite

    Science.gov (United States)

    Clinton, Jessica A.; Morrison, Rachel L.; Carter, Jennifer L. W.

    2017-07-01

    Tensile and fracture toughness behavior of a Zr-based bulk metallic glass matrix composite (BMGMC) containing a body-centered cubic crystalline phase was examined over temperatures from 77 K to 653 K (-196 °C to 380 °C). The BMGMC exhibited tensile plasticity at all test temperatures. The sample tested in tension at 173 K (-100 °C) exhibited work hardening but the remaining samples tested at higher temperatures exhibited work softening. EBSD analysis of the crystalline phase after tensile testing provides insight into active deformation mechanisms in the crystalline phase. At 603 K (330 °C), the dendrites exhibit significant plastic strain, with the dendrites oriented {101} parallel to the loading direction exhibiting the least amount of strain. Schmid factor analysis leads to the hypothesis that {110} dislocation mechanisms are active at this temperature. Additionally, measurements of dendrite shape as a function of macroscopic strain state in the tension experiments provide insight into cooperative deformation mechanisms in the composite. At low temperatures, the fracture toughness of the notch toughness samples exceeded that of fatigue precracked samples; but at and above room temperature, the toughness values of notched and fatigue precracked samples converge. These observations are rationalized based on the changes to the flow and fracture behavior of the glass and the crystalline phases over this temperature range. At low temperatures, the crystalline phase is sensitive to defects and changes in stress state that reduce its energy absorbing ability. At higher temperatures, both constituents possess lower strength and are less sensitive to defects, enabling more significant crack tip blunting in the fatigue precracked samples. This produces toughness values that are similar to those obtained for the notched samples.

  7. Oxidation and the Effects of High Temperature Exposures on Notched Fatigue Life of an Advanced Powder Metallurgy Disk Superalloy

    Science.gov (United States)

    Sudbrack, Chantal K.; Draper, Susan L.; Gorman, Timothy T.; Telesman, Jack; Gab, Timothy P.; Hull, David R.

    2012-01-01

    Oxidation and the effects of high temperature exposures on notched fatigue life were considered for a powder metallurgy processed supersolvus heat-treated ME3 disk superalloy. The isothermal static oxidation response at 704 C, 760 C, and 815 C was consistent with other chromia forming nickel-based superalloys: a TiO2-Cr2O3 external oxide formed with a branched Al2O3 internal subscale that extended into a recrystallized - dissolution layer. These surface changes can potentially impact disk durability, making layer growth rates important. Growth of the external scales and dissolution layers followed a cubic rate law, while Al2O3 subscales followed a parabolic rate law. Cr- rich M23C6 carbides at the grain boundaries dissolved to help sustain Cr2O3 growth to depths about 12 times thicker than the scale. The effect of prior exposures was examined through notched low cycle fatigue tests performed to failure in air at 704 C. Prior exposures led to pronounced debits of up to 99 % in fatigue life, where fatigue life decreased inversely with exposure time. Exposures that produced roughly equivalent 1 m thick external scales at the various isotherms showed statistically equivalent fatigue lives, establishing that surface damage drives fatigue debit, not exposure temperature. Fractographic evaluation indicated the failure mode for the pre-exposed specimens involved surface crack initiations that shifted with exposure from predominately single intergranular initiations with transgranular propagation to multi-initiations from the cracked external oxide with intergranular propagation. Weakened grain boundaries at the surface resulting from the M23C6 carbide dissolution are partially responsible for the intergranular cracking. Removing the scale and subscale while leaving a layer where M23C6 carbides were dissolved did not lead to a significant fatigue life improvement, however, also removing the M23C6 carbide dissolution layer led to nearly full recovery of life, with a

  8. Evaluation of fatigue process zone dimensions in notched specimens by two-step phase shifting interferometry technique

    Science.gov (United States)

    Muravsky, Leonid I.; Picart, Pascal; Kmet', Arkady B.; Voronyak, Taras I.; Ostash, Orest P.; Stasyshyn, Ihor V.

    2016-10-01

    A method for evaluation of fatigue process zone (FPZ) dimensions near a notch root in metal and alloy specimens by using a two-step phase shifting interferometry (TS PSI) technique is proposed. In comparison with other destructive and nondestructive methods evaluating the FPZ dimensions, it possesses higher accuracy and performance. The method uses a criterion for the FPZ dimensions definition based on an assumption that the surface roughness of notched specimens after cyclic loading reaches its maximum values at the FPZ boundary. To realize this method, first, a phase map (PM) of a total surface relief near a notch root is retrieved; second, roughness and waviness PMs are extracted from the retrieved total surface relief PM by using the TS PSI; and finally, a surface roughness parameter Ra spatial distribution is calculated according to the offered criterion and the FPZ size d* is defined. The FPZ size was measured for specimens made of low-carbon steel and aluminum alloys 2024-T6 and 7075-T3. Obtained experimental results have shown that the proposed criterion allows defining the FPZ size for notched specimens made of metals and alloys possessing high, moderate, and low plasticity.

  9. Effect of load ratio, testing frequency, temperature, moisture, notch and stacking sequence on the fatigue resistance of woven CFRP laminates

    OpenAIRE

    Lani, Frédéric; 6th International Conference on Fatigue of Composite ICFC2015

    2015-01-01

    A woven CFRP composite laminate has been thoroughly characterized under fatigue. Over 150 tests were performed in order to address the effect of sample geometry (Open Hole Tension, Open Hole Compression, Plain Compression, …), testing frequency (5Hz, 30Hz) with and without cooling system, load ratio (R=10., R=-1., R=0.1), temperature (RT and 120°C), moisture intake (50% RH and 85+% RH at RT), notch (Open Hole Vs. Plain Specimen), stacking sequence (3 different stacking sequences) on the measu...

  10. SEAFARER FATIGUE: A REVIEW OF RISK FACTORS

    DEFF Research Database (Denmark)

    Jepsen, Jørgen Riis; Zhao, Zhiwei; Tu, Mingshan;

    2016-01-01

    Background: The widespread occurrence of fatigue in the maritime industry and the consequences for the health and safety of seafarers have caused concern, and indicates the importance of research into risk factors at sea. This review gives an overview of the currently recognized key determinants...... of seafarer fatigue. Methods: A literature study was conducted aiming to collect publications that address work-related risk factors for fatigue. Due to the limited number of publications that deals with seafarers, experiences from other populations sharing the same exposures (e.g. shift work) were also...

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

    Directory of Open Access Journals (Sweden)

    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

  12. The Effect of Residual Stress State in the Notch Root Region Caused by the Hold Period of the Overload to the Fatigue Life

    OpenAIRE

    Anindito Purnowidodo; Ari Wahyudi; Rudy Soenoko; Khairul Anam

    2015-01-01

    In the present study, the effect of the overload together with the hold period of the overload to the fatigue life associating with the crack emerging from the notch root region is investigated because the region is vulnerable to the plastic deformation. The result of the study shows that the fatigue life is affected by the residual stress state in front of the notch root, and the state of the residual stress depends on the constant amplitude load condition following of the overload. The resi...

  13. Modeling and fatigue assessment of weld start-end locations based on the effective notch stress approach

    Energy Technology Data Exchange (ETDEWEB)

    Malikoutsakis, M. [Aristotle University of Thessaloniki, Faculty of Mechanical Engineering, Laboratory of Machine Elements Machine Design, 54124 Thessaloniki (Greece); Savaidis, G.

    2011-04-15

    The present paper contains a methodology for modeling and life assessment of fatigue loaded welded components providing distinct weld start and end locations. The proposed methodology follows the IIW recommendation regarding modeling and finite element meshing of weld toe and root by means of an effective notch radius and uses the corresponding Woehler curve (FAT class) to assess the durability. Geometrical singularities and, therewith, numerical discontinuities, can be overcome especially when 3D weld root problems are treated. The fatigue life assessment is performed on the basis of normal stresses acting at the failure-critical weld toe and root locations. Comprehensive experimental database containing stress and fatigue life results derived from motor truck's hypoid rear axles providing complex 3D welds subject to vertical, longitudinal, and torsional loading is used to verify the calculation accuracy of the proposed methodology. The agreement between experimentally determined and calculated fatigue results is satisfactory. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  14. High-cycle fatigue investigations of notched Glare under different stress ratio's in various environments

    National Research Council Canada - National Science Library

    Bhat, Sunil; Narayanan, Sockalingam

    2014-01-01

    Notched Glare 4A-3/2 laminates, comprising thin 2014-T6 aerospace aluminum alloy sheets alternately bonded with unidirectional E-glass fiber-based composite prepregs, are tested under tensile-tensile...

  15. METHOD TO CALCULATE STRESS INTENSITY FACTOR OF V-NOTCH IN BI-MATERIALS

    Institute of Scientific and Technical Information of China (English)

    Youtang Li; Ming Song

    2008-01-01

    Based on Zak's stress function,the eigen-equation of stress singularity of bi-materials with a Ⅴ-notch was obtained.A new definition of stress intensity factor for a perpendicular inter facial Ⅴ-notch of bi-material was put forward.The effects of shear modulus and Poisson's ratio of the matrix material and attaching material on eigen-values were analyzed.A generalized ex pression for calculating KI of the perpendicular V-notch of bi-materials was obtained by means of stress extrapolation.Effects of notch depth,notch angle and Poisson's ratio of materials on the singular stress field near the tip of the Ⅴ-notch were analyzed systematically with numerical simulations.As an example,a finite plate with double edge notches under uniaxial uniform ten sion was calculated by the method presented and the influence of the notch angle and Poisson's ratio on the stress singularity near the tip of notch was obtained.

  16. Notch Sensitivity Factor Determination With Artificial Neural Network For Shafts Under The Bending Stress

    Directory of Open Access Journals (Sweden)

    Murat Tolga Özkan

    2013-01-01

    Full Text Available Notch, hole, tap and a variety of geometric shapes such as curves or discontinuities can be found with various reasons in the design of Machine Element. Stress is caused by sudden changes in section aggregating. Stress concentration can occur with the reason of material features of size or direction of forces application. This type of stress concentration in the material brings out the effect of notch. Notch impact can lead to distortions and breakage of materials. In this study, the notch sensitivity factor values have been modelled Artificial Neural Networks (ANN for shafts that is under the influence of bending stress, and the accuracy of the model has been verified by using Statistica software. The model has been developed using Pythia. With this software, the user can be obtained the accurate value by inputing shaft dimension and the applied force without the need for notch sensitivity factor tables and any calculations.

  17. 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.

  18. New Methods of Determining the Mixed Mode Stress Intensity Factors for V-Shaped Notch

    Institute of Scientific and Technical Information of China (English)

    Lin Zhong-qin; Yu Haiyan; Chen Guanlong; Li Shu-hui

    2004-01-01

    In this paper, on the basis of the stress field given by D.H.Chen, three new photoelastic methods are developed for determining the stress intensity factors K1 and K2 of V-shaped notch. Some photoelastic experiments are performed on a skew -symmetric 45° notch. Measurements of the coordinates components of r,θand fringe order N are made for progressively smaller fringes and used in the proposed methods to solve K1 and K2.Plots of apparent K vs. r/l are made and extrapolated to the notch tip to yield the true values of K1 and K2.The results obtained by the three methods are very close to each other. When the notch problem is simplified as a crack problem, the corresponding equation is identical to the one proposed by D.G. Smith, which shows that the proposed methods are applicable for both notch and crack problems.

  19. Interferon regulatory factor 4 attenuates Notch signaling to suppress the development of chronic lymphocytic leukemia.

    Science.gov (United States)

    Shukla, Vipul; Shukla, Ashima; Joshi, Shantaram S; Lu, Runqing

    2016-07-05

    Molecular pathogenesis of Chronic Lymphocytic Leukemia (CLL) is not fully elucidated. Genome wide association studies have linked Interferon Regulatory Factor 4 (IRF4) to the development of CLL. We recently established a causal relationship between low levels of IRF4 and development of CLL. However, the molecular mechanism through which IRF4 suppresses CLL development remains unclear. Deregulation of Notch signaling pathway has been identified as one of the most recurrent molecular anomalies in the pathogenesis of CLL. Yet, the role of Notch signaling as well as its regulation during CLL development remains poorly understood. Previously, we demonstrated that IRF4 deficient mice expressing immunoglobulin heavy chain Vh11 (IRF4-/-Vh11) developed spontaneous CLL with complete penetrance. In this study, we show that elevated Notch2 expression and the resulting hyperactivation of Notch signaling are common features of IRF4-/-Vh11 CLL cells. Our studies further reveal that Notch signaling is indispensable for CLL development in the IRF4-/-Vh11 mice. Moreover, we identify E3 ubiquitin ligase Nedd4, which targets Notch for degradation, as a direct target of IRF4 in CLL cells and their precursors. Collectively, our studies provide the first in vivo evidence for an essential role of Notch signaling in the development of CLL and establish IRF4 as a critical regulator of Notch signaling during CLL development.

  20. Risk factors for fatigue among airline pilots.

    Science.gov (United States)

    van Drongelen, Alwin; Boot, Cécile R L; Hlobil, Hynek; Smid, Tjabe; van der Beek, Allard J

    2017-01-01

    The objective of this study is to determine risk factors for fatigue among airline pilots, taking into account person-, work-, health-, sleep-, and lifestyle-related characteristics. The study population consisted of 502 pilots who participated in the MORE Energy study. Included risk factors were either measured through an online questionnaire or provided by the company. The outcome of this study, fatigue, was assessed using the Checklist Individual Strength (CIS), and was defined as scoring more than 76 points on this questionnaire. The association of the risk factors with fatigue was determined using univariate and multivariate logistic regression analyses. Of the participating pilots, 29.5 % scored more than 76 points on the CIS and were classified as being fatigued. The fully adjusted regression model showed that person-, work-, health-, and lifestyle-related characteristics were associated with fatigue. Pilots who were aged 31 to 40 (OR 3.36, 95 % CI 1.32-8.53) or 41 to 50 (OR 4.19, 95 % CI 1.40-12.47), an evening type (OR 2.40, 95 % CI 1.38-4.16), scored higher on work-life balance disturbance (OR 1.22, 95 % CI 1.10-1.36), scored higher on need for recovery (OR 1.02, 95 % CI 1.01-1.04), scored lower on general health perception (OR 0.31, 95 % CI 0.20-0.47), were less physically active (OR 0.77, 95 % CI 0.66-0.89), and had a moderate alcohol consumption (OR 3.88, 95 % CI 1.21-12.43), were at higher risk for fatigue. Higher age, being an evening type, disturbance of the work-life balance, more need for recovery, a lower perceived health, less physical activity, and moderate alcohol consumption were shown to be risk factors for fatigue. Further longitudinal research is needed to elucidate the direction of the associations found and to evaluate the effects of possible countermeasures in airline pilots.

  1. Effect of Kruppel-like factor 4 on Notch pathway in hepatic stellate cells.

    Science.gov (United States)

    Xue, Yin-Kai; Tan, Jun; Dou, Dong-Wei; Chen, Ding; Chen, Lu-Jia; Ren, Huan-Ping; Chen, Li-Bo; Xiong, Xin-Gao; Zheng, Hai

    2016-12-01

    The relationship between Kruppel-like factor 4 (KLF4) and the Notch pathway was determined to investigate the effect of KLF4 on the activation of hepatic stellate cells and underlying mechanisms. Fifty SPF BALB/c mice were randomly divided into two groups. A liver fibrosis model was established in 25 mice as the experimental group, and the remaining 25 mice served as controls. On the day 0, 7, 14, and 35, liver tissues were removed for immunofluorescent detection. The Notch pathway inhibitor DAPT was added to the primary original hepatic stellate cells, and KLF4 and Notch-associated factor expression was detected by qRT-PCR. Additionally, the hepatic stellate cell line LX-2 was used to establish control and experimental groups, and was cultured in vitro. LX-2 cells in the experimental groups were treated with DAPT and the Notch activator transforming growth factor-beta 1 separately, whereas those in the control group were given isotonic culture medium. After 48 h, KLF4 expression was examined by Western blotting. After transient transfection of LX-2 cells to increase KLF4, the expression of Notch factor was examined. Immunofluorescence analysis showed that, with the aggravation of liver fibrosis, the absorbance (A) values of KLF4 were decreased (day 0: 980.73±153.19; day 7: 1087.99±230.23; day 14: 390.95±93.56; day 35: 245.99±87.34). The expression of Notch pathway- related factors (Notch-1, Notch-2, and Jagged-1) in the hepatic stellate cell membrane was negatively correlated to KLF4 expression. With the increase of KLF4 expression, Notch-2 (0.73±0.13) and Jagged-1 (0.43±0.12) expression decreased, whereas Notch-1 level was not detectable. When the Notch pathway was inhibited, KLF4 levels generally increased (18.12±1.31). Our results indicate that KLF4 expression is negatively correlated to the Notch pathway in hepatic stellate cells, which may provide a reference for the treatment of hepatic fibrosis.

  2. Fatigue Analysis and Life Prediction of Dumpers with Cumulative Fatigue Damage Approach

    Institute of Scientific and Technical Information of China (English)

    LI Shouju; LIU Yingxi; SUN Huiling

    2004-01-01

    A fatigue damage model is developed for evaluating accumulative fatigue damage of dumpers. The loading spectrums acted on dumpers are created according to measured strain data in field. The finite element analysis is carried out for assessing stress distribution and strength characteristics of dumpers. Fatigue damage indexes and service life are calculated by a modified Palmgren-Miner rule. The investigation shows that fatigue notch factor has a significant influence on the calculation of fatigue damage of dumpers.

  3. Von Willebrand factor inhibits mature smooth muscle gene expression through impairment of Notch signaling.

    Directory of Open Access Journals (Sweden)

    He Meng

    Full Text Available Von Willebrand factor (vWF, a hemostatic protein normally synthesized and stored by endothelial cells and platelets, has been localized beyond the endothelium in vascular disease states. Previous studies have implicated potential non-hemostatic functions of vWF, but signaling mechanisms underlying its effects are currently undefined. We present evidence that vWF breaches the endothelium and is expressed in a transmural distribution pattern in cerebral small vessel disease (SVD. To determine the potential molecular consequences of vWF permeation into the vessel wall, we also tested whether vWF impairs Notch regulation of key smooth muscle marker genes. In a co-culture system using Notch ligand expressing cells to stimulate Notch in A7R5 cells, vWF strongly inhibited both the Notch pathway and the activation of mature smooth muscle gene promoters. Similar repressive effects were observed in primary human cerebral vascular smooth muscle cells. Expression of the intracellular domain of NOTCH3 allowed cells to bypass the inhibitory effects of vWF. Moreover, vWF forms molecular complexes with all four mammalian Notch ectodomains, suggesting a novel function of vWF as an extracellular inhibitor of Notch signaling. In sum, these studies demonstrate vWF in the vessel wall as a common feature of cerebral SVD; furthermore, we provide a plausible mechanism by which non-hemostatic vWF may play a novel role in the promotion of vascular disease.

  4. Fatigue Reliability and Calibration of Fatigue Design Factors for Offshore Wind Turbines

    DEFF Research Database (Denmark)

    Dominguez, Sergio Marquez; Sørensen, John Dalsgaard

    2012-01-01

    Consequences of failure of offshore wind turbines (OWTs) are in general lower than consequences of failure of, e.g., oil & gas platforms. It is reasonable that lower fatigue design factors can be applied for fatigue design of OWTs when compared to other fixed offshore structures. Calibration...... is discussed and results are presented for calibrated optimal fatigue design factors. Further, the influence of inspections is considered in order to extend and maintain a given target safety level....... of appropriate partial safety factors/Fatigue Design Factors (FDF) for steel substructures for OWTs is the scope of this paper. A reliability-based approach is used and a probabilistic model has been developed, where design and limit state equations are established for fatigue failure. The strength and load...

  5. Corrosion Fatigue Crack Growth Behavior at Notched Hole in 7075 T6 Under Different Biaxial Stress Ratios

    Science.gov (United States)

    2016-08-18

    strain energy release rate I mode one (opening) K stress intensity factor (MPa*m^0.5) M molar mass R stress ratio for cyclic loading (unit less) r...Finally, 7 the third phase of the fatigue failure occurs when the resistance is exceeded, and a structure occurs, Figure 2.1 [30]. Figure 2.1...Alloy 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT UU 18. NUMBER OF PAGES 92 19a. NAME OF RESPONSIBLE PERSON Shankar

  6. Influence of laser treatment on the fatigue of notched bar%激光处理对切口棒料疲劳性能的影响

    Institute of Scientific and Technical Information of China (English)

    张辉; 凌维业; 蒋寿伟

    2003-01-01

    Fatigue cutting is a new approach for separating material. Man-made fatigue can be realized by applying a rotating bending load to a notched bar. To better utilize the new method, laser treatment is adopted in this study. After laser radiation at the notch root, the fatigue cycle of the bar drops dramatically. Based on the experimental result, we draw the conclusion that the fatigue of the bar is influenced by the shape of the hardened area. A hardened area that has a small axial dimension and a relatively large radial dimension facilitates the fatigue. The desirable hardened area can be obtained by controlling the laser treatment parameters.%疲劳断料是一种新的分离材料方法.通过对棒料进行切口并施加旋弯载荷,可人为制造疲劳.为了进一步提高断裂的效率,采用激光对棒料切口的根部进行了处理,处理后的棒料疲劳周次大大降低.通过分析实验结果得到:棒料的疲劳受硬化区形状影响,具有较小轴向尺寸和较大径向尺寸的硬化区会促进疲劳.硬化区的形状可以通过调整激光处理参数来控制.

  7. Risk factors for lower extremity fatigue among assembly plant workers.

    Science.gov (United States)

    Gell, Nancy; Werner, Robert A; Hartigan, Anne; Wiggermann, Neal; Keyserling, W Monroe

    2011-03-01

    Work-related fatigue of the lower extremities is a known cause of lost productivity and significant employer costs. Common workplace solutions to reduce fatigue levels include anti-fatigue matting, shoe orthoses, or sit/stand work stations. However, assessment of these anti-fatigue measures within the workplace has been limited. This was a cross sectional study in an automotive assembly plant on employees with at least 6 months tenure. Subject data were collected via questionnaires including Likert-scale questions to define fatigue severity. Jobs were evaluated for lower extremity ergonomic exposures via videotaping, pedometers, interviews, and industrial engineering records. Lower extremity fatigue at the end of the work day was associated with a higher prevalence of smoking, rheumatoid arthritis, job dissatisfaction, use of shoes with firmer outsoles, and increased time on the job spent standing or walking. Supervisor support and increased time spent on carpet were protective. Lower extremity fatigue that interfered with activities outside of work had additional risk factors including higher BMI, prior diagnosis of osteoarthritis, and increased hours per week spent working. While these results identify carpet as being protective against lower extremity fatigue, no similar relationship was identified for anti-fatigue mats. No adverse relationship was found between hard surfaces such as concrete and lower extremity fatigue. Given the high costs associated with work-related fatigue, future areas for potential intervention include smoking cessation, specific shoe recommendations, and enhancing psychosocial aspects of work such as supervisor support. Copyright © 2010 Wiley-Liss, Inc.

  8. Fatigue Reliability and Calibration of Fatigue Design Factors for Offshore Wind Turbines

    Directory of Open Access Journals (Sweden)

    Sergio Márquez-Domínguez

    2012-06-01

    Full Text Available Consequences of failure of offshore wind turbines (OWTs is in general lower than consequences of failure of, e.g., oil & gas platforms. It is reasonable that lower fatigue design factors can be applied for fatigue design of OWTs when compared to other fixed offshore structures. Calibration of appropriate partial safety factors/Fatigue Design Factors (FDF for steel substructures for OWTs is the scope of this paper. A reliability-based approach is used and a probabilistic model has been developed, where design and limit state equations are established for fatigue failure. The strength and load uncertainties are described by stochastic variables. SN and fracture mechanics approaches are considered for to model the fatigue life. Further, both linear and bi-linear SN-curves are formulated and various approximations are investigated. The acceptable reliability level for fatigue failure of OWTs is discussed and results are presented for calibrated optimal fatigue design factors. Further, the influence of inspections is considered in order to extend and maintain a given target safety level.

  9. Idealization of a Gas Turbine Compressor Blade to a Rectangular Plate and Analyzing the Variation of Stress Concentration Factor for U-Notches

    Directory of Open Access Journals (Sweden)

    Mohammad Rafi Nadaf

    2014-01-01

    Full Text Available Aircraft turbine engines routinely experience the ingestion of debris resulting in "foreign object damage‟ FOD. The ingestion of foreign object into aircraft engines leads to severe structural damage of the fan or compressor blades. Foreign object damage by hard particles mostly occurs during motion of the aircraft on the airfield, during take-off and during landing. Typical objects ingested are stones and other debris; sizes in the millimeter regime form the airfield. The worst case condition is experienced during take-off maximum thrusts leads to maximum impact velocity. Typical impact velocities are in the regime of 100 – 400m/sec, depending on the types of engine and impact location on the blades. Foreign object damage does not always lead to sudden catastrophic failure, yet such damage can have a detrimental effect on the fatigue strength of fan and compressor aero foils. However complex stress fields and geometry of the aerofoil make it difficult to use of simple notch analysis. For finding the stress concentration factor on the notches grinded on the typical aerofoil FOD damaged gas turbine compressor blade closed form solutions are difficult proportion. In this paper a finite element analysis is carried out by idealization of the typical aerofoil to rectangular cantilever plate with single edge U-notches for finding the stress concentration factor and is then compared with the standard stress concentration data by R.E.Peterson. The study can then be extended to a typical aerofoil.

  10. Epidermal growth factor promotes proliferation of dermal papilla cells via Notch signaling pathway.

    Science.gov (United States)

    Zhang, Haihua; Nan, Weixiao; Wang, Shiyong; Zhang, Tietao; Si, Huazhe; Wang, Datao; Yang, Fuhe; Li, Guangyu

    2016-08-01

    The effect of epidermal growth factor (EGF) on the development and growth of hair follicle is controversial. In the present study, 2-20 ng/ml EGF promoted the growth of mink hair follicles in vitro, whereas 200 ng/ml EGF inhibited follicle growth. Further, dermal papilla (DP) cells, a group of mesenchymal cells that govern hair follicle development and growth, were isolated and cultured in vitro. Treatment with or forced expression of EGF accelerated proliferation and induced G1/S transition in DP cells. Moreover, EGF upregulated the expression of DP mesenchymal genes, such as alkaline phosphatase (ALP) and insulin-like growth factor (IGF-1), as well as the Notch pathway molecules including Notch1, Jagged1, Hes1 and Hes5. In addition, inhibition of Notch signaling pathway by DAPT significantly reduced the basal and EGF-enhanced proliferation rate, and also suppressed cell cycle progression. We also show that the expression of several follicle-regulatory genes, such as Survivin and Msx2, were upregulated by EGF, and was inhibited by DAPT. In summary, our study demonstrates that the concentration of EGF is critical for the switch between hair follicle growth and inhibition, and EGF promotes DP cell proliferation via Notch signaling pathway.

  11. Partial Safety Factors for Fatigue Design of Wind Turbine Blades

    DEFF Research Database (Denmark)

    Toft, Henrik Stensgaard; Sørensen, John Dalsgaard

    2010-01-01

    In the present paper calibration of partial safety factors for fatigue design of wind turbine blades is considered. The stochastic models for the physical uncertainties on the material properties are based on constant amplitude fatigue tests and the uncertainty on Miners rule for linear damage...

  12. Targeting Notch1 inhibits invasion and angiogenesis of human breast cancer cells via inhibition Nuclear Factor-κB signaling.

    Science.gov (United States)

    Liu, Yuan; Su, Chuanfu; Shan, Yuqing; Yang, Shouxiang; Ma, Guifeng

    2016-01-01

    Notch-1, a type-1 transmembrane protein, plays critical roles in the pathogenesis and progression of human malignancies, including breast cancer; however, the precise mechanism by which Notch-1 causes tumor cell invasion and angiogenesis remain unclear. Nuclear factor-κB (NF-κB), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether targeting Notch-1 could be mechanistically associated with the down-regulation of NF-κB, IL-8, VEGF, and MMP-9, resulting in the inhibition of invasion and angiogenesis of breast cancer cells. Our data showed that down-regulation of Notch-1 leads to the inactivation of NF-κB activity and inhibits the expression of its target genes, such as IL-8, VEGF and MMP-9. We also found that down-regulation of Notch-1 decreased cell invasion, and vice versa Consistent with these results, we also found that the down-regulation of Notch-1 not only decreased MMP-9 mRNA and its protein expression but also inhibited MMP-9 active form. Moreover, conditioned medium from Notch-1 siRNA-transfected breast cancer cells showed reduced levels of IL-8 and VEGF and, in turn, inhibited the tube formation of HUVECs, suggesting that down-regulation of Notch-1 leads to the inhibition of angiogenesis. Furthermore, conditioned medium from Notch-1 cDNA-transfected breast cancer cells showed increased levels of IL-8 and VEGF and, in turn, promoted the tube formation of HUVECs, suggesting that Notch-1 overexpression leads to the promotion of angiogenesis.We therefore concluded that down-regulation of Notch-1 leads to the inactivation NF-κB and its target genes (IL-8, MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.

  13. Various methods of numerical estimation of generalized stress intensity factors of bi-material notches

    Directory of Open Access Journals (Sweden)

    Klusák J.

    2009-12-01

    Full Text Available The study of bi-material notches becomes a topical problem as they can model efficiently geometrical or material discontinuities. When assessing crack initiation conditions in the bi-material notches, the generalized stress intensity factors H have to be calculated. Contrary to the determination of the K-factor for a crack in an isotropic homogeneous medium, for the ascertainment of the H-factor there is no procedure incorporated in the calculation systems. The calculation of these fracture parameters requires experience. Direct methods of estimation of H-factors need choosing usually length parameter entering into calculation. On the other hand the method combining the application of the reciprocal theorem (Ψ-integral and FEM does not require entering any length parameter and is capable to extract the near-tip information directly from the far-field deformation.

  14. Risk factors for fatigue in patients with epilepsy.

    Science.gov (United States)

    Yan, Song; Wu, Yuanbin; Deng, Yanchun; Liu, Yonghong; Zhao, Jingjing; Ma, Lei

    2016-11-01

    Fatigue is highly prevalent in patients with epilepsy and has a major impact on quality of life, but little data is available on its effects and management in epilepsy. To identify the incidence and risk factors of fatigue in patients with epilepsy, 105 epilepsy patients (45 women and 60 men) were enrolled in our study. Demographic and clinical data were collected and psychological variables including fatigue, sleep quality, excess daytime sleepiness, anxiety, and depression were measured by Fatigue Severity Scale, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Hospital Anxiety and Depression Scale, respectively. Of 105 patients, 29.5% exhibited fatigue (FSS score ⩾4). We found no correlation between the occurrence of fatigue and any of our demographic or clinical variables. Fatigue is correlated with low sleep quality, anxiety, and depression, but not with excess daytime sleepiness. Thus, we concluded that fatigue is highly prevalent in patients with epilepsy, and that low sleep quality, anxiety, and depression are significantly correlated with fatigue in epileptics, while excess daytime sleepiness not.

  15. Advanced methods of fatigue assessment

    CERN Document Server

    Radaj, Dieter

    2013-01-01

    The book in hand presents advanced methods of brittle fracture and fatigue assessment. The Neuber concept of fictitious notch rounding is enhanced with regard to theory and application. The stress intensity factor concept for cracks is extended to pointed and rounded corner notches as well as to locally elastic-plastic material behaviour. The averaged strain energy density within a circular sector volume around the notch tip is shown to be suitable for strength-assessments. Finally, the various implications of cyclic plasticity on fatigue crack growth are explained with emphasis being laid on the DJ-integral approach.   This book continues the expositions of the authors’ well known reference work in German language ‘Ermüdungsfestigkeit – Grundlagen für Ingenieure’ (Fatigue strength – fundamentals for engineers).

  16. Factors related to fatigue; priority of interventions to reduce or eliminate fatigue and the exploration of a multidisciplinary research model for further study of fatigue

    NARCIS (Netherlands)

    Tiesinga, LJ; Dassen, TWN; Halfens, RJG; van den Heuvel, WJA

    1999-01-01

    A growing interest in the health problem presented by fatigue, both in clinical practice and research, coupled with a decreasing number of reported studies on fatigue in the last decade, make an updated and systematic review of factors related to fatigue necessary. A search of the literature, compri

  17. Partial Safety Factors for Fatigue Design of Wind Turbine Blades

    DEFF Research Database (Denmark)

    Toft, Henrik Stensgaard; Sørensen, John Dalsgaard

    In the present paper calibration of partial safety factors for fatigue design of wind turbine blades is considered. The stochastic models for the physical uncertainties on the material properties are based on constant amplitude fatigue tests and the uncertainty on Miners rule for linear damage...... from rainflow-counting of simulated time series for a 5MW reference wind turbine [1]. A possible influence of a complex stress state in the blade is not taken into account and only longitudinal stresses are considered....

  18. Determination of stress intensity factors in ultrasonic fatigue loading

    Institute of Scientific and Technical Information of China (English)

    倪金刚; 张学仁; 聂景旭

    1996-01-01

    The application of displacement and energy approaches to the determination of stress intensity factors in ultrasonic fatigue crack growth (fcg) studies is discussed.The particular advantages as well as the limitations of the two approaches are evaluated.Two types of ultrasonic fatigue loading with different stress ratios are exerted on the specimen respectively: the ultrasonic fatigue loading with a stress ratio R=-1 and the ultrasonic fatigue excitations superposed upon a static mean stress with R>-1 From comparison the conclusion is formed that the energy approach developed in the investigation is more accurate,concise and suitable than commonly adopted approaches and/or formulas proposed.Experimental fcg data on a titanium alloy Ti-6Al-4V and the characteristic mechanism of the ultrasonic fcg are investigated.

  19. FATIGUE LIFE PREDICTION FOR NOTCHED SPECIMEN UNDER MULTIAXIAL LOADING%多轴载荷下缺口试件疲劳寿命预测研究

    Institute of Scientific and Technical Information of China (English)

    李静; 孙强; 李春旺; 张忠平; 乔艳江

    2011-01-01

    Based on the critical plane approach,the recently proposed multiaxial fatigue life prediction model applied to the smoothing tubular specimen is extended to assess the multiaxial fatigue life of notched one. Besides,with the aid of finite element analysis (FEA),the orientation of the critical plane and the effective cyclic parameter are determined by using the coordinate transformation principle. In the meantime,the proposed model is modified to take into consideration of the effect of mean stress when existing the mean stress.%基于临界平面法,在分析光滑薄壁圆管试件疲劳寿命预测模型的基础上,借助有限元应力应变分析,进一步将模型推广应用到了缺口试件的多轴疲劳寿命预测中,并利用坐标变换原理,明确了临界平面及有效循环变量的确定方法.在存在平均应力的情况下,分析了平均应力对疲劳寿命的影响,并对所建模型进行了平均应力修正.

  20. Repeated-sprint ability - part I: factors contributing to fatigue.

    Science.gov (United States)

    Girard, Olivier; Mendez-Villanueva, Alberto; Bishop, David

    2011-08-01

    Short-duration sprints (ability to recover and to reproduce performance in subsequent sprints is probably an important fitness requirement of athletes engaged in these disciplines, and has been termed repeated-sprint ability (RSA). This review (Part I) examines how fatigue manifests during repeated-sprint exercise (RSE), and discusses the potential underpinning muscular and neural mechanisms. A subsequent companion review to this article will explain a better understanding of the training interventions that could eventually improve RSA. Using laboratory and field-based protocols, performance analyses have consistently shown that fatigue during RSE typically manifests as a decline in maximal/mean sprint speed (i.e. running) or a decrease in peak power or total work (i.e. cycling) over sprint repetitions. A consistent result among these studies is that performance decrements (i.e. fatigue) during successive bouts are inversely correlated to initial sprint performance. To date, there is no doubt that the details of the task (e.g. changes in the nature of the work/recovery bouts) alter the time course/magnitude of fatigue development during RSE (i.e. task dependency) and potentially the contribution of the underlying mechanisms. At the muscle level, limitations in energy supply, which include energy available from phosphocreatine hydrolysis, anaerobic glycolysis and oxidative metabolism, and the intramuscular accumulation of metabolic by-products, such as hydrogen ions, emerge as key factors responsible for fatigue. Although not as extensively studied, the use of surface electromyography techniques has revealed that failure to fully activate the contracting musculature and/or changes in inter-muscle recruitment strategies (i.e. neural factors) are also associated with fatigue outcomes. Pending confirmatory research, other factors such as stiffness regulation, hypoglycaemia, muscle damage and hostile environments (e.g. heat, hypoxia) are also likely to compromise

  1. High-cycle notch sensitivity of alloy steel ASTM A743 CA6NM used in hydrogenator turbine components

    Directory of Open Access Journals (Sweden)

    José Alexander Araújo

    2010-10-01

    Full Text Available The presence of notches and other stress concentrations in turbine blades and other notch hydraulic components is a current problem in engineering. It causes a reduction of endurance limit of material. In that sense, specimens of the ASTM A743 CA6NM alloy steel using in several hydrogenator turbine components was tested. The specimens were tested under uniaxial fatigue loading with a load ratio equal to -1, and the considered stress concentration factors, Kt, values, calculated with respect to net area, were 1.55, 2.04 and 2.42. In order to determine the fatigue limit for such notch type, a reduction data method by Dixon and Mood, Staircase method was used. This approach is based on the assumed target distribution of the fatigue limit. For such geometry at least 8 specimens were tested. In addition, the Peterson and Neuber’s notch fatigue factor were compared through fatigue notch reduction factor, Kf, obtained from experimental data. According to results obtained it was possible to conclude that the tested material is less sensitive to notches than the prediction of the Peterson and Neuber’s empirical models.

  2. Mechanical behaviors of notched composite laminates

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Presents the study on the mechanical behaviors of composite laminates with both static and fatigue tests per formed with different notched specimens and concludes with experimental results that ultimate strength and initial stiff ness of various notched composite laminates is almost as same as un-notched ones but the fatigue life of notched speci mens is much higher than un-notched ones. Compared with metals, composite materials are notch insensitive. The properties measured by using bar type specimens can not represent the real properties of composite laminates. Notches on the free edge may be helpful to the structure. The fatigue life can be predicted through theoretical models estab lished using the residual stiffness model.

  3. The translation initiation factor 3f (eIF3f exhibits a deubiquitinase activity regulating Notch activation.

    Directory of Open Access Journals (Sweden)

    Julien Moretti

    Full Text Available Activation of the mammalian Notch receptor after ligand binding relies on a succession of events including metalloprotease-cleavage, endocytosis, monoubiquitination, and eventually processing by the gamma-secretase, giving rise to a soluble, transcriptionally active molecule. The Notch1 receptor was proposed to be monoubiquitinated before its gamma-secretase cleavage; the targeted lysine has been localized to its submembrane domain. Investigating how this step might be regulated by a deubiquitinase (DUB activity will provide new insight for understanding Notch receptor activation and downstream signaling. An immunofluorescence-based screening of an shRNA library allowed us to identify eIF3f, previously known as one of the subunits of the translation initiation factor eIF3, as a DUB targeting the activated Notch receptor. We show that eIF3f has an intrinsic DUB activity. Knocking down eIF3f leads to an accumulation of monoubiquitinated forms of activated Notch, an effect counteracted by murine WT eIF3f but not by a catalytically inactive mutant. We also show that eIF3f is recruited to activated Notch on endocytic vesicles by the putative E3 ubiquitin ligase Deltex1, which serves as a bridging factor. Finally, catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway. Our results support two new and provocative conclusions: (1 The activated form of Notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. (2 The enzyme accounting for this deubiquitinase activity is eIF3f, known so far as a translation initiation factor. These data improve our knowledge of Notch signaling but also open new avenues of research on the Zomes family and the translation initiation factors.

  4. Leptin-induced transphosphorylation of vascular endothelial growth factor receptor increases Notch and stimulates endothelial cell angiogenic transformation.

    Science.gov (United States)

    Lanier, Viola; Gillespie, Corey; Leffers, Merle; Daley-Brown, Danielle; Milner, Joy; Lipsey, Crystal; Webb, Nia; Anderson, Leonard M; Newman, Gale; Waltenberger, Johannes; Gonzalez-Perez, Ruben Rene

    2016-10-01

    Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2). Interestingly, in the absence of VEGF, leptin induced the expression of several components of Notch signaling pathway in endothelial cells. Inhibition of VEGFR and Notch signaling significantly decreased leptin-induced S-phase progression, proliferation, and tube formation in endothelial cells. Moreover, leptin/OB-R induced transphosphorylation of VEGFR-1 and VEGFR-2 was essential for leptin's effects. These results unveil for the first time a novel mechanism by which leptin could induce angiogenic features via upregulation/trans-activation of VEGFR and downstream expression/activation of Notch in endothelial cells. Thus, high levels of leptin found in overweight and obese patients might lead to increased angiogenesis by activating VEGFR-Notch signaling crosstalk in endothelial cells. These observations might be highly relevant for obese patients with cancer, where leptin/VEGFR/Notch crosstalk could play an important role in cancer growth, and could be a new target for the control of tumor angiogenesis.

  5. Factors involved in mechanical fatigue degradation of dental resin composites.

    Science.gov (United States)

    Lohbauer, U; Belli, R; Ferracane, J L

    2013-07-01

    The design of clinical trials allows for limited insights into the fatigue processes occurring in resin composites and the factors involved therein. In vitro studies, in contrast, can fundamentally narrow study interests to focus on particular degradation mechanisms and, to date, represent the major contributors to the state of knowledge on the subject. These studies show that microstructural features are important in determining strength and fracture toughness, whereas fatigue resistance is mainly related to the susceptibility of the matrix and the filler/matrix interface to mechanical and chemical degradation. In this review, we focus on fracture mechanisms occurring during fatigue, on the methods used to assess them, and on additional phenomena involved in the degradation of initial mechanical properties of resin composites.

  6. Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor β in the Mouse Model.

    Science.gov (United States)

    Kramer, Jan; Schwanbeck, Ralf; Pagel, Horst; Cakiroglu, Figen; Rohwedel, Jürgen; Just, Ursula

    2016-01-01

    Ischemic acute kidney injury (AKI) is associated with high morbidity and frequent complications. Repeated episodes of AKI may lead to end-stage renal failure. The pathobiology of regeneration in AKI is not well understood and there is no effective clinical therapy that improves regeneration. The Notch signaling pathway plays an essential role in kidney development and has been implicated in tissue repair in the adult kidney. Here, we found that kidneys after experimental AKI in mice showed increased expression of Notch receptors, specifically Notch1-3, of the Notch ligands Jagged-1 (Jag1), Jag2 and Delta-like-4 (Dll4) and of the Notch target genes Hes1, Hey2, HeyL, Sox9 and platelet-derived growth factor receptor β (Pdgfrb). Treatment of ischemic mice with the x03B3;-secretase inhibitor DBZ blocked Notch signaling and specifically downregulated the expression of Notch3 and the Notch target genes Hes1, Hey2, HeyL and Pdgfrb. After DBZ treatment, the mice developed less interstitial edema and displayed altered interstitial inflammation patterns. Furthermore, serum urea and creatinine levels were significantly decreased from 6 h onwards when compared to control mice treated with DMSO only. Our data are consistent with an amelioration of the severity of kidney injury by blocking Notch activation following AKI, and suggest an involvement of Notch-regulated Pdgfrb in AKI pathogenesis.

  7. Clinical Relevant Fatigue in Women with Breast Cancer: Prevalence and Associated Factors

    OpenAIRE

    Lamino, Daniela de Araujo; Sra Cibele, Cibele Andruciolli de Mattos Pimenta; Sra Patricia, Patricia Emilia Braga; Sra Dalete, Dalete Delalibera Corrêa de Faria Mota

    2014-01-01

    Introduction: Fatigue is a common symptom in patients with cancer. Objective: Toexamine the prevalence and independent predictors of fatigue in women with breastcancer. Material and Method: A cross-sectional study with a nonrandom sample of163 patients in outpatient follow-up. Fatigue was assessed by the Piper Fatigue Scale.Results: Clinical relevant fatigue (score ≥ 4) was present in 31.9% of the sample andthe average intensity was 6 (SD = 1.3).Pain and depression were factors independentlya...

  8. Effects of hepatocyte growth factor-mediated activation of Dll4-Notch-Hey2 signaling pathway

    Institute of Scientific and Technical Information of China (English)

    GAO Yu-fang; HA Xiao-qin; L(U) Tong-de; HAN Juan-ping

    2011-01-01

    Background Hepatocyte growth factor (HGF) treats ischemic disease by promoting arteriogenesis, however, its mechanism of action is not known. The notch signaling pathway plays an important role in neovascularization. The relationship between the proliferation and migration ability of artery endothelial cells and the Dll4-Notch-Hey2 signaling pathway in the process of arteriogenesis was investigated as a mechanism of action of HGF.Methods Based on the prophase study cells and supernatant were harvested at the indicated time after human femoral artery endothelial cells (HFAECs) were infected with adenovirus-HGF (Ad-HGF) at 200 pfu/cell. Cells were analyzed for HGF expression and Notch1, Dll4 and Hey2 expression by ELISA and reverse transcription-PCR (RT-PCR). The changes in the proliferation and migration ability of HFAECs were observed by MTT and Transwell migration experiments.Ad-GFP-infected HFAECs were used as control.Results Compared with the control group the Ad-HGF group's HGF expression was not increased with time, and the induction by HGF of Notch1, Dll4 and Hey2 gene transcription was not enhanced with an increase of HGF. The proliferation ability of Ad-HGF-transduced HFAECs was enhanced and their migration ability was also enhanced in the presence of HGF.Conclusions Through activating the Dll4-Notch-Hey2 signaling pathway, HGF indirectly promotes the proliferation and migration ability of cells, so that offspring artery branches are formed.

  9. Fatigue in the Danish general population. Influence of sociodemographic factors and disease

    DEFF Research Database (Denmark)

    Watt, T; Groenvold, M; Bjorner, J B;

    2000-01-01

    -77 with an equal gender distribution (response rate 67%). MAIN OUTCOME MEASURES: Five fatigue scales from the questionnaire Multidimensional Fatigue Inventory: General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation and Mental Fatigue. RESULTS: Fatigue scores were skewed towards absence of fatigue...... showed that respondents of low social status and respondents with a depression had high fatigue scores on all scales, independent of other factors. Chronic somatic disease had an independent direct effect on Mental Fatigue, but for the rest of the scales, the effect of somatic disease depended on age......, gender and/or whether the person was living alone. For example, General and Physical Fatigue decreased with age among healthy people, whereas scores on these scales increased with age among those with a somatic disease. CONCLUSIONS: Physical and mental diseases play essential parts for the level...

  10. The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway.

    Science.gov (United States)

    Rankin, Lucille C; Groom, Joanna R; Chopin, Michaël; Herold, Marco J; Walker, Jennifer A; Mielke, Lisa A; McKenzie, Andrew N J; Carotta, Sebastian; Nutt, Stephen L; Belz, Gabrielle T

    2013-04-01

    NKp46+ innate lymphoid cells (ILCs) serve important roles in regulating the intestinal microbiota and defense against pathogens. Whether NKp46+ ILCs arise directly from lymphoid tissue-inducer (LTi) cells or represent a separate lineage remains controversial. We report here that the transcription factor T-bet (encoded by Tbx21) was essential for the development of NKp46+ ILCs but not of LTi cells or nuocytes. Deficiency in interleukin 22 (IL-22)-producing NKp46+ ILCs resulted in greater susceptibility of Tbx21-/- mice to intestinal infection. Haploinsufficient T-bet expression resulted in lower expression of the signaling molecule Notch, and Notch signaling was necessary for the transition of LTi cells into NKp46+ ILCs. Furthermore, NKp46+ ILCs differentiated solely from the CD4- LTi population, not the CD4+ LTi population. Our results pinpoint the regulation of Notch signaling by T-bet as a distinct molecular pathway that guides the development of NKp46+ ILCs.

  11. Developing Fatigue Pre-crack Procedure to Evaluate Fracture Toughness of Pipeline Steels Using Spiral Notch Torsion Test

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jy-An John [ORNL; Tan, Ting [ORNL; Jiang, Hao [ORNL; Zhang, Wei [ORNL; Feng, Zhili [ORNL

    2012-10-01

    The spiral notch torsion test (SNTT) has been utilized to investigate the crack growth behavior of X52 steel base and welded materials used for hydrogen infrastructures. The X52 steel materials are received from a welded pipe using friction stir welding techniques. Finite element models were established to study the crack growth behavior of steel SNTT steel samples, which were assumed to be isotropic material. A series SNTT models were set up to cover various crack penetration cases, of which the ratios between crack depth to diameter (a/D ratio) ranging from 0.10 to 0.45. The evolution of compliance and energy release rates in the SNTT method have been investigated with different cases, including different geometries and materials. Indices of characteristic compliance and energy release rates have been proposed. Good agreement has been achieved between predictions from different cases in the same trend. These work shed lights on a successful protocol for SNTT application in wide range of structural materials. The further effort needed for compliance function development is to extend the current developed compliance function to the deep crack penetration arena, in the range of 0.55 to 0.85 to effectively determine fracture toughness for extremely tough materials.

  12. Stochastic simulation of notch signaling reveals novel factors that mediate the differentiation of neural stem cells.

    Science.gov (United States)

    Tzou, Wen-Shyong; Lo, Ying-Tsang; Pai, Tun-Wen; Hu, Chin-Hwa; Li, Chung-Hao

    2014-07-01

    Notch signaling controls cell fate decisions and regulates multiple biological processes, such as cell proliferation, differentiation, and apoptosis. Computational modeling of the deterministic simulation of Notch signaling has provided important insight into the possible molecular mechanisms that underlie the switch from the undifferentiated stem cell to the differentiated cell. Here, we constructed a stochastic model of a Notch signaling model containing Hes1, Notch1, RBP-Jk, Mash1, Hes6, and Delta. mRNA and protein were represented as a discrete state, and 334 reactions were employed for each biochemical reaction using a graphics processing unit-accelerated Gillespie scheme. We employed the tuning of 40 molecular mechanisms and revealed several potential mediators capable of enabling the switch from cell stemness to differentiation. These effective mediators encompass different aspects of cellular regulations, including the nuclear transport of Hes1, the degradation of mRNA (Hes1 and Notch1) and protein (Notch1), the association between RBP-Jk and Notch intracellular domain (NICD), and the cleavage efficiency of the NICD. These mechanisms overlap with many modifiers that have only recently been discovered to modulate the Notch signaling output, including microRNA action, ubiquitin-mediated proteolysis, and the competitive binding of the RBP-Jk-DNA complex. Moreover, we identified the degradation of Hes1 mRNA and nuclear transport of Hes1 as the dominant mechanisms that were capable of abolishing the cell state transition induced by other molecular mechanisms.

