Small Notch Research Articles

Evaluation of the fatigue life of AISI 347 specimens with small notches based on local strain considerations

The use of materials data for cyclic loading determined on unnotched specimens to predict the fatigue life of notched components has a long tradition, specifically when it comes to nuclear engineering. The basic principle is that the material behaviour of the unnotched specimens can be transferred to what the material is exposed to be in a notch root. This principle has been proven for large notches. However, what happens when the notch is relatively small? Can the fatigue life still be predicted on the grounds of what has been considered as the local strain or Neuber approach? A key reference in that regard is the Neuber equation or generally the load versus notch stress, notch strain – or any combination of those – relationship. In a larger study, unnotched and notched specimens from the metastable austenitic steel AISI 347 have been tested and characterized providing a database that may give some answers to the question raised above.The unnotched specimens considered here had a cross-section diameter of 10 mm while the notch radii of the notched components were only 0.5 and 0.35 mm, respectively. Notch radii of such dimensions will easily reach a fully plastic condition once the material has exceeded the yield limit, because the difference in load between yield start in the notch and full plastification is relatively small. This fully plastic state exceeds the validity of the Neuber equation and requires respective corrections. In this paper it is shown how such corrections can be obtained through a finite element analysis and how this applies to the cases mentioned above.

Small Intercondylar Notch Size Is Not Associated with Poor Surgical Outcomes of Anatomical Single-Bundle Anterior Cruciate Ligament Reconstructions.

Although many studies have been conducted on the association between the intercondylar notch size and the risk of anterior cruciate ligament (ACL) injury, few studies have examined its relationship with the condition after surgical treatment. Therefore, this study aimed to investigate the surgical outcomes of anatomical single-bundle ACL reconstruction according to intercondylar notch volumes. Medical records of patients who underwent anatomical single-bundle ACL reconstruction using a tibialis anterior allograft between 2015 and 2019 were retrospectively reviewed. For each sex, eligible patients were classified into two groups based on their percentile of intercondylar notch volumes, which were measured using postoperative three-dimensional computed tomography images (group S, ≤ 50th percentile of included patients; group L, > 50th percentile of included patients). Additional grouping was performed based on the group's percentiles of normalized values of intercondylar notch volumes to body heights. Between-group comparative analyses were performed on the perioperative data and surgical outcomes in both objective and subjective aspects. One hundred patients were included in the study. For male patients, there were no differences in the overall surgical outcomes between groups, whereas group L showed a significantly greater knee anteroposterior (AP) laxity than group S at the final follow-up (p = 0.042 for the side-to-side differences [SSD] at the maximum manual force). Similarly, there were no differences in the female patients in the overall surgical results between the groups, whereas group L showed a significantly greater knee AP laxity at the final follow-up (p = 0.020 for the SSD at 134 N; p = 0.011 for the SSD at the maximum manual force). Additional analyses based on the normalized values of the intercondylar notch volume showed consistent results for male patients, and additional grouping for female patients was identical to the existing grouping. The surgical outcomes of anatomical single-bundle ACL reconstruction in patients with relatively small intercondylar notch volumes were comparable to those with large notch volumes, but rather showed favorable outcomes in postoperative knee AP laxity.

Evaluation of the anticancer activity of RIN-1, a Notch signaling modulator, in head and neck squamous cell carcinoma

Notch signalling is one of the key molecular pathways involved in cell-to-cell signal transduction. Although the mechanisms of action of the NOTCH receptors are already relatively well known, their biological implications remain unclear, especially during the initiation and progression of head and neck squamous cell carcinoma (HNSCC). Here, we present the growth- and differentiation-modulating effects of various “next generation” small molecule Notch modulators represented by RIN-1, and CB-103, on HNSCC, compared to gamma secretase inhibitors as “conventional” NOTCH interfering compounds, like DAPT. These molecules were tested in different cell- and tissue culture conditions represented by 2D monolayer, non-adherent or spheroid culture, 3D organoid cultures, and zebrafish in vivo model. The most pronounced, pleiotropic effects were observed for the NOTCH modulator RIN-1. At the molecular level, RIN-1-dependent activation of Notch signalling led to characteristic changes in the expression of NOTCH-regulated targets, i.e., the transcriptional suppressors HES1 and HEY1, p21 (CDKN1A) cell cycle inhibitor, and pro-apoptotic BAX markers. These changes led to restriction of proliferation, growth, and reduced motility of HNSCC cells in 2D cultures. Consequently, cell cycle arrest in the G2-M phase and induction of apoptosis were observed. Similar anticancer effects were observed in 3D cultures and in the zebrafish model. In contrast, RIN-1 treatment resulted in inhibition of Notch signalling and the growth of HNSCC spheroids under non-adherent cell culture conditions. Our results suggest that modulation of Notch signalling could be used as a chemotherapeutic agent in selected patients with intact NOTCH signaling.

