Sample records for v-notch impact toughness

  1. Laser notching ceramics for reliable fracture toughness testing

    DOE PAGES

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

    2015-09-19

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

  2. A modified correlation between KJIC and Charpy V-notch impact energy of Chinese SA508-III steel at the upper shelf

    NASA Astrophysics Data System (ADS)

    Li, Xiangqing; Song, Yuxuan; Ding, Zhenyu; Bao, Shiyi; Gao, Zengliang

    2018-07-01

    The fracture toughness plays a significant role in the structural integrity assessment of reactor pressure vessels (RPVs) in service temperature. The Charpy V-notch (CVN) impact test is used to estimate fracture toughness (KIC or KJIC) indirectly since universal fracture toughness tests are costly, sophisticated and frequently invalid. In this study, a modified correlation which based on the typical model of KJIC-CVN at the upper shelf was established for Chinese SA508-III steel. Thereinto, the effect of test temperature (T) was directly considered in the correlation. To assess the accuracy of fracture toughness when calculating from the value of Charpy-V notch impact energy by using the modified correlation, both the Charpy-V notch impact tests and fracture toughness tests for Chinese SA508-III steel were conducted at different temperatures (100 °C, 150 °C, 200 °C, 250 °C and 320 °C). The results showed that the modified correlation exhibited the high precision for estimating fracture toughness of Chinese SA508-III steel and the relative error for tested and estimated results is within 8%, which is lower than that of other correlations.

  3. Short Time Elevated Temperature Tensile Properties and Notch Toughness of Some Chromium-Iron Alloys

    DTIC Science & Technology

    1957-06-07

    toughness of matcrials A, B, and C was determined by using subsize V-notch Charpy Specimens, 1 inch long by 0.197 inch square prepared with their...elevated temperature tensile tests and V-notch Charpy imapact tests of som recently developed alloys with 4O,’a and 50,,1 ohromiuma are presented in this...lengths parallel to the longitudinal uxis of the alloy bars. In addition, some standard size V-notch Charpy specimens waro mach-ined from material B, for

  4. 46 CFR 54.05-5 - Toughness test specimens.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Toughness test specimens. 54.05-5 Section 54.05-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PRESSURE VESSELS Toughness Tests § 54.05-5 Toughness test specimens. (a) Charpy V-notch impact tests. Where required, Charpy V-notch tests shall be conducted in accordanc...

  5. 46 CFR 54.05-15 - Weldment toughness tests-procedure qualifications.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) Plate for which Charpy V-notch impact testing is required in the parent material and for which V-notch minima are specified shall similarly have welding procedures qualified for toughness by Charpy V-notch testing. For these tests, the test plates shall be oriented with their final rolling direction parallel to...

  6. Development of plane strain fracture toughness test for ceramics using Chevron notched specimens

    NASA Technical Reports Server (NTRS)

    Bubsey, R. T.; Shannon, J. L., Jr.; Munz, D.

    1983-01-01

    Chevron-notched four-point-bend and short-bar specimens have been used to determine the fracture toughness of sintered aluminum oxide and hot-pressed silicon nitride ceramics. The fracture toughness for Si3N4 is found to be essentially independent of the specimen size and chevron notch configuration, with values ranging from 4.6 to 4.9 MNm exp -3/2. In contrast, significant specimen size and notch geometry effects have been observed for Al2O3, with the fracture toughness ranging from 3.1 to 4.7 MNm exp -3/2. These effects are attributed to a rising crack growth resistance curve for the Al2O3 tested.

  7. Low temperature impact toughness of the main gas pipeline steel after long-term degradation

    NASA Astrophysics Data System (ADS)

    Maruschak, Pavlo O.; Danyliuk, Iryna M.; Bishchak, Roman T.; Vuherer, Tomaž

    2014-12-01

    The correlation of microstructure, temperature and Charpy V-notch impact properties of a steel 17G1S pipeline steel was investigated in this study. Within the concept of physical mesomechanics, the dynamic failure of specimens is represented as a successive process of the loss of shear stability, which takes place at different structural/scale levels of the material. Characteristic stages are analyzed for various modes of failure, moreover, typical levels of loading and oscillation periods, etc. are determined. Relations between low temperature derived through this test, microstructures and Charpy (V-notch) toughness test results are also discussed in this paper.

  8. Fractured toughness of Si3N4 measured with short bar chevron-notched specimens

    NASA Technical Reports Server (NTRS)

    Salem, J. A.; Shannon, J. L., Jr.

    1985-01-01

    The short bar chevron-notched specimen is used to measure the plane strain fracture toughness of hot pressed Si3N4. Specimen proportions and chevron-notch angle are varied, thereby varying the amount of crack extension to maximum load (upon which K sub IC is based). The measured toughness (4.68 + or - 0.19 MNm to the 3/2 power) is independent of these variations, inferring that the material has a flat crack growth resistance curve.

  9. Fracture toughness of Si3N4 measured with short bar chevron-notched specimens

    NASA Technical Reports Server (NTRS)

    Salem, Jonathan A.; Shannon, John L., Jr.

    1987-01-01

    The short bar chevron-notched specimen is used to measure the plane strain fracture toughness of hot pressed Si3N4. Specimen proportions and chevron-notch angle are varied, thereby varying the amount of crack extension to maximum load (upon which K sub IC is based). The measured toughness (4.68 + or 0.19 MNm to the 3/2 power) is independent of these variations, inferring that the material has a flat crack growth resistance curve.

  10. Performance of Chevron-notch short bar specimen in determining the fracture toughness of silicon nitride and aluminum oxide

    NASA Technical Reports Server (NTRS)

    Munz, D.; Bubsey, R. T.; Shannon, J. L., Jr.

    1980-01-01

    Ease of preparation and testing are advantages unique to the chevron-notch specimen used for the determination of the plane strain fracture toughness of extremely brittle materials. During testing, a crack develops at the notch tip and extends stably as the load is increased. For a given specimen and notch configuration, maximum load always occurs at the same relative crack length independent of the material. Fracture toughness is determined from the maximum load with no need for crack length measurement. Chevron notch acuity is relatively unimportant since a crack is produced during specimen loading. In this paper, the authors use their previously determined stress intensity factor relationship for the chevron-notch short bar specimen to examine the performance of that specimen in determining the plane strain fracture toughness of silicon nitride and aluminum oxide.

  11. Preparation of reconstituted Charpy V-notch impact specimens for generating pressure vessel steel fracture toughness data

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

    Perrin, J.S.; Fromm, E.O.; Server, W.L.

    1982-01-01

    The arc stud welding process has been adapted for use in producing reconstituted Charpy V-notch impact specimens. In this process, each half of a tested and fractured Charpy specimen is used as the central region of a reconstituted specimen. End tabs are joined to one half of a fractured specimen by a specially designed stud welding apparatus. SA533B-1 and SA508-2 unirradiated and irradiated pressure vessel steel specimens have been produced. Both conventional and precracked reconstituted specimen data have been produced. Both types of data have been shown to be in excellent agreement with original specimen data. The arc stud weldingmore » process can therefore be used to increase the amount of data obtainable from a limited number of specimens or to obtain Charpy data when full size specimens cannot otherwise be obtained.« less

  12. Effect of microstructure and notch root radius on fracture toughness of an aluminum metal matrix composite

    NASA Technical Reports Server (NTRS)

    Manoharan, M.; Lewandowski, J. J.

    1989-01-01

    Recent results on the effects of matrix aging condition (matrix temper) and notch root radius on the measured fracture toughness of a SiC particulate reinforced aluminum alloy are reviewed. Stress intensity factors at catastrophic fracture were obtained for both underaged and overaged composites reveal. The linear relation found between apparent fracture toughness and the square root of the notch root radius implies a linear dependence of the crack opening displacement on the notch root radius. The results suggest a strain controlled fracture process, and indicate that there are differences in the fracture micromechanisms of the two aging conditions.

  13. Impact fracture toughness evaluation for high-density polyethylene materials

    NASA Astrophysics Data System (ADS)

    Cherief, M. N. D.; Elmeguenni, M.; Benguediab, M.

    2017-03-01

    The impact fracture behavior of a high-density polyethylene (HDPE) material is investigated experimentally and theoretically. Single-edge notched bending (SENB) specimens are tested in experiments with three-point bending and in the Charpy impact tests. An energy model is proposed for evaluating the HDPE impact toughness, which provides a description of both brittle and ductile fracture.

  14. Ultrahigh Charpy impact toughness (~450J) achieved in high strength ferrite/martensite laminated steels

    PubMed Central

    Cao, Wenquan; Zhang, Mingda; Huang, Chongxiang; Xiao, Shuyang; Dong, Han; Weng, Yuqing

    2017-01-01

    Strength and toughness are a couple of paradox as similar as strength-ductility trade-off in homogenous materials, body-centered-cubic steels in particular. Here we report a simple way to get ultrahigh toughness without sacrificing strength. By simple alloying design and hot rolling the 5Mn3Al steels in ferrite/austenite dual phase temperature region, we obtain a series of ferrite/martensite laminated steels that show up-to 400–450J Charpy V-notch impact energy combined with a tensile strength as high as 1.0–1.2 GPa at room temperature, which is nearly 3–5 times higher than that of conventional low alloy steels at similar strength level. This remarkably enhanced toughness is mainly attributed to the delamination between ferrite and martensite lamellae. The current finding gives us a promising way to produce high strength steel with ultrahigh impact toughness by simple alloying design and hot rolling in industry. PMID:28150692

  15. Ultrahigh Charpy impact toughness (~450J) achieved in high strength ferrite/martensite laminated steels

    NASA Astrophysics Data System (ADS)

    Cao, Wenquan; Zhang, Mingda; Huang, Chongxiang; Xiao, Shuyang; Dong, Han; Weng, Yuqing

    2017-02-01

    Strength and toughness are a couple of paradox as similar as strength-ductility trade-off in homogenous materials, body-centered-cubic steels in particular. Here we report a simple way to get ultrahigh toughness without sacrificing strength. By simple alloying design and hot rolling the 5Mn3Al steels in ferrite/austenite dual phase temperature region, we obtain a series of ferrite/martensite laminated steels that show up-to 400-450J Charpy V-notch impact energy combined with a tensile strength as high as 1.0-1.2 GPa at room temperature, which is nearly 3-5 times higher than that of conventional low alloy steels at similar strength level. This remarkably enhanced toughness is mainly attributed to the delamination between ferrite and martensite lamellae. The current finding gives us a promising way to produce high strength steel with ultrahigh impact toughness by simple alloying design and hot rolling in industry.

  16. Interfacial toughness of bilayer dental ceramics based on a short-bar, chevron-notch test

    PubMed Central

    Anunmana, Chuchai; Anusavice, Kenneth J.; Mecholsky, John J.

    2009-01-01

    Objective The objective of this study was to test the null hypothesis that the interfacial toughness of each of two types of bonded core-veneer bilayer ceramics is not significantly different from the apparent fracture toughness of the control monolithic glass veneer. Methods T-shaped short bars of a lithia-disilicate glass-ceramic core (LC) and yttria-stabilized polycrystalline zirconia core ceramic (ZC) were prepared according to the manufacturer's recommendations. V-shaped notches were prepared by using 25-μm-thick palladium foil, leaving the chevron notch area exposed, and the bars were veneered with a thermally compatible glass veneer (LC/GV and ZC/GV). Additionally, we also bonded the glass veneer to itself as a control group (GV/GV). Specimens were kept in distilled water for 30 days before testing in tension. Eight glass veneer bars were prepared for the analysis of fracture toughness test using the indentation-strength technique. Results The mean interfacial toughness of the LC/GV group was 0.69 [0.11] MPa·m1/2, and did not significantly differ from that of the GV/GV control group, 0.74 (0.17) MPa·m1/2 (p > 0.05). However, the difference between the mean interfacial toughness of the ZC/GV group, 0.13 (0.07) MPa·m1/2, and the LC/GV and the GV/GV groups was statistically significant (p<0.05). Significance For bilayer all-ceramic restorations with high-strength core materials, the veneering ceramics are the weakest link in the design of the structure. Since all-ceramic restorations often fail from chipping of veneer layers or crack initiation at the interface, the protective effects of thermal mismatch stresses oral prosthesis design should be investigated. PMID:19818486

  17. Fracture toughness and Charpy impact properties of several RAFMS before and after irradiation in HFIR

    NASA Astrophysics Data System (ADS)

    Sokolov, M. A.; Tanigawa, H.; Odette, G. R.; Shiba, K.; Klueh, R. L.

    2007-08-01

    As part of the development of candidate reduced-activation ferritic steels for fusion applications, several steels, namely F82H, 9Cr-2WVTa steels and F82H weld metal, are being investigated in the joint DOE-JAEA collaboration program. Within this program, three capsules containing a variety of specimen designs were irradiated at two design temperatures in the ORNL High Flux Isotope Reactor (HFIR). Two capsules, RB-11J and RB-12J, were irradiated in the HFIR removable beryllium positions with europium oxide (Eu 2O 3) thermal neutron shields in place. Specimens were irradiated up to 5 dpa. Capsule JP25 was irradiated in the HFIR target position to 20 dpa. The design temperatures were 300 °C and 500 °C. Precracked third-sized V-notch Charpy (3.3 × 3.3 × 25.4 mm) and 0.18 T DC(T) specimens were tested to determine transition and ductile shelf fracture toughness before and after irradiation. The master curve methodology was applied to evaluate the fracture toughness transition temperature, T0. Irradiation induced shifts of T0 and reductions of JQ were compared with Charpy V-notch impact properties. Fracture toughness and Charpy shifts were also compared to hardening results.

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

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

    Wereszczak, Andrew; Jadaan, Osama; Modugno, Max

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

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

    DOE PAGES

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

    2017-01-18

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

  20. Microstructure, Composition, and Impact Toughness Across the Fusion Line of High-Strength Bainitic Steel Weldments

    NASA Astrophysics Data System (ADS)

    Lan, Liangyun; Kong, Xiangwei; Chang, Zhiyuan; Qiu, Chunlin; Zhao, Dewen

    2017-09-01

    This paper analyzed the evolution of microstructure, composition, and impact toughness across the fusion line of high-strength bainitic steel weldments with different heat inputs. The main purpose was to develop a convenient method to evaluate the HAZ toughness quickly. The compositions of HAZ were insensitive to higher contents of alloy elements ( e.g., Ni, Mo) in the weld metal because their diffusion distance is very short into the HAZ. The weld metal contained predominantly acicular ferrite at any a heat input, whereas the main microstructures in the HAZ changed from lath martensite/bainite to upper bainite with the increasing heat input. The evolution of HAZ toughness in relation to microstructural changes can be revealed clearly combined with the impact load curve and fracture morphology, although the results of impact tests do not show an obvious change with heat input because the position of Charpy V notch contains the weld metal, HAZ as well as a part of base metal. As a result, based on the bead-on-plate welding tests, the welding parameter affecting the HAZ toughness can be evaluated rapidly.

  1. Experimental and Numerical Study on the Cracked Chevron Notched Semi-Circular Bend Method for Characterizing the Mode I Fracture Toughness of Rocks

    NASA Astrophysics Data System (ADS)

    Wei, Ming-Dong; Dai, Feng; Xu, Nu-Wen; Liu, Jian-Feng; Xu, Yuan

    2016-05-01

    The cracked chevron notched semi-circular bending (CCNSCB) method for measuring the mode I fracture toughness of rocks combines the merits (e.g., avoidance of tedious pre-cracking of notch tips, ease of sample preparation and loading accommodation) of both methods suggested by the International Society for Rock Mechanics, which are the cracked chevron notched Brazilian disc (CCNBD) method and the notched semi-circular bend (NSCB) method. However, the limited availability of the critical dimensionless stress intensity factor (SIF) values severely hinders the widespread usage of the CCNSCB method. In this study, the critical SIFs are determined for a wide range of CCNSCB specimen geometries via three-dimensional finite element analysis. A relatively large support span in the three point bending configuration was considered because the fracture of the CCNSCB specimen in that situation is finely restricted in the notch ligament, which has been commonly assumed for mode I fracture toughness measurements using chevron notched rock specimens. Both CCNSCB and NSCB tests were conducted to measure the fracture toughness of two different rock types; for each rock type, the two methods produce similar toughness values. Given the reported experimental results, the CCNSCB method can be reliable for characterizing the mode I fracture toughness of rocks.

  2. Small-scale fracture toughness of ceramic thin films: the effects of specimen geometry, ion beam notching and high temperature on chromium nitride toughness evaluation

    NASA Astrophysics Data System (ADS)

    Best, James P.; Zechner, Johannes; Wheeler, Jeffrey M.; Schoeppner, Rachel; Morstein, Marcus; Michler, Johann

    2016-12-01

    For the implementation of thin ceramic hard coatings into intensive application environments, the fracture toughness is a particularly important material design parameter. Characterisation of the fracture toughness of small-scale specimens has been a topic of great debate, due to size effects, plasticity, residual stress effects and the influence of ion penetration from the sample fabrication process. In this work, several different small-scale fracture toughness geometries (single-beam cantilever, double-beam cantilever and micro-pillar splitting) were compared, fabricated from a thin physical vapour-deposited ceramic film using a focused ion beam source, and then the effect of the gallium-milled notch on mode I toughness quantification investigated. It was found that notching using a focused gallium source influences small-scale toughness measurements and can lead to an overestimation of the fracture toughness values for chromium nitride (CrN) thin films. The effects of gallium ion irradiation were further studied by performing the first small-scale high-temperature toughness measurements within the scanning electron microscope, with the consequence that annealing at high temperatures allows for diffusion of the gallium to grain boundaries promoting embrittlement in small-scale CrN samples. This work highlights the sensitivity of some materials to gallium ion penetration effects, and the profound effect that it can have on fracture toughness evaluation.

  3. 46 CFR 154.605 - Toughness test.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 5 2010-10-01 2010-10-01 false Toughness test. 154.605 Section 154.605 Shipping COAST....605 Toughness test. (a) Each toughness test under §§ 154.610 through 154.625 must meet Subpart 54.05 of this chapter. (b) If subsize test specimens are used for the Charpy V-notch toughness test, the...

  4. On the feasibility of the Chevron Notch Beam method to measure fracture toughness of fine-grained zirconia ceramics.

    PubMed

    Kailer, Andreas; Stephan, Marc

    2016-10-01

    The fracture toughness determination of fine-grained zirconia ceramics using the chevron notched beam method (CNB) was investigated to assess the feasibility of this method for quality assurance and material characterization. CNB tests were performed using four different yttria-stabilized zirconia ceramics under various testing modes and conditions, including displacement-controlled and load-rate-controlled four point bending to assess the influence of slow crack growth and identify most suitable test parameters. For comparison, tests using single-edge V-notch beams (SEVNB) were conducted. It was observed that the CNB method yields well-reproducible results. However, slow crack growth effects significantly affect the measured KIC values, especially when slow loading rates are used. To minimize the effect of slow crack growth, the application of high loading rates is recommended. Despite a certain effort needed for setting up a sample preparation routine, the CNB method is considered to be very useful for measuring and controlling the fracture toughness of zirconia ceramics. Copyright © 2016 The Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  5. Impact toughness of layered VT6 alloy semiproducts

    NASA Astrophysics Data System (ADS)

    Ganeeva, A. A.; Kruglov, A. A.; Lutfullin, R. Ya.

    2010-10-01

    Layered semiproducts produced by pressure welding of sheet workpieces of a VT6 titanium alloy are studied. Possible methods of achieving isotropic mechanical properties of the semiproducts are discussed. The pores that are present in solid-phase joint zones are found not to influence the impact toughness of the samples in which layers lie perpendicular to a notch. The fracture surface has a ductile character with certain fracture zones.

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

    NASA Technical Reports Server (NTRS)

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

    1980-01-01

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

  7. Specimen size and geometry effects on fracture toughness of Al2O3 measured with short rod and short bar chevron-notch specimens

    NASA Technical Reports Server (NTRS)

    Shannon, J. L., Jr.; Munz, D. G.

    1983-01-01

    Plane strain fracture toughness measurements were made on Al2O3 using short rod and short bar chevron notch specimens previously calibrated by the authors for their dimensionless stress intensity factor coefficients. The measured toughness varied systematically with variations in specimen size, proportions, and chevron notch angle apparently due to their influence on the amount of crack extension to maximum load (the measurement point). The toughness variations are explained in terms of a suspected rising R curve for the material tested, along with a discussion of an unavoidable imprecision in the calculation of K sub Ic for materials with rising R curves when tested with chevron notch specimens.

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

    NASA Technical Reports Server (NTRS)

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

    1981-01-01

    Short bar, short rod, and four-point-bend chevron-notch specimens were used to determine the plane strain fracture toughness of hot-pressed silicon nitride and sintered aluminum oxide brittle ceramics. The unique advantages of this specimen type are: (1) the production of a sharp natural crack during the early stage of test loading, so that no precracking is required, and (2) the load passes through a maximum at a constant, material-independent crack length-to-width ratio for a specific geometry, so that no post-test crack measurement is required. The plane strain fracture toughness is proportional to the maximum test load and functions of the specimen geometry and elastic compliance. Although results obtained for silicon nitride are in good mutual agreement and relatively free of geometry and size effects, aluminum oxide results were affected in both these respects by the rising crack growth resistance curve of the material.

  9. A method for evaluating the fatigue crack growth in spiral notch torsion fracture toughness test

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

    Wang, Jy -An John; Tan, Ting

    The spiral notch torsion test (SNTT) has been a recent breakthrough in measuring fracture toughness for different materials, including metals, ceramics, concrete, and polymers composites. Due to its high geometry constraint and unique loading condition, SNTT can be used to measure the fracture toughness with smaller specimens without concern of size effects. The application of SNTT to brittle materials has been proved to be successful. The micro-cracks induced by original notches in brittle materials could ensure crack growth in SNTT samples. Therefore, no fatigue pre-cracks are needed. The application of SNTT to the ductile material to generate valid toughness datamore » will require a test sample with sufficient crack length. Fatigue pre-crack growth techniques are employed to introduce sharp crack front into the sample. Previously, only rough calculations were applied to estimate the compliance evolution in the SNTT crack growth process, while accurate quantitative descriptions have never been attempted. This generates an urgent need to understand the crack evolution during the SNTT fracture testing process of ductile materials. Here, the newly developed governing equations for SNTT crack growth estimate are discussed in the paper.« less

  10. A method for evaluating the fatigue crack growth in spiral notch torsion fracture toughness test

    DOE PAGES

    Wang, Jy -An John; Tan, Ting

    2018-05-21

    The spiral notch torsion test (SNTT) has been a recent breakthrough in measuring fracture toughness for different materials, including metals, ceramics, concrete, and polymers composites. Due to its high geometry constraint and unique loading condition, SNTT can be used to measure the fracture toughness with smaller specimens without concern of size effects. The application of SNTT to brittle materials has been proved to be successful. The micro-cracks induced by original notches in brittle materials could ensure crack growth in SNTT samples. Therefore, no fatigue pre-cracks are needed. The application of SNTT to the ductile material to generate valid toughness datamore » will require a test sample with sufficient crack length. Fatigue pre-crack growth techniques are employed to introduce sharp crack front into the sample. Previously, only rough calculations were applied to estimate the compliance evolution in the SNTT crack growth process, while accurate quantitative descriptions have never been attempted. This generates an urgent need to understand the crack evolution during the SNTT fracture testing process of ductile materials. Here, the newly developed governing equations for SNTT crack growth estimate are discussed in the paper.« less

  11. On impact testing of subsize Charpy V-notch type specimens

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

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

    1994-12-31

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

  12. Transition Fracture Toughness Characterization of Eurofer 97 Steel using Pre-Cracked Miniature Multi-notch Bend Bar Specimens

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

    Chen, Xiang; Sokolov, Mikhail A.; Linton, Kory D.

    In this report, we present the feasibility study of using pre-cracked miniature multi-notch bend bar specimens (M4CVN) with a dimension of 45mm (length) x 3.3mm (width) x 1.65mm (thickness) to characterize the transition fracture toughness of Eurofer97 based on the ASTM E1921 Master Curve method. From literature survey results, we did not find any obvious specimen size effects on the measured fracture toughness of unirradiated Eurofer97. Nonetheless, in order to exclude the specimen size effect on the measured fracture toughness of neutron irradiated Eurofer97, comparison of results obtained from larger size specimens with those from smaller size specimens after neutronmore » irradiation is necessary, which is not practical and can be formidably expensive. However, limited literature results indicate that the transition fracture toughness of Eurofer97 obtained from different specimen sizes and geometries followed the similar irradiation embrittlement trend. We then described the newly designed experimental setup to be used for testing neutron irradiated Eurofer97 pre-cracked M4CVN bend bars in the hot cell. We recently used the same setup for testing neutron irradiated F82H pre-cracked miniature multi-notch bend bars with great success. Considering the similarity in materials, specimen types, and the nature of tests between Eurofer97 and F82H, we believe the newly designed experimental setup can be used successfully in fracture toughness testing of Eurofer97 pre-cracked M4CVN specimens.« less

  13. Compliance calibration of the short rod chevron-notch specimen for fracture toughness testing of brittle materials

    NASA Technical Reports Server (NTRS)

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

    1982-01-01

    The short rod chevron-notch specimen has the advantages of (1) crack development at the chevron tip during the early stage of test loading, and (2) convenient calculation of plane-strain fracture toughness from the maximum test load and from a calibration factor which depends only on the specimen geometry and manner of loading. For generalized application, calibration of the specimen over a range of specimen proportions and chevron-notch configurations is necessary. Such was the objective of this investigation, wherein calibration of the short rod specimen was made by means of experimental compliance measurements converted into dimensionless stress intensity factor coefficients.

  14. Fracture Toughness Determination of Cracked Chevron Notched Brazilian Disc Rock Specimen via Griffith Energy Criterion Incorporating Realistic Fracture Profiles

    NASA Astrophysics Data System (ADS)

    Xu, Yuan; Dai, Feng; Zhao, Tao; Xu, Nu-wen; Liu, Yi

    2016-08-01

    The cracked chevron notched Brazilian disc (CCNBD) specimen has been suggested by the International Society for Rock Mechanics to measure the mode I fracture toughness of rocks, and has been widely adopted in laboratory tests. Nevertheless, a certain discrepancy has been observed in results when compared with those derived from methods using straight through cracked specimens, which might be due to the fact that the fracture profiles of rock specimens cannot match the straight through crack front as assumed in the measuring principle. In this study, the progressive fracturing of the CCNBD specimen is numerically investigated using the discrete element method (DEM), aiming to evaluate the impact of the realistic cracking profiles on the mode I fracture toughness measurements. The obtained results validate the curved fracture fronts throughout the fracture process, as reported in the literature. The fracture toughness is subsequently determined via the proposed G-method originated from Griffith's energy theory, in which the evolution of the realistic fracture profile as well as the accumulated fracture energy is quantified by DEM simulation. A comparison between the numerical tests and the experimental results derived from both the CCNBD and the semi-circular bend (SCB) specimens verifies that the G-method incorporating realistic fracture profiles can contribute to narrowing down the gap between the fracture toughness values measured via the CCNBD and the SCB method.

  15. A parametric study of fracture toughness of fibrous composite materials

    NASA Technical Reports Server (NTRS)

    Poe, C. C., Jr.

    1987-01-01

    Impacts to fibrous composite laminates by objects with low velocities can break fibers giving crack-like damage. The damage may not extend completely through a thick laminate. The tension strength of these damage laminates is reduced much like that of cracked metals. The fracture toughness depends on fiber and matrix properties, fiber orientations, and stacking sequence. Accordingly, a parametric study was made to determine how fiber and matrix properties and fiber orientations affect fracture toughness and notch sensitivity. The values of fracture toughness were predicted from the elastic constants of the laminate and the failing strain of the fibers using a general fracture toughness parameter developed previously. For a variety of laminates, values of fracture toughness from tests of center-cracked specimens and values of residual strength from tests of thick laminates with surface cracks were compared to the predictions to give credibility to the study. In contrast to the usual behavior of metals, it is shown that both ultimate tensile strength and fracture toughness of composites can be increased without increasing notch sensitivity.

  16. TOUGH3 v1.0

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

    PAU, GEORGE; JUNG, YOOJIN; FINSTERLE, STEFAN

    2016-09-14

    TOUGH3 V1.0 capabilities to simulate multi-dimensional, multi-phase, multi-component, non-isothermal flow and transport in fractured porous media, with applications geosciences and reservoir engineering and other application areas. TOUGH3 V1.0 supports a number of different combinations of fluids and components (updated equation-of-state (EOS) modules from previous versions of TOUGH, including EOS1, EOS2, EOS3, EOS4, EOS5, EOS7, EOS7R, EOS7C, EOS7CA, EOS8, EOS9, EWASG, TMVOC, ECO2N, and ECO2M). This upgrade includes (a) expanded list of updated equation-of-state (EOS) modules, (b) new hysteresis models, (c) new implementation of parallel and solver functionalities, (d) new linear solver options based on PETSc libraries, (e) new automatic buildmore » system that automatically downloads and builds third-party libraries and TOUGH3, (f) new printout in CSV format, (g) dynamic memory allocation, (h) various user features, and (i) bug fixes.« less

  17. Effective grain size and charpy impact properties of high-toughness X70 pipeline steels

    NASA Astrophysics Data System (ADS)

    Hwang, Byoungchul; Kim, Yang Gon; Lee, Sunghak; Kim, Young Min; Kim, Nack J.; Yoo, Jang Yong

    2005-08-01

    The correlation of microstructure and Charpy V-notch (CVN) impact properties of a high-toughness API X70 pipeline steel was investigated in this study. Six kinds of steel were fabricated by varying the hot-rolling conditions, and their microstructures, effective grain sizes, and CVN impact properties were analyzed. The CVN impact test results indicated that the steels rolled in the single-phase region had higher upper-shelf energies (USEs) and lower energy-transition temperatures (ETTs) than the steels rolled in the two-phase region because their microstructures were composed of acicular ferrite (AF) and fine polygonal ferrite (PF). The decreased ETT in the steels rolled in the single-phase region could be explained by the decrease in the overall effective grain size due to the presence of AF having a smaller effective grain size. On the other hand, the absorbed energy of the steels rolled in the two-phase region was considerably lower because a large amount of dislocations were generated inside PFs during rolling. It was further decreased when coarse martensite or cementite was formed during the cooling process.

  18. Grain refinement of high strength steels to improve cryogenic toughness

    NASA Technical Reports Server (NTRS)

    Rush, H. F.

    1985-01-01

    Grain-refining techniques using multistep heat treatments to reduce the grain size of five commercial high-strength steels were investigated. The goal of this investigation was to improve the low-temperature toughness as measured by Charpy V-notch impact test without a significant loss in tensile strength. The grain size of four of five alloys investigated was successfully reduced up to 1/10 of original size or smaller with increases in Charpy impact energy of 50 to 180 percent at -320 F. Tensile properties were reduced from 0 to 25 percent for the various alloys tested. An unexpected but highly beneficial side effect from grain refining was improved machinability.

  19. Influence of Texture on Impact Toughness of Ferritic Fe-20Cr-5Al Oxide Dispersion Strengthened Steel

    PubMed Central

    Sánchez-Gutiérrez, Javier; Chao, Jesus; Vivas, Javier; Galvez, Francisco; Capdevila, Carlos

    2017-01-01

    Fe-based oxide dispersion strengthened (ODS) steels are oriented to applications where high operating temperatures and good corrosion resistance is paramount. However, their use is compromised by their fracture toughness, which is lower than other competing ferritic-martenstic steels. In addition, the route required in manufacturing these alloys generates texture in the material, which induces a strong anisotropy in properties. The V-notched Charpy tests carried out on these alloys, to evaluate their impact toughness, reveal that delaminations do not follow the path that would be expected. There are many hypotheses about what triggers these delaminations, but the most accepted is that the joint action of particles in the grain boundaries, texture induced in the manufacturing process, and the actual microstructure of these alloys are responsible. In this paper we focused on the actual role of crystallographic texture on impact toughness in these materials. A finite elements simulation is carried out to solely analyze the role of texture and eliminate other factors, such as grain boundaries and the dispersed particles. The work allows us to conclude that crystallographic texture plays an important role in the distribution of stresses in the Charpy specimens. The observed delaminations might be explained on the basis that the crack in the grain, causing the delamination, is directly related to the shear stresses τ12 on both sides of the grain boundary, while the main crack propagation is a consequence of the normal stress to the crack. PMID:28773104

  20. Assessment of Ductile-to-Brittle Transition Behavior of Localized Microstructural Regions in a Friction-Stir Welded X80 Pipeline Steel with Miniaturized Charpy V-Notch Testing

    NASA Astrophysics Data System (ADS)

    Avila, Julian A.; Lucon, Enrico; Sowards, Jeffrey; Mei, Paulo Roberto; Ramirez, Antonio J.

    2016-06-01

    Friction-stir welding (FSW) is an alternative welding process for pipelines. This technology offers sound welds, good repeatability, and excellent mechanical properties. However, it is of paramount importance to determine the toughness of the welds at low temperatures in order to establish the limits of this technology. Ductile-to-brittle transition curves were generated in the present study by using a small-scale instrumented Charpy machine and miniaturized V-notch specimens (Kleinstprobe, KLST); notches were located in base metal, heat-affected, stirred, and hard zones within a FSW joint of API-5L X80 Pipeline Steel. Specimens were tested at temperatures between 77 K (-196 °C) and 298 K (25 °C). Based on the results obtained, the transition temperatures for the base material and heat-affected zone were below 173 K (-100 °C); conversely, for the stirred and hard zones, it was located around 213 K (-60 °C). Fracture surfaces were characterized and showed a ductile fracture mechanism at high impact energies and a mixture of ductile and brittle mechanisms at low impact energies.

  1. TOUGH+ v1.5 Core Code

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

    Moridis, George J.

    TOUGH+ v1.5 is a numerical code for the simulation of multi-phase, multi-component flow and transport of mass and heat through porous and fractured media, and represents the third update of the code since its first release [Moridis et al., 2008]. TOUGH+ is a successor to the TOUGH2 [Pruess et al., 1991; 2012] family of codes for multi-component, multiphase fluid and heat flow developed at the Lawrence Berkeley National Laboratory. It is written in standard FORTRAN 95/2003, and can be run on any computational platform (workstations, PC, Macintosh). TOUGH+ v1.5 employs dynamic memory allocation, thus minimizing storage requirements. It has amore » completely modular structure, follows the tenets of Object-Oriented Programming (OOP), and involves the advanced features of FORTRAN 95/2003, i.e., modules, derived data types, the use of pointers, lists and trees, data encapsulation, defined operators and assignments, operator extension and overloading, use of generic procedures, and maximum use of the powerful intrinsic vector and matrix processing operations. TOUGH+ v1.5 is the core code for its family of applications, i.e., the part of the code that is common to all its applications. It provides a description of the underlying physics and thermodynamics of non-isothermal flow, of the mathematical and numerical approaches, as well as a detailed explanation of the general (common to all applications) input requirements, options, capabilities and output specifications. The core code cannot run by itself: it needs to be coupled with the code for the specific TOUGH+ application option that describes a particular type of problem. The additional input requirements specific to a particular TOUGH+ application options and related illustrative examples can be found in the corresponding User's Manual.« less

  2. Toughness testing and high-temperature oxidation evaluations of advanced alloys for core internals

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

    Tan, Lizhen; Pint, Bruce A.; Chen, Xiang

    2016-09-16

    Alloy X-750 was procured from Carpenter Technology and Bodycote in this year. An appropriate TMT was developed on Alloy 439 to obtain materials with refined grain size for property screening tests. Charpy V-notch impact tests were completed for the three ferritic steels Grade 92, Alloy 439, and 14YWT. Fracture toughness tests at elevated temperatures were completed for 14YWT. The tests will be completed for the other alloys in next fiscal year. Steam oxidation tests of the three ferritic steels, 316L, and Zr–2.5Nb have been completed. The steam tests of the Ni-based superalloys and the other austenitic stainless steels will bemore » continued and finished in next fiscal year. Performance ranking in terms of steam oxidation resistance and impact/fracture toughness of the alloys will be deduced.« less

  3. Effect of nano/micro B4C and SiC particles on fracture properties of aluminum 7075 particulate composites under chevron-notch plane strain fracture toughness test

    NASA Astrophysics Data System (ADS)

    Morovvati, M. R.; Lalehpour, A.; Esmaeilzare, A.

    2016-12-01

    Reinforcing aluminum with SiC and B4C nano/micro particles can lead to a more efficient material in terms of strength and light weight. The influence of adding these particles to an aluminum 7075 matrix is investigated using chevron-notch fracture toughness test method. The reinforcing factors are type, size (micro/nano), and weight percent of the particles. The fracture parameters are maximum load, notch opening displacement, the work up to fracture and chevron notch plane strain fracture toughness. The findings demonstrate that addition of micro and nano size particles improves the fracture properties; however, increasing the weight percent of the particles leads to increase of fracture properties up to a certain level and after that due to agglomeration of the particles, the improvement does not happen for both particle types and size categories. Agglomeration of particles at higher amounts of reinforcing particles results in improper distribution of particles and reduction in mechanical properties.

  4. Effect of TiC addition on fracture toughness of Al6061 alloy

    NASA Astrophysics Data System (ADS)

    Raviraj, M. S.; Sharanprabhu, C. M.; Mohankumar, G. C.

    2018-04-01

    Al 6061 matrix was reinforced with different proportions of TiC particles such as 3wt%, 5wt% and 7wt% and the effect on fracture toughness was studied. Al-TiC metal matrix composites were produced by stir casting method to ensure uniform distribution of the TiC particulates in the Al matrix. LEFM (Linear Elastic Fracture Mechanics) has been used to characterize the fracture toughness using various specimen geometries. The compact tension (CT) specimens with straight through notch were machined as per ASTM E399 specifications. All the specimens were machined to have constant a/W=0.5 and B/W was varied from 0.2 to 0.7. A sharp crack initiation was done at the end of notch by fatigue loading using servo-hydraulic controlled testing machine. Load v/s crack mouth opening displacement (CMOD) data was plotted and stress intensity factor, KQ determined. Critical stress intensity factor KIC was obtained by plotting KQ v/s thickness of specimen data. The fracture toughness of the composites varied between 16-19 MPa√m as compared to 23MPa√m for base alloy Al6061. Composites with 3wt% and 7wt% TiC showed better fracture toughness than 5wt% TiC reinforced Al metal matrix composites.

  5. Effects of subcritical crack growth on fracture toughness of ceramics assessed in chevron-notched three-point bend tests

    NASA Technical Reports Server (NTRS)

    Chao, L. Y.; Singh, D.; Shetty, D. K.

    1988-01-01

    A numerical computational study was carried out to assess the effects of subcritical crack growth on crack stability in the chevron-notched three-point bend specimens. A power-law relationship between the subcritical crack velocity and the applied stress intensity were used along with compliance and stress-intensity relationships for the chevron-notched bend specimen to calculate the load response under fixed deflection rate and a machine compliance. The results indicate that the maximum load during the test occurs at the same crack length for all the deflection rates; the maximum load, however, is dependent on the deflection rate for rates below the critical rate. The resulting dependence of the apparent fracture toughness on the deflection rate is compared to experimental results on soda-lime glass and polycrystalline alumina.

  6. Effect of Aging Isothermal Time on the Microstructure and Room-Temperature Impact Toughness of Fe-24.8Mn-7.3Al-1.2C Austenitic Steel with κ-Carbides Precipitation

    NASA Astrophysics Data System (ADS)

    Feng, Yifan; Song, Renbo; Pei, Zhongzheng; Song, Renfeng; Dou, Guoyu

    2018-03-01

    The microstructure and impact toughness of the as-cast Fe-24.8Mn-7.3Al-1.2C austenitic steel after solution treatment and subsequent aging treatment were investigated in the present work. Research on the κ-carbides precipitation behavior was carried out by transmission electron microscope. The results show that nano-sized coherent κ-carbides were obtained in the as-solutionized steel after aging treatment, which produced precipitation hardening. After being aging treated at 550 °C for 1 h, the steel with regular hexagonal grain structure exhibited a good combination of yield strength ( 574 MPa) and room-temperature impact toughness ( 168 J). In the present steel, the typical cube-on-cube orientation relationship between austenite and κ-carbides was observed. However, due to the long aging isothermal time and high C content, the coarse intergranular κ'-carbide was formed and grew along the austenite grain boundary, which caused this orientation relationship to be destroyed and a dramatical increase of the coherency strain energy at grain boundary. Furthermore, serious embrittlement of grain boundaries caused that cleavage cracks trend to propagate along the grain boundaries. Accordingly, the room-temperature impact toughness decreased sharply. After aging isothermal time prolonging to 13 h, the Charpy V-notch impact toughness was only 5 J and fracture mode turned to fully brittle fracture accompanied with flat facets, shear cracks and well-developed secondary crack.

  7. Correlation of rolling condition, microstructure, and low-temperature toughness of X70 pipeline steels

    NASA Astrophysics Data System (ADS)

    Hwang, Byoungchul; Kim, Young Min; Lee, Sunghak; Kim, Nack J.; Yoo, Jang Yong

    2005-07-01

    Correlation of rolling conditions, microstructure, and low-temperature toughness of high-toughness X70 pipeline steels was investigated in this study. Twelve kinds of steel specimens were fabricated by vacuum-induction melting and hot rolling, and their microstructures were varied by rolling conditions. Charpy V-notch (CVN) impact test and drop-weight tear test (DWTT) were conducted on the rolled steel specimens in order to analyze low-temperature fracture properties. Charpy impact test results indicated that the energy transition temperature (ETT) was below -100 °C when the finish cooling temperature range was 350 °C to 500 °C, showing excellent low-temperature toughness. The ETT increased because of the formation of bainitic ferrite and martensite at low finish cooling temperatures and because of the increase in effective grain size due to the formation of coarse ferrites at high finish cooling temperatures. Most of the specimens also showed excellent DWTT properties as the percent shear area well exceeded 85 pct, irrespective of finish rolling temperatures or finish cooling temperatures, although a large amount of inverse fracture occurred at some finish cooling temperatures.

  8. HYDRATE v1.5 OPTION OF TOUGH+ v1.5

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

    Moridis, George

    HYDRATE v1.5 is a numerical code that for the simulation of the behavior of hydrate-bearing geologic systems, and represents the third update of the code since its first release [Moridis et al., 2008]. It is an option of TOUGH+ v1.5 [Moridis and Pruess, 2014], a successor to the TOUGH2 [Pruess et al., 1999, 2012] family of codes for multi-component, multiphase fluid and heat flow developed at the Lawrence Berkeley National Laboratory. HYDRATE v1.5 needs the TOUGH+ v1.5 core code in order to compile and execute. It is written in standard FORTRAN 95/2003, and can be run on any computational platformmore » (workstation, PC, Macintosh) for which such compilers are available. By solving the coupled equations of mass and heat balance, the fully operational TOUGH+HYDRATE code can model the non-isothermal gas release, phase behavior and flow of fluids and heat under conditions typical of common natural CH 4-hydrate deposits (i.e., in the permafrost and in deep ocean sediments) in complex geological media at any scale (from laboratory to reservoir) at which Darcy's law is valid. TOUGH+HYDRATE v1.5 includes both an equilibrium and a kinetic model of hydrate formation and dissociation. The model accounts for heat and up to four mass components, i.e., water, CH 4, hydrate, and water-soluble inhibitors such as salts or alcohols. These are partitioned among four possible phases (gas phase, liquid phase, ice phase and hydrate phase). Hydrate dissociation or formation, phase changes and the corresponding thermal effects are fully described, as are the effects of inhibitors. The model can describe all possible hydrate dissociation mechanisms, i.e., depressurization, thermal stimulation, salting-out effects and inhibitor-induced effects.« less

  9. Mechanical Properties and Seawater Behavior of Nitronic 50 (22Cr-13Ni- 5Mn) Plate

    DTIC Science & Technology

    1976-01-01

    Bal - balance misc - miscellaneous cfh - cubic feet per hour mpy - mils per year c/m - cycles per minute my - millivolts CVN - Charpy V-notch No...High-Cycle Fatigue Specimens F_gure 6 - Drawings; Low-Cycle Fatigue Specimens Figure 7 - Curve; Charpy V-Notch Impact Toughness Versus Temperature...for Nitronic 50 Base Plate FiGure 8 - Curve; Charpy V-Notch Toughness Versus Tempera- ture for Nitrcnic 50 Weldments Figure 9 - Photographs; Fracture

  10. Strength and toughness of structural fibres for composite material reinforcement.

    PubMed

    Herráez, M; Fernández, A; Lopes, C S; González, C

    2016-07-13

    The characterization of the strength and fracture toughness of three common structural fibres, E-glass, AS4 carbon and Kevlar KM2, is presented in this work. The notched specimens were prepared by means of selective carving of individual fibres by means of the focused ion beam. A straight-fronted edge notch was introduced in a plane perpendicular to the fibre axis, with the relative notch depth being a0/D≈0.1 and the notch radius at the tip approximately 50 nm. The selection of the appropriate beam current during milling operations was performed to avoid to as much as possible any microstructural changes owing to ion impingement. Both notched and un-notched fibres were submitted to uniaxial tensile tests up to failure. The strength of the un-notched fibres was characterized in terms of the Weibull statistics, whereas the residual strength of the notched fibres was used to determine their apparent toughness. To this end, the stress intensity factor of a fronted edge crack was computed by means of the finite-element method for different crack lengths. The experimental results agreed with those reported in the literature for polyacrylonitrile-based carbon fibres obtained by using similar techniques. After mechanical testing, the fracture surface of the fibres was analysed to ascertain the failure mechanisms. It was found that AS4 carbon and E-glass fibres presented the lower toughness with fracture surfaces perpendicular to the fibre axis, emanating from the notch tip. The fractured region of Kevlar KM2 fibres extended along the fibre and showed large permanent deformation, which explains their higher degree of toughness when compared with carbon and glass fibres. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'. © 2016 The Author(s).

  11. Strength and toughness of structural fibres for composite material reinforcement

    PubMed Central

    Herráez, M.; Fernández, A.; Lopes, C. S.

    2016-01-01

    The characterization of the strength and fracture toughness of three common structural fibres, E-glass, AS4 carbon and Kevlar KM2, is presented in this work. The notched specimens were prepared by means of selective carving of individual fibres by means of the focused ion beam. A straight-fronted edge notch was introduced in a plane perpendicular to the fibre axis, with the relative notch depth being a0/D≈0.1 and the notch radius at the tip approximately 50 nm. The selection of the appropriate beam current during milling operations was performed to avoid to as much as possible any microstructural changes owing to ion impingement. Both notched and un-notched fibres were submitted to uniaxial tensile tests up to failure. The strength of the un-notched fibres was characterized in terms of the Weibull statistics, whereas the residual strength of the notched fibres was used to determine their apparent toughness. To this end, the stress intensity factor of a fronted edge crack was computed by means of the finite-element method for different crack lengths. The experimental results agreed with those reported in the literature for polyacrylonitrile-based carbon fibres obtained by using similar techniques. After mechanical testing, the fracture surface of the fibres was analysed to ascertain the failure mechanisms. It was found that AS4 carbon and E-glass fibres presented the lower toughness with fracture surfaces perpendicular to the fibre axis, emanating from the notch tip. The fractured region of Kevlar KM2 fibres extended along the fibre and showed large permanent deformation, which explains their higher degree of toughness when compared with carbon and glass fibres. This article is part of the themed issue ‘Multiscale modelling of the structural integrity of composite materials’. PMID:27242306

  12. Compliance and stress intensity coefficients for short bar specimens with chevron notches

    NASA Technical Reports Server (NTRS)

    Munz, D.; Bubsey, R. T.; Srawley, J. E.

    1980-01-01

    For the determination of fracture toughness especially with brittle materials, a short bar specimen with rectangular cross section and chevron notch can be used. As the crack propagates from the tip of the triangular notch, the load increases to a maximum then decreases. To obtain the relation between the fracture toughness and maximum load, calculations of Srawley and Gross for specimens with a straight-through crack were applied to the specimens with chevron notches. For the specimens with a straight-through crack, an analytical expression was obtained. This expression was used for the calculation of the fracture toughness versus maximum load relation under the assumption that the change of the compliance with crack length for the specimen with a chevron notch is the same as for a specimen with a straight-through crack.

  13. Critical Fracture Toughness Measurements of an Antarctic Ice Core

    NASA Astrophysics Data System (ADS)

    Christmann, Julia; Müller, Ralf; Webber, Kyle; Isaia, Daniel; Schader, Florian; Kippstuhl, Sepp; Freitag, Johannes; Humbert, Angelika

    2014-05-01

    Fracture toughness is a material parameter describing the resistance of a pre-existing defect in a body to further crack extension. The fracture toughness of glacial ice as a function of density is important for modeling efforts aspire to predict calving behavior. In the presented experiments this fracture toughness is measured using an ice core from Kohnen Station, Dronning Maud Land, Antarctica. The samples were sawed in an ice lab at the Alfred Wegener Institute in Bremerhaven at -20°C and had the dimensions of standard test samples with thickness 14 mm, width 28 mm and length 126 mm. The samples originate from a depth of 94.6 m to 96 m. The grain size of the samples was also identified. The grain size was found to be rather uniform. The critical fracture toughness is determined in a four-point bending approach using single edge V-notch beam samples. The initial notch length was around 2.5 mm and was prepared using a drilling machine. The experimental setup was designed at the Institute of Materials Science at Darmstadt. In this setup the force increases linearly, until the maximum force is reached, where the specific sample fractures. This procedure was done in an ice lab with a temperature of -15°C. The equations to calculate the fracture toughness for pure bending are derived from an elastic stress analysis and are given as a standard test method to detect the fracture toughness. An X-ray computer tomography (CT scanner) was used to determine the ice core densities. The tests cover densities from 843 kg m-3 to 871 kg m-3. Thereby the influence of the fracture toughness on the density was analyzed and compared to previous investigations of this material parameter. Finally the dependence of the measured toughness on thickness, width, and position in the core cross-section was investigated.