  13. Notch2 controls prolactin and insulin-like growth factor binding protein-1 expression in decidualizing human stromal cells of early pregnancy.

    Directory of Open Access Journals (Sweden)

    Gerlinde R Otti

    Full Text Available Decidualization, the transformation of the human uterine mucosa into the endometrium of pregnancy, is critical for successful implantation and embryonic development. However, key regulatory factors controlling differentiation of uterine stromal cells into hormone-secreting decidual cells have not been fully elucidated. Hence, we herein investigated the role of the Notch signaling pathway in human decidual stromal cells (HDSC isolated from early pregnancy samples. Immunofluorescence of first trimester decidual tissues revealed expression of Notch2 receptor and its putative, membrane-anchored interaction partners Jagged1, Delta-like (DLL 1 and DLL4 in stromal cells whereas other Notch receptors and ligands were absent from these cells. During in vitro differentiation with estrogen/progesterone (E2P4 and/or cyclic adenosine monophosphate (cAMP HDSC constitutively expressed Notch2 and weakly downregulated Jagged1 mRNA and protein, measured by quantitative PCR (qPCR and Western blotting, respectively. However, increased levels of DLL1 and DLL4 were observed in the decidualizing cultures. Transfection of a Notch luciferase reporter and qPCR of the Notch target gene hairy and enhancer of split 1 (HES1 revealed an induction of canonical Notch activity during in vitro differentiation. In contrast, treatment of HDSC with a chemical Notch/γ-secretase inhibitor decreased cAMP/E2P4-stimulated Notch luciferase activity, HES1 transcript levels and mRNA expression of the decidual marker genes prolactin (PRL and insulin-like growth factor binding protein 1 (IGFBP1. Similarly, siRNA-mediated gene silencing or antibody-mediated blocking of Notch2 diminished HES1, PRL and IGFBP1 mRNA levels as well as secreted PRL protein. In summary, the data suggest that canonical, Notch2-dependent signaling plays a role in human decidualization.

  14. Notch maintains Drosophila type II neuroblasts by suppressing expression of the Fez transcription factor Earmuff.

    Science.gov (United States)

    Li, Xiaosu; Xie, Yonggang; Zhu, Sijun

    2016-07-15

    Notch signaling is crucial for maintaining neural stem cell (NSC) self-renewal and heterogeneity; however, the underlying mechanism is not well understood. In Drosophila, loss of Notch prematurely terminates the self-renewal of larval type II neuroblasts (NBs, the Drosophila NSCs) and transforms type II NBs into type I NBs. Here, we demonstrate that Notch maintains type II NBs by suppressing the activation of earmuff (erm) by Pointed P1 (PntP1). We show that loss of Notch or components of its canonical pathway leads to PntP1-dependent ectopic Erm expression in type II NBs. Knockdown of Erm significantly rescues the loss-of-Notch phenotypes, and misexpression of Erm phenocopies the loss of Notch. Ectopically expressed Erm promotes the transformation of type II NBs into type I NBs by inhibiting PntP1 function and expression in type II NBs. Our work not only elucidates a key mechanism of Notch-mediated maintenance of type II NB self-renewal and identity, but also reveals a novel function of Erm.

  15. Mode I Critical Stress Intensity Factor of Medium - Density Fiberboard Obtained by Single-Edge - Notched Bending Test

    Directory of Open Access Journals (Sweden)

    Hiroshi Yoshihara

    2014-06-01

    Full Text Available The Mode I critical stress intensity factor (KIc obtained by single-edge-notched bending (SENB tests of medium-density fiberboard (MDF was experimentally analyzed. In the SENB test, the critical load for crack propagation (Pc was determined from the relationship between load/loading-line displacement and load/crack opening displacement (COD. A double cantilever beam (DCB test was also conducted and the results were compared with those of SENB tests. The value of Mode I critical stress intensity factor was obtained by introducing an additional crack length, when the crack length ranged from 0.5 to 0.7 times the depth of the specimen. This range coincided well with that used to derive the appropriate KIc value in the single-edge-notched tension (SENT test, which was conducted using the specimens with a similar confi guration cut from the MDF panel used in this study.

  16. Application of Weakest Link Probabilistic Framework for Fatigue Notch Factor to Aero Engine Materials

    Science.gov (United States)

    2014-08-25

    where m  is the density of mobile dislocation, b is the burgers vector and v  is the average velocity of the burgers vector. Using Equations...complicated interaction of dislocations created by cross slip which result in an increased dislocation density and restricts the motion of mobile ...137, pp. 173-210 , 2006. [150] McGinty R D , "Multiscale representation of polycrystaline inelasticity PhD Thesis," Georgia Institute of Technolgy , Atlanta USA , 2001.

  17. Notched strength of beryllium powder and ingot sheets.

    Science.gov (United States)

    Moss, R. G.

    1972-01-01

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

  18. Comparison of Fatigue Properties and Fatigue Crack Growth Rates of Various Implantable Metals

    Directory of Open Access Journals (Sweden)

    Yoshimitsu Okazaki

    2012-12-01

    Full Text Available The fatigue strength, effects of a notch on the fatigue strength, and fatigue crack growth rate of Ti-15Zr-4Nb-4Ta alloy were compared with those of other implantable metals. Zr, Nb, and Ta are important alloying elements for Ti alloys for attaining superior long-term corrosion resistance and biocompatibility. The highly biocompatible Ti-15Zr-4Nb-4Ta alloy exhibited an excellent balance between strength and ductility. Its notched tensile strength was much higher than that of a smooth specimen. The strength of 20% cold-worked commercially pure (C.P. grade 4 Ti was close to that of Ti alloy. The tension-to-tension fatigue strength of an annealed Ti-15Zr-4Nb-4Ta rod at 107 cycles was approximately 740 MPa. The fatigue strength of this alloy was much improved by aging treatment after solution treatment. The fatigue strengths of C.P. grade 4 Ti and stainless steel were markedly improved by 20% cold working. The fatigue strength of Co-Cr-Mo alloy was markedly increased by hot forging. The notch fatigue strengths of 20% cold-worked C.P. grade 4 Ti, and annealed and aged Ti-15Zr-4Nb-4Ta, and annealed Ti-6Al-4V alloys were less than those of the smooth specimens. The fatigue crack growth rate of Ti-15Zr-4Nb-4Ta was the same as that of Ti-6Al-4V. The fatigue crack growth rate in 0.9% NaCl was the same as that in air. Stainless steel and Co-Cr-Mo-Ni-Fe alloy had a larger stress-intensity factor range (ΔK than Ti alloy.

  19. Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes.

    Directory of Open Access Journals (Sweden)

    Chiara Lambertini

    Full Text Available In specific cell types like keratinocytes, Notch signaling plays an important pro-differentiation and tumor suppressing function, with down-modulation of the Notch1 gene being associated with cancer development. Besides being controlled by p53, little else is known on regulation of Notch1 gene expression in this context. We report here that transcription of this gene is driven by a TATA-less "sharp peak" promoter and that the minimal functional region of this promoter, which extends from the -342 bp position to the initiation codon, is differentially active in normal versus cancer cells. This GC rich region lacks p53 binding sites, but binds Klf4 and Sp3. This finding is likely to be of biological significance, as Klf4 and, to a lesser extent, Sp3 are up-regulated in a number of cancer cells where Notch1 expression is down-modulated, and Klf4 over-expression in normal cells is sufficient to down-modulate Notch1 gene transcription. The combined knock-down of Klf4 and Sp3 was necessary for the reverse effect of increasing Notch1 transcription, consistent with the two factors exerting an overlapping repressor function through their binding to the Notch1 promoter.

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

    OpenAIRE

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

    2017-01-01

    Notch signaling plays a key role in the development of pancreatic cancer. Among the four identified Notch receptors, Notch1 and Notch2 share the highest homology. Notch1 has been reported to be an oncogene but some reports indicate that Notch2, not Notch1, plays a key role in pancreatic carcinogenesis. As both are transcription factors, examination of their genomic binding sites might reveal interesting functional differences between them. Notch proteins do not have DNA-binding domain. In the...

  1. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Wei-Ming Wang

    Full Text Available Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC. The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab-induced epidermal growth factor receptor (EGFR inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1α (HIF-1α was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/Pten deletion (2cKO mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1α and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1α and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1α and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxia- and Notch-induced angiogenesis may benefit HNSCC therapy.

  2. Application of Support Vector Machine in the Prediction of Fatigue Stress Concentration Factor%基于支持矢量机的疲劳应力集中系数预测模型研究

    Institute of Scientific and Technical Information of China (English)

    侯哲哲; 杜彦良; 赵维刚

    2012-01-01

    Fatigue stress concentration factors as fatigue limit of material fatigue resistance not only reflected the extent of fatigue stress concentration but also reflected for notch sensitive degree. The newly developed technical support vector machine(SVM) into the domain of fatigue stress concentration factor is introduced. Support vector machine theory is introduced, LIBSVM is used, and RBF is chosen as kernel function to build a mode. The input parameters are tensile strength, yield strength, fatigue strength, stress concentration factor, notch root radius, samples size and notch fatigue limit; Fatigue stress concentration factor is output. The calculations of SVM model, experimental formula Neural and Peterson are compared. The results show that the relative maximum predicting error is 0.7% under the condition of using a small quantity of samples to build the mathematical model. The accuracy and applicability for the present model are thus verified.%疲劳应力集中系数作为材料疲劳抗力指标的疲劳极限,不仅反映了疲劳应力集中的程度,还反映了材料对缺口的敏感程度,将近年来飞速发展的支持矢量机(Support vector machine,SVM)应用于疲劳应力集中系数的研究.介绍支持矢量机的基本原理,利用LIBSVM,选择高斯型径向基函数(Radial basis function,RBF)作为核函数,建立以材料的抗拉强度、屈服强度、光棒疲劳强度、理论应力集中系数、缺口根部半径、试样尺寸及缺口疲劳极限作为输入值,疲劳应力集中系数为输出值的模型,从而对疲劳应力集中系数进行分析和预测.同时,SVM模型与经验公式Neuber式和Peterson式的计算值进行比较.结果表明,在小样本条件下,应用SVM技术构建的数学模型,模型的拟合相对误差小于7.4%,从而证明该SVM模型的准确性和适用性.

  3. Reliability-based Calibration of Fatigue Safety Factors for Offshore Wind Turbines

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard

    2011-01-01

    This paper describes reliability-based investigations on the required safety factors / Fatigue Design Factors (FDF) values to be used for fatigue design of steel substructures for offshore wind turbines. Design and limit state equations are formulated and stochastic models for the uncertain...

  4. Fatigue in patients receiving maintenance dialysis: a review of definitions, measures, and contributing factors.

    Science.gov (United States)

    Jhamb, Manisha; Weisbord, Steven D; Steel, Jennifer L; Unruh, Mark

    2008-08-01

    Fatigue is a debilitating symptom or side effect experienced by many patients on long-term dialysis therapy. Fatigue has a considerable effect on patient health-related quality of life and is viewed as being more important than survival by some patients. Renal providers face many challenges when attempting to reduce fatigue in dialysis patients. The lack of a reliable, valid, and sensitive fatigue scale complicates the accurate identification of this symptom. Symptoms of daytime sleepiness and depression overlap with fatigue, making it difficult to target specific therapies. Moreover, many chronic health conditions common in the long-term dialysis population may lead to the development of fatigue and contribute to the day-to-day and diurnal variation in fatigue in patients. Key to improving the assessment and treatment of fatigue is improving our understanding of potential mediators, as well as potential therapies. Cytokines have emerged as an important mediator of fatigue and have been studied extensively in patients with cancer-related fatigue. In addition, although erythropoietin-stimulating agents have been shown to mitigate fatigue, the recent controversy regarding erythropoietin-stimulating agent dosing in patients with chronic kidney disease suggests that erythropoietin-stimulating agent therapy may not serve as the sole therapy to improve fatigue in this population. In conclusion, fatigue is an important and often underrecognized symptom in the dialysis population. Possible interventions for minimizing fatigue in patients on long-term dialysis therapy should aim at improving health care provider awareness, developing improved methods of measurement, understanding the pathogenesis better, and managing known contributing factors.

  5. Physical factors associated with fatigue after stroke: an exploratory study.

    Science.gov (United States)

    Hoang, Chi Lan Nguyen; Salle, Jean-Yves; Mandigout, Stéphane; Hamonet, Julia; Macian-Montoro, Francisco; Daviet, Jean-Christophe

    2012-01-01

    To look for a relationship between physical fatigue and physical parameters in patients at least 3 months post stroke. We conducted a prospective cross-sectional study of 32 poststroke patients (average duration of stroke 40 months) who were recruited among in- and outpatients followed by the Department of Physical and Rehabilitation Medicine of a university hospital. Fatigue was defined as a Fatigue Severity Scale (FSS) score of 4 or more. The parameters studied were age, sex, time since stroke, Demeurisse Motor Index, Barthel Index score, new Functional Ambulation Category, Berg Balance Scale, 10-meter walk test, 6-minute walk test, Dijon Physical Activity Score, Montgomery and Asberg Depression Rating Scale, Epworth Sleepiness Scale, presence of pain, and length and area of the center of pressure displacement obtained posturographically. Two-thirds of patients (65.6%) were fatigued. The mean FSS score was 4.3 ± 1.8. Fatigue was not associated with the physical parameters studied; notably, there was no correlation with motor impairment, autonomy and walking capacity, or balance and physical activity. However, after multivariate analysis, we found an association between physical fatigue and time since the occurrence of stroke (P = .05). Our study revealed a relationship between pain and physical fatigue, as reported by 2 other studies. Poststroke fatigue management should include appropriate pain management. Further studies are necessary to determine the causes of physical fatigue after stroke.

  6. Stomaching Notch

    Science.gov (United States)

    Yin, Xiaolei; Karp, Jeffrey M

    2015-01-01

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

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

    Science.gov (United States)

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

    2016-07-01

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

  8. Blockade of Jagged/Notch pathway abrogates transforming growth factor β2-induced epithelial-mesenchymal transition in human retinal pigment epithelium cells.

    Science.gov (United States)

    Chen, X; Xiao, W; Liu, X; Zeng, M; Luo, L; Wu, M; Ye, S; Liu, Y

    2014-05-01

    The epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells plays a key role in proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), which lead to the loss of vision. The Jagged/Notch pathway has been reported to be essential in EMT during embryonic development, fibrotic diseases and cancer metastasis. However, the function of Jagged/Notch signaling in EMT of RPE cells is unknown. Thus, we hypothesized that a crosstalk between Notch and transforming growth factor β2 (TGF-β2) signaling could induce EMT in RPE cells, which subsequently contributes to PVR and PDR. Here, we demonstrate that Jagged-1/Notch pathway is involved in the TGF-β2-mediated EMT of human RPE cells. Blockade of Notch pathway with DAPT (a specific inhibitor of Notch receptor cleavage) and knockdown of Jagged-1 expression inhibited TGF-β2-induced EMT through regulating the expression of Snail, Slug and ZEB1. Besides the canonical Smad signaling pathway, the noncanonical PI3K/Akt and MAPK pathway also contributed to TGF-β2-induced up-regulation of Jagged-1 in RPE cells. Overexpression of Jagged-1 could mimic TGF-β2 induce EMT. Our data suggest that the Jagged-1/Notch signaling pathway plays a critical role in TGF-β2-induced EMT in human RPE cells, and may contribute to the development of PVR and PDR. Inhibition of the Jagged/Notch signaling pathway, therefore, may have therapeutic value in the prevention and treatment of PVR and PDR.

  9. Notch 1 Receptor, Delta 1 Ligand and HES 1 Transcription Factor are Expressed in the Lining Epithelium of Periapical Cysts (Preliminary Study)

    Science.gov (United States)

    Meliou, E; Kerezoudis, NP; Tosios, KI; Kiaris, H

    2010-01-01

    Periapical cyst is a chronic inflammatory disorder of periradicular tissues. The precise pathological mechanisms involved in periapical cyst enlargement remain unclear. Notch signaling is an evolutionarily conserved pathway with a regulatory role in cell fate decisions during development and in carcinogenesis. To date, there are no published data available on the expression of Notch signaling components in periapical cysts or any other jaw cyst. In this immunohistochemical study we have examined the expression of the receptor Notch 1, the ligand Delta 1 and the transcription factor HES 1 in the epithelium of well defined periapical cysts. Immunostaining reaction of Notch 1, Delta 1 and HES 1 was observed in the cytoplasm and/or the cytoplasmic membrane and occasionally in the nucleus in the majority of epithelial cells of all periapical cysts. The present observations indicate that Notch pathway is active in the epithelium of periapical cysts. It can be speculated that activation of epithelial cells of periapical cysts is associated with activation of Notch pathway and imply involvement of this pathway in periapical cyst growth and expansion. PMID:21116324

  10. Fatigue of Chinese railway employees and its influential factors: Structural equation modelling.

    Science.gov (United States)

    Tsao, Liuxing; Chang, Jing; Ma, Liang

    2017-07-01

    Fatigue is an identifiable and preventable cause of accidents in transport operations. Regarding the railway sector, incident logs and simulation studies show that employee fatigue leads to lack of alertness, impaired performance, and occurrence of incidents. China has one of the largest rail systems in the world, and Chinese railway employees work under high fatigue risks; therefore, it is important to assess their fatigue level and find the major factors leading to fatigue. We designed a questionnaire that uses Multidimensional Fatigue Instrument (MFI-20), NASA-TLX and subjective rating of work overtime feelings to assess employee fatigue. The contribution of each influential factor of fatigue was analysed using structural equation modelling. In total, 297 employees from the rail maintenance department and 227 employees from the locomotive department returned valid responses. The average scores and standard deviations for the five subscales of MFI-20, namely General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, and Mental Fatigue, were 2.9 (0.8), 2.8 (0.8), 2.5 (0.8), 2.5 (0.7), and 2.4 (0.8) among the rail maintenance employees and 3.5 (0.8), 3.5 (0.7), 3.3 (0.7), 3.0 (0.6), and 3.1 (0.7), respectively, among the locomotive employees. The fatigue of the locomotive employees was influenced by feelings related to working overtime (standardized r = 0.22) and workload (standardized r = 0.27). The work overtime control and physical working environment significantly influenced subjective feelings (standardized r = -0.25 and 0.47, respectively), while improper work/rest rhythms and an adverse physical working environment significantly increased the workload (standardized r = 0.48 and 0.33, respectively). Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Exploring the contribution of psychosocial factors to fatigue in patients with advanced incurable cancer

    NARCIS (Netherlands)

    Peters, Marlies E. W. J.; Goedendorp, Martine M.; Verhagen, Stans A. H. H. V. M.; van der Graaf, Winette T. A.; Bleijenberg, Gijs

    2014-01-01

    Objective: Fatigue is the most frequently occurring and distressing symptom in patients with advanced cancer, caused by multiple factors. Neither a specific histological diagnosis of malignancy nor the type of anticancer treatment seem to be strongly related to fatigue, which support the idea that o

  12. [Expression changes of Notch and nuclear factor-κB signaling pathways in the rat heart with myocardial infarction].

    Science.gov (United States)

    Jin, J L; Deng, Z T; Lyu, R G; Liu, X H; Wei, J R

    2017-06-24

    Objective: To observe the expression changes of Notch and nuclear factor-κB (NF-κB) signaling pathways in rat myocardium post myocardial infarction. Methods: Myocardial infarction was established by ligation of the left anterior descending coronary artery(MI group), sham rats (similar surgical procedure without coronary artery ligation) served as control, the rats were sacrificed at first week, 4th and 8th week after operation, the non-infarct myocardial tissue in both groups was obtained to detect the mRNA expression of Notch1, Dll4 and Hes1 by RT-PCR, the protein expression of NICD1 was detected by Western blot, the nuclear protein p65 content was detected to reflect the activation degree of NF-κB signaling in the cardiomyocytes. Results: The myocardial mRNA expression of Notch1 in MI group was significantly higher than in control group (1.68±0.35 vs. 0.47±0.12, P0.05). The mRNA expression of Dll4 and Hes1 was similar between the two groups at the three time points. NICD1 protein level was increased at the first week in MI group as compared with control group (1.31±0.33 vs.0.45±0.11, P0.05). For NF-κB activation study, the nuclear protein p65 content was higher at first week, 4th week and 8th week in MI group as compared with respective control groups (0.286±0.052 vs.0.049±0.016 (Pmyocardial infarction. Notch1 and NF-κB signaling pathways are both activated at the first week after myocardial infarction, NF-κB signaling pathway activation after myocardial infarction continues up to 8 weeks. These two signal transduction pathways may thus serve as new targets for future intervention studies to prevent heart failure.

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

    Science.gov (United States)

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

    2017-02-01

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

  14. Fatigue growth of a surface crack in a V-shaped notched round bar under cyclic tension%反复张力下V形切口圆条的表面裂纹的疲劳扩展

    Institute of Scientific and Technical Information of China (English)

    Devi CHANDRA; Judha PURBOLAKSONO; Yusoff NUKMAN; Haw-ling LIEW; Singh RAMESH; Mohsen-abdel HASSAN

    2014-01-01

    This paper presents modeling results for fatigue crack growths of a semi-elliptical surface crack in a V-shaped notched round bar under uniform cyclic tension. All the analyses were carried out by using a software package featuring the boundary element method. The J-integral technique was used to compute the stress intensity factors (SIFs), and the NASGRO crack growth rate was chosen to simulate the fatigue crack growths. Mechanical and fracture properties of AZ-6A-T5 magnesium alloy were used for our analysis. Crack shape evolutions for different crack aspect ratios and the corresponding SIFs may be correlated to study the behavior of crack growths. An unstable crack growth was observed when the evolving crack aspect ratio was between 0.6 and 0.7. Careful consideration should be taken if the cylinder contains a defect which has a straight shape on the crack front or a smaller crack aspect ratio.%研究目的:在相同的反复张力下,研究V形切口圆条表面裂纹的疲劳扩展规律。  研究方法:1.构建V形切口圆条模型(图1),基于线性二次元将模型表面离散成一个个网格点(图2);2.以AZ-6A-T5镁合金为例,利用J积分计算应力强度因数,利用NASGRO裂纹增长率模拟裂纹的疲劳扩展;3.通过研究不同的裂纹纵横比和对应的应力强度因数之间的相关性来研究裂纹的扩展。  重要结论:1.在裂纹扩展时裂纹纵横比的初始值对断裂形状的发展有重要影响;2.裂纹纵横比对疲劳负荷寿命的作用比缺口半径更加明显;3.当裂纹前缘演变成一条直线形时可观察到不稳定的裂纹扩展;4.裂纹深度一定时,断裂纵横比越小,疲劳负荷寿命越短;5.当裂纹纵横比为0.6-0.7时,出现了不稳定的裂纹扩展。

  15. Factors that affect the fatigue strength of power transmission shafting and their impact on design

    Science.gov (United States)

    Leowenthal, S. H.

    1986-01-01

    A long standing objective in the design of power transmission shafting is to eliminate excess shaft material without compromising operational reliability. A shaft design method is presented which accounts for variable amplitude loading histories and their influence on limited life designs. The effects of combined bending and torsional loading are considered along with a number of application factors known to influence the fatigue strength of shafting materials. Among the factors examined are surface condition, size, stress concentration, residual stress and corrosion fatigue.

  16. Factors Affecting Quality of Life and Fatigue in Gynaecologic Cancer Patients

    Directory of Open Access Journals (Sweden)

    Güngör İ

    2017-06-01

    Full Text Available Background: Cancer-related fatigue (CRF is the most commonly reported and most distressing symptom in cancer patients. Health-related quality of life (QOL is an important outcome in cancer management, the authors sought to better understand its determinants. Aim: This study aims to identify quality of life and fatigue levels and the affecting factors in gynaecologic cancer patients. Method: This descriptive and cross-sectional study was conducted with 154 volunteer women with gynaecologic cancer. The data were collected through the interview form, functional assessment of cancer therapy-general (FACT-G Quality of Life Scale, and Piper Fatigue Scale. Results: The mean score of total quality of life in gynaecologic cancer patients was low, 53.4 ± 15.4. Physical and emotional states were found to be the mostly affected states in the quality of life. According to the Piper Fatigue Scale, the total fatigue score was mild, 3.5 ± 2.4. Total fatigue scores were found to be high in metastatic cancers. Multivariate analyses indicate that the most important factor affecting the quality of life is economic condition, and the most important variables affecting fatigue are the level of activity and use of medicine. Conclusion: This study found that quality of life dimensions in women with gynaecologic cancer was affected by factors such as cancer type, time of diagnosis, and stage and spread of the cancer.

  17. Factors influencing healthcare provider respondent fatigue answering a globally administered in-app survey.

    Science.gov (United States)

    O'Reilly-Shah, Vikas N

    2017-01-01

    Respondent fatigue, also known as survey fatigue, is a common problem in the collection of survey data. Factors that are known to influence respondent fatigue include survey length, survey topic, question complexity, and open-ended question type. There is a great deal of interest in understanding the drivers of physician survey responsiveness due to the value of information received from these practitioners. With the recent explosion of mobile smartphone technology, it has been possible to obtain survey data from users of mobile applications (apps) on a question-by-question basis. The author obtained basic demographic survey data as well as survey data related to an anesthesiology-specific drug called sugammadex and leveraged nonresponse rates to examine factors that influenced respondent fatigue. Primary data were collected between December 2015 and February 2017. Surveys and in-app analytics were collected from global users of a mobile anesthesia calculator app. Key independent variables were user country, healthcare provider role, rating of importance of the app to personal practice, length of time in practice, and frequency of app use. Key dependent variable was the metric of respondent fatigue. Provider role and World Bank country income level were predictive of the rate of respondent fatigue for this in-app survey. Importance of the app to the provider and length of time in practice were moderately associated with fatigue. Frequency of app use was not associated. This study focused on a survey with a topic closely related to the subject area of the app. Respondent fatigue rates will likely change dramatically if the topic does not align closely. Although apps may serve as powerful platforms for data collection, responses rates to in-app surveys may differ on the basis of important respondent characteristics. Studies should be carefully designed to mitigate fatigue as well as powered with the understanding of the respondent characteristics that may have higher

  18. Factors influencing healthcare provider respondent fatigue answering a globally administered in-app survey

    Directory of Open Access Journals (Sweden)

    Vikas N. O’Reilly-Shah

    2017-09-01

    Full Text Available Background Respondent fatigue, also known as survey fatigue, is a common problem in the collection of survey data. Factors that are known to influence respondent fatigue include survey length, survey topic, question complexity, and open-ended question type. There is a great deal of interest in understanding the drivers of physician survey responsiveness due to the value of information received from these practitioners. With the recent explosion of mobile smartphone technology, it has been possible to obtain survey data from users of mobile applications (apps on a question-by-question basis. The author obtained basic demographic survey data as well as survey data related to an anesthesiology-specific drug called sugammadex and leveraged nonresponse rates to examine factors that influenced respondent fatigue. Methods Primary data were collected between December 2015 and February 2017. Surveys and in-app analytics were collected from global users of a mobile anesthesia calculator app. Key independent variables were user country, healthcare provider role, rating of importance of the app to personal practice, length of time in practice, and frequency of app use. Key dependent variable was the metric of respondent fatigue. Results Provider role and World Bank country income level were predictive of the rate of respondent fatigue for this in-app survey. Importance of the app to the provider and length of time in practice were moderately associated with fatigue. Frequency of app use was not associated. This study focused on a survey with a topic closely related to the subject area of the app. Respondent fatigue rates will likely change dramatically if the topic does not align closely. Discussion Although apps may serve as powerful platforms for data collection, responses rates to in-app surveys may differ on the basis of important respondent characteristics. Studies should be carefully designed to mitigate fatigue as well as powered with the

  19. Notch Antennas

    Science.gov (United States)

    Lee, Richard Q.

    2004-01-01

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

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

    OpenAIRE

    2015-01-01

    Notch receptors play an essential role in the regulation of central cellular processes during embryonic and postnatal development. The mammalian genome encodes for four Notch paralogs (Notch 1–4), which are activated by three Delta-like (Dll1/3/4) and two Serrate-like (Jagged1/2) ligands. Further, non-canonical Notch ligands such as epidermal growth factor like protein 7 (EGFL7) have been identified and serve mostly as antagonists of Notch signaling. The Notch pathway prevents neuronal differ...

  1. The bHLH transcription factor Ascl1a is essential for the specification of the intestinal secretory cells and mediates Notch signaling in the zebrafish intestine.

    Science.gov (United States)

    Flasse, Lydie C; Stern, David G; Pirson, Justine L; Manfroid, Isabelle; Peers, Bernard; Voz, Marianne L

    2013-04-15

    Notch signaling has a fundamental role in stem cell maintenance and in cell fate choice in the intestine of different species. Canonically, Notch signaling represses the expression of transcription factors of the achaete-scute like (ASCL) or atonal related protein (ARP) families. Identifying the ARP/ASCL genes expressed in the gastrointestinal tract is essential to build the regulatory cascade controlling the differentiation of gastrointestinal progenitors into the different intestinal cell types. The expression of the ARP/ASCL factors was analyzed in zebrafish to identify, among all the ARP/ASCL factors found in the zebrafish genome, those expressed in the gastrointestinal tract. ascl1a was found to be the earliest factor detected in the intestine. Loss-of-function analyses using the pia/ascl1a mutant, revealed that ascl1a is crucial for the differentiation of all secretory cells. Furthermore, we identify a battery of transcription factors expressed during secretory cell differentiation and downstream of ascl1a. Finally, we show that the repression of secretory cell fate by Notch signaling is mediated by the inhibition of ascl1a expression. In conclusion, this work identifies Ascl1a as a key regulator of the secretory cell lineage in the zebrafish intestine, playing the same role as Atoh1 in the mouse intestine. This highlights the diversity in the ARP/ASCL family members acting as cell fate determinants downstream from Notch signaling. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Common and unique associated factors for medically unexplained chronic widespread pain and chronic fatigue.

    Science.gov (United States)

    McBeth, J; Tomenson, B; Chew-Graham, C A; Macfarlane, G J; Jackson, J; Littlewood, A; Creed, F H

    2015-12-01

    Chronic widespread pain and chronic fatigue share common associated factors but these associations may be explained by the presence of concurrent depression and anxiety. We mailed questionnaires to a randomly selected sample of people in the UK to identify participants with chronic widespread pain (ACR 1990 definition) and those with chronic fatigue. The questionnaire assessed sociodemographic factors, health status, healthcare use, childhood factors, adult attachment, and psychological stress including anxiety and depression. To identify persons with unexplained chronic widespread pain or unexplained chronic fatigue; we examined participant's medical records to exclude medical illness that might cause these symptoms. Of 1443 participants (58.0% response rate) medical records of 990 were examined. 9.4% (N=93) had unexplained chronic widespread pain and 12.6% (N=125) had unexplained chronic fatigue. Marital status, childhood psychological abuse, recent threatening experiences and other somatic symptoms were commonly associated with both widespread pain and fatigue. No common effect was found for few years of education and current medical illnesses (more strongly associated with chronic widespread pain) or recent illness in a close relative, neuroticism, depression and anxiety scores (more strongly associated with chronic fatigue). Putative associated factors with a common effect were associated with unexplained chronic widespread pain or unexplained chronic fatigue only when there was concurrent anxiety and/or depression. This study suggests that the associated factors for chronic widespread pain and chronic fatigue need to be studied in conjunction with concurrent depression/anxiety. Clinicians should be aware of the importance of concurrent anxiety or depression. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Notch filter

    Science.gov (United States)

    Shelton, G. B. (Inventor)

    1977-01-01

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

  4. Assessment of fatigue life for a crack emanated from a notch. ; Algorithm of fatigue life assessment by [delta]K[sub RP] approach without distinguishing between the crack Initiaion and the propagation. Kirikakitei kara hasseisuru bishi bisho kiretsu no hiro kiretsu jumyo hyokaho ni tsuite. ; Hassei to denpa no toitsu riron ni yoru jumyo yosoku no algorithm (RPG kijun ni yoru hiro kiretsu denpa kyodo no kenkyu)

    Energy Technology Data Exchange (ETDEWEB)

    Toyosada, M.; Niwa, T. (Kyushu University, Fukuoka (Japan). Faculty of Engineering)

    1993-08-01

    Fatigue life has been estimated as a sum of crack initiation life and crack propagation life, by using a fracture dynamical method. In order to make the method more reliable, a method is being discussed to estimate a growth curve for fatigue cracks from notch bottom under a unified theoretical system without a need of introducing the presence of initial cracks. Subsequently to the previous report, this paper describes a fatigue test that uses CT test pieces with the notch bottom finished in arc, an investigation on initiation and propagation behaviors of micro cracks, and discussions on their possibilities. From a large number of findings obtained, an algorithm was proposed to estimate the crack growth curve in approximation. The proposal was made by introducing a hypothesis that the growth of compressed plastic region is restricted by such a barrier as crystal particle boundaries until a developed crack can reach the first crystal particle boundary when the effective loading is maintained constant. The estimated curves and the experimental results have agreed well with each other. Stagnating crack phenomenon at a notch bottom and coaxing effect were explained qualitatively. 30 refs., 24 figs.

  5. Clinically Significant Fatigue: Prevalence and Associated Factors in an International Sample of Adults with Multiple Sclerosis Recruited via the Internet

    OpenAIRE

    Weiland, Tracey J.; Jelinek, George A.; Claudia H. Marck; Emily J Hadgkiss; van der Meer, Dania M.; Pereira, Naresh G.; Taylor, Keryn L.

    2015-01-01

    Background Fatigue contributes a significant burden of disease for people with multiple sclerosis (PwMS). Modifiable lifestyle factors have been recognized as having a role in a range of morbidity outcomes in PwMS. There is significant potential to prevent and treat fatigue in PwMS by addressing modifiable risk factors. Objectives To explore the associations between clinically significant fatigue and demographic factors, clinical factors (health-related quality of life, disability and relapse...

  6. All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells: ROLE OF NOTCH1 AND TRANSFORMING GROWTH FACTOR (TGFβ).

    Science.gov (United States)

    Zanetti, Adriana; Affatato, Roberta; Centritto, Floriana; Fratelli, Maddalena; Kurosaki, Mami; Barzago, Maria Monica; Bolis, Marco; Terao, Mineko; Garattini, Enrico; Paroni, Gabriela

    2015-07-17

    All-trans-retinoic acid (ATRA) is a natural compound proposed for the treatment/chemoprevention of breast cancer. Increasing evidence indicates that aberrant regulation of epithelial-to-mesenchymal transition (EMT) is a determinant of the cancer cell invasive and metastatic behavior. The effects of ATRA on EMT are largely unknown. In HER2-positive SKBR3 and UACC812 cells, showing co-amplification of the ERBB2 and RARA genes, ATRA activates a RARα-dependent epithelial differentiation program. In SKBR3 cells, this causes the formation/reorganization of adherens and tight junctions. Epithelial differentiation and augmented cell-cell contacts underlie the anti-migratory action exerted by the retinoid in cells exposed to the EMT-inducing factors EGF and heregulin-β1. Down-regulation of NOTCH1, an emerging EMT modulator, is involved in the inhibition of motility by ATRA. Indeed, the retinoid blocks NOTCH1 up-regulation by EGF and/or heregulin-β1. Pharmacological inhibition of γ-secretase and NOTCH1 processing also abrogates SKBR3 cell migration. Stimulation of TGFβ contributes to the anti-migratory effect of ATRA. The retinoid switches TGFβ from an EMT-inducing and pro-migratory determinant to an anti-migratory mediator. Inhibition of the NOTCH1 pathway not only plays a role in the anti-migratory action of ATRA; it is relevant also for the anti-proliferative activity of the retinoid in HCC1599 breast cancer cells, which are addicted to NOTCH1 for growth/viability. This effect is enhanced by the combination of ATRA and the γ-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-l-alanyl)-S-phenylglycine t-butyl ester, supporting the concept that the two compounds act at the transcriptional and post-translational levels along the NOTCH1 pathway.

  7. Notch1 induces cell cycle arrest and apoptosis in human cervical cancer cells : involvement of nuclear factor kappa B inhibition

    NARCIS (Netherlands)

    Yao, J.; Duan, L.; Fan, M.; Yuan, J.; Wu, X.

    2007-01-01

    Notch signaling can serve as a tumor suppressor or tumor promoter in the same kind of cancer, such as human papillomavirus-positive cervical cancer cells. However, the exact mechanisms remain poorly characterized. Our studies demonstrated that constitutively overexpressed active Notch1 via stable tr

  8. Notch1 induces cell cycle arrest and apoptosis in human cervical cancer cells : involvement of nuclear factor kappa B inhibition

    NARCIS (Netherlands)

    Yao, J.; Duan, L.; Fan, M.; Yuan, J.; Wu, X.

    2007-01-01

    Notch signaling can serve as a tumor suppressor or tumor promoter in the same kind of cancer, such as human papillomavirus-positive cervical cancer cells. However, the exact mechanisms remain poorly characterized. Our studies demonstrated that constitutively overexpressed active Notch1 via stable tr

  9. Residual fatigue strength of 48MnV crankshaft based on safety factor

    Institute of Scientific and Technical Information of China (English)

    WANG Xiang; CHEN Ming; PU Geng-qiang; WANG Cheng-tao

    2005-01-01

    Residual fatigue strength of 48MnV crankshaft was studied and analyzed based on safety factor. Three different status crankshafts were used to the hop-up tests, which maintain new after 500 h hop-up tests and after 1 000 h hop-up tests. Then, crankshafts were cut into unit cranks. The unit cranks were used to do endurance bending tests to get the residual fatigue strength. Finally, the results were analyzed based on safety factor. The results show that safety factor of crankshaft descends a little with the increase of the running time, and the residual safety factor is still much bigger than the endurable safety factor. Furthermore, after the crankshaft accomplishes a full life cycle, the residual fatigue strength of the crankshaft is enough to remanufacture and fulfill the next life cycle.

  10. RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth.

    Science.gov (United States)

    Gunnell, Andrea; Webb, Helen M; Wood, C David; McClellan, Michael J; Wichaidit, Billy; Kempkes, Bettina; Jenner, Richard G; Osborne, Cameron; Farrell, Paul J; West, Michelle J

    2016-06-02

    In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a -97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (-139 to -250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type-specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth.

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  13. Association of fatigue and depression with circulating levels of proinflammatory cytokines and epidermal growth factor receptor ligands: a correlative study of a placebo-controlled fatigue trial

    Science.gov (United States)

    Rich, Tyvin; Zhao, Fengmin; Cruciani, Ricardo A; Cella, David; Manola, Judith; Fisch, Michael J

    2017-01-01

    Context The biology of fatigue and depression in cancer patients is poorly understood. Hypotheses regarding cytokines and growth factors related to sickness behavior and disruption of circadian signaling have been proposed. Objectives We prospectively examined proinflammatory cytokines (e.g., sickness behavior model) and epidermal growth factor receptor (EGFR) ligands (e.g., circadian disruption model) in the serum of cancer patients enrolled in a clinical trial testing levocarnitine for fatigue. Methods Serum samples were collected at baseline and week 4. Cytokine/growth factor analyses were performed with a Luminex analyzer. The Brief Fatigue Index and the Center for Epidemiologic Studies Depression Index were used to measure fatigue and depression severity. The association between cytokine and symptoms was examined using logistic models. Results Among 101 analyzable patients, all ten cytokines/growth factors examined were highly elevated at baseline and all significantly decreased at week 4 (pfatigue significantly increased for patients with higher level of interleukin-1 receptor antagonist (IL-1Ra), whereas patients with higher levels of IL-1Ra, tumor necrosis factor-α, interleukin (IL)-6, IL-8, interferon-γ, transforming growth factor α, and vascular endothelial growth factor had higher odds of severe depression. At week 4, fatigue (p=0.023) and depression (p=0.007) responders had less decrease in IL-1 level than the corresponding non-responders. Conclusion In this correlative analysis of a fatigue clinical trial, levels of fatigue were significantly associated with levels of IL-1 and IL-1Ra. Circadian-signaling pathways related to EGFR signaling were correlated with depression as were other cytokines. A major placebo effect was associated with a global decrease in cytokine and growth factors. These data provide further basis for testing hypotheses regarding the mechanisms of fatigue and depression in cancer patients.

  14. Factors that influence the development of compassion fatigue, burnout, and compassion satisfaction in emergency department nurses.

    Science.gov (United States)

    Hunsaker, Stacie; Chen, Hsiu-Chin; Maughan, Dale; Heaston, Sondra

    2015-03-01

    The purpose of this study was twofold: (a) to determine the prevalence of compassion satisfaction, compassion fatigue, and burnout in emergency department nurses throughout the United States and (b) to examine which demographic and work-related components affect the development of compassion satisfaction, compassion fatigue, and burnout in this nursing specialty. This was a nonexperimental, descriptive, and predictive study using a self-administered survey. Survey packets including a demographic questionnaire and the Professional Quality of Life Scale version 5 (ProQOL 5) were mailed to 1,000 selected emergency nurses throughout the United States. The ProQOL 5 scale was used to measure the prevalence of compassion satisfaction, compassion fatigue, and burnout among emergency department nurses. Multiple regression using stepwise solution was employed to determine which variables of demographics and work-related characteristics predicted the prevalence of compassion satisfaction, compassion fatigue, and burnout. The α level was set at .05 for statistical significance. The results revealed overall low to average levels of compassion fatigue and burnout and generally average to high levels of compassion satisfaction among this group of emergency department nurses. The low level of manager support was a significant predictor of higher levels of burnout and compassion fatigue among emergency department nurses, while a high level of manager support contributed to a higher level of compassion satisfaction. The results may serve to help distinguish elements in emergency department nurses' work and life that are related to compassion satisfaction and may identify factors associated with higher levels of compassion fatigue and burnout. Improving recognition and awareness of compassion satisfaction, compassion fatigue, and burnout among emergency department nurses may prevent emotional exhaustion and help identify interventions that will help nurses remain empathetic and

  15. Concepts for estimating the fatigue strength of sintered steel components

    Directory of Open Access Journals (Sweden)

    Götz Sebastian

    2014-06-01

    Full Text Available The fatigue notch effect can be estimated using fracture mechanics-based support factors. Stress intensity factors for cracks in notches must therefore be calculated. There is a problem of transferability when 2D reference geometries are used for this. This can be avoided when modelling 3D cracks in the notch of the actual part to be assessed. This is more laborious, but leads to better results, which will be shown in this presentation. The questions of aspect ratio and to point on the crack front, where stresses are evaluated, will be discussed. The approach is validated using a broad database of different sintered steels. The statistical evaluation shows an almost exact prediction of the mean value with a relatively small scatter.

  16. Fatigue Crack Growth Analysis Under Spectrum Loading in Various Environmental Conditions

    Science.gov (United States)

    Mikheevskiy, S.; Glinka, G.; Lee, E.

    2013-03-01

    The fatigue process consists, from the engineering point of view, of three stages: crack initiation, fatigue crack growth, and the final failure. It is also known that the fatigue process near notches and cracks is governed by local strains and stresses in the regions of maximum stress and strain concentrations. Therefore, the fatigue crack growth can be considered as a process of successive crack increments, and the fatigue crack initiation and subsequent growth can be modeled as one repetitive process. The assumptions mentioned above were used to derive a fatigue crack growth model based, called later as the UniGrow model, on the analysis of cyclic elastic-plastic stresses-strains near the crack tip. The fatigue crack growth rate was determined by simulating the cyclic stress-strain response in the material volume adjacent to the crack tip and calculating the accumulated fatigue damage in a manner similar to fatigue analysis of stationary notches. The fatigue crack growth driving force was derived on the basis of the stress and strain history at the crack tip and the Smith-Watson-Topper (SWT) fatigue damage parameter, D = σmaxΔɛ/2. It was subsequently found that the fatigue crack growth was controlled by a two-parameter driving force in the form of a weighted product of the stress intensity range and the maximum stress intensity factor, Δ K p K {max/1- p }. The effect of the internal (residual) stress induced by the reversed cyclic plasticity has been accounted for and therefore the two-parameter driving force made it possible to predict the effect of the mean stress including the influence of the applied compressive stress, tensile overloads, and variable amplitude spectrum loading. It allows estimating the fatigue life under variable amplitude loading without using crack closure concepts. Several experimental fatigue crack growth datasets obtained for the Al 7075 aluminum alloy were used for the verification of the proposed unified fatigue crack growth

  17. Risk factors and visual fatigue of baggage X-ray security screeners: a structural equation modelling analysis.

    Science.gov (United States)

    Yu, Rui-Feng; Yang, Lin-Dong; Wu, Xin

    2016-06-03

    This study identified the risk factors influencing visual fatigue in baggage X-ray security screeners and estimated the strength of correlations between those factors and visual fatigue using structural equation modelling approach. Two hundred and five X-ray security screeners participated in a questionnaire survey. The result showed that satisfaction with the VDT's physical features and the work environment conditions were negatively correlated with the intensity of visual fatigue, whereas job stress and job burnout had direct positive influences. The path coefficient between the image quality of VDT and visual fatigue was not significant. The total effects of job burnout, job stress, the VDT's physical features and the work environment conditions on visual fatigue were 0.471, 0.469, -0.268 and -0.251 respectively. These findings indicated that both extrinsic factors relating to VDT and workplace environment and psychological factors including job burnout and job stress should be considered in the workplace design and work organisation of security screening tasks to reduce screeners' visual fatigue. Practitioner Summary: This study identified the risk factors influencing visual fatigue in baggage X-ray security screeners and estimated the strength of correlations between those factors and visual fatigue. The findings were of great importance to the workplace design and the work organisation of security screening tasks to reduce screeners' visual fatigue.

  18. The prevalence of fatigue and associated health and safety risk factors among taxi drivers in Singapore.

    Science.gov (United States)

    Lim, See Ming; Chia, Sin Eng

    2015-02-01

    Driver fatigue is one of the biggest health and safety concerns within the road transport sector. This study aimed to find out the prevalence of fatigue among taxi drivers in Singapore, to better understand the general working and health conditions of this group of people and to determine the risk factors associated with fatigued driving. A total of 340 taxi drivers were randomly selected for participation in this self-administered questionnaire survey, with height and weight measurements. The response rate was 68.2%. The survey consisted of four main categories: personal particulars; social habits; work patterns and sleep profile; and Epworth Sleepiness Scale, which was used to estimate the level of daytime sleepiness and fatigue. Multiple logistic regression analysis was used to estimate the adjusted odd ratios and 95% confidence intervals associated with the risk factors related to fatigue among the taxi drivers. A high proportion of the taxi drivers were obese and had self-reported hypertension, diabetes mellitus and high cholesterol. Driver fatigue was associated with very poor/poor self-rating of the quality of sleep, having an additional part-time job, drinking three or more caffeinated drinks daily, and driving more than 10 hours a day. We hope that the findings of the present study will improve the awareness regarding the work and health conditions of taxi drivers, and contribute toward the effort to achieve a healthier workforce. A lower prevalence of fatigued driving will lead to lower risks of road traffic accidents, decreased economic loss, increased productivity, and safer roads for all.

  19. Electroacupuncture Pretreatment Attenuates Cerebral Ischemic Injury via Notch Pathway-Mediated Up-Regulation of Hypoxia Inducible Factor-1α in Rats.

    Science.gov (United States)

    Zhao, Yu; Deng, Bin; Li, Yichong; Zhou, Lihua; Yang, Lei; Gou, Xingchun; Wang, Qiang; Chen, Guozhong; Xu, Hao; Xu, Lixian

    2015-11-01

    We have reported electroacupuncture (EA) pretreatment induced the tolerance against focal cerebral ischemia through activation of canonical Notch pathway. However, the underlying mechanisms have not been fully understood. Evidences suggest that up-regulation of hypoxia inducible factor-1α (HIF-1α) contributes to neuroprotection against ischemia which could interact with Notch signaling pathway in this process. Therefore, the current study is to test that up-regulation of HIF-1α associated with Notch pathway contributes to the neuroprotection of EA pretreatment. Sprague-Dawley rats were treated with EA at the acupoint "Baihui (GV 20)" 30 min per day for successive 5 days before MCAO. HIF-1α levels were measured before and after reperfusion. Then, HIF-1α antagonist 2ME2 and γ-secretase inhibitor MW167 were used. Neurologic deficit scores, infarction volumes, neuronal apoptosis, and Bcl2/Bax were evaluated. HIF-1α and Notch1 intracellular domain (NICD) were assessed. The results showed EA pretreatment enhanced the neuronal expression of HIF-1α, reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis, up-regulated expression of Bcl-2, and down-regulated expression of Bax after reperfusion in the penumbra, while the beneficial effects were attenuated by 2ME2. Furthermore, intraventricular injection with MW167 efficiently suppressed both up-regulation of NICD and HIF-1α after reperfusion. However, administration with 2ME2 could only decrease the expression of HIF-1α in the penumbra. In conclusion, EA pretreatment exerts neuroprotection against ischemic injury through Notch pathway-mediated up-regulation of HIF-1α.

  20. Probabilistic Calibration of Fatigue Design Factors for Offshore Wind Turbine Support Structures

    DEFF Research Database (Denmark)

    Ramirez, José Rangel; Sørensen, John Dalsgaard

    2010-01-01

    This paper describes a reliability-based approach to determine fatigue design factors (FDF) for offshore wind turbine support structures made of steel. The FDF values are calibrated to a specific reliability level and linked to a specific inspection and maintenance (I&M) strategy used for the con......This paper describes a reliability-based approach to determine fatigue design factors (FDF) for offshore wind turbine support structures made of steel. The FDF values are calibrated to a specific reliability level and linked to a specific inspection and maintenance (I&M) strategy used...... for the considered offshore wind turbines in such a way that the specific uncertainties for the fatigue life are accounted in a rational manner. Similar approaches have been used for offshore oil & gas sub-structures, but the required reliability level for offshore wind turbines is generally lower and the fatigue...... if inspections are planned during the design life, and thereby the basis is available for selecting a cost-effective fatigue design. Further, the results can be used as basis for recommendations in standardization....

  1. Bending-fatigue damage-detection on notched-tooth spiral-bevel gears using the average-log-ratio, ALR, algorithm

    Science.gov (United States)

    Hines, Jason A.; Mark, William D.