CT Imaging, Macroanatomical and Morphometric Analysis of Os penis in Brown Bear (Ursus arctos)

The aim of this study is to reveal the macroscopic features of the brown bear (Ursus arctos) os penis (baculum), as well as its morphometric measurements with the help of computerized tomography and digital electronic caliper. The study material was obtained from an adult male brown bear weighing approximately 400 kg, which was brought to the Wildlife Protection and Rehabilitation Unit of Kafkas University and died as a result of a traffic accident in the Sarıkamış district of Kars. After the skin and soft tissues around the baculum were removed, they were kept in hydrogen peroxide for 2-3 hours. In the macroscopic examination, it was determined that the baculum was straight, close to the pen, except for a slight curve in the distal part, and ended with a small tubercle at the distal end. A small notch was found in the proximal part. In addition to the prominent sulcus urethralis in the ventral of the baculum, a short groove was also detected in its lateral. In addition to the prominent sulcus urethralis in the ventral of the baculum, a short groove was also detected in its lateral. A cartilage tissue of 11.08 mm in length and 4.67 mm in thickness was determined in the distal of the bone. In the morphometric measurements made with a digital electronic caliper, the length of the baculum was 148.95 mm, while the diameters were measured as 4.58 mm in the distal and 13.72 mm in the proximal, respectively. In computed tomography, baculum length was 148.84 mm, distal diameter length was 5.63 mm, and proximal diameter length was 13.12 mm. In addition, computed tomography measured the length of the cortex as 0.76 mm, the length of the medulla as 5.74 mm in the distal, and the cortex length of 0.77 mm and the medulla length of 5.32 mm in the proximal region. As a result, in this study, the macroanatomical and morphometric features of the brown bear baculum, which live in high altitude and cold climate conditions, were revealed.

Study on Numerical Simulation Method of Fracture Behavior of Pipeline Girth Weld

Abstract The failure accidents in girth weld of pipelines occur frequently due to the combination of internal defects and external loads. However, the research on the fracture behavior of girth weld defects is relatively poor at present. To solve this problem, the cracking behavior and strain evolution law of the inner wall defects of the pipe girth weld are studied in combination with full-scale tests (FST). The constitutive and Gurson-Tvergaard-Needleman damage parameters of the pipe base metal zone, weld zone and heat-affected zone (HAZ) are calibrated through the small punch test (SPT) and single edge notch bending (SENB) test. On this basis, the welded pipe model with inner wall defects is established, and a numerical simulation method for dynamic fracture behavior based on damage mechanics is formed. The numerical simulation method is verified by FST data and theoretical calculation. The results show that the numerical results are consistent with the FST and theoretical calculation in the elastic stage, plastic stage, and fracture stage, and the error is within 10%. The novel numerical simulation method is provided as a means for the fracture behavior research of pipeline girth weld.

Influence of notched baffles on aerothermal performance behaviors in a channel

The proper designs of modified heat transfer surfaces or turbulence enhancement inserts for heat transfer augmentation are extremely important for improving overall aerothermal performances relating to the energy-saving capabilities of thermal systems. A major challenge is to control friction loss as little as possible while maintaining reasonable heat transfer enhancement. Transverse baffles with rectangular notches or notched baffles (NBs) were applied for improving aerothermal performance in a channel with a constant aspect ratio of 3.75 while notch height-to-baffle height ratio (a/e) ranged from 0.125 to 0.5. Reynolds number ranged from 6000 to 24,000, in experiments. Heat transfer enhancement, pressure loss, and aerothermal performance in a rectangular channel with notched baffles were examined. Compared to the solid transverse baffle (SB, a/e = 0), the NBs with a/e = 0.125 increased the heat transfer rate while lessening the pressure loss, as shown by the experimental findings. Obviously, Nusselt number, friction factor and aerothermal performance increased as the a/e ratio decreased. The NBs with the smallest notch height-to-baffle height ratio (a/e = 0.125) exhibited the highest aerothermal performance of 1.17, which can be attributed to the efficient heat transfer enhancement by the strong multi-jet impingements and the moderate friction loss penalty resulting from the presence of notches (spaces) on the baffles.