  14. The Influence of Notch Root Radius and Austenitizing Temperature on Fracture Appearance of As-Quenched Charpy-V Type AISI4340 Steel Specimens

    NASA Astrophysics Data System (ADS)

    Firrao, D.; Begley, J. A.; Silva, G.; Roberti, R.; de Benedetti, B.

    1982-06-01

    Charpy-V type samples either step-quenched from 1200 °C or directly quenched from the usual 870 °C temperature, fractured by a slow bend test procedure, have been fractographically examined. Their notch root radius, ρ, ranged from almost zero (fatigue precrack) up to 2.0 mm. The fracture initiation process at the notch differs according to root radius and heat treatment. Conventionally austenitized samples with ρ values larger than 0.07 mm approximately ( ρ eff) always display a continuous shear lip formation along the notch surface, whereas specimens with smaller notches do not exhibit a similar feature. Moreover, shear lip width in specimens with ρ > ρ eff is linearly related to the applied J-integral at fracture. In high temperature austenitized samples similar shear lips are almost nonexistent. The above findings, as well as overall fractographic features, are combined to explain why blunt notch AISI 4340 steel specimens display a better fracture resistance if they are conventionally heat treated, whereas fatigue precracked samples show a superior fracture toughness when they are step-quenched from 1200 °C. Variations of fracture morphologies with the notch root radius and heat treating procedures are associated with a shift toward higher Charpy transition temperatures under the combined influence of decreasing root radii and coarsening of the prior austenitic grain size at high austenitizing temperatures.

  15. Correlation of Toughness between H-Plate and Charpy Impact Tests

    DTIC Science & Technology

    1959-09-01

    thermal cycles having peak temperatures in or near the range of critical transformation temperatures. Notch sensitivity in these regions has been...21- In their recent work the transition temperatures of heat-affected-zone struc- tures produced by thermal cycles having peak temperatures in the...gradient of thermal cycles associated with welding is too complex to have been included in the scope of this report. The superior toughness of the Ni

  16. Fracture Toughness (KIC) of Lithography Based Manufactured Alumina Ceramic

    NASA Astrophysics Data System (ADS)

    Nindhia, T. G. T.; Schlacher, J.; Lube, T.

    2018-04-01

    Precision shaped ceramic components can be obtained by an emerging technique called Lithography based Ceramic Manufacturing (LCM). A green part is made from a slurry consisting of a ceramic powder in a photocurable binder with addition of dispersant and plasticizer. Components are built in a layer–by-layer way by exposing the desired cross- sections to light. The parts are subsequently sintered to their final density. It is a challenge to produce ceramic component with this method that yield the same mechanical properties in all direction. The fracture toughness (KIc) of of LCM-alumina (prepared at LITHOZ GmbH, Austria) was tested by using the Single-Edge-V-Notched Beam (SEVNB) method. Notches are made into prismatic bend-bars in all three direction X, Y and Z to recognize the value of fracture toughness of the material in all three directions. The microstructure was revealed with optical microscopy as well as Scanning Electron Microscopy (SEM). The results indicate that the fracture toughness in Y-direction has the highest value (3.10 MPam1/2) that is followed by the one in X-direction which is just a bit lower (2.90 MPam1/2). The Z-direction is found to have a similar fracture toughness (2.95 MPam1/2). This is supported by a homogeneous microstructure showing no hint of the layers used during production.

  17. Assessments of Fracture Toughness of Monolithic Ceramics-SEPB Versus SEVNB Methods

    NASA Technical Reports Server (NTRS)

    Choi, Sung R.; Gyekenyesi, John P.

    2006-01-01

    Fracture toughness of a total of 13 advanced monolithic ceramics including silicon nitrides, silicon carbide, aluminas, and glass ceramic was determined at ambient temperature by using both single edge precracked beam (SEPB) and single edge v-notched beam (SEVNB) methods. Relatively good agreement in fracture toughness between the two methods was observed for advanced ceramics with flat R-curves; whereas, poor agreement in fracture toughness was seen for materials with rising R-curves. The discrepancy in fracture toughness between the two methods was due to stable crack growth with crack closure forces acting in the wake region of cracks even in SEVNB test specimens. The effect of discrepancy in fracture toughness was analyzed in terms of microstructural feature (grain size and shape), toughening exponent in R-curve, and stable crack growth determined using back-face strain gaging.

  18. Effects of microstructure on inverse fracture occurring during drop-weight tear testing of high-toughness X70 pipeline steels

    NASA Astrophysics Data System (ADS)

    Hwang, Byoungchul; Kim, Yang Gon; Lee, Sunghak; Kim, Nack J.; Yoo, Jang Yong

    2005-02-01

    The effects of microstructure on inverse fracture occurring in the hammer-impacted region were analyzed after conducting a drop-weight tear test (DWTT) on high-toughness pipeline steels. Three kinds of steels were fabricated by varying the alloying elements, and their microstructures were varied by the rolling conditions. The pressed-notch (PN) or chevron-notch (CN) DWTT and Charpy V-notch (CVN) impact tests were conducted on the rolled steel specimens, and the results were discussed in comparison with the data obtained from CVN tests of prestrained specimens. In the hammer-impacted region of the DWTT specimens, abnormal inverse fracture having a cleavage fracture mode appeared, and the inverse fracture area correlated well with the upper-shelf energy (USE) obtained from the CVN test and with the grain size. The steel specimens having a higher USE or having coarse polygonal ferrite tended to have a larger inverse fracture area than those having a lower USE or having fine acicular ferrite. This was because steels having a higher impact absorption energy required higher energy for fracture initiation and propagation during the DWTT. These results were confirmed by the CVN data of prestrained steel specimens.

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

    PubMed Central

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

    2012-01-01

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

  20. Fracture-Toughness Analysis in Transition-Temperature Region of Three American Petroleum Institute X70 and X80 Pipeline Steels

    NASA Astrophysics Data System (ADS)

    Shin, Sang Yong; Woo, Kuk Je; Hwang, Byoungchul; Kim, Sangho; Lee, Sunghak

    2009-04-01

    The fracture toughness in the transition-temperature region of three American Petroleum Institute (API) X70 and X80 pipeline steels was analyzed in accordance with the American Society for Testing and Materials (ASTM) E1921-05 standard test method. The elastic-plastic cleavage fracture toughness ( K Jc ) was determined by three-point bend tests, using precracked Charpy V-notch (PCVN) specimens; the measured K Jc values were then interpreted by the three-parameter Weibull distribution. The fracture-toughness test results indicated that the master curve and the 98 pct confidence curves explained the variation in the measured fracture toughness well. The reference temperatures obtained from the fracture-toughness test and index temperatures obtained from the Charpy impact test were lowest in the X70 steel rolled in the two-phase region, because this steel had smaller effective grains and the lowest volume fraction of hard phases. In this steel, few hard phases led to a higher resistance to cleavage crack initiation, and the smaller effective grain size led to a higher possibility of crack arrest, thereby resulting in the best overall fracture properties. Measured reference temperatures were then comparatively analyzed with the index temperatures obtained from the Charpy impact test, and the effects of microstructures on these temperatures were discussed.

  1. Effects of radiation on crack-initiation and crack-arrest toughness for SA508 Cl. 3 steel

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

    Milella, P.P.; Pini, A.; Iskander, S.K.

    1995-11-01

    An investigation was carried out to determine the effects of neutron irradiation, conducted in several different test-reactors at approximately 280 C, on the mechanical properties of an SA508 Class 3 carbon steel ring forging produced in Italy as a prototype of a pressurized water reactor vessel. The research had two primary objectives: (1) to investigate the effect of a various levels of neutron irradiation (fluences from 1 to 5.5 10{sup 19} n/cm{sup 2} [E>1 MeV]) on the strength, initiation and arrest toughness and ductile-to-brittle transition temperature, and (2) to determine if Charpy data and empirical prediction equations provide conservative estimatesmore » of irradiation effects on the K{sub Ic} and K{sub Ia} transition curves. The paper reports results from tension, Charpy V-notch (CVN) fracture toughness, and crack-arrest tests performed on both unirradiated and irradiated material. It was found that both Charpy V-notch transition temperature shifts and two prediction equations provided conservative estimates of shifts in fracture initiation and fracture arrest transition temperatures for the steel investigated. The 54 C shift of the Charpy V-notch transition curves at a fluence level of 5.5 10{sup 19} n/cm{sup 2} suggests the possibility of extending the component life beyond the common 40 year design life.« less

  2. Development of Low-Carbon, Copper-Strengthened HSLA Steel Plate for Naval Ship Construction

    DTIC Science & Technology

    1990-06-01

    steel plate microstructures, 2% nital etch . ...................................................... 13 2. Charpy V-notch impact energy transition for...met a minimum yield strength requirement of 80 ksi yield strength through 3/4 inch gage, had high Charpy V-notch impact energy at low tempera- tures...tempered HSLA line-pipe steels, which typically could not meet the minimum Charpy V-notch impact toughness requirement of 35 ft-lb at -1 200 F. In 1984

  3. Fracture toughness of fibrous composite materials

    NASA Technical Reports Server (NTRS)

    Poe, C. C., Jr.

    1984-01-01

    Laminates with various proportions of 0 deg, 45 deg, and 90 deg plies were fabricated from T300/5208 and T300/BP-907 graphite/epoxy prepreg tape material. The fracture toughness of each laminate orientation or lay-up was determined by testing center-cracked specimens, and it was also predicted with the general fracture-toughness parameter. The predictions were good except when crack-tip splitting was large, at which time the toughness and strengths tended to be underpredicted. By using predictions, a parametric study was also made of factors that influence fracture toughness. Fiber and matrix properties as well as lay-up were investigated. Without crack-tip splitting, fracture toughness increases in proportion to fiber strength and fiber volume fraction, increases linearly with E(22)/E(11), is largest when the modulus for non-0 deg fibers is greater than that of 0 deg fibers, and is smallest for 0(m)/90(p)(s) lay-ups. (The E(11) and E(22) are Young's moduli of the lamina parallel to and normal to the direction of the fibers, respectively). For a given proportion of 0 deg plies, the most notch-sensitive lay-ups are 0(m)/90(p)(s) and the least sensitive are 0(m)/45(n)(s) and alpha(s). Notch sensitivity increases with the proportion of 0 deg plies and decreases with alpha. Strong, tough matrix materials, which inhibit crack-tip splitting, generally lead to minimum fracture toughness.

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

    NASA Astrophysics Data System (ADS)

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

    2010-02-01

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

  5. Preliminary report on tests of tensile specimens with a part-through surface notch for a filament wound graphite/epoxy material

    NASA Technical Reports Server (NTRS)

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

    1985-01-01

    The behavior of tensile coupons with surface notches of various semi-elliptical shapes were evaluated for specimens obtained from a filament wound graphite/epoxy cylinder. The quasi-static test results, in some instances, are inadequate for defining complete trend curves and the interpretive analysis is considered to be preliminary. Specimens with very shallow notches were observed to be notch insensitive and the unnotched strength from these specimens was determined to be 54.97 Ksi. The failure strain of the laminate was found to be 1.328%. Specimens with deeper notches were sensitive to notch depth, notch aspect ratio, and specimen width. Using the unnotched strength of 54.97 Ksi and Poe's general toughness parameter, the fracture toughness was estimated to be 27.2 Ksi square root of In. Isotropic linear elastic fracture mechanics together with the estimated fracture toughness correctly predicted the influence of notch depth, aspect ratio, and specimen finitewidth.

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

    NASA Astrophysics Data System (ADS)

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

    2018-01-01

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

  7. Toughness characterization by small specimen test technique for HIPed joints of F82H steel aiming at first wall fabrication in fusion

    NASA Astrophysics Data System (ADS)

    Kishimoto, H.; Ono, T.; Sakasegawa, H.; Tanigawa, H.; Kohno, Y.; Kohyama, A.

    2013-09-01

    Reduced activation ferritic/martensitic steels (RAFMs), such as F82H steels, have been developed as candidates of structural materials for fusion. In the design of a fusion reactor, cooling channels are built in the first wall of the blanket. One large issue is to determine how to join rectangular tubes to thin panels to fabricate the first wall. Hot Isostatic Pressing (HIPing) is a solution to solve the issue. Because of the thin HIPed walls of the channels, the specimen size for inspection of HIPed interface is limited. In the present research, Small Specimen Test Techniques (SSTT) are screened for the destructive toughness investigation technique of HIPed F82H joints. 1/3 size Charpy V-notch impact (1/3 CVN) and small punch (SP) tests are employed for the present research. The toughness of the HIPed joints is strongly affected by various surface finishing of specimens treated previous to the HIPing. In the present research, several kinds of HIPed joints were surface finished by different methods and investigated by 1/3 CVN impact test. The HIPed F82H joints had different toughness ranging from 20% to 70% of the toughness of the F82H base metal. The SP test is also available for the investigation of toughness change by the HIPing. The sensitivity of 1/3 CVN impact test against toughness change was better than the SP test, it revealed that the SP test has some limitations.

  8. Rupture Predictions of Notched Ti-6Al-4V Using Local Approaches

    PubMed Central

    Peron, Mirco; Berto, Filippo

    2018-01-01

    Ti-6Al-4V has been extensively used in structural applications in various engineering fields, from naval to automotive and from aerospace to biomedical. Structural applications are characterized by geometrical discontinuities such as notches, which are widely known to harmfully affect their tensile strength. In recent years, many attempts have been done to define solid criteria with which to reliably predict the tensile strength of materials. Among these criteria, two local approaches are worth mentioning due to the accuracy of their predictions, i.e., the strain energy density (SED) approach and the theory of critical distance (TCD) method. In this manuscript, the robustness of these two methods in predicting the tensile behavior of notched Ti-6Al-4V specimens has been compared. To this aim, two very dissimilar notch geometries have been tested, i.e., semi-circular and blunt V-notch with a notch root radius equal to 1 mm, and the experimental results have been compared with those predicted by the two models. The experimental values have been estimated with low discrepancies by either the SED approach and the TCD method, but the former results in better predictions. The deviations for the SED are in fact lower than 1.3%, while the TCD provides predictions with errors almost up to 8.5%. Finally, the weaknesses and the strengths of the two models have been reported. PMID:29693565

  9. Effect of Bimodal Grain Size Distribution on Scatter in Toughness

    NASA Astrophysics Data System (ADS)

    Chakrabarti, Debalay; Strangwood, Martin; Davis, Claire

    2009-04-01

    Blunt-notch tests were performed at -160 °C to investigate the effect of a bimodal ferrite grain size distribution in steel on cleavage fracture toughness, by comparing local fracture stress values for heat-treated microstructures with uniformly fine, uniformly coarse, and bimodal grain structures. An analysis of fracture stress values indicates that bimodality can have a significant effect on toughness by generating high scatter in the fracture test results. Local cleavage fracture values were related to grain size distributions and it was shown that the largest grains in the microstructure, with an area percent greater than approximately 4 pct, gave rise to cleavage initiation. In the case of the bimodal grain size distribution, the large grains from both the “fine grain” and “coarse grain” population initiate cleavage; this spread in grain size values resulted in higher scatter in the fracture stress than in the unimodal distributions. The notch-bend test results have been used to explain the difference in scatter in the Charpy energies for the unimodal and bimodal ferrite grain size distributions of thermomechanically controlled rolled (TMCR) steel, in which the bimodal distribution showed higher scatter in the Charpy impact transition (IT) region.

  10. USE OF SMALL SPECIMENS FOR FRACTURE TOUGHNESS EVALUATION OF RPV STEELS

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

    Sokolov, Mikhail A; Nanstad, Randy K

    2016-01-01

    Small specimens are playing the key role in evaluating properties of irradiated materials. The use of small specimens provides several advantages. Typically, only a small volume of material can be irradiated in a reactor at desirable conditions in terms of temperature, neutron flux, and neutron dose. A small volume of irradiated material may also allow for easier handling of specimens. Smaller specimens reduce the amount of radioactive material, minimizing personnel exposures and waste disposal. However, use of small specimens imposes a variety of challenges as well. These challenges are associated with proper accounting for size effects and transferability of smallmore » specimen data to the real structures of interest. Any fracture toughness specimen that can be made out of standard Charpy specimen or its broken half may have exceptional utility for evaluation of reactor pressure vessels (RPVs) since it would allow one to determine and monitor directly actual fracture toughness instead of requiring indirect predictions using correlations established with impact data. The Charpy V-notch specimen is the most commonly used specimen geometry in surveillance programs and most likely to be used in advanced reactors as per ASME code.« less

  11. iTOUGH2 v7.1

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

    FINSTERLE, STEFAN; JUNG, YOOJIN; KOWALSKY, MICHAEL

    2016-09-15

    iTOUGH2 (inverse TOUGH2) provides inverse modeling capabilities for TOUGH2, a simulator for multi-dimensional, multi-phase, multi-component, non-isothermal flow and transport in fractured porous media. iTOUGH2 performs sensitivity analyses, data-worth analyses, parameter estimation, and uncertainty propagation analyses in geosciences and reservoir engineering and other application areas. iTOUGH2 supports a number of different combinations of fluids and components (equation-of-state (EOS) modules). In addition, the optimization routines implemented in iTOUGH2 can also be used for sensitivity analysis, automatic model calibration, and uncertainty quantification of any external code that uses text-based input and output files using the PEST protocol. iTOUGH2 solves the inverse problem bymore » minimizing a non-linear objective function of the weighted differences between model output and the corresponding observations. Multiple minimization algorithms (derivative-free, gradient-based, and second-order; local and global) are available. iTOUGH2 also performs Latin Hypercube Monte Carlo simulations for uncertainty propagation analyses. A detailed residual and error analysis is provided. This upgrade includes (a) global sensitivity analysis methods, (b) dynamic memory allocation (c) additional input features and output analyses, (d) increased forward simulation capabilities, (e) parallel execution on multicore PCs and Linux clusters, and (f) bug fixes. More details can be found at http://esd.lbl.gov/iTOUGH2.« less

  12. Influence of Stacking Sequence and Notch Angle on the Charpy Impact Behavior of Hybrid Composites

    NASA Astrophysics Data System (ADS)

    Behnia, S.; Daghigh, V.; Nikbin, K.; Fereidoon, A.; Ghorbani, J.

    2016-09-01

    The low-velocity impact behavior of hybrid composite laminates was investigated. The epoxy matrix was reinforced with aramid, glass, basalt, and carbon fabrics using the hand lay-up technique. Different stacking sequences and notch angles were and notch angles considered and tested using a Charpy impact testing machine to study the hybridization and notch angle effects on the impact response of the hybrid composites. The energy absorption capability of specimens with different stacking sequences and notch angles is compared and discussed. It is shown that the hybridization can enhance the mechanical performance of composite materials.

  13. Fracture toughness of irradiated modified 9Cr-1Mo steel

    NASA Astrophysics Data System (ADS)

    Kim, Sung Ho; Yoon, Ji-Hyun; Ryu, Woo Seog; Lee, Chan Bock; Hong, Jun Hwa

    2009-04-01

    The effects of irradiation on fracture toughness of modified 9Cr-1Mo steel in the transition region were investigated. Half size precracked Charpy specimens were irradiated up to 1.2 × 10 21n/cm 2 ( E > 0.1 MeV) at 340 °C and 400 °C in the Korean research reactor. The irradiation induced transition temperature shift for a modified 9Cr-1Mo was evaluated by using the Master Curve methodology. The T0 temperature for the unirradiated specimens were measured as -67.7 °C and -72.4 °C from the tests with standard PCVN (precracked charpy V-notch) and half sized PCVN specimens, respectively. The T0 shifts of specimens after irradiation at 340 °C and 400 °C were 70.7 °C and 66.1 °C, respectively. The Weibull slopes for the fracture toughness data obtained from the unirradiated and irradiated modified 9Cr-1Mo steels were determined to confirm the applicability of master curve methodology to modified 9Cr-1Mo steel.

  14. Improving the toughness of ultrahigh strength steel

    NASA Astrophysics Data System (ADS)

    Sato, Koji

    2002-01-01

    The ideal structural steel combines high strength with high fracture toughness. This dissertation discusses the toughening mechanism of the Fe/Co/Ni/Cr/Mo/C steel, AerMet 100, which has the highest toughness/strength combination among all commercial ultrahigh strength steels. The possibility of improving the toughness of this steel was examined by considering several relevant factors. Chapter 1 reviews the mechanical properties of ultrahigh strength steels and the physical metallurgy of AerMet 100. It also describes the fracture mechanisms of steel, i.e. ductile microvoid coalescence, brittle transgranular cleavage, and intergranular separation. Chapter 2 examines the strength-toughness relationship for three heats of AerMet 100. A wide variation of toughness is obtained at the same strength level. The toughness varies despite the fact that all heat fracture in the ductile fracture mode. The difference originates from the inclusion content. Lower inclusion volume fraction and larger inclusion spacing gives rise to a greater void growth factor and subsequently a higher fracture toughness. The fracture toughness value, JIc, is proportional to the particle spacing of the large non-metallic inclusions. Chapter 3 examines the ductile-brittle transition of AerMet 100 and the effect of a higher austenitization temperature, using the Charpy V-notch test. The standard heat treatment condition of AerMet 100 shows a gradual ductile-brittle transition due to its fine effective grain size. Austenitization at higher temperature increases the prior austenite grain size and packet size, leading to a steeper transition at a higher temperature. Both transgranular cleavage and intergranular separation are observed in the brittle fracture mode. Chapter 4 examines the effect of inclusion content, prior austenite grain size, and the amount of austenite on the strength-toughness relationship. The highest toughness is achieved by low inclusion content, small prior austenite grain size

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

    NASA Astrophysics Data System (ADS)

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

    2015-11-01

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

  16. Pendulum impact resistance of tungsten fiber/metal matrix composites.

    NASA Technical Reports Server (NTRS)

    Winsa, E. A.; Petrasek, D. W.

    1972-01-01

    The impact properties of copper, copper-10 nickel, and a superalloy matrix reinforced with tungsten fibers were studied. In most cases the following increased composite impact strength: increased fiber or matrix toughness, decreased fiber-matrix reaction, increased test temperature, hot working and heat treatment. Notch sensitivity was reduced by increasing fiber or matrix toughness. The effect of fiber content depended on the relative toughness of the fibers and matrix. Above 530 K a 60 volume per cent superalloy matrix composite had a greater impact strength than a turbine blade superalloy, whereas below 530 K a hot worked 56 volume per cent composite had a greater impact strength than the superalloy.

  17. Effects of stitching on fracture toughness of uniweave textile graphite/epoxy laminates

    NASA Technical Reports Server (NTRS)

    Sankar, Bhavani V.; Sharma, Suresh

    1995-01-01

    The effects of through-the-thickness stitching on impact damage resistance, impact damage tolerance, and Mode 1 and Mode 2 fracture toughness of textile graphite/epoxy laminates were studied experimentally. Graphite/epoxy laminates were fabricated from AS4 graphite uniweave textiles and 3501-6 epoxy using Resin Transfer Molding. The cloths were stitched with Kevlar(tm) and glass yarns before resin infusion. Delamination was implanted during processing to simulate impact damage. Sublaminate buckling tests were performed in a novel fixture to measure Compression After Impact (CAI) strength of stitched laminates. The results show that CAI strength can be improved up to 400% by through-the-thickness stitching. Double Cantilever Beam tests were performed to study the effect of stitching on Mode 1 fracture toughness G(sub 1c). It was found that G(sub 1c) increased 30 times for a low stitching density of 16 stitches/sq in. Mode 2 fracture toughness was measured by testing the stitched beams in End Notch Flexure tests. Unlike in the unstitiched beams, crack propagation in the stitched beams was steady. The current formulas for ENF tests were not found suitable for determining G(sub 2C) for stitched beams. Hence two new methods were developed - one based on crack area measured from ultrasonic C-scanning and the other based on equivalent crack area measured from the residual stiffness of the specimen. The G(sub 2c) was found to be at least 5-15 times higher for the stitched laminates. The mechanisms by which stitching increases the CAI strength and fracture toughness are discussed.

  18. Finite element analysis of end notch flexure specimen

    NASA Technical Reports Server (NTRS)

    Mall, S.; Kochhar, N. K.

    1986-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Mall, S.; Kochhar, N. K.

    1986-01-01

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

  20. iTOUGH2 V6.5

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

    Finsterle, Stefan A.

    2010-11-01

    iTOUGH2 (inverse TOUGH2) provides inverse modeling capabilities for TOUGH2, a simulator for multi-dimensional , multi-phase, multi-component, non-isothermal flow and transport in fractured porous media. It performs sensitivity analysis, parameter estimation, and uncertainty propagation, analysis in geosciences and reservoir engineering and other application areas. It supports a number of different combination of fluids and components [equation-of-state (EOS) modules]. In addition, the optimization routines implemented in iTOUGH2 can also be used or sensitivity analysis, automatic model calibration, and uncertainty quantification of any external code that uses text-based input and output files. This link is achieved by means of the PEST application programmingmore » interface. iTOUGH2 solves the inverse problem by minimizing a non-linear objective function of the weighted differences between model output and the corresponding observations. Multiple minimization algorithms (derivative fee, gradient-based and second-order; local and global) are available. iTOUGH2 also performs Latin Hypercube Monte Carlos simulation for uncertainty propagation analysis. A detailed residual and error analysis is provided. This upgrade includes new EOS modules (specifically EOS7c, ECO2N and TMVOC), hysteretic relative permeability and capillary pressure functions and the PEST API. More details can be found at http://esd.lbl.gov/iTOUGH2 and the publications cited there. Hardware Req.: Multi-platform; Related/auxiliary software PVM (if running in parallel).« less

  1. Fracture toughness versus micro-tensile bond strength testing of adhesive-dentin interfaces.

    PubMed

    De Munck, Jan; Luehrs, Anne-Katrin; Poitevin, André; Van Ende, Annelies; Van Meerbeek, Bart

    2013-06-01

    To assess interfacial fracture toughness of different adhesive approaches and compare to a standard micro-tensile bond-strength (μTBS) test. Chevron-notched beam fracture toughness (CNB) was measured following a modified ISO 24370 standard. Composite bars with dimensions of 3.0×4.0×25 mm were prepared, with the adhesive-dentin interface in the middle. At the adhesive-dentin interface, a chevron notch was prepared using a 0.15 mm thin diamond blade mounted in a water-cooled diamond saw. Each specimen was loaded until failure in a 4-point bend test setup and the fracture toughness was calculated according to the ISO specifications. Similarly, adhesive-dentin micro-specimens (1.0×1.0×8-10 mm) were stressed in tensile until failure to determine the μTBS. A positive correlation (r(2)=0.64) was observed between CNB and μTBS, which however was only nearly statistically significant, mainly due to the dissimilar outcome of Scotchbond Universal (3M ESPE). While few μTBS specimens failed at the adhesive-dentin interface, almost all CNB specimens failed interfacially at the notch tip. Weibull moduli for interfacial fracture toughness were much higher than for μTBS (3.8-11.5 versus 2.7-4.8, respectively), especially relevant with regard to early failures. Although the ranking of the adhesives on their bonding effectiveness tested using CNB and μTBS corresponded well, the outcome of CNB appeared more reliable and less variable. Fracture toughness measurement is however more laborious and requires specific equipment. The μTBS nevertheless appeared to remain a valid method to assess bonding effectiveness in a versatile way. Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  2. Toughness of Wear-Resistant Cu-Zr-Based Bulk Metallic Glasses

    NASA Astrophysics Data System (ADS)

    Andersen, Laura M.

    Bulk metallic glasses (BMGs) have the potential to exhibit exceptional wear-resistance due to their high hardness and strength. Combined with their other unique properties, this makes them ideal candidates for a wide range of technological applications (e.g. gears, bearings, biomaterials). In the course of this dissertation, high-glass-forming bulk metallic glasses are prepared and characterized in order to identify wear-resistant compositions and optimize their toughness. First, a comprehensive study identifies a class of Cu-Zr-based BMGs that exhibit more exceptional wear performance than other BMGs. The results demonstrate that when BMGs are designed properly, they exhibit wear properties that compete with, and can surpass, state-of-the-art engineering materials. It is identified that, in order to optimize the wear performance of Cu-Zr-based BMG gears, toughness should be maximized. Second, the notch toughness of wear-resistant Cu43Zr 43Al7Be7 BMGs with in-situ crystallization is investigated. In order to identify in-situ crystallization using X-ray diffraction (XRD) with Cu K? radiation, extremely long dwell times and high X-ray fluxes are required. This demonstrates the importance of reporting operating parameters when trying to evaluate the amorphous nature of BMGs. XRD, energy-dispersive X-ray spectroscopy (EDS) and electron backscatter diffraction (EBSD) are used to identify the metastable crystalline phase. The notch toughness is found to correlate closely with the amount of crystallization and the composition of the remaining amorphous matrix. Finally, the effect of substituting standard-grade zirconium lump (99.8% excluding up to 4% hafnium) for high-purity zirconium crystal bar (99.5%) in Cu43Zr43Al7Be7 is investigated. Introducing low-purity zirconium significantly decreases the glass-forming-ability and reduces the notch toughness of the BMG. Furthermore, Weibull statistics provide an analysis of the variability in toughness for high-purity ingots

  3. Fracture toughness of heat cured denture base acrylic resin modified with Chlorhexidine and Fluconazole as bioactive compounds.

    PubMed

    Al-Haddad, Alaa; Vahid Roudsari, Reza; Satterthwaite, Julian D

    2014-02-01

    This study investigated the impact of incorporating Chlorhexidine and Fluconazole as bioactive compounds on the fracture toughness of conventional heat cured denture base acrylic resin material (PMMA). 30 single edge-notched (SEN) samples were prepared and divided into three groups. 10% (mass) Chlorhexidine and 10% (mass) Diflucan powder (4.5% mass Fluconazole) were added to heat cured PMMA respectively to create the two study groups. A third group of conventional heat cured PMMA was prepared as the control group. Fracture toughness (3-point bending test) was carried out for each sample and critical force (Fc) and critical stress intensity factor (KIC) values measured. Data were subject to parametric statistical analysis using one-way ANOVA and Post hoc Bonferroni test (p=0.05). Fluconazole had no significant effect on the fracture toughness of the PMMA while Chlorhexidine significantly reduced the KIC and therefore affected the fracture toughness. When considering addition of a bioactive material to PMMA acrylic, Chlorhexidine will result in reduced fracture toughness of the acrylic base while Fluconazole has no effect. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

    DOEpatents

    Grondahl, Clayton M.; Germain, Malcolm R.

    1981-01-01

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

  5. Microstructure and fracture toughness of Mn-stabilized cubic titanium trialuminide

    NASA Astrophysics Data System (ADS)

    Zbroniec, Leszek Ireneusz

    This thesis project is related to the fracture toughness aspects of the mechanical behavior of the selected Mn-modified cubic Ll2 titanium trialuminicles. Fracture toughness was evaluated using two specimen types: Single-Edge-Precracked-Beam (SEPB) and Chevron-Notched-Beam (CNB). The material tested was in cast, homogenized and HIP-ed condition. In the preliminary stage of the project due to lack of the ASTM Standard for fracture toughness testing of the chevron-notched specimens in bending the analyses of the CNB configuration were done to establish the optimal chevron notch dimensions. Two types of alloys were investigated: (a) boron-free and boron doped low-Mn (9at.% Mn), as well as (b) boron-free and boron-doped high-Mn (14at.% Mn). Toughness was investigated in the temperature range from room temperature to 1000°C and was calculated from the maximum load. It has been found that toughness of coarse-grained "base" 9Mn-25Ti alloy exhibits a broad peak at the 200--500°C temperature range and then decreases with increasing temperature, reaching its room temperature value at 10000°C. However, the work of fracture (gammaWOF) and the stress intensity factor calculated from it (KIWOF) increases continuously with increasing temperature. Also the fracture mode dependence on temperature has been established. To understand the effect of environment on the fracture toughness of coarse-grained "base", boron-free 9Mn-25Ti alloy, the tests were carried out in vacuum (˜1.3 x 10-5 Pa), argon, oxygen, water and liquid nitrogen. It has been shown that fracture toughness at ambient temperature is not affected by the environments containing moisture (water vapor). It seems that at ambient temperatures these materials are completely immune to the water-vapor hydrogen embrittlement and their cause of brittleness is other than environment. To explore the influence of the grain size on fracture toughness the fracture toughness tests were also performed on the dynamically

  6. Fracture toughness and the master curve for modified 9Cr-1Mo steel

    NASA Astrophysics Data System (ADS)

    Yoon, Ji-Hyun; Yoon, Eui-Pak

    2006-12-01

    Modified 9Cr-1Mo steel is a primary candidate material for the reactor pressure vessel of a Very High Temperature Gas-Cooled Reactor (VHTR) in the Korean Nuclear Hydrogen Development and Demonstration (NHDD) program. In this study, the T0 reference temperature, J-R fracture resistance and Charpy impact properties were evaluated for commercial Grade 91 steel as part of the preliminary testing for a selection of the RPV material for the VHTR. The fracture toughness of the modified 9Cr-1Mo steel was compared with that of SA508-Gr.3. The objective of this study was to obtain the pre-irradiation fracture toughness properties of the modified 9Cr-1Mo steel as reference data for an investigation of radiation effects. Charpy impact properties of the modified 9Cr-1Mo steel were similar to those of SA508-Gr.3. T0 reference temperatures were measured as -67.7 and -72.4°C from the tests with standard PCVN (pre-cracked Charpy V-notch) and half-sized PCVN specimens respectively, which were similar to the results for SA508-Gr.3. The KJc values of the modified 9Cr-1Mo steel with the test temperatures are successfully expressed by the Master Curve. The J-R fracture resistance of the modified 9Cr-1Mo steel at room temperature was nearly identical to that of SA508-Gr.3; in contrast, it was slightly higher at an elevated temperature.

  7. The Influence of Specimen Type on Tensile Fracture Toughness of Rock Materials

    NASA Astrophysics Data System (ADS)

    Aliha, Mohammad Reza Mohammad; Mahdavi, Eqlima; Ayatollahi, Majid Reza

    2017-03-01

    Up to now, several methods have been proposed to determine the mode I fracture toughness of rocks. In this research, different cylindrical and disc shape samples, namely: chevron bend (CB), short rod (SR), cracked chevron notched Brazilian disc (CCNBD), and semi-circular bend (SCB) specimens were considered for investigating mode I fracture behavior of a marble rock. It is shown experimentally that the fracture toughness values of the tested rock material obtained from different test specimens are not consistent. Indeed, depending on the geometry and loading type of the specimen, noticeable discrepancies can be observed for the fracture toughness of a same rock material. The difference between the experimental mode I fracture resistance results is related to the magnitude and sign of T-stress that is dependent on the geometry and loading configuration of the specimen. For the chevron-notched samples, the critical value of T-stress corresponding to the critical crack length was determined using the finite element method. The CCNBD and SR specimens had the most negative and positive T-stress values, respectively. The dependency of mode I fracture resistance to the T-stress was shown using the extended maximum tangential strain (EMTSN) criterion and the obtained experimental rock fracture toughness data were predicted successfully with this criterion.

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

    PubMed

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

    2015-01-01

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

  9. Charpy V-notch properties and microstructures of narrow gap ferritic welds of a quenched and tempered steel plate

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

    Powell, G.L.F.; Herfurth, G.

    1998-11-01

    Multipass welds of quenched and tempered 50-mm-thick steel plate have been deposited by a single wire narrow gap process using both gas metal arc welding (GMAW) and submerged arc welding (SAW). Of the five welds, two reported much lower Charpy V-notch (CVN) values when tested at {minus} 20 C. The CVN toughness did not correlate with either the welding process or whether the power source was pulsed or nonpulsed. The only difference in the ferritic microstructure between the two welds of low Charpy values and the three of high values was the percentage of acicular ferrite. There was no effectmore » of the percentage of as-deposited reheated zones intersected by the Charpy notch or the microhardness of the intercellular-dendritic regions. In all welds, austenite was the microconstituent between the ferrite laths. The percentage of acicular ferrite correlated with the presence of MnO, TiO{sub 2}, {gamma} Al{sub 2}O{sub 3}, or MnO. Al{sub 2}O{sub 3} as the predominant crystalline compound in the oxide inclusions. In turn, the crystalline compound depended on the aluminum-to-titanium ratio in both the weld deposits and the oxide inclusions. In addition to the presence of less acicular ferrite, the two welds that showed lower Charpy values also reported more oxide inclusions greater than 1 {micro}m in diameter. The combination of more oxide inclusions greater than 1 {micro}m and less acicular ferrite is considered to be the explanation for the lower Charpy values.« less

  10. Influence of Chemical Composition and Heat Treatment Condition on Impact Toughness of 15Cr Ferritic Creep Resistant Steel

    NASA Astrophysics Data System (ADS)

    Toda, Yoshiaki; Tohyama, Hideaki; Kushima, Hideaki; Kimura, Kazuhiro; Abe, Fujio

    Influences of chemical compositions, heat treatment and microstructure on impact toughness of 15Cr ferritic steel have been investigated. Charpy impact values of the furnace cooled steels were lower than 15J/cm2 at room temperature independent of chemical compositions. Drastic improvement in impact toughness has been attained by controlling the carbon and nitrogen contents, by the addition of nickel and by the increase in cooling rate after annealing. However, the effect of nickel on impact toughness strongly depends on carbon and nitrogen contents. Improvement in impact toughness of the 15Cr ferritic steel has not been explained by individual microstructural factors of grain size, distribution of precipitates, volume fraction of martensitic phase. It has been supposed that the increase in Charpy impact toughness of the 15Cr ferritic steel was attained by improvement in toughness of ferrite matrix itself.

  11. Master Curve and Conventional Fracture Toughness of Modified 9Cr-1Mo Steel

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

    Ji-Hyun, Yoon; Sung-Ho, Kim; Bong-Sang, Lee

    2006-07-01

    Modified 9Cr-1Mo steel is a primary candidate material for reactor pressure vessel of Very High Temperature Gas-Cooled Reactor (VHTR) in Korean Nuclear Hydrogen Development and Demonstration (NHDD) program. In this study, T0 reference temperature, J-R fracture resistance and Charpy impact properties were evaluated for commercial Grade 91 steel as preliminary tests for the selection of the RPV material for VHTR. The fracture toughness of the modified 9Cr-1Mo steel was compared with those of SA508-Gr.3. The objective of this study was to obtain pre-irradiation fracture toughness properties of modified 9Cr-1Mo steel as reference data for the radiation effects investigation. The resultsmore » are as follows. Charpy impact properties of the modified 9Cr-1Mo steel were similar to those of SA508-Gr.3. T0 reference temperatures were measured as -67.7 deg C and -72.4 deg C from the tests with standard PCVN (pre-cracked Charpy V-notch) and half sized PCVN specimens respectively, which were similar to results for SA508-Gr.3. The K{sub Jc} values of modified 9Cr-1Mo with test temperatures are successfully expressed with the Master Curve. The J-R fracture resistance of modified 9Cr-1Mo steel at room temperature was almost the same as that of SA508-Gr.3. On the other hand it was a little bit higher at an elevated temperature. (authors)« less

  12. Impact Toughness of Subzones in the Intercritical Heat-Affected Zone of Low-Carbon Bainitic Steel.

    PubMed

    Li, Zhenshun; Zhao, Xuemin; Shan, Dongri

    2018-06-06

    The subzones of the intercritical heat-affected zone (IC HAZ) of low-carbon bainitic steel were simulated by using a Gleeble-3500 simulator to study the impact toughness. The results showed that the IC HAZ is not entirely brittle and can be further divided into three subzones according to the impact toughness or peak welding temperature; the invariant subzone heated between the critical transformation start temperature ( A c1 ) and 770 °C exhibited unchanged high impact toughness. Furthermore, an extremely low impact toughness was found in the embrittlement subzone, heated between 770 and 830 °C, and the reduction subzone heated between 830 °C and the critical transformation finish temperature ( A c3 ) exhibited toughness below that of the original metal. The size of the blocky martensite-austenite (M-A) constituents was found to have a remarkable level of influence on the impact toughness when heated below 830 °C. Additionally, it was found that, once the constituent size exceeds a critical value of 3.0 µm at a peak temperature of 770 °C, the IC HAZ becomes brittle regardless of lath or twinned martensite constitution in the M-A constituent. Essentially, embrittlement was observed to occur when the resolved length of initial cracks (in the direction of the overall fracture) formed as a result of the debonding of M-A constituents exceeding the critical Griffith size. Furthermore, when the heating temperature exceeded 830 °C, the M-A constituents formed a slender shape, and the impact toughness increased as the area fraction of the slender M-A constituents decreased.

  13. Factors affecting miniature Izod impact strength of tungsten-fiber-metal-matrix

    NASA Technical Reports Server (NTRS)

    Winsa, E. A.; Petrasek, D. W.

    1973-01-01

    The miniature Izod and Charpy impact strengths of copper, copper-nickel, and nickel-base superalloy uniaxially reinforced with continuous tungsten fibers were studied. In most cases, impact strength was increased by increasing fiber or matrix toughness, decreasing fibermatrix reaction, increasing test temperature, hot working, or heat treating. Notch sensitivity was reduced by increasing fiber content or matrix toughness. An equation relating impact strength to fiber and matrix properties and fiber content was developed. Program results imply that tungsten alloy-fiber/superalloy matrix composites can be made with adequate impact resistance for turbine blade or vane applications.

  14. Initiation and propagation toughness of delamination crack under an impact load

    NASA Astrophysics Data System (ADS)

    Kumar, Prashant; Kishore, N. N.

    1998-10-01

    A combined experimental and finite element method is developed to determine the interlaminar dynamic fracture toughness. An interlaminar crack is propagated at very high speed in a double cantilever beam (DCB) specimen made of two steel strips with a precrack. A special fixture is designed to apply impact load to one cantilever and determine the deflection of the cantilever-end, initiation time and crack propagation history. The experimental results are used as input data in a FE code to calculate J-integral by the gradual release of nodal forces to model the propagation of the interlaminar crack. The initiation fracture toughness and propagation fracture toughness are evaluated for interlaminar crack propagating between 850 and 1785 ms. The initiation and propagation toughness were found to vary between 90-200 Jm 2 and 2-13 Jm 2 respectively. The technique is extended to study initiation and propagation toughness of interlaminar crack in unidirectional FRP laminates. 1998 Elsevier Science Ltd.

  15. Mode II Interlaminar Fracture Toughness and Fatigue Characterization of a Graphite Epoxy Composite Material

    NASA Technical Reports Server (NTRS)

    O'Brien, T. Kevin; Johnston, William M.; Toland, Gregory J.

    2010-01-01

    Mode II interlaminar fracture toughness and delamination onset and growth characterization data were generated for IM7/8552 graphite epoxy composite materials from two suppliers for use in fracture mechanics analyses. Both the fracture toughness testing and the fatigue testing were conducted using the End-notched Flexure (ENF) test. The ENF test for mode II fracture toughness is currently under review by ASTM as a potential standard test method. This current draft ASTM protocol was used as a guide to conduct the tests on the IM7/8552 material. This report summarizes the test approach, methods, procedures and results of this characterization effort.

  16. Procedure improves line pipe Charpy test interpretation

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

    Rosenfeld, M.J.

    1997-04-14

    The Charpy V-notch (CVN) impact test is a method of characterizing a line-pipe material`s notch toughness and resistance to fracture growth. Although CVN testing of line pipe material is routine, test results are sometimes misinterpreted because of specimen size and load rate on actual toughness transition behavior. These effects are readily accounted for by a simple mathematical procedure, offered here, which enables extrapolation of the full-scale transition curve from as little as a single subsize specimen test. This procedure is useful when the toughness transition curve is incomplete or nonexistent. Toughness data may be incomplete because the API 5L toughnessmore » test establishes minimum performance at a single temperature, which does not reveal the full transition curve. Toughness data may be nonexistent because the first requirements for toughness testing of line pipe appeared in the 16th Edition of API 5LX in 1969, and those requirements remain at the option of the purchaser today.« less

  17. Effect of matrix material on the fracture behavior and toughness of high temperature polymer composites

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

    Chenock, T.A.Jr.; Heshmet, A.

    1990-07-01

    The effect of matrix material on the strength, toughness, and fracture behavior of two high temperature polyimide/carbon fiber composites has been studied and compared. The polyimide matrix resins under investigation are PMR-II-20, PMR-15. Each system was reinforced with epoxy sized Celion G30-500 carbon fabric (8HSW, 3K tow). Un-notched and notched specimens were tested under 4-point bend loading in both translaminar and crosslaminar directions.

  18. Heavy section fracture toughness screening specimen

    NASA Technical Reports Server (NTRS)

    Shannon, J. L., Jr.; Donald, J. K.; Brown, W. F., Jr.

    1976-01-01

    Size requirements for a pin loaded double edge notch + crack tension specimen proposed for fracture toughness screening heavy section alloys were studied. Ranking of eight selected alloys based on the specimen's net strength was compared with that based on the valid plane strain fracture toughness separately determined. Performance of the specimen was judged on the basis of that comparison. The specimen's net strength was influenced by three critical specimen dimensions: distance between the crack plane and the loading hole, specimen width, and specimen thickness. Interaction between the stress fields of the crack and the loading holes reduced the net strength, but this effect disappeared as the separation reached a dimension equal to the specimen width. The effects of specimen width and thickness are interrelated and affect the net strength through their influence on the development of the crack tip plastic zone.

  19. A new tensile impact test for the toughness characterization of sheet material

    NASA Astrophysics Data System (ADS)

    Könemann, Markus; Lenz, David; Brinnel, Victoria; Münstermann, Sebastian

    2018-05-01

    In the past, the selection of suitable steels has been carried out primarily based on the mechanical properties of different steels. One of these properties is the resistance against crack propagation. For many constructions, this value plays an important role, because it can compare the impact toughness of different steel grades easily and gives information about the loading capacity of the specific materials. For thin sheets, impact toughness properties were usually not considered. One of the reasons for this is that the Charpy-impact test is not applicable for sheets with thicknesses below 2 mm. For a long time, this was not relevant because conventional steels had a sufficient impact toughness in a wide temperature range. However, since new multiphase steel grades with improved mechanical property exploitations are available, it turned out that impact toughness properties need to be considered during the component design phase, as the activation of the cleavage fracture mechanism is observed under challenging loading conditions. Therefore, this work aims to provide a new and practical testing procedure for sheet material or thin walled structures. The new testing procedure is based on tensile tests conducted in an impact pendulum similar to the Charpy impact hammer. A new standard geometry is provided, which enables a comparison between different steels or steel grades. A connection to the conventional Charpy test is presented using a damage mechanics model, which predicts material failure with consideration of to the stress state at various temperatures. Different specimen geometries are analysed to cover manifold stress states. A special advantage of the damage mechanics model is also the possibility to predict the materials behaviour in the transition area. To verify the method a conventional steel was tested in Charpy tests as well as in the new tensile impact test.

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

    NASA Technical Reports Server (NTRS)

    Hill, Charles S.; Oliveras, Ovidio M.

    2011-01-01

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

  1. Factors Affecting Impact Toughness in Stabilized Intermediate Purity 21Cr Ferritic Stainless Steels and Their Simulated Heat-Affected Zones

    NASA Astrophysics Data System (ADS)

    Anttila, Severi; Alatarvas, Tuomas; Porter, David A.

    2017-12-01

    The correlation between simulated weld heat-affected zone microstructures and toughness parameters has been investigated in four intermediate purity 21Cr ferritic stainless steels stabilized with titanium and niobium either separately or in combination. Extensive Charpy V impact toughness testing was carried out followed by metallography including particle analysis using electron microscopy. The results confirmed that the grain size and the number density of particle clusters rich in titanium nitride and carbide with an equivalent circular diameter of 2 µm or more are statistically the most critical factors influencing the ductile-to-brittle transition temperature. Other inclusions and particle clusters, as well as grain boundary precipitates, are shown to be relatively harmless. Stabilization with niobium avoids large titanium-rich inclusions and also suppresses excessive grain growth in the heat-affected zone when reasonable heat inputs are used. Thus, in order to maximize the limited heat-affected zone impact toughness of 21Cr ferritic stainless steels containing 380 to 450 mass ppm of interstitials, the stabilization should be either titanium free or the levels of titanium and nitrogen should be moderated.

  2. User's Guide for TOUGH2-MP - A Massively Parallel Version of the TOUGH2 Code

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

    Earth Sciences Division; Zhang, Keni; Zhang, Keni

    TOUGH2-MP is a massively parallel (MP) version of the TOUGH2 code, designed for computationally efficient parallel simulation of isothermal and nonisothermal flows of multicomponent, multiphase fluids in one, two, and three-dimensional porous and fractured media. In recent years, computational requirements have become increasingly intensive in large or highly nonlinear problems for applications in areas such as radioactive waste disposal, CO2 geological sequestration, environmental assessment and remediation, reservoir engineering, and groundwater hydrology. The primary objective of developing the parallel-simulation capability is to significantly improve the computational performance of the TOUGH2 family of codes. The particular goal for the parallel simulator ismore » to achieve orders-of-magnitude improvement in computational time for models with ever-increasing complexity. TOUGH2-MP is designed to perform parallel simulation on multi-CPU computational platforms. An earlier version of TOUGH2-MP (V1.0) was based on the TOUGH2 Version 1.4 with EOS3, EOS9, and T2R3D modules, a software previously qualified for applications in the Yucca Mountain project, and was designed for execution on CRAY T3E and IBM SP supercomputers. The current version of TOUGH2-MP (V2.0) includes all fluid property modules of the standard version TOUGH2 V2.0. It provides computationally efficient capabilities using supercomputers, Linux clusters, or multi-core PCs, and also offers many user-friendly features. The parallel simulator inherits all process capabilities from V2.0 together with additional capabilities for handling fractured media from V1.4. This report provides a quick starting guide on how to set up and run the TOUGH2-MP program for users with a basic knowledge of running the (standard) version TOUGH2 code, The report also gives a brief technical description of the code, including a discussion of parallel methodology, code structure, as well as mathematical and numerical

  3. Aging Degradation of Austenitic Stainless Steel Weld Probed by Electrochemical Method and Impact Toughness Evaluation

    NASA Astrophysics Data System (ADS)

    Singh, Raghuvir; Das, Goutam; Mahato, B.; Singh, P. K.