    2014-02-01

    The frequency-domain ALR (average-log-ratio) damage-detection algorithm [MSSP 24 (2010) 2807-2823] is utilized to illustrate damage detection and progression on notched-tooth spiral-bevel gears. Use of equal weighting of increases or decreases of individual rotational-harmonic amplitudes caused by damage, for early ALR detections, is substantiated. Continuously improving statistical reliability of ALR is documented by using increasing numbers of rotational-harmonic amplitude-ratios and increasing numbers of waveforms in the synchronous averaging. Sensitivity of the ALR algorithm to incipient damage is observed to be comparable to that obtained from the kurtosis-based Figure of Merit 4 (FM4). In contrast to FM4, ALR is shown to monotonically increase with increasing damage and running time. Interestingly, this diagnostic technique can be implemented with remarkably low analog-to-digital conversion rates. Computation of ALR for differing torque levels shows strong indications of weakening tooth-stiffness and increasing tooth-plastic-deformation. ALR computation utilizing tooth-rotational-location windowing also is illustrated.

  2. Subgrouping of rheumatoid arthritis patients based on pain, fatigue, inflammation and psychosocial factors

    Science.gov (United States)

    Lee, Yvonne C.; Frits, Michelle L.; Iannaccone, Christine K.; Weinblatt, Michael E.; Shadick, Nancy A.; Williams, David A.; Cui, Jing

    2014-01-01

    Objective Among rheumatoid arthritis (RA) patients, pain may be due to peripheral inflammation or other causes, such as central pain mechanisms. The objective was to use self-report measures and physical examination to identify clusters of RA patients who may have different causes of pain and different prognoses and treatment options. Methods Data were analyzed from 169 RA patients in the Brigham Rheumatoid Arthritis Sequential Study who had pain > 0/10 and completed questionnaires on pain, fatigue and psychosocial factors. A hierarchical agglomerative clustering procedure with Ward’s method was used to obtain subgroups. Multivariate analysis of variance was used to determine the contribution of each variable in a cluster. General linear regression models were used to examine differences in clinical characteristics across subgroups. Discriminant analyses were performed to determine coefficients for linear combinations of variables that assigned cluster membership to individual cases. Results Three clusters best fit these data. Cluster 1 consisted of 89 individuals with low inflammation, pain, fatigue and psychosocial distress. Cluster 2 consisted of 57 individuals with minimal inflammation but high pain, fatigue and psychosocial distress. Cluster 3 consisted of 23 individuals with active inflammatory disease, manifested by high joint counts, high C-reactive protein and high pain and fatigue. Conclusion Although most patients had low levels of inflammation, pain and fatigue, 47.3% continued to report moderate to high pain and fatigue. Most of these patients had minimal signs of inflammation but high levels of fatigue, pain catastrophizing and sleep disturbance, indicative of a chronic widespread pain syndrome. PMID:24782222

  3. Female gender is a risk factor for pain, discomfort, and fatigue after laparoscopic groin hernia repair

    DEFF Research Database (Denmark)

    Strandfelt, P; Tolver, M A; Rosenberg, Jacob;

    2013-01-01

    Female gender is a risk factor for early pain after several specific surgical procedures but has not been studied in detail after laparoscopic groin hernia repair. The aim of this study was to compare early postoperative pain, discomfort, fatigue, and nausea and vomiting between genders undergoing...

  4. Risk Factors for Persistent Fatigue With Significant School Absence in Children and Adolescents

    NARCIS (Netherlands)

    Bakker, Robert J.; van de Putte, Elise M.; Kuis, Wietse; Sinnema, Gerben

    2009-01-01

    OBJECTIVE: To assess children and adolescents with severe fatigue who are referred to pediatricians and to examine whether factors can be identified at their first visit that predict worse outcomes at 1 year. METHODS: Ninety-one patients, aged 8 to 18 years completed questionnaires about sleep, soma

  5. Probabilistic Calibration of Fatigue Design Factors for Offshore Wind Turbine Support Structures

    DEFF Research Database (Denmark)

    Ramirez, José Rangel; Sørensen, John Dalsgaard

    2010-01-01

    This paper describes a reliability-based approach to determine fatigue design factors (FDF) for offshore wind turbine support structures made of steel. The FDF values are calibrated to a specific reliability level and linked to a specific inspection and maintenance (I&M) strategy used for the con...

  6. Factor analysis of the Revised Piper Fatigue Scale in a caregiver sample.

    Science.gov (United States)

    Clark, Patricia C; Ashford, Susan; Burt, Rachel; Aycock, Dawn M; Kimble, Laura P

    2006-01-01

    The Revised Piper Fatigue Scale (R-PFS) is an instrument designed to measure subjective fatigue that was developed in samples with physical illness. Its psychometric properties in nonclinical samples are unknown. The purpose of this study was to examine the psychometric properties of the R-PFS in a sample of caregivers of stroke survivors. The convenience sample of 132 caregivers was primarily women (74%), White (71%), college-educated (73%), and employed (52%), with a mean age of 56.7 years (SD = 13.71). Internal consistency reliabilities for the four R-PFS subscales and the total scale were excellent, ranging from .90 to .97. Principal axis factor analysis with oblique rotation was conducted to examine construct validity of the R-PFS. A three-factor solution explained 75.9% of the common variance. Two factors totally replicated the behavioral/severity and affective meaning subscales of the R-PFS. The third factor incorporated a combination of Piper's sensory and cognitive/mood subscales and appeared to summarize how fatigue makes the caregiver feel. The R-PFS demonstrated strong internal consistency reliability and construct validity in this sample. However, data suggest that caregivers may perceive certain feelings associated with fatigue as conceptually similar when these feelings are conceptually distinct in Piper's breast cancer sample. The study supports the need for psychometric evaluation of instruments developed in clinical populations prior to their use in nonclinical populations.

  7. FACTORS AFFECTING FATIGUE CRACK GROWTH RATES OF FIBER REINFORCED METAL LAMINATES

    Institute of Scientific and Technical Information of China (English)

    1998-01-01

    Based upon an analytical model for predicting the crack growth in fiber reinforced metal laminates (FRMLs), some factors affecting the fatigue crack growth rates of FRMLs were analyzed, including the lay-up of FRMLs, the modulus of the fibers, the residual stresses in FRMLs, the bonding strength and the shear modulus of the adhesive, etc.It was shown from the present analysis that the interface number of the laminates, the modulus of the fibers and the residual stresses in FRMLs have very great effects on the fatigue lives of FRMLs, but the effects of the bonding strength and the shear modulus of the adhesive are relatively small.

  8. Research on the Factors of Fatigue of Coal Mine Workers and Its Control Measures

    Directory of Open Access Journals (Sweden)

    Zhang Jing-Gang

    2013-07-01

    Full Text Available China is the largest coal producer in the world, it play a important role in the international field of coal production, but due to the frequent occurrence of coal mining accidents, it cause a enormous damage to the state's manpower and material resources. This article on research of the cause of the coal mining accident, it describes the fatigue of the coal mine workers assignment is the main cause of the accident and the threat to the safety of workers, and points out the important factors in ergonomics. MMEC theory is introduced and using for reference MMEC theory, finding out influence the cause of the coal mine worker fatigue, and combined with the relevant laws and regulations system to control and reduce the proposed method of coal mine worker fatigue to reduce and prevent the occurrence of coal mine accidents have some guidance Significance.

  9. Fatigue reliability and calibration of fatigue design factors of wave energy converters

    DEFF Research Database (Denmark)

    Ambühl, Simon; Ferri, Francesco; Kofoed, Jens Peter

    2015-01-01

    Target reliability levels, which are chosen dependent on the consequences in case of structural collapse, are used in this paper to calibrate partial safety factors for structural details of wave energy converters (WECs). The consequences in case of structural failure are similar for WECs...... and offshore wind turbines (no fatalities, low environmental pollution). Therefore, it can be assumed that the target reliability levels for WEC applications can be overtaken from offshore wind turbine studies. The partial safety factors cannot be directly overtaken from offshore wind turbines because the load...... is considered in order to extend and maintain a certain target safety level. This paper uses the Wavestar prototype located at Hanstholm (DK) as case study in order to calibrate FDFs for welded and bolted details in steel structures of an offshore bottom-fixed WEC with hydraulic floaters....

  10. Notch, lipids, and endothelial cells

    Science.gov (United States)

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

    2017-01-01

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

  11. Surface Irregularity Factor as a Parameter to Evaluate the Fatigue Damage State of CFRP

    Directory of Open Access Journals (Sweden)

    Pablo Zuluaga-Ramírez

    2015-11-01

    Full Text Available This work presents an optical non-contact technique to evaluate the fatigue damage state of CFRP structures measuring the irregularity factor of the surface. This factor includes information about surface topology and can be measured easily on field, by techniques such as optical perfilometers. The surface irregularity factor has been correlated with stiffness degradation, which is a well-accepted parameter for the evaluation of the fatigue damage state of composite materials. Constant amplitude fatigue loads (CAL and realistic variable amplitude loads (VAL, representative of real in- flight conditions, have been applied to “dog bone” shaped tensile specimens. It has been shown that the measurement of the surface irregularity parameters can be applied to evaluate the damage state of a structure, and that it is independent of the type of fatigue load that has caused the damage. As a result, this measurement technique is applicable for a wide range of inspections of composite material structures, from pressurized tanks with constant amplitude loads, to variable amplitude loaded aeronautical structures such as wings and empennages, up to automotive and other industrial applications.

  12. Epidermal growth factor-like domain 7 promotes migration and invasion of human trophoblast cells through activation of MAPK, PI3K and NOTCH signaling pathways.

    Science.gov (United States)

    Massimiani, M; Vecchione, L; Piccirilli, D; Spitalieri, P; Amati, F; Salvi, S; Ferrazzani, S; Stuhlmann, H; Campagnolo, L

    2015-05-01

    Epidermal growth factor-like domain 7 (Egfl7) is a gene that encodes a partially secreted protein and whose expression is largely restricted to the endothelia. We recently reported that EGFL7 is also expressed by trophoblast cells in mouse and human placentas. Here, we investigated the molecular pathways that are regulated by EGFL7 in trophoblast cells. Stable EGFL7 overexpression in a Jeg3 human choriocarcinoma cell line resulted in significantly increased cell migration and invasiveness, while cell proliferation was unaffected. Analysis of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways showed that EGFL7 promotes Jeg3 cell motility by activating both pathways. We show that EGFL7 activates the epidermal growth factor receptor (EGFR) in Jeg3 cells, resulting in downstream activation of extracellular regulated kinases (ERKs). In addition, we provide evidence that EGFL7-triggered migration of Jeg3 cells involves activation of NOTCH signaling. EGFL7 and NOTCH1 are co-expressed in Jeg3 cells, and blocking of NOTCH activation abrogates enhanced migration of Jeg3 cells overexpressing EGFL7. We also demonstrate that signaling through EGFR and NOTCH converged to mediate EGFL7 effects. Reduction of endogenous EGFL7 expression in Jeg3 cells significantly decreased cell migration. We further confirmed that EGFL7 stimulates cell migration by using primary human first trimester trophoblast (PTB) cells overexpressing EGFL7. In conclusion, our data suggest that in trophoblast cells, EGFL7 regulates cell migration and invasion by activating multiple signaling pathways. Our results provide a possible explanation for the correlation between reduced expression of EGFL7 and inadequate trophoblast invasion observed in placentopathies.

  13. A study of several factors governing the fatigue limits of austempered ductile cast iron with various microstructures

    Science.gov (United States)

    Kim, Jinhak; Kim, Sangtae; Kim, Mingun

    2000-06-01

    The effects the leading factors bearing on fatigue limits were investigated with three kinds of ductile iron specimens various microstructures. As a result of examination, the fatigue limits in relationship to hardness and tensile strength, the expected higher improvement for fatigue limits in the case of the high strength specimens that experienced austempering treatment are not observed in comparison with the specimens treated with stress relief treatment. The estimated maximum defect size is one of the important parameters in predicting and evaluating fatigue limits for three different heat-treated ductile cast irons. Also, a quantitative relationship can be established between the fatigue limit and maximum defect size. Moreover, it is possible to explain the difference in fatigue limits in the three ductile cast irons by application of the rates of non-propagating crack which connects the adjacent graphite nodules before it stops.

  14. NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis.

    Science.gov (United States)

    Weaver, Kelly L; Alves-Guerra, Marie-Clotilde; Jin, Ke; Wang, Zhiqiang; Han, Xiaoqing; Ranganathan, Prathibha; Zhu, Xiaoxia; DaSilva, Thiago; Liu, Wei; Ratti, Francesca; Demarest, Renee M; Tzimas, Cristos; Rice, Meghan; Vasquez-Del Carpio, Rodrigo; Dahmane, Nadia; Robbins, David J; Capobianco, Anthony J

    2014-09-01

    The Notch signaling pathway governs many distinct cellular processes by regulating transcriptional programs. The transcriptional response initiated by Notch is highly cell context dependent, indicating that multiple factors influence Notch target gene selection and activity. However, the mechanism by which Notch drives target gene transcription is not well understood. Herein, we identify and characterize a novel Notch-interacting protein, Notch activation complex kinase (NACK), which acts as a Notch transcriptional coactivator. We show that NACK associates with the Notch transcriptional activation complex on DNA, mediates Notch transcriptional activity, and is required for Notch-mediated tumorigenesis. We demonstrate that Notch1 and NACK are coexpressed during mouse development and that homozygous loss of NACK is embryonic lethal. Finally, we show that NACK is also a Notch target gene, establishing a feed-forward loop. Thus, our data indicate that NACK is a key component of the Notch transcriptional complex and is an essential regulator of Notch-mediated tumorigenesis and development.

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

    Science.gov (United States)

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

    2017-04-01

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

  16. The factors associated with the burnout syndrome and fatigue in Cypriot nurses: a census report

    Science.gov (United States)

    2012-01-01

    Background Fatigue and burnout are two concepts often linked in the literature. However, regardless of their commonalities they should be approached as distinct concepts. The current and ever-growing reforms regarding the delivery of nursing care in Cyprus, stress for the development of ways to prevent burnout and effectively manage fatigue that can result from working in stressful clinical environments. Methods To explore the factors associated with the burnout syndrome in Cypriot nurses working in various clinical departments. A random sampling method taking into account geographical location, specialty and type of employment has been used. Results A total of 1,482 nurses (80.4% were females) working both in the private and public sectors completed and returned an anonymous questionnaire that included several aspects related to burnout; the MBI scale, questions related to occupational stress, and questions pertaining to self reported fatigue. Two-thirds (65.1%) of the nurses believed that their job is stressful with the majority reporting their job as stressful being female nurses (67.7%). Twelve point eight percent of the nurses met Maslach’s criteria for burnout. The prevalence of fatigue in nurses was found 91.9%. The prevalence of fatigue was higher in females (93%) than in males (87.5%) (p = 0.003). As opposed to the burnout prevalence, fatigue prevalence did not differ among the nursing departments (p = 0.166) and among nurses with a different marital status (p = 0.553). Burnout can be associated adequately knowing if nurses find their job stressful, their age, the level of emotional exhaustion and depersonalization. It has been shown that the fatigue may be thought of as a predictor of burnout, but its influence is already accounted by emotional exhaustion and depersonalization. Conclusion The clinical settings in Cyprus appear as stress generating environment for nurses. Nurses working both in the private and public sector appear to

  17. Suppression of Fatigue Crack Propagation of Duralumin by Cavitation Peening

    Directory of Open Access Journals (Sweden)

    Hitoshi Soyama

    2015-08-01

    Full Text Available It was demonstrated in the present paper that cavitation peening which is one of the mechanical surface modification technique can suppress fatigue crack propagation in duralumin. The impacts produced when cavitation bubble collapses can be utilised for the mechanical surface modification technique in the same way as laser peening and shot peening, which is called “cavitation peening”. Cavitation peening employing a cavitating jet in water was used to treat the specimen made of duralumin Japanese Industrial Standards JIS A2017-T3. After introducing a notch, fatigue test was conducted by a load-controlled plate bending fatigue tester, which has been originally developed. The fatigue crack propagation behavior was evaluated and the relationship between the fatigue crack propagation rate versus stress intensity factor range was obtained. From the results, the fatigue crack propagation rate was drastically reduced by cavitation peening and the fatigue life of duralumin plate was extended 4.2 times by cavitation peening. In addition, the fatigue crack propagation can be suppressed by 88% in the stable crack propagation stage by cavitation peening.

  18. The role of psychological factors in oncology nurses' burnout and compassion fatigue symptoms.

    Science.gov (United States)

    Duarte, Joana; Pinto-Gouveia, José

    2017-06-01

    This study explored the role of several psychological factors in professional quality of life in nurses. Specifically, we tried to clarify the relationships between several dimensions of empathy, self-compassion, and psychological inflexibility, and positive (compassion satisfaction) and negative (burnout and compassion fatigue) domains of professional quality of life. Using a cross-sectional design, a convenience sample of 221 oncology nurses recruited from several public hospitals filling out a battery of self-report measures. Results suggested that nurses that benefit more from their work of helping and assisting others (compassion satisfaction) seem to have more empathic feelings and sensibility towards others in distress and make an effort to see things from others' perspective. Also, they are less disturbed by negative feelings associated with seeing others' suffering and are more self-compassionate. Nurses more prone to experience the negative consequences associated with care-providing (burnout and compassion fatigue) are more self-judgmental and have more psychological inflexibility. In addition, they experience more personal feelings of distress when seeing others in suffering and less feelings of empathy and sensibility to others' suffering. Psychological factors explained 26% of compassion satisfaction, 29% of burnout and 18% of compassion fatigue. We discuss the results in terms of the importance of taking into account the role of these psychological factors in oncology nurses' professional quality of life, and of designing nursing education training and interventions aimed at targeting such factors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. The Transport Properties of Concrete under the Simultaneous Coupling of Fatigue Load and Environment Factors

    Institute of Scientific and Technical Information of China (English)

    WANG Caihui; SUN Wei; JING Jinyang; HAN Jiande; RONG Hui

    2012-01-01

    A set of coupling experimental instrument was designed to study the transport properties of chloride ion in concrete under simultaneous coupling action of fatigue load and environmental factors.Firstly the water-saturated performance of modern concrete was investigated,then diffusion performance of chloride ion under different stress levels and different temperature were studied respectively; meanwhile,the timedependent behavior of the chloride ion diffusion in concrete was also researched.The results showed that the saturation degree of concrete can reach as high as 99%.Besides,diffusion coefficient of chloride ion increased with increasing of the stress level and temperature,and when the stress level and temperature are at 0.6 and 60 ℃ respectively,the diffusion coefficient is 6.3 × 10 14 m2/s,moreover the diffusion coefficient of chloride ion in concrete decreased with time under the simultaneous coupling action of fatigue load and environment factors.

  20. Notch in mammary gland development and breast cancer.

    Science.gov (United States)

    Politi, Katerina; Feirt, Nikki; Kitajewski, Jan

    2004-10-01

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

  1. Incorporating mesh-insensitive structural stress into the fatigue assessment procedure of common structural rules for bulk carriers

    Directory of Open Access Journals (Sweden)

    Kim Seong-Min

    2015-01-01

    Full Text Available This study introduces a fatigue assessment procedure using mesh-insensitive structural stress method based on the Common Structural Rules for Bulk Carriers by considering important factors, such as mean stress and thickness effects. The fatigue assessment result of mesh-insensitive structural stress method have been compared with CSR procedure based on equivalent notch stress at major hot spot points in the area near the ballast hold for a 180 K bulk carrier. The possibility of implementing mesh-insensitive structural stress method in the fatigue assessment procedure for ship structures is discussed.

  2. Transcription Factor KLF2 in Dendritic Cells Downregulates Th2 Programming via the HIF-1α/Jagged2/Notch Axis

    Directory of Open Access Journals (Sweden)

    Ye Xiong

    2016-06-01

    Full Text Available The adaptive immune response is tightly regulated by complex signals in dendritic cells (DCs. Although Th2 polarization is dictated by defined functional DC subsets, the molecular factors that govern the amplitude of these responses are not well understood. Kruppel-like factor 2 (KLF2 is a transcription factor that negatively regulates the activation of numerous immune cells in response to stimuli. Here, we demonstrate that suppression of KLF2 in conditioned DCs preferentially amplifies Th2 responses in two model systems, one of which is a prototypical intracellular pathogen and the other an allergen. This elevation in Th2 responses was dependent on contact-mediated Notch signaling in vitro and in vivo. A deficiency of KLF2 increased the expression of Notch ligand Jagged2 via hypoxia-inducible factor 1α (HIF-1α, which led to Th2 amplification. Our results revealed a novel circuit in DCs for Th2 polarization that is governed by KLF2.

  3. Fatigue and related factors among hotel workers: the effects of emotional labor and non-standard working hours.

    Science.gov (United States)

    Lee, Ju Jong; Moon, Hyun Jey; Lee, Kyung-Jae; Kim, Joo Ja

    2014-01-01

    This study assessed fatigue and its association with emotional labor and non-standard working hours among hotel workers. A structured self-administered questionnaire was distributed to 1,320 employees of five hotels located in Seoul. The questionnaire survey included questions concerning the participants' sociodemographics, health-related behaviors, job-related factors, emotional labor, and fatigue. Fatigue was assessed using the Multidimensional Fatigue Scale (MFS). Multiple logistic regression modeling was used to determine the associations between fatigue and emotional labor. Among male workers, there was a significant association between fatigue and both emotional disharmony (OR=5.52, 95% CI=2.35-12.97) and emotional effort (OR=3.48, 95% CI=1.54-7.86). These same associations were seen among the female workers (emotional disharmony: OR=6.91, 95% CI=2.93-16.33; emotional effort: OR=2.28, 95% CI=1.00-5.16). These results indicate that fatigue is associated with emotional labor and, especially, emotional disharmony among hotel workers. Therefore, emotional disharmony management would prove helpful for the prevention of fatigue.

  4. Fatigue assessment of load-carrying welded cruciform joints

    Directory of Open Access Journals (Sweden)

    S.V. Petinov

    2013-04-01

    Full Text Available T-form and cruciform joints in which the stress flow is transferred via weld material are widely applied in welded structures. A special type of these joints is presented by fillet-welded joints with incomplete penetration used by economical and manufacturing reasons. At a certain width of the cavity it becomes an active notch which in current design rules is regarded as an initial crack. In that way, fatigue life of the joint is characterized by the crack extensions towards the outer surface of weld bead. Fatigue assessment of these joints requires reliable data on the stress intensity factors values along the crack path. The results of systematic FEA-based calculations of stress intensity factors and respective S-N curves for the considered welded joints are presented. Main results obtained during this investigation can be used in solution of engineering tasks in reference to the fatigue assessment of welded cruciform joints with incomplete penetration.

  5. Notch Inhibitors for Cancer Treatment

    OpenAIRE

    Espinoza, Ingrid; Miele, Lucio

    2013-01-01

    Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been de...

  6. Increased levels of NOTCH1, NF-kappaB, and other interconnected transcription factors characterize primitive sets of hematopoietic stem cells.

    Science.gov (United States)

    Panepucci, Rodrigo Alexandre; Oliveira, Lucila Habib B; Zanette, Dalila Luciola; Viu Carrara, Rita de Cassia; Araujo, Amélia Goes; Orellana, Maristela Delgado; Bonini de Palma, Patrícia Vianna; Menezes, Camila C B O; Covas, Dimas Tadeu; Zago, Marco Antonio

    2010-03-01

    As previously shown, higher levels of NOTCH1 and increased NF-kappaB signaling is a distinctive feature of the more primitive umbilical cord blood (UCB) CD34+ hematopoietic stem cells (HSCs), as compared to bone marrow (BM). Differences between BM and UCB cell composition also account for this finding. The CD133 marker defines a more primitive cell subset among CD34+ HSC with a proposed hemangioblast potential. To further evaluate the molecular basis related to the more primitive characteristics of UCB and CD133+ HSC, immunomagnetically purified human CD34+ and CD133+ cells from BM and UCB were used on gene expression microarrays studies. UCB CD34+ cells contained a significantly higher proportion of CD133+ cells than BM (70% and 40%, respectively). Cluster analysis showed that BM CD133+ cells grouped with the UCB cells (CD133+ and CD34+) rather than to BM CD34+ cells. Compared with CD34+ cells, CD133+ had a higher expression of many transcription factors (TFs). Promoter analysis on all these TF genes revealed a significantly higher frequency (than expected by chance) of NF-kappaB-binding sites (BS), including potentially novel NF-kappaB targets such as RUNX1, GATA3, and USF1. Selected transcripts of TF related to primitive hematopoiesis and self-renewal, such as RUNX1, GATA3, USF1, TAL1, HOXA9, HOXB4, NOTCH1, RELB, and NFKB2 were evaluated by real-time PCR and were all significantly positively correlated. Taken together, our data indicate the existence of an interconnected transcriptional network characterized by higher levels of NOTCH1, NF-kappaB, and other important TFs on more primitive HSC sets.

  7. Eye movements discriminate fatigue due to chronotypical factors and time spent on task--a double dissociation.

    Directory of Open Access Journals (Sweden)

    Dario Cazzoli

    Full Text Available Systematic differences in circadian rhythmicity are thought to be a substantial factor determining inter-individual differences in fatigue and cognitive performance. The synchronicity effect (when time of testing coincides with the respective circadian peak period seems to play an important role. Eye movements have been shown to be a reliable indicator of fatigue due to sleep deprivation or time spent on cognitive tasks. However, eye movements have not been used so far to investigate the circadian synchronicity effect and the resulting differences in fatigue. The aim of the present study was to assess how different oculomotor parameters in a free visual exploration task are influenced by: a fatigue due to chronotypical factors (being a 'morning type' or an 'evening type'; b fatigue due to the time spent on task. Eighteen healthy participants performed a free visual exploration task of naturalistic pictures while their eye movements were recorded. The task was performed twice, once at their optimal and once at their non-optimal time of the day. Moreover, participants rated their subjective fatigue. The non-optimal time of the day triggered a significant and stable increase in the mean visual fixation duration during the free visual exploration task for both chronotypes. The increase in the mean visual fixation duration correlated with the difference in subjectively perceived fatigue at optimal and non-optimal times of the day. Conversely, the mean saccadic speed significantly and progressively decreased throughout the duration of the task, but was not influenced by the optimal or non-optimal time of the day for both chronotypes. The results suggest that different oculomotor parameters are discriminative for fatigue due to different sources. A decrease in saccadic speed seems to reflect fatigue due to time spent on task, whereas an increase in mean fixation duration a lack of synchronicity between chronotype and time of the day.

  8. NOTCH1 is a poor prognostic factor for breast cancer and is associated with breast cancer stem cells

    OpenAIRE

    Zhong Y; Shen S; Zhou Y.; Mao F; Lin Y; Guan J; Xu Y.; Zhang S.; Liu X; Sun Q.

    2016-01-01

    Ying Zhong,1 Songjie Shen,1 Yidong Zhou,1 Feng Mao,1 Yan Lin,1 Jinghong Guan,1 Yali Xu,1 Shu Zhang,2 Xu Liu,3 Qiang Sun1 1Department of Breast Disease, 2Department of Dermatology, Peking Union Medical College Hospital, 3Centralab Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Abstract: Recently, the human gene NOTCH1 has been found to be implicated in cancer cell metastasis and the maintenance of cancer stem cells. How...

  9. Clinically significant fatigue: prevalence and associated factors in an international sample of adults with multiple sclerosis recruited via the internet.

    Directory of Open Access Journals (Sweden)

    Tracey J Weiland

    Full Text Available Fatigue contributes a significant burden of disease for people with multiple sclerosis (PwMS. Modifiable lifestyle factors have been recognized as having a role in a range of morbidity outcomes in PwMS. There is significant potential to prevent and treat fatigue in PwMS by addressing modifiable risk factors.To explore the associations between clinically significant fatigue and demographic factors, clinical factors (health-related quality of life, disability and relapse rate and modifiable lifestyle, disease-modifying drugs (DMD and supplement use in a large international sample of PwMS.PwMS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic, lifestyle and clinical characteristics, including health-related quality of life, disability, and relapse rate.Of 2469 participants with confirmed MS, 2138 (86.6% completed a validated measure of clinically significant fatigue, the Fatigue Severity Scale. Participants were predominantly female from English speaking countries, with relatively high levels of education, and due to recruitment methods may have been highly pro-active about engaging in lifestyle management and self-help. Approximately two thirds of our sample (1402/2138; 65.6% (95% CI 63.7-67.7 screened positive for clinically significant fatigue. Bivariate associations were present between clinically significant fatigue and several demographic, clinical, lifestyle, and medication variables. After controlling for level of disability and a range of stable socio-demographic variables, we found increased odds of fatigue associated with obesity, DMD use, poor diet, and reduced odds of fatigue with exercise, fish consumption, moderate alcohol use, and supplementation with vitamin D and flaxseed oil.This study supports strong and significant associations between clinically significant fatigue and modifiable lifestyle factors. Longitudinal follow-up of this sample may help clarify the contribution

  10. Insulin growth factor 1 receptor expression is associated with NOTCH1 mutation, trisomy 12 and aggressive clinical course in chronic lymphocytic leukaemia.

    Directory of Open Access Journals (Sweden)

    Francesco Maura

    Full Text Available IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540. High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM status (p<0.0001, high CD38 expression (p<0.0001, trisomy 12 (p<0.0001, and del(11(q23 (p=0.014. Interestingly, higher IGF1R expression (p=0.002 characterized patients with NOTCH1 mutation (c.7541_7542delCT, identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation.

  11. Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation, Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

    Science.gov (United States)

    Maura, Francesco; Mosca, Laura; Fabris, Sonia; Cutrona, Giovanna; Matis, Serena; Lionetti, Marta; Agnelli, Luca; Barbieri, Marzia; D’Anca, Marianna; Manzoni, Martina; Colombo, Monica; Massucco, Carlotta; Reverberi, Daniele; Gentile, Massimo; Recchia, Anna Grazia; Bossio, Sabrina; Ilariucci, Fiorella; Musolino, Caterina; Di Raimondo, Francesco; Cortelezzi, Agostino; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2015-01-01

    IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation. PMID:25786252

  12. Low-Cycle Fatigue Life and Fatigue Crack Propagation of Sintered Ag Nanoparticles

    Science.gov (United States)

    Shioda, Ryutaro; Kariya, Yoshiharu; Mizumura, Noritsuka; Sasaki, Koji

    2017-02-01

    The low-cycle fatigue life and fatigue crack propagation behavior of sintered silver nanoparticles were investigated using miniature specimens sintered at two different temperatures. The fatigue crack initiation life and fatigue crack propagation rate of sintered Ag nanoparticles were extremely sensitive to changes in the range of inelastic energy density and the cyclic J integral, exhibiting brittle characteristics, in contrast to tin-based lead-free solder alloys. With increasing sintering temperature, the fatigue crack propagation rate decreased. On the other hand, the effect of sintering temperature on the fatigue crack initiation life differed depending on the use of either a smooth specimen (low-cycle fatigue test) or notched specimen (fatigue crack propagation test). For the notched specimens, the probability of grain boundaries around the notch decreased due to increased sintering temperature. Therefore, the fatigue crack initiation life was increased with an increase in sintering temperature in the fatigue crack propagation test. In the smooth specimen, however, the fatigue life decreased with an increase in sintering temperature, as the elastic modulus of the specimen increased with increasing sintering temperature. In the low-cycle fatigue test, the specimen sintered with high internal stress started to develop crack initiation early, causing a decrease in the crack initiation life.

  13. Fatigue in Rheumatoid Arthritis.

    Science.gov (United States)

    Katz, Patricia

    2017-05-01

    The purpose of this study was to review the current information on fatigue in rheumatoid arthritis (RA). Severe fatigue is common among individuals with RA and has a significant impact on quality of life (QOL). RA-related factors (e.g., inflammation, pain) are associated with greater fatigue, but other factors, such as obesity, physical inactivity, sleep disturbance, and depression, explain the majority of variation in fatigue. Medications targeting RA have little effect on fatigue. Instead, the most effective interventions seem to address non-RA-specific factors such as physical inactivity or use cognitive behavioral approaches. No recommendations have been made for tools to measure fatigue in RA, leading to potential difficulty comparing studies. Although fatigue has great impact on patients' QOL, effective interventions that are feasible for broad dissemination remain elusive. Additional multi-faceted research is needed to identify modifiable sources of fatigue. Such research would be enhanced by harmonization of fatigue measurement across studies.

  14. Waveform frequency notching

    Energy Technology Data Exchange (ETDEWEB)

    Doerry, Armin W.; Andrews, John

    2017-05-09

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

  15. Short fatigue cracks growth and closure behavior in an austenitic stainless steel at 600 C and 650 C

    Energy Technology Data Exchange (ETDEWEB)

    Polvora, J.P.; Laiarinandrasana, L.; Drubay, B.; Piques, R.; Martelet, B. [Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, SP (Brazil)

    1995-12-31

    In this work, following fatigue crack growth tests carried out at the CEN-SACLAY (AMORFIS program) by Laiarinandrasana (1994) on 316 L(N) CT specimens at 650{sup 0}C and 600{sup 0}C, short crack behavior of cracks emanating from machined notches is investigated. Experimental results are presented and discussions are directed to notch plasticity effect in relation with variations in crack opening stress intensity factor, K{sub op}, with crack lenght (author). 12 refs., 5 figs., 2 tab.

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

    Directory of Open Access Journals (Sweden)

    Ge Changhui

    2010-03-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Poststroke fatigue : Course and its relation to personal and stroke-related factors

    NARCIS (Netherlands)

    Schepers, VP; Visser-Meily, AM; Ketelaar, M; Lindeman, E

    2006-01-01

    Objectives: To describe the course of fatigue during the first year poststroke and to determine the relation between fatigue at 1 year poststroke and personal characteristics, stroke characteristics, and poststroke impairments. Design: Inception cohort. Setting: Rehabilitation center. Participants:

  19. Study of fatigue, depression, and associated factors in type 2 diabetes mellitus in industrial workers

    Directory of Open Access Journals (Sweden)

    Akhilesh Jain

    2015-01-01

    Full Text Available Introduction: Type 2 diabetes mellitus is a significant health problem and imposes great physical, financial and psychological burden among the affected population. Among people with diabetes, fatigue is a pervasive and distressing complaint, which is further accentuated by presence of depression. Objective: To assess the prevalence of fatigue and depression and associated clinical and socio demographic correlates in type 2diabetes. Materials and Methods: This cross sectional study included 100 patients of diabetes type 2 and equal number of healthy controls between the ages of 18 to 70 years . A detailed evaluation of socio demographic and clinical parameters was made. Participants were also assessed for presence of depression and fatigue using PHQ-9 and Fatigue Severity Scale(FSSrespectively. Results: Fatigue and depression was found in 68 % and 53 % of diabetic participants. Diabetic patients were 10.37 times and 4.80 times more likely to suffer from fatigue and depression respectively. Both fatigue and depression were found to be significantly associated with duration of illness, fasting and post prandial blood glucose level ,diabetic complications and Body Mass Index (BMI. Fatigue was also strongly correlated with depression in study sample. Conclusions: Fatigue and depression are reasonably correlated with type 2 diabetes. Various clinical parameters of diabetes are strongly associated with both fatigue and depression. Fatigue itself has significant correlation with depression in type 2 diabetes. Regular monitoring of biochemical parameters are paramount to predict the development of fatigue and depression in type 2 diabetes.

  20. Empirical Approach to Understanding the Fatigue Behavior of Metals Made Using Additive Manufacturing

    Science.gov (United States)

    Witkin, David B.; Albright, Thomas V.; Patel, Dhruv N.

    2016-08-01

    High-cycle fatigue measurements were performed on alloys prepared by powder-bed fusion additive manufacturing techniques. Selective laser melted (SLM) nickel-based superalloy 625 and electron beam melted (EBM) Ti-6Al-4V specimens were prepared as round fatigue specimens and tested with as-built surfaces at stress ratios of -1, 0.1 and 0.5. Data collected at R = -1 were used to construct Goodman diagrams that correspond closely to measured experimental data collected at R > 0. A second way to interpret the HCF data is based on the influence of surface roughness on fatigue, and approximate the surface feature size as a notch. On this basis, the data were interpreted using the fatigue notch factor k f and average stress models relating k f and stress concentration factor K t. The depth and root radius of surface features associated with fatigue crack initiation were used to estimate a K t of 2.8 for SLM 625. For Ti-6Al-4V, a direct estimate of K t from HCF data was not possible, but approximate values of k f based on HCF data and K t from crack initiation site geometry are found to explain other published EBM Ti-6Al-4V.

  1. The role of Notch in the cardiovascular system: potential adverse effects of investigational Notch inhibitors

    Directory of Open Access Journals (Sweden)

    Paola eRizzo

    2015-01-01

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

  2. Tumor necrosis factor inhibitor therapy in ankylosing spondylitis: differential effects on pain and fatigue and brain correlates.

    Science.gov (United States)

    Wu, Qi; Inman, Robert D; Davis, Karen D

    2015-02-01

    Ankylosing spondylitis is associated with back pain and fatigue and impacts mobility but can be treated with tumor necrosis factor inhibitors (TNFi). The differential effects of TNFi treatment on multiple symptoms and the brain is not well delineated. Thus, we conducted a 2-part study. In study 1, we conducted a retrospective chart review in 129 ankylosing spondylitis patients to assess TNFi effects on pain, fatigue, motor function, mobility, and quality of life (QoL). After at least 10 weeks of TNFi treatment, patients had clinically significant improvements (>30%) in pain (including neuropathic pain), most disease and QoL factors, and normalized sensory detection thresholds. However, residual fatigue (mean = 5.3) was prominent. Although 60% of patients had significant relief of pain, only 22% of patients had significant relief of both pain and fatigue. Therefore, the preferential TNFi treatment effect on pain compared with fatigue could contribute to suboptimal effects on QoL. Part 2 was a prospective study in 14 patients to identify TNFi treatment effects on pain, fatigue, sensory and psychological factors, and brain cortical thickness based on 3T magnetic resonance imaging. Centrally, TNFi was associated with statistically significant cortical thinning of motor, premotor, and posterior parietal regions. Pain intensity reduction was associated with cortical thinning of the secondary somatosensory cortex, and pain unpleasantness reduction was associated with the cortical thinning of motor areas. In contrast, fatigue reduction correlated with cortical thinning of the insula, primary sensory cortex/inferior parietal sulcus, and superior temporal polysensory areas. This indicates that TNFi treatment produces changes in brain areas implicated in sensory, motor, affective, and cognitive functions.

  3. Fatigue in adults with Marfan syndrome, occurrence and associations to pain and other factors.

    Science.gov (United States)

    Bathen, Trine; Velvin, Gry; Rand-Hendriksen, Svend; Robinson, Hilde Stendal

    2014-08-01

    This study aims to investigate how fatigue affects adults with verified Marfan syndrome (MFS) in their daily lives, by examining fatigue levels and prevalence of severe fatigue compared to the general Norwegian population and individuals with other comparable chronic conditions. We investigated associations between socio-demographic characteristics, Marfan-related health problems, pain and fatigue. A cross-sectional study was conducted, using a postal questionnaire including the Fatigue Severity Scale (FSS) and questions on socio-demographic characteristics, Marfan-related health problems and pain. One hundred seventeen persons with MFS were invited to participate, 73 answered (62%). Participants reported significantly higher FSS scores and prevalence of severe fatigue compared to the general Norwegian population and patients with rheumatoid arthritis (RA), but lower than for other chronic conditions. Participants with chronic pain reported higher fatigue scores than those without chronic pain. Participants on disability benefits reported higher fatigue scores than participants who were working or enrolled in higher education. Marfan-related health problems like aortic dissection and use of blood pressure medication were not significantly associated with fatigue. In multivariable regression analyses chronic pain and employment status were significantly associated with fatigue. The final multivariable model explained 24% of the variance in fatigue scores. Our results show that fatigue is common in MFS patients and that it interferes with their daily lives. Chronic pain and employment status show significant associations to fatigue. This implies that fatigue is important to address when meeting MFS patients in clinical practice. There is need for more research on fatigue in Marfan syndrome.

  4. Discerning Primary and Secondary Factors Responsible for Clinical Fatigue in Multisystem Diseases

    Directory of Open Access Journals (Sweden)

    David Maughan

    2014-09-01

    Full Text Available Fatigue is a common symptom of numerous acute and chronic diseases, including myalgic encephalomyelitis/chronic fatigue syndrome, multiple sclerosis, heart failure, cancer, and many others. In these multi-system diseases the physiological determinants of enhanced fatigue encompass a combination of metabolic, neurological, and myofibrillar adaptations. Previous research studies have focused on adaptations specific to skeletal muscle and their role in fatigue. However, most have neglected the contribution of physical inactivity in assessing disease syndromes, which, through deconditioning, likely contributes to symptomatic fatigue. In this commentary, we briefly review disease-related muscle phenotypes in the context of whether they relate to the primary disease or whether they develop secondary to reduced physical activity. Knowledge of the etiology of the skeletal muscle adaptations in these conditions and their contribution to fatigue symptoms is important for understanding the utility of exercise rehabilitation as an intervention to alleviate the physiological precipitants of fatigue.

  5. Notch Signaling Inhibits Axon Regeneration

    OpenAIRE

    Bejjani, Rachid El; Hammarlund, Marc

    2012-01-01

    Many neurons have limited capacity to regenerate their axons after injury. Neurons in the mammalian CNS do not regenerate, and even neurons in the PNS often fail to regenerate to their former targets. This failure is likely due in part to pathways that actively restrict regeneration; however, only a few factors that limit regeneration are known. Here, using single-neuron analysis of regeneration in vivo, we show that Notch/lin-12 signaling inhibits the regeneration of mature C. elegans neuron...

  6. Fatigue acceptance test limit criterion for larger diameter rolled thread fasteners

    Energy Technology Data Exchange (ETDEWEB)

    Kephart, A.R.

    1997-05-01

    This document describes a fatigue lifetime acceptance test criterion by which studs having rolled threads, larger than 1.0 inches in diameter, can be assured to meet minimum quality attributes associated with a controlled rolling process. This criterion is derived from a stress dependent, room temperature air fatigue database for test studs having a 0.625 inch diameter threads of Alloys X-750 HTH and direct aged 625. Anticipated fatigue lives of larger threads are based on thread root elastic stress concentration factors which increase with increasing thread diameters. Over the thread size range of interest, a 30% increase in notch stress is equivalent to a factor of five (5X) reduction in fatigue life. The resulting diameter dependent fatigue acceptance criterion is normalized to the aerospace rolled thread acceptance standards for a 1.0 inch diameter, 0.125 inch pitch, Unified National thread with a controlled Root radius (UNR). Testing was conducted at a stress of 50% of the minimum specified material ultimate strength, 80 Ksi, and at a stress ratio (R) of 0.10. Limited test data for fastener diameters of 1.00 to 2.25 inches are compared to the acceptance criterion. Sensitivity of fatigue life of threads to test nut geometry variables was also shown to be dependent on notch stress conditions. Bearing surface concavity of the compression nuts and thread flank contact mismatch conditions can significantly affect the fastener fatigue life. Without improved controls these conditions could potentially provide misleading acceptance data. Alternate test nut geometry features are described and implemented in the rolled thread stud specification, MIL-DTL-24789(SH), to mitigate the potential effects on fatigue acceptance data.

  7. ON FATIGUE CRACK PATH DEVIATION AT ELEVATED TEMPERATURE IN ELECTRON BEAM REPAIRED WELDMENTS OF TURBINE DISK

    Institute of Scientific and Technical Information of China (English)

    H.Q. Zhang; H.Y. Zhao; Y.H. Zhang; L.H. Li; X.A. Zhang

    2004-01-01

    Fatigue crack growth behaviors in electron beam weldments of a nickel-base superalloy are studied. The objective of this paper is to discuss effects of the inhomogeneity of mechanical performance on fatigue crack growth (FCG) rate and crack path deviation (CPD). The base metal served in a turbine disk of aerospace engine was selected to fabricate bead-on-plate weldments by using electron beam welding. Some wedge-type opening loading specimens, notched in three different zone of weld metal, HAZ and base metal, were employed and performed fatigue crack growth tests at 650℃. The results show that the fatigue crack growth of electron beam welded joints is instable due to the influence of mechanical heterogeneities. Owing to the crack deviation at the weld metal and hcat-affected-zone (HAZ), the effective growth driving force at the tip of fatigue crack was reduced with the reduction of the effective stress intensity factor (SIF) which finally causes fatigue crack rate decrease. Fatigue crack was strongly affected by size and the symmetrical characteristics of the plastic zone at the crack tip, which means that the integrity of the welded structure containing the fatigue crack mainly depended on the toughness of the low strength zone.

  8. Time-dependent confidence factor for structures with degradation caused by fatigue

    Directory of Open Access Journals (Sweden)

    Ruiz-Gómez Sonia E.

    2014-07-01

    Full Text Available An approach to evaluate the confidence factor for structures at the end of an interval of time is proposed. The confidence factor indicates the adequacy of the performance level of a structure subjected to external loads. The factor considers the uncertainties implicit in the structural capacity and in the structural demand. The formulation is made in accordance with the Demand and Capacity Factor Design Format. Four scenarios are compared: a structural capacity deteriorates over a time interval, while structural demand remains constant, b only structural demand (for a given intensity varies in time, c both structural capacity and structural demand vary simultaneously in time, and d the effect of structural deterioration is neglected. The approach is applied to an offshore jacket platform. Deterioration is taken into account by analyzing the growth of fatigue cracks in both ends of several critical structural elements. It is concluded that for the evaluation of the confidence factor over an interval of interest, for the case analyzed, it is more significant to consider the variation in time of the structural capacity rather than that of the structural demand; however, it is recommended to consider both (structural capacity and structural demand in the analysis.

  9. Fatigue Behaviour of CFRP Strengthened Out-of-Plane Gusset Welded Joints with Double Cracks

    Directory of Open Access Journals (Sweden)

    Qian-Qian Yu

    2015-09-01

    Full Text Available This paper investigates the fatigue behaviour of out-of-plane gusset welded joints strengthened with carbon fibre reinforced polymer (CFRP laminates. Two notches were introduced at the weld toes adjacent to longitudinal plate ends to simulate the initial damage. Variables including the stress range, single- or double-sided strengthening and modulus of CFRP materials were considered. It was found that both cracks propagated under fatigue loading. All the specimens fractured along one predefined notch when the fatigue crack reached a certain length while the other crack also grew to some extent. Test results showed that the addition of composite materials significantly prolonged the fatigue life of specimens by as much as 1.28 to 8.17 times. Double-sided bond and ultra-high modulus CFRP materials led to a better strengthening efficiency. Thereafter, a series of numerical analyses were performed to study the stress intensity factor (SIF and crack opening displacement (COD. Local debonding around the crack tip at the adhesive-steel interface was taken into consideration. Finally, the fatigue life of all the specimens was evaluated based on the linear elastic fracture mechanism (LEFM theory and the predicted results agreed well with the experimental data.

  10. Psychosocial factors involved in memory and cognitive failures in people with myalgic encephalomyelitis/chronic fatigue syndrome

    Directory of Open Access Journals (Sweden)

    Attree EA

    2014-02-01

    Full Text Available Elizabeth A Attree,1 Megan A Arroll,1 Christine P Dancey,1 Charlene Griffith,1 Amolak S Bansal1,2 1Chronic Illness Research Team, School of Psychology, University of East London, London, UK; 2Department of Immunology and the Sutton CFS Service, St Helier Hospital, Carshalton, UK Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS is characterized by persistent emotional, mental, and physical fatigue accompanied by a range of neurological, autonomic, neuroendocrine, immune, and sleep problems. Research has shown that psychosocial factors such as anxiety and depression as well as the symptoms of the illness, have a significant impact on the quality of life of people with ME/CFS. In addition, individuals may suffer from deficits in memory and concentration. This study set out to explore the relationships between variables which have been found to contribute to cognitive performance, as measured by prospective and retrospective memory, and cognitive failures. Methods: Eighty-seven people with ME/CFS answered questionnaires measuring fatigue, depression, anxiety, social support, and general self-efficacy. These were used in a correlational design (multiple regression to predict cognitive function (self-ratings on prospective and retrospective memory, and cognitive failures. Results: Our study found that fatigue, depression, and general self-efficacy were directly associated with cognitive failures and retrospective (but not prospective memory. Conclusion: Although it was not possible in this study to determine the cause of the deficits, the literature in this area leads us to suggest that although the pathophysiological mechanisms of ME/CFS are unclear, abnormalities in the immune system, including proinflammatory cytokines, can lead to significant impairments in cognition. We suggest that fatigue and depression may be a result of the neurobiological effects of ME/CFS and in addition, that the neurobiological effects of the illness

  11. Physical and Cognitive-Affective Factors Associated with Fatigue in Individuals with Fibromyalgia: A Multiple Regression Analysis

    Science.gov (United States)

    Muller, Veronica; Brooks, Jessica; Tu, Wei-Mo; Moser, Erin; Lo, Chu-Ling; Chan, Fong

    2015-01-01

    Purpose: The main objective of this study was to determine the extent to which physical and cognitive-affective factors are associated with fibromyalgia (FM) fatigue. Method: A quantitative descriptive design using correlation techniques and multiple regression analysis. The participants consisted of 302 members of the National Fibromyalgia &…

  12. Glass fibre reinforced cement based composite: fatigue and fracture parameters

    Directory of Open Access Journals (Sweden)

    Seitl S.

    2009-12-01

    Full Text Available This paper introduces the basic fracture mechanics parameters of advanced building material – glass fibres reinforced cement based composite and its fracture and fatigue behaviour is investigated. To this aim three-point bend (3PB specimens with starting notch were prepared and tested under static (l–d diagram and cyclic loading (Paris law and Ẅöhler curve. To evaluate the results, the finite element method was used for estimation of the corresponding values of stress intensity factor for the 3PB specimen used. The results obtained are compared with literature data.

  13. STUDY ON FATIGUE SHORT CRACK GROWTH LAW AND FATIGUE LIFE FOR MEDIUM CARBON STEELS

    Institute of Scientific and Technical Information of China (English)

    1998-01-01

    The fatigue crack initiation from notch root and the short-crack growth laws of two medium carbon alloying structural steels-35CrMo and 42CrMo are investigated under the different stress ratios R=0.1, 0.3) and three-point bending condition. The relationships between the maximum stress range at the notch root Δσmax and the number of cycles before fatigue crack initiation Ni are determined. The threshold stresses of fatigue crack initiation (Δσmax)th are got, and the smallcrack growth laws are obtained for these steels. An effective and convenient method is proposed for predicting the fatigue life of the notch specimens.