Triple band terahertz metamaterial absorber within (0.4-0.46thz) frequency range

An ultrathin Terahertz Triple-band ideal meta material absorber with a brand-new design that is straightforward has been presented. The suggested terahertz meta material absorber has a unit cell that is made up of two D-shaped resonators with slots and a ground metallic plane. These elements are separated from one another by a polyimide dielectric substrate that has a thickness of 500 micrometers. The absorber construction that has been presented provides three distinct absorption peaks within the narrow frequency range of (0.4-0.46 THz) without producing any interference. In order to get a deeper comprehension of the mechanism behind the absorption process, an investigation into the electric field, the magnetic field, the surface current distribution, and the independence of the polarization angle has been carried out. It is anticipated that the configuration of the terahertz absorber that has been described would find use in applications relating to the lowering of radar cross-section, detection, imaging, and sensing. One of the contributions of this study is the description of a downsized and compact triple-band terahertz meta material absorber. In order to generate the unit cell of a terahertz absorber, an identical I-typed resonator, which is represented by a rectangular patch with two very small notches, is first deposited on top of a dielectric sheet and then a metallic mirror. The terahertz regime reveals three distinct frequency spots, and the design of the very small structure allows for virtually full absorption of all of them.

2D numerical modeling of solid materials with virtual boundary particles in ordinary state-based peridynamics

The peridynamic method has become an important theory for predicting crack propagation in solid materials, but due to its non-locality, the boundary material particles will affect the accuracy of the simulation results. For some specimens without a notch or small notch, it is even impossible to simulate the correct path of crack propagation. Therefore, based on the ordinary state-based peridynamic theory, this paper proposes a virtual boundary particles method for simulating solid materials and gives the force formula of virtual particles. The accuracy and precision of the results are improved by arranging virtual particles on the boundary of the model. For quasi-static problems, the simulation results show that the model with virtual boundary particles has higher accuracy. The three-point bending simulation of the long-notch specimen shows that the virtual boundary particles method can reduce the influence of boundary particles on the simulation results. Then, three-point bending simulations are performed on unnotched and small-notched specimens, and the results show that the model with virtual boundary particles could accurately predict crack propagation direction and is more consistent with the experimental results, which verify the validity of the model.

Discharge coefficient, effective head and limit head in the Kindsvater-Shen formula for small discharges measured by thin-plate weirs with a triangular notch

Abstract The paper deals with the determination of the discharge coefficient, effective head and newly the limit head in the Kindsvater-Shen formula for the determination of a relatively small discharge of clear water using a thin-plate weir with a triangular notch. The determination of the discharge coefficient, effective head and limit head is based on extensive experimental research and is verified by previous measurements by other authors. The experimental research was characterised by a large range of notch angles (from 5.25° to 91.17°), weir heights (from 0.00 m to 0.20 m), and water temperatures (from 15 °C to 45 °C), as well as a focus on relatively small heads (from 0.02 m to 0.18 m), which is where the strengths of the Kindsvater-Shen formula stand out. The experimental research supplemented existing knowledge about the overflow occurring with small heads and small weir notch angles. The newly determined dependencies in the Kindsvater-Shen formula extended its applicability to weirs with small notch angles and newly enabled the determination of the limit head, which restricts its applicability in the determination of small discharges.

Морфология второй личиночной стадии козырькового шримса Argis ochotensis kamtschatica Sokolov, 2001 (Caridea, Crangonidae) из Авачинского залива (юго-восточная Камчатка)

The second larval stage of the trumped shrims Argis ochotensis kamtschatica (Crangonidae) from the plankton of the Avacha Gulf (northwestern part of the Pacific Ocean, Southeast Kamchatka) is described. The existing larvae with the older larvae of Argis ochotensis ochotensis and Argis dentata were carried out, previously described for sinking waters. The main distinguishing features of the senior Zoea of the Kamchatka subspecies A. ochotensis: the presence of spines in the terminal margins of the tergits; a different length of the spine of the right and left skale; three-segment exopod of antennules; nine setae in the basial endites of maxillule; relatively short flagellum of the antenna; a different number of anteroventral margin on the right and left side of carapas; a small notch on the terminal margim of telson. An assumption has been expressed that A. ochotensis is more widespread in Pacific waters than this was considered before. It is shown that this subspecies can have two or three stages of Zoea.