    2017-03-01

    The present study discriminates the spinodal decomposition and G-phase precipitation in stainless steel welds by double loop electrochemical potentio-kinetic reactivation method and correlates it with the degradation in toughness property. The welds produced with different heat inputs were aged up to 10,000 hours at 673 K to 723 K (400 to 450 °C) and evaluated subsequently for the degree of sensitization (DOS) and impact toughness. The DOS values obtained were attributed to the spinodal decomposition and precipitation of G-phase. Study shows that the DOS correlates well with the impact toughness of the 304LN weld. Prolonged aging at 673 K and 723 K (400 °C and 450 °C) increased the DOS values while the impact toughness was decreased. The weld fabricated at 1 kJ/mm of heat input, produced higher DOS, compared to that at 3 kJ/mm. The geometrical location along the weld is shown to influence the DOS; higher values were obtained at the root than at the topside of the weld. Vermicular and columnar microstructure, in addition to the spinodal decomposition and G-phase precipitation, observed in the root side of the weld appear risky for the impact toughness.

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

    PubMed Central

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

    2013-01-01

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

  5. ADM guidance-Ceramics: Fracture toughness testing and method selection.

    PubMed

    Cesar, Paulo Francisco; Della Bona, Alvaro; Scherrer, Susanne S; Tholey, Michael; van Noort, Richard; Vichi, Alessandro; Kelly, Robert; Lohbauer, Ulrich

    2017-06-01

    The objective is within the scope of the Academy of Dental Materials Guidance Project, which is to provide dental materials researchers with a critical analysis of fracture toughness (FT) tests such that the assessment of the FT of dental ceramics is conducted in a reliable, repeatable and reproducible way. Fracture mechanics theory and FT methodologies were critically reviewed to introduce basic fracture principles and determine the main advantages and disadvantages of existing FT methods from the standpoint of the dental researcher. The recommended methods for FT determination of dental ceramics were the Single Edge "V" Notch Beam (SEVNB), Single Edge Precracked Beam (SEPB), Chevron Notch Beam (CNB), and Surface Crack in Flexure (SCF). SEVNB's main advantage is the ease of producing the notch via a cutting disk, SEPB allows for production of an atomically sharp crack generated by a specific precracking device, CNB is technically difficult, but based on solid fracture mechanics solutions, and SCF involves fracture from a clinically sized precrack. The IF test should be avoided due to heavy criticism that has arisen in the engineering field regarding the empirical nature of the calculations used for FT determination. Dental researchers interested in FT measurement of dental ceramics should start with a broad review of fracture mechanics theory to understand the underlying principles involved in fast fracture of ceramics. The choice of FT methodology should be based on the pros and cons of each test, as described in this literature review. Copyright © 2017 The Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  6. The Use of Doublers in Delamination Toughness Testing

    NASA Technical Reports Server (NTRS)

    Reeder, James R.; Demarco, Kevin; Whitley, Karen S.

    2002-01-01

    In this paper, the data reduction equations for common delamination toughness tests are rederived for use with specimens which have bonded doublers. The common toughness tests considered here are the double cantilever beam (DCB) for mode I toughness; the end notch flexure (3ENF) and 4 point ENF (4ENF) for mode II toughness; and the mixed mode bending (MMB) test for testing under combined mode I and mode II loading. Because the addition of the doublers changes the bending stiffness of the specimens, these data reduction equations may need to be corrected. Doublers were added to the delamination test specimens to solve a premature failure problem. Delamination toughness is normally tested using a beam with an imbedded insert so that one end of the specimen is split into two arms. If the specimen is too thin, or if the toughness of the material is too high, an arm of the specimen may fail in bending before the delamination grows. When this occurs, the toughness of the material cannot be determined. To delay the bending failure so that delamination growth occurs, doubler plates were bonded to both top and bottom surfaces of the specimen. A doubler parameter, beta, which describes how much the use of doubler plates changed the ratio of full thickness to delaminated bending stiffnesses, was defined. When changes to the data reduction equations were required, the changes were minor when written in terms of the beta parameter. The doubler plate technique was demonstrated by measuring the mixed-mode fracture toughness of a carbon-carbon composite using test specimens which would otherwise have failed before delamination growth occurred. The doubler plate technique may solve several problems that can be encountered when testing delamination fracture toughness.

  7. Interlaminar shear fracture toughness and fatigue thresholds for composite materials

    NASA Technical Reports Server (NTRS)

    Obrien, T. Kevin; Murri, Gretchen B.; Salpekar, Satish A.

    1987-01-01

    Static and cyclic end notched flexure tests were conducted on a graphite epoxy, a glass epoxy, and graphite thermoplastic to determine their interlaminar shear fracture toughness and fatigue thresholds for delamination in terms of limiting values of the mode II strain energy release rate, G-II, for delamination growth. The influence of precracking and data reduction schemes are discussed. Finite element analysis indicated that the beam theory calculation for G-II with the transverse shear contribution included was reasonably accurate over the entire range of crack lengths. Cyclic loading significantly reduced the critical G-II for delamination. A threshold value of the maximum cyclic G-II below which no delamination occurred after one million cycles was identified for each material. Also, residual static toughness tests were conducted on glass epoxy specimens that had undergone one million cycles without delamination. A linear mixed-mode delamination criteria was used to characterize the static toughness of several composite materials; however, a total G threshold criterion appears to characterize the fatigue delamination durability of composite materials with a wide range of static toughness.

  8. Double Cantilever Beam and End Notched Flexure Fracture Toughness Testing of Two Composite Materials

    NASA Technical Reports Server (NTRS)

    Kessler, Jeff A.; Adams, Donald F.

    1993-01-01

    Two different unidirectional composite materials were provided by NASA Langley Research Center and tested by the Composite Materials Research Group within the Department of Mechanical Engineering at the University of Wyoming. Double cantilever beam and end notched flexure tests were performed to measure the mode I (crack opening) and mode II (sliding or shear) interlaminar fracture toughness of the two materials. The two composites consisted of IM7 carbon fiber combined with either RP46 resin toughened with special formulation of LaRC IA resin, known as JJS1356; or PES chain extended thermoplastic resin known as JJS1361. Double Cantilever Beam Specimen Configuration and Test Methods As received from NASA, the test specimens were nominally 0.5 inch wide, 6 inches long, and 0.2 inch thick. A 1 inch long Kapton insert at the midplane of one end of the specimen (placed during laminate fabrication) facilitated crack initiation and extension. It was noted that the specimens provided were smaller than the nominal 1.5 inch wide, 9.0 inch long configuration specified. Similarly, the Kapton inserts were of greater length than those in the present specimens. Hence, the data below should not be compared directly to those generated with the referenced methods. No preconditioning was performed on the specimens prior to testing. In general, the methodology was used for the present work. Crack opening loads were introduced to the specimens via piano hinges attached to the main specimen faces at a single end of each specimen. Hinges were bolted to the specimens using the technique presented. The cracks were extended a small distance from the end of the Kapton insert prior to testing. Just before precracking, the sides of the specimens were coated with water-soluble typewriter correction fluid to aid in crack visualization. Scribe marks were then made in the coating at half-inch intervals.

  9. A New Test Method for Determining the Strength and Fracture Toughness of Cement Mortar and Concrete

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

    Wang, Jy-An John; Liu, Ken C; Naus, Dan J

    2010-01-01

    The Spiral Notch Torsion Fracture Toughness Test (SNTT) was developed recently to determine the intrinsic fracture toughness (KIC) of structural materials. The SNTT system operates by applying pure torsion to uniform cylindrical specimens with a notch line that spirals around the specimen at a 45 a pitch. KIC values are obtained with the aid of a three-dimensional finite-element computer code, TOR3D-KIC. The SNTT method is uniquely suitable for testing a wide variety of materials used extensively in pressure vessel and piping structural components and weldments. Application of the method to metallic, ceramic, and graphite materials has been demonstrated. One importantmore » characteristic of SNTT is that neither a fatigue precrack or a deep notch are required for the evaluation of brittle materials, which significantly reduces the sample size requirement. In this paper we report results for a Portland cement-based mortar to demonstrate applicability of the SNTT method to cementitious materials. The estimated KIC of the tested mortar samples with compressive strength of 34.45 MPa was found to be 0.19 MPa m^(1/2).« less

  10. Notched bar Izod impact properties of zinc die castings

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

    Schrems, K.K.; Dogan, O.N.; Goodwin, F.E.

    2007-03-01

    Notched bar Izod impact testing of zinc die cast Alloy 3, Alloy 5, ZA-8, and AcuZinc 5 was performed at five temperatures between -40\\mDC and room temperature in accordance with ASTM E23 for impact testing of metallic materials. A direct comparison between ASTM D256 for impact testing of plastics and ASTM E23 was performed using continuously cast zinc specimens of Alloy 5 and ZA-8 at -40\\mDC and room temperature. There are differences in sample sizes, impact velocity, and striker geometry between the two tests. Bulk zinc tested according to ASTM E23 resulted in higher impact energies at -40\\mDC and lowermore » impact energies at room temperature then did the same alloys when tested according to ASTM D256.« less

  11. TOUGH3: A new efficient version of the TOUGH suite of multiphase flow and transport simulators

    NASA Astrophysics Data System (ADS)

    Jung, Yoojin; Pau, George Shu Heng; Finsterle, Stefan; Pollyea, Ryan M.

    2017-11-01

    The TOUGH suite of nonisothermal multiphase flow and transport simulators has been updated by various developers over many years to address a vast range of challenging subsurface problems. The increasing complexity of the simulated processes as well as the growing size of model domains that need to be handled call for an improvement in the simulator's computational robustness and efficiency. Moreover, modifications have been frequently introduced independently, resulting in multiple versions of TOUGH that (1) led to inconsistencies in feature implementation and usage, (2) made code maintenance and development inefficient, and (3) caused confusion to users and developers. TOUGH3-a new base version of TOUGH-addresses these issues. It consolidates both the serial (TOUGH2 V2.1) and parallel (TOUGH2-MP V2.0) implementations, enabling simulations to be performed on desktop computers and supercomputers using a single code. New PETSc parallel linear solvers are added to the existing serial solvers of TOUGH2 and the Aztec solver used in TOUGH2-MP. The PETSc solvers generally perform better than the Aztec solvers in parallel and the internal TOUGH3 linear solver in serial. TOUGH3 also incorporates many new features, addresses bugs, and improves the flexibility of data handling. Due to the improved capabilities and usability, TOUGH3 is more robust and efficient for solving tough and computationally demanding problems in diverse scientific and practical applications related to subsurface flow modeling.

  12. Progress Report on Alloy 617 Notched Specimen Testing

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

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

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

  13. Fatigue pre-cracking and fracture toughness in polycrystalline tungsten and molybdenum

    NASA Astrophysics Data System (ADS)

    Taguchi, Katsuya; Nakadate, Kazuhito; Matsuo, Satoru; Tokunaga, Kazutoshi; Kurishita, Hiroaki

    2018-01-01

    Fatigue pre-cracking performance and fracture toughness in polycrystalline tungsten (W) and molybdenum (Mo) have been investigated in relation to grain boundary (GB) configuration with respect to the crack advance direction. Sub-sized, single edge notched bend (SENB) specimens with three different orientations, R-L (ASTM notation) for a forged Mo rod and L-S and T-S for a rolled W plate, were pre-cracked in two steps: fully uniaxial compression fatigue loading to provoke crack initiation and its stable growth from the notch root, and subsequent 3-point bend (3PB) fatigue loading to extend the crack. The latter step intends to minimize the influence of the residual tensile stresses generated during compression fatigue by moving the crack tip away from the plastic zone. It is shown that fatigue pre-cracking performance, especially pre-crack extension behavior, is significantly affected by the specimen orientation. The R-L orientation, giving the easiest cracking path, permitted crack extension completely beyond the plastic zone, while the L-S and T-S orientations with the thickness cracking direction of the rolled plate sustained the crack lengths around or possibly within the plastic zone size due to difficulty in crack advance through an aligned grain structure. Room temperature fracture toughness tests revealed that the 3PB fatigued specimens exhibited appreciably higher fracture toughness by about 30% for R-L, 40% for L-S and 60% for T-S than the specimens of each orientation pre-cracked by compression fatigue only. This indicates that 3PB fatigue provides the crack tip front out of the residual tensile stress zone by crack extension or leads to reduction in the residual stresses at the crack tip front. Strong dependence of fracture toughness on GB configuration was evident. The obtained fracture toughness values are compared with those in the literature and its strong GB configuration dependence is discussed in connection with the appearance of pop-in.

  14. An Effective Modal Approach to the Dynamic Evaluation of Fracture Toughness of Quasi-Brittle Materials

    NASA Astrophysics Data System (ADS)

    Ferreira, L. E. T.; Vareda, L. V.; Hanai, J. B.; Sousa, J. L. A. O.; Silva, A. I.

    2017-05-01

    A modal dynamic analysis is used as the tool to evaluate the fracture toughness of concrete from the results of notched-through beam tests. The dimensionless functions describing the relation between the frequencies and specimen geometry used for identifying the variation in the natural frequency as a function of crack depth is first determined for a 150 × 150 × 500-mm notched-through specimen. The frequency decrease resulting from the propagating crack is modeled through a modal/fracture mechanics approach, leading to determination of an effective crack length. This length, obtained numerically, is used to evaluate the fracture toughness of concrete, the critical crack mouth opening displacements, and the brittleness index proposed. The methodology is applied to tests performed on high-strength concrete specimens. The frequency response for each specimen is evaluated before and after each crack propagation step. The methodology is then validated by comparison with results from the application of other methodologies described in the literature and suggested by RILEM.

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

    PubMed

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

    2007-04-15

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

  16. Effects of Zr, Ti, and Al Additions on Nonmetallic Inclusions and Impact Toughness of Cast Low-Alloy Steel

    NASA Astrophysics Data System (ADS)

    Bizyukov, Pavel V.; Giese, Scott R.

    2017-04-01

    A microalloying of the low-carbon and low-alloy cast steel was conducted with Zr, Ti, and Al that were added to the steel in four combinations. After heat treatment, the samples were tested for impact toughness at room temperature using the Charpy method. The highest values of impact toughness were obtained in the group treated with Zr, while Zr-Ti and Zr-Ti-Al groups showed moderate toughness values; the lowest values were observed in the Zr-Al group. Difference among the treatment groups was observed in the fracture mechanisms, morphology, and area distribution of the inclusions. High toughness values achieved in the trials treated with zirconium corresponded with smooth ductile fracture. The metal treated with a combination of zirconium and titanium had a relatively small area occupied by inclusions, but its toughness was also moderate. Lowest impact toughness values corresponded with the larger area occupied by the inclusions in the trials treated with aluminum. Also, a connection between the solubility product [Al][N] and impact toughness was established. The study also provides a qualitative description and quantitative analysis of the nonmetallic inclusions formation as a result of microalloying treatment. The precipitation sequence of the inclusions was described based on the thermochemical calculations for the nonmetallic compounds discovered in the experimental steel. A description of the size distribution, morphology, and composition was conducted for the oxides, nitrides, sulfides, and multiphase particles.

  17. Study of fracture toughness of ZrO2 ceramics

    NASA Astrophysics Data System (ADS)

    Deryugin, Yevgeny; Narkevich, Natalya; Vlasov, Ilya; Panin, Victor; Danilenko, Igor; Schmauder, Siegfried

    2017-12-01

    The fracture toughness characteristics of ZrO2ceramics were determined experimentally using an original technique of wedging small-sized chevron notch specimens developed at the Institute of Strength Physics and Materials Science SB RAS (Russia) in the laboratory of physical mesomechanics of materials and non-destructive testing. Measurements have shown that inelastic displacements can be more than 22% of the total displacement of the consoles by the time of the specimen failure. The effect of the Y2O3 stabilizer on the critical stress intensity factor KIc was verified. It was shown that an increase in the Y2O3 stabilizer content from 3 to 8% significantly decreases the fracture toughness. The stress intensity factor KIc falls within the range from 5.7 to 2.35 MPa m1/2.

  18. Reciprocal signalling by Notch-Collagen V-CALCR retains muscle stem cells in their niche.

    PubMed

    Baghdadi, Meryem B; Castel, David; Machado, Léo; Fukada, So-Ichiro; Birk, David E; Relaix, Frederic; Tajbakhsh, Shahragim; Mourikis, Philippos

    2018-05-01

    The cell microenvironment, which is critical for stem cell maintenance, contains both cellular and non-cellular components, including secreted growth factors and the extracellular matrix 1-3 . Although Notch and other signalling pathways have previously been reported to regulate quiescence of stem cells 4-9 , the composition and source of molecules that maintain the stem cell niche remain largely unknown. Here we show that adult muscle satellite (stem) cells in mice produce extracellular matrix collagens to maintain quiescence in a cell-autonomous manner. Using chromatin immunoprecipitation followed by sequencing, we identified NOTCH1/RBPJ-bound regulatory elements adjacent to specific collagen genes, the expression of which is deregulated in Notch-mutant mice. Moreover, we show that Collagen V (COLV) produced by satellite cells is a critical component of the quiescent niche, as depletion of COLV by conditional deletion of the Col5a1 gene leads to anomalous cell cycle entry and gradual diminution of the stem cell pool. Notably, the interaction of COLV with satellite cells is mediated by the Calcitonin receptor, for which COLV acts as a surrogate local ligand. Systemic administration of a calcitonin derivative is sufficient to rescue the quiescence and self-renewal defects found in COLV-null satellite cells. This study reveals a Notch-COLV-Calcitonin receptor signalling cascade that maintains satellite cells in a quiescent state in a cell-autonomous fashion, and raises the possibility that similar reciprocal mechanisms act in diverse stem cell populations.

  19. Calculation for tensile strength and fracture toughness of granite with three kinds of grain sizes using three-point-bending test.

    PubMed

    Yu, Miao; Wei, Chenhui; Niu, Leilei; Li, Shaohua; Yu, Yongjun

    2018-01-01

    Tensile strength and fracture toughness, important parameters of the rock for engineering applications are difficult to measure. Thus this paper selected three kinds of granite samples (grain sizes = 1.01mm, 2.12mm and 3mm), used the combined experiments of physical and numerical simulation (RFPA-DIP version) to conduct three-point-bending (3-p-b) tests with different notches and introduced the acoustic emission monitor system to analyze the fracture mechanism around the notch tips. To study the effects of grain size on the tensile strength and toughness of rock samples, a modified fracture model was established linking fictitious crack to the grain size so that the microstructure of the specimens and fictitious crack growth can be considered together. The fractal method was introduced to represent microstructure of three kinds of granites and used to determine the length of fictitious crack. It is a simple and novel method to calculate the tensile strength and fracture toughness directly. Finally, the theoretical model was verified by the comparison to the numerical experiments by calculating the nominal strength σn and maximum loads Pmax.

  20. Bone tissue heterogeneity is associated with fracture toughness: a polarization Raman spectroscopy study

    NASA Astrophysics Data System (ADS)

    Makowski, Alexander J.; Granke, Mathilde; Uppuganti, Sasidhar; Mahadevan-Jansen, Anita; Nyman, Jeffry S.

    2015-02-01

    Polarization Raman Spectroscopy has been used to demonstrate microstructural features and collagen fiber orientation in human and mouse bone, concurrently measuring both organization and composition; however, it is unclear as to what extent these measurements explain the mechanical quality of bone. In a cohort of age and gender matched cadaveric cortical bone samples (23-101 yr.), we show homogeneity of both composition and structure are associated with the age related decrease in fracture toughness. 64 samples were machined into uniform specimens and notched for mechanical fracture toughness testing and polished for Raman Spectroscopy. Fingerprint region spectra were acquired on wet bone prior to mechanical testing by sampling nine different microstructural features spaced in a 750x750 μm grid in the region of intended crack propagation. After ASTM E1820 single edge notched beam fracture toughness tests, the sample was dried in ethanol and the osteonal-interstitial border of one osteon was samples in a 32x32 grid of 2μm2 pixels for two orthogonal orientations relative to the long bone axis. Standard peak ratios from the 9 separate microstructures show heterogeneity between structures but do not sufficiently explain fracture toughness; however, peak ratios from mapping highlight both lamellar contrast (ν1Phos/Amide I) and osteon-interstitial contrast (ν1Phos/Proline). Combining registered orthogonal maps allowed for multivariate analysis of underlying biochemical signatures. Image entropy and homogeneity metrics of single principal components significantly explain resistance to crack initiation and propagation. Ultimately, a combination of polarization content and multivariate Raman signatures allowed for the association of microstructural tissue heterogeneity with fracture resistance.

  1. Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

    NASA Astrophysics Data System (ADS)

    Baek, Jong-Hyuk; Byun, Thak Sang; Maloy, Start A.; Toloczko, Mychailo B.

    2014-01-01

    The temperature dependence of fracture toughness in HT9 steel irradiated to 3-145 dpa at 380-503 °C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm × 3 mm × 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperature than the irradiation dose. At an irradiation temperature <430 °C, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180-200 MPa √{m} at 350-450 °C, and then decreased with the test temperature. At an irradiation temperature ⩾430 °C, the fracture toughness was nearly unchanged up to about 450 °C and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.

  2. Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

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

    Baek, Jong-Hyuk; Byun, Thak Sang; Maloy, S

    2014-01-01

    The temperature dependence of fracture toughness in HT9 steel irradiated to 3 145 dpa at 380 503 C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm 3mm 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperaturemore » than the irradiation dose. At an irradiation temperature <430 C, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180 200 MPa ffiffiffiffiffi m p at 350 450 C, and then decreased with the test temperature. At an irradiation temperatureP430 C, the fracture toughness was nearly unchanged up to about 450 C and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.« less

  3. Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

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

    Baek, Jong-Hyuk; Byun, Thak Sang; Maloy, Stuart A.

    2014-01-01

    The temperature dependence of fracture toughness in HT9 steel irradiated to 3–145 dpa at 380–503 degrees*C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm *3mm* 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperature than themore » irradiation dose. At an irradiation temperature <430 *degreesC, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180—200 MPa*m^.5 at 350–450 degrees*C, and then decreased with the test temperature. At an irradiation temperature >430 degrees*C, the fracture toughness was nearly unchanged up to about 450 *degreesC and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.« less

  4. Understanding the Interdependencies Between Composition, Microstructure, and Continuum Variables and Their Influence on the Fracture Toughness of α/β-Processed Ti-6Al-4V

    NASA Astrophysics Data System (ADS)

    Collins, P. C.; Koduri, S.; Dixit, V.; Fraser, H. L.

    2018-03-01

    The fracture toughness of a material depends upon the material's composition and microstructure, as well as other material properties operating at the continuum level. The interrelationships between these variables are complex, and thus difficult to interpret, especially in multi-component, multi-phase ductile engineering alloys such as α/β-processed Ti-6Al-4V (nominal composition, wt pct). Neural networks have been used to elucidate how variables such as composition and microstructure influence the fracture toughness directly ( i.e., via a crack initiation or propagation mechanism)—and independent of the influence of the same variables influence on the yield strength and plasticity of the material. The variables included in the models and analysis include (i) alloy composition, specifically, Al, V, O, and Fe; (ii) materials microstructure, including phase fractions and average sizes of key microstructural features; (iii) the yield strength and reduction in area obtained from uniaxial tensile tests; and (iv) an assessment of the degree to which plane strain conditions were satisfied by including a factor related to the plane strain thickness. Once trained, virtual experiments have been conducted which permit the determination of each variable's functional dependency on the resulting fracture toughness. Given that the database includes both K 1 C and K Q values, as well as the in-plane component of the stress state of the crack tip, it is possible to quantitatively assess the effect of sample thickness on K Q and the degree to which the K Q and K 1 C values may vary. These interpretations drawn by comparing multiple neural networks have a significant impact on the general understanding of how the microstructure influences the fracture toughness in ductile materials, as well as an ability to predict the fracture toughness of α/β-processed Ti-6Al-4V.

  5. Recent development in low-constraint fracture toughness testing for structural integrity assessment of pipelines

    NASA Astrophysics Data System (ADS)

    Kang, Jidong; Gianetto, James A.; Tyson, William R.

    2018-03-01

    Fracture toughness measurement is an integral part of structural integrity assessment of pipelines. Traditionally, a single-edge-notched bend (SE(B)) specimen with a deep crack is recommended in many existing pipeline structural integrity assessment procedures. Such a test provides high constraint and therefore conservative fracture toughness results. However, for girth welds in service, defects are usually subjected to primarily tensile loading where the constraint is usually much lower than in the three-point bend case. Moreover, there is increasing use of strain-based design of pipelines that allows applied strains above yield. Low-constraint toughness tests represent more realistic loading conditions for girth weld defects, and the corresponding increased toughness can minimize unnecessary conservatism in assessments. In this review, we present recent developments in low-constraint fracture toughness testing, specifically using single-edgenotched tension specimens, SENT or SE(T). We focus our review on the test procedure development and automation, round-robin test results and some common concerns such as the effect of crack tip, crack size monitoring techniques, and testing at low temperatures. Examples are also given of the integration of fracture toughness data from SE(T) tests into structural integrity assessment.

  6. A simple procedure for synthesizing Charpy impact energy transition curves from limited test data

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

    Rosenfeld, M.J.

    1996-12-31

    The importance of Charpy V-notch testing of pipe has been well established in the pipeline industry. Until now, it has been necessary to perform a number of tests in order to develop the toughness transition curve. A method is described which makes possible forecasting the full-scale toughness transition from a single subsize test datum to an acceptable degree of accuracy. This is potentially useful where historical test results or material samples available for testing are limited in quantity. Worked examples illustrating the use of the relationships are given.

  7. Tough and Water-Insensitive Self-Healing Elastomer for Robust Electronic Skin.

    PubMed

    Kang, Jiheong; Son, Donghee; Wang, Ging-Ji Nathan; Liu, Yuxin; Lopez, Jeffrey; Kim, Yeongin; Oh, Jin Young; Katsumata, Toru; Mun, Jaewan; Lee, Yeongjun; Jin, Lihua; Tok, Jeffrey B-H; Bao, Zhenan

    2018-03-01

    An electronic (e-) skin is expected to experience significant wear and tear over time. Therefore, self-healing stretchable materials that are simultaneously soft and with high fracture energy, that is high tolerance of damage or small cracks without propagating, are essential requirements for the realization of robust e-skin. However, previously reported elastomers and especially self-healing polymers are mostly viscoelastic and lack high mechanical toughness. Here, a new class of polymeric material crosslinked through rationally designed multistrength hydrogen bonding interactions is reported. The resultant supramolecular network in polymer film realizes exceptional mechanical properties such as notch-insensitive high stretchability (1200%), high toughness of 12 000 J m -2 , and autonomous self-healing even in artificial sweat. The tough self-healing materials enable the wafer-scale fabrication of robust and stretchable self-healing e-skin devices, which will provide new directions for future soft robotics and skin prosthetics. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. The Assessment and Validation of Mini-Compact Tension Test Specimen Geometry and Progress in Establishing Technique for Fracture Toughness Master Curves for Reactor Pressure Vessel Steels

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

    Sokolov, Mikhail A.; Nanstad, Randy K.

    Small specimens are playing the key role in evaluating properties of irradiated materials. The use of small specimens provides several advantages. Typically, only a small volume of material can be irradiated in a reactor at desirable conditions in terms of temperature, neutron flux, and neutron dose. A small volume of irradiated material may also allow for easier handling of specimens. Smaller specimens reduce the amount of radioactive material, minimizing personnel exposures and waste disposal. However, use of small specimens imposes a variety of challenges as well. These challenges are associated with proper accounting for size effects and transferability of smallmore » specimen data to the real structures of interest. Any fracture toughness specimen that can be made out of the broken halves of standard Charpy specimens may have exceptional utility for evaluation of reactor pressure vessels (RPVs) since it would allow one to determine and monitor directly actual fracture toughness instead of requiring indirect predictions using correlations established with impact data. The Charpy V-notch specimen is the most commonly used specimen geometry in surveillance programs. Assessment and validation of mini-CT specimen geometry has been performed on previously well characterized HSST Plate 13B, an A533B class 1 steel. It was shown that the fracture toughness transition temperature measured by these Mini-CT specimens is within the range of To values that were derived from various large fracture toughness specimens. Moreover, the scatter of the fracture toughness values measured by Mini-CT specimens perfectly follows the Weibull distribution function providing additional proof for validation of this geometry for the Master Curve evaluation of rector pressure vessel steels. Moreover, the International collaborative program has been developed to extend the assessment and validation efforts to irradiated weld metal. The program is underway and involves ORNL, CRIEPI, and

  9. Improvement of Strength-Toughness-Hardness Balance in Large Cross-Section 718H Pre-Hardened Mold Steel

    PubMed Central

    Liu, Hanghang; Fu, Paixian; Liu, Hongwei; Li, Dianzhong

    2018-01-01

    The strength-toughness combination and hardness uniformity in large cross-section 718H pre-hardened mold steel from a 20 ton ingot were investigated with three different heat treatments for industrial applications. The different microstructures, including tempered martensite, lower bainite, and retained austenite, were obtained at equivalent hardness. The microstructures were characterized by using metallographic observations, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and electron back-scattered diffraction (EBSD). The mechanical properties were compared by tensile, Charpy U-notch impact and hardness uniformity tests at room temperature. The results showed that the test steels after normalizing-quenching-tempering (N-QT) possessed the best strength-toughness combination and hardness uniformity compared with the conventional quenched-tempered (QT) steel. In addition, the test steel after austempering-tempering (A-T) demonstrated the worse hardness uniformity and lower yield strength while possessing relatively higher elongation (17%) compared with the samples after N-QT (14.5%) treatments. The better ductility of A-T steel mainly depended on the amount and morphology of retained austenite and thermal/deformation-induced twined martensite. This work elucidates the mechanisms of microstructure evolution during heat treatments and will highly improve the strength-toughness-hardness trade-off in large cross-section steels. PMID:29642642

  10. Investigation of Microstructural Features Determining the Toughness of 980 MPa Bainitic Weld Metal

    NASA Astrophysics Data System (ADS)

    Cao, R.; Zhang, X. B.; Wang, Z.; Peng, Y.; Du, W. S.; Tian, Z. L.; Chen, J. H.

    2014-02-01

    The microstructural features that control the impact toughness of weld metals of a 980 MPa 8 pct Ni high-strength steel are investigated using instrumented Charpy V tester, optical microscope (OM), scanning electron microscope (SEM), transmission electron microscope (TEM), electron back-scattered diffraction (EBSD), and finite-element method (FEM) calculation. The results show that the critical event for cleavage fracture in this high-strength steel and weld metals is the propagation of a bainite packet-sized crack across the packet boundary into contiguous packets, and the bainitic packet sizes control the impact toughness. The high-angle misorientation boundaries detected in a bainite packet by EBSD form fine tear ridges on fracture surfaces. However, they are not the decisive factors controlling the cleavage fracture. The effects of Ni content are essential factors for improving the toughness. The extra large cleavage facets seriously deteriorate the toughness, which are formed on the interfaces of large columnar crystals growing in welding pools with high heat input.

  11. Notch signaling in lung diseases: focus on Notch1 and Notch3

    PubMed Central

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

    2016-01-01

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

  12. Mechanical properties and fracture toughness of rail steels and thermite welds at low temperature

    NASA Astrophysics Data System (ADS)

    Wang, Yuan-qing; Zhou, Hui; Shi, Yong-jiu; Feng, Bao-rui

    2012-05-01

    Brittle fracture occurs frequently in rails and thermite welded joints, which intimidates the security and reliability of railway service. Railways in cold regions, such as Qinghai-Tibet Railway, make the problem of brittle fracture in rails even worse. A series of tests such as uniaxial tensile tests, Charpy impact tests, and three-point bending tests were carried out at low temperature to investigate the mechanical properties and fracture toughness of U71Mn and U75V rail steels and their thermite welds. Fracture micromechanisms were analyzed by scanning electron microscopy (SEM) on the fracture surfaces of the tested specimens. The ductility indices (percentage elongation after fracture and percentage reduction of area) and the toughness indices (Charpy impact energy A k and plane-strain fracture toughness K IC) of the two kinds of rail steels and the corresponding thermite welds all decrease as the temperature decreases. The thermite welds are more critical to fracture than the rail steel base metals, as indicated by a higher yield-to-ultimate ratio and a much lower Charpy impact energy. U71Mn rail steel is relatively higher in toughness than U75V, as demonstrated by larger A k and K IC values. Therefore, U71Mn rail steel and the corresponding thermite weld are recommended in railway construction and maintenance in cold regions.

  13. Calculation for tensile strength and fracture toughness of granite with three kinds of grain sizes using three-point-bending test

    PubMed Central

    Yu, Miao; Wei, Chenhui; Niu, Leilei; Li, Shaohua; Yu, Yongjun

    2018-01-01

    Tensile strength and fracture toughness, important parameters of the rock for engineering applications are difficult to measure. Thus this paper selected three kinds of granite samples (grain sizes = 1.01mm, 2.12mm and 3mm), used the combined experiments of physical and numerical simulation (RFPA-DIP version) to conduct three-point-bending (3-p-b) tests with different notches and introduced the acoustic emission monitor system to analyze the fracture mechanism around the notch tips. To study the effects of grain size on the tensile strength and toughness of rock samples, a modified fracture model was established linking fictitious crack to the grain size so that the microstructure of the specimens and fictitious crack growth can be considered together. The fractal method was introduced to represent microstructure of three kinds of granites and used to determine the length of fictitious crack. It is a simple and novel method to calculate the tensile strength and fracture toughness directly. Finally, the theoretical model was verified by the comparison to the numerical experiments by calculating the nominal strength σn and maximum loads Pmax. PMID:29596422

  14. Advanced Nanocrystalline Ceramic Matrix Composites with Improved Toughness

    DTIC Science & Technology

    2009-01-09

    Based Nanocomposites," Dongtao Jiang and Amiya Mukherjee, Scripta Materialia, 58, pp. 991-993, 2008. 7) "In Situ Boron Carbide- Titanium Diboride...specimen and polished to 1 µm finish. The single edge V-notched beam (SEVNB) samples were first notched using a 0.5-mm diamond saw blade to a depth of...600 µm and the final notches were created by hand using a razor blade and1-µm diamond paste. An optical microscope was used to measure the notch

  15. Impact resistance and interlaminar fracture toughness of through-the-thickness reinforced graphite/epoxy

    NASA Technical Reports Server (NTRS)

    Dexter, H. B.; Funk, J. G.

    1986-01-01

    Five through-the-thickness stitch configurations are analyzed to determine the effect of impact resistance and interlaminar fracture toughness on T3000/3501-6 graphite/epoxy. The test specimens were stitched with either polyester or Kevlar yarns and with various stitch parameters. Tension and compression mechanical, impact and compression-after-impact, and double cantilever beam tests were conducted. It is observed that the stitched laminates have tension and compression strengths 20-25 percent lower than the strengths of unstitched laminates, the tension strength of stitched laminates is reduced with increasing number of stitches, and the compression strength increases as the number of stitches are increased. The impact data reveal that the Kevlar stitched laminates have less damage than unstitched laminates; the most effective configuration for suppressing impact damage and improving interlaminar fracture toughness consists of Kevlar yarns 1/4 inch apart with eight stitches per inch. The mode 1 critical strain energy release rate for the 1/4 inch Kevlar eight stitch laminate was calculated as 30 times higher than that of the unstitched.

  16. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells

    PubMed Central

    Domenga, Valérie; Fardoux, Peggy; Lacombe, Pierre; Monet, Marie; Maciazek, Jacqueline; Krebs, Luke T.; Klonjkowski, Bernard; Berrou, Eliane; Mericskay, Matthias; Li, Zhen; Tournier-Lasserve, Elisabeth; Gridley, Thomas; Joutel, Anne

    2004-01-01

    Formation of a fully functional artery proceeds through a multistep process. Here we show that Notch3 is required to generate functional arteries in mice by regulating arterial differentiation and maturation of vascular smooth muscle cells (vSMC). In adult Notch3–/– mice distal arteries exhibit structural defects and arterial myogenic responses are defective. The postnatal maturation stage of vSMC is deficient in Notch3–/– mice. We further show that Notch3 is required for arterial specification of vSMC but not of endothelial cells. Our data reveal Notch3 to be the first cell-autonomous regulator of arterial differentiation and maturation of vSMC. PMID:15545631

  17. The development of in situ fracture toughness evaluation techniques in hydrogen environment

    DOE PAGES

    Wang, John Jy-An; Ren, Fei; Tan, Tin; ...

    2014-12-19

    Reliability of hydrogen pipelines and storage tanks is significantly influenced by the mechanical performance of the structural materials exposed in the hydrogen environment. Fracture behavior and fracture toughness are of specific interest since they are relevant to many catastrophic failures. However, many conventional fracture testing techniques are difficult to be realized under the presence of hydrogen. Thus it is desired to develop novel in situ techniques to study the fracture behavior of structural materials in hydrogen environments. In this study, special testing apparatus were designed to facilitate in situ fracture testing in H 2. A torsional fixture was developed tomore » utilize an emerging fracture testing technique, Spiral Notch Torsion Test (SNTT). The design concepts will be discussed. Preliminary in situ testing results indicated that the exposure to H 2 significantly reduces the fracture toughness of 4340 high strength steels by up to 50 percent. Furthermore, SNTT tests conducted in air demonstrated a significant fracture toughness reduction in samples subject to simulated welding heat treatment using Gleeble, which illustrated the effect of welding on the fracture toughness of this material.« less

  18. 46 CFR 54.05-20 - Impact test properties for service of 0 °F and below.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    .... See § 54.05-5(c) for retest requirements. Table 54.05-20(a)—Charpy v-notch impact requirements Size of... permitted. (b) Transversely oriented Charpy V-notch impact specimens of ASTM A 203 (incorporated by... correlation with drop-weight tests, Charpy V-notch tests may be specially considered by the Commandant in lieu...

  19. The weak interfaces within tough natural composites: experiments on three types of nacre.

    PubMed

    Khayer Dastjerdi, Ahmad; Rabiei, Reza; Barthelat, Francois

    2013-03-01

    Mineralization is a typical strategy used in natural materials to achieve high stiffness and hardness for structural functions such as skeletal support, protection or predation. High mineral content generally leads to brittleness, yet natural materials such as bone, mollusk shells or glass sponge achieve relatively high toughness considering the weakness of their constituents through intricate microstructures. In particular, nanometers thick organic interfaces organized in micro-architectures play a key role in providing toughness by various processes including crack deflection, crack bridging or energy dissipation. While these interfaces are critical in these materials, their composition, structure and mechanics is often poorly understood. In this work we focus on nacre, one of the most impressive hard biological materials in terms of toughness. We performed interfacial fracture tests on chevron notched nacre samples from three different species: red abalone, top shell and pearl oyster. We found that the intrinsic toughness of the interfaces is indeed found to be extremely low, in the order of the toughness of the mineral inclusions themselves. Such low toughness is required for the cracks to follow the interfaces, and to deflect and circumvent the mineral tablets. This result highlights the efficacy of toughening mechanisms in natural materials, turning low-toughness inclusions and interfaces into high-performance composites. We found that top shell nacre displayed the highest interfacial toughness, because of higher surface roughness and a more resilient organic material, and also through extrinsic toughening mechanisms including crack deflection, crack bridging and process zone. In the context of biomimetics, the main implication of this finding is that the interface in nacre-like composite does not need to be tough; the extensibility or ductility of the interfaces may be more important than their strength and toughness to produce toughness at the macroscale

  20. Plane elasto-plastic analysis of v-notched plate under bending by boundary integral equation method. Ph.D. Thesis

    NASA Technical Reports Server (NTRS)

    Rzasnicki, W.

    1973-01-01

    A method of solution is presented, which, when applied to the elasto-plastic analysis of plates having a v-notch on one edge and subjected to pure bending, will produce stress and strain fields in much greater detail than presently available. Application of the boundary integral equation method results in two coupled Fredholm-type integral equations, subject to prescribed boundary conditions. These equations are replaced by a system of simultaneous algebraic equations and solved by a successive approximation method employing Prandtl-Reuss incremental plasticity relations. The method is first applied to number of elasto-static problems and the results compared with available solutions. Good agreement is obtained in all cases. The elasto-plastic analysis provides detailed stress and strain distributions for several cases of plates with various notch angles and notch depths. A strain hardening material is assumed and both plane strain and plane stress conditions are considered.

  1. A modified split Hopkinson pressure bar for toughness tests

    NASA Astrophysics Data System (ADS)

    Granier, N.; Grunenwald, T.

    2006-08-01

    In order to characterize material toughness or to study crack arrest under dynamic loading conditions, a new testing device has been developed at CEA/Valduc. A new Split Hopkinson Pressure Bar (SHPB) has been modified: it is now composed of a single incident bar and a double transmitter bar. With this facility, a notched specimen can be loaded under three points bending conditions. Qualification tests with titanium and steel notched samples are presented. Data treatment software has been adapted to estimate the sample deflection as a function of time and treat the energy balance. These results are compared with classical Charpy experiments. Effect of various contact areas between specimen and bars are studied to point out their influence on obtained measurements. The advantage of a “knife” contact compared to a plane one is then clearly demonstrated. All results obtained with this new testing device are in good agreement and show a reduced scattering.

  2. Stress Intensity Factors of Semi-Circular Bend Specimens with Straight-Through and Chevron Notches

    NASA Astrophysics Data System (ADS)

    Ayatollahi, M. R.; Mahdavi, E.; Alborzi, M. J.; Obara, Y.

    2016-04-01

    Semi-circular bend specimen is one of the useful test specimens for determining fracture toughness of rock and geo-materials. Generally, in rock test specimens, initial cracks are produced in two shapes: straight-edge cracks and chevron notches. In this study, the minimum dimensionless stress intensity factors of semi-circular bend specimen (SCB) with straight-through and chevron notches are calculated. First, using finite element analysis, a suitable relation for the dimensionless stress intensity factor of SCB with straight-through crack is presented based on the normalized crack length and half-distance between supports. For evaluating the validity and accuracy of this relation, the obtained results are then compared with numerical and experimental results reported in the literature. Subsequently, by performing some experiments and also finite element analysis of the SCB specimen with chevron notch, the minimum dimensionless stress intensity factor of this specimen is obtained. Using the new equation for the dimensionless stress intensity factor of SCB with straight-through crack and an analytical method, i.e., Bluhm's slice synthesis method, the minimum (critical) dimensionless stress intensity factor of chevron notched semi-circular bend specimens is calculated. Good agreement is observed between the results of two mentioned methods.

  3. Characteristic of retained austenite decomposition during tempering and its effect on impact toughness in SA508 Gr.3 steel

    NASA Astrophysics Data System (ADS)

    Yan, Guanghua; Han, Lizhan; Li, Chuanwei; Luo, Xiaomeng; Gu, Jianfeng

    2017-01-01

    Retained austenite(RA) usually presents in the quenched Nuclear Pressure-Vessel SA508 Gr.3 steel. In the present work, the characteristic of RA decomposition and its effect on the impact toughness were investigated by microstructure observation, dilatometric experiments and Charpy impact tests. The results show that the RA transformed into martensite and bainite during tempering at 230 °C and 400 °C respectively, while mixture of long rod carbides and ferrite formed at 650 °C. The long rod carbides formed from RA decomposition decrease the critical cleavage stress for initiation of micro-cracks, and deteriorate the impact toughness of the steel. Pre-tempering at a low temperature such as 230 °C or 400 °C leading to the decomposition of RA into martensite or baintie can eliminate the deterioration of the toughness caused by direct decomposition into long rod carbides. The absorbed energy indicate that pre-tempering at 400 °C can drive dramatically improvement in the toughness of the steel.

  4. Determination of fracture toughness of calcium phosphate coatings deposited onto Ti6Al4V substrate by using indentation technique

    NASA Astrophysics Data System (ADS)

    Aydin, Ibrahim; Cetinel, Hakan; Pasinli, Ahmet

    2012-09-01

    In this study, fracture toughness values of calcium phosphate (CaP) coatings deposited onto Ti6Al4V substrate were determined by using Vickers indentation method. In this new patent holding method, the activation processes were performed with NaOH and NaOH+H2O2 on the Ti6Al4V material surface. Thicknesses of CaP coatings were measured from cross-sections of the samples by using optical microscopy. Vickers indentation tests were performed by using microhardness tester. Young's modulus values of the coatings were determined by using ultra microhardness tester. As a result, fracture toughness (K1C) values of the CaP coatings produced by using two different activation processes, were calculated by using experimental study results. These were found to be 0.43 MPa m1/2 and 0.39 MPa m1/2, respectively. It was determined that the CaP coating on Ti6Al4V activated by NaOH+H2O2 had higher fracture toughness than the CaP coating on Ti6Al4V activated by NaOH.

  5. Investigation of Acoustic Emission during Fracture Toughness Testing of Chevron-Notched Specimens.

    DTIC Science & Technology

    1984-03-01

    chevron-notched specimlens was employed to investigate crack growth in four steels )rel)ared by electroslag-remelt casting. 15-5PH, AISI 4140 , D6AC, and...this investigation: 15-SPH, AISI 4140 , D6AC and AISI 440C. The composition of each steel is given in Table 1. Castings were prepared by electro- slag...well defined, it appears that the AISI 4140 (Figure 2b) and the D6AC (Figure 2c) failed primarily by cleavage also. The fracture illustrated in Figure

  6. Evaluation of fracture toughness of human dentin using elastic-plastic fracture mechanics.

    PubMed

    Yan, Jiahau; Taskonak, Burak; Platt, Jeffrey A; Mecholsky, John J

    2008-01-01

    Dentin, the mineralized tissue forming the bulk of the tooth, lies between the enamel and the pulp chamber. It is a rich source of inspiration for designing novel synthetic materials due to its unique microstructure. Most of the previous studies investigating the fracture toughness of dentin have used linear-elastic fracture mechanics (LEFM) that ignores plastic deformation and could underestimate the toughness of dentin. With the presence of collagen (approximately 30% by volume) aiding the toughening mechanisms in dentin, we hypothesize that there is a significant difference between the fracture toughness estimated using LEFM (Kc) and elastic-plastic fracture mechanics (EPFM) (KJc). Single-edge notched beam specimens with in-plane (n=10) and anti-plane (n=10) parallel fractures were prepared following ASTM standard E1820 and tested in three-point flexure. KJc of the in-plane parallel and anti-plane parallel specimens were found to be 3.1 and 3.4 MPa m 1/2 and Kc were 2.4 and 2.5 MPa m 1/2, respectively. The fracture toughness estimated based on KJc is significantly greater than that estimated based on Kc (32.5% on average; p<0.001). In addition, KJc of anti-plane parallel specimens is significantly greater than that of in-plane parallel specimens. We suggest that, in order to critically evaluate the fracture toughness of human dentin, EPFM should be employed.

  7. NOTCH signalinio kelio ir ginekologinių piktybinių navikų sąsaja

    PubMed Central

    Lachej, Nadežda; Dabkevičienė, Daiva; Sasnauskienė, Aušra; Trimonytė, Rūta Marija; Kanopienė, Daiva; Kazbarienė, Birutė; Didžiapetrienė, Janina

    2017-01-01

    Įvadas. Organizmo ląstelėse vykstančius procesus kontroliuoja įvairūs signaliniai keliai. Vienas iš jų yra NOTCH signalinis kelias. Nustatyta, kad dalinis NOTCH funkcijos praradimas arba nenormalus NOTCH signalo aktyvinimas susijęs su įvairiais žmogaus vystymosi sutrikimais ir ligomis. Medžiaga ir metodika. Pagrindinis informacijos šaltinis ieškant duomenų – PubMed duomenų bazė. Rezultatai. Straipsnyje nagrinėjama onkologinių ligų bei NOTCH signalinio kelio dalyvių sąsaja. NOTCH signalas, vystantis vėžiui, gali veikti dvejopai: kaip onkogenas ir kaip naviko augimo slopiklis. Tikslus tokio poveikio mechanizmas dar nėra žinomas. NOTCH signalinio kelio tyrimai svarbūs siekiant atrasti naujus vėžio gydymo būdus, farmakologiniais ir genetiniais metodais valdant NOTCH signalinį kelią. Šioje apžvalgoje daugiausia dėmesio skiriama ginekologiniams piktybiniams navikams, ypač gimdos kūno vėžiui. Išvados. Pastarųjų metų mokslinių tyrimų duomenys rodo, kad NOTCH signalinis kelias yra neabejotinai svarbus formuojantis gimdos kūno vėžiui, todėl jo komponentai gali būti potencialūs prognoziniai biožymenys ir molekuliniai terapiniai taikiniai. Siekiant patikslinti NOTCH signalinio kelio dalyvių reikšmę bei jų sąveiką su kitų signalinių kelių dalyviais, kurie taip pat gali būti svarbūs formuojantis ir progresuojant gimdos kūno vėžiui, reikalingi tolesni šios srities moksliniai tyrimai. PMID:28630591

  8. Effect of Heat Treatment Technique on the Low Temperature Impact Toughness of Steel EQ70 for Offshore Structure

    NASA Astrophysics Data System (ADS)

    Tao, Su-Fen; Xia, Yun-Jin; Wang, Fu-Ming; Li, Jie; Fan, Ding-Dong

    2017-09-01

    Circle quenching and tempering (CQ&T), intercritical quenching and tempering (IQ&T) and regular quenching and tempering (Q&T) were used to study the influence of heat treatment techniques on the low temperature impact toughness of steel EQ70 for offshore structure. The steels with 2.10 wt. % Ni (steel A) and 1.47 wt. % Ni (steel B) were chosen to analyze the effect of Ni content on the low temperature impact toughness of steel EQ70 for offshore structure. The fracture morphologies were examined by using a scanning electron microscope (SEM, JSM-6480LV), and microstructures etched by 4 vol. % nitric acid were observed on a type 9XB-PC optical microscope. The results show that the impact toughness of steel A is higher than that of steel B at the same test temperature and heat treatment technique. For steel B, the energy absorbed is, in descending order, CQ&T, Q&T and IQ&T, while for steel A, that is CQ&T, IQ&T and Q&T. The effects of heat treatment on the low temperature impact toughness are different for steels A and B, the absorbed energy changes more obviously for steel A. The results can be significant references for actual heat treatment techniques in steel plant.