  14. Notch Signaling in Vascular Smooth Muscle Cells.

    Science.gov (United States)

    Baeten, J T; Lilly, B

    2017-01-01

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

  15. Fatigue and fracture assessment of cracks in steel elements using acoustic emission

    Science.gov (United States)

    Nemati, Navid; Metrovich, Brian; Nanni, Antonio

    2011-04-01

    Single edge notches provide a very well defined load and fatigue crack size and shape environment for estimation of the stress intensity factor K, which is not found in welded elements. ASTM SE(T) specimens do not appear to provide ideal boundary conditions for proper recording of acoustic wave propagation and crack growth behavior observed in steel bridges, but do provide standard fatigue crack growth rate data. A modified versions of the SE(T) specimen has been examined to provide small scale specimens with improved acoustic emission(AE) characteristics while still maintaining accuracy of fatigue crack growth rate (da/dN) versus stress intensity factor (ΔK). The specimens intend to represent a steel beam flange subjected to pure tension, with a surface crack growing transverse to a uniform stress field. Fatigue test is conducted at low R ratio. Analytical and numerical studies of stress intensity factor are developed for single edge notch test specimens consistent with the experimental program. ABAQUS finite element software is utilized for stress analysis of crack tips. Analytical, experimental and numerical analysis were compared to assess the abilities of AE to capture a growing crack.

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

    Science.gov (United States)

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

    2017-02-01

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

  17. The Prevalence of Compassion Fatigue among Veterinary Students in Australia and the Associated Psychological Factors.

    Science.gov (United States)

    McArthur, Michelle L; Andrews, Jena R; Brand, Conor; Hazel, Susan J

    2017-01-01

    Compassion fatigue, compassion satisfaction, and other characteristics such as mindfulness and mental health stigma have not been investigated in veterinary students. The aims of this study were twofold: first to determine the prevalence of compassion, satisfaction, burnout, and secondary traumatic stress among Australian veterinary students and second to investigate the association between these factors and self-stigma, coping, empathy, and mindfulness. A cross-sectional online survey consisting of demographic questions and four validated psychological measures sampled 828 students, with a response rate of 31% (255/828). We obtained a usable sample of completed surveys from 193 of 828 (23%) veterinary students from six of the seven Australian veterinary schools. Bivariate correlations and multiple regression analyses were used to examine associations between the psychological predictors and the outcome variables. Approximately 30% of veterinary students were at high risk of burnout, 24% were at high risk of secondary traumatic stress, and 21% reported low compassion satisfaction. High empathic concern, low personal distress, female gender, and employment history at a veterinary clinic were associated with high compassion satisfaction. High dysfunctional coping, low nonjudgmental and acting-with-awareness mindfulness, and lack of previous employment at a veterinary clinic were associated with high burnout. High dysfunctional coping, low acting-with-awareness mindfulness, high self-stigma, and high personal distress were associated with high secondary traumatic stress. As a result of these findings, certain emotional characteristics can be identified as targets for intervention to minimize the frequency and potentially negative impact of compassion fatigue and burnout in veterinary students.

  18. [Auditory fatigue].

    Science.gov (United States)

    Sanjuán Juaristi, Julio; Sanjuán Martínez-Conde, Mar

    2015-01-01

    Given the relevance of possible hearing losses due to sound overloads and the short list of references of objective procedures for their study, we provide a technique that gives precise data about the audiometric profile and recruitment factor. Our objectives were to determine peripheral fatigue, through the cochlear microphonic response to sound pressure overload stimuli, as well as to measure recovery time, establishing parameters for differentiation with regard to current psychoacoustic and clinical studies. We used specific instruments for the study of cochlear microphonic response, plus a function generator that provided us with stimuli of different intensities and harmonic components. In Wistar rats, we first measured the normal microphonic response and then the effect of auditory fatigue on it. Using a 60dB pure tone acoustic stimulation, we obtained a microphonic response at 20dB. We then caused fatigue with 100dB of the same frequency, reaching a loss of approximately 11dB after 15minutes; after that, the deterioration slowed and did not exceed 15dB. By means of complex random tone maskers or white noise, no fatigue was caused to the sensory receptors, not even at levels of 100dB and over an hour of overstimulation. No fatigue was observed in terms of sensory receptors. Deterioration of peripheral perception through intense overstimulation may be due to biochemical changes of desensitisation due to exhaustion. Auditory fatigue in subjective clinical trials presumably affects supracochlear sections. The auditory fatigue tests found are not in line with those obtained subjectively in clinical and psychoacoustic trials. Copyright © 2013 Elsevier España, S.L.U. y Sociedad Española de Otorrinolaringología y Patología Cérvico-Facial. All rights reserved.

  19. Stress intensity factors for fatigue loaded details between crossbeams and trapezoidal stringers

    NARCIS (Netherlands)

    Maljaars, J.; Pijpers, R.J.M.

    2013-01-01

    A number of orthotropic deck structures of existing bridges are suffering from fatigue cracks. Maintenance of these deck structures may consist of regular inspections and repair of detected cracks. The usual fatigue design life procedure for aswelded structures based on S-N curves is not feasible fo

  20. Exploring Fatigue in Inflammatory Bowel Disease Patients : Associated Factors and Management

    NARCIS (Netherlands)

    L. Vogelaar (Lauran)

    2015-01-01

    markdownabstractAbstract Fatigue is a common phenomenon in IBD patients, which contributes significantly to the burden of the disease. The pathophysiology of IBD-related fatigue is considered multifactorial, but at present the underlying mechanisms are largely unknown. Based on the literature and

  1. Seafarer fatigue

    DEFF Research Database (Denmark)

    Jepsen, Jørgen Riis; Zhao, Zhiwei; van Leeuwen, Wessel M. A.

    2015-01-01

    Background: The consequences of fatigue for the health and safety of seafarers has caused concern in the industry and among academics, and indicates the importance of further research into risk factors and preventive interventions at sea. This review gives an overview of the key issues relating...

  2. Role of hypoxia-related proteins in invasion of ameloblastoma cells: crosstalk between NOTCH1, hypoxia-inducible factor 1α, a disintegrin and metalloproteinase 12, and heparin-binding epidermal growth factor.

    Science.gov (United States)

    da Costa, Natacha Malu Miranda; Fialho, Amanda Dalla Vechia; Proietti, Carolina Carmine; da Silva Kataoka, Maria Sueli; Jaeger, Ruy Gastaldoni; de Alves-Júnior, Sérgio Melo; de Jesus Viana Pinheiro, João

    2016-07-01

    Ameloblastoma AME is a benign tumour characterized by local invasiveness, high recurrence rates, and diverse histological patterns. The oxygen concentration is reduced in specific areas of the tumour microenvironment, which leads to intratumoral hypoxia. Crosstalk between NOTCH1, a disintegrin and metalloproteinase 12 (ADAM-12), hypoxia-inducible factor 1α (HIF-1α) and heparin-binding epidermal growth factor (HB-EGF) under hypoxic conditions has been implicated in invadopodia formation, tumour invasiveness, and metastasis development. The aim of this study was to analyse the expression of these proteins, in order to further elucidate the mechanisms underlying AME invasiveness. Twenty cases of AME, eight calcifying cystic odontogenic tumours CCOTs and 10 samples of dental follicle were used to investigate the expression of these proteins by immunohistochemistry with the primary antibodies anti-NOTCH1, anti-ADAM-12, anti-HIF-1α, and anti-HB-EGF. Immunostaining results were expressed as the percentage of stained area in images acquired in an AxioScope microscope equipped with an AxioCamHRc camera and a × 40 objective. The results showed that immunoexpression of all proteins was higher in the AME samples than in the CCOT and dental follicle samples (P < 0.05). AME showed an increased presence of proteins associated with tumour invasiveness, which indicates a possible role of these proteins in the biological behaviour of this tumour. © 2015 John Wiley & Sons Ltd.

  3. Fatigue as a long-term risk factor for limitations in instrumental activities of daily living and/or mobility performance in older adults after 10 years

    Science.gov (United States)

    Mueller-Schotte, Sigrid; Bleijenberg, Nienke; van der Schouw, Yvonne T; Schuurmans, Marieke J

    2016-01-01

    Objectives Decline in the performance of instrumental activities of daily living (IADL) and mobility may be preceded by symptoms the patient experiences, such as fatigue. The aim of this study is to investigate whether self-reported non-task-specific fatigue is a long-term risk factor for IADL-limitations and/or mobility performance in older adults after 10 years. Methods A prospective study from two previously conducted cross-sectional studies with 10-year follow-up was conducted among 285 males and 249 females aged 40–79 years at baseline. Fatigue was measured by asking “Did you feel tired within the past 4 weeks?” (males) and “Do you feel tired?” (females). Self-reported IADLs were assessed at baseline and follow-up. Mobility was assessed by the 6-minute walk test. Gender-specific associations between fatigue and IADL-limitations and mobility were estimated by multivariable logistic and linear regression models. Results A total of 18.6% of males and 28.1% of females were fatigued. After adjustment, the odds ratio for fatigued versus non-fatigued males affected by IADL-limitations was 3.3 (P=0.023). In females, the association was weaker and not statistically significant, with odds ratio being 1.7 (P=0.154). Fatigued males walked 39.1 m shorter distance than those non-fatigued (P=0.048). For fatigued females, the distance was 17.5 m shorter compared to those non-fatigued (P=0.479). Conclusion Our data suggest that self-reported fatigue may be a long-term risk factor for IADL-limitations and mobility performance in middle-aged and elderly males but possibly not in females. PMID:27877027

  4. Experiences of Fatigue at Sea

    DEFF Research Database (Denmark)

    Zhao, Zhiwei; Jepsen, Jørgen Riis; Chen, Zhonglong

    2016-01-01

    Fatigue has negative impacts on the general working population as well as on seafarers. In order to study seafarers’ fatigue, a questionnaire-base survey was conducted to gain information about potential risk factors for fatigue and construct indexes indicating fatigue. The study applies T-test t...

  5. Experiences of Fatigue at Sea

    DEFF Research Database (Denmark)

    Zhao, Zhiwei; Jepsen, Jørgen Riis; Chen, Zhonglong;

    2016-01-01

    Fatigue has negative impacts on the general working population as well as on seafarers. In order to study seafarers’ fatigue, a questionnaire-base survey was conducted to gain information about potential risk factors for fatigue and construct indexes indicating fatigue. The study applies T...

  6. Fatigue as a long-term risk factor for limitations in instrumental activities of daily living and/or mobility performance in older adults after 10 years

    NARCIS (Netherlands)

    Mueller-Schotte, Sigrid; Bleijenberg, Nienke; van der Schouw, Yvonne T.; Schuurmans, Marieke J.

    2016-01-01

    Objectives: Decline in the performance of instrumental activities of daily living (IADL) and mobility may be preceded by symptoms the patient experiences, such as fatigue. The aim of this study is to investigate whether self-reported non-task-specific fatigue is a long-term risk factor for IADL-limi

  7. Some considerations about improvement for fatigue strength of structures; Shatai kozobutsu no hiro kyodo kojo ni kansuru ichikosatsu

    Energy Technology Data Exchange (ETDEWEB)

    Kimoto, H.; Toyama, K.; Maruyama, H.; Magara, S. [Press Kogyo Co. Ltd., Kanagawa (Japan)

    1997-10-01

    To reduce weight, higher tensile strength and/or thinner plate are used or considered in vehicle structures. In general, welded or notch sections, fatigue strength decreases because of increasing concentrated stress or effect of notch sensitivity and so on. In this paper, some methods are studied to improve fatigue strength and obtain a long life. 2 refs., 11 figs., 5 tabs.

  8. FACTORS INFLUENCING JOB FATIGUE AND STRESS AMONG EMPLOYEES OF YOGYAKARTA STATE UNIVERSITY ION COLUMN TECHNIC WITH LOCAL ZEOLITE AND ACTIVE CARBON

    Directory of Open Access Journals (Sweden)

    Siti Mariyam

    2016-05-01

    Full Text Available Stress and fatigue related to workplace may interrupt with the effectivity and productivity workers, including the employees who work in the office. This research aims to determine the level of stress and fatigue related to workplace and to describe determinant factors invloved in job stress and musculosceletal fatigue. It is designed as an analytical survey, designed as cross sectional approach. Population were the employees of Yogyakarta State University, samples were taken with purposive sampling technique. The respondents were they who fulfilled the inclusion criteria. Job stress and fatigue were taken with observation and structured intervie, using adapted instrument from Berutu Soetopo (2010 and Andininsari (2009. Musculosceletal fatigue were measured with nordic body map method. Other paramater included anthropometry and ergonometry measurement and individual characteristics. The finding shows that most respondents (95% suffered mild job stress and more than half of respondents (73% had mild musculosceletal fatigue. About 60% of workplace facilities were not suitable according to ergonomic requirement. Determinant factors for job stress such as age, employment status and workplace ergonometry, while determinant factors for musculosceletal fatigue includes age body mass index and also ergonometry.   Keywords: workplace, stress, fatigue, musculosceletal

  9. 正交异性钢桥面板横隔板切口疲劳应力幅分析%ANALYSIS OF FATIGUE STRESS AMPLITUDE OF DIAPHRAGM NOTCH IN ORTHOTROPIC STEEL BRIDGE DECK

    Institute of Scientific and Technical Information of China (English)

    吉伯海; 田圆; 傅中秋; 徐汉江

    2014-01-01

    建立全桥模型和简化的钢桥面板局部节段模型,通过子模型法插值得到横隔板疲劳细节模型的边界条件,计算不同车轮横向分布对应的疲劳细节局部应力,研究横隔板参数变化对横隔板疲劳细节损伤的影响。结果表明:混合单元模型与钢桥面板简化模型对应的应力幅相差小于5.0%,采用钢桥面板简化模型分析横隔板疲劳细节受力简单合理。横隔板疲劳细节在车轮偏离中心位置150 mm时应力幅最大,随着车轮偏离中心位置距离的增大,应力幅下降明显。横隔板间距增大,横隔板疲劳细节应力幅上升,增加横隔板厚度可有效改善其疲劳受力性状。%The overall bridge FE model and simplified steel bridge deck FE model were built .The boundary conditions of diaphragm fatigue detail FEM were interpolated from the FEM of the steel bridge deck .The local stresses under variable wheels lateral distribution were calculated .Influence of diaphragm ’ s parameters on fatigue damage of diaphragm fatigue detail was investigated .The results showed that the differences of stress amplitude between the FEM of mixed-element and simplified steel bridge deck were less than 5.0%.It was simple and reliable to calculate the fatigue stress of diaphragm fatigue detail by using steel bridge deck model .Stress amplitude of diaphragm fatigue detail reached maximum when the off-center distance of wheel position was 150 mm, which decreased obviously with the increasing off-center distance of wheel position .Stress amplitude of diaphragm fatigue detail increased with the increasing interval of diaphragms .And increasing diaphragm ’ s thickness could improve the fatigue behavior of stress of steel bridge deck .

  10. Memory for Fatigue in Chronic Fatigue Syndrome: Relationships to Fatigue Variability, Catastrophizing, and Negative Affect

    Science.gov (United States)

    Sohl, Stephanie J.; Friedberg, Fred

    2008-01-01

    Fatigue in chronic fatigue syndrome (CFS) is usually assessed with retrospective measures rather than real-time momentary symptom assessments. In this study, the authors hypothesized that in participants with CFS, discrepancies between recalled and momentary fatigue would be related to catastrophizing, anxiety, and depression and to variability of momentary fatigue. They also expected that catastrophizing, anxiety, and depression would be associated with momentary fatigue. The authors asked 53 adults with CFS to carry electronic diaries for 3 weeks and record their experiences of momentary fatigue. The authors assessed participants' fatigue recall with weekly ratings and administered questionnaires for catastrophizing, depression, and anxiety. Recall discrepancy was significantly related to the variability of momentary fatigue. In addition, catastrophizing, depression, and momentary fatigue were all significantly related to recall discrepancy. Catastrophizing, depression, anxiety, and momentary negative affect were all significantly associated with momentary fatigue. The findings suggest that momentary fatigue in patients with CFS is related to modifiable psychological factors. PMID:18400687

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

    OpenAIRE

    2014-01-01

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

  12. AIP4/Itch regulates Notch receptor degradation in the absence of ligand.

    Directory of Open Access Journals (Sweden)

    Patricia Chastagner

    Full Text Available BACKGROUND: The regulation of Notch signaling heavily relies on ubiquitination events. Drosophila Su(dx, a member of the HECT family of ubiquitin-ligases, has been described as a negative regulator of Notch signaling, acting on the post-endocytic sorting of Notch. The mammalian ortholog of Su(dx, Itch/AIP4, has been shown to have multiple substrates, including Notch, but the precise events regulated by Itch/AIP4 in the Notch pathway have not been identified yet. METHODOLOGY/PRINCIPAL FINDINGS: Using Itch-/- fibroblasts expressing the Notch1 receptor, we show that Itch is not necessary for Notch activation, but rather for controlling the degradation of Notch in the absence of ligand. Itch is indeed required after the early steps of Notch endocytosis to target it to the lysosomes where it is degraded. Furthermore Itch/AIP4 catalyzes Notch polyubiquitination through unusual K29-linked chains. We also demonstrate that although Notch is associated with Itch/AIP4 in cells, their interaction is not detectable in vitro and thus requires either a post-translational modification, or a bridging factor that remains to be identified. CONCLUSIONS/SIGNIFICANCE: Taken together our results identify a specific step of Notch regulation in the absence of any activation and underline differences between mammalian and Drosophila Notch pathways.

  13. Chemotherapy-induced Fatigue among Jordanian Cancer Patients: What are the Contributing Factors?

    Directory of Open Access Journals (Sweden)

    Kholoud Abu Obead

    2014-03-01

    Full Text Available Background: The purposes of this study were to examine the impact of chemotherapy treatment on Jordanian cancer patients’ fatigue and to correlate their fatigue with selected sociodemographic variables at the beginning of treatment and after four weeks of treatment. Methods: This was a single group quasi-experimental correlational design study that enrolled 43 patients diagnosed with cancer who required chemotherapy treatment. Fatigue was measured according to the Piper Fatigue Scale (PFS before starting chemotherapy treatment and after four weeks of receiving the first dose of chemotherapy. Data were collected over a period of four weeks and analyzed with descriptive statistics, the paired-sample t-test, and Pearson product-moment correlation. Results: The study included 17 (39.5% males and 26 (60.5% females with a mean age of 45.98 years. Most (n=17 were diagnosed with breast cancer. Obesity was present in about 64.4% of patients. The majority (46% received an anthracycline-based regimen. There were statistically significant differences between respondents’ total mean scores of fatigue pre-treatment and four weeks following chemotherapy treatment (t= -2.31, df=42, P<0.05. In addition, significant differences were found in the scores for behavioral, affective, sensory, and cognitive dimensions subscales (t= -2.24, -2.19, - 2.4, -2.4, df=42, P<0.05 between pre-treatment and four weeks after receiving the first dose of chemotherapy treatment. We observed a significant negative relationship between fatigue scores and hemoglobin levels (r= -0.04, P<0.01. Conclusion: Cancer-related fatigue is common among cancer patients who received chemotherapy and result in substantial adverse physical, behavioral, cognitive and affective consequences for patient. Given the impact of fatigue, treatment options should be routinely considered in the care of patients with cancer.

  14. Experimental examination of fatigue life of welded joint with stress concentration

    Directory of Open Access Journals (Sweden)

    Miodrag Arsic

    2016-03-01

    Full Text Available This paper presents results of experimental examinations of stress concentration influence to fatigue life of butt welded joints with K-groove, produced from the most frequently used structural steel S355J2+N. One group of experiments comprised examinations carried out on the K-groove specimens with stress concentrators of edged notch type. Specimens with short cracks (limited length of initial crack, defined on the basis of the experience from fracture mechanics by the three points bending examinations, have been examined according to standard for the determination of S-N curve, and aimed to determine fatigue strengths for different lengths of initial crack and Relationship between fatigue strength and crack length. Other group of experiments comprised examinations of specimens with edge notch, prepared in accordance with ASTM E 399 for three points bending, in order to establish regularity between crack growth and range of exerted stress intensity factor aimed to determine resistance of welded joint to initial crack growth, namely fatigue threshold (ΔKth.

  15. Bi-variable damage model for fatigue life prediction of metal components

    Institute of Scientific and Technical Information of China (English)

    Miao Zhang; Qing-Chun Meng; Xing Zhang; Wei-Ping Hu

    2011-01-01

    Based on the theory of continuum damage mechanics, a bi-variable damage mechanics model is developed, which, according to thermodynamics, is accessible to derivation of damage driving force, damage evolution equation and damage evolution criteria. Furthermore, damage evolution equations of time rate are established by the generalized Drucker's postulate. The damage evolution equation of cycle rate is obtained by integrating the time damage evolution equations, and the fatigue life prediction method for smooth specimens under repeated loading with constant strain amplitude is constructed. Likewise, for notched specimens under the repeated loading with constant strain amplitude, the fatigue life prediction method is obtained on the ground of the theory of conservative integral in damage mechanics. Thus, the material parameters in the damage evolution equation can be obtained by reference to the fatigue test results of standard specimens with stress concentration factor equal to 1, 2 and 3.

  16. The bHLH factors Dpn and members of the E(spl complex mediate the function of Notch signalling regulating cell proliferation during wing disc development

    Directory of Open Access Journals (Sweden)

    Beatriz P. San Juan

    2012-05-01

    The Notch signalling pathway plays an essential role in the intricate control of cell proliferation and pattern formation in many organs during animal development. In addition, mutations in most members of this pathway are well characterized and frequently lead to tumour formation. The Drosophila imaginal wing discs have provided a suitable model system for the genetic and molecular analysis of the different pathway functions. During disc development, Notch signalling at the presumptive wing margin is necessary for the restricted activation of genes required for pattern formation control and disc proliferation. Interestingly, in different cellular contexts within the wing disc, Notch can either promote cell proliferation or can block the G1-S transition by negatively regulating the expression of dmyc and bantam micro RNA. The target genes of Notch signalling that are required for these functions have not been identified. Here, we show that the Hes vertebrate homolog, deadpan (dpn, and the Enhancer-of-split complex (E(splC genes act redundantly and cooperatively to mediate the Notch signalling function regulating cell proliferation during wing disc development.

  17. The number of sectors and other risk factors related to fatigue among shorthaul commercial pilots in Indonesia

    Directory of Open Access Journals (Sweden)

    Inne Yuliawati

    2016-03-01

     AbstractBackground: Fatigue could impair cognitive function in pilots which may lead to accidents in short-haul flight. Theaim of this study was to identify the risk factors related to fatigue among short-haul commercial pilots in Indonesia.Methods: A cross-sectional study with purposive sampling was conducted among Boeing 737 seriestyped-rating pilots taking medical examination at the Civil Aviation Medical Center, Jakarta from May5-26, 2014. Fatigue was measured with Self-Reporting Questionnaire, Fatigue Severity Scale (FSS. Datawere collected using anonymous self-reporting questionnaire on demographics, workload, sleep restriction(Epworth Sleepiness Scale-ESS, personal factors, and managerial support. Linear regression was used toidentify dominant risk factors related to fatigue.Results: During data collection, 785 pilots were taking medical examination, 382 pilots were willing toparticipate, and 239 pilots met the criteria. The FSS mean was 4.66 ± 1.202. The number of sectors in 24hours, flight times of unplanned flights in 30 days, and sleep restriction were dominant factors of fatigue.Each additional sector increased FSS by 0.371 points [regression coefficient (β = 0.371; P = 0.000].Furthermore, each additional ESS, increased FSS by 0.043 points (β = 0.043; P = 0.008, while eachadditional unplanned flights increased FSS by 0.033 points (β = 0.033; P = 0.000.Conclusions: Additional number of sectors in 24 hours, additional unplanned flight times within 30 days,and sleep restriction increased the risk of fatigue among short-haul commercial pilots in Indonesia. (HealthScience Journal of Indonesia 2015;6:69-75Keyword: Fatigue, number of sectors, pilots, Indonesia

  18. The number of sectors and other risk factors related to fatigue among shorthaul commercial pilots in Indonesia

    Directory of Open Access Journals (Sweden)

    Inne Yuliawati

    2016-03-01

     AbstractBackground: Fatigue could impair cognitive function in pilots which may lead to accidents in short-haul flight. Theaim of this study was to identify the risk factors related to fatigue among short-haul commercial pilots in Indonesia.Methods: A cross-sectional study with purposive sampling was conducted among Boeing 737 seriestyped-rating pilots taking medical examination at the Civil Aviation Medical Center, Jakarta from May5-26, 2014. Fatigue was measured with Self-Reporting Questionnaire, Fatigue Severity Scale (FSS. Datawere collected using anonymous self-reporting questionnaire on demographics, workload, sleep restriction(Epworth Sleepiness Scale-ESS, personal factors, and managerial support. Linear regression was used toidentify dominant risk factors related to fatigue.Results: During data collection, 785 pilots were taking medical examination, 382 pilots were willing toparticipate, and 239 pilots met the criteria. The FSS mean was 4.66 ± 1.202. The number of sectors in 24hours, flight times of unplanned flights in 30 days, and sleep restriction were dominant factors of fatigue.Each additional sector increased FSS by 0.371 points [regression coefficient (β = 0.371; P = 0.000].Furthermore, each additional ESS, increased FSS by 0.043 points (β = 0.043; P = 0.008, while eachadditional unplanned flights increased FSS by 0.033 points (β = 0.033; P = 0.000.Conclusions: Additional number of sectors in 24 hours, additional unplanned flight times within 30 days,and sleep restriction increased the risk of fatigue among short-haul commercial pilots in Indonesia. (HealthScience Journal of Indonesia 2015;6:69-75Keyword: Fatigue, number of sectors, pilots, Indonesia

  19. Notch Signaling in Pancreatic Development

    OpenAIRE

    2015-01-01

    The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep involvement of Notch signaling in the development of the pancreas and the lateral inhibition of Notch signaling in pancreatic progenitor differentiation and maintenance. The targeted inactivation of the Notch pathway components promotes premature differentiation of the endocrine pancreas. However, there is still the contrary opinion...

  20. 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 ...

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Development and Application of a Clinical Microsystem Simulation Methodology for Human Factors-Based Research of Alarm Fatigue.

    Science.gov (United States)

    Kobayashi, Leo; Gosbee, John W; Merck, Derek L

    2017-07-01

    (1) To develop a clinical microsystem simulation methodology for alarm fatigue research with a human factors engineering (HFE) assessment framework and (2) to explore its application to the comparative examination of different approaches to patient monitoring and provider notification. Problems with the design, implementation, and real-world use of patient monitoring systems result in alarm fatigue. A multidisciplinary team is developing an open-source tool kit to promote bedside informatics research and mitigate alarm fatigue. Simulation, HFE, and computer science experts created a novel simulation methodology to study alarm fatigue. Featuring multiple interconnected simulated patient scenarios with scripted timeline, "distractor" patient care tasks, and triggered true and false alarms, the methodology incorporated objective metrics to assess provider and system performance. Developed materials were implemented during institutional review board-approved study sessions that assessed and compared an experimental multiparametric alerting system with a standard monitor telemetry system for subject response, use characteristics, and end-user feedback. A four-patient simulation setup featuring objective metrics for participant task-related performance and response to alarms was developed along with accompanying structured HFE assessment (questionnaire and interview) for monitor systems use testing. Two pilot and four study sessions with individual nurse subjects elicited true alarm and false alarm responses (including diversion from assigned tasks) as well as nonresponses to true alarms. In-simulation observation and subject questionnaires were used to test the experimental system's approach to suppressing false alarms and alerting providers. A novel investigative methodology applied simulation and HFE techniques to replicate and study alarm fatigue in controlled settings for systems assessment and experimental research purposes.

  3. Group cohesion and organizational commitment: protective factors for nurse residents' job satisfaction, compassion fatigue, compassion satisfaction, and burnout.

    Science.gov (United States)

    Li, Angela; Early, Sean F; Mahrer, Nicole E; Klaristenfeld, Jessica L; Gold, Jeffrey I

    2014-01-01

    Stress can have detrimental effects on nurse residents' levels of job satisfaction, compassion, fatigue, and burnout. This can lead to high turnover rates and poor quality of care among novice nurses. Therefore, it is critical to identify protective factors to prevent the onset of negative nurse outcomes (compassion fatigue, burnout, and job dissatisfaction) and to promote positive nurse outcomes (job satisfaction, compassion satisfaction). This study aimed to determine whether factors such as group cohesion and organizational commitment would be protective and moderate the association between stress exposure and posttraumatic stress symptoms and other negative nurse outcomes, thus facilitating positive outcomes. Findings showed that group cohesion was effective in moderating the negative effects of current stress exposure and posttraumatic stress symptoms on negative nurse outcomes, specifically on increased compassion fatigue and burnout, and reduced compassion satisfaction. In addition, organizational commitment was determined to promote positive nurse outcomes such as job satisfaction and compassion satisfaction. The study findings are promising, as retention of quality nurses is a significant problem for hospitals. Nurse managers and hospital administrators should be aware of the benefits of group cohesion and organizational commitment and strive to make the promotion of these factors a priority.

  4. Comparative Notched Box Plots.

    Science.gov (United States)

    1983-06-01

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

  5. Bidirectional Notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma

    Science.gov (United States)

    Delgado-Calle, Jesus; Anderson, Judith; Cregor, Meloney D.; Hiasa, Masahiro; Chirgwin, John M.; Carlesso, Nadia; Yoneda, Toshiyuki; Mohammad, Khalid S.; Plotkin, Lilian I.; Roodman, G. David; Bellido, Teresita

    2016-01-01

    In multiple myeloma (MM) increased numbers of monoclonal plasma cells in the bone marrow induce localized osteolytic lesions that rarely heal, due to increased bone resorption and suppressed bone formation. Numerous studies reported the contributions that different cell types in the MM microenvironment make to MM growth and bone disease, but the role of matrix-embedded osteocytes in MM, which comprise >95% of bone cells and are major regulators of osteoclast and osteoblast activity, is unclear. We report that osteocytes in MM-bearing bones physically interact with MM cells in vivo, undergo caspase3-dependent apoptosis, and express higher RANKL and Sclerostin levels than osteocytes from control mice. Mechanistic studies revealed that osteocyte apoptosis is initiated by activation of Notch signaling in osteocytes through direct contact with MM cells, and is further amplified by MM cell-secreted TNFα. This Notch/TNFα induced osteocyte apoptosis increases osteocytic Rankl expression, the osteocytic Rankl/Opg ratio and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Further, osteocytes in contact with MM cells express high levels of Sost/Sclerostin that decrease Wnt signaling in osteoblasts and inhibit osteoblast differentiation. Importantly, direct contact between osteocytes and MM cells reciprocally activates Notch signaling and increases Notch receptor expression in MM cells, in particular Notch3 and 4, and stimulates MM cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling between MM cells and osteocytes that enhances MM growth and bone disease, and suggest the potential of targeting osteocyte-MM cell interactions as a novel MM treatment. PMID:26833121

  6. Electrochemical polishing of notches

    Science.gov (United States)

    Kephart, Alan R.; Alberts, Alfred H.

    1989-01-01

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

  7. Notch strength of composites

    Science.gov (United States)

    Whitney, J. M.

    1983-01-01

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

  8. Roles of Pofut1 and O-fucose in mammalian Notch signaling.

    Science.gov (United States)

    Stahl, Mark; Uemura, Kazuhide; Ge, Changhui; Shi, Shaolin; Tashima, Yuko; Stanley, Pamela

    2008-05-16

    Mammalian Notch receptors contain 29-36 epidermal growth factor (EGF)-like repeats that may be modified by protein O-fucosyltransferase 1 (Pofut1), an essential component of the canonical Notch signaling pathway. The Drosophila orthologue Ofut1 is proposed to function as both a chaperone required for stable cell surface expression of Notch and a protein O-fucosyltransferase. Here we investigate these dual roles of Pofut1 in relation to endogenous Notch receptors of Chinese hamster ovary and murine embryonic stem (ES) cells. We show that fucosylation-deficient Lec13 Chinese hamster ovary cells have wild type levels of Pofut1 and cell surface Notch receptors. Nevertheless, they have reduced binding of Notch ligands and low levels of Delta1- and Jagged1-induced Notch signaling. Exogenous fucose but not galactose rescues both ligand binding and Notch signaling. Murine ES cells lacking Pofut1 also have wild type levels of cell surface Notch receptors. However, Pofut1-/- ES cells do not bind Notch ligands or exhibit Notch signaling. Although overexpression of fucosyltransferase-defective Pofut1 R245A in Pofut1-/- cells partially rescues ligand binding and Notch signaling, this effect is not specific. The same rescue is achieved by an unrelated, inactive, endoplasmic reticulum glucosidase. Therefore, mammalian Notch receptors require Pofut1 for the generation of optimally functional Notch receptors, but, in contrast to Drosophila, Pofut1 is not required for stable cell surface expression of Notch. Importantly, we also show that, under certain circumstances, mammalian Notch receptors are capable of signaling in the absence of Pofut1 and O-fucose.

  9. An evaluation on fatigue crack growth in a fine-grained isotropic graphite

    Energy Technology Data Exchange (ETDEWEB)

    Wang Hongtao; Sun Libin [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing 100084 (China); Li Chenfeng [College of Engineering, Swansea University, Singleton Park, Swansea SA2 8PP (United Kingdom); Shi Li [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing 100084 (China); Wang Haitao, E-mail: wanght@tsinghua.edu.cn [Institute of Nuclear and New Energy Technology, Tsinghua University, Beijing 100084 (China)

    2012-09-15

    Highlights: Black-Right-Pointing-Pointer The propagation of micro- and macro-fatigue cracks in IG-11 graphite was studied. Black-Right-Pointing-Pointer The curves of the fatigue crack growth rate versus the SIF range show three stages. Black-Right-Pointing-Pointer The fatigue microcrack propagation is very sensitive to graphite's microstructures. Black-Right-Pointing-Pointer Graphite's microstructures have no significant impact on fatigue macrocrack growth. Black-Right-Pointing-Pointer The fatigue fracture surface indicates the fracture mechanism of the IG-11 graphite. - Abstract: The aim of this paper is to investigate the mechanism of fatigue crack propagation in IG-11 graphite, and determine the crack growth rate in relation to the stress level. Experimental studies were performed at both micro and macro scales. For fatigue microcrack propagation, single-edge-notch specimens were chosen for testing and the fatigue crack growth was measured in situ with a scanning electron microscope. For fatigue macrocrack propagation, CT specimens were used and the fatigue crack growth was measured with a high-accuracy optic microscope. Combining the two groups of experimental results, the following conclusions are derived: (1) The heterogeneous microstructures of the graphite material have significant impact on the fatigue microcrack growth, while their influence on fatigue macrocrack growth is very limited. (2) The relationship between the fatigue crack growth rate and the crack-tip stress intensity factor range can be expressed in the form of Paris formulae, which contains three stages: an initial rising part with a small slope, an abrupt rise with a very large acceleration, and a short final part with a small slope. (3) The fatigue fracture surface of the graphite material contains considerable sliding of leaf-shape graphite flakes combined with small cotton-shape plastic deformations. These sliding traces are approximately aligned at 45 Degree-Sign , showing the

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

    Science.gov (United States)

    Stanley, Pamela; Guidos, Cynthia J

    2009-07-01

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

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

    Science.gov (United States)

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

    2006-03-10

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

  12. FATIGUE STRENGTH OF HIGH-STRENGTH STEEL,

    Science.gov (United States)

    coldhardened by deforming to 83%. It was found that it has low static notch sensitivity (lower than that of heat-treated steels), that static strength ...is raised appreciably by increased cold plastic deformation, and that its fatigue strength is raised substantially by mechanical polishing. (Author)

  13. Fatigue associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis.

    Science.gov (United States)

    Li, Jing; Gu, Jian

    2017-07-21

    The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44-2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

  14. Low cycle fatigue of irradiated LMFBR materials

    Energy Technology Data Exchange (ETDEWEB)

    Blackburn, L D

    1976-01-01

    A review of low cycle fatigue data on irradiated LMFBR materials was conducted and extensive graphical representations of available data are presented. Representative postirradiation tensile properties of annealed 304 and 316 SS are selected and employed in several predictive methods to estimate irradiated material fatigue curves. Experimental fatigue data confirm the use of predictive methods for establishing conservative design curves over the range of service conditions relevant to such CRBRP components as core former, fixed radial shielding, core barrel, lower inlet module and upper internals structures. New experimental data on fatigue curves and creep-fatigue interaction in irradiated 20 percent cold worked (CW) 316 SS and Alloy 718 would support the design of removable radial shielding and upper internals in CRBRP. New experimental information on notched fatigue behavior and cyclic stress-strain curves of all these materials in the irradiated condition could provide significant design data.

  15. A fatigue initiation parameter for gas pipe steel submitted to hydrogen absorption

    Energy Technology Data Exchange (ETDEWEB)

    Capelle, J.; Gilgert, J.; Pluvinage, G. [LaBPS - Ecole Nationale d' Ingenieurs de Metz et Universite Paul Verlaine Metz, Ile du Saulcy, 57045 Metz (France)

    2010-01-15

    Fatigue initiation resistance has been determined on API 5L X52 gas pipe steel. Tests have been performed on Roman Tile (RT) specimen and fatigue initiation was detected by acoustic emission. A comparison between specimens electrolytically charged with hydrogen and specimens without hydrogen absorption were made and it has been noted that fatigue initiation time is reduced of about 3 times when hydrogen embrittlement occurs. It has been proposed to use the concept of Notch Stress Intensity Factor as parameter to describe the fatigue initiation process. Due to the fact that hydrogen is localised in area with high hydrostatic pressure, definitions of local effective stress and distance have been modified when hydrogen is absorbed. This modification can be explained by existence of a ductile-brittle transition with hydrogen concentration. The fatigue initiation resistance curve allows that to determine a threshold for large number of cycles of fatigue non initiation. This parameter introduced in a Failure Assessment Diagram (FAD) provides supplementary information about defect nocivity in gas pipes: a non-critical defect can be detected as dormant or not dormant defect i.e., as non propagating defect. (author)

  16. Fatigue as a long-term risk factor for limitations in instrumental activities of daily living and/or mobility performance in older adults after 10 years

    Directory of Open Access Journals (Sweden)

    Mueller-Schotte S

    2016-11-01

    Full Text Available Sigrid Mueller-Schotte,1–3 Nienke Bleijenberg,1,2,4 Yvonne T van der Schouw,1 Marieke J Schuurmans2,4 1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands; 2Department for the Chronically Ill, University of Applied Sciences Utrecht, the Netherlands; 3Department of Optometry and Orthoptics, University of Applied Sciences Utrecht, the Netherlands; 4Department of Rehabilitation, Nursing Science and Sports, University Medical Center Utrecht, the Netherlands Objectives: Decline in the performance of instrumental activities of daily living (IADL and mobility may be preceded by symptoms the patient experiences, such as fatigue. The aim of this study is to investigate whether self-reported non-task-specific fatigue is a long-term risk factor for IADL-limitations and/or mobility performance in older adults after 10 years. Methods: A prospective study from two previously conducted cross-sectional studies with 10-year follow-up was conducted among 285 males and 249 females aged 40–79 years at baseline. Fatigue was measured by asking “Did you feel tired within the past 4 weeks?” (males and “Do you feel tired?” (females. Self-reported IADLs were assessed at baseline and follow-up. Mobility was assessed by the 6-minute walk test. Gender-specific associations between fatigue and IADL-limitations and mobility were estimated by multivariable logistic and linear regression models. Results: A total of 18.6% of males and 28.1% of females were fatigued. After adjustment, the odds ratio for fatigued versus non-fatigued males affected by IADL-limitations was 3.3 (P=0.023. In females, the association was weaker and not statistically significant, with odds ratio being 1.7 (P=0.154. Fatigued males walked 39.1 m shorter distance than those non-fatigued (P=0.048. For fatigued females, the distance was 17.5 m shorter compared to those non-fatigued (P=0.479. Conclusion: Our data suggest that self-reported fatigue

  17. Compassion Fatigue, Compassion Satisfaction, and Burnout: Factors Impacting a Professional's Quality of Life

    Science.gov (United States)

    Sprang, Ginny; Whitt-Woosley, Adrienne; Clark, James J.

    2007-01-01

    This study examined the relationship between three variables, compassion fatigue (CF), compassion satisfaction (CS), and burnout, and provider and setting characteristics in a sample of 1,121 mental health providers in a rural southern state. Respondents completed the Professional Quality of Life Scale as part of a larger survey of provider…

  18. Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome

    NARCIS (Netherlands)

    Eede, F. van den; Moorkens, G.; Hulstijn, W.; Houdenhove, B. van; Cosyns, P.; Claes, S.J.

    2008-01-01

    Background Studies of hypothalamic–pituitary–adrenal (HPA) axis function in chronic fatigue syndrome (CFS) point to hypofunction, although there are negative reports. Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the ne

  19. Predictive factors of postpartum fatigue: a prospective cohort study among working women

    NARCIS (Netherlands)

    Bakker, M.; Beek, A.J. van der; Hendriksen, I.J.M.; Bruinvels, D.J.; Poppel, M.N. van

    2014-01-01

    Objectives The aim of this study was to investigate which prepartum determinants contribute to the development of postpartum (PP) fatigue among working women in the Netherlands. Methods A prospective cohort study in 15 Dutch companies was conducted to measure different potential predictors using sel

  20. SHORT FATIGUE CRACK PARAMETER BASED ON THE TOTAL CRACK AREA

    Institute of Scientific and Technical Information of China (English)

    Z.X.Wu; X.C.Wu

    2001-01-01

    The progressive fatigue damage of a material is closely related to the whole populationof cracks on the surface of an un-notched specimen.In order to understand whichparameter is a more useful indicator of fatigue damage,rotatory bending fatigue testswere carried out using smooth specimens of medium-carbon steel.The behavior ofshort crack propagation during fatigue was examined and a new parameter "totalcrack area" was suggested.The aim of this paper is to extend the research on fatiguedamage in the already studied steel and to study how these damage parameters arecorrelated with the process of fatigue damage in order to evaluate the effectiveness ofdamage detection methods.

  1. 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

  2. Notch in Pathological Angiogenesis and Lymphangiogenesis

    Science.gov (United States)

    2012-05-01

    endothelial cells ( HUVEC ). Notch family receptors and ligands (Notch 1, Notch 4, Dll-4, Jag1) are present in HUVEC . Activation of Notch in HUVEC inhibits...associated gene, which is also repressed in HUVEC upon Notch activation) (data not shown). Figure 2a

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

    Science.gov (United States)

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

    2016-06-24

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

  4. Notch activation by phenethyl isothiocyanate attenuates its inhibitory effect on prostate cancer cell migration.

    Directory of Open Access Journals (Sweden)

    Su-Hyeong Kim

    Full Text Available Phenethyl isothiocyanate (PEITC is a promising cancer chemopreventive component of edible cruciferous vegetables with in vivo efficacy against prostate cancer in experimental rodents. Cancer chemopreventive response to PEITC is characterized by its ability to inhibit multiple oncogenic signaling pathways, including nuclear factor-κB, Akt, and androgen receptor. The present study demonstrates, for the first time, that PEITC treatment activates Notch signaling in malignant as well as normal human prostate cells. Exposure of human prostate cancer cells (LNCaP, PC-3, and DU145 and a normal human prostate epithelial cell line (PrEC to PEITC resulted in cleavage (active form of Notch1 and Notch2, and increased transcriptional activity of Notch. In PC-3 and LNCaP cells, PEITC treatment caused induction of Notch ligands Jagged1 and Jagged2 (PC-3, overexpression of γ-secretase complex components Presenilin1 and Nicastrin (PC-3, nuclear enrichment of cleaved Notch2, and/or up-regulation of Notch1, Notch2, Jagged1, and/or Jagged2 mRNA. PEITC-induced apoptosis in LNCaP and PC-3 cells was significantly attenuated by RNA interference of Notch2, but not by pharmacological inhibition of Notch1. Inhibition of PC-3 and LNCaP cell migration resulting from PEITC exposure was significantly augmented by knockdown of Notch2 protein as well as pharmacological inhibition of Notch1 activation. Nuclear expression of cleaved Notch2 protein was significantly higher in PC-3 xenografts from PEITC-treated mice and dorsolateral prostates from PEITC-fed TRAMP mice compared with respective control. Because Notch signaling is implicated in epithelial-mesenchymal transition and metastasis, the present study suggests that anti-metastatic effect of PEITC may be augmented by a combination regimen involving a Notch inhibitor.

  5. Strong Coupling between On Chip Notched Ring Resonator and Nanoparticle

    CERN Document Server

    Wang, S; Smith, H; Yi, Y

    2010-01-01

    We have demonstrated a new photonic structure to achieve strong optical coupling between nanoparticle and photonic molecule by utilizing a notched micro ring resonators. By creating a notch in the ring resonator and putting a nanoparticle inside the notch, large spectral shifts and splittings at nm scale can be achieved, compared to only pm scale observed by fiber tip evanescently coupled to the surface of microsphere, thereby significantly lowered the quality factor requirement for single nanoparticle detection. The ability for sorting the type of nanoparticles due to very different mode shift and splitting behavior of dielectric and metallic nanoparticles is also emphasized.

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

    Science.gov (United States)

    Koenig, Sara N; Bosse, Kevin M; Nadorlik, Holly A; Lilly, Brenda; Garg, Vidu

    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.

  7. Factors affecting the corrosion fatigue life in nickel based superalloys for disc applications

    Directory of Open Access Journals (Sweden)

    Rosier Hollie

    2014-01-01

    Full Text Available The nickel based superalloy 720Li is employed in the gas turbine due to its mechanical performance at elevated temperature. A comprehensive assessment of the materials behaviour under representative service conditions is reported to address the drive for ever increasing temperatures and more arduous environmental exposure. Fatigue experiments have been performed in an air and air/SOx environment at 700 ∘C containing a mixed salt as a contaminant. There is an intimate relationship between local salt level (flux, stress level and stress state, i.e. static or cyclic. The interaction with these variables with the work hardened layer present on the surface of all tested specimens as a result of the shot peening process directly affects the crack initiation process. If specific conditions of environment and stress are achieved, a significant reduction in fatigue life is observed.

  8. Factors affecting the corrosion fatigue life in nickel based superalloys for disc applications

    OpenAIRE

    Rosier Hollie; Perkins Karen; Girling Andrew; Leggett Jonathan; Gibson Grant

    2014-01-01

    The nickel based superalloy 720Li is employed in the gas turbine due to its mechanical performance at elevated temperature. A comprehensive assessment of the materials behaviour under representative service conditions is reported to address the drive for ever increasing temperatures and more arduous environmental exposure. Fatigue experiments have been performed in an air and air/SOx environment at 700 ∘C containing a mixed salt as a contaminant. There is an intimate relationship between loca...

  9. NOTCH FILTER USING SIMULATED INDUCTOR

    Directory of Open Access Journals (Sweden)

    D.SUSAN,

    2011-06-01

    Full Text Available The design of analog filters at low frequencies is not possible because the size of inductors becomes very large. In such cases, the simulated inductors using operational amplifiers are used. This paper deals with the implementation of notch filter using band pass filter which uses simulated inductor where the direct implementation of notch filter using simulated inductor is not possible because of floating inductor. The design of notch filter and the simulation done in PSPICE is presented.

  10. Notch Charge-Coupled Devices

    Science.gov (United States)

    Janesick, James

    1992-01-01

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

  11. Fatigue risk management: Organizational factors at the regulatory and industry/company level.

    Science.gov (United States)

    Gander, Philippa; Hartley, Laurence; Powell, David; Cabon, Philippe; Hitchcock, Edward; Mills, Ann; Popkin, Stephen

    2011-03-01

    This paper focuses on the development of fatigue risk management systems (FRMS) in the transport sector. The evolution of regulatory frameworks is traced, from uni-dimensional hours of service regulations through to frameworks that enable multi-dimensional FRMS. These regulatory changes reflect advances in understanding of human error in the aetiology of accidents, and in fatigue and safety science. Implementation of FRMS shifts the locus of responsibility for safety away from the regulator towards companies and individuals, and requires changes in traditional roles. Organizational, ethnic, and national culture need to be considered. Recent trends in the work environment have potential to adversely affect FRMS, including precarious employment and shortages of skilled labour. Essential components of an FRMS, and examples of FRMS in different transport modes, are described. It is vital that regulators, employer, and employees have an understanding of the causes and consequences of fatigue that is sufficient for them to meet their responsibilities in relation to FRMS. While there is a strong evidence base supporting the principles of FRMS, experience with implementation is more limited. The evidence base for effective implementation will expand, since FRMS is data-driven, and ongoing evaluation is integral. We strongly advocate that experience be shared wherever possible. Copyright © 2009 Elsevier Ltd. All rights reserved.

  12. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB signaling in glioblastoma cancer stem cells regulates the Notch pathway.

    Science.gov (United States)

    Garner, Jo Meagan; Fan, Meiyun; Yang, Chuan He; Du, Ziyun; Sims, Michelle; Davidoff, Andrew M; Pfeffer, Lawrence M

    2013-09-06

    Malignant gliomas are locally aggressive, highly vascular tumors that have a dismal prognosis, and present therapies provide little improvement in the disease course and outcome. Many types of malignancies, including glioblastoma, originate from a population of cancer stem cells (CSCs) that are able to initiate and maintain tumors. Although CSCs only represent a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance drives tumorigenesis. Therefore, it is imperative to identify pathways associated with CSCs to devise strategies to selectively target them. In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. Glioma CSCs were isolated and maintained in vitro using an adherent culture system, and the biological properties were compared with the traditional cultures of CSCs grown as multicellular spheres under nonadherent culture conditions. Interestingly, both adherent and spheroid glioma CSCs show constitutive activation of the STAT3/NF-κB signaling pathway and up-regulation of STAT3- and NF-κB-dependent genes. Gene expression profiling also identified components of the Notch pathway as being deregulated in glioma CSCs, and the deregulated expression of these genes was sensitive to treatment with STAT3 and NF-κB inhibitors. This finding is particularly important because Notch signaling appears to play a key role in CSCs in a variety of cancers and controls cell fate determination, survival, proliferation, and the maintenance of stem cells. The constitutive activation of STAT3 and NF-κB signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma.

