• Title/Summary/Keyword: Resistance mechanism

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Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy

  • Bisan El Dakkak;Jalal Taneera;Waseem El-Huneidi;Eman Abu-Gharbieh;Rifat Hamoudi;Mohammad H. Semreen;Nelson C. Soares;Eman Y. Abu-Rish;Mahmoud Y. Alkawareek;Alaaldin M. Alkilany;Yasser Bustanji
    • Biomolecules & Therapeutics
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    • v.32 no.3
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    • pp.267-280
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    • 2024
  • Apoptosis, programmed cell death pathway, is a vital physiological mechanism that ensures cellular homeostasis and overall cellular well-being. In the context of cancer, where evasion of apoptosis is a hallmark, the overexpression of anti-apoptotic proteins like Bcl2, Bcl-xL and Mcl-1 has been documented. Consequently, these proteins have emerged as promising targets for therapeutic interventions. The BCL-2 protein family is central to apoptosis and plays a significant importance in determining cellular fate serving as a critical determinant in this biological process. This review offers a comprehensive exploration of the BCL-2 protein family, emphasizing its dual nature. Specifically, certain members of this family promote cell survival (known as anti-apoptotic proteins), while others are involved in facilitating cell death (referred to as pro-apoptotic and BH3-only proteins). The potential of directly targeting these proteins is examined, particularly due to their involvement in conferring resistance to traditional cancer therapies. The effectiveness of such targeting strategies is also discussed, considering the tumor's propensity for anti-apoptotic pathways. Furthermore, the review highlights emerging research on combination therapies, where BCL-2 inhibitors are used synergistically with other treatments to enhance therapeutic outcomes. By understanding and manipulating the BCL-2 family and its associated pathways, we open doors to innovative and more effective cancer treatments, offering hope for resistant and aggressive cases.

Temperature Dependence of Tensile Properties in Single Crystal Superalloy CMSX-4 (단결정 초내열 합금 CMSX-4의 온도에 따른 인장특성의 변화)

  • Baig-Gyu Choi;Jeonghyeon Do;Joong Eun Jung;Sangwon Lee;In Soo Kim
    • Journal of Korea Foundry Society
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    • v.44 no.3
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    • pp.59-69
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    • 2024
  • The tensile properties of the single crystal superalloy CMSX-4 were examined at various temperatures. In the heat-treated state, some portion of the eutectic γ-γ' remained, and a uniform cuboidal γ' particles existed across the entire material. The yield strength and tensile strength reached highest at 750℃ and decreased with raising testing temperature. The elongation was lowest at 650℃ due t℃oncentrated deformation near the fracture area. However, the elongation increased at higher temperatures due to uniform deformation throughout the entire specimen. Fracture surface analysis tested at 850℃ and 950℃ revealed that cracks originated from casting defects. TEM observations conducted after the tensile test indicated that the primary deformation mechanism at room temperature involved dislocation shearing within the γ' phase. However, the increased strength both at 750℃ where stacking faults generated and at 650℃ was caused by the increased resistance of γ' phase to dislocation. The strength decreased because the movement of dislocations became easier due to the thermal activation process at and above 850℃.

Effects of Isometric Hip Extension Using Thera-band on Hip Muscle Activities During Side-lying Hip Abduction Exercise in Participants With Gluteus Medius Weakness

  • Sae-hwa Kim;Hyun-ji Lee;Seok-hyun Kim;Seung-min Baik;Heon-seock Cynn
    • Physical Therapy Korea
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    • v.31 no.2
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    • pp.123-130
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    • 2024
  • Background: Weakness of gluteus medius (Gmed) is related with musculoskeletal disorders. Individuals who experience weakness in the Gmed may activate the tensor fasciae latae (TFL) as a compensatory mechanism. Application of isometric hip extension (IHE) with Thera-band may affect the activities of the Gmed, gluteus maximus (Gmax), and TFL, and the activity ratio of Gmed/TFL during side-lying hip abduction (SHA). Objects: To determine the influences of IHE during SHA on Gmed, Gmax, and TFL activities in participants with Gmed weakness. Methods: Three types of SHA exercises were performed: 1) traditional SHA in the frontal plane (SHA-T), 2) SHA with IHE applying Thera-band in the frontal plane (SHA-IHE), 3) and SHA with isometric hip flexion (IHF) applying Thera-band in the frontal plane (SHA-IHF). Results: SHA-IHE significantly showed higher Gmed and Gmax activities than SHA-T and SHA-IHF. SHA-IHF significantly showed higher activity of TFL than SHA-T or SHA-IHE. The activity ratio of Gmed/TFL was significantly higher in the SHA-IHE, SHA-T, and SHA-IHF, in that order. Conclusion: The SHA-IHE resulted in higher activities of Gmed, Gmax and a higher muscle ratio of Gmed/TFL.

평행식 진동탄환 암거 천공기의 연구 (IV)(V)-실기 설계 제작 및 보장실험-Development of Balanced-Type Oscillating Mole Drainer(IV)(V)