  9. Fracture Behavior of Zr-BASED Bulk Metallic Glass Under Impact Loading

    NASA Astrophysics Data System (ADS)

    Shin, Hyung-Seop; Kim, Ki-Hyun; Oh, Sang-Yeob

    The fracture behavior of a Zr-based bulk amorphous metal under impact loading using subsize V-shaped Charpy specimens was investigated. Influences of loading rate on the fracture behavior of amorphous Zr-Al-Ni-Cu alloy were examined. As a result, the maximum load and absorbed fracture energy under impact loading were lower than those under quasi-static loading. A large part of the absorbed fracture energy in the Zr-based BMG was consumed in the process for crack initiation and not for crack propagation. In addition, fractographic characteristics of BMGs, especially the initiation and development of shear bands at the notch tip were investigated. Fractured surfaces under impact loading are smoother than those under quasi-static loading. The absorbed fracture energy appeared differently depending on the appearance of the shear bands developed. It can be found that the fracture energy and fracture toughness of Zr-based BMG are closely related with the extent of shear bands developed during fracture.

  10. The shear fracture toughness, KIIc, of graphite

    DOE PAGES

    Burchell, Timothy D.; Erdman, III, Donald L.

    2015-11-05

    In this study, the critical shear stress intensity factor, KIIc, here-in referred to as the shear fracture toughness, KIIc (MPa m), of two grades of graphite are reported. The range of specimen volumes was selected to elucidate any specimen size effect, but smaller volume specimen tests were largely unsuccessful, shear failure did not occur between the notches as expected. This was probably due to the specimen geometry causing the shear fracture stress to exceed the compressive failure stress. In subsequent testing the specimen geometry was altered to reduce the compressive footprint and the notches (slits) made deeper to reduce themore » specimen's ligament length. Additionally, we added the collection of Acoustic Emission (AE) during testing to assist with the identification of the shear fracture load. The means of KIIc from large specimens for PCEA and NBG-18 are 2.26 MPa m with an SD of 0.37 MPa m and 2.20 MPa m with an SD of 0.53 MPa m, respectively. The value of KIIc for both graphite grades was similar, although the scatter was large. In this work we found the ratio of KIIc/ KIc ≈ 1.6. .« less

  11. TOUGH+HYDRATE v1.2 User's Manual: A Code for the Simulation of System Behavior in Hydrate-Bearing Geologic Media

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

    Moridis, George J.; Kowalsky, Michael B.; Pruess, Karsten

    TOUGH+HYDRATE v1.2 is a code for the simulation of the behavior of hydratebearing geologic systems, and represents the second update of the code since its first release [Moridis et al., 2008]. By solving the coupled equations of mass and heat balance, TOUGH+HYDRATE can model the non-isothermal gas release, phase behavior and flow of fluids and heat under conditions typical of common natural CH4-hydrate deposits (i.e., in the permafrost and in deep ocean sediments) in complex geological media at any scale (from laboratory to reservoir) at which Darcy’s law is valid. TOUGH+HYDRATE v1.2 includes both an equilibrium and a kinetic modelmore » of hydrate formation and dissociation. The model accounts for heat and up to four mass components, i.e., water, CH4, hydrate, and water-soluble inhibitors such as salts or alcohols. These are partitioned among four possible phases (gas phase, liquid phase, ice phase and hydrate phase). Hydrate dissociation or formation, phase changes and the corresponding thermal effects are fully described, as are the effects of inhibitors. The model can describe all possible hydrate dissociation mechanisms, i.e., depressurization, thermal stimulation, salting-out effects and inhibitor-induced effects. TOUGH+HYDRATE is a member of TOUGH+, the successor to the TOUGH2 [Pruess et al., 1991] family of codes for multi-component, multiphase fluid and heat flow developed at the Lawrence Berkeley National Laboratory. It is written in standard FORTRAN 95/2003, and can be run on any computational platform (workstation, PC, Macintosh) for which such compilers are available.« less

  12. Effect of decreased hot-rolling reduction treatment on fracture toughness of low-alloy structural steels

    NASA Astrophysics Data System (ADS)

    Tomita, Yoshiyuki

    1990-09-01

    Commercial low-alloy structural steels, 0.45 pct C (AISI 1045 grade), 0.40 pct C-Cr-Mo (AISI 4140 grade), and 0.40 pct C-Ni-Cr-Mo (AISI 4340 grade), have been studied to determine the effect of the decreased hot-rolling reduction treatment (DHRRT) from 98 to 80 pct on fracture toughness of quenched and highly tempered low-alloy structural steels. The significant conclusions are as follows: (1) the sulfide inclusions were modified through the DHRRT from a stringer (mean aspect ratio: 16.5 to 17.6) to an ellipse (mean aspect ratio: 3.8 to 4.5), independent of the steels studied; (2) the DHRRT significantly improved J Ic in the long-transverse and shorttransverse orientations, independent of the steels studied; and (3) the shelf energy in the Charpy V-notch impact test is also greatly improved by the DHRRT, independent of testing orientation and steels studied; however, (4) the ductile-to-brittle transition temperature was only slightly affected by the DHRRT. The beneficial effect on the J Ic is briefly discussed in terms of a crack extension model involving the formation of voids at the inclusion sites and their growth and eventual linking up through the rupture of the intervening ligaments by local shear.

  13. A novel algorithm for notch detection

    NASA Astrophysics Data System (ADS)

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

    2013-06-01

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

  14. Effect of Heat Treatment on Microstructure and Hot Impact Toughness of Various Zones of P91 Welded Pipes

    NASA Astrophysics Data System (ADS)

    Pandey, C.; Mahapatra, M. M.

    2016-06-01

    The new generation super critical thermal power plants are required to operate at enhanced thermal efficiency of over 50% to reduce the fuel consumption and environmental pollution. Creep strength-enhanced ferritic steels, commonly known as Cr-Mo alloys such as P91 (X10CrMoVNb 9-1) are such material of choice for the next generation power plants. The operating requirement of these next generation power plants is that steam temperature of around 650 °C is maintained. For such high-temperature application, creep strength of material is the primary consideration together with adequate weld heat-affected zone (HAZ) toughness. Present work deals with the effect of high service temperature on impact toughness of P91 (X10CrMoVNb 9-1) base material, weld fusion zone, and HAZ. The impact toughness of HAZ for conventional weld groove design and narrow weld groove design has been evaluated experimentally in as-welded and at different post-weld heat treatment conditions. Fractography of the impact toughness specimens of base metal, weld fusion zone, and HAZ was carried out using scanning electron microscope. The effects of heat treatment schemes on the percentage of element present at the fracture surface were also studied.

  15. Metallurgical Examination of Failed T-158 Cast Austempered Ductile Iron (CADI) Track Shoes

    DTIC Science & Technology

    1994-06-01

    hardness testing, fracture toughness testing and Charpy impact testing were performed. In each case, the largest possible specimens were fabricated...However, due to geometrical restrictions, the tensile, fracture toughness and impact specimens were subsized . Tensile Testing Tensile coupons were...at 5OOoF for 4 hours. Mag. 1000x. 36 ‘_ Fracture Face A bolt holes Fracture Face C T = Tensile FT = Fracture Toughness NC =Notched Charpy Impact UN

  16. Regulation of pancreatic stellate cell activation by Notch3.

    PubMed

    Song, Haiyan; Zhang, Yuxiang

    2018-01-05

    Activated pancreatic stellate cells (PaSCs) are the key cellular source of cancer-associated fibroblasts in the pancreatic stroma of patients with pancreatic ductal adenocarcinoma (PDAC), however, the activation mechanism of PaSCs is not yet known. The Notch signaling pathway, components of which are expressed in stromal cells, is involved in the fibrosis of several organs, including the lung and liver. In the current study, we investigated whether Notch signal transduction is involved in PaSC activation in PDAC. The expression of Notch signaling pathway components in human PDAC was examined via immunohistochemical staining and assessed in mouse PaSCs using RT-qPCR and western blotting. Notch3 expression in both PDAC stromal cells and activated mouse PaSCs was evaluated using immunofluorescence, RT-qPCR and western blotting. The impact of siRNA-mediated Notch3 knockdown on PaSC activation was detected with RT-qPCR and western blotting, and the impact on PaSC proliferation and migration was detected using CCK-8 assays and scratch experiments. The effect of conditioned medium from PaSCs activated with Notch3 siRNA on pancreatic cancer (LTPA) cells was also detected with CCK-8 assays and scratch experiments. The data were analyzed for statistical significance using Student's t-test. Notch3 was overexpressed in both human PDAC stromal cells and activated mouse PaSCs, and Notch3 knockdown with Notch3 siRNA decreased the proliferation and migration of mouse PaSCs. The levels of markers related to PaSC activation, such as α-smooth muscle actin (α-SMA), collagen I and fibronectin, decreased in response to Notch3 knockdown, indicating that Notch3 plays an important role in PaSC activation. Furthermore, we confirmed that inhibition of PaSC activation via Notch3 siRNA reduced the proliferation and migration of PaSC-induced mouse pancreatic cancer (LTPA) cells. Notch3 inhibition in PaSCs can inhibit the activation, proliferation and migration of PaSCs and reduce the Pa

  17. Development of Mini-Compact Tension Test Method for Determining Fracture Toughness Master Curves for Reactor Pressure Vessel Steels

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

    Sokolov, Mikhail A.

    Small specimens are playing the key role in evaluating properties of irradiated materials. The use of small specimens provides several advantages. Typically, only a small volume of material can be irradiated in a reactor at desirable conditions in terms of temperature, neutron flux, and neutron dose. A small volume of irradiated material may also allow for easier handling of specimens. Smaller specimens reduce the amount of radioactive material, minimizing personnel exposures and waste disposal. However, use of small specimens imposes a variety of challenges as well. These challenges are associated with proper accounting for size effects and transferability of smallmore » specimen data to the real structures of interest. Any fracture toughness specimen that can be made out of the broken halves of standard Charpy specimens may have exceptional utility for evaluation of reactor pressure vessels (RPVs) since it would allow one to determine and monitor directly actual fracture toughness instead of requiring indirect predictions using correlations established with impact data. The Charpy V-notch specimen is the most commonly used specimen geometry in surveillance programs. Validation of the mini compact tension specimen (mini-CT) geometry has been performed on previously well characterized Midland beltline Linde 80 (WF-70) weld in the unirradiated condition. It was shown that the fracture toughness transition temperature, To, measured by these Mini-CT specimens is almost the same as To value that was derived from various larger fracture toughness specimens. Moreover, an International collaborative program has been established to extend the assessment and validation efforts to irradiated Linde 80 weld metal. The program is underway and involves the Oak Ridge National Laboratory (ORNL), Central Research Institute for Electrical Power Industry (CRIEPI), and Electric Power Research Institute (EPRI). The irradiated Mini-CT specimens from broken halves of previously tested

  18. Dynamic Fracture Properties of Rocks Subjected to Static Pre-load Using Notched Semi-circular Bend Method

    NASA Astrophysics Data System (ADS)

    Chen, Rong; Li, Kang; Xia, Kaiwen; Lin, Yuliang; Yao, Wei; Lu, Fangyun

    2016-10-01

    A dynamic load superposed on a static pre-load is a key problem in deep underground rock engineering projects. Based on a modified split Hopkinson pressure bar test system, the notched semi-circular bend (NSCB) method is selected to investigate the fracture initiation toughness of rocks subjected to pre-load. In this study, a two-dimensional ANSYS finite element simulation model is developed to calculate the dimensionless stress intensity factor. Three groups of NSCB specimen are tested under a pre-load of 0, 37 and 74 % of the maximum static load and with the loading rate ranging from 0 to 60 GPa m1/2 s-1. The results show that under a given pre-load, the fracture initiation toughness of rock increases with the loading rate, resembling the typical rate dependence of materials. Furthermore, the dynamic rock fracture toughness decreases with the static pre-load at a given loading rate. The total fracture toughness, defined as the sum of the dynamic fracture toughness and initial stress intensity factor calculated from the pre-load, increases with the pre-load at a given loading rate. An empirical equation is used to represent the effect of loading rate and pre-load force, and the results show that this equation can depict the trend of the experimental data.

  19. Tough Composite Materials

    NASA Technical Reports Server (NTRS)

    Vosteen, L. F. (Compiler); Johnson, N. J. (Compiler); Teichman, L. A. (Compiler)

    1984-01-01

    Papers and working group summaries are presented which address composite material behavior and performance improvement. Topic areas include composite fracture toughness and impact characterization, constituent properties and interrelationships, and matrix synthesis and characterization.

  20. Effect of Control Mode and Test Rate on the Measured Fracture Toughness of Advanced Ceramics

    NASA Technical Reports Server (NTRS)

    Hausmann, Bronson D.; Salem, Jonathan A.

    2018-01-01

    The effects of control mode and test rate on the measured fracture toughness of ceramics were evaluated by using chevron-notched flexure specimens in accordance with ASTM C1421. The use of stroke control gave consistent results with about 2% (statistically insignificant) variation in measured fracture toughness for a very wide range of rates (0.005 to 0.5 mm/min). Use of strain or crack mouth opening displacement (CMOD) control gave approx. 5% (statistically significant) variation over a very wide range of rates (1 to 80 µm/m/s), with the measurements being a function of rate. However, the rate effect was eliminated by use of dry nitrogen, implying a stress corrosion effect rather than a stability effect. With the use of a nitrogen environment during strain controlled tests, fracture toughness values were within about 1% over a wide range of rates (1 to 80 micons/m/s). CMOD or strain control did allow stable crack extension well past maximum force, and thus is preferred for energy calculations. The effort is being used to confirm recommendations in ASTM Test Method C1421 on fracture toughness measurement.

  1. Impact Toughness and Heat Treatment for Cast Aluminum

    NASA Technical Reports Server (NTRS)

    Lee, Jonathan A (Inventor)

    2016-01-01

    A method for transforming a cast component made of modified aluminum alloy by increasing the impact toughness coefficient using minimal heat and energy. The aluminum alloy is modified to contain 0.55%-0.60% magnesium, 0.10%-0.15% titanium or zirconium, less than 0.07% iron, a silicon-tomagnesium product ratio of 4.0, and less than 0.15% total impurities. The shortened heat treatment requires an initial heating at 1,000deg F. for up to I hour followed by a water quench and a second heating at 350deg F. to 390deg F. for up to I hour. An optional short bake paint cycle or powder coating process further increase.

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

    PubMed Central

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

    2015-01-01

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

  3. A nondestructive method for estimation of the fracture toughness of CrMoV rotor steels based on ultrasonic nonlinearity.

    PubMed

    Jeong, Hyunjo; Nahm, Seung-Hoon; Jhang, Kyung-Young; Nam, Young-Hyun

    2003-09-01

    The objective of this paper is to develop a nondestructive method for estimating the fracture toughness (K(IC)) of CrMoV steels used as the rotor material of steam turbines in power plants. To achieve this objective, a number of CrMoV steel samples were heat-treated, and the fracture appearance transition temperature (FATT) was determined as a function of aging time. Nonlinear ultrasonics was employed as the theoretical basis to explain the harmonic generation in a damaged material, and the nonlinearity parameter of the second harmonic wave was the experimental measure used to be correlated to the fracture toughness of the rotor steel. The nondestructive procedure for estimating the K(IC) consists of two steps. First, the correlations between the nonlinearity parameter and the FATT are sought. The FATT values are then used to estimate K(IC) using the K(IC) versus excess temperature (i.e., T-FATT) correlation that is available in the literature for CrMoV rotor steel.

  4. The development of ultrahigh strength low alloy cast steels with increased toughness

    NASA Astrophysics Data System (ADS)

    Lynch, Paul C.

    This work describes the initial work on the development of the next generation of ultrahigh strength low alloy (UHSLA) cast steels. These UHSLA cast steels have both ultrahigh strength levels and good impact toughness. The influence of heat treatment, secondary processing using hot isostatic processing (HIP), and chemical composition on the microstructure and properties of UHSLA cast steels have been evaluated. The extent of microsegregation reduction expected during the heat treatment of UHSLA cast steels has also been estimated by diffusion modeling. This new family of UHSLA cast steels is similar in composition and properties to UHSLA wrought steels. However, the heat treatment and secondary processing of the UHSLA cast steels is used to develop microstructures and properties typically developed through thermomechanical processing and heat treatment for wrought UHSLA steels. Two martensitic UHSLA steels, 4340+ (silicon modified 4340) and ES-1 were investigated for this study. For the 4340+ alloy, heat treatment variables evaluated include homogenization temperature and time, tempering temperature, and austempering temperature and time. For the ES-1 alloy, heat treatment variables evaluated include homogenization temperature and time, austenization temperature, cryogenic treatment, and tempering temperature. The effect of high temperature hot isostatic processing (HIP) on the 4340+ and ES- 1 alloys was also investigated. Tensile properties, charpy v-notch impact toughness (CVN), microstructures, and fractographs have all been characterized after heat treatment. The effects of HIP on microporosity reduction in the ES-1 alloy were also investigated. The experiments carried out on the investment cast 4340+ alloy have shown that increasing the homogenization temperature can increase CVN without changing the ultimate tensile strength (UTS) or yield strength (YS) of the cast material. By replacing the homogenization step in the conventional heat treatment process with

  5. N-acetylcysteine negatively regulates Notch3 and its malignant signaling

    PubMed Central

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

    2016-01-01

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

  6. N-acetylcysteine negatively regulates Notch3 and its malignant signaling.

    PubMed

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

    2016-05-24

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

  7. Enzymatic mineralization generates ultrastiff and tough hydrogels with tunable mechanics

    NASA Astrophysics Data System (ADS)

    Rauner, Nicolas; Meuris, Monika; Zoric, Mirjana; Tiller, Joerg C.

    2017-03-01

    The cartilage and skin of animals, which are made up of more than fifty per cent water, are rather stiff (having elastic moduli of up to 100 megapascals) as well as tough and hard to break (with fracture energies of up to 9,000 joules per square metre). Such features make these biological materials mechanically superior to existing synthetic hydrogels. Lately, progress has been made in synthesizing tough hydrogels, with double-network hydrogels achieving the toughness of skin and inorganic-organic composites showing even better performance. However, these materials owe their toughness to high stretchability; in terms of stiffness, synthetic hydrogels cannot compete with their natural counterparts, with the best examples having elastic moduli of just 10 megapascals or less. Previously, we described the enzyme-induced precipitation and crystallization of hydrogels containing calcium carbonate, but the resulting materials were brittle. Here we report the enzyme-induced formation of amorphous calcium phosphate nanostructures that are homogenously distributed within polymer hydrogels. Our best materials have fracture energies of 1,300 joules per square metre even in their fully water-swollen state—a value superior to that of most known water-swollen synthetic materials. We are also able to modulate their stiffness up to 440 megapascals, well beyond that of cartilage and skin. Furthermore, the highly filled composite materials can be designed to be optically transparent and to retain most of their stretchability even when notched. We show that percolation drives the mechanical properties, particularly the high stiffness, of our uniformly mineralized hydrogels.

  8. Cr-W-V bainitic/ferritic steel with improved strength and toughness and method of making

    DOEpatents

    Klueh, Ronald L.; Maziasz, Philip J.

    1994-01-01

    A high strength, high toughness Cr-W-V ferritic steel composition suitable for fast induced-radioactivity (FIRD) decay after irradiation in a fusion reactor comprises 2.5-3.5 wt % Cr, 2. This invention was made with Government support under contract DE-AC05-840R21400 awarded by the U.S. Department of Energy to Martin Marietta Energy Systems, Inc. and the Government has certain rights in this invention.

  9. A comparative evaluation of dental luting cements by fracture toughness tests and fractography.

    PubMed

    Ryan, A K; Orr, J F; Mitchell, C A

    2001-01-01

    In recent years there has been a shift from traditional methods of investigating dental materials to a fracture mechanics approach. Fracture toughness (KIC) is an intrinsic material property which can be considered to be a measure of a material's resistance to crack propagation. Glass-ionomer cements are biocompatible and bioactive dental restorative materials, but they suffer from poor fracture toughness and are extremely susceptible to dehydration. The main objective of this study was to evaluate the fracture toughness of three types of commercially available dental cements (polyacid-modified composite resin, resin-modified and conventional glass ionomer) using a short-rod chevron-notch test and to investigate and interpret the results by means of fractography using scanning electron microscopy. Ten specimens of each cement were fabricated according to manufacturers' instructions, coated in varnish, and stored at ambient laboratory humidity, 100 per cent relative humidity, or in water at 37 degrees C for 7 days prior to preparation for testing. Results indicated that significant differences existed between each group of materials and that the fracture toughness ranged from 0.27 to 0.72 MN/m3/2. It was concluded that the resin-modified glass-ionomer cement demonstrated the highest resistance to crack propagation. Fractographs clearly showed areas of stable and unstable crack growth along the fractured surfaces for the three materials examined.

  10. Fracture toughness and the effects of stress state on fracture of nickel aluminides

    NASA Technical Reports Server (NTRS)

    Lewandowski, John J.; Michal, Gary M.; Locci, Ivan; Rigney, Joseph D.

    1991-01-01

    The effects of stress state on the fracture behavior of Ni3Al, Ni3Al + B, and NiAl were determined using either notched or fatigue-precracked bend bars tested to failure at room temperature, in addition to testing specimens in tension under superposed hydrostatic pressure. Although Ni3Al is observed to fail in a macroscopically brittle intergranular manner in tension tests conducted at room temperature, the fracture toughnesses presently obtained on Ni3Al exceeded 20 MPam, and R-curve behavior was exhibited. In situ monitoring of the fracture experiments was utilized to aid in interpreting the source(s) of the high toughness in Ni3Al, while SEM fractography was utilized to determine the operative fracture modes. The superposition by hydrostatic pressure during tensile testing of NiAl specimens was observed to produce increased ductility without changing the fracture mode.

  11. Notch3 is involved in adipogenesis of human adipose-derived stromal/stem cells.

    PubMed

    Sandel, Demi A; Liu, Mengcheng; Ogbonnaya, Ngozi; Newman, Jamie J

    2018-07-01

    Human adipose-derived stromal/stem cells (hASCs) have tremendous therapeutic potential and the ability to offer insight into human development and disease. Here we subject human ASCs to siRNA-mediated knockdown of Notch3 cultured under both self-renewing and adipogenic differentiation conditions. Self-renewal was monitored by assessing viability and proliferation rates through staining and alamarBlue assays, respectively. Adipogenesis was measured through Oil-Red O staining, western blot, and quantitative real-time RT-PCR that determined expression levels of multipotency and adipogenic markers over time. Notch3 was expressed in self-renewing hASCs but knockdown, as validated by qRT-PCR and western blot, showed no impact on cell viability, as measured through live-dead staining, or cell proliferation rates, as measured through alamarBlue assays. However, although Notch3 expression was observed to increase during adipogenesis, in the absence of Notch3 there was a significant increase in hASC adipogenesis as demonstrated through an increased number of lipid vesicles, and increased expression of adipogenic markers ppar-γ, adiponectin, fabp4, and plin2. Although Notch3 is only one of four Notch receptors expressed on the surface of hASCs, this receptor appears important for proper regulation of adipogenic differentiation, possibly serving as a negative regulator to prevent inappropriate adipogenesis or promote other lineage commitments of ASCs. Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2018-05-31

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

  14. Investigation of Three-Dimensional Stress Fields and Slip Systems for FCC Single Crystal Superalloy Notched Specimens

    NASA Technical Reports Server (NTRS)

    Arakere, Nagaraj K.; Magnan, Shannon; Ebrahimi, Fereshteh; Ferroro, Luis

    2004-01-01

    Metals and their alloys, except for a few intermetallics, are inherently ductile, i.e. plastic deformation precedes fracture in these materials. Therefore, resistance to fracture is directly related to the development of the plastic zone at the crack tip. Recent studies indicate that the fracture toughness of single crystals depends on the crystallographic orientation of the notch as well as the loading direction. In general, the dependence of crack propagation resistance on crystallographic orientation arises from the anisotropy of (i) elastic constants, (ii) plastic deformation (or slip), and (iii) the weakest fracture planes (e.g. cleavage planes). Because of the triaxial stress state at the notch tips, many slip systems that otherwise would not be activated during uniaxial testing, become operational. The plastic zone formation in single crystals has been tackled theoretically by Rice and his co-workers and only limited experimental work has been conducted in this area. The study of the stresses and strains in the vicinity of a FCC single crystal notch tip is of relatively recent origin. We present experimental and numerical investigation of 3D stress fields and evolution of slip sector boundaries near notches in FCC single crystal tension test specimens, and demonstrate that a 3D linear elastic finite element model that includes the effect of material anisotropy is shown to predict active slip planes and sectors accurately. The slip sector boundaries are shown to have complex curved shapes with several slip systems active simultaneously near the notch. Results are presented for surface and mid-plane of the specimens. The results demonstrate that accounting for 3D elastic anisotropy is very important for accurate prediction of slip activation near FCC single crystal notches loaded in tension. Results from the study will help establish guidelines for fatigue damage near single crystal notches.

  15. Effect of 0.1 wt.% Co on the Hot Deformation and Toughness of Fine-Grained Low-Carbon Steel at Sub-zero Temperatures

    NASA Astrophysics Data System (ADS)

    Liu, Xiqin; Zhou, Shuangshuang; Liu, Zili; Hou, Zhiguo; Tian, Qingchao

    2017-12-01

    The effect of 0.1 wt.% Co on the hot deformation behavior of fine-grained low-carbon microalloyed steel was investigated at temperatures of 850-1200 °C and a strain rate of 5 s-1. Furthermore, the toughness of the steel with and without Co at sub-zero temperatures was evaluated. The results suggest that the addition of 0.1 wt.% Co increases the flow stress and delays the occurrence of dynamic recrystallization (DRX) at the same deformation temperature and strain. The DRX fraction of steel specimens without and with 0.1 wt.% Co was about 67.4 and 43.9% at 850 °C, respectively. Then, it increased to 100% at 1100 °C. Compared with steel without Co, cementite particles in the tempered sorbite of steel with 0.1 wt.% Co decreased in size but increased in quantity, yield strength increased from 756 to 787 MPa, and Charpy V-notch energy at - 20 and - 50 °C improved from 69 and 41 to 102 and 65 J, respectively. The fracture morphology and crack propagation characteristics were consistent with the variation in impact energy.

  16. Effect of 0.1 wt.% Co on the Hot Deformation and Toughness of Fine-Grained Low-Carbon Steel at Sub-zero Temperatures

    NASA Astrophysics Data System (ADS)

    Liu, Xiqin; Zhou, Shuangshuang; Liu, Zili; Hou, Zhiguo; Tian, Qingchao

    2018-01-01

    The effect of 0.1 wt.% Co on the hot deformation behavior of fine-grained low-carbon microalloyed steel was investigated at temperatures of 850-1200 °C and a strain rate of 5 s-1. Furthermore, the toughness of the steel with and without Co at sub-zero temperatures was evaluated. The results suggest that the addition of 0.1 wt.% Co increases the flow stress and delays the occurrence of dynamic recrystallization (DRX) at the same deformation temperature and strain. The DRX fraction of steel specimens without and with 0.1 wt.% Co was about 67.4 and 43.9% at 850 °C, respectively. Then, it increased to 100% at 1100 °C. Compared with steel without Co, cementite particles in the tempered sorbite of steel with 0.1 wt.% Co decreased in size but increased in quantity, yield strength increased from 756 to 787 MPa, and Charpy V-notch energy at - 20 and - 50 °C improved from 69 and 41 to 102 and 65 J, respectively. The fracture morphology and crack propagation characteristics were consistent with the variation in impact energy.

  17. Investigation on Microstructure and Impact Toughness of Different Zones in Duplex Stainless Steel Welding Joint

    NASA Astrophysics Data System (ADS)

    Zhang, Zhiqiang; Jing, Hongyang; Xu, Lianyong; Han, Yongdian; Li, Guolu; Zhao, Lei

    2017-01-01

    This paper investigated on microstructure and impact toughness of different zones in duplex stainless steel welding joint. High-temperature heat-affected zone (HTHAZ) contained coarse ferrite grains and secondary precipitates such as secondary austenite, Cr2N, and sigma. Intergranular secondary austenite was prone to precipitation in low-temperature heat-affected zone (LTHAZ). Both in weld metal (WM) and in HTHAZ, the austenite consisted of different primary and secondary austenite. The ferrite grains in base metal (BM) presented typical rolling texture, while the austenite grains showed random orientation. Both in the HTHAZ and in the LTHAZ, the ferrite grains maintained same texture as the ferrite in the BM. The secondary austenite had higher Ni but lower Cr and Mo than the primary austenite. Furthermore, the WM exhibited the highest toughness because of sufficient ductile austenite and unapparent ferrite texture. The HTHAZ had the lowest toughness because of insufficient austenite formation in addition to brittle sigma and Cr2N precipitation. The LTHAZ toughness was higher than the BM due to secondary austenite precipitation. In addition, the WM fracture was dominated by the dimple, while the cleavage was main fracture mode of the HTHAZ. Both BM and LTHAZ exhibited a mixed fracture mode of the dimple and quasi-cleavage.

  18. The effect of aging treatment on the fracture toughness and impact strength of injection molded Ni-625 superalloy parts

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

    Özgün, Özgür, E-mail: oozgun@bingol.edu.tr; Yılmaz, Ramazan; Özkan Gülsoy, H.

    In this study, the effect of aging heat treatment on fracture toughness and impact strength of Ni-625 superalloy fabricated by using powder injection molding (PIM) method was examined. After a feedstock was prepared by mixing the prealloyed Ni-625 superalloy powder, which was fabricated by gas atomisation, with a polymeric binder system and then it was granulated, it was shaped through the use of injection. The molded specimens were sintered at 1300 °C for 3 h after a two-stage debinding process. Once the sintered specimens were treated in the solution at 1150 °C for 2 h, they were quenched. Aging treatmentmore » was performed by keeping specimens at 745 °C for 22 h. Fracture toughness and impact tests were performed on sintered and aged specimens. Microstructure examinations were performed by using optical microscope, scanning electron microscope, and transmission electron microscope. The results revealed that aging heat treatment led to the formation of some carbides and intermetallic phases in the microstructure. While the hardness of the aged specimens increased due to these phases, their fracture toughness and impact strength values decreased. - Highlights: • Ni-625 superalloy components were produced by means of powder injection molding. • The produced components were subjected to aging treatment. • Aging process provided approximately 50% increase in the hardness of components. • Intermetallic precipitates, carbides and TCP phases occurred within the aged parts. • Fracture toughness and impact strength values decreased due to the hard phases.« less

  19. A review of the effect of a/W ratio on fracture toughness (II) —experimental investigation in LEFM

    NASA Astrophysics Data System (ADS)

    Li, Qing-Fen; Fu, Yu-Dong; Xu, Xiao-Xue

    2005-06-01

    In part I of this series, experimental investigation in EPFM (elastic-plastic fracture mechanics) had been discussed. In this paper, experimental investigation in LEFM (linear elastic fracture mechanics) is given. Fracture toughness tests had been carried out on three different strength steels, using both through-cracked specimens with different a/W ratio and semi-elliptical cracked specimens with variable crack size and shape. Results show that the fracture toughness K IC increases with decreasing a/W when a/W<0.3 for three-point-bend specimens, and that for a/W>0.3, it is independent of a/W. Shallow crack specimens, both through-cracked and surface-cracked, gave markedly higher values than deeply notched specimens. However, the effect of crack shape on fracture toughness is negligible. Results also show that the LEFM approach to fracture is not tenable for design stresses where a c is often very small, far less than 2.5(K IC/σ y )2.

  20. A critical role of Notch signaling in osteosarcoma invasion and metastasis

    PubMed Central

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

    2010-01-01

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

  1. The effect of thermocycling on the fracture toughness and hardness of core buildup materials.

    PubMed

    Medina Tirado, J I; Nagy, W W; Dhuru, V B; Ziebert, A J

    2001-11-01

    Thermocycling has been shown to cause surface degradation of many dental materials, but its effect on the fracture toughness and hardness of direct core buildup materials is unknown. This study was designed to determine the effect of thermocycling on the fracture toughness and hardness of 5 core buildup materials. Fifteen specimens were prepared from each of the following materials: Fluorocore, VariGlass VLC, Valiant PhD, Vitremer, and Chelon-Silver. American Standard for Testing Materials guidelines for single-edge notch, bar-shaped specimens were used. Ten specimens of each material were thermocycled for 2000 cycles; the other 5 specimens were not thermocycled. All specimens were subjected to 3-point bending in a universal testing machine. The load at fracture was recorded, and the fracture toughness (K(IC)) was calculated. Barcol hardness values were also determined. Data were analyzed with 1-way analysis of variance and compared with the Tukey multiple range test (P<.05). Pearson's correlation coefficient was also calculated to measure the association between fracture toughness and hardness. Fluorocore had the highest thermocycled mean K(IC) and Valiant PhD the highest non-thermocycled K(IC). Chelon-Silver demonstrated the lowest mean K(IC) both before and after thermocycling. One-way analysis of variance demonstrated significant differences between conditions, and the Tukey test showed significant differences (P<.05) between materials for both conditions. Most specimens also showed significant hardness differences between conditions. Pearson's correlation coefficient indicated only a mild-to-moderate correlation between hardness and fracture toughness. Within the limitations of this study, the thermocycling process negatively affected the fracture toughness and hardness of the core buildup materials tested.

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

    PubMed

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

    2004-12-20

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

  3. Comparison of irradiation-induced shifts of K{sub Jc} and Charpy impact toughness for reactor pressure vessel steels

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

    Sokolov, M.A.; Nanstad, R.K.

    1999-10-01

    The current provisions for determination of the upward temperature shift of the lower-bound static fracture toughness curve due to irradiation of reactor pressure vessel steels are based on the assumption that they are the same as the Charpy 41-J shifts as a consequence of irradiation. The objective of this paper is to evaluate this assumption relative to data reported in open publications. Depending on the specific source, different sizes of fracture toughness specimens, procedures of the K{sub Jc} determination, and fitting functions were used. It was anticipated that the scatter might be reduced by using a consistent approach to analyzemore » the published data. A method employing Weibull statistics is applied to analyze original fracture toughness data of unirradiated and irradiated pressure vessel steels. Application of the master curve concept is used to determine shifts of fracture toughness transition curves. A hyperbolic tangent function is used to fit charpy absorbed energy data. The fracture toughness shifts are compared to Charpy impact shifts evaluated with various criteria. Linear regression analysis showed that for weld metals, on average, the fracture toughness shift is the same as the Charpy 41-J temperature shift, while for base metals, on average, the fracture toughness shift at 41 J is 16% greater than the shift of the Charpy 41-J transition temperature, with both correlations having relatively large 95% confidence intervals.« less

  4. Epithelial transformation by KLF4 requires Notch1 but not canonical Notch1 signaling

    PubMed Central

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

    2009-01-01

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

  5. Evaluation of Orientation Dependence of Fracture Toughness and Fatigue Crack Propagation Behavior of As-Deposited ARCAM EBM Ti-6Al-4V

    NASA Astrophysics Data System (ADS)

    Seifi, Mohsen; Dahar, Matthew; Aman, Ron; Harrysson, Ola; Beuth, Jack; Lewandowski, John J.

    2015-03-01

    This preliminary work documents the effects of test orientation with respect to build and beam raster directions on the fracture toughness and fatigue crack growth behavior of as-deposited EBM Ti-6Al-4V. Although ASTM/ISO standards exist for determining the orientation dependence of various mechanical properties in both cast and wrought materials, these standards are evolving for materials produced via additive manufacturing (AM) techniques. The current work was conducted as part of a larger America Makes funded project to begin to examine the effects of process variables on the microstructure and fracture and fatigue behavior of AM Ti-6Al-4V. In the fatigue crack growth tests, the fatigue threshold, Paris law slope, and overload toughness were determined at different load ratios, R, whereas fatigue precracked samples were tested to determine the fracture toughness. The as-deposited material exhibited a fine-scale basket-weave microstructure throughout the build, and although fracture surface examination revealed the presence of unmelted powders, disbonded regions, and isolated porosity, the resulting mechanical properties were in the range of those reported for cast and wrought Ti-6Al-4V. Remote access and control of testing was also developed at Case Western Reserve University to improve efficiency of fatigue crack growth testing.

  6. Waveform frequency notching

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

    Doerry, Armin W.; Andrews, John

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

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

    PubMed

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

    2017-09-08

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

  8. Fracture Toughness and Fatigue Crack Growth Behavior of As-Cast High-Entropy Alloys

    NASA Astrophysics Data System (ADS)

    Seifi, Mohsen; Li, Dongyue; Yong, Zhang; Liaw, Peter K.; Lewandowski, John J.

    2015-08-01

    The fracture toughness and fatigue crack growth behavior of two as-vacuum arc cast high-entropy alloys (HEAs) (Al0.2CrFeNiTi0.2 and AlCrFeNi2Cu) were determined. A microstructure examination of both HEA alloys revealed a two-phase structure consisting of body-centered cubic (bcc) and face-centered cubic (fcc) phases. The notched and fatigue precracked toughness values were in the range of those reported in the literature for two-phase alloys but significantly less than recent reports on a single phase fcc-HEA that was deformation processed. Fatigue crack growth experiments revealed high fatigue thresholds that decreased significantly with an increase in load ratio, while Paris law slopes exhibited metallic-like behavior at low R with significant increases at high R. Fracture surface examinations revealed combinations of brittle and ductile/dimpled regions at overload, with some evidence of fatigue striations in the Paris law regime.

  9. Experimental investigation of CNT effect on curved beam strength and interlaminar fracture toughness of CFRP laminates

    NASA Astrophysics Data System (ADS)

    Arca, M. A.; Coker, D.

    2014-06-01

    High mechanical properties and light weight structures of composite materials and advances in manufacturing processes have increased the use of composite materials in the aerospace and wind energy industries as a primary load carrying structures in complex shapes. However, use of composite materials in complex geometries such as L-shaped laminates creates weakness at the radius which causes delamination. Carbon nanotubes (CNTs) is preferred as a toughening materials in composite matrices due to their high mechanical properties and aspect ratios. However, effect of CNTs on curved beam strength (CBS) is not investigated in literature comprehensively. The objective of this study is to investigate the effect of CNT on Mode I and Mode II fracture toughness and CBS. L-shaped beams are fabric carbon/epoxy composite laminates manufactured by hand layup technique. Curved beam composite laminates were subjected to four point bending loading according to ASTM D6415/D6415M-06a. Double cantilever beam (DCB) tests and end notch flexure (ENF) tests were conducted to determine mode-I and mode-II fracture toughness, respectively. Preliminary results show that 3% CNT addition to the resin increased the mode-I fracture toughness by %25 and mode-II fracture toughness by %10 compared to base laminates. In contrast, no effect on curved beam strength was found.

  10. Notch signaling genes

    PubMed Central

    Terragni, Jolyon; Zhang, Guoqiang; Sun, Zhiyi; Pradhan, Sriharsa; Song, Lingyun; Crawford, Gregory E; Lacey, Michelle; Ehrlich, Melanie

    2014-01-01

    Notch intercellular signaling is critical for diverse developmental pathways and for homeostasis in various types of stem cells and progenitor cells. Because Notch gene products need to be precisely regulated spatially and temporally, epigenetics is likely to help control expression of Notch signaling genes. Reduced representation bisulfite sequencing (RRBS) indicated significant hypomethylation in myoblasts, myotubes, and skeletal muscle vs. many nonmuscle samples at intragenic or intergenic regions of the following Notch receptor or ligand genes: NOTCH1, NOTCH2, JAG2, and DLL1. An enzymatic assay of sites in or near these genes revealed unusually high enrichment of 5-hydroxymethylcytosine (up to 81%) in skeletal muscle, heart, and cerebellum. Epigenetics studies and gene expression profiles suggest that hypomethylation and/or hydroxymethylation help control expression of these genes in heart, brain, myoblasts, myotubes, and within skeletal muscle myofibers. Such regulation could promote cell renewal, cell maintenance, homeostasis, and a poised state for repair of tissue damage. PMID:24670287

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

    PubMed

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

    2015-12-01

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

  12. Dynamic Fracture Toughness Evaluation by Measurement of CTOD (Crack Tip Opening Displacement).

    DTIC Science & Technology

    1988-03-15

    fracture toughness of structural steels were reported by Shoemaker and Rolfe [1]; these and similar results are also presented in the text by Rolfe and...8217 MPaV/-m/s. Following the dynamic tests of Shoemaker and Rolfe , extensions of the familiar ASTM E-399 static fracture toughness tests were examined. This...s.V.: **.4* .4 5, -~ 5 5 - 𔃿 .4.4 References [1] Shoemaker, A.K. and Rolfe , S.T., "The Static and Dynamic Low-Temperature Crack-Toughness

  13. Notch Signaling and Alloreactivity.

    PubMed

    Radojcic, Vedran; Maillard, Ivan

    2016-12-01

    Solid organ and allogeneic hematopoietic cell transplantation have become standard therapeutic interventions that save patient lives and improve quality of life. Our enhanced understanding of transplantation immunobiology has refined clinical management and improved outcomes. However, organ rejection and graft-versus-host disease remain major obstacles to the broader successful application of these therapeutic procedures. Notch signaling regulates multiple aspects of adaptive and innate immunity. Preclinical studies identified Notch signaling as a promising target in autoimmune diseases, as well as after allogeneic hematopoietic cell and solid organ transplantation. Notch was found to be a central regulator of alloreactivity across clinically relevant models of transplantation. Notch inhibition in T cells prevented graft-versus-host disease and organ rejection, establishing organ tolerance by skewing CD4 T helper polarization away from a proinflammatory response toward suppressive regulatory T cells. Notch ligand blockade also dampened alloantibody deposition and prevented chronic rejection through humoral mechanisms. Toxicities of systemic Notch blockade were observed with γ-secretase inhibitors in preclinical and early clinical trials across different indications, but they did not arise upon preclinical targeting of Delta-like Notch ligands, a strategy sufficient to confer full benefits of Notch ablation in T cell alloimmunity. Because multiple clinical grade reagents have been developed to target individual Notch ligands and receptors, the benefits of Notch blockade in transplantation are calling for translation of preclinical findings into human transplantation medicine.

  14. Fracture toughness measurements of three titanium alloy extrusions

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

    DeSisto, T.S.

    1973-07-01

    Plane strain static K/sub Ic/ and dynamic Kid measurements were obtained on 3-in. dia. titanium alloy extrusions which received a 5.9: 1 reduction followed by air cooling. The alloys investigated were Ti-6Al--6V--2Sn, Ti--8Mo-- 8V--2Fe--3Al, and Ti-- 11.5Mo-6Zr-4.5Sn (Beta III). Compact tension specimens were used to obtain K/sub Ic/ measurements and precracked standard Charpy V- notched specimens were used to obtain Kid measurements. The highest K/sub Ic/ and K /sub Id/ values were obtained from the Beta III extrusion while the lowest K/sub Ic/ and K/sub Id/ values were obtained for the Ti-8Mo--8V--2Fe -- 3Al extrusion. Good agreement was found tomore » exist between K/sub Ic/ values obtained from precracked Charpy V-notch specimens and compact tension specimens. (auth)« less

  15. Notch Inhibitors for Cancer Treatment

    PubMed Central

    Espinoza, Ingrid; Miele, Lucio

    2013-01-01

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

  16. High temperature homogenization improves impact toughness of vitamin E-diffused, irradiated UHMWPE.

    PubMed

    Oral, Ebru; O'Brien, Caitlin; Doshi, Brinda; Muratoglu, Orhun K

    2017-06-01

    Diffusion of vitamin E into radiation cross-linked ultrahigh molecular weight polyethylene (UHMWPE) is used to increase stability against oxidation of total joint implant components. The dispersion of vitamin E throughout implant preforms has been optimized by a two-step process of doping and homogenization. Both of these steps are performed below the peak melting point of the cross-linked polymer (<140°C) to avoid loss of crystallinity and strength. Recently, it was discovered that the exposure of UHMWPE to elevated temperatures, around 300°C, for a limited amount of time in nitrogen, could improve the toughness without sacrificing wear resistance. We hypothesized that high temperature homogenization of antioxidant-doped, radiation cross-linked UHMWPE could improve its toughness. We found that homogenization at 300°C for 8 h resulted in an increase in the impact toughness (74 kJ/m 2 compared to 67 kJ/m 2 ), the ultimate tensile strength (50 MPa compared to 43 MPa) and elongation at break (271% compared to 236%). The high temperature treatment did not compromise the wear resistance or the oxidative stability as measured by oxidation induction time. In addition, the desired homogeneity was achieved at a much shorter duration (8 h compared to >240 h) by using high temperature homogenization. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1343-1347, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  17. Over-Aging Effect on Fracture Toughness of Beryllium Copper Alloy C17200

    NASA Astrophysics Data System (ADS)

    Jen, Kei-Peng; Xu, Liqun; Hylinski, Steven; Gildersleeve, Nate

    2008-10-01

    This study experimentally increased the fracture toughness of Beryllium Copper (CuBe) UNS C17200 alloy using three different age hardening processes. At the same time, the micro- and macro-fracture behavior of this alloy were comprehensively studied. ASTM E399 fracture toughness, tensile, and Charpy impact tests were conducted for all three heat-treated rods. The fracture surfaces were examined under both an optical microscope and a scanning electron microscope to investigate the failure mechanisms. Multiple test orientations were considered to explore isotropy. Increasing the temperature and duration at which age hardening was performed increased fracture toughness while decreasing ultimate tensile strength. The maximum fracture toughness was reached on the most overaged specimen, while retaining a serviceable tensile strength. The specimen test data allowed a relationship to be established among Charpy impact toughness, fracture toughness, and yield strength. Analysis of fracture behavior revealed an interesting relationship between fracture toughness and pre-cracking fatigue propagation rate.

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

    PubMed

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

    2015-08-01

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

  19. Rapid Thermal Processing to Enhance Steel Toughness.

    PubMed

    Judge, V K; Speer, J G; Clarke, K D; Findley, K O; Clarke, A J

    2018-01-11

    Quenching and Tempering (Q&T) has been utilized for decades to alter steel mechanical properties, particularly strength and toughness. While tempering typically increases toughness, a well-established phenomenon called tempered martensite embrittlement (TME) is known to occur during conventional Q&T. Here we show that short-time, rapid tempering can overcome TME to produce unprecedented property combinations that cannot be attained by conventional Q&T. Toughness is enhanced over 43% at a strength level of 1.7 GPa and strength is improved over 0.5 GPa at an impact toughness of 30 J. We also show that hardness and the tempering parameter (TP), developed by Holloman and Jaffe in 1945 and ubiquitous within the field, is insufficient for characterizing measured strengths, toughnesses, and microstructural conditions after rapid processing. Rapid tempering by energy-saving manufacturing processes like induction heating creates the opportunity for new Q&T steels for energy, defense, and transportation applications.

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

    PubMed

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

    2017-01-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2017-08-15

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

  4. Effect of Solute Segregation on Fracture Toughness in a Ni-Cr Steel

    NASA Astrophysics Data System (ADS)

    Kameda, Jun

    1981-12-01

    A study has been made of the influence of intergranular solute segregation on fracture toughness K1c in a series of Ni-Cr steels individually doped with Sb, Sn, and P. By means of toughness measurements in steels having two different intergranular Sb distributions, of measurements of acoustic emissions and of scanning electron micrographs of a load-interrupted and post-test-fatigued specimen, the values of K1c, computed from the “pop-in” load of the load vs clip gauge displacement curves, are found to represent the formation of many patches of contiguous intergranular microcracks ahead of the precrack. The present experiments demonstrate that in the early stage of solute segregation, K1c decreases more substantially than does the strength of grain boundaries σ* (measured in the notched bar tests), although the embrittlement effects of metalloid elements are the same order for both K1c and σ*. A proposed model for the stress-gradient-control of brittle fracture supports the finding that the measurements of K1c give a distorted view of the progress of intergranular embrittlement.

  5. Influence of crystallographic texture in X70 pipeline steels on toughness anisotropy and delamination

    NASA Astrophysics Data System (ADS)

    Al-Jabr, Haytham M.

    The effects of microstructure and crystallographic texture in four commercially-produced API X70 pipeline steels and their relation to planar anisotropy of toughness and delamination were evaluated. The experimental steels were processed through either a hot strip mill, a Steckel mill, or a compact strip mill. Different processing routes were selected to obtain plates with potential variations in the microstructure and anisotropic characteristics. Tensile and Charpy impact testing were used to evaluate the mechanical properties in three orientations: longitudinal (L), transverse (T) and diagonal (D) with respect to the rolling direction to evaluate mechanical property anisotropy. The yield and tensile strengths were higher in the T orientation and toughness was lower in the D orientation for all plates. Delamination was observed in some of the ductile fracture surfaces of the impact samples. To further study the splitting behavior and effects on impact toughness, a modified impact test (MCVN) specimen with side grooves was designed to intensify induced stresses parallel to the notch root and thus facilitate evaluation of delamination. Scanning electron microscopy combined with electron backscattered diffraction (EBSD) were used to evaluate the grain size, microstructural constituents, and crystallographic texture to determine the factors leading to delamination and the anisotropy in toughness. The ferrite grain size is mainly responsible for the differences in DBTTs between the L and T orientations. The higher DBTT in the D orientation observed in pipeline steels is attributed to crystallographic texture. The higher DBTT in the D direction is due to the higher volume fraction of grains having their {100} planes parallel or close to the primary fracture plane for the D orientation. An equation based on a new "brittleness parameter," based on an assessment of grain orientations based on EBSD data, was developed to predict the changes in DBTTs with respect to sample

  6. Impact Behavior of Composite Fan Blade Leading Edge Subcomponent with Thermoplastic Polyurethane Interleave

    NASA Technical Reports Server (NTRS)

    Miller, Sandi G.; Roberts, Gary D.; Kohlman, Lee W.; Heimann, Paula J.; Pereira, J. Michael; Ruggeri, Charles R.; Martin, Richard E.; McCorkle, Linda S.