  13. Influence of surface finish on fatigue properties of metallic materials: a bibliographic study; Influence de l`etat de surface sur les proprietes de fatigue des materiaux metalliques: etude bibliographique

    Energy Technology Data Exchange (ETDEWEB)

    Akamatsu, M. [Electricite de France (EDF), Direction des Etudes et Recherches, 92 - Clamart (France)

    1997-12-31

    The investigation of a fatigue failed component very often shows that cracks initiated at the surface. It is actually well known that the surface finish notably influences the fatigue strength of a component. We have carried out a bibliographic study in order to clarify the influence of the different surface parameters. The analysis of the literature has shown that most of the data concerns high cycle fatigue. Three aspects of the surface finish have been examined: geometry (roughness), residual stresses and microstructure. In a general way, the influence of geometrical surface finish is tackled either empirically, with a factor assessing the fatigue limit decrease when the roughness and the tensile strength increase, or theoretically, with approaches modelling geometrical irregularities as notches or cracks. In all cases, the effect of roughness on fatigue strength depends on the material, through mechanical properties or microstructural features. The theoretical approaches seem particularly interesting, but their use is not straightforward and requires further development. The creation of residual stresses at the surface of a component can just as well reduce as improve its fatigue strength. In a first approach, these stresses can be regarded as a mean service stress. In fact, mechanical and metallurgical gradients near the surface have to be taken into account, which affect the relaxation of residual stresses during fatigue cycling. Actually, the effect of residual stresses can hardly be isolated, because these stresses are associated with geometrical and microstructural modifications. Microstructural features (metallurgical structure, grain size, inclusions, strain hardening) have an undoubted influence on fatigue strength, but the quantification of the effects remains tricky. The influence of the microstructure of surface layers on fatigue strength generally depends on the mechanical properties of materials. In short, fatigue strength predictions through a

  14. No evidence for a functional role of bi-directional Notch signaling during angiogenesis.

    Directory of Open Access Journals (Sweden)

    Sven S Liebler

    Full Text Available The Delta-Notch pathway is a signal exchanger between adjacent cells to regulate numerous differentiation steps during embryonic development. Blood vessel formation by sprouting angiogenesis requires high expression of the Notch ligand DLL4 in the leading tip cell, while Notch receptors in the trailing stalk cells are activated by DLL4 to achieve strong Notch signaling activity. Upon ligand binding, Notch receptors are cleaved by ADAM proteases and gamma-secretase. This releases the intracellular Notch domain that acts as a transcription factor. There is evidence that also Notch ligands (DLL1, DLL4, JAG1, JAG2 are processed upon receptor binding to influence transcription in the ligand-expressing cell. Thus, the existence of bi-directional Delta-Notch signaling has been proposed. We report here that the Notch ligands DLL1 and JAG1 are processed in endothelial cells in a gamma-secretase-dependent manner and that the intracellular ligand domains accumulate in the cell nucleus. Overexpression of JAG1 intracellular domain (ICD as well as DLL1-ICD, DLL4-ICD and NOTCH1-ICD inhibited endothelial proliferation. Whereas NOTCH1-ICD strongly repressed endothelial migration and sprouting angiogenesis, JAG1-ICD, DLL1-ICD and DLL4-ICD had no significant effects. Consistently, global gene expression patterns were only marginally affected by the processed Notch ligands. In addition to its effects as a transcription factor, NOTCH1-ICD promotes cell adhesion to the extracellular matrix in a transcription-independent manner. However, JAG1-ICD, DLL1-ICD and DLL4-ICD did not influence endothelial cell adhesion. In summary, reverse signaling of Notch ligands appears to be dispensable for angiogenesis in cellular systems.

  15. Uncovering Notch pathway in the parasitic flatworm Schistosoma mansoni.

    Science.gov (United States)

    Magalhães, Lizandra G; Morais, Enyara R; Machado, Carla B; Gomes, Matheus S; Cabral, Fernanda J; Souza, Julia M; Soares, Cláudia S; Sá, Renata G; Castro-Borges, William; Rodrigues, Vanderlei

    2016-10-01

    Several signaling molecules that govern development in higher animals have been identified in the parasite Schistosoma mansoni, including the transforming growth factor β, protein tyrosine kinases, nuclear hormone receptors, among others. The Notch pathway is a highly conserved signaling mechanism which is involved in a wide variety of developmental processes including embryogenesis and oogenesis in worms and flies. Here we aimed to provide the molecular reconstitution of the Notch pathway in S. mansoni using the available transcriptome and genome databases. Our results also revealed the presence of the transcripts coded for SmNotch, SmSu(H), SmHes, and the gamma-secretase complex (SmNicastrin, SmAph-1, and SmPen-2), throughout all the life stages analyzed. Besides, it was observed that the viability and separation of adult worm pairs were not affected by treatment with N-[N(3,5)-difluorophenacetyl)-L-Alanyl]-S-phenylglycine t-butyl ester (DAPT), a Notch pathway inhibitor. Moreover, DAPT treatment decreased the production of phenotypically normal eggs and arrested their development in culture. Our results also showed a significant decrease in SmHes transcript levels in both adult worms and eggs treated with DAPT. These results provide, for the first time, functional validation of the Notch pathway in S. mansoni and suggest its involvement in parasite oogenesis and embryogenesis. Given the complexity of the Notch pathway, further experiments shall highlight the full repertoire of Notch-mediated cellular processes throughout the S. mansoni life cycle.

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

    Directory of Open Access Journals (Sweden)

    Andrew T Baker

    2014-12-01

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

  17. Factors associated with cancer-related fatigue in breast cancer patients undergoing endocrine therapy in an urban setting: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Huang Xu

    2010-08-01

    Full Text Available Abstract Background Fatigue is prevalent in breast cancer survivors and has profound effects on daily life. The interference of fatigue with endocrine therapy may be difficult to separate. This study investigates the prevalence and severity of fatigue and identifies the demographic, clinical, and lifestyle factors associated with cancer-related fatigue (CRF in breast cancer patients undergoing endocrine therapy in an urban area. Methods Women with stage I-IIIA breast cancer were recruited and asked to participate (n = 371 in the study. The 315 women who responded to the questionnaire (84.9%, 54 (17.1% had completed endocrine therapy and 261 (82.9% were still undergoing endocrine therapy. The patients had been diagnosed at an average of 31 months prior to recruitment (range, 7 to 60 months; the average age was 48 (range, 33 to 72 years. The 11-point scale and Visual Analog Scale (VAS were employed to quantify the level of fatigue experienced by the patients. Logistic regression analyses and a trend test method were performed to evaluate factors associated with CRF. Results Among the 315 patients, 189 (60% had experienced or were experiencing CRF during endocrine therapy. Logistic regression analysis was performed to identify factors associated with CRF, including BMI (body mass index, clinical stage, menopausal status, duration of endocrine therapy, physical activity, and diet. Factors unrelated to CRF were age, marital status, treatment, endocrine therapy drugs, alcohol intake, and smoking. The trend test method revealed an association between physical activity and dietary level and the intensity of CRF. Conclusions The present findings suggest that fatigue is an important problem in the majority of breast cancer patients during endocrine therapy. We found that BMI, clinical stage, menopausal status, duration of endocrine therapy, physical activity, and diet are associated with fatigue. Future research should focus on the impact factors of CRF

  18. Local strain energy density to assess the multiaxial fatigue strength of titanium alloys

    Directory of Open Access Journals (Sweden)

    Filippo Berto

    2016-07-01

    Full Text Available The present paper investigates the multiaxial fatigue strength of sharp V-notched components made of titanium grade 5 alloy (Ti-6Al-4V. Axisymmetric notched specimens have been tested under combined tension and torsion fatigue loadings, both proportional and non-proportional, taking into account different nominal load ratios (R = -1 and 0. All tested samples have a notch root radius about equal to 0.1 mm, a notch depth of 6 mm and an opening angle of 90 degrees. The fatigue results obtained by applying multiaxial loadings are discussed together with those related to pure tension and pure torsion experimental fatigue tests, carried out on both smooth and notched specimens at load ratios R ranging between -3 and 0.5. Altogether, more than 250 fatigue results (19 S-N curves are examined, first on the basis of nominal stress amplitudes referred to the net area and secondly by means of the strain energy density averaged over a control volume embracing the V-notch tip. The effect of the loading mode on the control volume size has been analysed, highlighting a wide difference in the notch sensitivity of the considered material under tension and torsion loadings. Accordingly, the control radius of the considered titanium alloy (Ti-6Al-4V is found to be strongly affected by the loading mode.

  19. NOTCH Signaling and ATOH1 in Colorectal Cancers

    OpenAIRE

    2011-01-01

    The Notch receptor signaling pathway regulates expression of the basic helix-loop-helix transcription factor ATOH1 (Math1/Hath1) to determine cell fate in the intestine. In differentiating intestinal stem cells, high levels of Notch activity specify absorptive enterocyte/colonocyte differentiation, whereas high ATOH1 activity specifies secretory (goblet, enteroendocrine, and Paneth) cell differentiation. In colorectal cancer, ATOH1 is a tumor suppressor that is silenced in most tumors, while ...

  20. Impact of factors on fatigue in patients with Parkinson's disease%帕金森病疲劳的相关因素研究

    Institute of Scientific and Technical Information of China (English)

    楼跃; 肖勤; 陈生弟

    2012-01-01

    目的 探讨帕金森病(Parkinson disease,PD)患者疲劳的相关因素及其存在的可能机制.方法 入组PD患者73例,采用疲劳量表(Fatigue Severity Scale,FSS)评定患者是否存在疲劳,详细记录患者的年龄、病程、用药情况,并进行UPDRS、Hoehn-Yahr分期、汉密顿抑郁量表(HMDS)、PD自主神经症状量表(the scale for outcomes in PD for autonomic symptoms,SCOPA-AUT)等评定,比较疲劳组(FSS分值/9>4)和非疲劳组(FSS分值/9≤4)在各方面是否存在差别.结果 73例参与疲劳评价的PD患者中,56例(76.7%)存在疲劳.日常生活能力、运动障碍、治疗的并发症、自主神经功能及HMDS与疲劳相关.Logistic回归分析显示,UPDRS第二部分评分及HMDS是疲劳的独立危险因素.结论 疲劳是PD患者的常见非运动症状,日常生活能力、运动障碍、自主神经功能及抑郁对疲劳存在一定影响.%Objective To investigate the impact of factors on fatigue in the patients with Parkinson's disease. Methods 73 patients with Parkinson's disease (PD) were enrolled in the study. Fatigue Seventy scale was used to evaluate whether there is fatigue or not. The patient's age, course of disease, medication, UPDRS score, Hoehn-Yahr score, Hamilton Depression Rating Scale (HMDS), the scale for outcomes in PD for autonomic symptoms (SCOPA-AUT) were recorded, comparison between the fatigue group and the non-fatigue group was investigated. Results Of the 73 PD subjects, 36 (76.7%) were defined as fatigue. Daily living skills (UPDRS II), motor scores (UPDRS III), therapeutic complications, autonomic symptoms and HMDS were significantly associated with fatigue. Binary-Logistic regression analyses showed that UPDRS II and HMDS were independent risk factors for fatigue in patients with PD. Conclusions Fatigue is an independent non-motor symptom in the spectrum of PD. Daily living skills, motor scores, autonomic symptoms and depression have impact on fatigue in patients with PD.

  1. Ubiquitination of Notch1 is regulated by MAML1-mediated p300 acetylation of Notch1

    Energy Technology Data Exchange (ETDEWEB)

    Popko-Scibor, Anita E.; Lindberg, Mikael J.; Hansson, Magnus L.; Holmlund, Teresa [Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm (Sweden); Wallberg, Annika E., E-mail: Annika.Wallberg@ki.se [Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm (Sweden)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer p300 acetylates conserved lysines within Notch1 C-terminal nuclear localization signal. Black-Right-Pointing-Pointer MAML1 and CSL, components of Notch transcription complex, increase Notch acetylation. Black-Right-Pointing-Pointer MAML1-dependent acetylation of Notch1 by p300 decreases the ubiquitination of Notch1. Black-Right-Pointing-Pointer CDK8 inhibits Notch acetylation and Notch transcription enhanced by p300. -- Abstract: Earlier studies demonstrated the involvement of the p300 histone acetyltransferase in Notch signaling but the precise mechanisms by which p300 might modulate Notch function remains to be investigated. In this study, we show that p300 acetylates Notch1 ICD in cell culture assay and in vitro, and conserved lysines located within the Notch C-terminal nuclear localization signal are essential for Notch acetylation. MAML1 and CSL, which are components of the Notch transcription complex, enhance Notch acetylation and we suggest that MAML1 increases Notch acetylation by potentiating p300 autoacetylation. Furthermore, MAML1-dependent acetylation of Notch1 ICD by p300 decreases the ubiquitination of Notch1 ICD in cellular assays. CDK8 has been shown to target Notch1 for ubiquitination and proteosomal degradation. We show that CDK8 inhibits Notch acetylation and Notch transcription enhanced by p300. Therefore, we speculate that acetylation of Notch1 might be a mechanism to regulate Notch activity by interfering with ubiquitin-dependent pathways.

  2. Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway.

    Science.gov (United States)

    Chong, Lei; Zhang, Weixi; Nie, Ying; Yu, Gang; Liu, Liu; Lin, Li; Wen, Shunhang; Zhu, Lili; Li, Changchong

    2014-10-01

    Curcumin, a natural product derived from the plant Curcuma longa, has been found to have anti-inflammatory, antineoplastic and antifibrosis effects. It has been reported that curcumin attenuates allergic airway inflammation in mice through inhibiting NF-κB and its downstream transcription factor GATA3. It also has been proved the antineoplastic effect of curcumin through down-regulating Notch1 receptor and its downstream nuclear transcription factor NF-κB levels. In this study, we aimed to investigate the anti-inflammatory effect of curcumin on acute allergic asthma and its underlying mechanisms. 36 male BALB/c mice were randomly divided into four groups (normal, asthma, asthma+budesonide and asthma+curcumin groups). BALF (bronchoalveolar lavage fluid) and lung tissues were analyzed for airway inflammation and the expression of Notch1, Notch2, Notch3, Notch4 and the downstream transcription factor GATA3. Our findings showed that the levels of Notch1 and Notch2 receptors were up-regulated in asthma group, accompanied by the increased expression of GATA3. But the expression of Notch2 receptor was lower than Notch1 receptor. Curcumin pretreatment improved the airway inflammatory cells infiltration and reversed the increasing levels of Notch1/2 receptors and GATA3. Notch3 receptor was not expressed in all of the four groups. Notch4 receptor protein and mRNA expression level in the four groups had no significant differences. The results of the present study suggested that Notch1 and Notch2 receptor, major Notch1 receptor, played an important role in the development of allergic airway inflammation and the inhibition of Notch1-GATA3 signaling pathway by curcumin can prevent the development and deterioration of the allergic airway inflammation. This may be a possible therapeutic option of allergic asthma.

  3. SHH和Notch及其下游信号分子在人子宫内膜癌组织的表达与临床意义%Expression of SHH and Notch and their effective signaling factor in human endometrial carcinomas

    Institute of Scientific and Technical Information of China (English)

    程一苇; 解承兰; 王静; 王燕; 徐胜菊; 侯建青

    2011-01-01

    目的:探讨SHH,Notch信号通路和其下游信号分子Gli-1、Hes-1在人子宫内膜癌的表达及意义.方法:应用免疫组织化学方法检测37例正常人子宫内膜、增生内膜和子宫内膜癌中SHH、Notch信号的表达,同时采用RT-PCR方法检测上述新鲜组织中Gli-1、Hes-1的表达.结果:子宫内膜增生组和子宫内膜癌组SHH、Notch的表达均强于正常组(P<0.05).正常组和子宫内膜增生组Gli-1的表达类似,在子宫内膜癌组表达较低;正常组和子宫内膜增生组Hes-1的表达类似,在子宫内膜癌组表达升高.经随访,本研究选取的病例现均存活.结论:SHH和Notch表达与子宫内膜癌的发生密切相关,Gli-1和Hes-1主要参与子宫内膜癌的进展变化,但可能作用不同.%Objective: To explore the expression and significance of sonic hedgehog ( SHH ) , Notch and their effective signaling factor in endometnal carcinomas. Methods : The expression of SHH and Notch was examined in normal endometrial tissues ,hyperplasia and carcinomatous endometrium by immunohistochemistry. Gli-1 and Hes-1 as effective factor of SHH and Notch signaling on the endometrial carcinoma were also examined hy RT-PCR. Results : The expression of SHH and Notch was very weak in normal endometrium,but was increased in endometrial hyperplasia and carcinoma stepwisely with significant differences. There was no marked difference in the expression of these molecules in carcmomas according to stages and histologic grades. The expression of Hes-1 mRNAs was weak in normal endometrial tissues, with a slight predominance in the proliferative phase and endometrial careinomas. Gli-1 mRNA was weak in endometrial carcinoma, the expression of Gli-1 mRNAs was increased in normal and hyperplasia endometrium. Conclusion :The abnormal activation of SHH and Notch pathway is invojved in the endometrial carcinoma possibly in an auto/paracrine fashion, suggesting the possibility of the hedgehog and Notch pathway being a

  4. Fatigue design of hydraulic turbine runners

    Energy Technology Data Exchange (ETDEWEB)

    Huth, Hans-Joerg

    2005-07-01

    Turbine runners experience start-stop cycles and vibration cycles. Cracks initiated from service or manufacturing defects and propagated by start-stop cycles become critical when the stress intensity range due to vibrational loading exceeds the threshold for fatigue crack growth. In Francis turbine runners, semi-elliptical surface cracks tend to propagate from the quarter-circular transition of the welded T-joint transition between the blade and the band or crown. Assuming a crack to grow under a constant stress amplitude equal to that at the most highly loaded location at the welded joint between the blade and the band or crown of a Francis turbine runner yields a conservative estimate of the life of the runner. A more accurate prediction of fatigue life is obtained by considering the growth of a crack in the real, inhomogeneous stress field. For an idealised T-joint under pure bending, the stress field has been determined by means of plane strain finite element analysis. Finite element models of the entire Francis runner are built with respect to the calculation of fluid dynamic properties. Since in these models geometry transitions are modelled as a sharp notch, both a finite and a zero transition radius have been modelled, and the influence of the mesh size on the maximum stress has been investigated. For relatively small cracks, it is shown that the structural component geometry does not remarkably influence the stress intensity factor values, provided that the stress field in the vicinity of the crack is approximately the same. Therefore, in order to simplify the stress intensity factor retrieval and to generate a solution of extended applicability, a cracked finite-thickness plate is examined instead of the actual T-joint geometry. The stress intensity factors along the front of a semi-elliptical surface crack in such a plate are determined by means of an analysis using finite quarter-point wedge elements for different elementary loading conditions that can

  5. Physical activity and physical activity cognitions are potential factors maintaining fatigue in patients with primary Sjogren's syndrome

    NARCIS (Netherlands)

    Wouters, Eveline J. M.; van Leeuwen, Ninke; Bossema, Ercolie R.; Kruize, Aike A.; Bootsma, Hendrika; Bijlsma, Johannes W. J.; Geenen, Rinie

    Background Fatigue is a prevalent and debilitating problem in Sjogren's syndrome. It has been suggested that physical activity and cognitions about physical activity can influence fatigue. Objective The aim of this study was to examine fatigue and physical activity levels in patients with Sjogren's

  6. Physical activity and physical activity cognitions are potential factors maintaining fatigue in patients with primary Sjögren's syndrome

    NARCIS (Netherlands)

    Van Leeuwen; MD E.J.M. Wouters; Bossema; Bootsma; Geenen; Kruize; Bijlsma

    2012-01-01

    Background Fatigue is a prevalent and debilitating problem in Sjögren's syndrome. It has been suggested that physical activity and cognitions about physical activity can influence fatigue. Objective The aim of this study was to examine fatigue and physical activity levels in patients with Sjögren's

  7. Physical activity and physical activity cognitions are potential factors maintaining fatigue in patients with primary Sjogren's syndrome

    NARCIS (Netherlands)

    Wouters, Eveline J. M.; van Leeuwen, Ninke; Bossema, Ercolie R.; Kruize, Aike A.; Bootsma, Hendrika; Bijlsma, Johannes W. J.; Geenen, Rinie

    2012-01-01

    Background Fatigue is a prevalent and debilitating problem in Sjogren's syndrome. It has been suggested that physical activity and cognitions about physical activity can influence fatigue. Objective The aim of this study was to examine fatigue and physical activity levels in patients with Sjogren's

  8. Fatigue Crack Nucleation Studies on Sulfuric Acid Anodized 7075-T73 Aluminum

    Science.gov (United States)

    Savas, Terence P.; Earthman, James C.

    2014-06-01

    The influence of a sulfuric acid anodic coating process on the fatigue crack nucleation behavior of 7075-T73 aluminum alloy was investigated. Silicone surface replication in combination with carbon sputter coating and scanning electron microscopy (SEM) allowed for in situ monitoring of the number of cycles for crack nucleation. A single edge circular notch (SECN) coupon was designed for the present study to localize fatigue damage thus enhancing fatigue crack detection and capture the effects of multiaxial stress conditions indicative of a majority engineering applications. Linear elastic finite element modeling of the SECN coupon was performed to quantify the von Mises equivalent stress distribution and the stress concentration factor of the notched region. The experimental results indicate that the presence of localized pitting corrosion initiated during the anodic coating pretreatment process had an adverse effect on fatigue performance. Specifically, multiple crack nucleation sites were evident as opposed to a single crack origin for the untreated specimens. Post-cycling SEM surface examinations displayed networks of micro-cracks in the anodic coating emanating from the pits although these were not found to be fatigue crack origin sites during post SEM fractographic exams. Thus, the stress concentration effect of the corrosion pits was found to be predominant. The total cycles to failure on average was reduced by approximately 60% for the anodic coated versus untreated specimens. A strategy is also discussed on how to mitigate accelerated crack nucleation by controlled surface pretreatment and use of a chromated chemical conversion coating in lieu of an anodic coating for selective applications.

  9. Notch as a tumour suppressor.

    Science.gov (United States)

    Nowell, Craig S; Radtke, Freddy

    2017-03-01

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

  10. Notch Signaling in Neuroendocrine Tumors

    Directory of Open Access Journals (Sweden)

    Judy Sue Crabtree

    2016-04-01

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

  11. Complete Absence of Suprascapular Notch: A Case Report

    Directory of Open Access Journals (Sweden)

    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.

  12. Factors that influence fatigue status in patients with severe rheumatoid arthritis (RA) and good disease outcome following 6 months of TNF inhibitor therapy: a comparative analysis.

    LENUS (Irish Health Repository)

    Minnock, Patricia

    2015-11-01

    The objective of the present study is to determine the factors associated with persistent fatigue in patients with severe rheumatoid arthritis (RA) and good disease response to 6 months of tumour necrosis factor inhibitor therapy. Eligible patients with either persistent (PF) or no fatigue (NF) were compared. Using validated questionnaires and bivariate analysis, this cross-sectional survey explored if clinical characteristics, pain, self-efficacy, sleep and mood\\/depression differed between groups. Patients with PF (PF; NF) (n = 28; 28) reported significantly more overall pain (11.3 ± 9.4 (0-33); 6.9 ± 8.9 (0-33)), more recent and current pain intensity (41.4 ± 26.6 (0-80) 24.4 ± 26.6 (0-100) and depression (11.8 ± 7.5 (1-35); 8.2 ± 6.6 (0-26)), than the NF group. There was no significant difference between groups in self-efficacy and both groups experienced poor sleep quality (Pittsburgh Sleep Quality Index >5). Despite having good disease response, the PF group had significantly higher rheumatoid factor incidence, disease activity score-28, early morning stiffness duration and lower incidence of ever-failing disease-modifying anti-rheumatic drugs than the NF group. These findings enhance the fatigue literature in patients with RA prescribed tumour necrosis factor (TNF) inhibition therapy, identifying the potentially modifiable factors of pain and depression, previously demonstrated to be strongly associated with fatigue in non-biologic populations. In addition, this study highlights the association between persistent fatigue and an on-going state of low disease activity. This infers that more judicious disease management could minimise the symptom burden of pain and depression and consequentially fatigue.

  13. Nanoparticle optical notch filters

    Science.gov (United States)

    Kasinadhuni, Pradeep Kumar

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

  14. Fatigue approach for addressing environmental effects in fatigue usage calculation

    Energy Technology Data Exchange (ETDEWEB)

    Wilhelm, Paul; Rudolph, Juergen [AREVA GmbH, Erlangen (Germany); Steinmann, Paul [Erlangen-Nuremberg Univ., erlangen (Germany). Chair of Applied Mechanics

    2015-04-15

    Laboratory tests consider simple trapezoidal, triangle, and sinusoidal signals. However, actual plant components are characterized by complex loading patterns and periods of holds. Fatigue tests in water environment show, that the damage from a realistic strain variation or the presence of hold-times within cyclic loading results in an environmental reduction factor (Fen) only half that of a simple waveform. This study proposes a new fatigue approach for addressing environmental effects in fatigue usage calculation for class 1 boiler and pressure vessel reactor components. The currently accepted method of fatigue assessment has been used as a base model and all cycles, which have been comparable with realistic fatigue tests, have been excluded from the code-based fatigue calculation and evaluated directly with the test data. The results presented show that the engineering approach can successfully be integrated in the code-based fatigue assessment. The cumulative usage factor can be reduced considerably.

  15. Pain in People with Multiple Sclerosis: Associations with Modifiable Lifestyle Factors, Fatigue, Depression, Anxiety, and Mental Health Quality of Life

    Directory of Open Access Journals (Sweden)

    Claudia H. Marck

    2017-09-01

    Full Text Available BackgroundPeople with multiple sclerosis (MS often experience pain, which can interfere with mobility, employment, and quality of life (QOL.MethodsThis cross-sectional study explored associations between pain, demographic, disease, and modifiable lifestyle factors in an international sample of people with MS recruited online.ResultsSubstantial pain, of moderate/severe intensity and interfering at least moderately with work/household or enjoyment of life in the past 4 weeks, was reported by 682/2,362 (28.9%. Substantial pain was associated with fatigue (odds ratio (OR: 6.7, 95% confidence interval (CI: 4.9,9.3, depression (OR:4.0, 95% CI:3.2,5.1, anxiety (OR:2.4, 95% CI:1.9,2.9, and lower mental health QOL (Mean Difference: −14.7, 95% CI:−16.6,−12.8. Regression analyses showed that smoking (OR: 2.0, 95% CI:1.35,2.87 and obesity (OR:2.1, 95% CI: 1.5,2.8, moderate alcohol use (OR: 0.7, 95% CI:0.5,0.9, moderate (OR 0.7, 95% CI: 0.55,0.98 or high (OR 0.6, 95% CI: 0.4,0.8 physical activity level, and healthy diet (OR 0.8, 95% CI: 0.75,0.95, per 10 points were associated with substantial pain.ConclusionOur results show clear associations with modifiable lifestyle factors and substantial pain in MS. These factors are already considered in the prevention and management of pain in other populations but have not previously been considered in MS. Conversely, pain and associated common MS comorbidities, such as depression, anxiety, and fatigue, may hamper efforts to start or maintain healthy behaviors. Strategies to overcome these barriers need to be considered. Further research should clarify the direction of these associations.

  16. Double-notch-shaped microdisk resonator devices with gapless coupling on a silicon chip Invited Paper

    Institute of Scientific and Technical Information of China (English)

    Xianshu Luo; Andrew W. Poon

    2009-01-01

    We propose novel double-notch-shaped microdisk resonator-based devices with gapless waveguide-to- microdisk and inter-cavity coupling via the two notches of the microdisk. Both finite-difference time- domain simulations and experimental demonstrations reveal the high-quality-factor multimode resonances in such microdisks. Using such double-notch microdisk resonators, we experimentally demonstrate the many-element linearly cascaded-microdisk resonator devices with up to 50 elements on a silicon chip.

  17. Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways

    OpenAIRE

    2008-01-01

    Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6 and IL-12. Cooperation by these pathways to increase target gene expression was mediated the Notch pathway component and transcription factor RB...

  18. Thermal emission in fatigue described by power laws

    Directory of Open Access Journals (Sweden)

    Gallinatti A.E.

    2010-06-01

    Full Text Available In the present work, a theoretical model proposed by the literature and focused on the relationship between microplasticizations thermal behaviour and fatigue scatter is analysed and applied to fatigue test results of standard and notched steel specimens. The same experimental data are subjected to the TCM (Two Curves Method thermographic elaboration technique, in order to quickly evaluate fatigue limit values. TCM method has been modified, aiming at interpolating thermal data referred to the region of loads upper than fatigue limit with a non linear regression law having the same mathematical structure of the theoretical model equations (power laws.

  19. Fatigue in repeated-sprint exercise is related to muscle power factors and reduced neuromuscular activity.

    Science.gov (United States)

    Mendez-Villanueva, Alberto; Hamer, Peter; Bishop, David

    2008-07-01

    The purpose of this study was (1) to determine the relationship between each individual's anaerobic power reserve (APR) [i.e., the difference between the maximum anaerobic (Pana) and aerobic power (Paer)] and fatigability during repeated-sprint exercise and (2) to examine the acute effects of repeated sprints on neuromuscular activity, as evidenced by changes in the surface electromyogram (EMG) signals. Eight healthy males carried out tests to determine Pana (defined as the highest power output attained during a 6-s cycling sprint), Paer (defined as the highest power output achieved during a progressive, discontinuous cycling test to failure) and a repeated cycling sprint test (10 x 6-s max sprints with 30 s rest). Peak power output (PPO) and mean power output (MPO) were calculated for each maximal 6-s cycling bout. Root mean square (RMS) was utilized to quantify EMG activity from the vastus lateralis (VL) muscle of the right leg. Over the ten sprints, PPO and MPO decreased by 24.6 and 28.3% from the maximal value (i.e., sprint 1), respectively. Fatigue index during repeated sprints was significantly correlated with APR (R = 0.87; P < 0.05). RMS values decreased over the ten sprints by 14.6% (+/-6.3%). There was a strong linear relationship (R2 = 0.97; P < 0.05) between the changes in MPO and EMG RMS from the vastus lateralis muscle during the ten sprints. The individual advantage in fatigue-resistance when performing a repeated sprint task was related with a lower anaerobic power reserve. Additionally, a suboptimal net motor unit activity might also impair the ability to repeatedly generate maximum power outputs.

  20. Notch sensitivity of aliphatic polyketone terpolymers

    NARCIS (Netherlands)

    Zuiderduin, W.C.J.; Huetink, J.; Gaymans, R.J.

    2004-01-01

    The notch sensitivity of aliphatic polyketone (PK) terpolymers was investigated in this article. The notch-tip radius was varied between the size of an actual propagating crack tip of 1-2 m and the largest notch tip of 1000 m radius. The larger notch-tip radii (1000-15 m) were milled into the polyme

  1. Muscle Deoxygenation Causes Muscle Fatigue

    Science.gov (United States)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D.

    1999-01-01

    Muscle fatigue is a common musculoskeletal disorder in the work place, and may be a harbinger for more disabling cumulative trauma disorders. Although the cause of fatigue is multifactorial, reduced blood flow and muscle oxygenation may be the primary factor in causing muscle fatigue during low intensity muscle exertion. Muscle fatigue is defined as a reduction in muscle force production, and also occurs among astronauts who are subjected to postural constraints while performing lengthy, repetitive tasks. The objectives of this research are to: 1) develop an objective tool to study the role of decreased muscle oxygenation on muscle force production, and 2) to evaluate muscle fatigue during prolonged glovebox work.

  2. Drosophila p53 controls Notch expression and balances apoptosis and proliferation.

    Science.gov (United States)

    Simón, Rocío; Aparicio, Ricardo; Housden, Ben E; Bray, Sarah; Busturia, Ana

    2014-10-01

    A balance between cell proliferation and apoptosis is important for normal development and tissue homeostasis. Under stress conditions, the conserved tumor suppressor and transcription factor Dp53 induces apoptosis to contribute to the maintenance of homeostasis. However, in some cases Dp53-induced apoptosis results in the proliferation of surrounding non-apoptotic cells. To gain insight into the Dp53 function in the control of apoptosis and proliferation, we studied the interaction between the Drosophila Dp53 and Notch genes. We present evidence that simultaneous reduction of Dp53 and Notch function synergistically increases the wing phenotype of Notch heterozygous mutant flies. Further, we found that a Notch cis-regulatory element is responsive to loss and gain of Dp53 function and that over-expression of Dp53 up-regulates Notch mRNA and protein expression. These findings suggest not only that Dp53 and Notch act together to control wing development but also indicate that Dp53 transcriptionally regulates Notch expression. Moreover, using Notch  gain and loss of function mutations we examined the relevance of Dp53 and Notch interactions in the process of Dp53-apoptosis induced proliferation. Results show that proliferation induced by Dp53 over-expression is dependent on Notch, thus identifying Notch as a new player in Dp53-induced proliferation. Interestingly, we found that Dp53-induced Notch activation and proliferation occurs even under conditions where apoptosis was inhibited. Our findings highlight the conservation between flies and vertebrates of the Dp53 and Notch cross-talk and suggest that Dp53 has a dual role regulating cell death and proliferation gene networks to control the homeostatic balance between apoptosis and proliferation.

  3. The influence of the notches on the natural frequencies

    Directory of Open Access Journals (Sweden)

    Dekýš V.

    2007-10-01

    Full Text Available The simplification of the FEM model (the missing of a notch or a crack generally means the modification of the natural frequencies. An analysis of these changes is matter of this paper. The direct and semicircle notches were made on the testing specimens (by cut depth in the specimens and the naturals frequencies were measured and computed. The results are compared.In the paper is discussed the choice of the FEM element for FEM model and the comparison with experiment is made too.The influence of the crack on the natural frequencies is discussed in the case of specimen for high cycle fatigue test. The changes of the first three frequencies are compared for specimens with and without crack.

  4. Angiotensin II contributes to renal fibrosis independently of Notch pathway activation.

    Directory of Open Access Journals (Sweden)

    Carolina Lavoz

    Full Text Available Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1 has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.

  5. Angiotensin II contributes to renal fibrosis independently of Notch pathway activation.

    Science.gov (United States)

    Lavoz, Carolina; Rodrigues-Diez, Raquel; Benito-Martin, Alberto; Rayego-Mateos, Sandra; Rodrigues-Diez, Raúl R; Alique, Matilde; Ortiz, Alberto; Mezzano, Sergio; Egido, Jesús; Ruiz-Ortega, Marta

    2012-01-01

    Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.

  6. Improved Fatigue Performance of Threaded Drillstring Connections by Cold Rolling

    Energy Technology Data Exchange (ETDEWEB)

    Kristoffersen, Steinar

    2002-01-01

    The research work presented in this thesis is concerned with analytical, numerical and experimental studies of the effect of cold rolling on the fatigue behaviour of threaded drillstring connections. A comprehensive literature study is made of the various effects on the fatigue behaviour of residual stresses introduced by mechanical deformation of notched components. Some of the effects studied are cyclic hardening behaviour after prestraining, cyclic creep, fatigue initiation in prestrained materials, short cracks and crack growth models including crack closure. Residual stresses were introduced in the surface of a smooth pipe by a rolling device to simulate a cold rolling process and verify the calculated residual stresses by measurements. Strain hardening and contact algorithm of the two bodies were incorporated in the FE analyses. Two significant errors were found in the commercial software package for residual stress evaluation, Restran v. 3.3.2a also called SINT, when using the Schajer method. The Schajer algorithm is the only hole-drilling algorithm without theoretical shortcomings, and is recommended when measuring large residual stress gradients in the depth direction. Using the Schajer method solved by in-house Matlab-routines good agreement between measured residual stress gradients and residual stress gradients from FE analyses was found. Full scale fatigue tests were performed on pipes cut from used drillstrings with notches of similar geometry as threads used in drillstring connections. The simulated threads consisted of four full depth helix notches with runouts at the surface. The pipe threads were cold rolled and fatigue tested in a full-scale four-point rotating bending fatigue testing rig. The test results showed that cold rolling had an effect on the crack initiation period. A major part of the fatigue life was with cracks observed at the notch root, but due to the increased fatigue crack propagation resistance the final fracture initiated at

  7. Fatigue after Stroke: The Patient's Perspective

    Directory of Open Access Journals (Sweden)

    Victoria Louise Barbour

    2012-01-01

    Full Text Available Background. Fatigue after stroke is common and distressing to patients. Aims. Our aims were to explore patients' perceptions of post-stroke fatigue, including the causes of fatigue and the factors that alleviate fatigue, in a mixed methods study. Results. We interviewed 15 patients who had had a stroke and were inpatients on stroke rehabilitation wards. A substantial proportion of patients reported that their fatigue started at the time of their stroke. Various different factors were reported to improve fatigue, including exercise, good sleep, rehabilitation and rest. Fatigue influences patients' sense of “control” after their stroke. Conclusion. Our results are consistent with the possibility that poststroke fatigue might be triggered by factors that occur at the time of the stroke (e.g., the stroke lesion itself, or admission to hospital and then exacerbated by poor sleep and boredom. These factors should be considered when developing complex interventions to improve post-stroke fatigue.

  8. Involvement of Notch1/Hes signaling pathway in ankylosing spondylitis.

    Science.gov (United States)

    Xu, Wei; Liang, Chao-Ge; Li, Yi-Fan; Ji, Yun-Han; Qiu, Wen-Jun; Tang, Xian-Zhong

    2015-01-01

    We aimed to investigate the role of Notch1/Hes signaling pathway in the pathogenesis of abnormal ossification of hip ligament in patients with ankylosing spondylitis (AS). 22 AS patients scheduled for artificial hip arthroplasty were randomly chosen as AS group. As controls, we used 4 patients diagnosed with transcervical fracture who underwent hip replacement surgery. Notch1 and Hes mRNA expressions were detected by real-time fluorescent quantitative polymerase chain reaction (RFQ-PCR). Immunohistochemistry (IHC) was used to detect Notch1 and Hes protein expression. Correlation analyses of Notch-l and Hes with AS-related clinical factors were conducted with spearman's correlation analysis and partial correlation analysis. RFQ-PCR results showed significant differences in Notch1 and Hes mRNA expressions between AS group and the control group (all Phip joint ligaments of AS patients, Hes protein expression was associated with the clinical course of AS. Taken together, we suggest that signaling pathways mediated by Notch1-Hes may contribute to ligament ossification of hip joints in AS patients.

  9. THEORETICAL AND EXPERIMENTAL STUDIES ON FRACTURE PLANE CONTROL BLAST WITH NOTCHED BOREHOLES

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    The results of theoretical studies and field tests on fracture plane control blast with notched boreholes have been introduced. In these studies, the single symmetrical notched borehole was simplified to a pressurized hole with two symmetrical cracks under the state of plane strain. In analyzing the growth and termination of the notch, only quasi-static pressure was considered. In the mean time, the rock to be blasted was considered to be isotropic. Based on the principles of fracture mechanics, the stress components near the tip of the notch were calculated, and the criteria for growth and termination of the notch were established. The growth direction of the notch was also predicted on the basis of strain energy density factor. An approach for estimating the amount of explosive for each hole and the spacing of holes was suggested. Furthermore, field tests were conducted to check the results from the theoretical studies.

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

    Science.gov (United States)

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

    2004-11-01

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

  11. The experience of pain severity and pain interference in vulvodynia patients: The role of cognitive-behavioural factors, psychological distress and fatigue.

    Science.gov (United States)

    Chisari, Claudia; Chilcot, Joseph

    2017-02-01

    Vulvodynia is a chronic pain condition characterised by severe pain affecting the vulva. Biopsychosocial models have revealed the importance of illness perceptions, cognitive-behavioural variables and psychological distress in explaining the experience of pain and disability across several conditions. These factors have never been collectively examined in vulvodynia. We predicted that distress, fatigue, illness perceptions, and cognitive-behavioural factors would be associated with pain severity and interference among women with vulvodynia. This online cross-sectional study recruited 335 vulvodynia patients from an Italian charity association (Vulvodiniapuntoinfo.com), who completed pain severity and interference measures in addition to the Hospital Anxiety and Depression scale, Revised Illness Perception Questionnaire, Chalder Fatigue Questionnaire, Cognitive-Behavioural Symptom Questionnaire and a demographic questionnaire. Hierarchical regression models controlling for demographic and illness characteristics, revealed that lower treatment control beliefs, greater illness identity, catastrophizing and psychological distress, were significant predictors of pain severity, explaining 35% of the variance. A second adjusted hierarchical regression model revealed that low treatment-control, higher fatigue, distress, and avoidance/resting behaviours were significant predictors of pain interference, explaining 48% of the variance. Distress, illness perceptions, fatigue, and cognitive-behavioural factors are associated with pain severity and interference in patients with vulvodynia, highlighting the importance of adopting a biopsychosocial approach in this setting. Future research should examine these factors over time to inform the development of future tailored interventions to help support women better manage vulvodynia. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Development of high-cycle fatigue design curves for a cast aluminum alloy

    Science.gov (United States)

    Cooper, R. A.

    1979-01-01

    Life prediction curves for rocket engine pump parts were developed from the results of high-cycle fatigue tests run on cast-aluminum specimens. Notched and smooth specimens were cyclically tested at different mean stress levels at -320 F (78 K). The notch size and mean stress enveloped the design operating conditions. Local stress computed in the groove of the notched specimen was used to represent its fatigue strength. The von Mises criterion was used to determine effective cyclic stresses. The Goodman rule was applied to determine equivalent reversed alternating stresses. The procedure permitted the notched and smooth data sets to each be described by a single curve. High-cycle fatigue life curves were provided for the stress state, mean stress, and stress concentration spanned by the data.

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

    Science.gov (United States)

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

    2014-04-01

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

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

    NARCIS (Netherlands)

    Li, H.; Koo, Y.; Mao, X.; Sifuentes-Dominguez, L.; Morris, L.L.; Jia, D.; Miyata, N; Faulkner, R.A.; Deursen, J.M.A. van; Vooijs, M.; Billadeau, D.D.; Sluis, B. van de; Cleaver, O.; Burstein, E.

    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 endolysosom

  15. Regulation of angiogenesis via Notch signaling in breast cancer and cancer stem cells.

    Science.gov (United States)

    Zhou, Weiqiang; Wang, Guangdi; Guo, Shanchun

    2013-12-01

    Breast cancer angiogenesis is elicited and regulated by a number of factors including the Notch signaling. Notch receptors and ligands are expressed in breast cancer cells as well as in the stromal compartment and have been implicated in carcinogenesis. Signals exchanged between neighboring cells through the Notch pathway can amplify and consolidate molecular differences, which eventually dictate cell fates. Notch signaling and its crosstalk with many signaling pathways play an important role in breast cancer cell growth, migration, invasion, metastasis and angiogenesis, as well as cancer stem cell (CSC) self-renewal. Therefore, significant attention has been paid in recent years toward the development of clinically useful antagonists of Notch signaling. Better understanding of the structure, function and regulation of Notch intracellular signaling pathways, as well as its complex crosstalk with other oncogenic signals in breast cancer cells will be essential to ensure rational design and application of new combinatory therapeutic strategies. Novel opportunities have emerged from the discovery of Notch crosstalk with inflammatory and angiogenic cytokines and their links to CSCs. Combinatory treatments with drugs designed to prevent Notch oncogenic signal crosstalk may be advantageous over λ secretase inhibitors (GSIs) alone. In this review, we focus on the more recent advancements in our knowledge of aberrant Notch signaling contributing to breast cancer angiogenesis, as well as its crosstalk with other factors contributing to angiogenesis and CSCs.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Survival Analysis of Factors Influencing Cyclic Fatigue of Nickel-Titanium Endodontic Instruments

    Directory of Open Access Journals (Sweden)

    Eva Fišerová

    2015-01-01

    Full Text Available Objective. The aim of this study was to validate a survival analysis assessing the effect of type of rotary system, canal curvature, and instrument size on cyclic resistance. Materials and Methods. Cyclic fatigue testing was carried out in stainless steel artificial canals with radii of curvature of 3 or 5 mm and the angle of curvature of 60 degrees. All the instruments were new and 25 mm in working length, and ISO colour coding indicated the instrument size (yellow for size 20; red for size 25. Wizard Navigator instruments, Mtwo instruments, ProTaper instruments, and Revo-S instruments were passively rotated at 250 rotations per minute, and the time fracture was being recorded. Subsequently, fractographic analysis of broken tips was performed by scanning electron microscope. The data were then analysed by the Kaplan-Meier estimator of the survival function, the Cox proportional hazards model, the Wald test for regression covariates, and the Wald test for significance of regression model. Conclusion. The lifespan registered for the tested instruments was Mtwo > Wizard Navigator > Revo-S > ProTaper; 5 mm radius > 3 mm radius; and yellow > red in ISO colour coding system.

  18. Notch2 and Notch3 Function Together to Regulate Vascular Smooth Muscle Development

    OpenAIRE

    Qingqing Wang; Ning Zhao; Simone Kennard; Brenda Lilly

    2012-01-01

    Notch signaling has been implicated in the regulation of smooth muscle differentiation, but the precise role of Notch receptors is ill defined. Although Notch3 receptor expression is high in smooth muscle, Notch3 mutant mice are viable and display only mild defects in vascular patterning and smooth muscle differentiation. Notch2 is also expressed in smooth muscle and Notch2 mutant mice show cardiovascular abnormalities indicative of smooth muscle defects. Together, these findings infer that N...

  19. Strengthening of old metallic structures in fatigue with prestressed and non-prestressed CFRP laminates

    DEFF Research Database (Denmark)

    Täljsten, Björn; Hansen, Christian Skodborg; Schmidt, Jacob Wittrup

    2009-01-01

    Test results and theoretical considerations on four different configurations of strengthened old steel plates with a centre notch loaded in fatigue are presented in this paper. The main interest of the research was to improve fatigue life by adhesive bonding of CFRP laminates on the steel surface...

  20. Determinants of fatigue and stress

    Directory of Open Access Journals (Sweden)

    Brähler Elmar

    2011-07-01

    Full Text Available Abstract Background Fatigue can be triggered by previous perceived stress which may lead to impairment of performance and function. The purpose of the study was to investigate the relationship between fatigue and perceived stress. Method Health determinants including sociodemographic factors for associations between fatigue and perceived stress in the general population (N = 2,483 are outlined. Fatigue and stress were assessed with the Chalder Fatigue Scale (CFS and the Perceived Stress Questionnaire (PSQ. Results Within the general population, 25.9% of male and 34.5% of female respondents reported moderate fatigue during the last six months; 9.7% of subjects reported substantial fatigue lasting six months or longer. An adjusted regression analysis (R2corr = .28, p Conclusion We conclude that the two conditions overlap most in terms of socio-economic status and self-perceived health status.

  1. FOUR NOTCH ROADLESS AREA, TEXAS.

    Science.gov (United States)

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

    1984-01-01

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

  2. Flight Fatigue Symptoms,Effect Factors and Detecting Techniques%飞行疲劳表现、影响因素及监测技术

    Institute of Scientific and Technical Information of China (English)

    吴锋广; 牟海鹰

    2015-01-01

    Based on data from aviation accident investigation ,75% accidents are caused by human factors , mostly related to the pilot fatigue driving .First of all ,pilot fatigue symptoms were exposited from the as‐pects of physiology ,mentality ,and emotion .Secondly ,factors affecting flight fatigue were analysed from personal ,organizational ,environmental and aircraft factors .Lastly ,the status of pilot fatigue monitoring technology was summarized ,and the development trend in the future was pointed out on the basis of analy‐sing the advantages and disadvantages .%航空事故调查数据表明,75%事故是人为因素造成的,其中多与飞行员疲劳驾驶有关。首先从生理、心理和情绪三个方面阐述飞行员疲劳症状;其次从机组个人因素、组织因素、环境因素和飞机设备因素四个方面分析飞行疲劳影响因素;最后对飞行员驾驶疲劳监测技术现状进行归纳整理,在分析优缺点的基础上,指出了未来发展趋势。

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

    Science.gov (United States)

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

    2017-06-01

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

  4. RNAi干扰Notch-1对人肝癌细胞BEL-7402AFP表达及细胞增殖的影响%Effects of RNAi-mediated gene silencing of Notch-1 transcriptional factor on the expression of AFP overexpression and cell proliferation in hepatocellular carcinoma cells BEL 7402

    Institute of Scientific and Technical Information of China (English)

    刘虹

    2012-01-01

    目的 采用RNAi干扰细胞通讯因子Notch-1对肝癌细胞BEL-7402中AFP表达及细胞增殖的影响.方法 通过siRNA抑制BEL-7402细胞中Notch-1的表达,采用qRT-PCR和Western blotting法,检测其对AFP表达的影响,采用MTI法测定细胞增殖情况.结果 siRNA抑制Notch-1达后,AFP mRNA及其蛋白水平显著下降,RNAi干扰组与对照组比较BEL-7402细胞生长明显受抑制(P<0.01).结论 Notch-1 siRNA可以下调肝癌细胞BEL-7402中AFP mRNA及其蛋白的表达水平,抑制BEL-7402细胞的生长,提示Notch-1基因在肝癌细胞的发生、发展中具有重要作用,Notch-1可能是AFP过量表达肝癌的治疗靶点.

  5. Notch signaling induces rapid degradation of achaete-scute homolog 1.

    Science.gov (United States)

    Sriuranpong, Virote; Borges, Michael W; Strock, Christopher L; Nakakura, Eric K; Watkins, D Neil; Blaumueller, Christine M; Nelkin, Barry D; Ball, Douglas W

    2002-05-01

    In neural development, Notch signaling plays a key role in restricting neuronal differentiation, promoting the maintenance of progenitor cells. Classically, Notch signaling causes transactivation of Hairy-enhancer of Split (HES) genes which leads to transcriptional repression of neural determination and differentiation genes. We now report that in addition to its known transcriptional mechanism, Notch signaling also leads to rapid degradation of the basic helix-loop-helix (bHLH) transcription factor human achaete-scute homolog 1 (hASH1). Using recombinant adenoviruses expressing active Notch1 in small-cell lung cancer cells, we showed that the initial appearance of Notch1 coincided with the loss of hASH1 protein, preceding the full decay of hASH1 mRNA. Overexpression of HES1 alone was capable of down-regulating hASH1 mRNA but could not replicate the acute reduction of hASH1 protein induced by Notch1. When adenoviral hASH1 was coinfected with Notch1, we still observed a dramatic and abrupt loss of the exogenous hASH1 protein, despite high levels of ongoing hASH1 RNA expression. Notch1 treatment decreased the apparent half-life of the adenoviral hASH1 protein and increased the fraction of hASH1 which was polyubiquitinylated. The proteasome inhibitor MG132 reversed the Notch1-induced degradation. The Notch RAM domain was dispensable but a lack of the OPA and PEST domains inactivated this Notch1 action. Overexpression of the hASH1-dimerizing partner E12 could protect hASH1 from degradation. This novel function of activated Notch to rapidly degrade a class II bHLH protein may prove to be important in many contexts in development and in cancer.

  6. STRESS FIELD AT A TIP OF A PREFABRICATED SPIRAL V-NOTCH

    Institute of Scientific and Technical Information of China (English)

    郑周练; 陈山林; 叶晓明

    2004-01-01

    Based on the tranditional V-notched blasting,a technique of spirally V-notched blasting to loosen earth and rock was presented.Fracture mechanics and Westergaard stress function were adopted to build a complex stress function to derive the plane stress and strain fields at one tip of the crack under a quasi-static pressure.An expression was formulated to define the stress intensity factor of spiral V-notch loosen blasting.Factors that have effects on the stress intensity factor were studied.It is demonstrated that spiral V-notch loosen blasting is an extension of vertical V-notch blasting,straight cracking,and alike theories.