A new species of Tharybis (Crustacea: Copepoda: Calanoida: Tharybidae) from northern Taiwan

A new species Tharybis kueishanensis sp. n. (Copepoda: Calanoida: Tharybidae) is described from the inshore surface waters of Kueishan Island off northern Taiwan, which is the first report of Tharybis from the China Seas. Its female is distinguished from the other species of Tharybis by the total body length (1.89-2.12 mm) larger than the other species, the shape of the genital double-somite, which is slightly asymmetrical with a small notch on the distal margin of the right side, and the length of the inner terminal spine of leg 5, which is about 1.5 times of the terminal spiniform projections. The male is distinguished by the presence of 3 triangular projections at the inner middle margin and the tip of the distal segment of the right leg 5.

Ust-Polui: bone objects with ornament and signs (technology and function)

The article is devoted to the studies of the function of bone artefacts with ornamentation and signs from the Ust-Polui sacral production center. Functional groups of items with and without décor were identified and compared to each other according to the use-wear pattern. The main elements and compositions of the decorations that are typical for the certain categories were studied. The location and ways of ornamentation and signs were analyzed. It was shown that buckles, combs and armored plates make up the largest percentage of ornamentally decorated items, while signs are often applied to scrapers-blades. Fish knives, hooks, chisel-shaped tools, wedges, needles, harpoons and arrowheads except two of them have no decoration elements. The oblique cuts and small notches on the edges of several items made of the reindeer harness apparently were technologically meaningful. The bone products of the Ust-Polui are characterized by geometric ornaments with a small set of elements and their combinations. A pattern consisting of one or more wavy lines, made using the technique of fine-contour or oval-notched carving, was a common decorative element for functionally various items. It was complemented by compositions of straight or broken lines. There is no correlation between degree of wear and the presence or absence of decor in tools of the same category. Armor plates, buckles, combs, scrapers-spatulas had most strong wear traces among the specimens with ornamentation. Geometric signs were found on a bow plate, 2 belt hooks, 3 spoons and 14 scrapers-spatulas. They have a different carving quality and shape. There were often 2 signs carved on the items; some signs were applied to the surface of the scrapers after their long-term use.

A new promising variety of black currant Estafeta

Relevance. Creation of new varieties with a complex of economically valuable characteristics in the conditions of the Republic of Bashkortostanis relevant. The climatic conditions of the republic require the creation of varieties with high resistance to the complex of biotic and abiotic stressors of the cultivation region.Materials and methodology. The objects of research are the hybrid fund, selected, promising, elite forms and varieties of black currant of local and foreign selection located in the Kushnarenkovsky breeding center for fruit and berry crops and grapes of the Bashkir Research Institute of the UFIC RAS. Research is carried out according to the program and methodology of selection and variety studies of fruit, berry and nut crops.Results. A new variety of black currant Estafeta has been created, which has a complex of economically valuable characteristics in the conditions of the Republic of Bashkortostan. According to the results of many years of research, the new variety of black currant Estafeta is resistant to diseases and pests. Over the years of research, leaf damage by anthracnose was 1,0 point (15%), in the control variety — 1,5 points (20%). Damage from grass moth — 2,0 points (30%), in control — 3,0 (40%), from aphids — 0,5 points (10%), in control — 1,0 (20%). New variety Estafeta is large-fruited, with berries of the standard sweet and sour taste. The average and maximum berry weight of 1,6-2,5 g is higher than that of the control of 1,4-2,1 g. According to the content of biologically active substances in black currant berries, the new variety has less sugar than the control, but has more vitamin C and carotene. The bush of the Estafeta variety is medium-sized, medium-spreading. Shoots are medium, straight, light green, slightly pubescent, matte. The buds are medium, oblong, green. The leaves are medium-sized, light green, three-lobed, with small notches. The fruit brush is medium, the berries in the brush are medium. The flowers are medium-sized, with a bright color. The sepals are medium-sized, with a bright color, with an average pubescence of the outer side, arranged horizontally. The berry is large, round-oval, black. The cup is open. The skin is of medium thickness. Pubescence is weak, simple. The peduncle is short, dark green, fleshy. The number of seeds is average. The taste is sweet and sour, refreshing. The timing of budding and the beginning of maturation is average, simultaneous. The period of the beginning of flowering is average. The variety is promising for industrial and amateur gardening. The optimal layout of plantings is 3,0-4,0 х 1,0-2,0 m. The self-fruitfulness of 40-45% is quite good for setting berries in single-grade plantings, although over-pollination with other varieties has a positive effect on the productivity and marketable qualities of berries.

Automatic segmentation model of intercondylar fossa based on deep learning: a novel and effective assessment method for the notch volume.