    2015-01-01

    Impact damage tolerance and damage resistance is a critical metric for application of polymer matrix composites where failure caused by impact damage could compromise structural performance and safety. As a result, several materials and/or design approaches to improve impact damage tolerance have been investigated over the past several decades. Many composite toughening methodologies impart a trade-off between increased fracture toughness and compromised in-plane strength and modulus. In large part, mechanical tests to evaluate composite damage tolerance include static methods such as Mode I, Mode II, and mixed mode failures. However, ballistic impact damage resistance does not always correlate with static properties. The intent of this paper is to evaluate the influence of a thermoplastic polyurethane veil interleave on the static and dynamic performance of composite test articles. Static coupon tests included tension, compression, double cantilever beam, and end notch flexure. Measurement of the resistance to ballistic impact damage were made to evaluate the composites response to high speed impact. The interlayer material showed a decrease of in-plane performance with only a moderate improvement to Mode I and Mode II fracture toughness. However, significant benefit to impact damage tolerance was observed through ballistic tests.

  7. Effect of Thermal Treatment on the Mechanical and Toughness Properties of Extruded Sic sub w/Aluminum 6061 Metal Matrix Composite.

    DTIC Science & Technology

    1987-01-31

    Charpy V-Notch_,,... i9,, STRACT (Continue on reverse if necessary and identify by block number) Mechanical, instrumented\\ Charpy V-potch (CVN) energy and...authors express their appreciation to Messrs. W. Willard and R. Gray for the fracture testing, Ensign M. Rennie for the instrumented Charpy V-notch...TO ALUMINUM GRAIN BOUNDARIES . . . . . . . . . 12 5 INSTRUMENTED CHARPY V-NOTCH LOAD AND ENERGY AGAINST TIME OUTPUTS FOR L-C ORIENTATION SiCwJAI 6061

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

    PubMed

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

    2017-11-24

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

  9. Fracture toughness, diametrical strength, and fractography of amalgam and of amalgam to amalgam bonds.

    PubMed

    Bapna, M S; Mueller, H J

    1993-01-01

    Chevron-notch fracture toughness, diametrical tensile strength and fractography were evaluated for bulk amalgams and for bonds formed between new and 1-day-old amalgams of the same type. Three types of bonded specimens were prepared: 1) by mechanically roughening the 1-day-old amalgam with 600-grit paper; 2) using a new mercury-rich amalgam; and 3) using a bonding resin, either 4-META or a phosphate ester monomer. Similar values in bond properties were obtained with all bonding techniques for two commercial dispersed-phase bonded amalgams, one of which contained palladium; however, bulk fracture toughness of the palladium-containing amalgam was significantly less than for the palladium-free amalgam. This result reveals that the bonding of amalgam to amalgam, at least for these two amalgams, is a surface-related phenomenon, and thus, the traditional reporting of bonding properties as a percentage of bulk properties loses meaning. Short-rod geometry was more representative of the interfacial bond properties since these samples fractured within the interfacial bonds, while diametrical strength samples often fractured slightly away from the interface. The use of bonding resins did not improve bond fracture toughness for either amalgam, while the diametrical strength improved for one of the amalgams. The use of mercury-rich amalgam significantly improved the fracture toughness over all other techniques for one amalgam while proving to be similar to a 600-grit preparation for the second amalgam.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. The Effect of Tempering Process on Microstructural Characteristics and Mechanical Properties of Induction Bend Pipe

    NASA Astrophysics Data System (ADS)

    Yu, Hao; Zhou, Tao

    The heat treatment during manufacturing process of induction bend pipe had been simulated. The evolutions of ferrite, M/A island and substructure after tempering at 500 700 °C were characterized by means of optical microscopy, positron annihilation technique, SEM, TEM, XRD and EBSD. The mechanical performance was evaluated by tensile test, Charpy V-notch impact test (-20 °C) and Vickers hardness test (10 kgf). Microstructure observations showed that fine and homogenous M/A islands as well as dislocation packages in quasi-polygonal ferrite matrix after tempering at 600 650 °C generated optimal combination of strength and toughness. After tempering at 700 °C, the yield strength decreased dramatically. EBSD analysis indicated that the effective grain size diminished with the tempering temperature increasing. It could cause more energy cost during microcrack propagation process with subsequent improvement in impact toughness. Dislocation analysis suggested that the decrease and pile-up of dislocation benefited the combination of strength and toughness.

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

    NASA Astrophysics Data System (ADS)

    Chan, Kwai S.

    2015-12-01

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

  12. Lineage-specific effects of Notch/Numb signaling in post-embryonic development of the Drosophila brain.

    PubMed

    Lin, Suewei; Lai, Sen-Lin; Yu, Huang-Hsiang; Chihara, Takahiro; Luo, Liqun; Lee, Tzumin

    2010-01-01

    Numb can antagonize Notch signaling to diversify the fates of sister cells. We report here that paired sister cells acquire different fates in all three Drosophila neuronal lineages that make diverse types of antennal lobe projection neurons (PNs). Only one in each pair of postmitotic neurons survives into the adult stage in both anterodorsal (ad) and ventral (v) PN lineages. Notably, Notch signaling specifies the PN fate in the vPN lineage but promotes programmed cell death in the missing siblings in the adPN lineage. In addition, Notch/Numb-mediated binary sibling fates underlie the production of PNs and local interneurons from common precursors in the lAL lineage. Furthermore, Numb is needed in the lateral but not adPN or vPN lineages to prevent the appearance of ectopic neuroblasts and to ensure proper self-renewal of neural progenitors. These lineage-specific outputs of Notch/Numb signaling show that a universal mechanism of binary fate decision can be utilized to govern diverse neural sibling differentiations.

  13. Microstructure, Pitting Corrosion Resistance and Impact Toughness of Duplex Stainless Steel Underwater Dry Hyperbaric Flux-Cored Arc Welds.

    PubMed

    Hu, Yu; Shi, Yong-Hua; Shen, Xiao-Qin; Wang, Zhong-Min

    2017-12-18

    Duplex stainless steel multi-pass welds were made at 0.15 MPa, 0.45 MPa, and 0.75 MPa pressure, simulating underwater dry hyperbaric welding by the flux-cored arc welding (FCAW) method, with welds of normal pressure as a benchmark. The purpose of this work was to estimate the effect of ambient pressure on the microstructure, pitting corrosion resistance and impact toughness of the weld metal. The microstructure measurement revealed that the ferrite content in the weld metal made at 0.45 MPa is the lowest, followed by that of 0.75 MPa and 0.15 MPa. The analysis of potentiodynamic polarization tests at 30 °C and 50 °C demonstrated that the pitting corrosion resistance depends on the phases of the lower pitting resistance equivalent numbers (PREN), secondary austenite and ferrite. The weld metal made at 0.45 MPa had the best resistance to pitting corrosion at 30 °C and 50 °C with the highest PRENs of secondary austenite and ferrite. The weld metal made at 0.15 MPa displayed the lowest pitting corrosion resistance at 30 °C with the lowest PREN of secondary austenite, while the weld metal made at 0.75 MPa was the most seriously eroded after being tested at 50 °C for the lowest PREN of ferrite, with large cluster pits seen in ferrite at 50 °C. The impact tests displayed a typical ductile-brittle transition because of the body-centered cubic (BCC) structure of the ferrite when the test temperature was lowered. All the weld metals met the required value of 34 J at -40 °C according to the ASTM A923. The highest ferrite content corresponded to the worst impact toughness, but the highest toughness value did not correspond to the greatest austenite content. With the decreasing of the test temperature, the drop value of absorbed energy was correlated to the ferrite content. Additionally, in this work, the weld metal made at 0.45 MPa had the best combined properties of pitting resistance and impact toughness.

  14. Tough composite materials: Recent developments

    NASA Technical Reports Server (NTRS)

    Vosteen, L. F. (Editor); Johnston, N. J. (Editor); Teichman, L. A. (Editor); Blankenship, C. P. (Editor)

    1985-01-01

    The present volume broadly considers topics in composite fracture toughness and impact behavior characterization, composite system constituent properties and their interrelationships, and matrix systems' synthesis and characterization. Attention is given to the characterization of interlaminar crack growth in composites by means of the double cantilever beam specimen, the characterization of delamination resistance in toughened resin composites, the effect of impact damage and open holes on the compressive strength of tough resin/high strain fiber laminates, the effect of matrix and fiber properties on compression failure mechanisms and impact resistance, the relation of toughened neat resin properties to advanced composite mechanical properties, and constituent and composite properties' relationships in thermosetting matrices. Also treated are the effect of cross-link density on the toughening mechanism of elastomer-modified epoxies, the chemistry of fiber/resin interfaces, novel carbon fibers and their properties, the development of a heterogeneous laminating resin, solvent-resistant thermoplastics, NASA Lewis research in advanced composites, and opportunities for the application of composites in commercial aircraft transport structures.

  15. A review of the effect of a/W ratio on fracture toughness (I) —Experimental investigation in EPFM

    NASA Astrophysics Data System (ADS)

    Li, Qing-Fen; Zheng, Wei; Shu, Hai-Sheng

    2005-03-01

    Many experimental investigations have previously been performed and recently done on different shipbuilding structural steels where the specimens size and crack depth/specimen width ( a/W) were varied. A series of interesting results have been gained. It is worthwhile to have a review on the effect of a/W ratio on fracture toughness, and further theoretical analysis is necessary. In this paper, experimental work in elasticplastic fracture mechanics (EPFM) was discussed. Tests had been carried out on 10 kinds of strength steels. Results showed that J i and δ1 values increased with decreasing a/W when a/W<0.3 for three-point bend specimens and that shallow crack specimens which have less constrained flow field give markedly higher values of toughness than deeply notched specimens. However, for a/W>0.3, the toughness was found to be independent of a/W. Slip line field analysis shows that for shallow cracks, the hydrostatic stress is lower than that from standard deeply cracked bend specimen which develops a high level of crack tip constraint, provides a lower bound estimate of toughness, and will ensure an unduly conservative approach when applied to structure defects especially if initiation values of COD/ J-integral are used.

  16. Enhancements to the TOUGH2 Simulator as Implemented in iTOUGH2

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

    Finsterle, Stefan

    iTOUGH2 is a program for parameter estimation, sensitivity analysis, and uncertainty propagation analysis. It is based on the TOUGH2 simulator for non-isothermal multiphase, multicomponent flow and transport in fractured and porous media [Pruess, 1987, 1991, 2005, 2011; Falta et al., 1995; Pruess et al., 1999, 2002, 2012; Doughty, 2013]. The core of iTOUGH2 contains slightly modified versions of TOUGH2 modules. Most code modifications are editorial and do not affect the simulation results. As a result, standard TOUGH2 input files can be used in iTOUGH2, and identical results are obtained if iTOUGH2 is run in forward mode. However, a number ofmore » modifications have been made as described in this report. They enhance the functionality, flexibilitu, and eas-of-use of the forward simulator. This report complements the reports iTOUGH2 User's Guide, iTOUGH2 Command Referecne, and the collection of tutorial examples in iTOUGH2 Sample Problems.« less

  17. Impact toughness of cellulose-fiber reinforced polypropylene : influence of microstructure in laminates and injection molded composites

    Treesearch

    Craig Clemons; Daniel Caulfield; A. Jeffrey Giacomin

    2003-01-01

    Unlike their glass reinforced counterparts, microstructure and dynamic fracture behavior of natural fiber-reinforced thermoplastics have hardly been investigated. Here, we characterize the microstructure of cellulose fiber-reinforced polypropylene and determined its effect on impact toughness. Fiber lengths were reduced by one-half when compounded in a high-intensity...

  18. Experimental Investigation of the Effect of Hydrogen on Fracture Toughness of 2.25Cr-1Mo-0.25V Steel and Welds after Annealing

    PubMed Central

    Song, Yan; Chai, Mengyu; Wu, Weijie; Liu, Yilun; Qin, Mu; Cheng, Guangxu

    2018-01-01

    Hydrogen embrittlement (HE) is a critical issue that hinders the reliability of hydrogenation reactors. Hence, it is of great significance to investigate the effect of hydrogen on fracture toughness of 2.25Cr-1Mo-0.25V steel and weld. In this work, the fracture behavior of 2.25Cr-1Mo-0.25V steel and welds was studied by three-point bending tests under hydrogen-free and hydrogen-charged conditions. The immersion charging method was employed to pre-charge hydrogen inside specimen and the fracture toughness of these joints was evaluated quantitatively. The microstructure and grain size of the specimens were observed by scanning electron microscopy (SEM) and by metallurgical microscopy to investigate the HE mechanisms. It was found that fracture toughness for both the base metal (BM) and the weld zone (WZ) significantly decreased under hydrogen-charged conditions due to the coexistence of the hydrogen-enhanced decohesion (HEDE) and hydrogen-enhanced localized plasticity (HELP) mechanisms. Moreover, the formation and growth of primary voids were observed in the BM, leading to a superior fracture toughness. In addition, the BM compared to the WZ shows superior resistance to HE because the finer grain size in the BM leads to a larger grain boundary area, thus distributing more of the diffusive hydrogen trapped in the grain boundary and reducing the hydrogen content. PMID:29584678

  19. Influence of specimen dimensions on ductile-to-brittle transition temperature in Charpy impact test

    NASA Astrophysics Data System (ADS)

    Rzepa, S.; Bucki, T.; Konopík, P.; Džugan, J.; Rund, M.; Procházka, R.

    2017-02-01

    This paper discusses the correlation between specimen dimensions and transition temperature. Notch toughness properties of Standard Charpy-V specimens are compared to samples with lower width (7.5 mm, 5 mm, 2.5 mm) and sub-size Charpy specimens with cross section 3×4. In this study transition curves are correlated with lateral ductile part of fracture related ones for 5 considered geometries. Based on the results obtained, correlation procedure for transition temperature determination of full size specimens defined by fracture appearance of sub-sized specimens is proposed.

  20. Microstructures and impact toughness behavior of Al 5083 alloy processed by cryorolling and afterwards annealing

    NASA Astrophysics Data System (ADS)

    Singh, Dharmendra; Rao, P. Nageswara; Jayaganthan, R.

    2013-08-01

    The influence of rolling at liquid nitrogen temperature and annealing on the microstructure and mechanical properties of Al 5083 alloy was studied in this paper. Cryorolled samples of Al 5083 show significant improvements in strength and hardness. The ultimate tensile strength increases up to 340 MPa and 390 MPa for the 30% and 50% cryorolled samples, respectively. The cryorolled samples, with 30% and 50% reduction, were subjected to Charpy impact testing at various temperatures from -190°C to 100°C. It is observed that increasing the percentage of reduction of samples during cryorolling has significant effect on decreasing impact toughness at all temperatures by increasing yield strength and decreasing ductility. Annealing of samples after cryorolling shows remarkable increment in impact toughness through recovery and recrystallization. The average grain size of the 50% cryorolled sample (14 μm) after annealing at 350°C for 1 h is found to be finer than that of the 30% cryorolled sample (25 μm). The scanning electron microscopy (SEM) analysis of fractured surfaces shows a large-size dimpled morphology, resembling the ductile fracture mechanism in the starting material and fibrous structure with very fine dimples in cryorolled samples corresponding to the brittle fracture mechanism.

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

    PubMed Central

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

    2015-01-01

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

  2. Perivascular Delivery of Notch 1 siRNA Inhibits Injury-Induced Arterial Remodeling

    PubMed Central

    Redmond, Eileen M.; Liu, Weimin; Hamm, Katie; Hatch, Ekaterina; Cahill, Paul A.; Morrow, David

    2014-01-01

    Objectives To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling. Methods and Results Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown. Conclusion These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA. PMID:24416200

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

    PubMed

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

    2014-10-02

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

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

    PubMed Central

    Baeten, Jeremy T.; Lilly, Brenda

    2015-01-01

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

  5. A Metallurgical Evaluation of the Powder-Bed Laser Additive Manufactured 4140 Steel Material

    NASA Astrophysics Data System (ADS)

    Wang, Wesley; Kelly, Shawn

    2016-03-01

    Using laser powder bed fusion (PBF-L) additive manufacturing (AM) process for steel or iron powder has been attempted for decades. This work used a medium carbon steel (AISI 4140) powder to explore the feasibility of AM. The high carbon equivalent of 4140 steel (CEIIW ≈ 0.83) has a strong tendency toward cold cracking. As such, the process parameters must be carefully controlled to ensure the AM build quality. Through an orthogonally designed experimental matrix, a laser-welding procedure was successfully developed to produce 4140 steel AM builds with no welding defects. In addition, the microstructure and micro-cleanliness of the as-welded PBF-L AM builds were also examined. The results showed an ultra-fine martensite lath structure and an ultra-clean internal quality with minimal oxide inclusion distribution. After optimizing the PBF-L AM process parameters, including the laser power and scan speed, the as-welded AM builds yielded an average tensile strength higher than 1482 MPa and an average 33 J Charpy V-notch impact toughness at -18°C. The surface quality, tensile strength, and Charpy V-notch impact toughness of AM builds were comparable to the wrought 4140 steel. The excellent mechanical properties of 4140 steel builds created by the PBF-L AM AM process make industrial production more feasible, which shows great potential for application in the aerospace, automobile, and machinery industries.

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

    PubMed

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

    2017-01-01

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

  7. Heat shock protein 70 (Hsp70) interacts with the Notch1 intracellular domain and contributes to the activity of Notch signaling in myelin-reactive CD4 T cells.

    PubMed

    Juryńczyk, Maciej; Lewkowicz, Przemysław; Domowicz, Małgorzata; Mycko, Marcin P; Selmaj, Krzysztof W

    2015-10-15

    Notch receptors (Notch1-4) are involved in the differentiation of CD4 T cells and the development of autoimmunity. Mechanisms regulating Notch signaling in CD4 T cells are not fully elucidated. In this study we investigated potential crosstalk between Notch pathway molecules and heat shock protein 70 (Hsp70), the major intracellular chaperone involved in the protein transport during immune responses and other stress conditions. Using Hsp70(-/-) mice we found that Hsp70 is critical for up-regulation of NICD1 and induction of Notch target genes in Jagged1- and Delta-like1-stimulated CD4 T cells. Co-immunoprecipitation analysis of wild-type CD4 T cells stimulated with either Jagged1 or Delta-like1 showed a direct interaction between NICD1 and Hsp70. Both molecules co-localized within the nucleus of CD4 T cells stimulated with Notch ligands. Molecular interaction and nuclear colocalization of NICD1 and Hsp70 were also detected in CD4 T cells reactive against myelin oligodendrocyte glycoprotein (MOG)35-55, which showed Hsp70-dependent up-regulation of both NICD1 and Notch target genes. In conclusion, we demonstrate for the first time that Hsp70 interacts with NICD1 and contributes to the activity of Notch signaling in CD4 T cells. Interaction between Hsp70 and NICD1 may represent a novel mechanism regulating Notch signaling in activated CD4 T cells. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    PubMed

    Baeten, Jeremy T; Lilly, Brenda

    2015-06-26

    Notch signaling is a key regulator of vascular smooth muscle cell (VSMC) phenotypes, including differentiation, proliferation, and cell survival. However, the exact contribution of the individual Notch receptors has not been thoroughly delineated. In this study, we identify unique roles for NOTCH2 and NOTCH3 in regulating proliferation and cell survival in cultured VSMCs. Our results indicate that NOTCH2 inhibits PDGF-B-dependent proliferation and its expression is decreased by PDGF-B. In contrast, NOTCH3 promotes proliferation and receptor expression is increased by PDGF-B. Additionally, data show that NOTCH3, but not NOTCH2 protects VSMCs from apoptosis and apoptosis mediators degrade NOTCH3 protein. We identified three pro-survival genes specifically regulated by NOTCH3 in cultured VSMCs and in mouse aortas. This regulation is mediated through MAP kinase signaling, which we demonstrate can be activated by NOTCH3, but not NOTCH2. Overall, this study highlights discrete roles for NOTCH2 and NOTCH3 in VSMCs and connects these roles to specific upstream regulators that control their expression. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Effect of Retained Austenite on the Fracture Toughness of Quenching and Partitioning (Q&P)-Treated Sheet Steels

    NASA Astrophysics Data System (ADS)

    Wu, Riming; Li, Wei; Zhou, Shu; Zhong, Yong; Wang, Li; Jin, Xuejun

    2014-04-01

    Fracture toughness K IC was measured by double edge-notched tension (DENT) specimens with fatigue precracks on quenching and partitioning (Q&P)-treated high-strength (ultimate tensile strength [UTS] superior to 1200 MPa) sheet steels consisting of 4 to 10 vol pct of retained austenite. Crack extension force, G IC, evaluated from the measured K IC, is used to analyze the role of retained austenite in different fracture behavior. Meanwhile, G IC is deduced by a constructed model based on energy absorption by martensite transformation (MT) behavior of retained austenite in Q&P-treated steels. The tendency of the change of two results is in good agreement. The Q&P-treated steel, quenched at 573 K (300 °C), then partitioned at 573 K (300 °C), holding for 60 seconds, has a fracture toughness of 74.1 MPa·m1/2, which is 32 pct higher than quenching and tempering steel (55.9 MPa·m1/2), and 16 pct higher than quenching and austempering (QAT) steel (63.8 MPa·m1/2). MT is found to occur preferentially at the tips of extension cracks on less stable retained austenite, which further improves the toughness of Q&P steels; on the contrary, the MT that occurs at more stable retained austenite has a detrimental effect on toughness.

  10. Effect of Precipitation on Cryogenic Toughness in Isothermally Aged Austenitic Stainless Steel

    NASA Astrophysics Data System (ADS)

    Saucedo-Muñoz, M. L.; Lopez-Hirata, V. M.; Avila-Davila, E. O.; Villegas-Cardenas, J. D.; Gonzalez-Velazquez, J. L.

    2017-03-01

    The effect of grain-boundary precipitates on cryogenic impact toughness of two corrosion steels (standard AISI 316 and a steel with a nitrogen additive) is studied. The steels are aged at 600 - 900°C with a hold of up to 1000 min. The KCV impact toughness at -196°C is determined. It is shown that the impact toughness of the nitrogen-containing steel decreases under cooling after the aging at 700 and 800°C more considerably than that of steel 316 after aging at 800 and 900°C. The causes of the embrittlement of the nitrogen-containing steel are determined.

  11. Mental Toughness Moderates Social Loafing in Cycle Time-Trial Performance.

    PubMed

    Haugen, Tommy; Reinboth, Michael; Hetlelid, Ken J; Peters, Derek M; Høigaard, Rune

    2016-09-01

    The purpose of this study was to determine if mental toughness moderated the occurrence of social loafing in cycle time-trial performance. Twenty-seven men (Mage = 17.7 years, SD = 0.6) completed the Sport Mental Toughness Questionnaire prior to completing a 1-min cycling trial under 2 conditions: once with individual performance identified, and once in a group with individual performance not identified. Using a median split of the mental toughness index, participants were divided into high and low mental toughness groups. Cycling distance was compared using a 2 (trial) × 2 (high-low mental toughness) analysis of variance. We hypothesized that mentally tough participants would perform equally well under both conditions (i.e., no indication of social loafing) compared with low mentally tough participants, who would perform less well when their individual performance was not identifiable (i.e., demonstrating the anticipated social loafing effect). The high mental toughness group demonstrated consistent performance across both conditions, while the low mental toughness group reduced their effort in the non-individually identifiable team condition. The results confirm that (a) clearly identifying individual effort/performance is an important situational variable that may impact team performance and (b) higher perceived mental toughness has the ability to negate the tendency to loaf.

  12. Lineage-specific effects of Notch/Numb signaling in post-embryonic development of the Drosophila brain

    PubMed Central

    Lin, Suewei; Lai, Sen-Lin; Yu, Huang-Hsiang; Chihara, Takahiro; Luo, Liqun; Lee, Tzumin

    2010-01-01

    Numb can antagonize Notch signaling to diversify the fates of sister cells. We report here that paired sister cells acquire different fates in all three Drosophila neuronal lineages that make diverse types of antennal lobe projection neurons (PNs). Only one in each pair of postmitotic neurons survives into the adult stage in both anterodorsal (ad) and ventral (v) PN lineages. Notably, Notch signaling specifies the PN fate in the vPN lineage but promotes programmed cell death in the missing siblings in the adPN lineage. In addition, Notch/Numb-mediated binary sibling fates underlie the production of PNs and local interneurons from common precursors in the lAL lineage. Furthermore, Numb is needed in the lateral but not adPN or vPN lineages to prevent the appearance of ectopic neuroblasts and to ensure proper self-renewal of neural progenitors. These lineage-specific outputs of Notch/Numb signaling show that a universal mechanism of binary fate decision can be utilized to govern diverse neural sibling differentiations. PMID:20023159

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

    PubMed

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

    2015-12-29

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

  14. Notch signaling and ageing.

    PubMed

    Polychronidou, Eleftheria; Vlachakis, Dimitrios; Vlamos, Panayiotis; Baumann, Marc; Kossida, Sophia

    2015-01-01

    Notch signaling is a master controller of the neural stem cell and neural development maintaining a significant role in the normal brain function. Notch genes are involved in embryogenesis, nervous system, and cardiovascular and endocrine function. On the other side, there are studies representing the involvement of Notch mutations in sporadic Alzheimer disease, other neurodegenerative diseases such as Down syndrome, Pick's and Prion's disease, and CADASIL. This manuscript attempts to present a holistic view of the positive or negative contribution of Notch signaling in the adult brain, and at the same time to present and promote the promising research fields of study.

  15. Microstructure, Pitting Corrosion Resistance and Impact Toughness of Duplex Stainless Steel Underwater Dry Hyperbaric Flux-Cored Arc Welds

    PubMed Central

    Hu, Yu; Shen, Xiao-Qin; Wang, Zhong-Min

    2017-01-01

    Duplex stainless steel multi-pass welds were made at 0.15 MPa, 0.45 MPa, and 0.75 MPa pressure, simulating underwater dry hyperbaric welding by the flux-cored arc welding (FCAW) method, with welds of normal pressure as a benchmark. The purpose of this work was to estimate the effect of ambient pressure on the microstructure, pitting corrosion resistance and impact toughness of the weld metal. The microstructure measurement revealed that the ferrite content in the weld metal made at 0.45 MPa is the lowest, followed by that of 0.75 MPa and 0.15 MPa. The analysis of potentiodynamic polarization tests at 30 °C and 50 °C demonstrated that the pitting corrosion resistance depends on the phases of the lower pitting resistance equivalent numbers (PREN), secondary austenite and ferrite. The weld metal made at 0.45 MPa had the best resistance to pitting corrosion at 30 °C and 50 °C with the highest PRENs of secondary austenite and ferrite. The weld metal made at 0.15 MPa displayed the lowest pitting corrosion resistance at 30 °C with the lowest PREN of secondary austenite, while the weld metal made at 0.75 MPa was the most seriously eroded after being tested at 50 °C for the lowest PREN of ferrite, with large cluster pits seen in ferrite at 50 °C. The impact tests displayed a typical ductile-brittle transition because of the body-centered cubic (BCC) structure of the ferrite when the test temperature was lowered. All the weld metals met the required value of 34 J at −40 °C according to the ASTM A923. The highest ferrite content corresponded to the worst impact toughness, but the highest toughness value did not correspond to the greatest austenite content. With the decreasing of the test temperature, the drop value of absorbed energy was correlated to the ferrite content. Additionally, in this work, the weld metal made at 0.45 MPa had the best combined properties of pitting resistance and impact toughness. PMID:29258262

  16. Methylation of Notch3 modulates chemoresistance via P-glycoprotein.

    PubMed

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

    2016-12-05

    The global gene expression and DNA methylation of genes in adriamycin-resistant human breast cancer cells (MCF-7/ADM cells) are similar to those in paclitaxel-resistant MCF-7 cells (MCF-7/PTX) and are significantly different from those in wild-type MCF-7 cells. DNA methylation is associated with chemoresistance in breast cancer and changes the characteristics of chemoresistant and chemosensitive cells. Here, we showed that the tumor-suppressor gene Notch3 was inactivated due to epigenetic silencing DNA hypermethylation in MCF-7/ADM cells. In addition, the drug efflux pump P-glycoprotein was negatively regulated by Notch3 and highly expressed in MCF-7/ADM cells. Taken together, our findings demonstrated that hypermethylation of Notch3 causes activation of P-glycoprotein in adriamycin-resistant cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Enhanced Impact Toughness at Ambient Temperatures of Ultrafine-Grained Al-26 wt.% Si Alloy Produced by Equal-Channel Angular Pressing

    NASA Astrophysics Data System (ADS)

    Jiang, Jinghua; Yuan, Ting; Shi, Jun; Zhang, Lingling; Ma, Aibin; Song, Dan

    2018-05-01

    Overcoming general brittleness of hypereutectic Al-Si alloys is in urgent need for expanding their application in automotive, aerospace and construction industries. A unique phenomenon was observed that bulk ultrafine-grained Al-26 wt.% Si alloy, produced by severe plastic deformation via equal-channel angular pressing, exhibited higher toughness at the impact temperature of - 196 100 °C than the coarse-grained casting alloy. The improvement in impact toughness at all testing temperatures was mainly due to the homogeneous ultrafine-grained structure with the breakage of brittle primary silicon crystals, which generated more and deeper fracture dimples that consumed much higher fracture energy. It indicates the advantage of bulk ultrafine-grained Al-Si alloys and spurs their application interest at various ambient temperatures.

  18. Enhanced Impact Toughness at Ambient Temperatures of Ultrafine-Grained Al-26 wt.% Si Alloy Produced by Equal-Channel Angular Pressing

    NASA Astrophysics Data System (ADS)

    Jiang, Jinghua; Yuan, Ting; Shi, Jun; Zhang, Lingling; Ma, Aibin; Song, Dan

    2018-04-01

    Overcoming general brittleness of hypereutectic Al-Si alloys is in urgent need for expanding their application in automotive, aerospace and construction industries. A unique phenomenon was observed that bulk ultrafine-grained Al-26 wt.% Si alloy, produced by severe plastic deformation via equal-channel angular pressing, exhibited higher toughness at the impact temperature of - 196 100 °C than the coarse-grained casting alloy. The improvement in impact toughness at all testing temperatures was mainly due to the homogeneous ultrafine-grained structure with the breakage of brittle primary silicon crystals, which generated more and deeper fracture dimples that consumed much higher fracture energy. It indicates the advantage of bulk ultrafine-grained Al-Si alloys and spurs their application interest at various ambient temperatures.

  19. [The effect of notch's angle and depth on crack propagation of zirconia ceramics].

    PubMed

    Chen, Qingya; Chen, Xinmin

    2012-10-01

    This paper is aimed to study the effect of notch's angle and depth on crack propagation of zirconia ceramics. We fabricated cuboid-shaped zirconia ceramics samples with the standard sizes of 4. 4 mm x 2. 2 mm x 18 mm for the experiments, divided the samples into 6 groups, and prepared notches on these samples with different angles and depth. We placed the samples with loads until they were broke, and observe the fracture curve of each sample. We then drew coordinates and described the points of the fracture curve under a microscope, and made curve fitting by the software-Origin. When the notch angle beta = 90 degrees, the crack propagation is pure type I; when beta = 60 degrees, the crack propagation is mainly type I; and when beta = 30 degrees, the crack propagation is a compound of type I and type III. With the increasing of the notch depth, the effect of notch angles on crack propagation increases. In addition, Notch angle is a very important fracture mechanics parameter for crack propagation of zirconia ceramics. With the increasing of notch depth, the impact of notch angle increases.

  20. Molecular Pathways: Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer

    PubMed Central

    Previs, Rebecca A.; Coleman, Robert L.; Harris, Adrian L.; Sood, Anil K.

    2014-01-01

    Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and crosstalk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3–4, Jagged 1–2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Since the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway. PMID:25388163

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

    PubMed

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

    2017-05-01

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

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

    PubMed

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

    2017-04-11

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

  3. Evaluation of the Edge Crack Torsion (ECT) Test for Mode 3 Interlaminar Fracture Toughness of Laminated Composites

    NASA Technical Reports Server (NTRS)

    Li, Jian; Lee, Edward W.; OBrien, T. Kevin; Lee, Shaw Ming

    1996-01-01

    An analytical and experimental investigation was carried out on G40-800/R6376 graphite epoxy laminates to evaluate the Edge Crack Torsion (ECT) test as a candidate for a standard Mode 3 interlaminar fracture toughness test for laminated composites. The ECT test consists of a (90/(+/- 45)(sub 3)/(+/- 45)(sub 3)/90))(sub s) laminate with a delamination introduced by a non-adhesive film at the mid-plane along one edge and loaded in a special fixture to create torsion along the length of the laminate. Dye penetrate enhanced X-radiograph of failed specimens revealed that the delamination initiated at the middle of the specimen length and propagated in a self similar manner along the laminate mid-plane. A three-dimensional finite element analysis was performed that indicated that a pure Mode 3 delamination exists at the middle of specimen length away from both ends. At the ends near the loading point a small Mode 2 component exists. However, the magnitude of this Mode 2 strain energy release rate at the loading point is small compared to the magnitude of Mode 3 component in the mid-section of the specimen. Hence, the ECT test yielded the desired Mode 3 delamination. The Mode 3 fracture toughness was obtained from a compliance calibration method and was in good agreement with the finite element results. Mode 2 End-Notched Flexure (ENF) tests and Mode 1 Double Cantilever Beam (DCB) tests were also performed for the same composite material. The Mode 1 fracture toughness was much smaller than both the Mode 2 and Mode 3 fracture toughness. The Mode 2 fracture toughness was found to be 75% of the Mode 3 fracture toughness.

  4. Fracture toughness of ultrashort pulse-bonded fused silica

    NASA Astrophysics Data System (ADS)

    Richter, S.; Naumann, F.; Zimmermann, F.; Tünnermann, A.; Nolte, S.

    2016-02-01

    We determined the bond interface strength of ultrashort pulse laser-welded fused silica for different processing parameters. To this end, we used a high repetition rate ultrashort pulse laser system to inscribe parallel welding lines with a specific V-shaped design into optically contacted fused silica samples. Afterward, we applied a micro-chevron test to measure the fracture toughness and surface energy of the laser-inscribed welding seams. We analyzed the influence of different processing parameters such as laser repetition rate and line separation on the fracture toughness and fracture surface energy. Welding the entire surface a fracture toughness of 0.71 {MPa} {m}^{1/2}, about 90 % of the pristine bulk material ({≈ } 0.8 {MPa} {m}^{1/2}), is obtained.

  5. Influence of Heat Input on Microstructure and Toughness Properties in Simulated CGHAZ of X80 Steel Manufactured Using High-Temperature Processing

    NASA Astrophysics Data System (ADS)

    Zhu, Zhixiong; Han, Jian; Li, Huijun

    2015-11-01

    To determine and demonstrate the weldability of high-Nb high-temperature processed (HTP) steels and provide extremely valuable information for future line pipe steel design and general steel manufacture, in the current study the toughness in simulated coarse-grained heat-affected zone (CGHAZ) of an X80 grade steel manufactured using HTP was evaluated. The simulated CGHAZs subjected to thermal cycles with various heat inputs (HIs) (0.8 to 5.0 kJ/mm) were produced using a Gleeble 3500 simulator. The microstructures and corresponding mechanical properties were investigated by means of optical microscopy, scanning electron microscopy, electron backscatter diffraction, hardness testing, and Charpy V-notch (CVN) testing. The microstructural examination shows that the simulated CGHAZs consisted of a bainite-dominant microstructure and relatively low amount (<2 pct) of martensite-austenite (M-A) constituent. The prior austenite grain size was controlled to be 45 to 55 µm at HIs of 0.8 to 3.5 kJ/mm, and remarkably increased to 85 µm at an HI of 5 kJ/mm. The results of CVN testing suggest that superior toughness can be achieved in the studied range of HIs (0.8 to 5 kJ/mm). This is thought to be associated with the combined effects of bainitic microstructure and low M-A fraction as well as comparatively fine austenite grain size in the studied CGHAZs.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2016-04-01

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

  9. Effects of through-the-thickness stitching on impact and interlaminar fracture properties of textile graphite/epoxy laminates

    NASA Technical Reports Server (NTRS)

    Sharma, Suresh K.; Sankar, Bhavani V.

    1995-01-01

    This study investigated the effects of through-the-thickness stitching on impact damage resistance, impact damage tolerance, and mode I and mode II fracture toughness of textile graphite/epoxy laminates. Uniweave resin-transfer-molded 48 ply graphite/epoxy (AS4/3501-6) laminates were stitched with Kevlar and glass yarns of different linear densities and stitch spacings. Delaminations were implanted during processing to simulate impact damage. Sublaminate buckling tests were performed to determine the effects of stitching on the compressive strength. The results showed outstanding improvements of up to 400 percent in the compression strength over the unstitched laminates. In impact and static indentation tests the onset of damage occurred at the same level, but the extent of damage was less in stitched laminates. Mode I fracture toughness of 24 ply Uniweave unidirectional (AS4/3501-6) stitched laminates was measured by conducting double-cantilever-beam tests. The critical strain energy release rate (G(sub Ic)) was found to be up to 30 times higher than the unstitched laminates. Mode II fracture toughness of the Uniweave laminates was measured by performing end-notched-flexure tests. Two new methods to compute the apparent G(sub IIc) are presented. The apparent G(sub IIc) was found to be at least 5-15 times higher for the stitched laminates.

  10. One-Step Quenching and Partitioning Heat Treatment of Medium Carbon Low Alloy Steel

    NASA Astrophysics Data System (ADS)

    Tariq, Fawad; Baloch, Rasheed Ahmed

    2014-05-01

    This paper presents the results of novel one-step quenching and partitioning (Q&P) heat treatment conducted on medium carbon low alloy steel sheet. Samples were austenitised at 1193 K followed by interrupted quenching at 473 K for different partitioning times and finally they were quenched in water. Dilatometry was employed for selection of treatment temperatures. Optical and scanning electron microscopy was carried out to examine the microstructural changes. Volume fraction of retained austenite was measured by x-ray diffraction technique. Resulting microstructures were correlated with the mechanical properties such hardness, tensile strength, elongation, impact absorbed energy, etc. The notch tensile and fracture toughness properties of Q&P steels are still lacking therefore notch tensile strength and plain strain fracture toughness tests were conducted and results are reported here. Results of Q&P treatments were also compared with the properties obtained by conventional Quenching and Tempering (Q&T) and normalizing treatments. Optimum strength-ductility balance of about 2000 MPa tensile strength with 11% elongation was achieved in samples quenched at 473 K and isothermally partitioned for 100 s. Higher ductility of Q&P steel was attributed to the presence of 6.8% film-type interlath retained austenite. Fine-grained martensitic structure with high density of interphase boundaries imparted ultrahigh strength. It was further noted that the impact toughness, notch tensile strength and fracture toughness of 1000 s partitioned samples was higher than 100 s partitioned samples. Possible reasons for high toughness are synergetic effect of recovery of dislocations, partial loss of martensite tetragonality and precipitation of fine transition carbides.

  11. Coastal dune dynamics in response to excavated foredune notches

    NASA Astrophysics Data System (ADS)

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

    2018-04-01

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

  12. Origins location of the outflow tract ventricular arrhythmias exhibiting qrS pattern or QS pattern with a notch on the descending limb in lead V1.

    PubMed

    Lin, Cong; Zheng, Cheng; Zhou, De-Pu; Li, Xiao-Wei; Wu, Shu-Jie; Lin, Jia-Feng

    2017-05-15

    Ventricular outflow tract(VOT) ventricular arrhythmias(VAs) presenting qrS pattern or QS pattern with a notch on the descending limb in lead V1 were consistently thought of arising from the commissure between left and right coronary cusp (L-RCC) by previous studies. However, we found they could originate from other anatomic structures in VOT. This study aimed to investigate the exact origin of this kind VAs. Forty-nine patients of VOT premature ventricular contrations/ventricular tachycardia(PVCs/VT) with lead V1 presenting qrS pattern or QS pattern with a notch on the descending limb undergoing successful radiofrequency catheter ablation(RFCA) in our center were analyzed. 12-lead electrocardiogram(ECG) of these PVCs/VT were summarized. Among these PVCs/VT, 37 cases exhibited qrS morphology in lead V1, 12 cases presented QS pattern with a notch on the descending limb in the same lead. Based on the successful ablation sites, these PVCs/VT were divided into 2 groups: (1)Right ventricular outflow tract(RVOT) group (26 cases), and (2) Left ventricular outflow tract (LVOT) group(23 cases, 4 cases originating from the left coronary cusp(LCC), 2 from the right coronary cusp(RCC), 16 from the L-RCC, 1 from the area inferior to LCC(ILCC)). The ECG characteristics of each PVCs/VT were analyzed. Among these PVCs/VT, applying the precordial transitional zone index(TZ index) < 0 to predict LVOT origin was demonstrated with sensitivity of 95.65%, specificity of 96.15%, positive predicting value(PPV) of 95.65% and negative predicting value(NPV) of 96.15%. In LVOT group, further applying the r, R, m,or Rs morphology in lead I to predict L-RCC and RCC origin was demonstrated with sensitivity of 94.44%, specificity of 60.00%, PPV of 89.47% and NPV of 75.00%. Ventricular outflow tract PVCs/VT with lead V1 presenting qrS pattern or QS pattern with a notch on descending limb not only arising from L-RCC, but also RVOT, LCC, RCC and ILCC. Combining TZ index and QRS morphology in lead I

  13. Tough2{_}MP: A parallel version of TOUGH2

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

    Zhang, Keni; Wu, Yu-Shu; Ding, Chris

    2003-04-09

    TOUGH2{_}MP is a massively parallel version of TOUGH2. It was developed for running on distributed-memory parallel computers to simulate large simulation problems that may not be solved by the standard, single-CPU TOUGH2 code. The new code implements an efficient massively parallel scheme, while preserving the full capacity and flexibility of the original TOUGH2 code. The new software uses the METIS software package for grid partitioning and AZTEC software package for linear-equation solving. The standard message-passing interface is adopted for communication among processors. Numerical performance of the current version code has been tested on CRAY-T3E and IBM RS/6000 SP platforms. Inmore » addition, the parallel code has been successfully applied to real field problems of multi-million-cell simulations for three-dimensional multiphase and multicomponent fluid and heat flow, as well as solute transport. In this paper, we will review the development of the TOUGH2{_}MP, and discuss the basic features, modules, and their applications.« less

  14. Therapeutic antibody targeting of individual Notch receptors.

    PubMed

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

    2010-04-15

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

  15. Relationships between human cortical bone toughness and collagen cross-links on paired anatomical locations.

    PubMed

    Gauthier, Rémy; Follet, Hélène; Langer, Max; Gineyts, Evelyne; Rongiéras, Frédéric; Peyrin, Françoise; Mitton, David

    2018-07-01

    Human cortical bone fracture processes depend on the internal porosity network down to the lacunar length scale. Recent results show that at the collagen scale, the maturation of collagen cross-links may have a negative influence on bone mechanical behavior. While the effect of pentosidine on human cortical bone toughness has been studied, the influence of mature and immature enzymatic cross-links has only been studied in relation to strength and work of fracture. Moreover, these relationships have not been studied on different paired anatomical locations. Thus, the aim of the current study was to assess the relationships between both enzymatic and non-enzymatic collagen cross-links and human cortical bone toughness, on four human paired anatomical locations. Single Edge Notched Bending toughness tests were performed for two loading conditions: a quasi-static standard condition, and a condition representative of a fall. These tests were done with 32 paired femoral diaphyses, femoral necks and radial diaphyses (18 women, age 81 ± 12 y.o.; 14 men, age 79 ± 8 y.o.). Collagen enzymatic and non-enzymatic crosslinks were measured on the same bones. Maturation of collagen was defined as the ratio between immature and mature cross-links (CX). The results show that there was a significant correlation between collagen cross-link maturation and bone toughness when gathering femoral and radial diaphyses, but not when considering each anatomical location individually. These results show that the influence of collagen enzymatic and non-enzymatic cross-links is minor when considering human cortical bone crack propagation mechanisms. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Notched strength of beryllium powder and ingot sheets.

    NASA Technical Reports Server (NTRS)

    Moss, R. G.

    1972-01-01

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

  17. The Role of Notch3 in Cancer.

    PubMed

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

    2018-04-05

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2018-01-17

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

  20. Band-notched spiral antenna

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

    Jeon, Jae; Chang, John

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

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

    Code of Federal Regulations, 2011 CFR

    2011-10-01

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

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

    PubMed

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

    2015-08-01

    Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation. Wild-type (WT), Notch3 (Notch3-/-), and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hr. Relative to air-exposed controls, ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4-/- compared with WT and Notch3-/- mice. Significantly greater mean numbers of BALF neutrophils were found in Notch3-/- and Notch4-/- mice compared with WT mice after ozone exposure. Expression of whole lung Tnf was significantly increased after ozone in Notch3-/- and Notch4-/- mice, and was significantly greater in Notch3-/- compared with WT mice. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member. These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation.

  3. Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

    PubMed Central

    Champagne, Devin P.; Shockett, Penny E.

    2014-01-01

    Illegitimate V(D)J recombination at oncogenes and tumor suppressor genes is implicated in formation of several T cell malignancies. Notch1 and Bcl11b, genes involved in developing T cell specification, selection, proliferation, and survival, were previously shown to contain hotspots for deletional illegitimate V(D)J recombination associated with radiation-induced thymic lymphoma. Interestingly, these deletions were also observed in wild-type animals. In this study, we conducted frequency, clonality, and junctional processing analyses of Notch1 and Bcl11b deletions during mouse development and compared results to published analyses of authentic V(D)J rearrangements at the T cell receptor beta (TCRβ) locus and illegitimate V(D)J deletions observed at the human, nonimmune HPRT1 locus not involved in T cell malignancies. We detect deletions in Notch1 and Bcl11b in thymic and splenic T cell populations, consistent with cells bearing deletions in the circulating lymphocyte pool. Deletions in thymus can occur in utero, increase in frequency between fetal and postnatal stages, are detected at all ages examined between fetal and 7 months, exhibit only limited clonality (contrasting with previous results in radiation-sensitive mouse strains), and consistent with previous reports are more frequent in Bcl11b, partially explained by relatively high Recombination Signal Information Content (RIC) scores. Deletion junctions in Bcl11b exhibit greater germline nucleotide loss, while in Notch1 palindromic (P) nucleotides are more abundant, although average P nucleotide length is similar for both genes and consistent with results at the TCRβ locus. Non-templated (N) nucleotide insertions appear to increase between fetal and postnatal stages for Notch1, consistent with normal terminal deoxynucleotidyl transferase (TdT) activity; however, neonatal Bcl11b junctions contain elevated levels of N insertions. Finally, contrasting with results at the HPRT1 locus, we find no obvious age or

  4. iMatTOUGH: An open-source Matlab-based graphical user interface for pre- and post-processing of TOUGH2 and iTOUGH2 models

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

    Tran, Anh Phuong; Dafflon, Baptiste; Hubbard, Susan

    TOUGH2 and iTOUGH2 are powerful models that simulate the heat and fluid flows in porous and fracture media, and perform parameter estimation, sensitivity analysis and uncertainty propagation analysis. However, setting up the input files is not only tedious, but error prone, and processing output files is time consuming. Here, we present an open source Matlab-based tool (iMatTOUGH) that supports the generation of all necessary inputs for both TOUGH2 and iTOUGH2 and visualize their outputs. The tool links the inputs of TOUGH2 and iTOUGH2, making sure the two input files are consistent. It supports the generation of rectangular computational mesh, i.e.,more » it automatically generates the elements and connections as well as their properties as required by TOUGH2. The tool also allows the specification of initial and time-dependent boundary conditions for better subsurface heat and water flow simulations. The effectiveness of the tool is illustrated by an example that uses TOUGH2 and iTOUGH2 to estimate soil hydrological and thermal properties from soil temperature data and simulate the heat and water flows at the Rifle site in Colorado.« less

  5. iMatTOUGH: An open-source Matlab-based graphical user interface for pre- and post-processing of TOUGH2 and iTOUGH2 models

    DOE PAGES

    Tran, Anh Phuong; Dafflon, Baptiste; Hubbard, Susan

    2016-04-01

    TOUGH2 and iTOUGH2 are powerful models that simulate the heat and fluid flows in porous and fracture media, and perform parameter estimation, sensitivity analysis and uncertainty propagation analysis. However, setting up the input files is not only tedious, but error prone, and processing output files is time consuming. Here, we present an open source Matlab-based tool (iMatTOUGH) that supports the generation of all necessary inputs for both TOUGH2 and iTOUGH2 and visualize their outputs. The tool links the inputs of TOUGH2 and iTOUGH2, making sure the two input files are consistent. It supports the generation of rectangular computational mesh, i.e.,more » it automatically generates the elements and connections as well as their properties as required by TOUGH2. The tool also allows the specification of initial and time-dependent boundary conditions for better subsurface heat and water flow simulations. The effectiveness of the tool is illustrated by an example that uses TOUGH2 and iTOUGH2 to estimate soil hydrological and thermal properties from soil temperature data and simulate the heat and water flows at the Rifle site in Colorado.« less

  6. Notch3 protein expression in skin fibroblasts from CADASIL patients.

    PubMed

    Qualtieri, Antonio; Ungaro, Carmine; Bagalà, Angelo; Bianchi, Silvia; Pantoni, Leonardo; Moccia, Marcello; Mazzei, Rosalucia

    2018-07-15

    CADASIL is an inherited cerebrovascular disease caused by mutations in the NOTCH3 gene. Notch signaling is involved in a broad spectrum of function, from the cell proliferation to apoptosis. Thus far, because the molecular mechanism underlying the pathological alterations remains unclear and taking into account that fibroblasts contribute to the integrity of the vasculature, our aims was to establish whether fibroblasts, in subjects carrying different NOTCH3 mutations, show abnormalities in the protein expression. We performed the investigation on skin fibroblasts in culture obtained from three CADASIL patients and normal subjects. The patients were genetically characterized, and carried a p.R61W, a p.C174T, and p.R103X, mutation respectively. Notch3 expression was first evaluated on fibroblasts by immunofluorescence analysis, then western blot on cellular extract was utilized to validate the immunofluorescence results. The Notch3 immunoreactivity was clearly detected along the cellular body and in the cellular nuclei of the control fibroblasts. We observed a marked, statistically significant, reduction of the fluorescence immunoreactivity in the fibroblasts from patient with the classical C174T cysteine mutation and a less pronounced reduction in the other two subject's samples with respect to the normal controls. These data were confirmed by the immunoblot analysis. Our results show that the investigated three NOTCH3 mutations are associated with a reduction of the levels of Notch3 expression in vitro. Because the smooth muscle cells appear to be predominantly involved in this cerebrovascular disease, our result, despite the limitation of the sample size examinated, clearly suggest that also fibroblasts, directly involved in making the vascular basal lamina and in maintaining the vascular integrity, may play an important role in the mechanism responsible for the disease. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Contributions of Rare Earth Element (La,Ce) Addition to the Impact Toughness of Low Carbon Cast Niobium Microalloyed Steels

    NASA Astrophysics Data System (ADS)

    Torkamani, Hadi; Raygan, Shahram; Garcia Mateo, Carlos; Rassizadehghani, Jafar; Palizdar, Yahya; San-Martin, David

    2018-03-01

    In this research Rare Earth elements (RE), La and Ce (200 ppm), were added to a low carbon cast microalloyed steel to disclose their influence on the microstructure and impact toughness. It is suggested that RE are able to change the interaction between the inclusions and matrix during the solidification process (comprising peritectic transformation), which could affect the microstructural features and consequently the impact property; compared to the base steel a clear evolution was observed in nature and morphology of the inclusions present in the RE-added steel i.e. (1) they changed from MnS-based to (RE,Al)(S,O) and RE(S)-based; (2) they obtained an aspect ratio closer to 1 with a lower area fraction as well as a smaller average size. Besides, the microstructural examination of the matrix phases showed that a bimodal type of ferrite grain size distribution exists in both base and RE-added steels, while the mean ferrite grain size was reduced from 12 to 7 μm and the bimodality was redressed in the RE-added steel. It was found that pearlite nodule size decreases from 9 to 6 μm in the RE-added steel; however, microalloying with RE caused only a slight decrease in pearlite volume fraction. After detailed fractography analyses, it was found that, compared to the based steel, the significant enhancement of the impact toughness in RE-added steel (from 63 to 100 J) can be mainly attributed to the differences observed in the nature of the inclusions, the ferrite grain size distribution, and the pearlite nodule size. The presence of carbides (cementite) at ferrite grain boundaries and probable change in distribution of Nb-nanoprecipitation (promoted by RE addition) can be considered as other reasons affecting the impact toughness of steels under investigation.