  7. Tumor-Suppressive Activity of Lunatic Fringe in Prostate through Differential Modulation of Notch Receptor Activation

    Directory of Open Access Journals (Sweden)

    Shubing Zhang

    2014-02-01

    Full Text Available Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng, which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44+CD24− and CD49f+CD24− stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.

  8. 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.

  9. Dll1- and Dll4-mediated Notch signaling is 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

    2011-01-01

    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

  10. Analysis of Impact Factors on Wind Turbine Fatigue Loads (Ⅲ)%风电机组疲劳载荷影响因素分析(三)

    Institute of Scientific and Technical Information of China (English)

    许移庆

    2013-01-01

    Wind turbine design is mainly dominated by fatigue loads and extreme loads. Fatigue loads are especially important for some components design because of uncertainty and instability of wind turbine operation environment. Tere are many impact factors for wind turbine fatigue loads. Tis paper mostly compared two impact factors, namely diferent design operation wind speed range and diferent design turbulence intensity classes, and analyzed their efect extent for fatigue loads.%风电机组设计主要由疲劳载荷和极限载荷决定,而风电机组运行环境的不确定性和不稳定性使得疲劳载荷对一些部件的设计尤为重要。影响疲劳载荷的因素很多,本文主要从不同设计运行风速范围和不同设计湍流强度等级两个方面进行比较,分析了两者各自对疲劳载荷影响的程度。

  11. 风电机组疲劳载荷影响因素分析(二)%Analysis of Impact Factors on Wind Turbine Fatigue Loads (Ⅱ)

    Institute of Scientific and Technical Information of China (English)

    许移庆

    2013-01-01

    Wind turbine design is mainly dominated by fatigue loads and extreme loads. Fatigue loads are especially important for some components design because of uncertainty and instability of wind turbine operation environment. Tere are many impact factors for wind turbine fatigue loads. Tis paper mostly compared two impact factors, namely diferent design operation wind speed range and diferent design turbulence intensity classes, and analyzed their efect extent for fatigue loads.%风电机组设计主要由疲劳载荷和极限载荷决定,而风电机组运行环境的不确定性和不稳定性使得疲劳载荷对一些部件的设计尤为重要。影响疲劳载荷的因素很多,本文主要从不同设计运行风速范围和不同设计湍流强度等级两个方面进行比较,分析了两者各自对疲劳载荷影响的程度。

  12. Review: Gigacycle fatigue data sheets for advanced engineering materials

    Directory of Open Access Journals (Sweden)

    Koji Yamaguchi, Takayuki Abe, Kazuo Kobayashi, Etsuo Takeuchi, Hisashi Hirukawa, Yoshio Maeda, Nobuo Nagashima, Masao Hayakawa, Yoshiyuki Furuya, Masuo Shimodaira and Kensuke Miyahara

    2007-01-01

    Full Text Available Gigacycle fatigue data sheets have been published since 1997 by the National Institute for Materials Science. They cover several areas such as high-cycle-number fatigue for high-strength steels and titanium alloys, the fatigue of welded joints, and high-temperature fatigue for advanced ferritic heat-resistant steels. Some unique testing machines are used to run the tests up to an extremely high number of cycles such as 1010 cycles. A characteristic of gigacycle fatigue failure is that it is initiated inside smooth specimens; the fatigue strength decreases with increasing cycle number and the fatigue limit disappears, although ordinary fatigue failure initiates from the surface of a smooth specimen and a fatigue limit appears. For welded joints, fatigue failure initiates from the notch root of the weld, because a large amount of stress is concentrated at the weld toe. The fatigue strength of welded joints has been obtained for up to 108 cycles, which is an extremely high number of cycles for large welded joints. The project of producing gigacycle fatigue data sheets is still continuing and will take a few more years to complete.

  13. EFFECTS OF GC-MACROPHAGE ACTIVATING FACTOR IN HUMAN NEURONS; IMPLICATIONS FOR TREATMENT OF CHRONIC FATIGUE SYNDROME

    Directory of Open Access Journals (Sweden)

    Rodney Smith

    2013-01-01

    Full Text Available Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS is a debilitating disease of multifactorial aetiology characterized by immune system dysfunction, widespread inflammation, multisystemic neuropathology and persistent pain. Given the central role of the immune system in the pathogenesis of the syndrome, we studied the effects of a potent modulator of the immune system in in vitro and in vivo models that could help clarifying its role and indications in ME/CFS treatment. To this end, we studied the effects of vitamin D-binding protein-derived macrophage activating factor (also designated as Gc-Macrophage Activating Factor or (GcMAF on human neuronal cells (SH-SY5Y and on the persistent pain induced by osteoarticular damage in rats. GcMAF at pM concentration increased neuronal cell viability and metabolism through increased mitochondrial enzyme activity. These effects were accompanied by cAMP formation and by morphological changes that were representative of neuronal differentiation. We hypothesize that these effects are to be ascribed to the interconnection between the GcMAF and Vitamin D Receptor (VDR signalling pathways. The results presented here confirm at the experimental level the therapeutic effects of GcMAF in ME/CFS and elucidate the mechanisms of action through which GcMAF might be responsible for such therapeutic effects.

  14. Fatigue in systemic lupus erythematosus.

    Science.gov (United States)

    Ahn, Grace E; Ramsey-Goldman, Rosalind

    2012-04-01

    Systemic lupus erythematosus is a chronic inflammatory autoimmune disease often characterized by fatigue, with significant effects on physical functioning and wellbeing. The definition, prevalence and factors associated with fatigue, including physical activity, obesity, sleep, depression, anxiety, mood, cognitive dysfunction, vitamin D deficiency/insufficiency, pain, effects of medications and comorbidities, as well as potential therapeutic options of fatigue in the systemic lupus erythematosus population are reviewed. Due to variability in the reliability and validity of various fatigue measures used in clinical studies, clinical trial data have been challenging to interpret. Further investigation into the relationships between these risk factors and fatigue, and improved measures of fatigue, may lead to an improvement in the management of this chronic inflammatory disease.

  15. Patient and surgery related factors associated with fatigue type polyethylene wear on 49 PCA and DURACON retrievals at autopsy and revision

    Directory of Open Access Journals (Sweden)

    Ochsner Peter E

    2008-02-01

    Full Text Available Abstract Background Polyethylene wear is an important factor for longevity of total knee arthroplasty. Proven and suspicious factors causing wear can be grouped as material, patient and surgery related. There are more studies correlating design and/or biomaterial factors to in vivo wear than those to patient and surgery related factors. Many retrieval studies just include revision implants and therefore may not be representative. This study is aimed to correlate patient- and surgery- related factors to visual wear score by minimizing design influence and include both autopsy and revision implants. Comparison between the groups was expected to unmask patient and surgery-related factors responsible for wear. Methods The amount of joint side wear on polyethylene retrievals was measured using a modification of an established visual wear score. Fatigue type wear was defined as summation of the most severe wear modes of delamination, pitting and cracks. Analysis of patient and surgery related variables suspicious to cause wear included prospectively sampled patient activity which was measured by self reported walking capacity. Statistical analysis was done by univariate analysis of variance. Activity level and implantation time were merged to an index of use and correlated to the wear score. Results Wear score after comparable implantation time was significantly less in the autopsy group. Even so, fatigue type wear accounted for 84 and 93 % of total wear score on autopsy and revision implants respectively. A highly significant influence on wear score was found in time of implantation (p = 0.002, level of activity (p = 0.025 and inserts belonging to revision group (p = 0.006. No influence was found for the kind of patella replacement (p = 0.483. Body mass index and accuracy of component alignment had no significant influence on visual wear score. Fatigue-type wear in the medial compartment was closely correlated to the index of use in the autopsy (R2

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

    Science.gov (United States)

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

    2017-02-01

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

  17. Hyperthermia and fatigue

    DEFF Research Database (Denmark)

    Nybo, Lars

    2008-01-01

    of the cardiovascular function, which eventually reduces arterial oxygen delivery to the exercising muscles. Accordingly, aerobic energy turnover is impaired and anaerobic metabolism provokes peripheral fatigue. In contrast, metabolic disturbances of muscle homeostasis are less important during prolonged exercise......The present review addresses mechanisms of importance for hyperthermia-induced fatigue during short intense activities and prolonged exercise in the heat. Inferior performance during physical activities with intensities that elicit maximal oxygen uptake is to a large extent related to perturbation...... of the dopaminergic system, but may primarily relate to inhibitory signals from the hypothalamus arising secondary to an increase in brain temperature. Fatigue is an integrated phenomenon, and psychological factors, including the anticipation of fatigue, should not be neglected and the interaction between central...

  18. Genes implicated in stem cell identity and temporal programme are directly targeted by Notch in neuroblast tumours.

    Science.gov (United States)

    Zacharioudaki, Evanthia; Housden, Benjamin E; Garinis, George; Stojnic, Robert; Delidakis, Christos; Bray, Sarah J

    2016-01-15

    Notch signalling is involved in a multitude of developmental decisions and its aberrant activation is linked to many diseases, including cancers. One example is the neural stem cell tumours that arise from constitutive Notch activity in Drosophila neuroblasts. To investigate how hyperactivation of Notch in larval neuroblasts leads to tumours, we combined results from profiling the upregulated mRNAs and mapping the regions bound by the core Notch pathway transcription factor Su(H). This identified 246 putative direct Notch targets. These genes were highly enriched for transcription factors and overlapped significantly with a previously identified regulatory programme dependent on the proneural transcription factor Asense. Included were genes associated with the neuroblast maintenance and self-renewal programme that we validated as Notch regulated in vivo. Another group were the so-called temporal transcription factors, which have been implicated in neuroblast maturation. Normally expressed in specific time windows, several temporal transcription factors were ectopically expressed in the stem cell tumours, suggesting that Notch had reprogrammed their normal temporal regulation. Indeed, the Notch-induced hyperplasia was reduced by mutations affecting two of the temporal factors, which, conversely, were sufficient to induce mild hyperplasia on their own. Altogether, the results suggest that Notch induces neuroblast tumours by directly promoting the expression of genes that contribute to stem cell identity and by reprogramming the expression of factors that could regulate maturity.

  19. An experimental study on the effects of compressive stress on the fatigue crack growth of low-alloy steel

    Energy Technology Data Exchange (ETDEWEB)

    Jones, D.P.; Hoppe, R.G. [Westinghouse Electric Corp., West Mifflin, PA (United States). Bettis Atomic Power Lab.; Hechmer, J.L. [Babcock and Wilcox Co., Barberton, OH (United States); James, B.A. [Colorado School of Mines, Golden, CO (United States). Dept. of Metallurgy

    1993-12-01

    A series of fatigue crack growth rate tests was conducted in order to study effects of negative stress ratio on fatigue crack growth rate of low-alloy steel in air. Four-point bend specimens were used to simulate linear stress distributions typical of pressure vessel applications. This type of testing adds to knowledge on negative stress ratio effects for low-alloy steels obtained in the past from uniform tension-compression tests. Applied bending stress range was varied over twice the yield strength. Load control was used for tests for which the stress range was less than twice the yield strength and deflection control was used for the higher stress range tests. Crack geometries were both short and long fatigue cracks started at notches and tight fatigue cracks for which crack closure could occur over the full crack face. Results are presented in terms of the stress intensity factor ratio R = K{sub MIN}/K{sub MAX}. The negative R-ratio test results were correlated to an equation of the form da/dN = C[{Delta}K/(A-R)]{sup n}, where A, C, and n are curve fitting parameters. It was found that effects of negative R-ratio on fatigue crack growth rates for even the high stress range tests could be bounded by correlating the above equation to only positive R-ratio test results and extending the resulting equation into the negative R-ratio regime.

  20. Small Crack Growth and Fatigue Life Predictions for High-Strength Aluminium Alloys. Part 1; Experimental and Fracture Mechanics Analysis

    Science.gov (United States)

    Wu, X. R.; Newman, J. C.; Zhao, W.; Swain, M. H.; Ding, C. F.; Phillips, E. P.

    1998-01-01

    The small crack effect was investigated in two high-strength aluminium alloys: 7075-T6 bare and LC9cs clad alloy. Both experimental and analytical investigations were conducted to study crack initiation and growth of small cracks. In the experimental program, fatigue tests, small crack and large crack tests A,ere conducted under constant amplitude and Mini-TWIST spectrum loading conditions. A pronounced small crack effect was observed in both materials, especially for the negative stress ratios. For all loading conditions, most of the fatigue life of the SENT specimens was shown to be crack propagation from initial material defects or from the cladding layer. In the analysis program, three-dimensional finite element and A weight function methods were used to determine stress intensity factors and to develop SIF equations for surface and corner cracks at the notch in the SENT specimens. A plastisity-induced crack-closure model was used to correlate small and large crack data, and to make fatigue life predictions, Predicted crack-growth rates and fatigue lives agreed well with experiments. A total fatigue life prediction method for the aluminum alloys was developed and demonstrated using the crack-closure model.

  1. Stress-ratio effect on mode II propagation of interlaminar fatigue cracks in graphite/epoxy composites

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Keisuke; Tanaka, Hiroshi [Nagoya Univ. (Japan). Dept. of Mechanical Engineering

    1997-12-31

    The effect of the stress ratio on the propagation behavior of Mode II interlaminar fatigue cracks was studied with unidirectional graphite/epoxy laminates, Toray T800H/{number_sign}3631. End-notched flexure (ENF) specimens were used for fatigue tests under the stress ratios of R = 0.2, 0.5, and 0.6; and end-loaded split (ELS) specimens were used for tests under R = {minus}1.0, {minus}0.5, and 0.2. For each stress ratio, the crack propagation rate was given by a power function of the stress intensity range, {Delta}K{sub 11}, in the region of rates above 10{sup {minus}9} m/cycle. Below this region, there exists the threshold for fatigue crack propagation. The threshold condition is given by a constant value of the stress intensity range, {Delta}K{sub 11th} = 1.8 MPa{radical}m. The crack propagation rate is determined by {Delta}K{sub 11} near the threshold, while by the maximum stress identity factor, K{sub 11max}, at high rates. A fracture mechanics equation is proposed for predicting the propagation rate of Mode II fatigue cracks under various stress ratios. The effect of the stress ratio on the micromechanism of Mode II fatigue crack propagation was discussed on the basis of the microscopic observations of fracture surfaces and near-crack-tip regions.

  2. Effect of Prestrain on Fatigue Crack Growth in Low-carbon Steel

    Directory of Open Access Journals (Sweden)

    Melnikov B.E.

    2011-05-01

    Full Text Available The current procedures of fatigue design of marine pipeline components allow for extending service life by considering a certain portion of the crack growth well before it turns into the instable phase. In structural components of transport systems material may undergo plastic pre-strain during the construction. The effect of pre-strain on the crack growth may be different depending on the material properties. Fatigue crack propagation was examined in testing symmetrically notched specimens machined from pre-strained steel plate coupons. Non-simultaneous crack initiation and propagation at the notches was reduced to symmetrical scheme by a simple coordinate transformation procedure. It was found that tensile pre-strain up to 0.01 did not substantially change the crack growth rate related to the stress intensity factor scale. Further increase of plastic pre-strain of material up to 0.15 caused almost two-times slowing down the crack growth rate compared to that of virgin material.

  3. Improvement of the fatigue life of titanium alloys for biomedical devices through microstructural control.

    Science.gov (United States)

    Niinomi, Mitsuo; Akahori, Toshikazu

    2010-07-01

    A limited number of reports exist regarding the systematic investigation or comparison of the fatigue strength of titanium alloys for medical devices, including plain, fretting and notch fatigue, for improvement through various treatments and processes, with respect to related microstructures. This article focuses on the changes and improvements in fatigue strength of newly developed beta-type and practically used alpha + beta-titanium alloys for medical devices through heat treatments, thermomechanical treatments and surface modifications.

  4. A Modified Constant-Stress Coupon for Enhanced Natural Crack Start during Fatigue Testing

    Science.gov (United States)

    2016-05-01

    UNCLASSIFIED UNCLASSIFIED A Modified Constant- Stress Coupon for Enhanced Natural Crack Start during Fatigue Testing Witold Waldman, Robert...modified constant- stress coupon for use in fatigue testing . This novel coupon design has a significantly greater surface area along the notch boundary...modified constant- stress coupon for use in fatigue testing . A constant- stress coupon is a novel design that has a significantly greater surface area along

  5. Microstructural aspects of fatigue in Ni-base superalloys.

    Science.gov (United States)

    Antolovich, Stephen D

    2015-03-28

    Nickel-base superalloys are primarily used as components in jet engines and land-based turbines. While compositionally complex, they are microstructurally simple, consisting of small (50-1000 nm diameter), ordered, coherent Ni(3)(Al,Ti)-type L1(2) or Ni(3)Nb-type DO(22) precipitates (called γ(') and γ(''), respectively) embedded in an FCC substitutional solid solution consisting primarily of Ni and other elements which confer desired properties depending upon the application. The grain size may vary from as small as 2 μm for powder metallurgy alloys used in discs to single crystals the actual size of the component for turbine blades. The fatigue behaviour depends upon the microstructure, deformation mode, environment and cycle time. In many cases, it can be controlled or modified through small changes in composition which may dramatically change the mechanism of damage accumulation and the fatigue life. In this paper, the fundamental microstructural, compositional, environmental and deformation mode factors which affect fatigue behaviour are critically reviewed. Connections are made across a range of studies to provide more insight. Modern approaches are pointed out in which the wealth of available microstructural, deformation and damage information is used for computerized life prediction. The paper ends with a discussion of the very important and highly practical subject of thermo-mechanical fatigue (TMF). It is shown that physics-based modelling leads to significantly improved life prediction. Suggestions are made for moving forward on the critical subject of TMF life prediction in notched components. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  6. Regulation of Notch-mediated transcription by a bovine herpesvirus 1 encoded protein (ORF2) that is expressed in latently infected sensory neurons.

    Science.gov (United States)

    Liu, Yilin; Jones, Clinton

    2016-08-01

    Bovine herpesvirus 1 (BoHV-1) is an Alphaherpesvirinae subfamily member that establishes life-long latency in sensory neurons. The latency-related RNA (LR-RNA) is abundantly expressed during latency. An LR mutant virus containing stop codons at the amino-terminus of open reading frame (ORF)2 does not reactivate from latency and replicates less efficiently in tonsils and trigeminal ganglia. ORF2 inhibits apoptosis, interacts with Notch family members, and interferes with Notch-dependent transcription suggesting ORF2 expression enhances survival of infected neurons. The Notch signaling pathway is crucial for neuronal differentiation and survival suggesting that interactions between ORF2 and Notch family members regulate certain aspects of latency. Consequently, for this study, we compared whether ORF2 interfered with the four mammalian Notch family members. ORF2 consistently interfered with Notch1-3-mediated transactivation of three cellular promoters. Conversely, Notch4-mediated transcription was not consistently inhibited by ORF2. Electrophoretic shift mobility assays using four copies of a consensus-DNA binding site for Notch/CSL (core binding factor (CBF)-1, Suppressor of Hairless, Lag-2) as a probe revealed ORF2 interfered with Notch1 and 3 interactions with a CSL family member bound to DNA. Additional studies demonstrated ORF2 enhances neurite sprouting in mouse neuroblastoma cells that express Notch1-3, but not Notch4. Collectively, these studies indicate that ORF2 inhibits Notch-mediated transcription and signaling by interfering with Notch interacting with CSL bound to DNA.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Factor Analysis of Fatigue Damage of Aluminium Alloy Riveted Joint%铝合金铆接件疲劳损伤的影响因素分析

    Institute of Scientific and Technical Information of China (English)

    鲍敏; 陈福玉

    2014-01-01

    铆接在航空等结构中的应用非常广泛,而疲劳损伤是影响其使用寿命的主要因素。在铆接件疲劳试验基础上,以有限元软件ANSYS Workbench为平台,分析了铆接件模型的应力状态,研究了铆钉排列位置、接触面摩擦系数、过盈量对构件应力场分布的影响,预测了疲劳裂纹可能萌生的位置;其研究结果为铆接件的抗疲劳设计提供参考。%Riveting is extensively used in aviation structures. But fatigue damage induces a dramatic reduction of service life. Based on the fatigue test and the finite element software ANSYS Workbench, the stress state of the riveted model is calculated, the influ-ence factors of stress distribution of the components, such as array location, friction coefficient, interference fit are analyzed and the probable position of the initation of fatigue crack is predicted in this paper. The results provide the theoretical basis for the design a-gainst the fatigue damage of the riveted joint.

  9. The silent information regulator 1 (Sirt1) is a positive regulator of the Notch pathway in Drosophila.

    Science.gov (United States)

    Horvath, Matej; Mihajlovic, Zorana; Slaninova, Vera; Perez-Gomez, Raquel; Moshkin, Yuri; Krejci, Alena

    2016-11-15

    The silent information regulator 1 (Sirt1) has been shown to have negative effects on the Notch pathway in several contexts. We bring evidence that Sirt1 has a positive effect on Notch activation in Drosophila, in the context of sensory organ precursor specification and during wing development. The phenotype of Sirt1 mutant resembles weak Notch loss-of-function phenotypes, and genetic interactions of Sirt1 with the components of the Notch pathway also suggest a positive role for Sirt1 in Notch signalling. Sirt1 is necessary for the efficient activation of enhancer of split [E(spl)] genes by Notch in S2N cells. Additionally, the Notch-dependent response of several E(spl) genes is sensitive to metabolic stress caused by 2-deoxy-d-glucose treatment, in a Sirt1-dependent manner. We found Sirt1 associated with several proteins involved in Notch repression as well as activation, including the cofactor exchange factor Ebi (TBL1), the RLAF/LAF histone chaperone complex and the Tip60 acetylation complex. Moreover, Sirt1 participates in the deacetylation of the CSL transcription factor Suppressor of Hairless. The role of Sirt1 in Notch signalling is, therefore, more complex than previously recognized, and its diverse effects may be explained by a plethora of Sirt1 substrates involved in the regulation of Notch signalling.

  10. Fatigue of concrete subjected to biaxial loading in the tension region

    Science.gov (United States)

    Subramaniam, Kolluru V. L.

    Rigid airport pavement structures are subjected to repeated high-amplitude loads resulting from passing aircraft. The resulting stress-state in the concrete is a biaxial combination of compression and tension. It is of interest to model the response of plain concrete to such loading conditions and develop accurate fatigue-based material models for implementation in mechanistic pavement design procedures. The objective of this work is to characterize the quasi-static and low-cycle fatigue response of concrete subjected to biaxial stresses in the tensile-compression-tension (t-C-T) region, where the principal tensile stress is larger in magnitude than the principal compressive stress. An experimental investigation of material behavior in the biaxial t-C-T region is conducted. The experimental setup consists of the following test configurations: (a) notched concrete beams tested in three-point bend configuration, and (b) hollow concrete cylinders subjected to torsion with or without superimposed axial tensile force. The damage imparted to the material is examined using mechanical measurements and an independent nondestructive evaluation (NDE) technique based on vibration measurements. The failure of concrete in t-C-T region is shown to be a local phenomenon under quasi-static and fatigue loading, wherein the specimen fails owing to a single crack. The crack propagation is studied using the principles of fracture mechanics. It is shown that the crack propagation resulting from the t-C-T loading can be predicted using mode I fracture parameters. It is observed that crack growth in constant amplitude fatigue loading is a two-phase process: a deceleration phase followed by an acceleration stage. The quasi-static load envelope is shown to predict the crack length at fatigue failure. A fracture-based fatigue failure criterion is proposed, wherein the fatigue failure can be predicted using the critical mode I stress intensity factor. A material model for the damage evolution

  11. Suprascapular Notch Asymmetry: A Study on 311 Patients

    Directory of Open Access Journals (Sweden)

    Michał Polguj

    2014-01-01

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

  12. Investigation and analysis on fatigue status of military pilots

    Directory of Open Access Journals (Sweden)

    Jian-sheng GUO

    2012-03-01

    Full Text Available Objective To investigate the fatigue status and its characteristics and influential factors of military pilots. Methods Questionnaire survey was conducted on 924 military pilots by using Fatigue Assessment Instrument (FAI and Fatigue Scale (FS-14, χ2 test and Pearson correlation analysis were performed on the data results with SPSS 17.0 software. Results The findings of fatigue status indicated 343 subjects (37.1% with positive fatigue symptoms and 581 subjects (62.9% with negative fatigue symptoms. FAI factor 1 (severity of fatigue, factor 2 (mental fatigue factor, factor 3 (consequence of fatique and the total score, FS-14 factor 1 (physical fatigue factor and the total score in fatigue-positive group were all higher than those in fatiguenegative group, and the differences were all statistically significant (P 0.05 in the possibility of developing fatigue symptoms between subjects with different aircraft types. Age and flight time were positively correlated with factor 1 and total score in FAI and factor 1, factor 2 and total score in FS-14. However, the aircraft type was associated with neither the individual factors and total score in FAI nor the individual factors and total score in FS-14. Conclusion It is common for military pilots to develop fatigue symptoms, characterized by obvious manifestations of severity, environmental specificity, consequences of fatigue and physical fatigue, and the possibilities of developing fatigue symptoms for different ages and flight time were different.

  13. Fatigue analysis of aluminum drill pipes

    Directory of Open Access Journals (Sweden)

    João Carlos Ribeiro Plácido

    2005-12-01

    Full Text Available An experimental program was performed to investigate the fundamental fatigue mechanisms of aluminum drill pipes. Initially, the fatigue properties were determined through small-scale tests performed in an optic-mechanical fatigue apparatus. Additionally, full-scale fatigue tests were carried out with three aluminum drill pipe specimens under combined loading of cyclic bending and constant axial tension. Finally, a finite element model was developed to simulate the stress field along the aluminum drill pipe during the fatigue tests and to estimate the stress concentration factors inside the tool joints. By this way, it was possible to estimate the stress values in regions not monitored during the fatigue tests.

  14. 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...

  15. Notch sensitivity of hydrogenated oxygen-strengthened titanium

    Science.gov (United States)

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

    1990-01-01

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

  16. 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...... signaling plays a fundamental role during development. Recent findings have shown that Notch signaling is dysregulated, and contributes to the malignant potential of these tumors. Growing evidence point towards an important role for cancer stem cells in the initiation and maintenance of glioma...

  17. The Notch pathway: a novel target for myocardial remodelling therapy?

    Science.gov (United States)

    Ferrari, Roberto; Rizzo, Paola

    2014-08-21

    Pathological ventricle remodelling, which follows a cardiac insult, causes heart failure. Despite the existence of multiple pharmaceutical approaches, heart failure is one of the leading causes of death worldwide and there is an urgent need to explore new therapeutic avenues. The Notch pathway is an evolutionary conserved fundamental pathway that regulates cell fate during development as well as throughout postnatal life in self-renewing tissues. In the myocardium, Notch signalling is involved in the modulation of cardiomyocytes survival, cardiac stem cells differentiation, and angiogenesis which are factors known to determine the extent of pathological cardiac remodelling. Modulation of the Notch pathway could become a tool to limit ventricle remodelling and the associated inexorable deterioration of cardiac performance.

  18. Empirical formulas for description of the fatigue crack growth rate

    Energy Technology Data Exchange (ETDEWEB)

    Rozumek, D. [Opole University of Technology, Faculty of Mechanical Engineering, Opole (Poland)

    2010-02-15

    The paper presents the test results obtained for fatigue crack growth in flat specimens subjected to bending. The tests were conducted for different loading amplitudes and different load ratios using the {delta}J parameter. Accuracy of description of the fatigue crack growth rate was tested with use of different empirical formulas. One-side restrained specimens made of 10HNAP steel were tested. In each tested specimen, there was the external notch 5 mm in depth, and the notch rounding radius was {rho}=0.2 mm. The tests were carried out at the fatigue test stand MZGS-100 under loading frequency 28.8 Hz. It has been found that the obtained results depend on the applied empirical formula. (Abstract Copyright [2010], Wiley Periodicals, Inc.)

  19. Effect of ring notch radius on the decohesion mode in AlSi alloys

    Directory of Open Access Journals (Sweden)

    J. Pieklo

    2009-04-01

    Full Text Available The article discusses the effect of the, determined by tensile test, non-linear characteristics of AlSi alloys on the value of the shape factor k for the three different sizes of the radius of the ring notch made on round specimens. Applying a numerical solution, the changes of stress in the notch plane were determined in function of the notch configuration and the value of instantaneous load. Tensile tests were carried out on round bars with ring notches. The appearance of fractures was examined on scanning images. Differences in notch effect observed in the linear-elastic and elastic-plastic model of material hardening in a non-linear mode were described.

  20. A simple nonlocal damage model for predicting failure of notched laminates

    Science.gov (United States)

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

    1995-01-01

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

  1. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application.

    Science.gov (United States)

    Yuan, Xun; Wu, Hua; Han, Na; Xu, Hanxiao; Chu, Qian; Yu, Shiying; Chen, Yuan; Wu, Kongming

    2014-12-05

    Through epithelial-mesenchymal transition (EMT), cancer cells acquire enhanced ability of migration and invasion, stem cell like characteristics and therapeutic resistance. Notch signaling regulates cell-cell connection, cell polarity and motility during organ development. Recent studies demonstrate that Notch signaling plays an important role in lung cancer initiation and cross-talks with several transcriptional factors to enhance EMT, contributing to the progression of non-small cell lung cancer (NSCLC). Correspondingly, blocking of Notch signaling inhibits NSCLC migration and tumor growth by reversing EMT. Clinical trials have showed promising effect in some cancer patients received treatment with Notch1 inhibitor. This review attempts to provide an overview of the Notch signal in NSCLC: its biological significance and therapeutic application.

  2. The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFβ/BMP and hypoxia pathways.

    Science.gov (United States)

    Borggrefe, Tilman; Lauth, Matthias; Zwijsen, An; Huylebroeck, Danny; Oswald, Franz; Giaimo, Benedetto Daniele

    2016-02-01

    Notch signaling is a highly conserved signal transduction pathway that regulates stem cell maintenance and differentiation in several organ systems. Upon activation, the Notch receptor is proteolytically processed, its intracellular domain (NICD) translocates into the nucleus and activates expression of target genes. Output, strength and duration of the signal are tightly regulated by post-translational modifications. Here we review the intracellular post-translational regulation of Notch that fine-tunes the outcome of the Notch response. We also describe how crosstalk with other conserved signaling pathways like the Wnt, Hedgehog, hypoxia and TGFβ/BMP pathways can affect Notch signaling output. This regulation can happen by regulation of ligand, receptor or transcription factor expression, regulation of protein stability of intracellular key components, usage of the same cofactors or coregulation of the same key target genes. Since carcinogenesis is often dependent on at least two of these pathways, a better understanding of their molecular crosstalk is pivotal.

  3. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation

    Science.gov (United States)

    Timmerman, Luika A.; Grego-Bessa, Joaquín; Raya, Angel; Bertrán, Esther; Pérez-Pomares, José María; Díez, Juan; Aranda, Sergi; Palomo, Sergio; McCormick, Frank; Izpisúa-Belmonte, Juan Carlos; de la Pompa, José Luis

    2004-01-01

    Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types. In the embryonic heart, Notch functions via lateral induction to promote a selective transforming growth factor-β (TGFβ)-mediated EMT that leads to cellularization of developing cardiac valvular primordia. Embryos that lack Notch signaling elements exhibit severely attenuated cardiac snail expression, abnormal maintenance of intercellular endocardial adhesion complexes, and abortive endocardial EMT in vivo and in vitro. Accordingly, transient ectopic expression of activated Notch1 (N1IC) in zebrafish embryos leads to hypercellular cardiac valves, whereas Notch inhibition prevents valve development. Overexpression of N1IC in immortalized endothelial cells in vitro induces EMT accompanied by oncogenic transformation, with corresponding induction of snail and repression of VE-cadherin expression. Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis. PMID:14701881

  4. Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis

    Directory of Open Access Journals (Sweden)

    Richard C. Godby

    2014-12-01

    Full Text Available Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS, elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs. An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs, whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN and α-SMA (ACTA2. NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease.

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

    Science.gov (United States)

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

    2016-04-29

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

  6. NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors?

    Science.gov (United States)

    Huang, Tingting; Zhou, Yuhang; Cheng, Alfred S L; Yu, Jun; To, Ka Fai; Kang, Wei

    2016-12-09

    Gastric cancer (GC) ranks the most common cancer types and is one of the leading causes of cancer-related death. Due to delayed diagnosis and high metastatic frequency, 5-year survival rate of GC is rather low. It is a complex disease resulting from the interaction between environmental factors and host genetic alterations that deregulate multiple signaling pathways. The Notch signaling pathway, a highly conserved system in the regulation of the fate in several cell types, plays a pivotal role in cell differentiation, survival and proliferation. Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement. Whether Notch cascade exerts oncogenic or tumor suppressive function in different cancer types depends on the cellular context. Mammals have four NOTCH receptors that modulate Notch pathway activity. In this review, we provide a comprehensive summary on the functional role of NOTCH receptors in gastric and other gastrointestinal cancers. Increasing knowledge of NOTCH receptors in gastrointestinal cancers will help us recognize the underlying mechanisms of Notch signaling and develop novel therapeutic strategies for GC.

  7. NOTCH1 Mutations in Aortic Stenosis: Association with Osteoprotegerin/RANK/RANKL

    Science.gov (United States)

    Zhiduleva, Ekaterina; Freylikhman, Olga; Rotar, Oxana; Tarnovskaya, Svetlana; Kostareva, Anna; Moiseeva, Olga

    2017-01-01

    Background. The NOTCH pathway is known to be important in the pathogenesis of calcific aortic valve disease, possibly through regulators of osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK), and its ligand (RANKL) system. The purpose of the present study was to search for possible associations between NOTCH1 gene mutations and circulating levels of OPG and soluble RANKL (sRANKL) in patients with aortic stenosis (AS). Methods. The study was performed on 61 patients with AS including 31 with bicuspid and 30 with tricuspid aortic valves. We applied a strategy of targeted mutation screening for 10 out of 34 exons of the NOTCH1 gene by direct sequencing. Serum OPG and sRANKL levels were assessed. Results. In total, 6 genetic variants of the NOTCH1 gene including two new mutations were identified in the study group. In an age- and arterial hypertension-adjusted multivariable regression analysis, the serum OPG levels and the OPG/sRANKL ratio were correlated with NOTCH1 missense variants. All studied missense variants in NOTCH1 gene were found in Ca(2+)-binding EGF motif of the NOTCH extracellular domain bound to Delta-like 4. Conclusion. Our results suggest that the OPG/RANKL/RANK system might be directly influenced by genetic variants of NOTCH1 in aortic valve calcification.

  8. Fatigue Crack Growth Rate of Ti-6Al-4V Considering the Effects of Fracture Toughness and Crack Closure

    Institute of Scientific and Technical Information of China (English)

    ZHANG Junhong; YANG Shuo; LIN Jiewei

    2015-01-01

    Fatigue fracture is one of the main failure modes of Ti-6Al-4V alloy, fracture toughness and crack closure have strong effects on the fatigue crack growth(FCG) rate of Ti-6Al-4V alloy. The FCG rate of Ti-6Al-4V is investigated by using experimental and analytical methods. The effects of stress ratio, crack closure and fracture toughness on the FCG rate are studied and discussed. A modified prediction model of the FCG rate is proposed, and the relationship between the fracture toughness and the stress intensity factor(SIF) range is redefined by introducing a correcting coefficient. Notched plate fatigue tests (including the fracture toughness test and the FCG rate test) are conducted to investigate the influence of affecting factors on the FCG rate. Comparisons between the predicted results of the proposed model, the Paris model, the Walker model, the Sadananda model, and the experimental data show that the proposed model gives the best agreement with the test data particularly in the near–threshold region and the Paris region, and the corresponding calculated fatigue life is also accurate in the same regions. By considering the effects of fracture toughness and crack closure, the novel FCG rate prediction model not only improves the estimating accuracy, but also extends the adaptability of the FCG rate prediction model in engineering.

  9. Fatigue crack growth rate of Ti-6Al-4V considering the effects of fracture toughness and crack closure

    Science.gov (United States)

    Zhang, Junhong; Yang, Shuo; Lin, Jiewei

    2015-03-01

    Fatigue fracture is one of the main failure modes of Ti-6Al-4V alloy, fracture toughness and crack closure have strong effects on the fatigue crack growth(FCG) rate of Ti-6Al-4V alloy. The FCG rate of Ti-6Al-4V is investigated by using experimental and analytical methods. The effects of stress ratio, crack closure and fracture toughness on the FCG rate are studied and discussed. A modified prediction model of the FCG rate is proposed, and the relationship between the fracture toughness and the stress intensity factor(SIF) range is redefined by introducing a correcting coefficient. Notched plate fatigue tests (including the fracture toughness test and the FCG rate test) are conducted to investigate the influence of affecting factors on the FCG rate. Comparisons between the predicted results of the proposed model, the Paris model, the Walker model, the Sadananda model, and the experimental data show that the proposed model gives the best agreement with the test data particularly in the near-threshold region and the Paris region, and the corresponding calculated fatigue life is also accurate in the same regions. By considering the effects of fracture toughness and crack closure, the novel FCG rate prediction model not only improves the estimating accuracy, but also extends the adaptability of the FCG rate prediction model in engineering.

  10. Experimental Investigation of Fatigue Crack Growth Behavior in Friction Stir Welded 7075-T111 Aluminum Alloy Joints under Constant Stress Intensity Factor Range Control Testing (For L T Orientation Specimen)

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Yeui Han; Kim, Seon Jin [Pukyong Nat' l Univ., Busan (Korea, Republic of)

    2013-06-15

    In this study, as a series of studies aimed at investigating the spatial randomness of fatigue crack growth for friction stir welded (FSWed) 7075-T111 aluminum alloy joints, the fatigue crack growth behavior of FSWed 7075-T111 aluminum alloy joints was investigated for L T orientation specimens. Fatigue crack growth tests were conducted under constant stress intensity factor range (SEFOR) control for 5 specimens of the FSWed 7075-T111 aluminum alloy, including base metal (B M), heat affected zone (Haz), and weld metal (W M) specimens. The mean fatigue crack growth rate of W M specimens was found to be the highest, whereas that of Haz and W M specimens was the lowest. Furthermore, the variability of fatigue crack growth rate was found to be the highest in W M specimens and lowest in B M specimens.

  11. A Weakest-Link Approach for Fatigue Limit of 30CrNiMo8 Steels (Preprint)

    Science.gov (United States)

    2011-03-01

    used to predict the fatigue limit of notched and multiaxially loaded specimens of carburized steel [7]. The model was shown to be effective in... Carburized Steel 16mncrs5," Fatigue and Fracture of Engineering Materials and Structures, 28, pp. 983-995. [8] Bomas, H., Linkewitz, T., and Mayr, P., 1999

  12. Fatigue (PDQ)

    Science.gov (United States)

    ... of daily living . Better quality of life . More satisfaction with life. A greater sense of well-being. ... and decrease fatigue. The importance of eating enough food and drinking enough fluids. Physical therapy for patients ...

  13. Notch Signaling in Bone Regeneration

    Science.gov (United States)

    2011-10-01

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

  14. 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...

  15. 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...

  16. Notch4+ cancer stem-like cells promote the metastatic and invasive ability of melanoma.

    Science.gov (United States)

    Lin, Xian; Sun, Baocun; Zhu, Dongwang; Zhao, Xiulan; Sun, Ran; Zhang, Yanhui; Zhang, Danfang; Dong, Xueyi; Gu, Qiang; Li, Yanlei; Liu, Fang

    2016-08-01

    Sphere formation in conditioned serum-free culture medium supplemented with epidermal growth factor and basic fibroblast growth factor (tumorospheres) is considered useful for the enrichment of cancer stem-like cells, also known as tumor-initiating cells. We used a gene expression microarray to investigate the gene expression profile of melanoma cancer stem-like cells (MCSLCs). The results showed that MCSLCs highly expressed the following Notch signaling pathway molecules: Notch3 (NM_008716), Notch4 (NM_010929), Dtx4 (NM_172442), and JAG2 (NM_010588). Immunofluorescence staining showed tumorosphere cells highly expressed Notch4. Notch4(high) B16F10 cells were isolated by FACS, and Western blotting showed that high Notch4 expression is related to the expression of epithelial-mesenchymal transition (EMT)-associated proteins. Reduced invasive and migratory properties concomitant with the downregulation of the EMT markers Twist1, vimentin, and VE-cadherin and the overexpression of E-cadherin was observed in human melanoma A375 and MUM-2B cells. In these cells, Notch4 was also downregulated, both by Notch4 gene knockdown and by application of the γ-secretase inhibitor, DAPT. Mechanistically, the re-overexpression of Twist1 by the transfection of cells with a Twist1 expression plasmid led to an increase in VE-cadherin expression and a decrease in E-cadherin expression. Immunohistochemical analysis of 120 human melanoma tissues revealed a significant correlation between the high expression of Notch4 and the metastasis of melanoma. Taken together, our findings indicate that Notch4+ MCSLCs trigger EMT and promote the metastasis of melanoma cells.

  17. Quantification of fatigue crack propagation of an austenitic stainless steel in mercury embrittlement

    Science.gov (United States)

    Naoe, Takashi; Yamaguchi, Yoshihito; Futakawa, Masatoshi

    2012-12-01

    Liquid metals are expected to be used as nuclear materials, such as coolant for nuclear reactors and spallation targets for neutron sources, because of their good thermal conductivity and neutron production. However, in specific combinations, liquid metals have the potential to degrade structural integrity of solid metals because of Liquid Metal Embrittlement (LME). In this study, the effect of mercury immersion on fatigue crack propagation rate in SUS316 was investigated through fatigue tests with a notched specimen under mercury immersion. FRActure Surface Topography Analysis (FRASTA) with the measurement of the notch opening distance was performed to estimate the fatigue crack growth rate in mercury. The results showed that the fatigue crack growth rate was slightly higher in mercury than that in the air in the low cycle fatigue region. This suggests that the crack propagation is accelerated by mercury immersion in high stress imposition regions.

  18. Anabolic actions of Notch on mature bone

    Science.gov (United States)

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

    2016-01-01

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

  19. NOTCH pathway inactivation promotes bladder cancer progression.

    Science.gov (United States)

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

    2015-02-01

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

  20. Chronic fatigue in 812 testicular cancer survivors during long-term follow-up: increasing prevalence and risk factors.

    Science.gov (United States)

    Sprauten, M; Haugnes, H S; Brydøy, M; Kiserud, C; Tandstad, T; Bjøro, T; Bjerner, J; Cvancarova, M; Fosså, S D; Oldenburg, J

    2015-10-01

    Chronic fatigue (CF) has been reported to be slightly more prevalent in testicular cancer survivors (TCSs) than in the general population. In this study, we wished to explore possible determinants of CF in TCSs median 12 (survey I) and 19 years (survey II) after treatment, in particular the relation to late effects after treatment. Overall, 812 TCSs treated between 1980 and 1994 provided blood samples (testosterone and luteinizing hormone) and completed questionnaires at survey I (1998-2002) and survey II (2007-2008). Hormone levels were categorized according to quartile thresholds for decadal age groups of controls. Associations between CF and possible risk factors, including the Hospital Anxiety and Depression Scale (HADS), treatment, physical activity, hormone levels, neurotoxicity, and comorbidity, were analyzed by logistic regression. Prevalence of CF increased from 15% at survey I to 27% at survey II (P < 0.001). At survey II, risk for CF was increased three- to four-fold for high levels of neuropathy compared with no neuropathy, and two- to three-fold for high levels of Raynaud-like phenomena, and having testosterone levels in the lowest quartile, while being moderately and highly physically active, had a protective effect. Risk for CF in TCSs with higher levels of HADS-Anxiety and HADS-Depression was increased two- to five-fold, respectively. The increasing prevalence of CF in TCSs is a novel finding. Lifestyle interventions, early detection and treatment of depression and anxiety, and possibly testosterone substitution might reduce the risk of CF. Extended long-term follow-up seems to be important. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  1. An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Masaya Koshizaka

    2012-01-01

    Full Text Available Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1 is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

  2. An angiotensin II type 1 receptor blocker prevents renal injury via inhibition of the Notch pathway in Ins2 Akita diabetic mice.

    Science.gov (United States)

    Koshizaka, Masaya; Takemoto, Minoru; Sato, Seiya; Tokuyama, Hirotake; Fujimoto, Masaki; Okabe, Emiko; Ishibashi, Ryoichi; Ishikawa, Takahiro; Tsurutani, Yuya; Onishi, Shunichiro; Mezawa, Morito; He, Peng; Honjo, Satoshi; Ueda, Shiro; Saito, Yasushi; Yokote, Koutaro

    2012-01-01

    Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

  3. Stress-related psychosocial factors at work, fatigue, and risky driving behavior in bus rapid transport (BRT) drivers.

    Science.gov (United States)

    Useche, Sergio A; Ortiz, Viviola Gómez; Cendales, Boris E

    2017-07-01

    There is consistent scientific evidence that professional drivers constitute an occupational group that is highly exposed to work related stressors. Furthermore, several recent studies associate work stress and fatigue with unsafe and counterproductive work behaviors. This study examines the association between stress-related work conditions of Bus Rapid Transport (BRT) drivers and risky driving behaviors; and examines whether fatigue is a mechanism that mediates the association between the two. A sample of 524 male Bus Rapid Transit (BRT) operators were drawn from four transport companies in Bogotá, Colombia. The participants answered a survey which included an adapted version of the Driver Behavior Questionnaire (DBQ) for BRT operators, as well as the Effort-Reward Imbalance and Job Content Questionnaires, the Subjective Fatigue subscale of the Checklist Individual Strength (CIS) and the Need for Recovery after Work Scale (NFR). Utilizing Structural Equation Models (SEM) it was found that risky driving behaviors in BRT operators could be predicted through job strain, effort-reward imbalance and social support at work. It was also found that fatigue and need for recovery fully mediate the associations between job strain and risky driving, and between social support and risky driving, but not the association between effort/reward imbalance (ERI) and risky driving. The results of this study suggest that a) stress related working conditions (Job Strain, Social Support and ERI) are relevant predictors of risky driving in BRT operators, and b) that fatigue is the mechanism which links another kind of stress related to working conditions (job strain and low social support) with risky driving. The mechanism by which ERI increases risky driving in BRT operators remains unexplained. This research suggests that in addition to the individual centered stress-reduction occupational programs, fatigue management interventions aimed to changing some working conditions may reduce

  4. Fatigue Reliability of Offshore Wind Turbine Systems

    DEFF Research Database (Denmark)

    Marquez-Dominguez, Sergio; Sørensen, John Dalsgaard

    2012-01-01

    Optimization of the design of offshore wind turbine substructures with respect to fatigue loads is an important issue in offshore wind energy. A stochastic model is developed for assessing the fatigue failure reliability. This model can be used for direct probabilistic design and for calibration...... of appropriate partial safety factors / fatigue design factors (FDF) for steel substructures of offshore wind turbines (OWTs). The fatigue life is modeled by the SN approach. Design and limit state equations are established based on the accumulated fatigue damage. The acceptable reliability level for optimal...

  5. FATIGUE LIFE PREDICTION THEORY OF COMPOSITE LAMINATES AND EXPERIMENTAL VERIFICATION

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    According to traditional phenomenological fatigue methodology and modern continuum damage mechanics theory, dual fatigue cumulative damage rules to predict fatigue damage formation and propagation lives of the notched composite laminates are presented.A 3-dimensional damage constitutive equation of anisotropic composites is also established.Damage strain energy release rate is interpreted as a driving force of the fatigue delamination damage propagation.A new damage evolution equation and a damage propagation (a-(m-N( surface (stress amplitude-mean stress-life surface) are derived.Hence, using the method above, the fatigue life of composite components can be predicted.Finally, theoretically predicted results are compared with experimental data.It is found that the deviation of theoretic prediction from experimental results is about 22%.

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

    OpenAIRE

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

    2015-01-01

    Pericytes regulate vessel stability and pericyte dysfunction contributes to retinopathies, stroke, and cancer. Here we define Notch as a key regulator of pericyte function during angiogenesis. In Notch1 +/−; Notch3 −/− mice, combined deficiency of Notch1 and Notch3 altered pericyte interaction with the endothelium and reduced pericyte coverage of the retinal vasculature. Notch1 and Notch3 were shown to cooperate to promote proper vascular basement membrane formation and contribute to endothel...

  7. Evaluation method of multiaxial low cycle fatigue life for cubic single crystal material

    Institute of Scientific and Technical Information of China (English)

    CHEN Jiping; DING Zhiping

    2007-01-01

    The coupling effect of normal stress and shear stress on orthotropic materials happens when applied loading deflects from the directions of the principal axes of the material coordinate system.By taking account of the coupling effects,formulas of equivalent stress and strain for cubic single crystal materials are cited.Using the equivalent strain and equivalent stress for such material and a variable k,which is introduced to express the effect of asymmetrical cyclic loading on fatigue life,a low cycle fatigue (LCF) life prediction model for such material in multiaxial stress starts is proposed.On the basis of the yield criterion and constitutive model of cubic single crystal materials,a subroutine to calculate the thermo elastic-plastic stress-strain of the material on an ANSYS platform was developed.The cyclic stress-strain of DD3 notched specimens under asymmetrical loading at 680℃ was analyzed.Low cycle fatigue test data of the single crystal nickel-based superalloy are used to fit the different parameters of the power law with multiple linear regression analysis.The equivalent stress and strain for a cubic single crystal material as failure parameters have the largest correlation coefficient.A power law exists between k and the failure cycle.The model was validated with LCF test data of CMSX-2 and DD3 single crystal nickel-based superalloys.All the test data fall into the factor of 2.5 for CMSX-2 hollow cylinder specimens and 2.0 scatter band for DD3 notched specimens,respectively.