BackgroundNotch volume is associated with anterior cruciate ligament (ACL) injury. Manual tracking of intercondylar notch on MR images is time-consuming and laborious. Deep learning has become a powerful tool for processing medical images. This study aims to develop an MRI segmentation model of intercondylar fossa based on deep learning to automatically measure notch volume, and explore its correlation with ACL injury.MethodsThe MRI data of 363 subjects (311 males and 52 females) with ACL injuries incurred during non-contact sports and 232 subjects (147 males and 85 females) with intact ACL were retrospectively analyzed. Each layer of intercondylar fossa was manually traced by radiologists on axial MR images. Notch volume was then calculated. We constructed an automatic segmentation system based on the architecture of Res-UNet for intercondylar fossa and used dice similarity coefficient (DSC) to compare the performance of segmentation systems by different networks. Unpaired t-test was performed to determine differences in notch volume between ACL-injured and intact groups, and between males and females.ResultsThe DSCs of intercondylar fossa based on different networks were all more than 0.90, and Res-UNet showed the best performance. The notch volume was significantly lower in the ACL-injured group than in the control group (6.12 ± 1.34 cm3 vs. 6.95 ± 1.75 cm3, P < 0.001). Females had lower notch volume than males (5.41 ± 1.30 cm3 vs. 6.76 ± 1.51 cm3, P < 0.001). Males and females who had ACL injuries had smaller notch than those with intact ACL (p < 0.001 and p < 0.005). Men had larger notches than women, regardless of the ACL injuries (p < 0.001).ConclusionUsing a deep neural network to segment intercondylar fossa automatically provides a technical support for the clinical prediction and prevention of ACL injury and re-injury after surgery.

Miniaturized and Actively Tunable Triple-Band Terahertz Metamaterial Absorber Using an Analogy I-Typed Resonator

Triple-band terahertz metamaterial absorber with design of miniaturization and compactness is presented in this work. The unit cell of the terahertz absorber is formed by an analogy I-typed resonator (a rectangular patch with two small notches) deposited on top of dielectric sheet and metallic mirror. The miniaturized structure design exhibits three discrete frequency points with near-perfect absorption at terahertz regime. The three absorption peaks could be ascribed to localized resonances of analogy I-typed resonator, while the response positions of these absorption peaks at the analogy I-typed resonator are different by analyzing the near-field patterns of these resonance peaks. Changes in structure parameters of the analogy I-typed resonator are also investigated. Simulation results revealed that the notch sizes of the rectangular patch are the key factor to form the triple-band near-perfect absorption. Further structure optimization is given to demonstrate triple-band polarization insensitive performance. Moreover, actively tunable absorption properties are realized by inserting or introducing vanadium dioxide with adjustable conductivity into the metamaterial structure. It is revealed that the insulator–metal phase transition of vanadium dioxide is the main reason for the modulation of absorption performance. Compared with previous multiple-band absorbers, the device given here has excellent features of high degrees of simplification, miniaturization, and active modulation, these are important in practical applications.

Quantifying graft impingement in anterior cruciate ligament reconstruction

BackgroundAnterior cruciate ligament reconstructions (ACLR) fail at a rate of 10–15%, with graft impingement often a cause. In this study we investigate the prevalence and causes of impingement seen during ACLR surgery. MethodsWe reviewed consecutive primary ACLR from 2012-2018. Graft impingement was estimated intraoperatively by placing the arthroscope through the tibial tunnel and passively extending the knee, observing how much was obscured by the lateral femoral condyle from an anterior and lateral direction. Preoperative MRI scans were used to measure the intercondylar notch; Notch Width Index (NWI) and Notch Depth Index (NDI). Positioning of the tunnels was determined on postoperative radiographs. ResultsThere were 283 ACLRs performed with 33 failures diagnosed on MRI (11.7%). 257 patients had complete imaging and follow up (91%). The mean age was 28 (±9) years and mean follow-up 5.3 (±1.8) years. The mean NWI was 0.26(±0.03), and NDI was 0.49(±0.06). The tibial tunnel aperture was located 42(±6) % of the way from anterior-posterior and 39(±6) % from medial-lateral. Impingement requiring a notchplasty was observed in 80% of cases, with lateral impingement more prominent. ConclusionsThe amount of impingement did not correlate with tunnel position, which was located within the recommended area. There was a weak negative correlation between NWI and lateral impingement (rs = −0.16, p = 0.01), and NDI and anterior impingement (rs = −0.12, p = 0.04), therefore a smaller notch is associated with greater impingement. Despite optimal tunnel positioning, impingement still occurs in a significant number of cases therefore notchplasty should always be considered to keep revision rates low.