  8. Contributions of Rare Earth Element (La,Ce) Addition to the Impact Toughness of Low Carbon Cast Niobium Microalloyed Steels

    NASA Astrophysics Data System (ADS)

    Torkamani, Hadi; Raygan, Shahram; Garcia Mateo, Carlos; Rassizadehghani, Jafar; Palizdar, Yahya; San-Martin, David

    2018-07-01

    In this research Rare Earth elements (RE), La and Ce (200 ppm), were added to a low carbon cast microalloyed steel to disclose their influence on the microstructure and impact toughness. It is suggested that RE are able to change the interaction between the inclusions and matrix during the solidification process (comprising peritectic transformation), which could affect the microstructural features and consequently the impact property; compared to the base steel a clear evolution was observed in nature and morphology of the inclusions present in the RE-added steel i.e. (1) they changed from MnS-based to (RE,Al)(S,O) and RE(S)-based; (2) they obtained an aspect ratio closer to 1 with a lower area fraction as well as a smaller average size. Besides, the microstructural examination of the matrix phases showed that a bimodal type of ferrite grain size distribution exists in both base and RE-added steels, while the mean ferrite grain size was reduced from 12 to 7 μm and the bimodality was redressed in the RE-added steel. It was found that pearlite nodule size decreases from 9 to 6 μm in the RE-added steel; however, microalloying with RE caused only a slight decrease in pearlite volume fraction. After detailed fractography analyses, it was found that, compared to the based steel, the significant enhancement of the impact toughness in RE-added steel (from 63 to 100 J) can be mainly attributed to the differences observed in the nature of the inclusions, the ferrite grain size distribution, and the pearlite nodule size. The presence of carbides (cementite) at ferrite grain boundaries and probable change in distribution of Nb-nanoprecipitation (promoted by RE addition) can be considered as other reasons affecting the impact toughness of steels under investigation.

  9. Evaluation of the mechanical properties of electroslag refined iron alloys

    NASA Technical Reports Server (NTRS)

    Bhat, G. K.

    1976-01-01

    Nitronic 40 (21Cr-6N-9Mn), HY-130, 9Ni-4Co, and D-6 alloys were prepared and evaluated in the form of 15.2 mm thick plates. Smooth bar tensile tests, double-edge sharp notch fracture toughness tests Charpy V-notch impact tests were conducted on appropriate heat treated specimens of the four steel plates at 22 C, -50 C, -100 C, -150 C, and -196 C. Similar material characterization, including metallographic evaluation studies on air melt and vacuum arc melt grades of same four alloy steels were conducted for comparative purposes. A cost analysis of manufacturing plates of air melt, electroslag remelt and vacuum arc remelt grades was performed. The results of both material characterization and cost analyses pointed out certain special benefits of electroslag processing iron base alloys.

  10. PLANE STRAIN FRACTURE TOUGHNESS DATA FOR HANDBOOK PRESENTATION

    DTIC Science & Technology

    An experimental program was conducted to determine the plane strain fracture toughness (K sub IC) of the following classes of: (1) AISI Alloy Steels...4340, 4140 ); (2) 5Cr-Mo-V Steels; (3) Precipitation-Hardening Stainless Steels (17-7 PH, PH 15-7 Mo, 17-4, AM355); (4) Titanium Alloy, Ti-6Al-4V. The

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

    PubMed Central

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

    2015-01-01

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

  12. 76 FR 22745 - Three Notch Railway, LLC-Acquisition and Operation Exemption-Three Notch Railroad Co., Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-22

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

  13. Effects of Plasma ZrN Metallurgy and Shot Peening Duplex Treatment on Fretting Wear and Fretting Fatigue Behavior of Ti6Al4V Alloy.

    PubMed

    Tang, Jingang; Liu, Daoxin; Zhang, Xiaohua; Du, Dongxing; Yu, Shouming

    2016-03-23

    A metallurgical zirconium nitride (ZrN) layer was fabricated using glow metallurgy using nitriding with zirconiuming prior treatment of the Ti6Al4V alloy. The microstructure, composition and microhardness of the corresponding layer were studied. The influence of this treatment on fretting wear (FW) and fretting fatigue (FF) behavior of the Ti6Al4V alloy was studied. The composite layer consisted of an 8-μm-thick ZrN compound layer and a 50-μm-thick nitrogen-rich Zr-Ti solid solution layer. The surface microhardness of the composite layer is 1775 HK 0.1 . A gradient in cross-sectional microhardness distribution exists in the layer. The plasma ZrN metallurgical layer improves the FW resistance of the Ti6Al4V alloy, but reduces the base FF resistance. This occurs because the improvement in surface hardness results in lowering of the toughness and increasing in the notch sensitivity. Compared with shot peening treatment, plasma ZrN metallurgy and shot peening composite treatment improves the FW resistance and enhances the FF resistance of the Ti6Al4V alloy. This is attributed to the introduction of a compressive stress field. The combination of toughness, strength, FW resistance and fatigue resistance enhance the FF resistance for titanium alloy.

  14. Materials Research in Support of Superconducting Machinery V

    DTIC Science & Technology

    1976-04-01

    GTAW , EB, GMAW), brazing, and soldering from 4-300 K. Properties include tensile, notched tensile, fracture toughness, and fatigue crack growth...include: aluminum alloys 1100, 2014, 2219; a nicke1- chromium -iron alloy; iron-47.5 nickel; and the composite materials boron/aluminum, boron/epoxy, S...nickel" by H. M. Ledbetter and D. T. Read. (3) N. jkel- chromium -iron-molybdenum alloy. There is an accompanying reprint of our previously described

  15. The Challenge of Targeting Notch in Hematologic Malignancies

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-06-01

    Notch signaling is essential for vascular physiology. Neomorphic heterozygous mutations in NOTCH3, one of the four human NOTCH receptors, cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hypomorphic heterozygous alleles have been occasionally described in association with a spectrum of cerebrovascular phenotypes overlapping CADASIL, but their pathogenic potential is unclear. We describe a patient with childhood-onset arteriopathy, cavitating leukoencephalopathy with cerebral white matter abnormalities presented as diffuse cavitations, multiple lacunar infarctions and disseminated microbleeds. We identified a novel homozygous c.C2898A (p.C966*) null mutation in NOTCH3 abolishing NOTCH3 expression and causing NOTCH3 signaling impairment. NOTCH3 targets acting in the regulation of arterial tone (KCNA5) or expressed in the vasculature (CDH6) were downregulated. Patient's vessels were characterized by smooth muscle degeneration as in CADASIL, but without deposition of granular osmiophilic material (GOM), the CADASIL hallmark. The heterozygous parents displayed similar but less dramatic trends in decrease in the expression of NOTCH3 and its targets, as well as in vessel degeneration. This study suggests a functional link between NOTCH3 deficiency and pathogenesis of vascular leukoencephalopathies. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  17. Notch Promotes Dynamin-Dependent Endocytosis of Nephrin

    PubMed Central

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

    2012-01-01

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

  18. An investigation of fracture toughness, fatigue-crack growth, sustained-load flaw growth, and impact properties of three pressure vessel steels

    NASA Technical Reports Server (NTRS)

    Hudson, C. M.; Newman, J. C., Jr.; Lewis, P. E.

    1975-01-01

    The elastic fracture toughness of the three steels is shown to not decrease significantly with decreasing temperature from room temperature to about 244 K (-20 F.). The elastic fracture toughness of the three steels increased with increasing specimen width and thickness. The fatigue-crack-growth data for all three steels fall into relatively narrow scatter bands on plots of rate against stress-intensity range. An equation is shown to predict the upper bounds of the scatter bands reasonably well. Charpy impact energies decreased with decreasing temperature in the nominal temperature range from room temperature to 244 K (-20 F). The nil-ductility temperatures of the steels are discussed.

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

    NASA Astrophysics Data System (ADS)

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

    2010-02-01

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

  20. Improvement of the mode II interface fracture toughness of glass fiber reinforced plastics/aluminum laminates through vapor grown carbon fiber interleaves.

    PubMed

    Ning, Huiming; Li, Yuan; Hu, Ning; Cao, Yanping; Yan, Cheng; Azuma, Takesi; Peng, Xianghe; Wu, Liangke; Li, Jinhua; Li, Leilei

    2014-06-01

    The effects of acid treatment, vapor grown carbon fiber (VGCF) interlayer and the angle, i.e., 0° and 90°, between the rolling stripes of an aluminum (Al) plate and the fiber direction of glass fiber reinforced plastics (GFRP) on the mode II interlaminar mechanical properties of GFRP/Al laminates were investigated. The experimental results of an end notched flexure test demonstrate that the acid treatment and the proper addition of VGCF can effectively improve the critical load and mode II fracture toughness of GFRP/Al laminates. The specimens with acid treatment and 10 g m -2 VGCF addition possess the highest mode II fracture toughness, i.e., 269% and 385% increases in the 0° and 90° specimens, respectively compared to those corresponding pristine ones. Due to the induced anisotropy by the rolling stripes on the aluminum plate, the 90° specimens possess 15.3%-73.6% higher mode II fracture toughness compared to the 0° specimens. The improvement mechanisms were explored by the observation of crack propagation path and fracture surface with optical, laser scanning and scanning electron microscopies. Moreover, finite element analyses were carried out based on the cohesive zone model to verify the experimental fracture toughness and to predict the interface shear strength between the aluminum plates and GFRP laminates.

  1. Improvement of the mode II interface fracture toughness of glass fiber reinforced plastics/aluminum laminates through vapor grown carbon fiber interleaves

    PubMed Central

    Ning, Huiming; Li, Yuan; Hu, Ning; Cao, Yanping; Yan, Cheng; Azuma, Takesi; Peng, Xianghe; Wu, Liangke; Li, Jinhua; Li, Leilei

    2014-01-01

    The effects of acid treatment, vapor grown carbon fiber (VGCF) interlayer and the angle, i.e., 0° and 90°, between the rolling stripes of an aluminum (Al) plate and the fiber direction of glass fiber reinforced plastics (GFRP) on the mode II interlaminar mechanical properties of GFRP/Al laminates were investigated. The experimental results of an end notched flexure test demonstrate that the acid treatment and the proper addition of VGCF can effectively improve the critical load and mode II fracture toughness of GFRP/Al laminates. The specimens with acid treatment and 10 g m−2 VGCF addition possess the highest mode II fracture toughness, i.e., 269% and 385% increases in the 0° and 90° specimens, respectively compared to those corresponding pristine ones. Due to the induced anisotropy by the rolling stripes on the aluminum plate, the 90° specimens possess 15.3%–73.6% higher mode II fracture toughness compared to the 0° specimens. The improvement mechanisms were explored by the observation of crack propagation path and fracture surface with optical, laser scanning and scanning electron microscopies. Moreover, finite element analyses were carried out based on the cohesive zone model to verify the experimental fracture toughness and to predict the interface shear strength between the aluminum plates and GFRP laminates. PMID:27877680

  2. Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia.

    PubMed

    Tao, Yong-Kang; Zeng, Heng; Zhang, Guo-Qiang; Chen, Sean T; Xie, Xue-Jiao; He, Xiaochen; Wang, Shuo; Wen, Hongyan; Chen, Jian-Xiong

    2017-06-01

    Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development. This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI. Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2 + /Sca1 + and NG2 + /c-kit + progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b + macrophage infiltration into ischemic areas compared to that of WT mice. Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the pre-existing coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation. Copyright © 2016. Published by Elsevier B.V.

  3. Epidermal Notch signalling: differentiation, cancer and adhesion.

    PubMed

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

    2008-04-01

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

  4. Effects of substrate preheating during direct energy deposition on microstructure, hardness, tensile strength, and notch toughness

    NASA Astrophysics Data System (ADS)

    Baek, Gyeong Yun; Lee, Ki Yong; Park, Sang Hu; Shim, Do Sik

    2017-11-01

    This study examined the effects of substrate preheating for the hardfacing of cold-press dies using the high-speed tool steel AISI M4. The preheating of the substrate is a widely used technique for reducing the degree of thermal deformation and preventing crack formation. We investigated the changes in the metallurgical and mechanical properties of the high-speed tool steel M4 deposited on an AISI D2 substrate with changes in the substrate preheating temperature. Five preheating temperatures (100-500 °C; interval of 100 °C) were selected, and the changes in the temperature of the substrate during deposition were observed. As the preheating temperature of the substrate was increased, the temperature gradient between the melting layer and the substrate decreased; this prevented the formation of internal cracks, owing to thermal stress relief. Field-emission scanning electron microscopy showed that a dendritic structure was formed at the interface between the deposited layer and the substrate while a cellular microstructure was formed in the deposited layer. As the preheating temperature was increased, the sizes of the cells and precipitated carbides also increased. Furthermore, the hardness increased slightly while the strength and toughness decreased. Moreover, the tensile and impact properties deteriorated rapidly at excessively high preheating temperatures (greater than 500 °C). The results of this study can be used as preheating criteria for achieving the desired mechanical properties during the hardfacing of dies and molds.

  5. 46 CFR 54.05-5 - Toughness test specimens.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... V-notch tests shall be conducted in accordance with ASTM Specification E 23 (incorporated by... for that thickness shall be cut centered at the material's mid-thickness. For materials thicker than 1/2-inch, full size Charpy specimens shall be cut centered at a location as near as practicable to a...

  6. Mechanosensitivity of Jagged–Notch signaling can induce a switch-type behavior in vascular homeostasis

    PubMed Central

    Stassen, Oscar M. J. A.; ter Huurne, Fleur M.; Boareto, Marcelo; Sahlgren, Cecilia M.

    2018-01-01

    Hemodynamic forces and Notch signaling are both known as key regulators of arterial remodeling and homeostasis. However, how these two factors integrate in vascular morphogenesis and homeostasis is unclear. Here, we combined experiments and modeling to evaluate the impact of the integration of mechanics and Notch signaling on vascular homeostasis. Vascular smooth muscle cells (VSMCs) were cyclically stretched on flexible membranes, as quantified via video tracking, demonstrating that the expression of Jagged1, Notch3, and target genes was down-regulated with strain. The data were incorporated in a computational framework of Notch signaling in the vascular wall, where the mechanical load was defined by the vascular geometry and blood pressure. Upon increasing wall thickness, the model predicted a switch-type behavior of the Notch signaling state with a steep transition of synthetic toward contractile VSMCs at a certain transition thickness. These thicknesses varied per investigated arterial location and were in good agreement with human anatomical data, thereby suggesting that the Notch response to hemodynamics plays an important role in the establishment of vascular homeostasis. PMID:29610298

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

    Treesearch

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

    2002-01-01

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

  8. The Varied Roles of Notch in Cancer

    PubMed Central

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

    2018-01-01

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

  9. NOTCH pathway inactivation promotes bladder cancer progression

    PubMed Central

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

    2015-01-01

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

  10. Notch3 expression correlates with thyroid cancer differentiation, induces apoptosis, and predicts disease prognosis.

    PubMed

    Somnay, Yash R; Yu, Xiao-Min; Lloyd, Ricardo V; Leverson, Glen; Aburjania, Zviadi; Jang, Samuel; Jaskula-Sztul, Renata; Chen, Herbert

    2017-03-01

    Thyroid tumorigenesis is characterized by a progressive loss of differentiation exhibited by a range of disease variants. The Notch receptor family (1-4) regulates developmental progression in both normal and cancerous tissues. This study sought to characterize the third Notch isoform (Notch3) across the various differentiated states of thyroid cancer, and determine its clinical impact. Notch3 expression was analyzed in a tissue microarray of normal and pathologic thyroid biopsies from 155 patients. The functional role of Notch3 was then investigated by upregulating its expression in a follicular thyroid cancer (FTC) cell line. Notch3 expression regressed across decreasingly differentiated, increasingly malignant thyroid specimens, correlated with clinicopathological attributes reflecting poor prognosis, and independently predicted survival following univariate and multivariate analyses. Overexpression of the active Notch3 intracellular domain (NICD3) in a gain-of-function FTC line led to functional activation of centromere-binding protein 1, while increasing thyroid-specific gene transcription. NICD3 induction also reduced tumor burden in vivo and initiated the intrinsic apoptotic cascade, alongside suppressing cyclin and B-cell lymphoma 2 family expression. Loss of Notch3 expression may be fundamental to the process of dedifferentiation that accompanies thyroid oncogenesis. Conversely, activation of Notch3 in thyroid cancer exerts an antiproliferative effect and restores elements of a differentiated phenotype. These findings provide preclinical rationale for evaluating Notch3 as a disease prognosticator and therapeutic target in advanced thyroid cancer. Cancer 2017;123:769-82. © 2016 American Cancer Society. © 2016 American Cancer Society.

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

    PubMed

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

    2017-12-01

    Rhabdomyosarcoma (RMS), a cancer characterized by skeletal muscle features, is the most common soft-tissue sarcoma of childhood. While low- and intermediate-risk groups have seen improved outcomes, high-risk patients still face a 5-year survival rate of <30%, a statistic that has not changed in over 40 years. Understanding the biologic underpinnings of RMS is critical. The developmental pathways of Notch and YAP have been identified as potent but independent oncogenic signals that support the embryonal variant of RMS (eRMS). Here, the cross-talk between these pathways and the impact on eRMS tumorigenesis is reported. Using human eRMS cells grown as three-dimensional (3D) rhabdospheres, which enriches in stem cells, it was found that Notch signaling transcriptionally upregulates YAP1 gene expression and YAP activity. Reciprocally, YAP transcriptionally upregulates the Notch ligand genes JAG1 and DLL1 and the core Notch transcription factor RBPJ This bidirectional circuit boosts expression of key stem cell genes, including SOX2 , which is functionally required for eRMS spheres. Silencing this circuit for therapeutic purposes may be challenging, because the inhibition of one node (e.g., pharmacologic Notch blockade) can be rescued by upregulation of another (constitutive YAP expression). Instead, dual inhibition of Notch and YAP is necessary. Finally, supporting the existence of this circuit beyond a model system, nuclear Notch and YAP protein expression are correlated in human eRMS tumors, and YAP suppression in vivo decreases Notch signaling and SOX2 expression. Implications: This study identifies a novel oncogenic signaling circuit driving eRMS stemness and tumorigenesis, and provides evidence and rationale for combination therapies co-targeting Notch and YAP. Mol Cancer Res; 15(12); 1777-91. ©2017 AACR . ©2017 American Association for Cancer Research.

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

    NASA Technical Reports Server (NTRS)

    Dolan, Thomas J

    1942-01-01

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

  13. Anabolic actions of Notch on mature bone

    PubMed Central

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

    2016-01-01

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

  14. Experimental study of the fracture toughness of a ceramic/ceramic-matrix composite sandwich structure

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

    Li, Z.; Taya, M.; Dunn, M.L.

    A hybrid experimental-numerical approach has been used to measure the fracture resistance of a sandwich structure consisting of a 304 stainless steel/partially stabilized zirconia ceramic-matrix composite crack-arresting layer embedded in a partially stabilized zirconia ceramic specimen. The mode 1 fracture toughness increases significantly when the crack propagates from the ceramic into the ceramic-matrix composite region. The increased toughening due to the stainless steel particles is explained reasonably well by a toughening model based on processing-induced thermal residual stresses. In addition, several experimental modifications were made to the chevron-notch wedge-loaded double cantilever beam specimen to overcome numerous problems encountered in generatingmore » a precrack in the small, brittle specimens used in this study.« less

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2017-07-01

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

  17. Non-canonical NOTCH3 signalling limits tumour angiogenesis.

    PubMed

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

    2017-07-18

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

  18. Non-canonical NOTCH3 signalling limits tumour angiogenesis

    PubMed Central

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

    2017-01-01

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

  19. Effects of the HIF1 inhibitor, echinomycin, on growth and NOTCH signalling in leukaemia cells.

    PubMed

    Yonekura, Satoru; Itoh, Mai; Okuhashi, Yuki; Takahashi, Yusuke; Ono, Aya; Nara, Nobuo; Tohda, Shuji

    2013-08-01

    To examine the effects of echinomycin, a compound that inhibits DNA-binding activity of hypoxia-inducible factor-1 (HIF1), on leukaemia cell growth. Three acute myeloid leukaemia cell lines and three T-lymphoblastic leukaemia cell lines were cultured with echinomycin. Cell growth, mRNA and protein expression levels were examined by WST-1 assay, reverse-transcription polymerase chain reaction and immunoblotting, respectively. HIF1α protein was expressed in all cell lines under normoxia. Treatment with echinomycin suppressed cell growth and induced apoptosis in association with decreased mRNA expression of HIF1 targets, glucose transporter-1 (GLUT1) and B-cell CLL/lymphoma-2 (BCL2). Echinomycin also suppressed the protein expression of NOTCH1, cleaved NOTCH1, v-myc myelocytomatosis viral oncogene homolog (MYC), v-akt murine thymoma viral oncogene homolog-1 (AKT), phosphorylated AKT, mechanistic target of rapamycin (mTOR), and phosphorylated mTOR and increased that of cleaved caspase-3 in some cell lines. Echinomycin suppresses leukaemia cell growth in association with reduced NOTCH1 expression. This is the first report to show that HIF inhibitor treatment suppresses NOTCH1 signalling. HIF inhibitors could be novel candidates for a molecular-targeted therapy against leukaemia.

  20. Eddy current standards - Cracks versus notches

    NASA Astrophysics Data System (ADS)

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

    1992-10-01

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

  1. Continuum Damage Modeling for Dynamic Fracture Toughness of Metal Matrix Composites

    NASA Astrophysics Data System (ADS)

    Lee, Intaek; Ochi, Yasuo; Bae, Sungin; Song, Jungil

    Short fiber reinforced metal-matrix composites (MMCs) have widely adopted as structural materials and many experimental researches have been performed to study fracture toughness of it. Fracture toughness is often referred as the plane strain(maximum constraint) fracture toughness KIc determined by the well-established standard test method, such as ASTM E399. But the application for dynamic fracture toughness KId has not been popular yet, because of reliance in capturing the crack propagating time. This paper deals with dynamic fracture toughness testing and simulation using finite element method to evaluate fracture behaviors of MMCs manufactured by squeeze casting process when material combination is varied with the type of reinforcement (appearance, size), volume fraction and combination of reinforcements, and the matrix alloy. The instrumented Charphy impact test was used for KId determination and continuum damage model embedded in commercial FE program is used to investigate the dynamic fracture toughness with the influence of elasto-visco-plastic constitutive relation of quasi-brittle fracture that is typical examples of ceramics and some fibre reinforced composites. With Compared results between experimental method and FE simulation, the determination process for KId is presented. FE simulation coupled with continuum damage model is emphasized single shot simulation can predict the dynamic fracture toughness, KId and real time evolution of that directly.

  2. Effect of Heat Treatment on the Impact Toughness of `High-Chromium Cast Iron - Low Alloy Steel' Bimetal Components

    NASA Astrophysics Data System (ADS)

    Özdemir, Z.

    2017-03-01

    A bimetallic `low-alloy steel - high-chromium cast iron' composite obtained by successive sand casting is studied and shown to have good cohesion on the interface and no casting defects. The hardness and the impact toughness of the bimetal increase simultaneously. The microstructure is more homogeneous after diffusion annealing at 1040°C, rapid cooling, and 3-h tempering at 270°C.

  3. Evaluation of weldments in type 21-6-9 stainless steel for compact ignition tokamak structural applications, phase 1

    NASA Astrophysics Data System (ADS)

    Alexander, D. J.; Goodwin, G. M.; Bloom, E. E.

    1991-06-01

    Primary design considerations for the Compact Ignition Tokamak toroidal field-coil cases are yield strength and toughness in the temperature range from 77 to 300 K. Type 21-6-9 stainless steel, also still known by its original Armco Steel Company trade name Nitronic 40, is the proposed alloy for this application. It has high yield strength and usually adequate base metal toughness, but weldments in thick sections have not been adequately characterized in terms of mechanical properties or hot-cracking propensity. In this study, weldability of the alloy in heavy sections and the mechanical properties of the resultant welds were investigated including tensile yield strength and Charpy V-notch toughness at 77 K and room temperature. Weldments were made in four different base metals using seven different filler metals. None of the weldments showed any indication of hot-cracking problems. All base metals, including weldment heat-affected zones, were found to have adequate strength and impact toughness at both test temperatures. Weld metals, on the other hand, except ERNiCr-3 and ENiCrFe-3, had impact toughnesses of less than 67 J at 77 K. Inconel 82 had an average weld metal impact toughness of over 135 J at 77 K, and although its strength at 77 K is less than that of type 21-6-9 base metal, at this point it is considered to be the first-choice filler metal. Phase 2 of this program will concentrate on composition refinement and process/procedure optimization for the generic ERNiCr-3 composition and will generate a design data base for base and weld metal, including tensile, fracture toughness, and crack growth rate data.

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

    PubMed

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

    2016-11-24

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

  5. 46 CFR 54.05-16 - Production toughness testing.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... tests, the V-notch is to be centered between the fusion lines. For the heat affected zone tests, the... material shall be taken from one of the heats of material used in the vessel, and both the electrodes and... successive tests between the weld metal and heat affected zone. Thus, approximately half of all weld...

  6. 46 CFR 54.05-16 - Production toughness testing.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... tests, the V-notch is to be centered between the fusion lines. For the heat affected zone tests, the... material shall be taken from one of the heats of material used in the vessel, and both the electrodes and... successive tests between the weld metal and heat affected zone. Thus, approximately half of all weld...

  7. 46 CFR 54.05-16 - Production toughness testing.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... tests, the V-notch is to be centered between the fusion lines. For the heat affected zone tests, the... material shall be taken from one of the heats of material used in the vessel, and both the electrodes and... successive tests between the weld metal and heat affected zone. Thus, approximately half of all weld...

  8. 46 CFR 54.05-16 - Production toughness testing.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... tests, the V-notch is to be centered between the fusion lines. For the heat affected zone tests, the... material shall be taken from one of the heats of material used in the vessel, and both the electrodes and... successive tests between the weld metal and heat affected zone. Thus, approximately half of all weld...

  9. Benchmark notch test for life prediction

    NASA Technical Reports Server (NTRS)

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

    1982-01-01

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

  10. Modeling and simulation of Charpy impact test of maraging steel 300 using Abaqus

    NASA Astrophysics Data System (ADS)

    Madhusudhan, D.; Chand, Suresh; Ganesh, S.; Saibhargavi, U.

    2018-03-01

    This work emphasizes the modeling and simulation of Charpy impact test to evaluate fracture energy at different pendulum velocities of armor maraging steel 300 using ABAQUS. To evaluate the fracture energy, V-notch specimen is fractured using the Johnson and Cook Damage model. The Charpy impact tests are of great importance related to fracture properties of steels. The objective of this work is to present absorbed energy variation at pendulum velocities of 5 m/sec, 6 m/sec, 7 m/sec and 9 m/sec in addition to stress distribution at v-notch. Finite Element Method of modeling for three dimensional specimens is used for simulation in commercial software of ABAQUS.

  11. Effect of microstructure on the impact toughness and temper embrittlement of SA508Gr.4N steel for advanced pressure vessel materials.

    PubMed

    Yang, Zhiqiang; Liu, Zhengdong; He, Xikou; Qiao, Shibin; Xie, Changsheng

    2018-01-09

    The effect of microstructure on the impact toughness and the temper embrittlement of a SA508Gr.4N steel was investigated. Martensitic and bainitic structures formed in this material were examined via scanning electron microscopy, electron backscatter diffraction, transmission electron microscopy, and Auger electron spectroscopy (AES) analysis. The martensitic structure had a positive effect on both the strength and toughness. Compared with the bainitic structure, this structure consisted of smaller blocks and more high-angle grain boundaries (HAGBs). Changes in the ultimate tensile strength and toughness of the martensitic structure were attributed to an increase in the crack propagation path. This increase resulted from an increased number of HAGBs and refinement of the sub-structure (block). The AES results revealed that sulfur segregation is higher in the martensitic structure than in the bainitic structure. Therefore, the martensitic structure is more susceptible to temper embrittlement than the bainitic structure.

  12. Notch3 negatively regulates chemoresistance in breast cancers.

    PubMed

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

    2016-10-14

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

  13. Fracture Toughness of Thin Plates by the Double-Torsion Test Method

    NASA Technical Reports Server (NTRS)

    Salem, Jonathan A.; Radovic, Miladin; Lara-Curzio, Edgar; Nelson, George

    2006-01-01

    Double torsion testing can produce fracture toughness values without crack length measurement that are comparable to those measured via standardized techniques such as the chevron-notch, surface-crack-in-flexure and precracked beam if the appropriate geometry is employed, and the material does not exhibit increasing crack growth resistance. Results to date indicate that 8 < W/d < 80 and L/W > 2 are required if crack length is not considered in stress intensity calculations. At L/W = 2, the normalized crack length should be 0.35 < a/L < 0.65; whereas for L/W = 3, 0.2 < a/L < 0.75 is acceptable. In addition, the load-points need to roll to reduce friction. For an alumina exhibiting increasing crack growth resistance, values corresponding to the plateau of the R-curve were measured. For very thin plates (W/d > 80) nonlinear effects were encountered.

  14. Notch Antennas

    NASA Technical Reports Server (NTRS)

    Lee, Richard Q.

    2004-01-01

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

  15. Flexural toughness of steel fiber reinforced high performance concrete containing nano-SiO2 and fly ash.

    PubMed

    Zhang, Peng; Zhao, Ya-Nan; Li, Qing-Fu; Wang, Peng; Zhang, Tian-Hang

    2014-01-01

    This paper aims to clarify the effect of steel fiber on the flexural toughness of the high performance concrete containing fly ash and nano-SiO2. The flexural toughness was evaluated by two methods, which are based on ASTM C1018 and DBV-1998, respectively. By means of three-point bending method, the flexural toughness indices, variation coefficients of bearing capacity, deformation energy, and equivalent flexural strength of the specimen were measured, respectively, and the relational curves between the vertical load and the midspan deflection (P(V)-δ) were obtained. The results indicate that steel fiber has great effect on the flexural toughness parameters and relational curves (P(V)-δ) of the three-point bending beam specimen. When the content of steel fiber increases from 0.5% to 2%, the flexural toughness parameters increase gradually and the curves are becoming plumper and plumper with the increase of steel fiber content, respectively. However these flexural toughness parameters begin to decrease and the curves become thinner and thinner after the steel fiber content exceeds 2%. It seems that the contribution of steel fiber to the improvement of flexural toughness of the high performance concrete containing fly ash and nano-SiO2 is well performed only when the steel fiber content is less than 2%.

  16. Targeting the Notch signaling pathway in autoimmune diseases.

    PubMed

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

    2010-05-01

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

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

    PubMed Central

    Palomero, Teresa; Ferrando, Adolfo

    2008-01-01

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

  18. Influence of TiN Inclusions on the Cleavage Fracture Behavior of Low-Carbon Microalloyed Steels

    NASA Astrophysics Data System (ADS)

    Yan, W.; Shan, Y. Y.; Yang, K.

    2007-06-01

    Toughness is a major concern for low-carbon microalloyed steels. In this work, the impact fracture behavior of two low-carbon Ti-V microalloyed steels was investigated in order to better understand the role of TiN inclusions in the toughness of the steels. The steels had similar chemical compositions and were manufactured by the same rolling process. However, there was an obvious difference in the ductile brittle transition temperature (DBTT) in the Charpy V-notch (CVN) impact tests of the two steels; one (steel 1) possessing a DBTT below -20 °C, while the DBTT of the other (steel 2) was above 15 °C. Scanning electron microscopy (SEM) fractography revealed that there were TiN inclusions at the cleavage fracture initiation sites on the fracture surfaces of steel 2 at both low and room temperatures. It is shown that the TiN inclusions had nucleated on Al2O3 particles and that they had pre-existing interior flaws. A high density of TiN inclusions was found in steel 2, but there was a much lower density in steel 1. Analysis indicates that these inclusions were responsible for the shift of DBTT to a higher temperature in steel 2. A mechanism is proposed for understanding the effect of the size and density of TiN inclusions on the fracture behavior, and the cleavage fracture initiation process is analyzed in terms of the distribution and development of stresses ahead of the notch tip during fracture at both low and room temperatures.

  19. Biochemical Characterization and Cellular Effects of CADASIL Mutants of NOTCH3

    PubMed Central

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

    2012-01-01

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

  20. Characterization of Multilayered Multipass Friction Stir Weld on ASTM A572 G50 Steel

    DOE PAGES

    Lim, Yong Chae; Sanderson, Samuel; Mahoney, Murray; ...

    2014-01-01

    A multilayered multipass friction stir weld (MM-FSW) on ASTM A572 Grade 50 steel was characterized to understand its potential application for thick-section structures. The 15-mm-thick section was fabricated by stacking up three steel plates and then friction stir welding the plates together in a total of 5 passes. The unique butt/lap joint configuration encountered in the multilayer weld was examined to understand the effect of tool rotation direction on the joint quality especially the formation of hooking defect. Charpy V-notch impact toughness tests showed generally higher impact toughness energy for the stir zone than the base metal with a ductilemore » fracture mode. The microhardness value was measured from 195 to 220 HV in the stir zone, while the base metal showed an average value of 170 HV. The microstructure in the stir zone and the adjacent heat affected zone was quantified using Optical and Scanning Electron Microscopy (SEM) including Electron Backscatter Diffraction (EBSD). The increased toughness and hardness were correlated with the refined microstructure in stir zone, resulting from severe plastic deformation and subsequent dynamic recrystallization during friction stir welding.« less

  1. Inhibition of Delta-induced Notch signaling using fucose analogs

    PubMed Central

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

    2017-01-01

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

  2. TRITIUM EFFECTS ON WELDMENT FRACTURE TOUGHNESS

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

    Morgan, M; Michael Tosten, M; Scott West, S

    2006-07-17

    The effects of tritium on the fracture toughness properties of Type 304L stainless steel and its weldments were measured. Fracture toughness data are needed for assessing tritium reservoir structural integrity. This report provides data from J-Integral fracture toughness tests on unexposed and tritium-exposed weldments. The effect of tritium on weldment toughness has not been measured until now. The data include tests on tritium-exposed weldments after aging for up to three years to measure the effect of increasing decay helium concentration on toughness. The results indicate that Type 304L stainless steel weldments have high fracture toughness and are resistant to tritiummore » aging effects on toughness. For unexposed alloys, weldment fracture toughness was higher than base metal toughness. Tritium-exposed-and-aged base metals and weldments had lower toughness values than unexposed ones but still retained good toughness properties. In both base metals and weldments there was an initial reduction in fracture toughness after tritium exposure but little change in fracture toughness values with increasing helium content in the range tested. Fracture modes occurred by the dimpled rupture process in unexposed and tritium-exposed steels and welds. This corroborates further the resistance of Type 304L steel to tritium embrittlement. This report fulfills the requirements for the FY06 Level 3 milestone, TSR15.3 ''Issue summary report for tritium reservoir material aging studies'' for the Enhanced Surveillance Campaign (ESC). The milestone was in support of ESC L2-1866 Milestone-''Complete an annual Enhanced Surveillance stockpile aging assessment report to support the annual assessment process''.« less

  3. Effect of deformation twin on toughness in magnesium binary alloys

    NASA Astrophysics Data System (ADS)

    Somekawa, Hidetoshi; Inoue, Tadanobu; Tsuzaki, Kaneaki

    2015-08-01

    The impact of alloying elements on toughness was investigated using eight kinds of Mg-0.3 at.% X (X = Al, Ag, Ca, Gd, Mn, Pb, Y and Zn) binary alloys with meso-grained structures. These binary alloys had an average grain size of approximately 20 μm. The fracture toughness and crack propagation behaviour were influenced by the alloying elements; the Mg-Ag and Mg-Pb alloys had the highest and the lowest toughness amongst the alloys, respectively, irrespective of presence in their ? type deformation twins. The twin boundaries affected the crack propagation behaviour in most of the alloys; in contrast, not only was the fracture related to the twin boundaries, but also the intergranular fracture occurred in the alloys that included rare earth elements. The influential factor for toughness in the meso- and the coarse-grained magnesium alloys, which readily formed deformation twins during plastic deformation, was not the change in lattice parameter with chemical composition, but the twin boundary segregation energy.

  4. Finite element analysis of the end notched flexure specimen for measuring Mode II fracture toughness

    NASA Technical Reports Server (NTRS)

    Gillespie, J. W., Jr.; Carlsson, L. A.; Pipes, R. B.

    1986-01-01

    The paper presents a finite element analysis of the end-notched flexure (ENF) test specimen for Mode II interlaminar fracture testing of composite materials. Virtual crack closure and compliance techniques employed to calculate strain energy release rates from linear elastic two-dimensional analysis indicate that the ENF specimen is a pure Mode II fracture test within the constraints of small deflection theory. Furthermore, the ENF fracture specimen is shown to be relatively insensitive to process-induced cracks, offset from the laminate midplane. Frictional effects are investigated by including the contact problem in the finite element model. A parametric study investigating the influence of delamination length, span, thickness, and material properties assessed the accuracy of beam theory expressions for compliance and strain energy release rate, GII. Finite element results indicate that data reduction schemes based upon beam theory underestimate GII by approximately 20-40 percent for typical unidirectional graphite fiber composite test specimen geometries. Consequently, an improved data reduction scheme is proposed.

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

    PubMed Central

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

    2011-01-01

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

  6. Effects of Plasma ZrN Metallurgy and Shot Peening Duplex Treatment on Fretting Wear and Fretting Fatigue Behavior of Ti6Al4V Alloy

    PubMed Central

    Tang, Jingang; Liu, Daoxin; Zhang, Xiaohua; Du, Dongxing; Yu, Shouming

    2016-01-01

    A metallurgical zirconium nitride (ZrN) layer was fabricated using glow metallurgy using nitriding with zirconiuming prior treatment of the Ti6Al4V alloy. The microstructure, composition and microhardness of the corresponding layer were studied. The influence of this treatment on fretting wear (FW) and fretting fatigue (FF) behavior of the Ti6Al4V alloy was studied. The composite layer consisted of an 8-μm-thick ZrN compound layer and a 50-μm-thick nitrogen-rich Zr–Ti solid solution layer. The surface microhardness of the composite layer is 1775 HK0.1. A gradient in cross-sectional microhardness distribution exists in the layer. The plasma ZrN metallurgical layer improves the FW resistance of the Ti6Al4V alloy, but reduces the base FF resistance. This occurs because the improvement in surface hardness results in lowering of the toughness and increasing in the notch sensitivity. Compared with shot peening treatment, plasma ZrN metallurgy and shot peening composite treatment improves the FW resistance and enhances the FF resistance of the Ti6Al4V alloy. This is attributed to the introduction of a compressive stress field. The combination of toughness, strength, FW resistance and fatigue resistance enhance the FF resistance for titanium alloy. PMID:28773345

  7. Notch signaling regulates the responses of lipopolysaccharide-stimulated macrophages in the presence of immune complexes.

    PubMed

    Wongchana, Wipawee; Kongkavitoon, Pornrat; Tangtanatakul, Pattarin; Sittplangkoon, Chutamath; Butta, Patcharavadee; Chawalitpong, Supatta; Pattarakankul, Thitiporn; Osborne, Barbara A; Palaga, Tanapat

    2018-01-01

    Macrophages exhibit diverse effector phenotypes depending on the stimuli and their microenvironment. Classically activated macrophages are primed with interferon (IFN)γ and stimulated with pathogen-associated molecular patterns. They produce inflammatory mediators and inflammatory cytokines, such as IL-12. In the presence of immune complexes (ICs), activated macrophages have decreased IL-12 production and increased IL-10 production and presumably act as regulatory macrophages. Notch signaling has been shown to regulate the effector functions of classically activated macrophages. In this study, we investigated whether Notch signaling is active in lipopolysaccharide (LPS)-stimulated macrophages in the presence of ICs. LPS/IC stimulation increased the level of cleaved Notch1 in murine macrophages, while IC stimulation alone did not. Delta-like 4, but not Jagged1, was responsible for generating cleaved Notch1. The activation of Notch signaling by LPS/ICs depended upon NF-κB and MEK/Erk pathway activation. Macrophages with the targeted deletion of Rbpj, which encodes a DNA-binding protein central to canonical Notch signaling, produced significantly less IL-10 upon LPS/IC stimulation. A similar impact on IL-10 production was observed when Notch signaling was inhibited with a gamma-secretase inhibitor (GSI). Defects in NF-κB p50 nuclear localization were observed in GSI-treated macrophages and in Rbpj-/- macrophages, suggesting cross-regulation between the Notch and NF-κB pathways. Transcriptomic analysis revealed that Notch signaling regulates the transcription of genes involved in the cell cycle, macrophage activation, leukocyte migration and cytokine production in LPS/IC-stimulated macrophages. Taken together, these results suggest that the Notch signaling pathway plays an important role in regulating the functions of macrophages activated by LPS and ICs.

  8. Inland notches micromorphology

    NASA Astrophysics Data System (ADS)

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

    2017-04-01

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

  9. Notch and affinity boundaries in Drosophila.

    PubMed

    Herranz, Héctor; Milán, Marco

    2006-02-01

    Cells in multicellular organisms often do not intermingle freely with each other. Differential cell affinities can contribute to organizing cells into different tissues. Drosophila limbs and the vertebrate central nervous system are subdivided into compartments. Cells in adjacent compartments do not mix. Cell interactions mediated by Notch-family receptors have been implicated in the specification of these compartment boundaries. Two recent reports analyze the role of the Notch signaling pathway in the generation of an affinity boundary in the Drosophila wing. The first report analyzes the connection between Notch and the actin cytoskeleton. The second report analyzes the differential requirements of Notch and the transcription factor Suppressor of Hairless in generating the affinity boundary.

  10. Therapeutic targeting of NOTCH1 signaling in T-ALL

    PubMed Central

    Palomero, Teresa; Ferrando, Adolfo

    2010-01-01

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

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

    PubMed

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

    2014-09-01

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

  12. Mutations of NOTCH3 in childhood pulmonary arterial hypertension

    PubMed Central

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

    2014-01-01

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

  13. Flexural Toughness of Steel Fiber Reinforced High Performance Concrete Containing Nano-SiO2 and Fly Ash

    PubMed Central

    Zhao, Ya-Nan; Li, Qing-Fu; Wang, Peng; Zhang, Tian-Hang

    2014-01-01

    This paper aims to clarify the effect of steel fiber on the flexural toughness of the high performance concrete containing fly ash and nano-SiO2. The flexural toughness was evaluated by two methods, which are based on ASTM C1018 and DBV-1998, respectively. By means of three-point bending method, the flexural toughness indices, variation coefficients of bearing capacity, deformation energy, and equivalent flexural strength of the specimen were measured, respectively, and the relational curves between the vertical load and the midspan deflection (P V-δ) were obtained. The results indicate that steel fiber has great effect on the flexural toughness parameters and relational curves (P V-δ) of the three-point bending beam specimen. When the content of steel fiber increases from 0.5% to 2%, the flexural toughness parameters increase gradually and the curves are becoming plumper and plumper with the increase of steel fiber content, respectively. However these flexural toughness parameters begin to decrease and the curves become thinner and thinner after the steel fiber content exceeds 2%. It seems that the contribution of steel fiber to the improvement of flexural toughness of the high performance concrete containing fly ash and nano-SiO2 is well performed only when the steel fiber content is less than 2%. PMID:24883395

  14. Effect of Notched Strings on Tennis Racket Spin Performance: Ultrahigh-Speed Video Analysis of Spin Rate, Contact Time, and Post-Impact Ball Velocity

    NASA Astrophysics Data System (ADS)

    Kawazoe, Yoshihiko; Takeda, Yukihiro; Nakagawa, Masamichi

    While some tennis racket strings have more grip than others do, this does not guarantee that they will impart more spin to a tennis ball. Experiments with hand-held rackets are required to determine the longstanding question of how players can discern that different strings behave differently when laboratory tests indicate that they should play the same. In a previous study, we clarified the top-spin mechanism of a tennis racket by using high-speed video analysis on a tennis court for the first time. Furthermore, we improved it by using lubricated notched nylon strings. These experiments revealed that the more the main strings stretch and bend laterally, the more spin is imparted to the ball. This is due to the restoring force being parallel to the string face when the main strings spring back and the ball is released from the strings. Notched strings reduce the spin rate, but this can be effectively counteracted by employing lubricants. Furthermore, we found that imparting more spin reduces shock vibrations on the wrist during impact. The present study revealed that a ball has a 40% lower spin rate when hit with a racket with notched strings than with one with unnotched strings in the case of nylon (it had to be determined whether new strings or lubricated used strings give more spin). The experiments also showed that 30% more spin is imparted to a ball when the string intersections are lubricated by oil than when notched used nylon strings are used. Furthermore, we found that used natural gut notched strings reduced the spin rate by 70% compared to when new natural gut unnotched strings are used. We also investigated different top-spin behaviors obtained when professional and amateur tennis players hit a ball.

  15. Toughness and Matching Extension in Graphs,

    DTIC Science & Technology

    1986-05-01

    New York, 1977. V. CHVATAL 1973a. Tough graphs and Hamiltonian circuits, Discrete Math . 5, 1973, 215- 228. 1973b. New directions in Hamiltonian...PLUMMER 1986. Matching Theory, Ann. Discrete Math ., North-Holland, Amsterdam, 1986 (to appear). M. D. PLUMMER 1980. On n-extendable graphs, Discrete ... Math . 31, 1980, 201-210. 1985. A theorem on matchings in the plane, Conference in memory of Gabriel Dirac, Ann. Discrete Math ., North-Holland, Amsterdam

  16. A study of fiber volume fraction effects in notched unidirectional SCS-6/Ti-15V-3Cr-3Al-3Sn composite. Ph.D. Thesis Final Report

    NASA Technical Reports Server (NTRS)

    Covey, Steven J.