  8. The Notch pathway mediates the angiotensin II-induced synthesis of extracellular matrix components in podocytes.

    Science.gov (United States)

    Yao, Min; Wang, Xiaomei; Wang, Xiaomeng; Zhang, Tao; Chi, Yanqing; Gao, Feng

    2015-07-01

    The Notch pathway is known to contribute to the development of glomerular disease. Angiotensin II (Ang II), an important member of the renin-angiotensin system, stimulates the accumulation of extracellular matrix components in glomerular disease; however, the exact mechanisms involved remain to be elucidated. In the present study, we aimed to investigate the effects of the Notch pathway on the synthesis of extracellular matrix components in Ang II-stimulated podocytes. Mouse podocytes were stimulated with Ang II (10-6 mol/l). The activation of the Notch pathway was inhibited by a vector carrying short hairpin RNA (shRNA) targeting Notch1 (sh-Notch1) or by γ-secretase inhibitor (GSI). The protein levels of Notch1, Notch intracellular domain 1 (NICD1), hairy and enhancer of split-1 (Hes1), matrix metalloproteinase (MMP)-2, MMP-9, transforming growth factor-β1 (TGF-β1), type IV collagen and laminin were determined by western blot analysis. The Notch1, Hes1, MMP-2, MMP-9, TGF-β1, type IV collagen and laminin mRNA levels were detected by RT-PCR. The MMP-2 and MMP-9 activity was measured using a cell active fluorescence assay kit. The levels of TGF-β1, type IV collagen and laminin were determined in the culture medium of the podocytes by enzyme-linked immunosorbent assay (ELISA). Our results revealed that Ang II upregulated Notch1, NICD1, Hes1, TGF-β1, type IV collagen and laminin expression and downregulated MMP-2 and MMP-9 expression in the cultured podocytes. The inhibition of the Notch pathway by sh-Notch1 or GSI increased MMP-2 and MMP-9 expression, decreased the TGF-β1 level and suppressed type IV collagen and laminin expression. The inhibition of the Notch pathway by sh-Notch1 or GSI also increased MMP-2 and MMP-9 activity, and decreased TGF-β1 levels, type IV collagen levels and laminin secretion. These findings indicate that the Notch pathway potentially mediates the Ang II-induced synthesis of extracellular matrix components in podocytes through the

  9. Effect of the Machining Processes on Low Cycle Fatigue Behavior of a Powder Metallurgy Disk

    Science.gov (United States)

    Telesman, J.; Kantzos, P.; Gabb, T. P.; Ghosn, L. J.

    2010-01-01

    A study has been performed to investigate the effect of various machining processes on fatigue life of configured low cycle fatigue specimens machined out of a NASA developed LSHR P/M nickel based disk alloy. Two types of configured specimen geometries were employed in the study. To evaluate a broach machining processes a double notch geometry was used with both notches machined using broach tooling. EDM machined notched specimens of the same configuration were tested for comparison purposes. Honing finishing process was evaluated by using a center hole specimen geometry. Comparison testing was again done using EDM machined specimens of the same geometry. The effect of these machining processes on the resulting surface roughness, residual stress distribution and microstructural damage were characterized and used in attempt to explain the low cycle fatigue results.

  10. INVESTIGATION OF FRACTURE DESIGN FOR MEDIUM CARBON STEEL UNDER EXTRA-LOW CYCLIC FATIGUE IN AXIAL LOADING

    Institute of Scientific and Technical Information of China (English)

    Youtang Li; Shuai Tan; Hongyan Duan

    2008-01-01

    The extra-low cyclic fracture problem of medium carbon steel under axial fatigue loading was investigated.Several problems,such as the relations of the cycle times to the depth and tip radius of the notch,loading frequency,loading range and the parameters of fracture design for medium carbon steel on condition of extra-low axial fatigue loading were discussed based on the experiments.Experimental results indicated that the tension-pressure fatigue loading mode was suitable for extra-low cyclic fatigue fracture design of medium carbon steel and it resulted in low energy consumption,fracture surface with high quality,low cycle times,and high efficiency.The appropriate parameters were as follows:loading frequency 3-5 Hz,notch tip radius r=(0.2-0.3)mm,opening angle α=60°,and notch depth t=(0.14-0.17)D.

  11. Small fatigue cracks; Proceedings of the Second International Conference/Workshop, Santa Barbara, CA, Jan. 5-10, 1986

    Energy Technology Data Exchange (ETDEWEB)

    Ritchie, R.O.; Lankford, J.

    1986-01-01

    Topics discussed in this volume include crack initiation and stage I growth, microstructure effects, crack closure, environment effects, the role of notches, analytical modeling, fracture mechanics characterization, experimental techniques, and engineering applications. Papers are presented on fatigue crack initiation along slip bands, the effect of microplastic surface deformation on the growth of small cracks, short fatigue crack behavior in relation to three-dimensional aspects and the crack closure effect, the influence of crack depth on crack electrochemistry and fatigue crack growth, and nondamaging notches in fatigue. Consideration is also given to models of small fatigue cracks, short crack theory, assessment of the growth of small flaws from residual strength data, the relevance of short crack behavior to the integrity of major rotating aero engine components, and the relevance of short fatigue crack growth data to the durability and damage tolerance analyses of aircraft.

  12. Notch signalling inhibits CD4 expression during initiation and differentiation of human T cell lineage.

    Directory of Open Access Journals (Sweden)

    Stephen M Carlin

    Full Text Available The Delta/Notch signal transduction pathway is central to T cell differentiation from haemopoietic stem cells (HSCs. Although T cell development is well characterized using expression of cell surface markers, the detailed mechanisms driving differentiation have not been established. This issue becomes central with observations that adult HSCs exhibit poor differentiation towards the T cell lineage relative to neonatal or embryonic precursors. This study investigates the contribution of Notch signalling and stromal support cells to differentiation of adult and Cord Blood (CB human HSCs, using the Notch signalling OP9Delta co-culture system. Co-cultured cells were assayed at weekly intervals during development for phenotype markers using flow cytometry. Cells were also assayed for mRNA expression at critical developmental stages. Expression of the central thymocyte marker CD4 was initiated independently of Notch signalling, while cells grown with Notch signalling had reduced expression of CD4 mRNA and protein. Interruption of Notch signalling in partially differentiated cells increased CD4 mRNA and protein expression, and promoted differentiation to CD4(+ CD8(+ T cells. We identified a set of genes related to T cell development that were initiated by Notch signalling, and also a set of genes subsequently altered by Notch signal interruption. These results demonstrate that while Notch signalling is essential for establishment of the T cell lineage, at later stages of differentiation, its removal late in differentiation promotes more efficient DP cell generation. Notch signalling adds to signals provided by stromal cells to allow HSCs to differentiate to T cells via initiation of transcription factors such as HES1, GATA3 and TCF7. We also identify gene expression profile differences that may account for low generation of T cells from adult HSCs.

  13. Functional redundancy of the Notch pathway in ovarian cancer cell lines.

    Science.gov (United States)

    Silva, Fernanda; Félix, Ana; Serpa, Jacinta

    2016-10-01

    Epithelial ovarian cancer is the most lethal gynecologic malignancy, despite advances in treatment. The most common histological type, high-grade ovarian serous carcinoma (OSC) is usually diagnosed at an advanced stage, and although these types of tumors frequently respond to surgery and platinum-based chemotherapy, they usually recur. Ovarian clear cell carcinoma (OCCC) is an unusual histological type, which is known to be intrinsically chemoresistant and is associated with poor prognosis in advanced stages. In recent years, genetic alterations and epigenetic modulation of signaling pathways have been reported in OSC and OCCC, including the overexpression of Notch pathway elements and histone deacetylases. Histone deacetylase inhibitors (HDACis), including vorinostat (suberoylanilide hydroxamic acid), alter the transcription of genes involved in cell growth, survival and apoptosis, and have become an attractive therapeutic approach. However, no previous work has addressed the effect of HDACis, and in particular vorinostat, on Notch signaling in ovarian cancer. Therefore, the present study aimed to investigate the modulation of the Notch pathway by vorinostat in ovarian cancer. Using immunofluorescence and quantitative polymerase chain reaction, the present results revealed that vorinostat activated the Notch pathway in OCCC and OSC cell lines, through different Notch ligands. In OCCC, the activation of the Notch pathway appeared to occur through Delta-like (Dll) ligands 1, 2 and 3, whereas in OSC Dll1 and Jagged 1 and 2 ligands were involved. The activation of the Notch pathway by vorinostat, in OCCC and OSC cell lines, culminated in the increased expression of the same downstream transcription factors, hairy enhancer of split (Hes) 1 and 5, and Hes-related proteins 1 and 2. In conclusion, vorinostat modulates the expression of several downstream targets of the Notch pathway and independent Notch receptors and ligands that are expressed in OSC and OCCC. This

  14. Chronic Fatigue Syndrome

    Science.gov (United States)

    Chronic fatigue syndrome (CFS) is a disorder that causes extreme fatigue. This fatigue is not the kind of tired feeling that ... activities. The main symptom of CFS is severe fatigue that lasts for 6 months or more. You ...

  15. Fatigue status of elderly patients with COPD and its related factors%老年COPD患者疲乏状况及其相关因素分析

    Institute of Scientific and Technical Information of China (English)

    李慧; 龙纳; 陈茜

    2016-01-01

    目的:了解老年COPD患者疲乏状况及其相关因素,为临床干预提供依据。方法采用疲乏程度量表( FSS)对老年科142例老年COPD患者进行调查。结果老年COPD患者FSS疲乏平均分为(4.4±2.2)分,69.0%存在疲乏,且不同心功能、自理能力、卧床、睡眠障碍、呼吸困难程度者疲乏发生情况不同,有心力衰竭、自理能力障碍、卧床、睡眠障碍、呼吸困难指数高的老年COPD患者疲乏发生率较高,差异有统计学意义(P<0.05);多因素分析结果表明睡眠质量差、呼吸困难指数高及合并心力衰竭是影响老年COPD患者疲乏的主要因素。结论多数老年COPD患者存在疲乏症状,应该加强对患者睡眠障碍呼吸困难指数高及合并心力衰竭患者的临床干预,以减轻患者疲乏症状,从而提高其生活质量。%Objective To learn the fatigue conditions and the related factors of the patients with chronic obstructive pulmonary disease ( COPD ) and provide an evidence for clinical intervention .Methods We used fatigue severity scale ( FSS) to investigate 142 patients who had COPD in our geriatric department .Results The average scores of the FSS in those patients were (4.4 ±2.2).69.0% of them felt fatigued, and their fatigue conditions differ in their heart functions, self-care abilities, sleep qualities, dyspnea degrees when patients, who had heart failure, poor self-care abilities, dyssomnia or high score of dyspnea index, occurred the higher fatigue incidences (P<0.05).The results of multifactor analysis had shown poor sleep ability, high score of dyspnea index and complicated heart failure were the major factors of the fatigue in the patients with COPD.Conclusions Most COPD patients have fatigue .We should strengthen the clinical intervention of sleep quality , high score of dyspnea index and heart failure to decrease the fatigue of the patients , thus to increase their living quality .

  16. An exploratory study of the relationship between biomechanical factors and right-arm musculoskeletal discomfort and fatigue in a VDT data-entry task.

    Science.gov (United States)

    Pan, C S; Schleifer, L M

    1996-06-01

    The relationship of key force and keystroke rate with right-arm musculoskeletal discomfort and fatigue was explored in a video-display-terminal (VDT) data-entry task. Forty-three data transcribers entered bogus data from tax forms at a VDT for one workday with their right hand. Peak key force and keystroke rate were monitored on a continuous basis. Self-ratings of right-arm discomfort and fatigue were assessed at periodic intervals. Stepwise regression analyses indicated that both lower key forces and lower keystroke rates were associated with higher ratings of right-elbow discomfort. In addition, lower key forces were associated with higher ratings of right-hand discomfort and lower keystroke rates were associated with higher ratings of right-shoulder discomfort and fatigue. The amount of variance accounted for by these models ranged from 7 to 24%. These results appear to be contrary to conventional biomechanical models that postulate a positive association between key force, keystroke rate and musculoskeletal discomfort in VDT work. Further laboratory and field research under controlled conditions is needed to clarify the direction and extent of the cause-and-effect relationship between biomechanical factors and musculoskeletal discomfort in VDT data-entry work.

  17. Fatigue in U.S. Astronauts Onboard the International Space Station: Environmental factors, Operational Impacts, and Implementation of Countermeasures

    Science.gov (United States)

    Scheuring, R. A.; Moomaw, R. C.; Johnston, S. L.

    2015-01-01

    Crewmembers have experienced fatigue for reasons similar to military deployments. Astronauts experience psychological stressors such as: heavy workloads, extended duty periods, circadian misalignment, inadequate/ineffective sleep, distracting background noise, unexpected and variable mission schedules, unfavorable thermal control, unusual sleep environment with schedules that impinge on pre-sleep periods.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Correlation between vitamin D levels and muscle fatigue risk factors based on physical activity in healthy older adults

    Directory of Open Access Journals (Sweden)

    Al-Eisa ES

    2016-05-01

    Full Text Available Einas S Al-Eisa,1 Ahmad H Alghadir,1 Sami A Gabr1,2 1Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia; 2Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt Purpose: The purpose of this study was to investigate the relationship of serum vitamin D levels with physical activity, obesity, muscle fatigue biomarkers, and total antioxidant capacity (TAC in healthy older adults.Methods: A total of 85 healthy older subjects aged 64–96 years were recruited in this study. Based on estimated energy expenditure scores, the participants were classified into three groups: inactive (n=25, moderate (n=20, and physically active (n=35. Serum 25(OHD (25-hydroxy vitamin D levels, metabolic syndrome parameters, TAC activity, muscle fatigue biomarkers (Ca, creatine kinase, lactic acid dehydrogenase, troponin I, hydroxyproline, physical activity, body fatness, and fatigue score (visual analog scale were estimated using immunoassay techniques and prevalidated questionnaires, respectively.Results: Physical activity was estimated in 64.6% of the participants. Males showed higher physical activity (42.5% compared to females (26.25%. Compared to participants with lower activity, significant reduction in body mass index, waist circumference, hips, fasting blood sugar, triglycerides, total cholesterol, HDL-cholesterol, and LDL-cholesterol were observed in moderate and physically active participants. Also, significant increase in the levels of serum 25(OHD concentrations, calcium, and TAC activity along with reduction in the levels of muscle fatigue biomarkers: creatine kinase, lactic acid dehydrogenase, troponin I, hydroxyproline, and fatigue scores (visual analog scale were reported in physically active participants compared to those of lower physical activity. In all participants, serum 25(OHD concentrations correlated positively with Ca, TAC, physical activity scores

  20. DELAMINATION FORMATION AND DELAMINATION PROPAGATION OF COMPOSITE LAMINATES UNDER COMPRESSIVE FATIGUE LOADING

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Fatigue tests of the smooth composite laminates and the notched composite laminates under compressive cyclic loading have been carried out. The damage mechanism is discussed and analyzed. Damage evolution is monitored using stiffness decay. From these tests, it is found that the initial delamination occurs at the free boundary of smooth specimens, or the notch boundary of notched specimens, subjected to the compression-compression cyclic load. A point of view in relation to two-phases of compression fatigue delamination of composites is proposed, namely, compression-compression delamination consists of the delamination formation phase and the delamination propagation, and there is a "damage transition point" to separate this two-phases. Furthermore, an empirical modulus degradation formula and its parameters fitting method are presented. According to the test data handling results, it is shown that this formula is univocal and can fit the test data conveniently. In addition, two kinds of new anti-buckling devices are designed for these tests. At last, the E-N curves, the D-N curves and the S-N curve of the smooth carbon fiber reinforced composite laminates of T300/648C are determined to predict the fatigue life of the notched composite laminate. And the E-N curve of the notched specimens at the given load ratio R=10 and minimum load P min=-0.45 kN is also measured to verify the estimated result of fatigue life.

  1. Quantification of fatigue crack propagation of an austenitic stainless steel in mercury embrittlement

    Energy Technology Data Exchange (ETDEWEB)

    Naoe, Takashi, E-mail: naoe.takashi@jaea.go.jp [J-PARC Center, Japan Atomic Energy Agency, Tokai-mura, Naka-gun, Ibaraki 319-1195 (Japan); Yamaguchi, Yoshihito [Nucelar Safety Research Center, Japan Atomic Energy Agency, Tokai-mura, Naka-gun, Ibaraki 319-1195 (Japan); Futakawa, Masatoshi [J-PARC Center, Japan Atomic Energy Agency, Tokai-mura, Naka-gun, Ibaraki 319-1195 (Japan)

    2012-12-15

    Highlights: Black-Right-Pointing-Pointer The effect of mercury immersion on fatigue crack propagation rate in SUS316 was investigated through fatigue tests. Black-Right-Pointing-Pointer Fatigue crack growth rate in mercury was estimated by the FRActure Surface Topography Analysis (FRASTA). Black-Right-Pointing-Pointer The fatigue crack growth rate was slightly higher in mercury than that in the air in the low cycle fatigue region. Black-Right-Pointing-Pointer This suggests that the crack propagation is accelerated by mercury immersion in high stress imposition regions. - Abstract: Liquid metals are expected to be used as nuclear materials, such as coolant for nuclear reactors and spallation targets for neutron sources, because of their good thermal conductivity and neutron production. However, in specific combinations, liquid metals have the potential to degrade structural integrity of solid metals because of Liquid Metal Embrittlement (LME). In this study, the effect of mercury immersion on fatigue crack propagation rate in SUS316 was investigated through fatigue tests with a notched specimen under mercury immersion. FRActure Surface Topography Analysis (FRASTA) with the measurement of the notch opening distance was performed to estimate the fatigue crack growth rate in mercury. The results showed that the fatigue crack growth rate was slightly higher in mercury than that in the air in the low cycle fatigue region. This suggests that the crack propagation is accelerated by mercury immersion in high stress imposition regions.

  2. Study on influenc factors of fatigue in the general population in Daqing%大庆地区一般人群疲乏感的影响因素研究

    Institute of Scientific and Technical Information of China (English)

    姚大志; 张全志; 庄永志; 孙淑娟; 张润芝

    2014-01-01

    Objective:To investigate the incidence and influencing factors of fatigue inthe general population in Daqing,so as to provide a fundamental basis for the implementation of psychological intervention. Methods:600 general population were investigated with the general situationquestionnaire, fatigue scale-14(FS-14), trait coping style questionnaire (TCSQ), symptom checklist-90 (SCL-90), and so on. Results: The body fatigue, mental fatigue and total fatigue generally existed. Farmers and medical personnel had a higher fatigue level than the others. The fatigue was influenced by coping style, interpersonal relationship,somatization and the like. Conclusions: The incidence of the fatigue in the general population is high; and the fatigue is associated with coping styles,men-tal health and other factors.%目的:探讨大庆地区一般人群疲乏感的发生率及影响因素,为实施心理干预提供依据。方法:运用一般状况调查问卷、疲劳量表 FS-14、特质应对方式量表、SCL-90量表等对600名一般人群进行调查分析。结果:躯体疲劳、心理疲劳、总的疲劳普遍存在,农民及医护人员疲乏感程度重于其它各职业人群;疲乏感受应对方式、人际关系、躯体化等因素影响。结论:一般人群疲乏感普遍存在,疲乏感与应对方式、心理健康状况等因素有关。

  3. Lipid Replacement Therapy Functional Food Formulation with NT Factor for Reducing Weight, Girth, Body Mass, Appetite and Fatigue While Improving Blood Lipid Profiles

    Directory of Open Access Journals (Sweden)

    Rita R. Ellithorpe

    2012-01-01

    Full Text Available Background: Lipid Replacement Therapy using NT Factor® plus kidney bean alpha-amylase inhibitor (Healthy Curb® was used in a two month weight loss clinical trial to reduce weight and improve fatigue without changing easting or exercise patterns and without use of drugs, stimulants or herbs. Objectives: To determine the effects of an all-natural functional food, NT Factor® plus alpha-amylase inhibitor (Healthy Curb®, on weight loss, body girth, body mass and index, basal metabolic rate, appetite, carvings for sweets and fatigue as well as blood lipid profiles during a 2-month open label clinical trial without food restrictions or increases in physical activity.Methods: Thirty subjects (Mean Age = 56.8 ± 1.8; 24 females and 6 males used the functional food containing NT Factor® (500 mg and alpha-amylase inhibitor (500 mg 30 min before each meal in tablet form. Participants were told to eat and exercise normally. Weight, waist and hip measurements were taken weekly. Appetite and sweet cravings were assessed weekly by standard methods. Fatigue was determined using the Piper Fatigue Scale. Blood samples were taken prior to and at the end of the trial for lipid and chemical analyses. Results: Sixty-three percent of the participants lost an average of 6.11 ± 0.28 pounds (2.77 ± 0.12 Kg (p<0.001 along with average reductions of 2.51 ± 0.05 inches (6.4 ± 0.13 cm (p<0.0001 and 1.5 ± 0.04 inches (3.8 ± 0.10 cm (p<0.0001 from waist and hip circumferences, respectively. The entire Functional Foods in Health and Disease 2012, 2(1:11-24 group lost an average of 3.63 ± 0.13 pounds (1.65 ± 0.11 Kg (p<0.001 with average reductions of 1.59 ± 0.03 inches (4.04 ± 0.06 cm (p<0.0001 and 1.13 ± 0.02 inch (2.87 ± 0.05 cm (p<0.0001 from waist and hip circumferences, respectively. Weight loss and body measurement decreases were gradual, consistent and significant, along with reductions in body mass index (BMI and basal metabolic rate (BMR measurements

  4. Inclined defects and their effect on the fatigue limit and small crack growth

    Directory of Open Access Journals (Sweden)

    Roiko Andrew

    2014-06-01

    Full Text Available Small FIB (Focused Ion Beam milled notches were introduced in quenched and tempered 34CrNiMo6 steel to monitor initiation and growth of cracks in situ. The effect of the defects on the fatigue limit is discussed in terms of the √area model. Notches with projected √area of 30 to 56 μm normal to the applied stress were inclined by 0, 45, and 60 degrees. The effect of size and inclination on the small crack growth as well as the fatigue limit is discussed.

  5. carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) regulates Notch signaling and vascular development in zebrafish

    NARCIS (Netherlands)

    Coxam, Baptiste; Neyt, Christine; Grassini, Daniela R.; Le Guen, Ludovic; Smith, Kelly A.; Schulte-Merker, Stefan; Hogan, Benjamin M.

    2015-01-01

    Background: The interplay between Notch and Vegf signaling regulates angiogenesis in the embryo. Notch signaling limits the responsiveness of endothelial cells to Vegf to control sprouting. Despite the importance of this regulatory relationship, much remains to be understood about extrinsic factors

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

    Science.gov (United States)

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

    2007-04-15

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

  7. Effects of Supplementation with BCAA and L-glutamine on Blood Fatigue Factors and Cytokines in Juvenile Athletes Submitted to Maximal Intensity Rowing Performance.

    Science.gov (United States)

    Koo, Ga Hee; Woo, Jinhee; Kang, Sungwhun; Shin, Ki Ok

    2014-08-01

    [Purpose] This study was conducted to understand the impacts of BCAA (branched-chain amino acid) and glutamine supplementation on the degree of blood fatigue factor stimulation and cytokines along with performance of exercise at the maximal intensity. [Subjects] Five male juvenile elite rowing athletes participated in this study as the subjects; they took 3 tests and received placebo supplementation (PS), BCAA supplementation (BS), and glutamine supplementation (GS). [Methods] The exercise applied in the tests was 2,000 m of rowing at the maximal intensity using an indoor rowing machine, and blood samples were collected 3 times, while resting, at the end of exercise, and after 30 min of recovery, to analyze the blood fatigue factors (lactate, phosphorous, ammonia, creatine kinase (CK)) and blood cytokines (IL (interleukin)-6, 8, 15). [Results] The results of the analysis showed that the levels of blood phosphorous in the BS and GS groups at the recovery stage were decreased significantly compared with at the end of exercise, and the level of CK appeared lower in the GS group alone at recovery stage than at the end of exercise. The level of blood IL-15 in the PS and BS groups appeared higher at the end of exercise compared with the resting stage. [Conclusion] It seemed that glutamine supplementation had a positive effect on the decrease in fatigue factor stimulation at the recovery stage after maximal intensity exercise compared with supplementation with the placebo or BCAA. Besides, pre-exercise glutamine supplementation seemed to help enhance immune function and the defensive inflammatory reaction.

  8. Targeting of miR9/NOTCH1 interaction reduces metastatic behavior in triple-negative breast cancer.

    Science.gov (United States)

    Mohammadi-Yeganeh, Samira; Mansouri, Ardalan; Paryan, Mahdi

    2015-11-01

    Many reports have indicated deregulation of a variety of microRNAs (miRNAs) in human cancers. In this study, we appraised miR-9 correlation with NOTCH1 involved in Notch signaling in metastatic breast cancer. The Notch signaling pathway has been approved to be associated with the development and progression of many human cancers, including breast cancer, but the precise mechanism has remained unknown. To the best of our knowledge, this is the first study that introduces miR-9 and NOTCH1 correlation as an effective factor in breast cancer. We found that miR-9 expression was decreased in MDA-MB-231 breast cancer cells compared with MCF-10A normal breast cell line. However, NOTCH1 was upregulated in the metastatic breast cancer cells. Furthermore, luciferase assay revealed a significant inverse correlation between miR-9 and NOTCH1. Overexpression of Notch signaling via Notch1 intracellular domain in MDA-MB-231 cell line was suppressed by lentiviruses expressing miR-9. Taken together, the results obtained by MTT, flow cytometry, migration, and wound healing assays showed that it is possible to inhibit metastasis and induce pro-apoptotic state by induction of miR-9 expression in MDA-MB-231 cells but with no effect on cell proliferation. These results shows that miR-9, by direct targeting of NOTCH1, can reveal a suppressor-like activity in metastatic breast cancer cells.

  9. Notch inhibits Yorkie activity in Drosophila wing discs.

    Directory of Open Access Journals (Sweden)

    Alexandre Djiane

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

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

    Science.gov (United States)

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

    2016-04-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, is a hereditary cerebral small vessel disease caused by characteristic cysteine altering missense mutations in the NOTCH3 gene. NOTCH3 mutations in CADASIL result in an uneven number of cysteine residues in one of the 34 epidermal growth factor like-repeat (EGFr) domains of the NOTCH3 protein. The consequence of an unpaired cysteine residue in an EGFr domain is an increased multimerization tendency of mutant NOTCH3, leading to toxic accumulation of the protein in the (cerebro)vasculature, and ultimately reduced cerebral blood flow, recurrent stroke and vascular dementia. There is no therapy to delay or alleviate symptoms in CADASIL. We hypothesized that exclusion of the mutant EGFr domain from NOTCH3 would abolish the detrimental effect of the unpaired cysteine and thus prevent toxic NOTCH3 accumulation and the negative cascade of events leading to CADASIL. To accomplish this NOTCH3 cysteine correction by EGFr domain exclusion, we used pre-mRNA antisense-mediated skipping of specific NOTCH3 exons. Selection of these exons was achieved using in silico studies and based on the criterion that skipping of a particular exon or exon pair would modulate the protein in such a way that the mutant EGFr domain is eliminated, without otherwise corrupting NOTCH3 structure and function. Remarkably, we found that this strategy closely mimics evolutionary events, where the elimination and fusion of NOTCH EGFr domains led to the generation of four functional NOTCH homologues. We modelled a selection of exon skip strategies using cDNA constructs and show that the skip proteins retain normal protein processing, can bind ligand and be activated by ligand. We then determined the technical feasibility of targeted NOTCH3 exon skipping, by designing antisense oligonucleotides targeting exons 2-3, 4-5 and 6, which together harbour the majority of distinct CADASIL-causing mutations

  11. Calibration of partial safety factors for wind turbine rotor blades against fatigue failure; Kalibrering af partielle sikkerhedsfaktorer for udmattelse af vindmoellerotorer

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, C.J.; Ronold, K.O.; Thoegersen, M.L.

    2000-08-01

    The report describes a calibration of partial safety factors for wind turbine rotor blades subjected to fatigue loading in flapwise and edgewise bending. While earlier models - developed by the authors - dealt with such calibrations for site-specific individual turbines only, the calibration model applied herein covers an integrated analysis with different turbines on different sites and with different blade materials. The result is an optimized set of partial safety factors, i.e. a set of safety factors that lead to minimum deviation from the target reliability of the achieved reliabilities over the selected scope of turbines, sites and materials. The turbines included in the study cover rated powers of 450-600 kW. The result from the calibration are discussed in relation to the partial safety factors that are given in the Danish codes for design of glass fibre reinforced rotor blades (DS472 and DS456). (au)

  12. 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 me

  13. Involvement of notch signaling in wound healing.

    Directory of Open Access Journals (Sweden)

    Srinivasulu Chigurupati

    Full Text Available The Notch signaling pathway is critically involved in cell fate decisions during development of many tissues and organs. In the present study we employed in vivo and cell culture models to elucidate the role of Notch signaling in wound healing. The healing of full-thickness dermal wounds was significantly delayed in Notch antisense transgenic mice and in normal mice treated with gamma-secretase inhibitors that block proteolytic cleavage and activation of Notch. In contrast, mice treated with a Notch ligand Jagged peptide showed significantly enhanced wound healing compared to controls. Activation or inhibition of Notch signaling altered the behaviors of cultured vascular endothelial cells, keratinocytes and fibroblasts in a scratch wound healing model in ways consistent with roles for Notch signaling in wound healing functions all three cell types. These results suggest that Notch signaling plays important roles in wound healing and tissue repair, and that targeting the Notch pathway might provide a novel strategy for treatment of wounds and for modulation of angiogenesis in other pathological conditions.

  14. Notch Signaling Enhances Nestin Expression in Gliomas

    Directory of Open Access Journals (Sweden)

    Alan H. Shih

    2006-12-01

    Full Text Available Recent findings suggest that Notch signaling is active in brain tumors and stem cells, and that stem cells or cells with progenitor characteristics contribute to brain tumor formation. These stem cells are marked by expression of several markers, including nestin, an intermediate filament protein. We have studied how the Notch signaling pathway affects nestin expression in brain tumors. We find that Notch receptors and ligands are expressed in vitro and in human samples of glioblastomas, the highest grade of malignant gliomas. In culture, Notch activity activates the nestin promoter. Activation of the Notch pathway also occurs in a glioblastoma multiforme mouse model induced by Kras, with translational regulation playing a role in Notch expression. Combined activation of Notch and Kras in wild-type nestin-expressing cells leads to their expansion within the subventricular zone and retention of proliferation and nestin expression. However, activation of Notch alone is unable to induce this cellular expansion. These data suggest that Notch may have a contributing role in the stem-like character of glioma cells.

  15. Zebrafish phenotypic screen identifies novel Notch antagonists.

    Science.gov (United States)

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

    2017-04-01

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

  16. Notch Signaling Molecules Activate TGF-β in Rat Mesangial Cells under High Glucose Conditions

    Directory of Open Access Journals (Sweden)

    Li Liu

    2013-01-01

    Full Text Available The involvement of the Notch signaling pathway in the cellular differentiation of the mammalian kidney is established. Recently, the dysregulation of Notch signaling molecules has been identified in acute and chronic renal injuries, fibrosis models, and diabetic kidney biopsies. The canonical Notch ligand , Jagged1, is upregulated in a transforming growth factor-beta- (TGF-β- dependent manner during chronic kidney disease. TGF-β, a central mediator of renal fibrosis, also is a major contributor to the development of diabetic nephropathy. To explore the roles and possible mechanisms of Notch signaling molecules in the pathogenesis of diabetic nephropathy, we exposed cultured rat mesangial cells to a γ-secretase inhibitor (DAPT or high glucose and measured the expression of Notch signaling molecules and the fibrosis index. Notch pathway-related molecules, TGF-β, and fibronectin increased with exposure to high glucose and decreased with DAPT treatment. Our results suggest that the Notch signaling pathway may precipitate diabetic nephropathy via TGF-β activation.

  17. 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.

  18. Validating the Classical Failure Criteria for Applicability to the Notched Woven-Roving Composite Materials

    Directory of Open Access Journals (Sweden)

    Mohamed Mostafa Yousef Bassyouny Elshabasy

    2014-01-01

    Full Text Available The classical failure criteria are phenomenological theories as they ignore the actual failure mechanism and do not concentrate on the microscopic events of failure. The main objective of the current investigation is to modify the classical failure theories to comprise the essential failure mechanism (interfacial shear failure in the thin-layered woven-roving composite materials. An interfacial shear correction factor (MH6 is introduced into the nondimensional shear terms in the studied classical failure criteria. Thus the validity of applying these theories to the investigated material will be augmented. The experimental part of the current study is conducted on thin-layered circular specimens. The specimens are fabricated from two plies of fiber E-glass woven-roving fabric reinforced with polyester. The fabrics are laid to have [±45°] or [0°, 90°] fiber orientation. The specimens used are plain, where no macroscopic sources of stress concentration exist or having circular notches of five, seven, or nine mm radii. The specimens are subjected to low cycle completely reversed fatigue bending loading where the S-N and the R.D.-N curves are plotted for each group of specimens.

  19. Upregulation of Notch pathway molecules in oral squamous cell carcinoma

    OpenAIRE

    2010-01-01

    The constitutive activation of the Notch pathway has been demonstrated in various types of malignancies. However, it remains unclear how the Notch pathway is involved in the pathogenesis of oral squamous cell carcinoma (OSCC). We investigated the expression of Notch pathway molecules in OSCC cell lines and biopsy specimens and examined the effect of Notch pathway inhibition. Reverse transcription-polymerase chain reaction revealed upregulation of Notch1, Notch2, Jagged1, HES1 and HEY1 in both...

  20. Reducing the extraction loss via laser notching the H- beam at the Booster injection revolution frequency

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xi; Ankenbrandt, Charles M.; /Fermilab

    2005-05-01

    With the requirement for more protons per hour from Booster, the radiation is a limiting factor. Laser notching the H{sup -} beam at the Booster injection revolution frequency and properly aligning those notches on top of each other at the injection and relative to the trigger of firing extraction kickers can remove most of the extraction loss caused by the slow rise time of the kicker field.

  1. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application

    OpenAIRE

    Yuan, Xun; Wu, Hua; Han, Na; Xu, Hanxiao; Chu, Qian; Yu, Shiying; Chen, Yuan; Wu, Kongming

    2014-01-01

    Through epithelial-mesenchymal transition (EMT), cancer cells acquire enhanced ability of migration and invasion, stem cell like characteristics and therapeutic resistance. Notch signaling regulates cell-cell connection, cell polarity and motility during organ development. Recent studies demonstrate that Notch signaling plays an important role in lung cancer initiation and cross-talks with several transcriptional factors to enhance EMT, contributing to the progression of non-small cell lung c...

  2. Fatigue crack initiation for Al-Zn-Mg alloy welded joint

    Institute of Scientific and Technical Information of China (English)

    Liang ZHANG; Xuesong LIU; Linsen WANG; Ping WANG; Hongyuan FANG

    2012-01-01

    To investigate fatigue crack initiation characteristics of A1-Zn-Mg alloy welded joint,notched specimens were used in fatigue test for the base metal,welding bead and heat affected zone (HAZ).The fatigue fracture surface near the fatigue crack initiation site was observed by scanning electron microscope (SEM).The results show that the differences of fatigue crack initiation life among base metal,welding bead and HAZ are not obvious.Inhomogeneity in microstructure and mechanical performance of HAZ influences the fatigue crack initiation life.The ratio of fatigue crack initiation life (Ni) to fatigue failure life (Nf) for the base metal,welding bead and HAZ of A7N01 aluminium alloy welded joint are 26.32%,40.21% and 60.67%,respectively.Fatigue crack initiation life can be predicted using a uniform model.Observation of fatigue fracture surfaces shows that for the welding bead a fatigue crack initiates from the smooth surface due to the welding process,the blowhole in HAZ causes fatigue crack and the crushed second phase particles play an important role in fatigue crack initiation for the base metal.

  3. Notch signaling modulates proliferative vitreoretinopathy via regulating retinal pigment epithelial-to-mesenchymal transition.

    Science.gov (United States)

    Zhang, Jingjing; Yuan, Gongqiang; Dong, Muchen; Zhang, Ting; Hua, Gao; Zhou, Qingjun; Shi, Weiyun

    2016-09-07

    Elevated Notch signaling has been verified in a large range of fibrotic diseases developed in the kidney, liver, and lung, inducing the development of the epithelial-mesenchymal transition (EMT). The aim of this study was to observe the involvement of Notch signaling in the EMT of retinal pigment epithelial (RPE) cells and the pathogenesis of proliferative vitreoretinopathy (PVR). In vitro cultivated human RPE cells (ARPE-19) were treated with 10 ng/mL transforming growth factor (TGF)-β1 for 24, 48, and 72 h. The expression levels of ZO-1, α-SMA, vimentin, Notch1 intracellular domain (NICD1), and Hes-1 were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining or Western blot. TGF-β1 induced EMT and the activation of Notch signaling in ARPE-19 cells. To examine the effect of Notch inhibition on TGF-β1-induced EMT and PVR formation, ARPE-19 cells were preincubated with γ-secretase inhibitor LY411575 before TGF-β1 treatment. Mouse PVR model was used for in vivo study. ARPE-19 cells were injected intravitreously with or without the LY411575 to examine the effect of Notch inhibition on PVR formation. LY411575 significantly attenuated EMT by inhibiting the Notch signaling activation in vitro. PVR was induced by intravitreal injections of ARPE-19 cells, while LY411575 inhibited mouse PVR formation in vivo. Notch signaling plays a critical role in TGF-β1-induced EMT in vitro and mice PVR model, which provides a novel insight into the pathogenesis of PVR. The specific inhibition of Notch signaling by γ-secretase inhibitor may provide a new approach for the prevention of PVR.

  4. Notch receptors in human choroid plexus tumors.

    Science.gov (United States)

    Beschorner, R; Waidelich, J; Trautmann, K; Psaras, T; Schittenhelm, J

    2013-08-01

    Notch signaling plays a role in development and formation of the normal choroid plexus (nCP), and in formation of various tumors in humans. Activation of Notch3 has been reported to promote tumor growth in invasive gliomas and to initiate formation of choroid plexus tumors (CPT) in mice. We investigated the expression of all currently known Notch receptors (Notch 1-4) in 55 samples of nCP and 88 CPT, including 61 choroid plexus papillomas (CPP), 22 atypical CPP and 5 choroid plexus carcinomas by immunohistochemistry. Notch expression was semiquantitatively evaluated separately for membranous/cytoplasmic and for nuclear staining. In addition, we examined Her2 expression (EGFR2, Her2/neu, ErbB2, CD340) because of its functional link to Notch signaling. All samples were negative for Notch3. Membranous/cytoplasmic expression of Notch1 (pnCP compared to CPT. Nuclear expression of Notch1, -2 and -4 was significantly higher in CPT compared to nCP (pnCP to a predominant nuclear expression in CPT. Her2 was weakly expressed in 42/84 CPT but only in 2/53 nCP (p=0.0001) and positively correlated with nuclear expression of Notch1, -2 and 4 in CPT. In summary, a shift between membranous/cytoplasmic (non-canonical signaling pathway) and nuclear expression (canonical signaling pathway) of Notch1, -2 and -4 and upregulation of Her2 indicate neoplastic transformation in human CP and may reveal new therapeutic approaches.

  5. Influence of water cavitation peening with aeration on fatigue behaviour of SAE1045 steel

    Science.gov (United States)

    Han, B.; Ju, D. Y.; Jia, W. P.

    2007-10-01

    Water cavitation peening (WCP) with aeration is a recent potential method in the surface enhancement techniques. In this method, a ventilation nozzle is adopted to improve the process capability of WCP by increasing the impact pressure, which is induced by the bubble collapse on the surface of components in the similar way as conventional shot peening. In this paper, fatigue tests were conducted on the both-edge-notched flat tensile specimens to assess the influences of WCP on fatigue behaviour of SAE1045 steel. The notched specimens were treated by WCP, and the compressive residual stress distributions in the superficial layer were measured by X-ray diffraction method. The tension-tension ( R = Smin/ Smax = 0.1, f = 10 Hz) fatigue tests and the fracture surfaces observation by scan electron microscopy (SEM) were conducted. The experimental results show that WCP can improve the fatigue life by inducing the residual compressive stress in the superficial layer of mechanical components.

  6. Calibration of partial safety factors for wind turbine rotor blades against fatigue; Kalibrering af partielle sikkerhedsfaktorer for udmattelse af vindmoellerotorer. Bilagsrapport

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, C.J.; Ronold, K.O.; Thoegersen, M.L.

    2000-08-01

    The report describes a calibration of partial safety factors for wind turbine rotor blades subjected to fatigue loading in flapwise and edgewise bending. While earlier models - developed by the authors - dealt with such calibrations for site-specific individual turbines only, the calibration model applied herein covers an integrated analysis with different turbines on different sites and with different blade materials. The result is an optimized set of partial safety factors, i.e. a set of safety factors that lead to minimum deviation from the target reliability of the achieved reliabilities over the selected scope of turbines, sites and materials. The turbines included in the study cover rated powers of 450-600 kW. (au)

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Black, J. M. (Inventor)

    1980-01-01

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

  9. 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...

  10. Targeting Notch to overcome radiation resistance.

    Science.gov (United States)

    Yahyanejad, Sanaz; Theys, Jan; Vooijs, Marc

    2016-02-16

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

  11. IIW guidelines on weld quality in relationship to fatigue strength

    CERN Document Server

    Jonsson, Bertil; Hobbacher, A F; Kassner, M; Marquis, G

    2016-01-01

    This book presents guidelines on quantitative and qualitative measures of the geometric features and imperfections of welds to ensure that it meets the fatigue strength requirements laid out in the recommendations of the IIW (International Institute of Welding). Welds that satisfy these quality criteria can be assessed in accordance with existing IIW recommendations based on nominal stress, structural stress, notch stress or linear fracture mechanics. Further, the book defines more restrictive acceptance criteria based on weld geometry features and imperfections with increased fatigue strength. Fatigue strength for these welds is defined as S-N curves expressed in terms of nominal applied stress or hot spot stress. Where appropriate, reference is made to existing quality systems for welds.In addition to the acceptance criteria and fatigue assessment curves, the book also provides guidance on their inspection and quality control. The successful implementation of these methods depends on adequate training for o...

  12. Corrosion Fatigue

    Science.gov (United States)

    1981-10-01

    the applied protection systems, (2) crevices for moisture entrapment, (3) galvanic couples when steel or titanium fasteners are used, and (4) fatigue...Activ Material Structure Exposed Normal Environment* Unexposed Atmosphere Aluminum alloys Steel 1.25 2.0 4.0 Titanium " Magnesium " (4.0) (8.0) (10.0...APPRNDIX - Chromic Acid Anodizing The surface treatment consists in the following process : D egreasing with trichlorethylene vapor, * Pickling , Composition

  13. Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation

    Directory of Open Access Journals (Sweden)

    Vo Kevin

    2011-11-01

    Full Text Available Abstract Background Pancreas cancer is one of most aggressive human cancers with the survival rate for patients with metastatic pancreas cancer at 5-6 months. The poor survival demonstrates a clear need for better target identification, drug development and new therapeutic strategies. Recent discoveries have shown that the role for Notch pathway is important in both development and cancer. Its contribution to oncogenesis also involves crosstalks with other growth factor pathways, such as Akt and its modulator, PTEN. The mounting evidence supporting a role for Notch in cancer promotion and survival suggests that targeting this pathway alone or in combination with other therapeutics represents a promising therapeutic strategy. Results Using a pancreas cancer tissue microarray, we noted that Jagged1, Notch3 and Notch4 are overexpressed in pancreas tumors (26%, 84% and 31% respectively, whereas Notch1 is expressed in blood vessels. While there was no correlation between Notch receptor expression and survival, stage or tumor grade, Notch3 was associated with Jagged1 and EGFR expression, suggesting a unique relationship between Notch3 and Jagged1. Inhibition of the Notch pathway genetically and with gamma-secretase inhibitor (GSI resulted in tumor suppression and enhanced cell death. The observed anti-tumor activity appeared to be through Akt and modulation of PTEN phosphorylation. We discovered that transcriptional regulation of RhoA by Notch is important for PTEN phosphorylation. Finally, the mTOR inhibitor Rapamycin enhanced the effect of GSI on RhoA expression, resulting in down regulation of phospho-Akt and increased in vitro tumor cytotoxity. Conclusions Notch pathway plays an important role in maintaining pancreas tumor phenotype. Targeting this pathway represents a reasonable strategy for the treatment of pancreas cancers. Notch modulates the Akt pathway through regulation of PTEN phosphorylation, an observation that has not been made

  14. Fatigue management in the workplace

    Directory of Open Access Journals (Sweden)

    Khosro Sadeghniiat-Haghighi

    2015-01-01

    Full Text Available Workers′ fatigue is a significant problem in modern industry, largely because of high demand jobs, long duty periods, disruption of circadian rhythms, and accumulative sleep debt that are common in many industries. Fatigue is the end result of integration of multiple factors such as time awake, time of day, and workload. Then, the full understanding of circadian biologic clock, dynamics of transient and cumulative sleep loss, and recovery is required for effective management of workplace fatigue. It can be more investigated in a new field of sleep medicine called occupational sleep medicine. Occupational sleep medicine is concerned with maintaining best productivity and safety in the industrial settings. The fatigue risk management system (FRMS is a comprehensive approach that is based on applying scientific evidence of sleep knowledge to manage workers fatigue. It is developing rapidly in the highly safety demand jobs; especially truck drivers, pilots, and power plant workers. The objective of this review is to explain about fatigue in the workplace with emphasis on its association work performance and errors/accidents. Also, we discussed about different methods of fatigue measurement and management.

  15. The Notch pathway in colorectal cancer.

    Science.gov (United States)

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

    2016-04-15

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

  16. Fatigue in cold-forging dies: Tool life analysis

    DEFF Research Database (Denmark)

    Skov-Hansen, P.; Bay, Niels; Grønbæk, J.;

    1999-01-01

    In the present investigation it is shown how the tool life of heavily loaded cold-forging dies can be predicted. Low-cycle fatigue and fatigue crack growth testing of the tool materials are used in combination with finite element modelling to obtain predictions of tool lives. In the models...... the number of forming cycles is calculated first to crack initiation and then during crack growth to fatal failure. An investigation of a critical die insert in an industrial cold-forging tool as regards the influence of notch radius, the amount and method of pre-stressing and the selected tool material...

  17. Fatores clínicos, funcionais e inflamatórios associados à fadiga muscular e à fadiga autopercebida em idosas da comunidade Clinical, functional and inflammatory factors associated with muscle fatigue and self-perceived fatigue in elderly community-dwelling women

    Directory of Open Access Journals (Sweden)

    Juscelio P. Silva

    2011-06-01

    Full Text Available CONTEXTUALIZAÇÃO: A fadiga é um sintoma comum e inespecífico associado aos problemas crônicos de saúde nos idosos. As alterações e adaptações do processo de envelhecimento associadas à natureza complexa e multidimensional da fadiga favorecem a interação de múltiplos fatores na gênese desse fenômeno. OBJETIVOS: Investigar a associação dos fatores clínicos, funcionais e inflamatórios com a fadiga muscular e a autopercebida em idosas. MÉTODOS: Participaram 135 idosas sedentárias da comunidade, com média de idade de 71,2±4,57. Questionário estruturado e teste funcional foram utilizados para avaliar as características clínicas e funcionais. As concentrações plasmáticas dos mediadores inflamatórios (IL-6 e sTNFR1 foram dosadas pelo método ELISA. A fadiga muscular foi mensurada pelo dinamômetro isocinético, e a fadiga autopercebida, pela Escala Visual Analógica (EVA. A análise estatística foi realizada pela regressão linear múltipla e pelo Coeficiente de Correlação de Spearman, com nível de significância de 5%. RESULTADOS: Os modelos de regressão demonstraram que os fatores idade, índice de massa corporal (IMC, nível de atividade física, capacidade funcional e pico de torque foram associados à fadiga muscular (R²=0,216, pBACKGROUND: Fatigue is a common and nonspecific symptom associated with chronic health problems in the elderly. The modifications and adaptations of the aging process associated with complex and multidimensional nature of fatigue favors the interaction of multiple factors in the genesis of this phenomenon. OBJECTIVES: To investigate the association of clinical, functional and inflammatory factors with muscle fatigue and self perceived fatigue in elderly women. METHODS: Participated in the study one hundred and thirty five community elderly women, all sedentary, with a mean age of 71.2±4.57. A structured questionnaire and functional testing were used to evaluate clinical and functional

  18. Crack initiation behavior of notched specimens on heat resistant steel under service type loading at high temperature

    Directory of Open Access Journals (Sweden)

    Lu Cui

    2016-10-01

    Full Text Available Cracks at notches deserve special consideration in the design of steam turbine components. This work is addressed to investigate the crack initiation behavior a 10%Cr rotor steel with the help of notched specimens under service-type loading. A significant drifting down of the peak-values of axial deformation under constant amplitude load was observed. Crack initiation was evaluated with the help of the relationship between irreversible deformation energy and cycle number. Further, metallographic examinations were employed to characterize the superposition of creep and fatigue damage mechanisms. Both Neuber-hypothesis and von Mises equivalent strain at notch root were applied for lifetime prediction. Finally, the effectiveness of both methods is validated by comparing with experimental results

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

    Directory of Open Access Journals (Sweden)

    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

  20. Mef2 interacts with the Notch pathway during adult muscle development in Drosophila melanogaster.

    Science.gov (United States)

    Caine, Charlotte; Kasherov, Petar; Silber, Joël; Lalouette, Alexis

    2014-01-01

    Myogenesis of indirect flight muscles (IFMs) in Drosophila melanogaster follows a well-defined cellular developmental scheme. During embryogenesis, a set of cells, the Adult Muscle Precursors (AMPs), are specified. These cells will become proliferating myoblasts during the larval stages which will then give rise to the adult IFMs. Although the cellular aspect of this developmental process is well studied, the molecular biology behind the different stages is still under investigation. In particular, the interactions required during the transition from proliferating myoblasts to differentiated myoblasts ready to fuse to the muscle fiber. It has been previously shown that the Notch pathway is active in proliferating myoblasts, and that this pathway is inhibited in developing muscle fibers. Furthermore, the Myocyte Enhancing Factor 2 (Mef2), Vestigial (Vg) and Scalloped (Sd) transcription factors are necessary for IFM development and that Vg is required for Notch pathway repression in differentiating fibers. Here we examine the interactions between Notch and Mef2 and mechanisms by which the Notch pathway is inhibited during differentiation. We show that Mef2 is capable of inhibiting the Notch pathway in non myogenic cells. A previous screen for Mef2 potential targets identified Delta a component of the Notch pathway. Dl is expressed in Mef2 and Sd-positive developing fibers. Our results show that Mef2 and possibly Sd regulate a Dl enhancer specifically expressed in the developing IFMs and that Mef2 is required for Dl expression in developing IFMs.

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

    Directory of Open Access Journals (Sweden)

    Miguel Aste-Amézaga

    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

  2. Notch3/Jagged1 Circuitry Reinforces Notch Signaling and Sustains T-ALL

    Directory of Open Access Journals (Sweden)

    Maria Pelullo

    2014-12-01

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

  3. 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.