Исследование развития макроразрыва в эластомерных композитах

We carried out experimental studies of fracture processes under tension in elastomeric nanocomposites based on siloxane rubber with fillers of various shapes: single- and multi-walled carbon nanotubes (1D filler), few-layer graphene (2D filler), detonation nanodiamonds (3D filler). The tests were performed on standard blade samples with a small side notch in the middle of the working part. The tensile process was recorded on video, which made it possible to capture propagation trajectories of the main crack in the sample at different stages of deformation and to perform an appropriate analysis. The samples of unfilled siloxane rubber demonstrated a significant deviation of the trajectory of the main crack from the direction of the initiating notch. A similar picture was observed when testing composites with 1D and 2D fillers. In the case of using carbon nanotubes, the fracture process developed differently: the crack growth was accompanied by the appearance of small, rapidly decaying side branches. The use of double filler (1D+2D particles) enhanced this effect considerably.

A novel approach for the quantitative characterization of shrink lines in the Powder Bed Fusion of metals using a laser beam

The powder bed fusion of metals using a laser beam (PBF-LB/M) enables the manufacturing of complex geometric designs with no part-specific tooling. As a result of the high energy input, the temperature gradients lead to a warpage of the part. Particularly at the structural transitions, thermally induced deformations form a shrink line on the outer surface of the geometry during PBF-LB/M. These shrink lines present a small notch, which reduces the dimensional accuracy and the part lifetime. However, the quantitative analysis of the shrink lines and their influencing factors has not been investigated yet. To specify the geometric characteristics of the shrink lines, a measurement approach is presented to enable their reliable and precise evaluation. A suitable test specimen was identified and varied within its geometrical dimensions. The results demonstrate the reproducible quantification of the shrink lines and their geometric characteristics. A significant dependence of the shrink lines on the geometry of the specimens is observed.

Numerical investigation of stress concentration at the tip of the V-notch partially filled with material

One of the ways to reduce the stress level in the vicinity of V-shaped notches is to fill them with material. The effectiveness of achieving this result is largely determined by the mechanical characteristics of the filling material. The study of the stress state in the vicinity of the tip of a V-shaped notch is generally related to consideration of the composite wedge problem, which in the framework of the classical theory of elasticity, can have singular solutions with infinite values of stresses at the wedge vertex. The paper presents solutions for a composite closed wedge, which allows us to determine the range of mechanical characteristics and angles of the composite wedge, at which there is no stress singularity at the vertex. The proposed variant of the computational procedure, which is based on the finite element method, makes it possible to find a relationship for stresses in the vicinity of the wedge vertex, providing the evaluation of the stress singularity indices and constants known as stress singularity intensity factors. In real industrial technologies currently used for filling notches with another material, a small region (cavity) generally remains unfilled in the vicinity of the notch tip. This defect becomes more pronounced at small notch angles. In the presence of a cavity at the notch tip, a singular solution exists at any mechanical characteristics of the filling material. The developed algorithm has been used to calculate the values of the intensity factor of singularity for a V-shaped notch partially filled with materials, which either eliminate or preserve the stress singularity in the case of complete filling. The results obtained demonstrate that at the tip of the notch partially filled with another material the singularity intensity factor can be significantly reduced.

Identification of 1β,2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity.

Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development of Notch signaling inhibitors is eagerly awaited. Notch inhibitory activity-guided fractionation of a Spilanthes acmella extract led to the identification of five sesquiterpene lactones: tagitinin A (1), 1β,2α-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2α-hydroxytirotundin (5). 1β,2α-Epoxytagitinin C (2) exhibited Notch signaling inhibition, with an IC50 of 25.6μM, and was further evaluated for its activity against HPB-ALL, a Notch-activated leukemia cell line. Compound 2 showed potent cytotoxicity against HPB-ALL (IC50 1.7μM) and arrested the cell cycle at the G2/M phase, but did not induce apoptotic cell death. Notch inhibitory mechanism analysis suggested that compound 2 transcriptionally suppresses Notch1 mRNA. In addition, we found that oxidative stress induction is critical for Notch signaling inhibition and the cytotoxicity of compound 2. This is the first mechanism of small molecule Notch inhibition. Our results demonstrate that 1β,2α-epoxytagitinin C (2) is a potential anti-leukemia agent and further investigation of this compound is warranted.