    1993-01-01

    Notched unidirectional SCS-6/Ti-15-3 composite of three different fiber volume fractions (vf = 0.15, 0.37, and 0.41) was investigated for various room temperature microstructural and material properties including: fatigue crack initiation, fatigue crack growth, and fracture toughness. While the matrix hardness is similar for all fiber volume fractions, the fiber/matrix interfacial shear strength and matrix residual stress increases with fiber volume fraction. The composite fatigue crack initiation stress is shown to be matrix controlled and occurs when the net maximum matrix stress approaches the endurance limit stress of the matrix. A model is presented which includes residual stresses and presents the composite initiation stress as a function of fiber volume fraction. This model predicts a maximum composite initiation stress at vf approximately 0.15 which agrees with the experimental data. The applied composite stress levels were increased as necessary for continued crack growth. The applied Delta(K) values at crack arrest increase with fiber volume fraction by an amount better approximated using an energy based formulation rather than when scaled linear with modulus. After crack arrest, the crack growth rate exponents for vf37 and vf41 were much lower and toughness much higher, when compared to the unreinforced matrix, because of the bridged region which parades with the propagating fatigue crack. However, the vf15 material exhibited a higher crack growth rate exponent and lower toughness than the unreinforced matrix because once the bridged fibers nearest the crack mouth broke, the stress redistribution broke all bridged fibers, leaving an unbridged crack. Degraded, unbridged behavior is modeled using the residual stress state in the matrix ahead of the crack tip. Plastic zone sizes were directly measured using a metallographic technique and allow prediction of an effective matrix stress intensity which agrees with the fiber pressure model if residual stresses

  17. A revisit to high-rate mode-II fracture characterization of composites with Kolsky bar techniques.

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

    Lu, Wei-Yang; Song, Bo; Jin, Huiqing

    2010-03-01

    Nowadays composite materials have been extensively utilized in many military and industrial applications. For example, the newest Boeing 787 uses 50% composite (mostly carbon fiber reinforced plastic) in production. However, the weak delamination strength of fiber reinforced composites, when subjected to external impact such as ballistic impact, has been always potential serious threats to the safety of passengers. Dynamic fracture toughness is a critical indicator of the performance from delamination in such impact events. Quasi-static experimental techniques for fracture toughness have been well developed. For example, end notched flexure (ENF) technique, which is illustrated in Fig. 1, has become amore » typical method to determined mode-II fracture toughness for composites under quasi-static loading conditions. However, dynamic fracture characterization of composites has been challenging. This has resulted in conflictive and confusing conclusions in regard to strain rate effects on fracture toughness of composites.« less

  18. Some Correlations between Plate Shatter and Fracture Toughness.

    DTIC Science & Technology

    1987-02-01

    temperatures. In this manner, any test for plate cracking should be akin to a Charpy test, where a series of notched test bars are broken over a...cracking under ballistic impact. The PSTT test is analogous to the transition temperature in a Charpy impact test, or to the nil ductility transition (NDT...210 C to -730 C. Standard Charpy specimens were machined from the plates and subsequently precracked in fatigue to about 2.5 mm and dynamically tested

  19. An Assessment of the Ductile Fracture Behavior of Hot Isostatically Pressed and Forged 304L Stainless Steel

    NASA Astrophysics Data System (ADS)

    Cooper, A. J.; Smith, R. J.; Sherry, A. H.

    2017-05-01

    Type 300 austenitic stainless steel manufactured by hot isostatic pressing (HIP) has recently been shown to exhibit subtly different fracture behavior from that of equivalent graded forged steel, whereby the oxygen remaining in the component after HIP manifests itself in the austenite matrix as nonmetallic oxide inclusions. These inclusions facilitate fracture by acting as nucleation sites for the initiation, growth, and coalescence of microvoids in the plastically deforming austenite matrix. Here, we perform analyses based on the Rice-Tracey (RT) void growth model, supported by instrumented Charpy and J-integral fracture toughness testing at ambient temperature, to characterize the degree of void growth ahead of both a V-notch and crack in 304L stainless steel. We show that the hot isostatically pressed (HIP'd) 304L steel exhibits a lower critical void growth at the onset of fracture than that observed in forged 304L steel, which ultimately results in HIP'd steel exhibiting lower fracture toughness at initiation and impact toughness. Although the reduction in toughness of HIP'd steel is not detrimental to its use, due to the steel's sufficiently high toughness, the study does indicate that HIP'd and forged 304L steel behave as subtly different materials at a microstructural level with respect to their fracture behavior.

  20. Notch signaling drives multiple myeloma induced osteoclastogenesis

    PubMed Central

    Colombo, Michela; Thümmler, Katja; Mirandola, Leonardo; Garavelli, Silvia; Todoerti, Katia; Apicella, Luana; Lazzari, Elisa; Lancellotti, Marialuigia; Platonova, Natalia; Akbar, Moeed; Chiriva-Internati, Maurizio; Soutar, Richard; Neri, Antonino; Goodyear, Carl S.; Chiaramonte, Raffaella

    2014-01-01

    Multiple myeloma (MM) is closely associated with bone destruction. Once migrated to the bone marrow, MM cells unbalance bone formation and resorption via the recruitment and maturation of osteoclast precursors. The Notch pathway plays a key role in different types of cancer and drives several biological processes relevant in MM, including cell localization within the bone marrow, proliferation, survival and pharmacological resistance. Here we present evidences that MM can efficiently drive osteoclastogenesis by contemporaneously activating Notch signaling on tumor cells and osteoclasts through the aberrant expression of Notch ligands belonging to the Jagged family. Active Notch signaling in MM cells induces the secretion of the key osteoclastogenic factor, RANKL, which can be boosted in the presence of stromal cells. In turn, MM cells-derived RANKL causes the upregulation of its receptor, RANK, and Notch2 in pre-osteoclasts. Notch2 stimulates osteoclast differentiation by promoting autocrine RANKL signaling. Finally, MM cells through Jagged ligands expression can also activate Notch signaling in pre-osteoclast by direct contact. Such synergism between tumor cells and pre-osteoclasts in MM-induced osteoclastogenesis can be disrupted by silencing tumor-derived Jagged1 and 2. These results make the Jagged ligands new promising therapeutic targets in MM to contrast bone disease and the associated co-morbidities. PMID:25257302

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Lina, Ioan A; Lauer, Amanda M

    2013-04-01

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

  3. Notch2 blockade enhances hematopoietic stem cell mobilization and homing.

    PubMed

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

    2017-10-01

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

  4. Effects of Microstructure on CVN Impact Toughness in Thermomechanically Processed High Strength Microalloyed Steel

    NASA Astrophysics Data System (ADS)

    Jia, Tao; Zhou, Yanlei; Jia, Xiaoxiao; Wang, Zhaodong

    2017-02-01

    Investigation on the correlation between microstructure and CVN impact toughness is of practical importance for the microstructure design of high strength microalloyed steels. In this work, three steels with characteristic microstructures were produced by cooling path control, i.e., steel A with granular bainite (GB), steel B with polygonal ferrite (PF) and martensite-austenite (M-A) constituent, and steel C with the mixture of bainitic ferrite (BF), acicular ferrite (AF), and M-A constituent. Under the same alloy composition and controlled rolling, similar ductile-to-brittle transition temperatures were obtained for the three steels. Steel A achieved the highest upper shelf energy (USE), while large variation of impact absorbed energy has been observed in the ductile-to-brittle transition region. With apparently large-sized PF and M-A constituent, steel B shows the lowest USE and delamination phenomenon in the ductile-to-brittle transition region. Steel C exhibits an extended upper shelf region, intermediate USE, and the fastest decrease of impact absorbed energy in the ductile-to-brittle transition region. The detailed CVN impact behavior is studied and then linked to the microstructural features.

  5. Characterization of a polymer-infiltrated ceramic-network material

    PubMed Central

    Corazza, Pedro H.; Zhang, Yu

    2015-01-01

    Objectives To characterize the microstructure and determine some mechanical properties of a polymer-ingfiltrated ceramic-network (PICN) material (Vita Enamic, Vita Zahnfabrik) available for CAD–CAM systems. Methods Specimens were fabricated to perform quantitative and qualitative analyses of the material’s microstructure and to determine the fracture toughness (KIc), density (ρ), Poisson’s ratio (v) and Young’s modulus (E). KIc was determined using V-notched specimens and the short beam toughness method, where bar-shaped specimens were notched and 3-point loaded to fracture. ρ was calculated using Archimedes principle, and v and E were measured using an ultrasonic thickness gauge with a combination of a pulse generator and an oscilloscope. Results Microstructural analyses showed a ceramic- and a polymer-based interpenetrating network. Mean and standard deviation values for the properties evaluated were: KIc = 1.09 ± 0.05 MPa m1/2, ρ = 2.09 ± 0.01 g/cm3, v = 0.23 ± 0.002 and E = 37.95 ± 0.34 GPa. Significance The PICN material showed mechanical properties between porcelains and resin-based composites, reflecting its microstructural components. PMID:24656471

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

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

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

    2015-03-01

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

  7. Discrete shear-transformation-zone plasticity modeling of notched bars

    NASA Astrophysics Data System (ADS)

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

    2018-02-01

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

  8. Notch strength of composites

    NASA Technical Reports Server (NTRS)

    Whitney, J. M.

    1983-01-01

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

  9. The Influence of Notches Under Static Stress

    NASA Technical Reports Server (NTRS)

    Matthaes, K

    1938-01-01

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

  10. Jury Toughness: The Impact of Conservatism on Criminal Court Verdicts.

    ERIC Educational Resources Information Center

    Levine, James P.

    1983-01-01

    Compared criminal court verdicts after trials with and without juries. A study of 58,336 trials of persons charged with felonies showed that juries convict substantially more often than judges trying cases alone. Jury toughness is seen as a response to the growth of popular conservatism on criminal justice issues. (JAC)

  11. Notch3 overexpression enhances progression and chemoresistance of urothelial carcinoma.

    PubMed

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

    2017-05-23

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

  12. Notch3 overexpression enhances progression and chemoresistance of urothelial carcinoma

    PubMed Central

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

    2017-01-01

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

  13. EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling

    PubMed Central

    Arasada, Rajeswara Rao; Amann, Joseph M.; Rahman, Mohammad A; Huppert, Stacey S.; Carbone, David P.

    2014-01-01

    Mutations in the epidermal growth factor receptor (EGFR) are the most common actionable genetic abnormalities yet discovered in lung cancer. However, targeting these mutations with kinase inhibitors is not curative in advanced disease and has yet to demonstrate an impact on potentially curable, early-stage disease, with some data suggesting adverse outcomes. Here, we report that treatment of EGFR-mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem-like cells through EGFR-dependent activation of Notch3. Additionally, we demonstrate that erlotinib treatment increases the clonogenicity of lung cancer cells in a sphere-forming assay, suggesting increased stem-like cell potential. We demonstrate that inhibition of EGFR kinase activity leads to activation of Notch transcriptional targets in a gamma secretase inhibitor sensitive manner and causes Notch activation. leading to an increase in ALDH high+ cells. We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3. This could explain the worsened survival observed in some studies of erlotinib treatment at early-stage disease, and suggests that specific dual targeting might overcome this adverse effect. PMID:25125655

  14. New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).

    PubMed

    Abramycheva, Natalya; Stepanova, Maria; Kalashnikova, Lyudmila; Zakharova, Maria; Maximova, Marina; Tanashyan, Marine; Lagoda, Olga; Fedotova, Ekaterina; Klyushnikov, Sergey; Konovalov, Rodion; Sakharova, Alla; Illarioshkin, Sergey

    2015-02-15

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebrovascular small-vessel disease caused by stereotyped mutations in the Notch3 gene altering the number of cysteine residues. We directly sequenced exons 2-23 of the Notch3 gene in 30 unrelated Russian patients with clinical/neuroimaging picture suggestive of CADASIL. To confirm the pathogenicity of new nucleotide variants, we used the standard bioinformatics tools and screened 200 ethnically matched individuals as controls. We identified 16 different point mutations in the Notch3 gene in 18 unrelated patients, including 4 new missense mutations (C194G, V252M, C338F, and C484G). All but two mutations affected the cysteine residue. The non-cysteine change V322M was shown to be associated with CADASIL-specific deposits of granular osmiophilic material in the vascular smooth-muscle cells, which confirmed the pathogenicity of this Notch3 variant. Two patients were shown to be compound-heterozygotes carrying two pathogenic Notch3 mutations. The disease was characterized by marked clinical variability, without evident phenotype-genotype correlations. In our sample, 60% of Russian patients with 'clinically suspected' CADASIL received the definitive molecularly proven diagnosis. Careful assessment of genealogical, clinical, and neuroimaging data in patients with lacunar stroke can help selecting patients with a high probability of finding mutations on genetic screening. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. 46 CFR 54.05-17 - Weld toughness test acceptance criteria.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Weld toughness test acceptance criteria. 54.05-17 Section 54.05-17 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING... impact tests the energy absorbed in both the weld metal and heat affected zone impact tests in weld...

  16. 46 CFR 54.05-17 - Weld toughness test acceptance criteria.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 2 2011-10-01 2011-10-01 false Weld toughness test acceptance criteria. 54.05-17 Section 54.05-17 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING... impact tests the energy absorbed in both the weld metal and heat affected zone impact tests in weld...

  17. 46 CFR 54.05-17 - Weld toughness test acceptance criteria.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Weld toughness test acceptance criteria. 54.05-17 Section 54.05-17 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING... impact tests the energy absorbed in both the weld metal and heat affected zone impact tests in weld...

  18. 46 CFR 54.05-17 - Weld toughness test acceptance criteria.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Weld toughness test acceptance criteria. 54.05-17 Section 54.05-17 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING... impact tests the energy absorbed in both the weld metal and heat affected zone impact tests in weld...

  19. 46 CFR 54.05-17 - Weld toughness test acceptance criteria.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Weld toughness test acceptance criteria. 54.05-17 Section 54.05-17 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING... impact tests the energy absorbed in both the weld metal and heat affected zone impact tests in weld...

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

    PubMed

    Colin, Jérôme

    2012-06-06

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

  1. Strength, toughness and aging stability of highly-translucent Y-TZP ceramics for dental restorations.

    PubMed

    Zhang, Fei; Inokoshi, Masanao; Batuk, Maria; Hadermann, Joke; Naert, Ignace; Van Meerbeek, Bart; Vleugels, Jef

    2016-12-01

    The aim was to evaluate the optical properties, mechanical properties and aging stability of yttria-stabilized zirconia with different compositions, highlighting the influence of the alumina addition, Y 2 O 3 content and La 2 O 3 doping on the translucency. Five different Y-TZP zirconia powders (3 commercially available and 2 experimentally modified) were sintered under the same conditions and characterized by X-ray diffraction with Rietveld analysis and scanning electron microscopy (SEM). Translucency (n=6/group) was measured with a color meter, allowing to calculate the translucency parameter (TP) and the contrast ratio (CR). Mechanical properties were appraised with four-point bending strength (n=10), single edge V-notched beam (SEVNB) fracture toughness (n=8) and Vickers hardness (n=10). The aging stability was evaluated by measuring the tetragonal to monoclinic transformation (n=3) after accelerated hydrothermal aging in steam at 134°C, and the transformation curves were fitted by the Mehl-Avrami-Johnson (MAJ) equation. Data were analyzed by one-way ANOVA, followed by Tukey's HSD test (α=0.05). Lowering the alumina content below 0.25wt.% avoided the formation of alumina particles and therefore increased the translucency of 3Y-TZP ceramics, but the hydrothermal aging stability was reduced. A higher yttria content (5mol%) introduced about 50% cubic zirconia phase and gave rise to the most translucent and aging-resistant Y-TZP ceramics, but the fracture toughness and strength were considerably sacrificed. 0.2mol% La 2 O 3 doping of 3Y-TZP tailored the grain boundary chemistry and significantly improved the aging resistance and translucency. Although the translucency improvement by La 2 O 3 doping was less effective than for introducing a substantial amount of cubic zirconia, this strategy was able to maintain the mechanical properties of typical 3Y-TZP ceramics. Three different approaches were compared to improve the translucency of 3Y-TZP ceramics. Copyright

  2. The importance of fracture toughness in ultrafine and nanocrystalline bulk materials

    PubMed Central

    Pippan, R.; Hohenwarter, A.

    2016-01-01

    ABSTRACT The suitability of high-strength ultrafine and nanocrystalline materials processed by severe plastic deformation methods and aimed to be used for structural applications will strongly depend on their resistance against crack growth. In this contribution some general available findings on the damage tolerance of this material class will be summarized. Particularly, the occurrence of a pronounced fracture anisotropy will be in the center of discussion. In addition, the great potential of this generated anisotropy to obtain high-strength materials with exceptionally high fracture toughness in specific loading and crack growth directions will be enlightened. IMPACT STATEMENT Severely plastically deformed materials are reviewed in light of their damage tolerance. The frequently observed toughness anisotropy allows unprecedented fracture toughness – strength combinations. PMID:27570712

  3. Notch Signaling in Vascular Smooth Muscle Cells

    PubMed Central

    Baeten, J.T.; Lilly, B.

    2018-01-01

    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. PMID:28212801

  4. A review of chevron-notched fracture specimens

    NASA Technical Reports Server (NTRS)

    Newman, J. C., Jr.

    1984-01-01

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

  5. Change of Precipitation Behavior and Impact Toughness with Depths in Quenched Thick SAF 2507 Super Duplex Stainless Steel

    NASA Astrophysics Data System (ADS)

    Ahiale, Godwin Kwame; Kim, Doo-Hyun; Yang, Won-Jon; Lee, Jong-Hoon; Oh, Yong-Jun

    2018-03-01

    We investigated the change of precipitation behavior and impact resistance as a function of depth from the surface of thick block of SAF 2507 super duplex stainless steel with the thickness (T) of 200 mm after water quenching from 1050 °C. The amount of detrimental sigma phase increased smoothly until the depth of 0.25T, followed by a rapid increase from 0.25T to the center. However, the impact strength decreased significantly with only 1.3% of area fraction of sigma phase as the depth increased past 0.1T. Based on fractography analysis for the samples at such small depth ranges, the distance between the sigma phase particles affected the relative amount of initiating brittle cracks in front of the notch and was one of the crucial factors that dramatically reduced impact resistance with depth.

  6. Notch3 drives development and progression of cholangiocarcinoma

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  8. Subtask 12D3: Fracture properties of V-5Cr-5Ti Alloy

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

    Li, H.; Hamilton, M.L.; Jones, R.H.

    1995-03-01

    The purpose of this research is to investigate the effect of heat treatment on microstructure and fracture toughness of a V-5Cr-5Ti alloy in the range -50-100{degrees}C. Fracture toughness and impact tests were performed on a V-5Cr-5Ti alloy. Specimens annealed at 1125{degrees}C for 1 h and furnace cooled in a vacuum of 1.33 x 10{sup -5} Pa were brittle at room temperature (RT) and experienced a mixture of intergranular and cleavage fracture. Fracture toughness (J{sub IQ}) at RT was 52 kJ/m{sup 2} and the impact fracture energy (IFE) was 6 J. The IFE at -100{degrees}C was only 1 J. While specimensmore » exhibited high fracture toughness at 100{degrees}C (J{sub IQ} is 485 kj/m{sup 2}), fracture was a mixture of dimple and intergranular failure, with intergranular fracture making up 40% of the total fracture surface. The ductile to brittle transition temperature (DBTT) was estimated to be about 20{degrees}C. When some specimens were given an additional annealing at 890{degrees}C for 24 h, they became very ductile at RT and fractured by microvoid coalescence. The J{sub IQ} value increased from 52 kJ/m{sup 2} to {approximately}1100 kJ/m{sup 2}. The impact test failed to fracture specimens at RT due to a large amount of plastic deformation. 7 refs., 1 fig., 6 tabs.« less

  9. Electrochemical polishing of notches

    DOEpatents

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

    1989-02-21

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

  10. Electrochemical polishing of notches

    DOEpatents

    Kephart, Alan R.; Alberts, Alfred H.

    1989-01-01

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

  11. Sexual dimorphism of the suprascapular notch – morphometric study

    PubMed Central

    Jędrzejewski, Kazimierz S.; Topol, Mirosław

    2013-01-01

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

  12. Effects of irradiation to 4 dpa at 390 C on the fracture toughness of vanadium alloys

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

    Gruber, E.E.; Galvin, T.M.; Chopra, O.K.

    Fracture toughness J-R curve tests were conducted at room temperature on disk-shaped compact-tension DC(T) specimens of three vanadium alloys having a nominal composition of V-4Cr-4Ti. The alloys in the nonirradiated condition showed high fracture toughness; J{sub IC} could not be determined but is expected to be above 600 kJ/m{sup 2}. The alloys showed very poor fracture toughness after irradiation to 4 dpa at 390 C, e.g., J{sub IC} values of {approx}10 kJ/m{sup 2} or lower.

  13. Benchmark cyclic plastic notch strain measurements

    NASA Technical Reports Server (NTRS)

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

    1983-01-01

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

  14. Interpretation of Fracture Toughness and R-Curve Behavior by Direct Observation of Microfracture Process in Ti-Based Dendrite-Containing Amorphous Alloys

    NASA Astrophysics Data System (ADS)

    Jeon, Changwoo; Kim, Choongnyun Paul; Kim, Hyoung Seop; Lee, Sunghak

    2015-04-01

    Fracture properties of Ti-based amorphous alloys containing ductile β dendrites were explained by directly observing microfracture processes. Three Ti-based amorphous alloys were fabricated by adding Ti, Zr, V, Ni, Al, and Be into a Ti-6Al-4V alloy by a vacuum arc melting method. The effective sizes of dendrites varied from 63 to 104 μm, while their volume fractions were almost constant within the range from 74 to 76 pct. The observation of the microfracture of the alloy containing coarse dendrites revealed that a microcrack initiated at the amorphous matrix of the notch tip and propagated along the amorphous matrix. In the alloy containing fine dendrites, the crack propagation was frequently blocked by dendrites, and many deformation bands were formed near or in front of the propagating crack, thereby resulting in a zig-zag fracture path. Crack initiation toughness was almost the same at 35 to 36 MPa√m within error ranges in the three alloys because it was heavily affected by the stress applied to the specimen at the time of crack initiation at the crack tip as well as strength levels of the alloys. According to the R-curve behavior, however, the best overall fracture properties in the alloy containing fine dendrites were explained by mechanisms of blocking of the crack growth and crack blunting and deformation band formation at dendrites.

  15. Notch3 is necessary for blood vessel integrity in the central nervous system.

    PubMed

    Henshall, Tanya L; Keller, Annika; He, Liqun; Johansson, Bengt R; Wallgard, Elisabet; Raschperger, Elisabeth; Mäe, Maarja Andaloussi; Jin, Shaobo; Betsholtz, Christer; Lendahl, Urban

    2015-02-01

    Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution, and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood-brain barrier function is less well understood. In this report, we explored the impact of the loss of VSMC in the Notch3(-/-) mouse on blood vessel integrity in the central nervous system. Notch3(-/-) mice showed focal disruptions of the blood-brain barrier demonstrated by extravasation of tracers accompanied by fibrin deposition in the retinal vasculature. This blood-brain barrier leakage was accompanied by a regionalized and patchy loss of VSMC, with VSMC gaps predominantly in arterial resistance vessels of larger caliber. The loss of VSMC appeared to be caused by progressive degeneration of VSMC resulting in a gradual loss of VSMC marker expression and a progressive acquisition of an aberrant VSMC phenotype closer to the gaps, followed by enhanced apoptosis and cellular disintegration in the gaps. Arterial VSMC were the only mural cell type that was morphologically affected, despite Notch3 also being expressed in pericytes. Transcriptome analysis of isolated brain microvessels revealed gene expression changes in Notch3(-/-) mice consistent with loss of arterial VSMC and presumably secondary transcriptional changes were observed in endothelial genes, which may explain the compromised vascular integrity. We demonstrate that Notch3 is important for survival of VSMC, and reveal a critical role for Notch3 and VSMC in blood vessel integrity and blood-brain barrier function in the mammalian vasculature. © 2014 American Heart Association, Inc.

  16. Expression Profile of NOTCH3 in Mouse Spermatogonia.

    PubMed

    Okada, Ryu; Fujimagari, Megumi; Koya, Eri; Hirose, Yoshikazu; Sato, Tomomi; Nishina, Yukio

    2017-01-01

    Stable and sustainable spermatogenesis is supported by the strict regulation of self-renewal and differentiation of spermatogonial stem cells (SSC), which are a rare population of undifferentiated spermatogonia. It has been revealed that some signaling factors regulate the self-renewal of SSC; however, the molecular mechanism of SSC maintenance is still not completely understood. Notch signaling is an evolutionarily conserved juxtacrine signaling that plays important roles in the cell fate determination of various tissue stem cells. Recently, analyses of loss- and gain-of-function suggested that Notch signaling was necessary for normal spermatogenesis. However, the expression of Notch signal components in spermatogonia is still unclear. Here, we analyzed the distribution of NOTCH3-expressing spermatogonia and the target genes. Double immunostaining with differentiation markers revealed that NOTCH3 was expressed in some undifferentiated and differentiated spermatogonia in mouse testes. To define the target gene of Notch3 signaling in spermatogonia, we analyzed the mRNA expression pattern of Hes and Hey family genes during testis development. Hes1 abundance was decreased during testis development, suggesting that spermatogonia may express Hes1. Immunohistochemical analysis showed that HES1 was expressed in prepubertal spermatogonia, whereas it was expressed predominantly in adult Sertoli cells and weakly in adult spermatogonia. Furthermore, NOTCH3-HES1 double-positive spermatogonia were in pup and adult testes. These results suggest that Notch3 signaling in spermatogonia could promote Hes1 expression. © 2017 S. Karger AG, Basel.

  17. SOX1 links the function of neural patterning and Notch signalling in the ventral spinal cord during the neuron-glial fate switch

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

    Genethliou, Nicholas; Panayiotou, Elena; Department of Biological Sciences, University of Cyprus, P.O. Box 20537, 1678 Nicosia

    2009-12-25

    During neural development the transition from neurogenesis to gliogenesis, known as the neuron-glial ({Nu}/G) fate switch, requires the coordinated function of patterning factors, pro-glial factors and Notch signalling. How this process is coordinated in the embryonic spinal cord is poorly understood. Here, we demonstrate that during the N/G fate switch in the ventral spinal cord (vSC) SOX1 links the function of neural patterning and Notch signalling. We show that, SOX1 expression in the vSC is regulated by PAX6, NKX2.2 and Notch signalling in a domain-specific manner. We further show that SOX1 regulates the expression of Hes1 and that loss ofmore » Sox1 leads to enhanced production of oligodendrocyte precursors from the pMN. Finally, we show that Notch signalling functions upstream of SOX1 during this fate switch and is independently required for the acquisition of the glial fate perse by regulating Nuclear Factor I A expression in a PAX6/SOX1/HES1/HES5-independent manner. These data integrate functional roles of neural patterning factors, Notch signalling and SOX1 during gliogenesis.« less

  18. Ultrasonic ranking of toughness of tungsten carbide

    NASA Technical Reports Server (NTRS)

    Vary, A.; Hull, D. R.

    1983-01-01

    The feasibility of using ultrasonic attenuation measurements to rank tungsten carbide alloys according to their fracture toughness was demonstrated. Six samples of cobalt-cemented tungsten carbide (WC-Co) were examined. These varied in cobalt content from approximately 2 to 16 weight percent. The toughness generally increased with increasing cobalt content. Toughness was first determined by the Palmqvist and short rod fracture toughness tests. Subsequently, ultrasonic attenuation measurements were correlated with both these mechanical test methods. It is shown that there is a strong increase in ultrasonic attenuation corresponding to increased toughness of the WC-Co alloys. A correlation between attenuation and toughness exists for a wide range of ultrasonic frequencies. However, the best correlation for the WC-Co alloys occurs when the attenuation coefficient measured in the vicinity of 100 megahertz is compared with toughness as determined by the Palmqvist technique.

  19. Microstructure characterization and charpy toughness of P91 weldment for as-welded, post-weld heat treatment and normalizing & tempering heat treatment

    NASA Astrophysics Data System (ADS)

    Pandey, Chandan; Mahapatra, M. M.; Kumar, Pradeep; Giri, A.

    2017-09-01

    The effect of weld groove design and heat treatment on microstructure evolution and Charpy toughness of P91 pipe weldments was studied. The P91 pipe weldments were subjected to subcritical post weld heat treatment (760 °C-2 h) and normalizing/tempering conditions (normalized-1040 °C/40 min, air cooled; tempered 760 °C/2 h, air cooled) were employed. The influence of subsequent PWHT and N&T treatment on the microstructure of various zone of P91 pipe weldments were also investigated. The present investigation also described the effect of PWHT and N&T treatment on hardness, grain size, precipitate size, inter-particle spacing and fraction area of precipitates present in each zone of P91 pipe weldments. The result indicated great impact of heat treatment on the Charpy toughness and microstructure evolution of P91 weldments. The N&T treatment was found to be more effective heat treatment compared to subsequent PWHT. Charpy toughness value was found to be higher for narrow-groove design as compared to conventional V-groove design.

  20. Novel Mutation of the NOTCH3 Gene in a Chinese Pedigree with CADASIL.

    PubMed

    Hou, Xiaoxia; He, Chuan; Jin, Qingwen; Niu, Qi; Ren, Guang; Cheng, Hong

    2017-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) results from NOTCH3 gene mutations, which lead to the degeneration of vascular smooth muscle cells (VSMCs). The clinical presentation of CADASIL patients is dependent on the impact of other vascular risk factors and the type of NOTCH3 mutation present. Here, we report a rare pathogenic mutation on exon 14 of the NOTCH3 gene in a Chinese family affected by CADASIL with phenotypic peculiarities. We performed genetic testing, clinical and neuropsychological examination, brain magnetic resonance images (MRI), and electron microscopy (EM) in skin biopsies. NOTCH3 gene analysis revealed a c.2182CT substitution on exon 14, which is the first example of this mutation in a Chinese individual from the Han ancestry. Granular osmiophilic material (GOM) was found in the proband, and all patients had migraine, subcortical ischemic events, and mood disturbances, without progressive cognitive impairment. Cranial MRI further showed white matter hyperintensity, involving bilateral basal ganglia and multiple microbleeds (MBs), in the thalamus and brain stem. This study suggests that different missense mutations in NOTCH3 might contribute to atypical clinical features of CADASIL. This report also indicates that for individuals with a positive family history having clinical and neuroradiological findings suggestive of CADASIL, genetic testing and GOM detection should be performed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Magnetoresistance effect in permalloy nanowires with various types of notches

    NASA Astrophysics Data System (ADS)

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

    2018-05-01

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

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

    PubMed Central

    Butko, Emerald; Pouget, Claire; Traver, David

    2016-01-01

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

  3. The genetic spectrum and the evaluation of CADASIL screening scale in Chinese patients with NOTCH3 mutations.

    PubMed

    Liu, Xiao; Zuo, Yuehuan; Sun, Wei; Zhang, Wei; Lv, He; Huang, Yining; Xiao, Jiangxi; Yuan, Yun; Wang, Zhaoxia

    2015-07-15

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small artery disease caused by NOTCH3 gene mutation. Here we report clinical, pathological and genetic profiles of 29 newly-diagnosed CADASIL patients, evaluation of the CADASIL scale in Chinese CADASIL patients, and reanalysis of all reported mainland Chinese patients with identified NOTCH3 gene mutation. We found two novel mutations (p.C134G and p.C291Y) and 13 reported NOTCH3 mutations in the newly-diagnosed group. CADASIL scale score was less than the cutoff score in 19 of 53 Chinese patients with NOTCH3 mutation, generating only a sensitivity of 64.1%. At the time of study, the total number of genetically confirmed CADASIL cases reached 158 from 97 unrelated mainland Chinese families, with 9/97 (9.3%) sporadic patients. The NOTCH3 gene mutation profile showed 43 mutations, with hotspots in exon 4, followed by exon 3. The considerable variability in onset age and CADASIL scale score in patients carrying the same NOTCH3 missense mutation suggested no obvious phenotype-genotype correlation. In conclusion, we report two novel mutations which expand the NOTCH3 mutational spectrum. Exons 4 and 3 are hotspots in mainland Chinese patients with NOTCH3 mutation. The low sensitivity of CADASIL scale in our patients group indicated that the CADASIL scale should be refined according to the clinical characteristics of Chinese CADASIL patients when used in Chinese populations. Copyright © 2015. Published by Elsevier B.V.

  4. Oxide inclusions in laser additive manufactured stainless steel and their effects on impact toughness and stress corrosion cracking behavior

    NASA Astrophysics Data System (ADS)

    Lou, Xiaoyuan; Andresen, Peter L.; Rebak, Raul B.

    2018-02-01

    Intergranular and intragranular Si and Mn rich oxide inclusions are present in laser additive manufactured austenitic stainless steel. The uniform oxide dispersions in additive manufactured material promoted early initiation of microvoids and reduced its impact toughness relative to powder metallurgy (hot isostatic pressing) and wrought materials. For stress corrosion cracking in high temperature water, the silica inclusions along the grain boundaries preferentially dissolved and appeared to accelerate oxidation and caused extensive crack branching.

  5. Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry

    PubMed Central

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

    2013-01-01

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

  6. A methodology for the investigation of toughness and crack propagation in mouse bone.

    PubMed

    Carriero, Alessandra; Zimmermann, Elizabeth A; Shefelbine, Sandra J; Ritchie, Robert O

    2014-11-01

    Bone fracture is a health concern for those with aged bone and brittle bone diseases. Mouse bone is widely used as a model of human bone, especially to investigate preclinical treatment strategies. However, little is known about the mechanisms of mouse bone fracture and its similarities and differences from fracture in human bone. In this work we present a methodology to investigate the fracture toughness during crack initiation and crack propagation for mouse bone. Mouse femora were dissected, polished on their periosteal surface, notched on the posterior surface at their mid-diaphysis, and tested in three-point bending under displacement control at a rate of 0.1mm/min using an in situ loading stage within an environmental scanning electron microscope. We obtained high-resolution real-time imaging of the crack initiation and propagation in mouse bone. From the images we can measure the crack extension at each step of the crack growth and calculate the toughness of the bone (in terms of stress intensity factor (K) and work to fracture (Wf)) as a function of stable crack length (Δa), thus generating a resistance curve for the mouse bone. The technique presented here provides insight into the evolution of microdamage and the toughening mechanisms that resist crack propagation, which are essential for preclinical development of treatments to enhance bone quality and combat fracture risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    DOE PAGES

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

    2015-02-20

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

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

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

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

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

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

    PubMed

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

    2013-10-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    Lin, J.S.; Miyamoto, Y.

    The fracture behavior of graded Al{sub 2}O{sub 3}/TiC/Ni materials with a symmetric structure was investigated using single-edge notch-bend (SENB) specimens with surface compression. The fracture toughness of the graded materials was determined according to ASTM Standard E399. The results show that the effective fracture toughness increases with an increase in notch depth in the compressive stress zone, and reaches the maximum of 39.2 MPa m{sup 1/2} at the interface of compressive/tensile stress zones. Finite elements analysis reveals that the surface compression will be intensified at the notch root once the specimen is edge-notched because of the stress concentration, and themore » digress of the compressive stress intensification increases with an increase in notch depth. The dependence of the effective fracture toughness of the graded materials on the notch depth shows a behavior similar to the R-curve that is usually associated with microstructural toughening mechanisms. This toughening behavior is caused by the intensification of the compressive stress concentration with the increase of the notch depth. A theoretical analysis based on fracture mechanics verifies that the mechanical reliability of brittle ceramics can be improved effectively by tailoring and controlling the internal stresses.« less

  14. Scapular notching in reverse shoulder arthroplasty: validation of a computer impingement model.

    PubMed

    Roche, Christopher P; Marczuk, Yann; Wright, Thomas W; Flurin, Pierre-Henri; Grey, Sean G; Jones, Richard B; Routman, Howard D; Gilot, Gregory J; Zuckerman, Joseph D

    2013-01-01

    The purpose of this study is to validate a reverse shoulder computer impingement model and quantify the impact of implant position on scapular impingement by comparing it to that of a radiographic analysis of 256 patients who received the same prosthesis and were followed postoperatively for an average of 22.2 months. A geometric computer analysis quantified anterior and posterior scapular impingement as the humerus was internally and externally rotated at varying levels of abduction and adduction relative to a fixed scapula at defined glenoid implant positions. These impingement results were compared to radiographic study of 256 patients who were analyzed for notching, glenoid baseplate position, and glenosphere overhang. The computer model predicted no impingement at 0° humeral abduction in the scapular plane for the 38 mm, 42 mm, and 46 mm devices when the glenoid baseplate cage peg is positioned 18.6 mm, 20.4 mm, and 22.7 mm from the inferior glenoid rim (of the reamed glenoid) or when glenosphere overhang of 4.6 mm, 4.7 mm, and 4.5 mm was obtained with each size glenosphere, respectively. When compared to the radiographic analysis, the computer model correctly predicted impingement based upon glenoid base- plate position in 18 of 26 patients with scapular notching and based upon glenosphere overhang in 15 of 26 patients with scapular notching. Reverse shoulder implant positioning plays an important role in scapular notching. The results of this study demonstrate that the computer impingement model can effectively predict impingement based upon implant positioning in a majority of patients who developed scapular notching clinically. This computer analysis provides guidance to surgeons on implant positions that reduce scapular notching, a well-documented complication of reverse shoulder arthroplasty.

  15. 46 CFR 56.50-105 - Low-temperature piping.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... ASTM E 23 (incorporated by reference, see § 56.01-2), “Notched Bar Impact Testing of Metallic Materials”, Type A, Figure 4. The toughness testing requirements of subpart 54.05 of this subchapter shall be... testing of production weldments for low temperature piping systems and assemblies is not required. (3...

  16. Fracture toughness testing of polymer matrix composites

    NASA Technical Reports Server (NTRS)

    Grady, Joseph E.

    1992-01-01

    A review of the interlaminar fracture indicates that a standard specimen geometry is needed to obtain consistent fracture toughness measurements in polymer matrix composites. In general, the variability of measured toughness values increases as the toughness of the material increases. This variability could be caused by incorrect sizing of test specimens and/or inconsistent data reduction procedures. A standard data reduction procedure is therefore needed as well, particularly for the tougher materials. Little work has been reported on the effects of fiber orientation, fiber architecture, fiber surface treatment or interlaminar fracture toughness, and the mechanisms by which the fibers increase fracture toughness are not well understood. The little data that is available indicates that woven fiber reinforcement and fiber sizings can significantly increase interlaminar fracture toughness.

  17. Fracture Toughness and Strength in a New Class of Bainitic Chromium-Tungsten Steels

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

    Mao, S. X.; Sikka, V. K.

    This project dealt with developing an understanding of the toughening and stengthening mechanisms for a new class of Fe-3Cr-W(V) steels developed at Oak Ridge National Laboratory (ORNL) in collaboration with Nooter Corporation and other industrial partners. The new steele had 50% higher tensile strength up to 650 degrees Celsius than currently used steels and the potential for not requiring any postweld heat treatment (PWHT) and for reducing equipment weight by 25%. This project was closely related to the Nooter project described in the report Development of a New Class of Fe-3Cr-W(V) Ferritic steels for Industrial Process Applications (ORNL/TM-2005/82). The projectmore » was carried out jointly by the University of Pittsburgh and ORNL. The University of Pittsburgh carried out fracture toughness measurements and microstructural analysis on base metal and welded plates prepared at ORNL. The project focused on three areas. The first dealt with detailed microstructural analysis of base compositions of 3Cr-3WV and 3Cr-3WBV(Ta) in both normalized (N) and normalized and tempered (NT) conditions. The second aspect of the prject dealt with determining tensile properties and fracture toughness values of K{subIC} at room temperature for both 3Cr-3Wv and 3Cr-3WV(Ta) compositions. The third focus of the project was to measure the fracture toughness values of the base metal and the heat-affectged zone (HAZ) of a plate of Fe-3Cr-W(Mo)V steel plate welded by the gas tungsten are (GTA) process. The HAZ toughness was measured in both the as-welded and the PWHT condition.« less

  18. Tough Questions for Tough Times

    ERIC Educational Resources Information Center

    Parrett, William; Budge, Kathleen

    2009-01-01

    Six high-performing/high-poverty schools provide insights into what it takes to make a dramatic turnaround. School leaders had to make tough calls--and many of those decisions were about how to use resources. The budget in a high-performing, high-poverty school is a moral document, reflective of the school's beliefs about the conditions necessary…

  19. Control of lysosomal biogenesis and Notch-dependent tissue patterning by components of the TFEB-V-ATPase axis in Drosophila melanogaster.

    PubMed

    Tognon, Emiliana; Kobia, Francis; Busi, Ilaria; Fumagalli, Arianna; De Masi, Federico; Vaccari, Thomas

    2016-01-01

    In vertebrates, TFEB (transcription factor EB) and MITF (microphthalmia-associated transcription factor) family of basic Helix-Loop-Helix (bHLH) transcription factors regulates both lysosomal function and organ development. However, it is not clear whether these 2 processes are interconnected. Here, we show that Mitf, the single TFEB and MITF ortholog in Drosophila, controls expression of vacuolar-type H(+)-ATPase pump (V-ATPase) subunits. Remarkably, we also find that expression of Vha16-1 and Vha13, encoding 2 key components of V-ATPase, is patterned in the wing imaginal disc. In particular, Vha16-1 expression follows differentiation of proneural regions of the disc. These regions, which will form sensory organs in the adult, appear to possess a distinctive endolysosomal compartment and Notch (N) localization. Modulation of Mitf activity in the disc in vivo alters endolysosomal function and disrupts proneural patterning. Similar to our findings in Drosophila, in human breast epithelial cells we observe that impairment of the Vha16-1 human ortholog ATP6V0C changes the size and function of the endolysosomal compartment and that depletion of TFEB reduces ligand-independent N signaling activity. Our data suggest that lysosomal-associated functions regulated by the TFEB-V-ATPase axis might play a conserved role in shaping cell fate.

  20. Resin selection criteria for tough composite structures

    NASA Technical Reports Server (NTRS)

    Chamis, C. C.; Smith, G. T.

    1983-01-01

    Resin selection criteria are derived using a structured methodology consisting of an upward integrated mechanistic theory and its inverse (top-down structured theory). These criteria are expressed in a "criteria selection space" which are used to identify resin bulk properties for improved composite "toughness". The resin selection criteria correlate with a variety of experimental data including laminate strength, elevated temperature effects and impact resistance.

  1. Parkin mediates neuroprotection through activation of Notch1 signaling.

    PubMed

    Yoon, Ji-Hye; Ann, Eun-Jung; Kim, Mi-Yeon; Ahn, Ji-Seon; Jo, Eun-Hye; Lee, Hye-Jin; Lee, Hye-Won; Lee, Young Chul; Kim, Jeong-Sun; Park, Hee-Sae

    2017-02-04

    Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Inactivation of Parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins and ensuing neurodegeneration. In this study, we show that Parkin positively regulates the Notch1 signaling pathway. Overexpression of Parkin stabilized Notch1-IC protein levels, whereas knockdown of Parkin decreased Notch1-IC protein stability. Notably, overexpression of Parkin disrupted oxidative stress-induced apoptosis in neuronal cells. However, knockdown of Notch1 inhibited Parkin-induced neuronal cell survival. Together, these results indicate that Parkin is a novel regulator of the Notch1 signaling pathway, which promotes neuronal cell survival.

  2. Notch and the awesome power of genetics.

    PubMed

    Greenwald, Iva

    2012-07-01

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

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

    PubMed Central

    Gu, Yisu

    2016-01-01

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

  4. A Comparison of Mechanical Properties and Hydrogen Embrittlement Resistance of Austempered vs Quenched and Tempered 4340 Steel

    NASA Astrophysics Data System (ADS)

    Tartaglia, John M.; Lazzari, Kristen A.; Hui, Grace P.; Hayrynen, Kathy L.

    2008-03-01

    This study was conducted to compare the hydrogen embrittlement (HE) resistance of austempered 4340 steel with quenched and tempered (Q&T) 4340 steel with an identical yield strength (YS) of 1340 MPa (194 ksi). A baseline comparison showed that the austempered steel with a lower bainite microstructure exhibited higher hardness, tensile strengths, Charpy V-notch (CVN) impact toughness, and ductility at both low 233 K (-40 F) and ambient temperatures, as compared to the Q&T steel with a martensite microstructure. After machining and just prior to testing, subsized CVN specimens and notched bend specimens were immersed in hydrochloric acid-water baths. The HE resistance was higher for the austempered steel than the Q&T steel. No differences in room-temperature CVN energy resulted from hydrogen charging of the austempered and Q&T steels vs their unexposed counterparts. However, in the notched bend specimens, the hydrogen charging caused significant peak load decreases (40 pct) for the Q&T steel, while the austempered steel exhibited only small (6 pct) decreases in peak load. Intergranular (IG) fracture occurred solely in the charged Q&T bend samples, which is further evidence of their embrittlement.

  5. Mental toughness latent profiles in endurance athletes

    PubMed Central

    Zeiger, Robert S.

    2018-01-01

    Mental toughness in endurance athletes, while an important factor for success, has been scarcely studied. An online survey was used to examine eight mental toughness factors in endurance athletes. The study aim was to determine mental toughness profiles via latent profile analysis in endurance athletes and whether associations exist between the latent profiles and demographics and sports characteristics. Endurance athletes >18 years of age were recruited via social media outlets (n = 1245, 53% female). Mental toughness was measured using the Sports Mental Toughness Questionnaire (SMTQ), Psychological Performance Inventory-Alternative (PPI-A), and self-esteem was measured using the Rosenberg Self-Esteem Scale (RSE). A three-class solution emerged, designated as high mental toughness (High MT), moderate mental toughness (Moderate MT) and low mental toughness (Low MT). ANOVA tests showed significant differences between all three classes on all 8 factors derived from the SMTQ, PPI-A and the RSE. There was an increased odds of being in the High MT class compared to the Low MT class for males (OR = 1.99; 95% CI, 1.39, 2.83; P<0.001), athletes who were over 55 compared to those who were 18–34 (OR = 2.52; 95% CI, 1.37, 4.62; P<0.01), high sports satisfaction (OR = 8.17; 95% CI, 5.63, 11.87; P<0.001), and high division placement (OR = 2.18; 95% CI, 1.46,3.26; P<0.001). The data showed that mental toughness latent profiles exist in endurance athletes. High MT is associated with demographics and sports characteristics. Mental toughness screening in athletes may help direct practitioners with mental skills training. PMID:29474398

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

    PubMed Central

    Boucher, Joshua; Gridley, Thomas; Liaw, Lucy

    2012-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  8. Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma.

    PubMed

    Sajed, Dipti P; Faquin, William C; Carey, Chris; Severson, Eric A; H Afrogheh, Amir; A Johnson, Carl; Blacklow, Stephen C; Chau, Nicole G; Lin, Derrick T; Krane, Jeffrey F; Jo, Vickie Y; Garcia, Joaquín J; Sholl, Lynette M; Aster, Jon C

    2017-11-01

    NOTCH1 is frequently mutated in adenoid cystic carcinoma (ACC). To test the idea that immunohistochemical (IHC) staining can identify ACCs with NOTCH1 mutations, we performed IHC for activated NOTCH1 (NICD1) in 197 cases diagnosed as ACC from 173 patients. NICD1 staining was positive in 194 cases (98%) in 2 major patterns: subset positivity, which correlated with tubular/cribriform histology; and diffuse positivity, which correlated with a solid histology. To determine the relationship between NICD1 staining and NOTCH1 mutational status, targeted exome sequencing data were obtained on 14 diffusely NICD1-positive ACC specimens from 11 patients and 15 subset NICD1-positive ACC specimens from 15 patients. This revealed NOTCH1 gain-of-function mutations in 11 of 14 diffusely NICD1-positive ACC specimens, whereas all subset-positive tumors had wild-type NOTCH1 alleles. Notably, tumors with diffuse NICD1 positivity were associated with significantly worse outcomes (P=0.003). To determine whether NOTCH1 activation is unique among tumors included in the differential diagnosis with ACC, we performed NICD1 IHC on a cohort of diverse salivary gland and head and neck tumors. High fractions of each of these tumor types were positive for NICD1 in a subset of cells, particularly in basaloid squamous cell carcinomas; however, sequencing of basaloid squamous cell carcinomas failed to identify NOTCH1 mutations. These findings indicate that diffuse NICD1 positivity in ACC correlates with solid growth pattern, the presence of NOTCH1 gain-of-function mutations, and unfavorable outcome, and suggest that staining for NICD1 can be helpful in distinguishing ACC with solid growth patterns from other salivary gland and head and neck tumors.

  9. Notch and the Awesome Power of Genetics

    PubMed Central

    Greenwald, Iva

    2012-01-01

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

  10. Endothelial Notch signalling limits angiogenesis via control of artery formation

    PubMed Central

    Hasan, Sana S.; Tsaryk, Roman; Lange, Martin; Wisniewski, Laura; Moore, John C.; Lawson, Nathan D.; Wojciechowska, Karolina; Schnittler, Hans; Siekmann, Arndt F.

    2017-01-01

    Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial-venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation. PMID:28714969

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

    PubMed

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

    2013-10-14

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

  12. Notch3 marks clonogenic mammary luminal progenitor cells in vivo

    PubMed Central

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

    2013-01-01

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

  13. Expression of Notch1 and Numb in small cell lung cancer.

    PubMed

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

    2017-02-07

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

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

    PubMed

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

    2016-08-01

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

  15. Notched audiograms and noise exposure history in older adults.

    PubMed

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

    2009-12-01

    Using data from a population-based cohort study, we compared four published algorithms for identifying notched audiograms and compared their resulting classifications with noise exposure history. Four algorithms: (1) , (2) , (3) , and (4) were used to identify notched audiograms. Audiometric evaluations were collected as a part of the 10-yr follow-up examinations of the Epidemiology of Hearing Loss Study, in Beaver Dam, WI (2003-2005, N = 2395). Detailed noise exposure histories were collected by interview at the baseline examination (1993-1995) and updated at subsequent visits. An extensive history of occupational noise exposure, participation in noisy hobbies, and firearm usage was used to evaluate consistency of the notch classifications with the history of noise exposure. The prevalence of notched audiograms varied greatly by definition (31.7, 25.9, 47.2, and 11.7% for methods 1, 2, 3, and 4, respectively). In this cohort, a history of noise exposure was common (56.2% for occupational noise, 71.7% for noisy hobbies, 13.4% for firearms, and 81.2% for any of these three sources). Among participants with a notched audiogram, almost one-third did not have a history of occupational noise exposure (31.4, 33.0, 32.5, and 28.1% for methods 1, 2, 3, and 4, respectively), and approximately 11% did not have a history of exposure to any of the three sources of noise (11.5, 13.6, 10.3, and 7.6%). Discordance was greater in women than in men. These results suggest that there is a poor agreement across existing algorithms for audiometric notches. In addition, notches can occur in the absence of a positive noise history. In the absence of an objective consensus definition of a notched audiogram and in light of the degree of discordance in women between noise history and notches by each of these algorithms, researchers should be cautious about classifying noise-induced hearing loss by notched audiograms.