  4. Study of the family caregivers fatigue of patients with heavy brain and the relevant factors%重型颅脑损伤患者家属及照顾者疲劳与相关因素分析

    Institute of Scientific and Technical Information of China (English)

    蓝海; 邓秋容; 朱丽铃; 谢冠玲; 钟洪花

    2008-01-01

    Objective To explore family caregivers fatigue conditions of patients with heavy brain injury and factors related to fatigue.Methods To the brief fatigue inventory(BFI)and the general situation designed questionnaire was used to investigate the level of fatigue and the relevant factors.62 cases of family caregivers fatigue situation of patients with heavy brain injury and related factors were evaluated,and 65 cases of family caregiver of patients under intracranial tumor surgeries as s contrast. Results Family caregivers of.patients with heavy brain injury had more fatigue than comparison group,the impact factors of family caregivers fatigue of patients with heavy brain injury were:sleep time,time to take care of patients,sex and chronic history.Conclusion Family caregivers of patients with heavy brain injury has more serious degree of fatigue,it was necessary to take the relevant measures to reduce family caregivers fatigue and safeguard its physical and mental health.%目的 探讨重型颅脑损伤的患者家属及照顾者的疲劳状况及引起疲劳的相关因素.方法 采用简短疲劳评估表(BFI)及自行设计的一般情况调查表,对62例重型颅脑损伤患者的家属及照顾者的疲劳状况及相关因素进行测评,并以65例颅内肿瘤开颅术后患者的家属及照顾者作为对照.结果 重型颅脑损伤患者家属照顾者的疲劳程度明显高于对照组,影响重型颅脑损伤患者的家属及照顾者疲劳的因素有睡眠时间、照顾患者的时间、性别及有无慢性病史.结论 重型颅脑损伤患者家属照顾者疲劳程度较为严重.因此,有必要采取相关措施降低家属照顾者的疲劳,维护其身心健康.

  5. [Research Progress on the Interaction Effects and Its Neural Mechanisms between Physical Fatigue and Mental Fatigue].

    Science.gov (United States)

    Zhang, Lixin; Zhang, Chuncui; He, Feng; Zhao, Xin; Qi, Hongzhi; Wan, Baikun; Ming, Dong

    2015-10-01

    Fatigue is an exhaustion state caused by prolonged physical work and mental work, which can reduce working efficiency and even cause industrial accidents. Fatigue is a complex concept involving both physiological and psychological factors. Fatigue can cause a decline of concentration and work performance and induce chronic diseases. Prolonged fatigue may endanger life safety. In most of the scenarios, physical and mental workloads co-lead operator into fatigue state. Thus, it is very important to study the interaction influence and its neural mechanisms between physical and mental fatigues. This paper introduces recent progresses on the interaction effects and discusses some research challenges and future development directions. It is believed that mutual influence between physical fatigue and mental fatigue may occur in the central nervous system. Revealing the basal ganglia function and dopamine release may be important to explore the neural mechanisms between physical fatigue and mental fatigue. Future effort is to optimize fatigue models, to evaluate parameters and to explore the neural mechanisms so as to provide scientific basis and theoretical guidance for complex task designs and fatigue monitoring.

  6. Evaluation of Pressurization Fatigue Life of 1441 Al-li Fuselage Panel

    Science.gov (United States)

    Bird, R. Keith; Dicus, Dennis I.; Fridlyander, Joseph; Davydov, Valentin

    1999-01-01

    A study was conducted to evaluate the pressurization fatigue life of fuselage panels with skins fabricated from 1441 Al-Li, an attractive new Russian alloy. The study indicated that 1441 Al-Li has several advantages over conventional aluminum fuselage skin alloy with respect to fatigue behavior. Smooth 1441 Al-Li sheet specimens exhibited a fatigue endurance limit similar to that for 1163 Al (Russian version of 2024 Al) sheet. Notched 1441 Al-Li sheet specimens exhibited greater fatigue strength and longer fatigue life than 1163 Al. In addition, Tu-204 fuselage panels fabricated by Tupolev Design Bureau using Al-Li skin and ring frames with riveted 7000-series aluminum stiffeners had longer pressurization fatigue lives than did panels constructed from conventional aluminum alloys. Taking into account the lower density of this alloy, the results suggest that 1441 Al-Li has the potential to improve fuselage performance while decreasing structural weight.

  7. MANAGING FATIGUE IN SPORTS

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Fatigue is a multifactorial process. Depletion of energy sources, including adenosine triphosphate (ATP), phosphocreatine (PCr), plus carbohydrates (CHO) like muscle glycogen and blood glucose can contribute to fatigue.

  8. 预应力与非预应力AFRP加固腐蚀钢筋混凝土梁疲劳性能研究%Experimental study on fatigue performance corroded reinforced concrete beams strengthened with prestressed AFRP sheets

    Institute of Scientific and Technical Information of China (English)

    邓宗才; 李凯

    2009-01-01

    to estimate an equivalent fatigue notch factor for the main reinforcement bars of the tested specimens. Pitting corrosion resulted in an increase in the fatigue notch factor, which in turn resulted in a significant reduction of fatigue life. Based on the experimental results of moderate corroded concrete beams strengthened with AFRP sheets, the fatigue equation was obtained, and this equation can be used in strengthened design for damaged bridge.

  9. Notch signaling in acute promyelocytic leukemia.

    Science.gov (United States)

    Grieselhuber, N R; Klco, J M; Verdoni, A M; Lamprecht, T; Sarkaria, S M; Wartman, L D; Ley, T J

    2013-07-01

    Acute promyelocytic leukemia (APL) is initiated by the PML-RARA (PR) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (JAG1). In this study, we used a series of bioinformatic, in vitro, and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML-RARA). We identified a Notch expression signature in both human primary APL cells and in Kit+Lin-Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.

  10. The role of Notch signaling in kidney podocytes.

    Science.gov (United States)

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

    2017-02-01

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

  11. 76 FR 22745 - Three Notch Railway, LLC-Acquisition and Operation Exemption-Three Notch Railroad Co., Inc.

    Science.gov (United States)

    2011-04-22

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

  12. 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.

  13. FGF-dependent Notch signaling maintains the spinal cord stem zone

    Science.gov (United States)

    Akai, Jun; Halley, Pam A.; Storey, Kate G.

    2005-01-01

    Generation of the spinal cord relies on proliferation of undifferentiated cells located in a caudal stem zone. Although fibroblast growth factor (FGF) signaling is required to maintain this cell group, we do not know how it controls cell behavior in this context. Here we characterize an overlooked expression domain of the Notch ligand, Delta1, in the stem zone and demonstrate that this constitutes a proliferative cell group in which Notch signaling is active. We show that FGF signaling is required for expression of the proneural gene cash4 in the stem zone, which in turn induces Delta1. We further demonstrate that Notch signaling is required for cell proliferation within the stem zone; however, it does not regulate cell movement out of this region, nor is loss of Notch signaling sufficient to drive neuronal differentiation within this tissue. These data identify a novel role for the Notch pathway during vertebrate neurogenesis in which signaling between high Delta1-expressing cells maintains the neural precursor pool that generates the spinal cord. Our findings also suggest a mechanism for the establishment of the cell selection process, lateral inhibition: Mutual inhibition between Delta/Notch-expressing stem zone cells switches to single Delta1-presenting neurons as FGF activity declines in the newly formed neuroepithelium. PMID:16287717

  14. Notch Intracellular Domain (NICD) Suppresses Long-Term Memory Formation in Adult Drosophila Flies.

    Science.gov (United States)

    Zhang, Jiabin; Yin, Jerry C P; Wesley, Cedric S

    2015-08-01

    Notch receptor signaling is evolutionarily conserved and well known for its roles in animal development. Many studies in Drosophila have shown that Notch also performs important functions in memory formation in adult flies. An intriguing observation is that increased expression of the full-length Notch receptor (Nfull) triggers long-term memory (LTM) formation even after very weak training (single training). Canonical Notch signaling is mediated by Notch intracellular domain (NICD), but it is not known whether increased expression of NICD recapitulates the LTM enhancement induced by increased Nfull expression. Here, we report that increased NICD expression either has no impact on LTM formation or suppresses it. Furthermore, it either has no impact or decreases both the levels and activity of cAMP response element binding protein, a key factor supporting LTM. These results indicate that NICD signaling is not sufficient to explain Nfull-induced LTM enhancement. Our findings may also shed light on the molecular mechanisms of memory loss in neurological diseases associated with increased NICD expression and canonical Notch signaling.

  15. Notch2 signaling promotes osteoclast resorption via activation of PYK2.

    Science.gov (United States)

    Jin, Won Jong; Kim, Bongjun; Kim, Jung-Wook; Kim, Hong-Hee; Ha, Hyunil; Lee, Zang Hee

    2016-05-01

    Notch signaling plays a central role in various cell fate decisions, including skeletal development. Recently, Notch signaling was implicated in osteoclast differentiation and maturation, including the resorption activity of osteoclasts. However, the specific involvement of notch signaling in resorption activity was not fully investigated. Here, we investigated the roles of Notch signaling in the resorption activity of osteoclasts by use of the gamma-secretase inhibitor dibenzazepine (DBZ). Attenuating Notch signaling by DBZ suppressed the expression of NFATc1, a master transcription factor for osteoclast differentiation. However, overexpression of a constitutively active form of NFATc1 did not fully rescue the effects of DBZ. DBZ suppressed the autophosphorylation of PYK2, which is essential for the formation of the podosome belt and sealing zone, with reduced c-Src/PYK2 interaction. We found that RANKL increases PYK2 activation accompanied by increased NICD2 production in osteoclasts. Overexpression of NICD2 in osteoclasts rescued DBZ-mediated suppression of resorption activity with promotion of PYK2 autophosphorylation and microtubule acetylation. Consistent with the in vitro results, DBZ strongly suppressed bone destruction in an interleukin-1-induced bone loss model. Collectively, these results demonstrate that Notch2 in osteoclasts plays a role in the control of resorption activity via the PYK2-c-Src-microtubule signaling pathway.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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.

  18. An experimental study on the effects of compressive stress on the fatigue crack growth of low-alloy steel

    Energy Technology Data Exchange (ETDEWEB)

    Jones, D.P.; Hoppe, R.G. (Westinghouse Electric Corp., West Mifflin, PA (United States). Bettis Atomic Power Lab.); Hechmer, J.L. (Babcock Wilcox Co., Barberton, OH (United States)); James, B.A. (Colorado School of Mines, Golden, CO (United States). Metallurgy Dept.)

    1994-08-01

    A series of fatigue crack growth rate tests was conducted in order to study the effects of negative stress ratio upon the fatigue crack growth rate of low-alloy steel in air environment. The tests used four-point bend specimens in order to simulate linear stress distributions typical of many pressure vessel applications. This type of testing adds to the knowledge on negative stress ratio effects for low-alloy steels that in the past have been obtained from uniform tension-compression tests. Additionally, the applied bending stress range was varied from low values of applied stress to high values of applied stress over twice the yield strength. Load control was used for tests for which the stress range was less than twice the yield strength and deflection control was used for the higher stress range tests. The crack geometries involved were both short and long fatigue cracks started at notches and tight fatigue cracks for which crack closure could occur over the full crack face. The results are presented in terms of the stress intensity factor ratio R = K[sub MIN]/K[sub MAX]. The negative R-ratio test results were correlated to an equation of the form da/dN = C[[delta]K/(A-R)][sup n] where A, C and n are curve-fitting parameters. It was found that the effects of negative R-ratio on the fatigue crack growth rates for even the high stress range tests could be bounded by correlating the foregoing equation to only positive R-ratio test results and extending the resulting equation into the negative R-ratio regime.

  19. Improved Fatigue Performance of Threaded Drillstring Connections by Cold Rolling

    Energy Technology Data Exchange (ETDEWEB)

    Kristoffersen, Steinar

    2002-01-01

    The research work presented in this thesis is concerned with analytical, numerical and experimental studies of the effect of cold rolling on the fatigue behaviour of threaded drillstring connections. A comprehensive literature study is made of the various effects on the fatigue behaviour of residual stresses introduced by mechanical deformation of notched components. Some of the effects studied are cyclic hardening behaviour after prestraining, cyclic creep, fatigue initiation in prestrained materials, short cracks and crack growth models including crack closure. Residual stresses were introduced in the surface of a smooth pipe by a rolling device to simulate a cold rolling process and verify the calculated residual stresses by measurements. Strain hardening and contact algorithm of the two bodies were incorporated in the FE analyses. Two significant errors were found in the commercial software package for residual stress evaluation, Restran v. 3.3.2a also called SINT, when using the Schajer method. The Schajer algorithm is the only hole-drilling algorithm without theoretical shortcomings, and is recommended when measuring large residual stress gradients in the depth direction. Using the Schajer method solved by in-house Matlab-routines good agreement between measured residual stress gradients and residual stress gradients from FE analyses was found. Full scale fatigue tests were performed on pipes cut from used drillstrings with notches of similar geometry as threads used in drillstring connections. The simulated threads consisted of four full depth helix notches with runouts at the surface. The pipe threads were cold rolled and fatigue tested in a full-scale four-point rotating bending fatigue testing rig. The test results showed that cold rolling had an effect on the crack initiation period. A major part of the fatigue life was with cracks observed at the notch root, but due to the increased fatigue crack propagation resistance the final fracture initiated at

  20. Notch-1 Confers Chemoresistance in Lung Adenocarcinoma to Taxanes through AP-1/microRNA-451 Mediated Regulation of MDR-1.

    Science.gov (United States)

    Huang, Jiayuan; Chen, Yitian; Li, Junyang; Zhang, Kai; Chen, Jing; Chen, Dongqin; Feng, Bing; Song, Haizhu; Feng, Jifeng; Wang, Rui; Chen, Longbang

    2016-01-01

    We previously demonstrated that expression of Notch-1 is associated with poor prognosis in lung adenocarcinoma (LAD) patients. The aim of this study is to reveal whether Notch-1 was associated with Taxanes-resistant LAD and, the underlying mechanisms. We collected 39 patients of advanced LAD treated with Taxanes and found that positive Notch-1 expression is closely related to LAD lymph node metastasis, recurrence and poorer prognosis, and Notch-1 acts as an independent poor prognostic factor in LAD by multivariate analysis with Cox regression model. Then, by using the Docetaxel (DTX)-resistant LAD cell lines that we established previously, we found that Notch-1 contributes to resistance of LAD cells to DTX in vitro, and inhibition of Notch-1 sensitizes LAD to DTX in vivo. We further demonstrated that Notch-1 mediates chemoresistance response and strengthens proliferation capacity in LAD cells partially through negative regulation of miR-451 by transcription factor AP-1. Moreover, we found that MDR-1 is a direct target of miR-451 and influences chemoresistance of LAD cells. Taken together, our data revealed a novel Notch-1/AP-1/miR-451/MDR-1 signaling axis, and suggested a new therapeutic strategy of combining DTX with Notch inhibitors to treat DTX-resistant LAD.

  1. Experimental fatigue curves for aluminium brazed areas

    Science.gov (United States)

    Dimitescu, A.; Babiş, C.; Niţoi, D. F.; Radu, C.

    2017-08-01

    An important factor for the quality of joints is the brazed area. The fatigue check occupies a major position among many test procedures and methods, especially by the joining technologies. The results of processing the fatigue data experiments for aluminium brazed samples are used to find the regression function and the response surface methodology. The fatigue process of mechanical components under service loading is stochastic in nature. The prediction of time-dependent fatigue reliability is critical for the design and maintenance planning of many structural components.

  2. Countering compassion fatigue: a requisite nursing agenda.

    Science.gov (United States)

    Boyle, Deborah A

    2011-01-31

    Nurses have a longstanding history of witnessing the tragedy experienced by patients and families; however, their own reactions to profound loss and premature death have not been systematically addressed. There is a paucity of research describing interventions to prevent or minimize the ramifications of repeated exposure to traumatic events in the clinical workplace. Compassion fatigue is a contemporary label affixed to the concept of personal vicarious exposure to trauma on a regular basis. Yet this phenomenon of compassion fatigue lacks clarity. In this article, the author begins by describing compassion fatigue and distinguishing compassion fatigue from burnout. Next she discusses risk factors for, and the assessment of compassion fatigue. The need to support nurses who witness tragedy and workplace interventions to confront compassion fatigue are described.

  3. Mechanical fatigue of polysilicon: Effects of mean stress and stress amplitude

    Energy Technology Data Exchange (ETDEWEB)

    Kahn, H. [Department of Materials Science and Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 7204 (United States)]. E-mail: harold.kahn@case.edu; Chen, L. [Department of Civil Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 7201 (United States); Ballarini, R. [Department of Civil Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 7201 (United States); Heuer, A.H. [Department of Materials Science and Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 7204 (United States)

    2006-02-15

    Polycrystalline silicon (polysilicon) fatigue specimens with micrometer-sized dimensions were fabricated and subjected to cyclic loading using an integrated electrostatic actuator. The fatigue effects were determined by comparing the single edge-notched beam monotonic bend strength measured after cyclic loading to the monotonic strength of 'virgin' specimens that had received no cycling. Both strengthening and weakening were observed, depending on the levels of mean stress and fatigue stress amplitude during the cyclic loading. Monotonic loading with similar sub-critical stress levels had no effect. The physical mechanisms responsible for this behavior are discussed, and a model based on grain boundary plasticity is presented for the strengthening behavior.

  4. Fatigue of weld ends under combined in- and out-of-phase multiaxial loading

    Directory of Open Access Journals (Sweden)

    E. Shams

    2016-10-01

    Full Text Available Weld start and end points are fatigue failure sensitive locations. Their fatigue behaviour especially in thin sheet structures under multiaxial load conditions is not sufficiently explored so far. Therefore, a research project was initiated to increase the knowledge concerning this topic, which is of special interest in the automotive industry. In the present study, fatigue tests on welded joints were conducted. In the numerical part of the study, notch stresses were calculated with an idealised weld end model. A numerical method which combines the geometrical and statistical size effect to an integrated approach was used, in order to consider the size effects

  5. Notch sensitivity of space shuttle tile materials

    Science.gov (United States)

    Newman, J. C., Jr.

    1980-01-01

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

  6. Laminar flow downregulates Notch activity to promote lymphatic sprouting.

    Science.gov (United States)

    Choi, Dongwon; Park, Eunkyung; Jung, Eunson; Seong, Young Jin; Yoo, Jaehyuk; Lee, Esak; Hong, Mingu; Lee, Sunju; Ishida, Hiroaki; Burford, James; Peti-Peterdi, Janos; Adams, Ralf H; Srikanth, Sonal; Gwack, Yousang; Chen, Christopher S; Vogel, Hans J; Koh, Chester J; Wong, Alex K; Hong, Young-Kwon

    2017-04-03

    The major function of the lymphatic system is to drain interstitial fluid from tissue. Functional drainage causes increased fluid flow that triggers lymphatic expansion, which is conceptually similar to hypoxia-triggered angiogenesis. Here, we have identified a mechanotransduction pathway that translates laminar flow-induced shear stress to activation of lymphatic sprouting. While low-rate laminar flow commonly induces the classic shear stress responses in blood endothelial cells and lymphatic endothelial cells (LECs), only LECs display reduced Notch activity and increased sprouting capacity. In response to flow, the plasma membrane calcium channel ORAI1 mediates calcium influx in LECs and activates calmodulin to facilitate a physical interaction between Krüppel-like factor 2 (KLF2), the major regulator of shear responses, and PROX1, the master regulator of lymphatic development. The PROX1/KLF2 complex upregulates the expression of DTX1 and DTX3L. DTX1 and DTX3L, functioning as a heterodimeric Notch E3 ligase, concertedly downregulate NOTCH1 activity and enhance lymphatic sprouting. Notably, overexpression of the calcium reporter GCaMP3 unexpectedly inhibited lymphatic sprouting, presumably by disturbing calcium signaling. Endothelial-specific knockouts of Orai1 and Klf2 also markedly impaired lymphatic sprouting. Moreover, Dtx3l loss of function led to defective lymphatic sprouting, while Dtx3l gain of function rescued impaired sprouting in Orai1 KO embryos. Together, the data reveal a molecular mechanism underlying laminar flow-induced lymphatic sprouting.

  7. Notch Promotes Radioresistance of Glioma Stem Cells

    OpenAIRE

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

    2010-01-01

    Radiotherapy represents the most effective nonsurgical treatments for gliomas. Yet, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radioresistance in gliomas and breast cancers. The Notch pathway is critically implicated in stem cell fate determination and cancer. In this study, we showed that inhibition of Notch pathway with gamma-secretase inhibitors (GSIs) rendered the glioma st...

  8. Fatigue life extension

    Science.gov (United States)

    Matejczyk, D. E.; Lin, J.

    1985-01-01

    Potential fatigue rejuvenation processes were carried out on fatigue-damaged material both with and without observable surface-connected fatigue cracks. The fatigue life of fatigue-damaged MAR-M246(Hf)(DS), a directionally solidified nickel-base superalloy used in turbine airfoils, was extended by reheat treatment. The fatigue life of fatigue-cracked Inconel 718, a wrought nickel-base superalloy used in a wide variety of advanced rocket engine components, was extended by electron-beam welding to close off the surface-connected crack, followed by hot isostatic pressing and reheat treatment.

  9. Restraint of fatigue crack growth by wedge effects of fine particles

    CERN Document Server

    Takahashi, I; Kotani, N

    2000-01-01

    Presents some experimental results which demonstrate restraint of fatigue crack growth in an Al-Mg alloy by wedge effects of fine particles. Fatigue test specimens were machined from a JIS A5083P-O Al-Mg alloy plate of 5 mm thickness and an EDM starter notch was introduced to each specimen. Three kinds of fine particles were prepared as the materials to be wedged into the fatigue cracks, i.e. magnetic particles and two kinds of alumina particles having different mean particle sizes of 47.3 mu m and 15.2 mu m. Particles of each kind were suspended in an oil to form a paste, which was applied on the specimen surface covering the notch zone prior to the fatigue tests. In order to make some fracture mechanics approaches, in situ observations of fatigue cracks were performed for the two cases using a CCD microscope, with a magnification of *1000. The crack length and the crack opening displacement (COD) at the notch root, delta , were measured. The crack retardation effect continues almost through the entire lifet...

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Effects of Linker Length and Transient Secondary Structure Elements in the Intrinsically Disordered Notch RAM Region on Notch Signaling.

    Science.gov (United States)

    Sherry, Kathryn P; Johnson, Scott E; Hatem, Christine L; Majumdar, Ananya; Barrick, Doug

    2015-11-01

    Formation of the bivalent interaction between the Notch intracellular domain (NICD) and the transcription factor CBF-1/RBP-j, Su(H), Lag-1 (CSL) is a key event in Notch signaling because it switches Notch-responsive genes from a repressed state to an activated state. Interaction of the intrinsically disordered RBP-j-associated molecule (RAM) region of NICD with CSL is thought to both disrupt binding of corepressor proteins to CSL and anchor NICD to CSL, promoting interaction of the ankyrin domain of NICD with CSL through an effective concentration mechanism. To quantify the role of disorder in the RAM linker region on the effective concentration enhancement of Notch transcriptional activation, we measured the effects of linker length variation on activation. The resulting activation profile has general features of a worm-like chain model for effective concentration. However, deviations from the model for short sequence deletions suggest that RAM contains sequence-specific structural elements that may be important for activation. Structural characterization of the RAM linker with sedimentation velocity analytical ultracentrifugation and NMR spectroscopy reveals that the linker is compact and contains three transient helices and two extended and dynamic regions. To test if these secondary structure elements are important for activation, we made sequence substitutions to change the secondary structure propensities of these elements and measured transcriptional activation of the resulting variants. Substitutions to two of these nonrandom elements (helix 2, extended region 1) have effects on activation, but these effects do not depend on the nature of the substituting residues. Thus, the primary sequences of these elements, but not their secondary structures, are influencing signaling.

  12. 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.

  13. Predictors and Trajectories of Morning Fatigue Are Distinct from Evening Fatigue

    Science.gov (United States)

    Wright, Fay; Melkus, Gail D’Eramo; Hammer, Marilyn; Schmidt, Brian L.; Knobf, M. Tish; Paul, Steven M.; Cartwright, Frances; Mastick, Judy; Cooper, Bruce A.; Chen, Lee-May; Melisko, Michelle; Levine, Jon D.; Kober, Kord; Aouizerat, Bradley E.; Miaskowski, Christine

    2015-01-01

    Context Fatigue is the most common symptom in oncology patients during chemotherapy (CTX). Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients. Objectives An evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue. Methods A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. Results A large amount of interindividual variability was found in the morning fatigue trajectories. A piecewise model fit the data best. Patients with higher body mass index (BMI), who did not exercise regularly, with a lower functional status, and who had higher levels of state anxiety, sleep disturbance and depressive symptoms, reported higher levels of morning fatigue at enrollment. Variations in the trajectories of morning fatigue were predicted by the patients’ ethnicity and younger age. Conclusion The modifiable risk factors that were associated with only morning fatigue were BMI, exercise, and state anxiety. Modifiable risk factors that were associated with both morning and evening fatigue included functional status, depressive symptoms, and sleep disturbance. Using this information, clinicians can identify patients at higher risk for more severe morning fatigue and evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors. PMID:25828559

  14. An Experiment to Explain Depth of Cut Notch Wear of Ceramic Tools in Ni- based Super-alloy Machining

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Inconel 718, a high temperature alloy, is extensive ly used in aircraft, gas engines and nuclear-power plants. It is generally known that the life of ceramic cutting tools in machining Inconel 718 is often restric ted by depth-of-cut (DOC) notch wear. In view of the number of various factors involved and the variety of tool materi als and cutting conditions available, the analysis of the DOC notch wear is very difficult. According to previous work concerning the DOC notch wear of ceramics tools, some A...

  15. Random non-proportional fatigue tests with planar tri-axial fatigue testing machine

    Directory of Open Access Journals (Sweden)

    T. Inoue

    2016-10-01

    Full Text Available Complex stresses, which occur on the mechanical surfaces of transport machinery in service, bring a drastic degradation in fatigue life. However, it is hard to reproduce such complex stress states for evaluating the fatigue life with conventional multiaxial fatigue machines. We have developed a fatigue testing machine that enables reproduction of such complex stresses. The testing machine can reproduce arbitrary in-plane stress states by applying three independent loads to the test specimen using actuators which apply loads in the 0, 45, and 90 degree directions. The reproduction was tested with complex stress data obtained from the actual operation of transport machinery. As a result, it was found that the reproduced stress corresponded to the measured stress with an error range of less than 10 %. Then, we made a comparison between measured fatigue lives under random non-proportional loading conditions and predicted fatigue lives. It was found that predicted fatigue lives with cr, stress on critical plane, were over a factor of 10 against measured fatigue lives. On the other hand, predicted fatigue lives with ma, stress in consideration of a non-proportional level evaluated by using amplitude and direction of principal stress, were within a factor of 3 against measured fatigue lives

  16. Contrasty Tests on Fatigue Properties of Aluminum Alloys 2E12-T3 and 7050-T7451 in Pooding Environment of Fuel Tank

    Directory of Open Access Journals (Sweden)

    LI Kuang

    2017-01-01

    Full Text Available Fatigue properties in typical corrosion environments are the premise of fatigue life design for metallic structures in aircraft. Therefore, fatigue tests were performed on smooth and notched specimens subjected to constant amplitude loading in two environments of dry air and fuel tank ponding respectively to determine pure and corrosion fatigue properties of aluminum alloys 2E12-T3 and 7050-T7451. Corrosion fatigue properties in the two environments were analyzed and compared with each other, and the interaction mechanisms between corrosion and fatigue were deduced from fractographical studies by using scanning election microscope (SEM. It is showed that fuel tank ponding has a detrimental influence on fatigue properties and the adverse effect increases with the decreasing stress level. In addition, the notch of specimen enhances the severity of corrosion effects. Fatigue crack is easily initiate from the corrosion pits on the rough fatigue surface, and crack propagation is enhanced by the corrosion products and the hydrogen embrittlement effects at crack tips, thus the degradation of fatigue properties and the reduction of fatigue life are caused.

  17. Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice.

    Science.gov (United States)

    Chen, Bei-Yu; Zheng, Min-Hua; Chen, Yan; Du, Yan-Ling; Sun, Xiao-Long; Zhang, Xing; Duan, Li; Gao, Fang; Liang, Liang; Qin, Hong-Yan; Luo, Zhuo-Jing; Han, Hua

    2015-12-01

    The outcome of spinal cord injury (SCI) is determined by both neural cell-intrinsic survival pathways and tissue microenvironment-derived signals. Macrophages dominating the inflammatory responses in SCI possess both destructive and reparative potentials, according to their activation status. Notch signaling is involved in both cell survival and macrophage-mediated inflammation, but a comprehensive role of Notch signaling in SCI has been elusive. In this study, we compared the effects of general Notch blockade by a pharmaceutical γ-secretase inhibitor (GSI) and myeloid-specific Notch signal disruption by recombination signal binding protein Jκ (RBP-J) knockout on SCI. The administration of Notch signal inhibitor GSI resulted in worsened hind limb locomotion and exacerbated inflammation. However, mice lacking RBP-J, the critical transcription factor mediating signals from all four mammalian Notch receptors, in myeloid lineage displayed promoted functional recovery, attenuated glial scar formation, improved neuronal survival and axon regrowth, and mitigated inflammatory response after SCI. These benefits were accompanied by enhanced AKT activation in the lesion area after SCI. These findings demonstrate that abrogating Notch signal in myeloid cells ameliorates inflammation response post-SCI and promotes functional recovery, but general pharmaceutical Notch interception has opposite effects. Therefore, clinical intervention of Notch signaling in SCI needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.

  18. The putative Notch ligand HyJagged is a transmembrane protein present in all cell types of adult Hydra and upregulated at the boundary between bud and parent

    Directory of Open Access Journals (Sweden)

    Tischer Susanne

    2011-09-01

    Full Text Available Abstract Background The Notch signalling pathway is conserved in pre-bilaterian animals. In the Cnidarian Hydra it is involved in interstitial stem cell differentiation and in boundary formation during budding. Experimental evidence suggests that in Hydra Notch is activated by presenilin through proteolytic cleavage at the S3 site as in all animals. However, the endogenous ligand for HvNotch has not been described yet. Results We have cloned a cDNA from Hydra, which encodes a bona-fide Notch ligand with a conserved domain structure similar to that of Jagged-like Notch ligands from other animals. Hyjagged mRNA is undetectable in adult Hydra by in situ hybridisation but is strongly upregulated and easily visible at the border between bud and parent shortly before bud detachment. In contrast, HyJagged protein is found in all cell types of an adult hydra, where it localises to membranes and endosomes. Co-localisation experiments showed that it is present in the same cells as HvNotch, however not always in the same membrane structures. Conclusions The putative Notch ligand HyJagged is conserved in Cnidarians. Together with HvNotch it may be involved in the formation of the parent-bud boundary in Hydra. Moreover, protein distribution of both, HvNotch receptor and HyJagged indicate a more widespread function for these two transmembrane proteins in the adult hydra, which may be regulated by additional factors, possibly involving endocytic pathways.

  19. The incidence of burnout or compassion fatigue in medical dosimetrists as a function of various stress and psychologic factors

    Energy Technology Data Exchange (ETDEWEB)

    Howard, Michelle, E-mail: Mhoward24601@yahoo.com [University of Wisconsin—La Crosse, WI 54601 (United States)

    2013-04-01

    ABSTRACT: Burnout and compassion fatigue (CF) adversely affect medical professionals, including those employed in radiation oncology. Previously conducted research acknowledged the presence of burnout in populations of radiation therapists, radiation oncologists, and oncology nursing staff. The aim of the following research was to measure the incidence of burnout or CF in the specific population of medical dosimetrists surveyed. As professional members of the radiation oncology team, this group had not been included in published research data to date. The hypothesis of the subsequent study stated that a comparable incidence of burnout would be observed among medical dosimetrists as had been reported by earlier researchers for a population of radiation therapists. A survey tool based on the Maslach Burnout Inventory (MBI) and distributed to full members of the American Association of Medical Dosimetrists (AAMD) was utilized as the research measurement method. Results obtained indicated an incidence rates of burnout or CF for medical dosimetrists were less than the rates previously measured for radiation therapists (53% vs 11% for emotional exhaustion [EE] and 45% vs 27% for depersonalization [DP]). The incidence of burnout was based on the Burnout Inventory (BI) developed for the research project. Each of the subscales, EE, DP, and decreased personal accomplishment (PA), was considered and analyzed independently. Although not as prevalent among medical dosimetrists as a variety of additional radiation oncology professionals, a significant portion of the population demonstrated signs of burnout or CF. Future concerns abound for the population of medical dosimetrists as a large number of members scored positive for intermediate risk of burnout and CF. Additionally, a large portion of the population was found to be rapidly approaching retirement.

  20. Trastuzumab Resistance: Role for Notch Signaling

    Directory of Open Access Journals (Sweden)

    Kinnari Mehta

    2009-01-01

    Full Text Available Epidermal growth factor receptor-2 (ErbB-2/HER2 is a potent breast oncogene that has been shown to be amplified in 20% of breast cancers. Overexpression of ErbB-2 predicts for aggressive tumor behavior, resistance to some cytotoxic and antihormonal therapies, and poor overall survival. Trastuzumab, the humanized, monoclonal antibody directed against ErbB-2 has shown tremendous efficacy and improved overall survival for women when combined with a taxane-based chemotherapy. However, resistance to trastuzumab remains a major concern, most notably in women with metastatic breast cancer. Numerous mechanisms that include overexpression of alternate receptor tyrosine kinases and/or loss of critical tumor suppressors have been proposed in the last several years to elucidate trastuzumab resistance. Here we review the many possible mechanisms of action that could contribute to resistance, and novel therapies to prevent or reverse the resistant phenotype. Moreover, we provide a critical role for Notch signaling cross-talk with overlapping or new signaling networks in trastuzumab-resistant breast.

  1. Fatigue in ankylosing spondylitis: treatment should focus on pain management.

    Science.gov (United States)

    Brophy, Sinead; Davies, Helen; Dennis, Michael S; Cooksey, Roxanne; Husain, Muhammad J; Irvine, Elizabeth; Siebert, Stefan

    2013-02-01

    Fatigue is an important symptom associated with ankylosing spondylitis (AS). This study examines patients' perspectives and clinical associations of fatigue to help inform potential strategies to alleviate fatigue in AS. A mixed methods approach was taken to examine fatigue in a cohort of people with AS. Fatigue levels were evaluated from 3 consecutive monthly questionnaires. Open-ended questions on fatigue were analyzed using thematic analysis and logistic regression was used to examine quantitative data. In addition, fatigue levels were examined before and after treatment with anti-tumor necrosis factor (TNF) compared to nontreated controls. Three hundred forty-eight of 385 participants completed a fatigue questionnaire. Fatigue was reported to have significant physical, social, and psychological effects. A third of the participants reported that there was nothing they could do to reduce their fatigue, whereas other participants reported that medication, exercise, and resting helped. The main factor associated with fatigue was pain [β-coefficient: 0.74 (95% CI: 0.66 to 0.81)], whereas depression was much less strongly associated. However, these factors only explained 40% of the variation in fatigue levels. Starting anti-TNF therapy reduced fatigue and pain levels compared to the period of time before taking anti-TNF [difference: 14.4 (95% CI: 5.3 to 23.5) on a scale of 0-100] and this reduction was not seen in controls over the same period. Fatigue is not strongly associated with anxiety, motivation, and depression; instead the factor most associated with fatigue is pain. This suggests that in addition to treatments to reduce disease activity, strategies for alleviating fatigue in AS should focus on pain management techniques and actively treating inflammation. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2016-02-01

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

  3. Research progress of exercise-induced fatigue

    Directory of Open Access Journals (Sweden)

    Peng-yi DAI

    2016-12-01

    Full Text Available Exercise-induced fatigue is a comprehensive response to a variety of physiological and biochemical changes in the body, and can affect people's quality of life to different extents. If no timely recovery after occurrence of fatigue, accumulated gradually, it can lead to "burnout", a "overtraining syndrome", "chronic fatigue syndrome", etc., which will cause endocrine disturbance, immune suppression, even physical illness. Exercise-induced fatigue becomes an important factor endangering human health. In recent years, many experts and scholars at home and abroad are committed to the research of exercise-induced fatigue, and have put forward a variety of hypothesis to explain the cause of exercise-induced fatigue. They expect to find out the methods for preventing and eliminating exercise-induced fatigue. This article discusses mainly the pathogenesis, model building, elimination/ relief, etc. of exercise-induced fatigue to point out the research achievements of exercise-induced fatigue and its existing problems. DOI: 10.11855/j.issn.0577-7402.2016.11.14

  4. Fatigue and related psychosocial factors in Hemodialysis Patients%血液透析患者疲乏状况及其心理社会影响因素分析

    Institute of Scientific and Technical Information of China (English)

    张海林; 路潜; 文翠菊; 尹丽霞; 顾则娟

    2011-01-01

    目的:了解血液透析患者的疲乏状况,分析与疲乏相关的心理社会因素。方法:采用Piper疲乏修订量表测评120例血液透析患者的疲乏状况,同时收集患者睡眠质量、焦虑、抑郁、社会支持及一般情况等资料。结果:本组患者的RPFS得分为(4.5±3.1)分,89例(74.2%)患者存在不同程度的疲乏;多元逐步回归分析发现睡眠质量、焦虑、抑郁是与血液透析患者疲乏相关的心理社会因素(调整R2=0.264,P<0.001)。结论:应关注血液透析患者的疲乏状况,改善血液透析患者的睡眠质量和心理状态,以减少其疲乏的出现。%Objective: To investigate the fatigue status in hemodialysis patients and to explore the related psychosocial factors of fatigue. Methods: Fatigue was assessed by the Revised Piper Fatigue Scale (RPFS). Quality of sleep, anxiety, depression, social support and demographic data were assessed by different questionnairs. Results: The mean of RPFS was 4.51±3.06. The prevalence of fatigue was 74.2%. Multiple regression analysis indicated that quality of sleep, anxiety and depression were the main factors related to fatigue (adjusted R2= 0.264, P<0.001). Conclusions: We should pay more attention to the fatigue level among HD patients. Some interventions aiming to improve quality of sleep and mental health may decrease the fatigue level of HD patients.

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

    Science.gov (United States)

    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

  6. Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H/E(spl-HLH Signaling.

    Directory of Open Access Journals (Sweden)

    Caroline Bivik

    2016-04-01

    Full Text Available The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H/E(spl-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl-HLH genes are required in different neuroblast lineages. The Notch/Su(H/E(spl-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2. ChIP and DamID analysis of Su(H and E(spl-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.

  7. Protein O-fucosyltransferase 1 expression impacts myogenic C2C12 cell commitment via the Notch signaling pathway.

    Science.gov (United States)

    Der Vartanian, Audrey; Audfray, Aymeric; Al Jaam, Bilal; Janot, Mathilde; Legardinier, Sébastien; Maftah, Abderrahman; Germot, Agnès

    2015-01-01

    The Notch signaling pathway plays a crucial role in skeletal muscle regeneration in mammals by controlling the transition of satellite cells from quiescence to an activated state, their proliferation, and their commitment toward myotubes or self-renewal. O-fucosylation on Notch receptor epidermal growth factor (EGF)-like repeats is catalyzed by the protein O-fucosyltransferase 1 (Pofut1) and primarily controls Notch interaction with its ligands. To approach the role of O-fucosylation in myogenesis, we analyzed a murine myoblastic C2C12 cell line downregulated for Pofut1 expression by short hairpin RNA (shRNA) inhibition during the time course of differentiation. Knockdown of Pofut1 affected the signaling pathway activation by a reduction of the amount of cleaved Notch intracellular domain and a decrease in downstream Notch target gene expression. Depletion in Pax7(+)/MyoD(-) cells and earlier myogenic program entrance were observed, leading to an increase in myotube quantity with a small number of nuclei, reflecting fusion defects. The rescue of Pofut1 expression in knockdown cells restored Notch signaling activation and a normal course in C2C12 differentiation. Our results establish the critical role of Pofut1 on Notch pathway activation during myogenic differentiation.

  8. TNF-alpha and Notch signaling regulates the expression of HOXB4 and GATA3 during early T lymphopoiesis.

    Science.gov (United States)

    Dos Santos Schiavinato, Josiane Lilian; Oliveira, Lucila Habib Bourguignon; Araujo, Amélia Goes; Orellana, Maristela Delgado; de Palma, Patrícia Viana Bonini; Covas, Dimas Tadeu; Zago, Marco Antonio; Panepucci, Rodrigo Alexandre

    2016-10-01

    During the early thymus colonization, Notch signaling activation on hematopoietic progenitor cells (HPCs) drives proliferation and T cell commitment. Although these processes are driven by transcription factors such as HOXB4 and GATA3, there is no evidence that Notch directly regulates their transcription. To evaluate the role of NOTCH and TNF signaling in this process, human CD34(+) HPCs were cocultured with OP9-DL1 cells, in the presence or absence of TNF. The use of a Notch signaling inhibitor and a protein synthesis inhibitor allowed us to distinguish primary effects, mediated by direct signaling downstream Notch and TNF, from secondary effects, mediated by de novo synthesized proteins. A low and physiologically relevant concentration of TNF promoted T lymphopoiesis in OP9-DL1 cocultures. TNF positively modulated the expression of both transcripts in a Notch-dependent manner; however, GATA3 induction was mediated by a direct mechanism, while HOXB4 induction was indirect. Induction of both transcripts was repressed by a GSK3β inhibitor, indicating that activation of canonical Wnt signaling inhibits rather than induces their expression. Our study provides novel evidences of the mechanisms integrating Notch and TNF-alpha signaling in the transcriptional induction of GATA3 and HOXB4. This mechanism has direct implications in the control of self-renewal, proliferation, commitment, and T cell differentiation.

  9. Traffic jam functions in a branched pathway from Notch activation to niche cell fate.

    Science.gov (United States)

    Wingert, Lindsey; DiNardo, Stephen

    2015-07-01

    The niche directs key behaviors of its resident stem cells, and is thus crucial for tissue maintenance, repair and longevity. However, little is known about the genetic pathways that guide niche specification and development. The male germline stem cell niche in Drosophila houses two stem cell populations and is specified within the embryonic gonad, thus making it an excellent model for studying niche development. The hub cells that form the niche are specified early by Notch activation. Over the next few hours, these individual cells then cluster together and take up a defined position before expressing markers of hub cell differentiation. This timing suggests that there are other factors for niche development yet to be defined. Here, we have identified a role for the large Maf transcription factor Traffic jam (Tj) in hub cell specification downstream of Notch. Tj downregulation is the first detectable effect of Notch activation in hub cells. Furthermore, Tj depletion is sufficient to generate ectopic hub cells that can recruit stem cells. Surprisingly, ectopic niche cells in tj mutants remain dispersed in the absence of Notch activation. This led us to uncover a branched pathway downstream of Notch in which Bowl functions to direct hub cell assembly in parallel to Tj downregulation.

  10. 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.

  11. Targeting Notch to target cancer stem cells.

    Science.gov (United States)

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

    2010-06-15

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

  12. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells.

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca

    2012-02-01

    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro. Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription. ©2011 AACR.

  13. 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

    2016-07-29

    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.

  14. NOTCH SIGNALLING MODULATES HYPOXIA-INDUCED NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CANCER CELLS

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca

    2012-01-01

    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation has been associated with tumor progression, poor prognosis and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavourable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells, in vitro. Results exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent down regulation of Notch-mediated signalling, as demonstrated by reduced levels of the Notch target genes, Hes1 and Hey1. Neuroendocrine differentiation was promoted by attenuation of Hes1 transcription, as cells expressing a dominant negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia down regulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen independent cell lines, PC3 and Du145, it did not change the extent of NE differentiation in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Conclusions hypoxia induces neuroendocrine differentiation of LNCaP cells in vitro, which appears to be driven by the inhibition of Notch signalling with subsequent down-regulation of Hes1 transcription. PMID:22172337

  15. The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells.

    Science.gov (United States)

    Martin-Lannerée, Séverine; Halliez, Sophie; Hirsch, Théo Z; Hernandez-Rapp, Julia; Passet, Bruno; Tomkiewicz, Céline; Villa-Diaz, Ana; Torres, Juan-Maria; Launay, Jean-Marie; Béringue, Vincent; Vilotte, Jean-Luc; Mouillet-Richard, Sophie

    2017-03-01

    The prion protein is infamous for its involvement in a group of neurodegenerative diseases known as Transmissible Spongiform Encephalopathies. In the longstanding quest to decipher the physiological function of its cellular isoform, PrP(C) , the discovery of its participation to the self-renewal of hematopoietic and neural stem cells has cast a new spotlight on its potential role in stem cell biology. However, still little is known on the cellular and molecular mechanisms at play. Here, by combining in vitro and in vivo murine models of PrP(C) depletion, we establish that PrP(C) deficiency severely affects the Notch pathway, which plays a major role in neural stem cell maintenance. We document that the absence of PrP(C) in a neuroepithelial cell line or in primary neurospheres is associated with drastically reduced expression of Notch ligands and receptors, resulting in decreased levels of Notch target genes. Similar alterations of the Notch pathway are recovered in the neuroepithelium of Prnp(-/-) embryos during a developmental window encompassing neural tube closure. In addition, in line with Notch defects, our data show that the absence of PrP(C) results in altered expression of Nestin and Olig2 as well as N-cadherin distribution. We further provide evidence that PrP(C) controls the expression of the epidermal growth factor receptor (EGFR) downstream from Notch. Finally, we unveil a negative feedback action of EGFR on both Notch and PrP(C) . As a whole, our study delineates a molecular scenario through which PrP(C) takes part to the self-renewal of neural stem and progenitor cells. Stem Cells 2017;35:754-765.

  16. Prox1 regulates the notch1-mediated inhibition of neurogenesis.

    Directory of Open Access Journals (Sweden)

    Valeria Kaltezioti

    Full Text Available Activation of Notch1 signaling in neural progenitor cells (NPCs induces self-renewal and inhibits neurogenesis. Upon neuronal differentiation, NPCs overcome this inhibition, express proneural genes to induce Notch ligands, and activate Notch1 in neighboring NPCs. The molecular mechanism that coordinates Notch1 inactivation with initiation of neurogenesis remains elusive. Here, we provide evidence that Prox1, a transcription repressor and downstream target of proneural genes, counteracts Notch1 signaling via direct suppression of Notch1 gene expression. By expression studies in the developing spinal cord of chick and mouse embryo, we showed that Prox1 is limited to neuronal precursors residing between the Notch1+ NPCs and post-mitotic neurons. Physiological levels of Prox1 in this tissue are sufficient to allow binding at Notch1 promoter and they are critical for proper Notch1 transcriptional regulation in vivo. Gain-of-function studies in the chick neural tube and mouse NPCs suggest that Prox1-mediated suppression of Notch1 relieves its inhibition on neurogenesis and allows NPCs to exit the cell cycle and differentiate. Moreover, loss-of-function in the chick neural tube shows that Prox1 is necessary for suppression of Notch1 outside the ventricular zone, inhibition of active Notch signaling, down-regulation of NPC markers, and completion of neuronal differentiation program. Together these data suggest that Prox1 inhibits Notch1 gene expression to control the balance between NPC self-renewal and neuronal differentiation.

  17. Notch receptor expression in human brain arteriovenous malformations.

    Science.gov (United States)

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

    2015-08-01

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

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

    Science.gov (United States)

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

    2009-12-01

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

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

    Science.gov (United States)

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

    2003-03-01

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

  20. Association of Notch pathway down-regulation with Triple Negative/Basal-like breast carcinomas and high tumor-infiltrating FOXP3+ Tregs.

    Science.gov (United States)

    Ortiz-Martínez, Fernando; Gutiérrez-Aviñó, Francisco José; Sanmartín, Elena; Pomares-Navarro, Eloy; Villalba-Riquelme, Cristina; García-Martínez, Araceli; Lerma, Enrique; Peiró, Gloria

    2016-06-01

    T regulatory cells (Tregs) are a lineage of lymphocytes involved in immune response suppression that are characterized by the expression of the forkhead box P3 (FOXP3) transcription factor. Notch pathway regulates FOXP3 transcription in Tregs, but its role in breast cancer is unknown. We aimed at studying whether Notch pathway regulates FOXP3 expression and Tregs content in breast cancer, and its association with luminal breast carcinomas. We analyzed by quantitative Real-Time PCR the mRNA levels of FOXP3, Notch pathway genes (Notch1, Notch2, Notch4 and Jagged1) and STAT3 in a series of 152 breast carcinomas including hormone receptor-positive and -negative phenotypes (luminal and Triple Negative/Basal-like). We also studied the protein expression of Notch1, STAT3 and FOXP3 by immunohistochemistry. High FOXP3 mRNA levels correlated with larger tumor size (p=0.010), histological grade 3 (p=0.008) and positive lymph-node status (p=0.031). Also, low levels of Notch pathway genes mRNA correlated with poor prognostic factors such as larger tumor size, positive lymph-node status, tumor phenotype and infiltrating tumor Tregs. A survival analysis for the patients showed that large tumor size, histological grade 3, vascular invasion, infiltrating Tregs and low Notch1 mRNA expression were significantly associated with a decreased patients' overall survival (p≤0.05). On a multivariate analysis, high Tregs content (HR=3.00, 95% CI 1.04-8.90, p=0.042) and low Notch1 mRNA levels (HR=3.33, 95% CI 1.02-10.86, p=0.046) were independent markers for overall survival. Our results support that the Notch pathway up-regulation promotes luminal breast carcinomas, whereas down-regulation correlates with the expression of FOXP3, favors tumor Tregs infiltration and associates with Triple Negative/Basal-like tumors.

  1. A comparison of fatigue life prediction methodologies for rotorcraft

    Science.gov (United States)

    Everett, R. A., Jr.

    1990-01-01

    Because of the current U.S. Army requirement that all new rotorcraft be designed to a 'six nines' reliability on fatigue life, this study was undertaken to assess the accuracy of the current safe life philosophy using the nominal stress Palmgrem-Miner linear cumulative damage rule to predict the fatigue life of rotorcraft dynamic components. It has been shown that this methodology can predict fatigue lives that differ from test lives by more than two orders of magnitude. A further objective of this work was to compare the accuracy of this methodology to another safe life method called the local strain approach as well as to a method which predicts fatigue life based solely on crack growth data. Spectrum fatigue tests were run on notched (k(sub t) = 3.2) specimens made of 4340 steel using the Felix/28 tests fairly well, being slightly on the unconservative side of the test data. The crack growth method, which is based on 'small crack' crack growth data and a crack-closure model, also predicted the fatigue lives very well with the predicted lives being slightly longer that the mean test lives but within the experimental scatter band. The crack growth mo