  16. Notched Audiograms and Noise Exposure History in Older Adults

    PubMed Central

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

    2009-01-01

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

  17. Tough cryogenic alloys from the Fe-Mn and Fe-Mn-Cr systems

    NASA Technical Reports Server (NTRS)

    Schanfein, M. J.; Zackay, V. F.; Morris, J. W., Jr.

    1974-01-01

    By adjusting composition, metastable gamma (austenite) and epsilon (hexagonal) martensite may be retained in Fe-Mn and Fe-Mn-Cr alloys and used to impact toughness through the TRIP mechanism. The resulting alloys have excellent toughness at cryogenic temperatures. The best alloys obtained to date are: Fe-20Mn, with sigma (sub y) = 79ksi and K sub IC = 275ksi square root of (in) at 77 K, and Fc-16Mn-8Cr, with sigma sub y = 85ksi and K sub IC = 72ksi square root of (in) at 77 K.

  18. Fracture modes in notched angleplied composite laminates

    NASA Technical Reports Server (NTRS)

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

    1984-01-01

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

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

    PubMed Central

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

    2006-01-01

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

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

    PubMed

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

    2018-01-01

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

  1. 46 CFR 54.05-6 - Toughness test temperatures.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Toughness test temperatures. 54.05-6 Section 54.05-6... Toughness Tests § 54.05-6 Toughness test temperatures. Each toughness test must be conducted at temperatures not warmer than −20 °F or 10 °F below the minimum service temperature, whichever is lower, except that...

  2. 46 CFR 54.05-6 - Toughness test temperatures.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Toughness test temperatures. 54.05-6 Section 54.05-6... Toughness Tests § 54.05-6 Toughness test temperatures. Each toughness test must be conducted at temperatures not warmer than −20 °F or 10 °F below the minimum service temperature, whichever is lower, except that...

  3. 46 CFR 54.05-6 - Toughness test temperatures.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 2 2011-10-01 2011-10-01 false Toughness test temperatures. 54.05-6 Section 54.05-6... Toughness Tests § 54.05-6 Toughness test temperatures. Each toughness test must be conducted at temperatures not warmer than −20 °F or 10 °F below the minimum service temperature, whichever is lower, except that...

  4. 46 CFR 54.05-6 - Toughness test temperatures.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Toughness test temperatures. 54.05-6 Section 54.05-6... Toughness Tests § 54.05-6 Toughness test temperatures. Each toughness test must be conducted at temperatures not warmer than −20 °F or 10 °F below the minimum service temperature, whichever is lower, except that...

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

    PubMed Central

    2010-01-01

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

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

    PubMed Central

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

    2015-01-01

    The NOTCH family of membranous receptors plays key roles during development and carcinogenesis. Since NOTCH2, yet not NOTCH1 has been shown essential for murine hepatogenesis, NOTCH2 rather than NOTCH1 may be more relevant to human hepatocarcinogenesis; however, no previous studies have supported this hypothesis. We therefore assessed the role of NOTCH2 in human hepatocellular carcinoma (HCC) by immunohistochemistry and cell culture. Immunohistochemically, 19% of primary HCCs showed nuclear staining for NOTCH2, indicating activated NOTCH2 signaling. NOTCH2-positive HCCs were on average in more advanced clinical stages, and exhibited more immature cellular morphology, i.e. higher nuclear-cytoplasmic ratios and nuclear densities. Such features were not evident in NOTCH1-positive HCCs. In human HCC cell lines, abundant NOTCH2 expression was associated with anaplasia, represented by loss of E-cadherin. When NOTCH2 signaling was stably downregulated in HLF cells, an anaplastic HCC cell line, the cells were attenuated in potential for in vitro invasiveness and migration, as well as in vivo tumorigenicity accompanied by histological maturation. Generally, inverse results were obtained for a differentiated HCC cell line, Huh7, manipulated to overexpress activated NOTCH2. These findings suggested that the NOTCH2 signaling may confer aggressive behavior and immature morphology in human HCC cells. PMID:26252838

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

    PubMed

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

    2015-10-01

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

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

    PubMed

    Dominguez, Maria

    2014-04-01

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

  9. PI3K/AKT signaling inhibits NOTCH1 lysosome-mediated degradation.

    PubMed

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

    2015-06-06

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

  10. iTOUGH2 Universal Optimization Using the PEST Protocol

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

    Finsterle, S.A.

    2010-07-01

    iTOUGH2 (http://www-esd.lbl.gov/iTOUGH2) is a computer program for parameter estimation, sensitivity analysis, and uncertainty propagation analysis [Finsterle, 2007a, b, c]. iTOUGH2 contains a number of local and global minimization algorithms for automatic calibration of a model against measured data, or for the solution of other, more general optimization problems (see, for example, Finsterle [2005]). A detailed residual and estimation uncertainty analysis is conducted to assess the inversion results. Moreover, iTOUGH2 can be used to perform a formal sensitivity analysis, or to conduct Monte Carlo simulations for the examination for prediction uncertainties. iTOUGH2's capabilities are continually enhanced. As the name implies, iTOUGH2more » is developed for use in conjunction with the TOUGH2 forward simulator for nonisothermal multiphase flow in porous and fractured media [Pruess, 1991]. However, iTOUGH2 provides FORTRAN interfaces for the estimation of user-specified parameters (see subroutine USERPAR) based on user-specified observations (see subroutine USEROBS). These user interfaces can be invoked to add new parameter or observation types to the standard set provided in iTOUGH2. They can also be linked to non-TOUGH2 models, i.e., iTOUGH2 can be used as a universal optimization code, similar to other model-independent, nonlinear parameter estimation packages such as PEST [Doherty, 2008] or UCODE [Poeter and Hill, 1998]. However, to make iTOUGH2's optimization capabilities available for use with an external code, the user is required to write some FORTRAN code that provides the link between the iTOUGH2 parameter vector and the input parameters of the external code, and between the output variables of the external code and the iTOUGH2 observation vector. While allowing for maximum flexibility, the coding requirement of this approach limits its applicability to those users with FORTRAN coding knowledge. To make iTOUGH2 capabilities accessible to many

  11. Association between high levels of Notch3 expression and high invasion and poor overall survival rates in pancreatic ductal adenocarcinoma.

    PubMed

    Zhou, Jin-Xue; Zhou, Liang; Li, Qing-Jun; Feng, Wen; Wang, Pei-Min; Li, Er-Feng; Gong, Wen-Jing; Kou, Ming-Wen; Gou, Wei-Ting; Yang, Yan-Ling

    2016-11-01

    Pancreatic ductal adenocarcinoma (PDAC) is a commonly fatal tumour. It is characterized by early metastasis and high mortality. Many patients die as a result of PDAC tumour progression. However, the underlying mechanism of invasion and metastasis in PDAC is still not fully understood. Previous studies showed that the Notch signalling pathway may play an important role in the progression of tumour invasion and metastasis. However, it is not yet known whether the Notch signalling pathway participates in the progression of invasion in PDAC. In the present study, immunohistochemistry showed that a high expression of Notch3 was correlated with tumour grade, metastasis, venous invasion and American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage. Kaplan-Meier curves suggested that a high expression of Notch3 was a significant risk factor for shortened survival time. We also showed that inhibition of Notch3 had an anti‑invasion role in PDAC cells. In vitro, the inhibition of Notch3 reduced the migration and invasion capabilities of PDAC cells by regulating the expressions of E-cadherin, CD44v6, MMP-2, MMP-9, VEGF and uPA via regulating the COX-2 and ERK1/2 pathways. These results indicated that downregulation of the Notch signalling pathway may be a novel and useful approach for preventing and treating PDAC invasion.

  12. 46 CFR 54.05-6 - Toughness test temperatures.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Toughness test temperatures. 54.05-6 Section 54.05-6 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PRESSURE VESSELS Toughness Tests § 54.05-6 Toughness test temperatures. Each toughness test must be conducted at temperatures not warmer than −20 °F or 10 °F below the...

  13. Synergistic antileukemic therapies in NOTCH1-induced T-ALL

    PubMed Central

    Sanchez-Martin, Marta; Ambesi-Impiombato, Alberto; Qin, Yue; Herranz, Daniel; Bansal, Mukesh; Girardi, Tiziana; Paietta, Elisabeth; Tallman, Martin S.; Rowe, Jacob M.; Califano, Andrea; Ferrando, Adolfo A.

    2017-01-01

    The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation–mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL. PMID:28174276

  14. Improved toughness of silicon carbide

    NASA Technical Reports Server (NTRS)

    Palm, J. A.

    1976-01-01

    Impact energy absorbing layers (EALs) comprised of partially densified silicon carbide were formed in situ on fully sinterable silicon carbide substrates. After final sintering, duplex silicon carbide structures resulted which were comprised of a fully sintered, high density silicon carbide substrate or core, overlayed with an EAL of partially sintered silicon carbide integrally bonded to its core member. Thermal cycling tests proved such structures to be moderately resistant to oxidation and highly resistant to thermal shock stresses. The strength of the developed structures in some cases exceeded but essentially it remained the same as the fully sintered silicon carbide without the EAL. Ballistic impact tests indicated that substantial improvements in the toughness of sintered silicon carbide were achieved by the use of the partially densified silicon carbide EALs.

  15. Optimizing Wear Resistance and Impact Toughness in High Chromium Iron Mo-Ni Alloy

    NASA Astrophysics Data System (ADS)

    Singh, K. K.; Verma, R. S.; Murty, G. M. D.

    2009-06-01

    An alloy with carbon and chromium in the range of 2.0 to 2.5% and 20 to 25%, respectively, with the addition of Mo and Ni in the range of 1.0 to 1.5% each when heat-treated at a quenching temperature of 1010 °C and tempering temperature of 550 °C produces a hardness in the range of 54 to 56 HRC and a microstructure that consists of discontinuous bands of high volume (35-40%) of wear resistant primary (eutectic) carbides in a tempered martensitic matrix with uniformly dispersed secondary precipitates. This alloy has been found to possess adequate impact toughness (5-6 J/cm2) with a wear resistance of the order of 3-4 times superior to Mn steel and 1.25 times superior to martensitic stainless steel with a reduction in cost-to-life ratio by a factor of 1.25 in both the cases.

  16. 46 CFR 154.610 - Design temperature not colder than 0 °C (32 °F).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

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

  17. Far infrared promotes wound healing through activation of Notch1 signaling.

    PubMed

    Hsu, Yung-Ho; Lin, Yuan-Feng; Chen, Cheng-Hsien; Chiu, Yu-Jhe; Chiu, Hui-Wen

    2017-11-01

    The Notch signaling pathway is critically involved in cell proliferation, differentiation, development, and homeostasis. Far infrared (FIR) has an effect that promotes wound healing. However, the underlying molecular mechanisms are unclear. In the present study, we employed in vivo and HaCaT (a human skin keratinocyte cell line) models to elucidate the role of Notch1 signaling in FIR-promoted wound healing. We found that FIR enhanced keratinocyte migration and proliferation. FIR induced the Notch1 signaling pathway in HaCaT cells and in a microarray dataset from the Gene Expression Omnibus database. We next determined the mRNA levels of NOTCH1 in paired normal and wound skin tissues derived from clinical patients using the microarray dataset and Ingenuity Pathway Analysis software. The result indicated that the Notch1/Twist1 axis plays important roles in wound healing and tissue repair. In addition, inhibiting Notch1 signaling decreased the FIR-enhanced proliferation and migration. In a full-thickness wound model in rats, the wounds healed more rapidly and the scar size was smaller in the FIR group than in the light group. Moreover, FIR could increase Notch1 and Delta1 in skin tissues. The activation of Notch1 signaling may be considered as a possible mechanism for the promoting effect of FIR on wound healing. FIR stimulates keratinocyte migration and proliferation. Notch1 in keratinocytes has an essential role in FIR-induced migration and proliferation. NOTCH1 promotes TWIST1-mediated gene expression to assist wound healing. FIR might promote skin wound healing in a rat model. FIR stimulates keratinocyte migration and proliferation. Notch1 in keratinocytes has an essential role in FIR-induced migration and proliferation. NOTCH1 promotes TWIST1-mediated gene expression to assist wound healing. FIR might promote skin wound healing in a rat model.

  18. On "Tough" Movement in Spanish.

    ERIC Educational Resources Information Center

    Reider, Michael

    1993-01-01

    A survey of native Spanish speakers from both Spain and Latin America found that the choice of predicate adjectives governing "tough" constructions in Spanish (e.g., "el libro es facil de leer") varies by individual, but some patterns did emerge that suggest "tough" constructions and "it is" constructions…

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. Conditional ablation of the Notch2 receptor in the ocular lens

    PubMed Central

    Saravanamuthu, Senthil S.; Le, Tien T.; Gao, Chun Y.; Cojocaru, Radu I.; Pandiyan, Pushpa; Liu, Chunqiao; Zhang, Jun; Zelenka, Peggy S.; Brown, Nadean L.

    2011-01-01

    Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation. PMID:22173065

  2. Fragment analysis represents a suitable approach for the detection of hotspot c.7541_7542delCT NOTCH1 mutation in chronic lymphocytic leukemia.

    PubMed

    Vavrova, Eva; Kantorova, Barbara; Vonkova, Barbara; Kabathova, Jitka; Skuhrova-Francova, Hana; Diviskova, Eva; Letocha, Ondrej; Kotaskova, Jana; Brychtova, Yvona; Doubek, Michael; Mayer, Jiri; Pospisilova, Sarka

    2017-09-01

    The hotspot c.7541_7542delCT NOTCH1 mutation has been proven to have a negative clinical impact in chronic lymphocytic leukemia (CLL). However, an optimal method for its detection has not yet been specified. The aim of our study was to examine the presence of the NOTCH1 mutation in CLL using three commonly used molecular methods. Sanger sequencing, fragment analysis and allele-specific PCR were compared in the detection of the c.7541_7542delCT NOTCH1 mutation in 201 CLL patients. In 7 patients with inconclusive mutational analysis results, the presence of the NOTCH1 mutation was also confirmed using ultra-deep next generation sequencing. The NOTCH1 mutation was detected in 15% (30/201) of examined patients. Only fragment analysis was able to identify all 30 NOTCH1-mutated patients. Sanger sequencing and allele-specific PCR showed a lower detection efficiency, determining 93% (28/30) and 80% (24/30) of the present NOTCH1 mutations, respectively. Considering these three most commonly used methodologies for c.7541_7542delCT NOTCH1 mutation screening in CLL, we defined fragment analysis as the most suitable approach for detecting the hotspot NOTCH1 mutation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Increased Notch3 Activity Mediates pathological Changes in Structure of Cerebral arteries

    PubMed Central

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

    2016-01-01

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

  4. Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner

    PubMed Central

    Coutaz, Manuel; Hurrell, Benjamin P.; Auderset, Floriane; Wang, Haiping; Siegert, Stefanie; Eberl, Gerard; Ho, Ping-Chih; Radtke, Freddy; Tacchini-Cottier, Fabienne

    2016-01-01

    Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion. An increase in Th17 cell frequency was similarly observed following immunization of T cell specific Notch mutant mice with OVA/CFA. However, in this setting, Th17 cytokine secretion was impaired, and increased intracellular retention of IL-17 was observed. Intracellular IL-17 co-localized with the CD71 iron transporter in the draining lymph node of both control and Notch-deficient Th17 cells. Immunization induced CD71 surface expression in control, but not in Notch-deficient Th17 cells, revealing defective CD71 intracellular transport in absence of Notch signaling. Moreover, Notch receptor deficient Th17 cells had impaired mTORC2 activity. These data reveal a context-dependent impact of Notch on vesicular transport during high metabolic demand suggesting a role for Notch signaling in the bridging of T cell metabolic demands and effector functions. Collectively, our findings indicate a prominent regulatory role for Notch signaling in the fine-tuning of Th17 cell differentiation and effector function. PMID:27974744

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

    NASA Technical Reports Server (NTRS)

    Knospe, C. R.

    1992-01-01

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

  6. Control of Cell Morphology: Signalling by the Receptor Notch.

    DTIC Science & Technology

    1996-10-01

    missense mutations or small deletions at the extreme C-terminus of NOTCH, and lie within the minimal region that includes the C-terminal binding site for...20 Figure 4. Genetic interaction of null and hypomorphic alleles of Notch with abl mutations ...wide variety of cell types during Drosophila embryogenesis [1, 2]. Mutations in the Notch gene lead to severe defects in cell identity in the nervous

  7. NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence.

    PubMed

    Parry, Aled J; Hoare, Matthew; Bihary, Dóra; Hänsel-Hertsch, Robert; Smith, Stephen; Tomimatsu, Kosuke; Mannion, Elizabeth; Smith, Amy; D'Santos, Paula; Russell, I Alasdair; Balasubramanian, Shankar; Kimura, Hiroshi; Samarajiwa, Shamith A; Narita, Masashi

    2018-05-09

    Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. We have recently identified that NOTCH1 can drive 'lateral induction' of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell-cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.

  8. The emerging roles of Notch signaling in leukemia and stem cells

    PubMed Central

    2013-01-01

    The Notch signaling pathway plays a critical role in maintaining the balance between cell proliferation, differentiation and apoptosis, and is a highly conserved signaling pathway that regulates normal development in a context- and dose-dependent manner. Dysregulation of Notch signaling has been suggested to be key events in a variety of hematological malignancies. Notch1 signaling appears to be the central oncogenic trigger in T cell acute lymphoblastic leukemia (T-ALL), in which the majority of human malignancies have acquired mutations that lead to constitutive activation of Notch1 signaling. However, emerging evidence unexpectedly demonstrates that Notch signaling can function as a potent tumor suppressor in other forms of leukemia. This minireview will summarize recent advances related to the roles of activated Notch signaling in human lymphocytic leukemia, myeloid leukemia, stem cells and stromal microenvironment, and we will discuss the perspectives of Notch signaling as a potential therapeutic target as well. PMID:24252593

  9. NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma.

    PubMed

    Edwards, Andrew K; Glithero, Kyle; Grzesik, Peter; Kitajewski, Alison A; Munabi, Naikhoba Co; Hardy, Krista; Tan, Qian Kun; Schonning, Michael; Kangsamaksin, Thaned; Kitajewski, Jan K; Shawber, Carrie J; Wu, June K

    2017-11-02

    Infantile hemangioma (IH) is a vascular tumor that begins with rapid vascular proliferation shortly after birth, followed by vascular involution in early childhood. We have found that NOTCH3, a critical regulator of mural cell differentiation and maturation, is expressed in hemangioma stem cells (HemSCs), suggesting that NOTCH3 may function in HemSC-to-mural cell differentiation and pathological vessel stabilization. Here, we demonstrate that NOTCH3 is expressed in NG2+PDGFRβ+ perivascular HemSCs and CD31+GLUT1+ hemangioma endothelial cells (HemECs) in proliferating IHs and becomes mostly restricted to the αSMA+NG2loPDGFRβlo mural cells in involuting IHs. NOTCH3 knockdown in HemSCs inhibited in vitro mural cell differentiation and perturbed αSMA expression. In a mouse model of IH, NOTCH3 knockdown or systemic expression of the NOTCH3 inhibitor, NOTCH3 Decoy, significantly decreased IH blood flow, vessel caliber, and αSMA+ perivascular cell coverage. Thus, NOTCH3 is necessary for HemSC-to-mural cell differentiation, and adequate perivascular cell coverage of IH vessels is required for IH vessel stability.

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

    PubMed

    Gahan, James M; Schnitzler, Christine E; DuBuc, Timothy Q; Doonan, Liam B; Kanska, Justyna; Gornik, Sebastian G; Barreira, Sofia; Thompson, Kerry; Schiffer, Philipp; Baxevanis, Andreas D; Frank, Uri

    2017-08-01

    The function of Notch signaling was previously studied in two cnidarians, Hydra and Nematostella, representing the lineages Hydrozoa and Anthozoa, respectively. Using pharmacological inhibition in Hydra and a combination of pharmacological and genetic approaches in Nematostella, it was shown in both animals that Notch is required for tentacle morphogenesis and for late stages of stinging cell maturation. Surprisingly, a role for Notch in neural development, which is well documented in bilaterians, was evident in embryonic Nematostella but not in adult Hydra. Adult neurogenesis in the latter seemed to be unaffected by DAPT, a drug that inhibits Notch signaling. To address this apparent discrepancy, we studied the role of Notch in Hydractinia echinata, an additional hydrozoan, in all life stages. Using CRISPR-Cas9 mediated mutagenesis, transgenesis, and pharmacological interference we show that Notch is dispensable for Hydractinia normal neurogenesis in all life stages but is required for the maturation of stinging cells and for tentacle morphogenesis. Our results are consistent with a conserved role for Notch in morphogenesis and nematogenesis across Cnidaria, and a lineage-specific loss of Notch dependence in neurogenesis in hydrozoans. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Notch Signaling in Postnatal Pituitary Expansion: Proliferation, Progenitors, and Cell Specification

    PubMed Central

    Nantie, Leah B.; Himes, Ashley D.; Getz, Dan R.

    2014-01-01

    Mutations in PROP1 account for up to half of the cases of combined pituitary hormone deficiency that result from known causes. Despite this, few signaling molecules and pathways that influence PROP1 expression have been identified. Notch signaling has been linked to Prop1 expression, but the developmental periods during which Notch signaling influences Prop1 and overall pituitary development remain unclear. To test the requirement for Notch signaling in establishing the normal pituitary hormone milieu, we generated mice with early embryonic conditional loss of Notch2 (conditional knockout) and examined the consequences of chemical Notch inhibition during early postnatal pituitary maturation. We show that loss of Notch2 has little influence on early embryonic pituitary proliferation but is crucial for postnatal progenitor maintenance and proliferation. In addition, we show that Notch signaling is necessary embryonically and postnatally for Prop1 expression and robust Pit1 lineage hormone cell expansion, as well as repression of the corticotrope lineage. Taken together, our studies identify temporal and cell type–specific roles for Notch signaling and highlight the importance of this pathway throughout pituitary development. PMID:24673559

  12. Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers.

    PubMed

    Choy, Lisa; Hagenbeek, Thijs J; Solon, Margaret; French, Dorothy; Finkle, David; Shelton, Amy; Venook, Rayna; Brauer, Matthew J; Siebel, Christian W

    2017-03-15

    Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc , and the mammary stem cell regulator Id4 This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers. Cancer Res; 77(6); 1439-52. ©2017 AACR . ©2017 American Association for Cancer Research.

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

    PubMed

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

    2016-05-01

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

  14. Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma.

    PubMed

    Mann, Christopher D; Bastianpillai, Christopher; Neal, Christopher P; Masood, Muhammad M; Jones, Donald J L; Teichert, Friederike; Singh, Rajinder; Karpova, Elena; Berry, David P; Manson, Margaret M

    2012-01-01

    In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

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

    DOE PAGES

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

    2017-03-02

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

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

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

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

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2017-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Buffat, Stephen J.

    1997-07-01

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

  20. Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family.

    PubMed

    Abou Al-Shaar, Hussam; Qadi, Najeeb; Al-Hamed, Mohamed H; Meyer, Brian F; Bohlega, Saeed

    2016-08-15

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic. To describe the clinical, radiological, and neuropsychological features in an extended CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation. The pedigree included 3 generations of a family with 13 affected individuals. The patients were examined clinically and radiologically. Neuropsychological testing was performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing. Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the heterozygous state. Homozygous individuals showed a slightly more severe clinical and radiological phenotype of earlier onset compared to their heterozygous counterparts. This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes carrying the same mutation. Both genetic modifiers and environmental factors may play an essential role in modification and alteration of the clinical phenotype and white matter changes among CADASIL patients. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    PubMed

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

    2017-07-01

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

  2. Notched-noise embedded frequency specific chirps for objective audiometry using auditory brainstem responses

    PubMed Central

    Corona-Strauss, Farah I.; Schick, Bernhard; Delb, Wolfgang; Strauss, Daniel J.

    2012-01-01

    It has been shown recently that chirp-evoked auditory brainstem responses (ABRs) show better performance than click stimulations, especially at low intensity levels. In this paper we present the development, test, and evaluation of a series of notched-noise embedded frequency specific chirps. ABRs were collected in healthy young control subjects using the developed stimuli. Results of the analysis of the corresponding ABRs using a time-scale phase synchronization stability (PSS) measure are also reported. The resultant wave V amplitude and latency measures showed a similar behavior as for values reported in literature. The PSS of frequency specific chirp-evoked ABRs reflected the presence of the wave V for all stimulation intensities. The scales that resulted in higher PSS are in line with previous findings, where ABRs evoked by broadband chirps were analyzed, and which stated that low frequency channels are better for the recognition and analysis of chirp-evoked ABRs. We conclude that the development and test of the series of notched-noise embedded frequency specific chirps allowed the assessment of frequency specific ABRs, showing an identifiable wave V for different intensity levels. Future work may include the development of a faster automatic recognition scheme for these frequency specific ABRs. PMID:26557336

  3. Role of Notch Signaling in Human Breast Cancer Pathogenesis

    DTIC Science & Technology

    2006-11-01

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

  4. Notch3 orchestrates epithelial and inflammatory responses to promote acute kidney injury.

    PubMed

    Kavvadas, Panagiotis; Keuylian, Zela; Prakoura, Niki; Placier, Sandrine; Dorison, Aude; Chadjichristos, Christos E; Dussaule, Jean-Claude; Chatziantoniou, Christos

    2018-07-01

    Acute kidney injury is a major risk factor for subsequent chronic renal and/or cardiovascular complications. Previous studies have shown that Notch3 was de novo expressed in the injured renal epithelium in the early phases of chronic kidney disease. Here we examined whether Notch3 is involved in the inflammatory response and the epithelial cell damage that typifies ischemic kidneys using Notch3 knockout mice and mice with short-term activated Notch3 signaling (N3ICD) in renal epithelial cells. After ischemia/reperfusion, N3ICD mice showed exacerbated infiltration of inflammatory cells and severe tubular damage compared to control mice. Inversely, Notch3 knockout mice were protected against ischemia/reperfusion injury. Renal macrophages derived from Notch3 knockout mice failed to activate proinflammatory cytokines. Chromatin immunoprecipitation analysis of the Notch3 promoter identified NF-κB as the principal inducer of Notch3 in ischemia/reperfusion. Thus, Notch3 induced by NF-κB in the injured epithelium sustains a proinflammatory environment attracting activated macrophages to the site of injury leading to a rapid deterioration of renal function and structure. Hence, targeting Notch3 may provide a novel therapeutic strategy against ischemia/reperfusion and acute kidney injury by preservation of epithelial structure and disruption of proinflammatory signaling. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  5. When the going gets tough: Mental toughness and its relationship with behavioural perseverance.

    PubMed

    Gucciardi, Daniel F; Peeling, Peter; Ducker, Kagan J; Dawson, Brian

    2016-01-01

    This study examined the association between self-reported mental toughness and behavioural perseverance among a sample of male Australian footballers in a naturalistic context. Cross-sectional field study, with the multistage 20m shuttle run test (MST) employed as a proxy for behavioural perseverance. 330 male Australian footballers aged between 15 and 18 years (M=16.86; SD=.71) with between 2 and 14 years playing experience (M=9.32; SD=2.51) participated. Initially, footballers completed a mental toughness questionnaire, before having their height and body mass measurements taken. Subsequently, a performance testing session was completed, which included the 20m sprint, Australian football-specific agility run, vertical jump, and the MST. Bayesian estimation was employed to allow for the simultaneous examination of existing findings with our new data in a way that provides an automatic meta-analysis of evidence in this area. The analysis indicated a 95% probability that the association between mental toughness and behavioural perseverance lies between .14 and .34, even when controlling for other factors known to influence MST performance, including age, height, body mass, and years playing experience. Taken together with previous research, these findings support the theoretical proposition that persistence, effort or perseverance represents a behavioural signature of mental toughness. Copyright © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  6. Test-Free Fracture Toughness

    NASA Technical Reports Server (NTRS)

    Minnetyan, Levon; Chamis, Christos C. (Technical Monitor)

    2003-01-01

    Computational simulation results can give the prediction of damage growth and progression and fracture toughness of composite structures. The experimental data from literature provide environmental effects on the fracture behavior of metallic or fiber composite structures. However, the traditional experimental methods to analyze the influence of the imposed conditions are expensive and time consuming. This research used the CODSTRAN code to model the temperature effects, scaling effects and the loading effects of fiber/braided composite specimens with and without fiber-optic sensors on the damage initiation and energy release rates. The load-displacement relationship and fracture toughness assessment approach is compared with the test results from literature and it is verified that the computational simulation, with the use of established material modeling and finite element modules, adequately tracks the changes of fracture toughness and subsequent fracture propagation for any fiber/braided composite structure due to the change of fiber orientations, presence of large diameter optical fibers, and any loading conditions.

  7. Test-Free Fracture Toughness

    NASA Technical Reports Server (NTRS)

    Minnetyan, Levon; Chamis, Christos C. (Technical Monitor)

    2003-01-01

    Computational simulation results can give the prediction of damage growth and progression and fracture toughness of composite structures. The experimental data from literature provide environmental effects on the fracture behavior of metallic or fiber composite structures. However, the traditional experimental methods to analyze the influence of the imposed conditions are expensive and time consuming. This research used the CODSTRAN code to model the temperature effects, scaling effects and the loading effects of fiberbraided composite specimens with and without fiber-optic sensors on the damage initiation and energy release rates. The load-displacement relationship and fracture toughness assessment approach is compared with the test results from literature and it is verified that the computational simulation, with the use of established material modeling and finite element modules, adequately tracks the changes of fracture toughness and subsequent fracture propagation for any fiberbraided composite structure due to the change of fiber orientations, presence of large diameter optical fibers, and any loading conditions.

  8. Layup Configuration Effect on Notch Residual Strength in Composite Laminates

    PubMed Central

    Santhanakrishnan Balakrishnan, Venkateswaran; Seidlitz, Holger

    2018-01-01

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

  9. Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis.

    PubMed

    MacGrogan, Donal; D'Amato, Gaetano; Travisano, Stanislao; Martinez-Poveda, Beatriz; Luxán, Guillermo; Del Monte-Nieto, Gonzalo; Papoutsi, Tania; Sbroggio, Mauro; Bou, Vanesa; Gomez-Del Arco, Pablo; Gómez, Manuel Jose; Zhou, Bin; Redondo, Juan Miguel; Jiménez-Borreguero, Luis J; de la Pompa, José Luis

    2016-05-13

    The Notch signaling pathway is crucial for primitive cardiac valve formation by epithelial-mesenchymal transition, and NOTCH1 mutations cause bicuspid aortic valve; however, the temporal requirement for the various Notch ligands and receptors during valve ontogeny is poorly understood. The aim of this study is to determine the functional specificity of Notch in valve development. Using cardiac-specific conditional targeted mutant mice, we find that endothelial/endocardial deletion of Mib1-Dll4-Notch1 signaling, possibly favored by Manic-Fringe, is specifically required for cardiac epithelial-mesenchymal transition. Mice lacking endocardial Jag1, Notch1, or RBPJ displayed enlarged valve cusps, bicuspid aortic valve, and septal defects, indicating that endocardial Jag1 to Notch1 signaling is required for post-epithelial-mesenchymal transition valvulogenesis. Valve dysmorphology was associated with increased mesenchyme proliferation, indicating that Jag1-Notch1 signaling restricts mesenchyme cell proliferation non-cell autonomously. Gene profiling revealed upregulated Bmp signaling in Jag1-mutant valves, providing a molecular basis for the hyperproliferative phenotype. Significantly, the negative regulator of mesenchyme proliferation, Hbegf, was markedly reduced in Jag1-mutant valves. Hbegf expression in embryonic endocardial cells could be readily activated through a RBPJ-binding site, identifying Hbegf as an endocardial Notch target. Accordingly, addition of soluble heparin-binding EGF-like growth factor to Jag1-mutant outflow tract explant cultures rescued the hyperproliferative phenotype. During cardiac valve formation, Dll4-Notch1 signaling leads to epithelial-mesenchymal transition and cushion formation. Jag1-Notch1 signaling subsequently restrains Bmp-mediated valve mesenchyme proliferation by sustaining Hbegf-EGF receptor signaling. Our studies identify a mechanism of signaling cross talk during valve morphogenesis involved in the origin of congenital heart

  10. Dynamic toughness in elastic nonlinear viscous solids

    NASA Astrophysics Data System (ADS)

    Tang, S.; Guo, T. F.; Cheng, L.

    2009-02-01

    This work addresses the interrelationship among dissipative mechanisms—material separation in the fracture process zone (FPZ), nonelastic deformation in the surrounding background material and kinetic energy—and how they affect the macroscopic dynamic fracture toughness as well as the limiting crack speed in strain rate sensitive materials. To this end, a micromechanics-based model for void growth in a nonlinear viscous solid is incorporated into a microporous strip of cell elements that forms the FPZ. The latter is surrounded by background material described by conventional constitutive relations. In the first part of the paper, the background material is assumed to be purely elastic. Here, the computed dynamic fracture toughness is a convex function of crack velocity. In the second part, the background material as well as the FPZ are described by similar rate-sensitivity parameters. Voids grow in the strain rate strengthened FPZ as the crack velocity increases. Consequently, the work of separation increases. By contrast, the inelastic dissipation in the background material appears to be a concave function of crack velocity. At the lower crack velocity regime, where dissipation in the background material is dominant, toughness decreases as crack velocity increases. At high crack velocities, inelastic deformation enhanced by the inertial force can cause a sharp increase in toughness. Here, the computed toughness increases rapidly with crack velocity. There exist regimes where the toughness is a non-monotonic function of the crack velocity. Two length scales—the width of the FPZ and the ratio of the shear wave speed to the reference strain rate—can be shown to strongly affect the dynamic fracture toughness. Our computational simulations can predict experimental data for fracture toughness vs. crack velocity reported in several studies for amorphous polymeric materials.

  11. Identification of 4th intercostal space using sternal notch to xiphoid length for accurate electrocardiogram lead placement.

    PubMed

    Day, Kevin; Oliva, Isabel; Krupinski, Elizabeth; Marcus, Frank

    2015-01-01

    Precordial ECG lead placement is difficult in obese patients with increased chest wall soft tissues due to inaccurate palpation of the intercostal spaces. We investigated whether the length of the sternum (distance between the sternal notch and xiphoid process) can accurately predict the location of the 4th intercostal space, which is the traditional location for V1 lead position. Fifty-five consecutive adult chest computed tomography examinations were reviewed for measurements. The sternal notch to right 4th intercostal space distance was 67% of the sternal notch to xiphoid process length with an overall correlation of r=0.600 (p<0.001). The above measurement may be utilized to locate the 4th intercostal space for accurate placement of the precordial electrodes in adults in whom the 4th intercostal space cannot be found by physical exam. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Toughness and strength of nanocrystalline graphene

    DOE PAGES

    Shekhawat, Ashivni; Ritchie, Robert O.

    2016-01-28

    Pristine monocrystalline graphene is claimed to be the strongest material known with remarkable mechanical and electrical properties. However, graphene made with scalable fabrication techniques is polycrystalline and contains inherent nanoscale line and point defects—grain boundaries and grain-boundary triple junctions—that lead to significant statistical fluctuations in toughness and strength. These fluctuations become particularly pronounced for nanocrystalline graphene where the density of defects is high. Here we use large-scale simulation and continuum modelling to show that the statistical variation in toughness and strength can be understood with ‘weakest-link’ statistics. We develop the first statistical theory of toughness in polycrystalline graphene, and elucidatemore » the nanoscale origins of the grain-size dependence of its strength and toughness. Lastly, our results should lead to more reliable graphene device design, and provide a framework to interpret experimental results in a broad class of two-dimensional materials.« less

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

    PubMed

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

    2018-05-16

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

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

    PubMed Central

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

    2010-01-01

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

  15. Strong, Tough, and Pest Resistant MoSi2-Base Hybrid Composite for Structural Applications

    NASA Technical Reports Server (NTRS)

    Hebsur, M. G.; Nathal, M. V.

    1997-01-01

    Addition of about 30 to 50 vol % of Si3N4 particulate to MoSi2 improved resistance to low temperature accelerated oxidation by forming a Si2ON2 protective scale and thereby eliminating catastrophic 'pest failure'. The Si3N4 addition also improved the high temperature creep strength by nearly five orders of magnitude, doubled the room temperature toughness and significantly lowered the CTE of the MoSi2 and eliminated matrix cracking in SCS-6 reinforced composites even after thermal cycling. The SCS-6 fiber reinforcement improved the room temperature fracture toughness by seven times and impact resistance by five times. The composite exhibited excellent strength and toughness improvement up to 1400 C. More recently, tape casting was adopted as the preferred processing of MoSi2-base composites for improved fiber spacing, ability to use small diameter fibers, and for lower cost. Good strength and toughness values were also obtained with fine diameter Hi-Nicalon tow fibers. This hybrid composite remains competitive with ceramic matrix composites as a replacement for Ni-base superalloys in aircraft engine applications.

  16. Notch-Boosted Domain Wall Propagation in Magnetic Nanowires

    NASA Astrophysics Data System (ADS)

    Wang, Xiang Rong; Yuan, Hauiyang

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

  17. Design of band-notched antenna with DG-CEBG

    NASA Astrophysics Data System (ADS)

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

    2018-01-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2017-03-13

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

  20. Common NOTCH3 Variants and Cerebral Small-Vessel Disease.

    PubMed

    Rutten-Jacobs, Loes C A; Traylor, Matthew; Adib-Samii, Poneh; Thijs, Vincent; Sudlow, Cathie; Rothwell, Peter M; Boncoraglio, Giorgio; Dichgans, Martin; Bevan, Steve; Meschia, James; Levi, Christopher; Rost, Natalia S; Rosand, Jonathan; Hassan, Ahamad; Markus, Hugh S

    2015-06-01

    The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency>0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method. We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association. Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease. © 2015 The Authors.

  1. Toughness Properties of Nodular Iron

    NASA Astrophysics Data System (ADS)

    Bradley, Walter L.

    1985-01-01

    The German government recently certified ductile iron for construction of nuclear waste transport containers. This approved use of ductile iron for such a critical application represents the culmination of ten years worth of research bringing to light the surprising toughness of ductile iron. This article explains how modern fracture mechanics and microstructure/property relationships have altered the stereotype of ductile iron as a low toughness material.

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

    PubMed

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

    2007-02-01

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

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

    PubMed Central

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

    2016-01-01

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

  4. Bmp2 and Notch cooperate to pattern the embryonic endocardium.

    PubMed

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

    2018-05-31

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

  5. Could Notch signaling pathway be a potential therapeutic option in renal diseases?

    PubMed

    Marquez-Exposito, Laura; Cantero-Navarro, Elena; Lavoz, Carolina; Fierro-Fernández, Marta; Poveda, Jonay; Rayego-Mateos, Sandra; Rodrigues-Diez, Raúl R; Morgado-Pascual, José Luis; Orejudo, Macarena; Mezzano, Sergio; Ruiz-Ortega, Marta

    2018-02-10

    Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by γ-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells. Recent studies suggest an interaction between Notch and NF-κB pathway involved in the regulation of renal inflammatory process. On the other hand, there are some miRNAs that could regulate Notch components and down-stream responses. All these data suggest that Notch blockade could be a novel therapeutic option for renal diseases. Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  6. BCL6 antagonizes NOTCH2 to maintain survival of human follicular lymphoma cells

    PubMed Central

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

    2017-01-01

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

  7. 46 CFR 54.05-16 - Production toughness testing.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Production toughness testing. 54.05-16 Section 54.05-16... Toughness Tests § 54.05-16 Production toughness testing. (a) For vessels of welded construction, production... welding procedures shall be the same as used in the fabrication of the vessel. From each test plate, one...

  8. C. elegans Notch signaling regulates adult chemosensory response and larval molting quiescence

    PubMed Central

    Singh, Komudi; Chao, Michael Y.; Somers, Gerard A.; Komatsu, Hidetoshi; Corkins, Mark E.; Larkins-Ford, Jonah; Tucey, Tim; Dionne, Heather M.; Walsh, Melissa B.; Beaumont, Emma K.; Hart, Douglas P.; Lockery, Shawn; Hart, Anne C.

    2011-01-01

    Summary Background The conserved DOS motif proteins OSM-7 and OSM-11 function as co-ligands with canonical DSL ligands to activate C. elegans Notch receptors during development. We report herein that Notch ligands, co-ligands and the receptors LIN-12 and GLP-1 regulate two C. elegans behaviors: chemosensory avoidance of octanol and quiescence during molting lethargus. Results C. elegans lacking osm-7 or osm-11 are defective in their response to octanol. We find that OSM-11 is secreted from hypodermal seam cells into the pseudocoelomic body cavity and acts non-cell autonomously as a diffusible factor. OSM-11 acts with the DSL ligand LAG-2 to activate LIN-12 and GLP-1 Notch receptors in the neurons of adult animals,- thereby regulating octanol avoidance response. In adult animals, over-expression of osm-11 and consequent Notch receptor activation induces anachronistic sleep-like quiescence. Perturbation of Notch signaling altered basal activity in adults as well as arousal thresholds and quiescence during molting lethargus. Genetic epistasis studies revealed that Notch signaling regulates quiescence via previously identified circuits and genetic pathways including the egl-4 cGMP-dependent kinase. Conclusions Our findings indicate that the conserved Notch pathway modulates behavior in adult C. elegans in response to environmental stress. Additionally, Notch signaling regulates sleep-like quiescence in C. elegans suggesting Notch may regulate sleep in other species. PMID:21549604

  9. The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia

    PubMed Central

    Palomero, Teresa; Dominguez, Maria; Ferrando, Adolfo A.

    2008-01-01

    Activating mutations in NOTCH1 are the most prominent genetic abnormality in T-cell acute Lymphoblastic Leukemia (T-ALL) and inhibition of NOTCH1 signaling with γ-secretase inhibitors (GSIs) has been proposed as targeted therapy in this disease. However, most T-ALL cell lines with mutations in NOTCH1 fail to respond to GSI therapy. Using gene expression profiling and mutation analysis we showed that mutational loss of PTEN is a common event in T-ALL and is associated with resistance to NOTCH inhibition. Furthermore, our studies revealed that NOTCH1 induces upregulation of the PI3K-AKT pathway via HES1, which negatively controls the expression of PTEN. This regulatory circuitry is evolutionary conserved from Drosophila to humans as demonstrated by the interaction of overexpression of Delta and Akt in a model of Notch-induced transformation in the fly eye. Loss of PTEN and constitutive activation of AKT in T-ALL induce increased glucose metabolism and bypass the requirement of NOTCH1 signaling to sustain cell growth. Importantly, PTEN-null/GSI resistant T-ALL cells switch their oncogene addiction from NOTCH1 to AKT and are highly sensitive to AKT inhibitors. These results should facilitate the development of molecular therapies targeting NOTCH1 and AKT for the treatment of T-ALL. PMID:18414037

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

    PubMed

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

    2016-01-01

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

  11. Study of mixed mode fracture toughness and fracture trajectories in gypsum interlayers in corrosive environment

    PubMed Central

    Xiankai, Bao; Jinchang, Zhao

    2018-01-01

    Based on the engineering background of water dissolving mining for hydrocarbon storage in multi-laminated salt stratum, the mixed mode fracture toughness and fracture trajectory of gypsum interlayers soaked in half-saturated brine at various temperatures (20°C, 50°C and 80°C) were studied by using CSNBD (centrally straight-notched Brazilian disc) specimens with required inclination angles (0°, 7°, 15°, 22°, 30°, 45°, 60°, 75°, 90°) and SEM (scanning electron microscopy). The results showed: (i) The fracture load of gypsum specimens first decreased then increased with increasing inclination angle, due to the effect of friction coefficient. When soaked in brine, the fracture toughness of gypsum specimens gradually decreased with increasing brine temperature. (ii) When soaked in brine, the crystal boundaries of gypsum separated and became clearer, and the boundaries became more open between the crystals with increasing brine temperature. Besides, tensile micro-cracks appeared on the gypsum crystals when soaked in 50°C brine, and the intensity of tensile cracks became more severe when soaking in 80°C brine. (iii) The experimental fracture envelopes derived from the conventional fracture criteria and lay outside these conventional criteria. The experimental fracture envelopes were dependent on the brine temperature and gradually expanded outward as brine temperature increases. (iv) The size of FPZ (fracture process zone) was greatly dependent on the damage degree of materials and gradually increased with increase of brine temperature. The study has important implication for the control of shape and size of salt cavern. PMID:29410841

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

    NASA Technical Reports Server (NTRS)

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

    1995-01-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

    2011-01-01

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

  16. Motivational correlates of mentally tough behaviours in tennis.

    PubMed

    Gucciardi, Daniel F; Jackson, Ben; Hanton, Sheldon; Reid, Machar

    2015-01-01

    The purpose of this study was to examine motivational correlates of mentally tough behaviours among adolescent tennis players. Two-phase study, involving the development of an informant-rated measure of mentally tough behaviours, followed by a cross-sectional survey including athlete and parent assessments of study variables. In Phase One, 17 adult, high-performance tennis coaches and 20 athletes participated in focus group interviews. Four scholars with expertise in performance psychology also completed a short, online survey. In Phase Two, a total of 347 adolescent tennis players (nmales=184; nfemales=163) aged 12-18 years (M=13.93, SD=1.47) and one respective parent took part in this study. An online multisection survey containing dimensions of passion, inspiration, fear of failure, and mentally tough behaviours was completed. Athletes self-reported all motivational variables, whereas parents rated their child solely on mentally tough behaviours. Structural equation modelling revealed that harmonious passion (β=.26, p<.01) and frequency of inspiration (β=.32, p<.001) were associated with significantly higher levels of mentally tough behaviours. In contrast, fear of failure (β=-.32, p<.001) and obsessive passion (β=-.15, p<.01) were inversely related to mentally tough behaviours. Inspiration intensity was not significantly associated with mentally tough behaviour (β=.13, p=.21). Motivational variables that are dispositional in nature, contextualised and contingent upon features of the environment, and concern one's identity are important considerations for understanding mentally tough behaviours. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

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

    PubMed Central

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

    2014-01-01

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

  18. A central role for Notch in effector CD8+ T cell differentiation

    PubMed Central

    Backer, Ronald A.; Helbig, Christina; Gentek, Rebecca; Kent, Andrew; Laidlaw, Brian J.; Dominguez, Claudia X.; de Souza, Yevan S.; van Trierum, Stella E.; van Beek, Ruud; Rimmelzwaan, Guus F.; ten Brinke, Anja; Willemsen, A. Marcel; van Kampen, Antoine H. C.; Kaech, Susan M.; Blander, J. Magarian; van Gisbergen, Klaas; Amsen, Derk

    2014-01-01

    Activated CD8+ T cells choose between terminal effector cell (TEC) or memory precursor cell (MPC) fates. We show that Notch controls this choice. Notch promoted differentiation of immediately protective TECs and was correspondingly required for clearance of an acute influenza virus infection. Notch activated a major portion of the TEC-specific gene expression program and suppressed the MPC-specific program. Expression of Notch receptors was induced on naïve CD8+ T cells by inflammatory mediators and interleukin 2 (IL-2) via mTOR and T-bet dependent pathways. These pathways were subsequently amplified downstream of Notch, creating a positive feedback loop. Notch thus functions as a central hub where information from different sources converges to match effector T cell differentiation to the demands of the infection. PMID:25344724

  19. Effect of initial delamination on Mode 1 and Mode 2 interlaminar fracture toughness and fatigue fracture threshold

    NASA Technical Reports Server (NTRS)

    Murri, Gretchen Bostaph; Martin, Roderick H.

    1991-01-01

    Static and fatigue double-cantilever beam (DCB) and end-notch flexure (ENF) tests were conducted to determine the effect of the simulated initial delamination in interlaminar fracture toughness, G(sub c), and fatigue fracture threshold, G(sub th). Unidirectional, 24-ply specimens of S2/SP250 glass/epoxy were tested using Kapton inserts of four different thickness - 13, 25, 75, and 130 microns, at the midplane at one end, or with tension or shear precracks, to simulate an initial delamination. To determine G(sub c), the fatigue fracture threshold below which no delamination growth would occur in less than 1 x 10(exp 6) cycles, fatigue tests were conducted by cyclically loading specimens until delamination growth was detected. Consistent values of model 1 fracture toughness, G(sub Ic), were measured from DCB specimens with inserts of thickness 75 microns or thinner, or with shear precracks. The fatigue DCB tests gave similar values of G(sub Ith) for the 13, 25, and 75 microns specimens. Results for the shear precracked specimens were significantly lower that for specimens without precracks. Results for both the static and fatigue ENF tests showed that measured G(IIc) and G(IIth) values decreased with decreasing insert thickness, so that no limiting thickness could be determined. Results for specimens with inserts of 75 microns or thicker were significantly higher than the results for precracked specimens or specimens with 13 or 25 microns inserts.

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

    PubMed Central

    Sanjay, Archana; Yu, Jungeun; Zanotti, Stefano

    2017-01-01

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