  • 김용환;이승규;서상용
    • Journal of Biosystems Engineering
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    • v.2 no.1
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    • pp.7-24
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    • 1977
  • This paper is the forth and fifth one of the study on balanced type oscillating mole drainer. In the light of the results from previous reports about the model tests, some design criteria were established and a prototype machine was set up for experimental purpose. Motion characteristics and functionof the each parts of the machine were checked and analyzed. After that, performance tests of the prototype machine were carried out in thefield. Obtained results are summarized as follows ; 1. Ten centimeter of the bullet diameter was determined so as to be able to attach it to the tractors with capacity of 30 PS to 40 PS. 2. To maintain the balance between the moments of the front shank and rear shank, the oscillating amplitude of the rear bullet was determined to be larger than that of the front bullet. At the same time , the oscillating direction of the rear bullet was designed with the inclines of ten to thirty degrees. 3. An octagonal dynamo transduced was developed for measuring the compressive force of the upper link is measuring the draft force of the machine. Acceptable linear relationship between forces and strain responses from O.D.T. was obtained. 4. Analysing the balancing mechanism of the acting part of the machine , it was found that the total draft force of the machine was equal to the difference between the sum of the draft force produced from the right and left side bending moments of the lower drawber and the compressive force on the upper link. 5. There are acceptable linear relationship between the strain and twisting moment by driving shaft, and between strain and shank moment. Above results enable us to carry out the field experiment with prototype machine. 6. When the test machine was used in the field, it was possible to reduce the oscillating acceleration by forty percent in average as compared it with the single bullet mole drainer. 7. When the test machine was used under the oscillating condition, the dratt torce was reduced by 27 percent to 59 percent as compared it with the test machine under non-oscillating condition, while the draft force was increased by 7 percent to 20 percent as compared it with the mole drainer having oscillating single bullet. The reasoning behind this fact was considered as the resistance force due to the rear shank and bullet. 8. As the amplitude and frequency of the bullet were increased, the torque was increased accordingly. This tendency could be varied with the various characteristics of the given soils. And the larger frequency and amplitute, the more increasing oscil\ulcornerlating power but decreasing draft brce were needed, and draft force was increased as the velocity was increased.9. When the amplitude of the rear bullet was designed to be larger than that of the front bullet, the minimum value of the moment was lowered and oscillating acceleration was reduced. And when the oscillating direction of the rear bullet was declined back\ulcornerwards, oscillating acceleration was increased along with the increasing angle of decli\ulcornernation. When the test machine was operated in high speed, the difference between maximum moments and minimum ones became narrow. This varying magnitude of moments appeared on the moment oscillogram seems to be correlated to the oscillating acceleration and draft force. 10. From the analysis of variance, it was found that those factors such as frequency, amplitude, and operating velocity significantly affected in the oscillating acceleration, the draft resistance, the torque, the moment, and the total power required. And interaction between frequency and amplitude affected in the oscillating acceleration. 11. Within the given situation of this study, the most preferable operating conditions of the test machine were 7 Hz in oscillating frequency, 0.54 m/sec in operating velocity, and 39.1 mm in oscillating amplitude of front and rear bullets. However, it is necessary to select the proper frequency and magnitude of oscillation depending on the soil properties of the field in which the mole drainer is practiced by use of a bal1nced type oscillating mole drainer. 12. It is recommended that a comparative study of the mole drainers would be performed in the near future using two separate balanced oscillating bullet with the one which is operated by oscillating the movable bullet in a single cylinder or other balanced type which may be single oscillating bullet with spring, damper or balancing weight, and that of thing. To expand the applicability of the balanced type oscillating mole drainer in practical use, it is suggested to develop a new mechanism which perform mole drain with vinyl pipe or filling material such as rice hull.

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Investigation on Inhibitory Effect of ErmSF N-Terminal End Region Peptide on ErmSF Methyltansferase Activity In Vivo Through Development of Co-Expression System of Two Different Proteins in One Cell (서로 다른 두 단백질의 세포 내 동시 발현 체계의 개발을 통한 ErmSF에서 특이적으로 발견되는 N-Terminal End Region (NTER)을 포함하는 펩타이드의 생체내에서의 ErmSF 활성 억제 효과 검색)

  • Jin, Hyung-Jong
    • Korean Journal of Microbiology
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    • v.47 no.3
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    • pp.200-208
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    • 2011
  • Most problematic antibiotic resistance mechanism for MLS (macrolide-lincosamide-streptogramn B) antibiotics encountered in clinical practice is mono- or dimethylation of specific adenine residue at 2058 (E. coli coordinate) of 23S rRNA which is performed by Erm (erythromycin ribosome resistance) protein through which bacterial ribosomes reduce the affinity to the antibiotics and become resistant to them. ErmSF is one of the four gene products produced by Streptomyces fradiae to be resistant to its own antibiotic, tylosin. Unlike other Erm proteins, ErmSF harbors idiosyncratic long N-terminal end region (NTER) 25% of which is comprised of arginine well known to interact with RNA. Furthermore, NTER was found to be important because when it was truncated, most of the enzyme activity was lost. Based on these facts, capability of NTER peptide to inhibit the enzymatic activity of ErmSF was sought. For this, expression system for two different proteins to be expressed in one cell was developed. In this system, two plasmids, pET23b and pACYC184 have unique replication origins to be compatible with each other in a cell. And expression system harboring promoter, ribosome binding site and transcription termination signal is identical but disparate amount of protein could be expressed according to the copy number of each vector, 15 for pACYC and 40 for pET23b. Expression of NTER peptide in pET23b together with ErmSF in pACYC 184 in E. coli successfully gave more amounts of NTER than ErmSF but no inhibitory effects were observed suggesting that there should be dynamicity in interaction between ErmSF and rRNA rather than simple and fixed binding to each other in methylation of 23S rRNA by ErmSF.

Uptake of Butachlor by Rice Seedlings and Its Phytotoxic Action to the Physiological Activities (수도묘(水稻苗)의 Butachlor 흡수(吸收) 및 약해발생(藥害發生) 특성(特性)에 관한 생리적(生理的) 연구(硏究))

  • Chung, Bong-Jin;Kwon, Yong-Woong
    • Korean Journal of Weed Science
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    • v.1 no.1
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    • pp.57-68
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    • 1981
  • To clarify the mode of uptake of butachlor (2-chloro-2', 6'-diethyl-N-(butoxymethyl) acetanilide) by rice seedlings, its phytotoxic action to growth and physiological activities, studies were conducted with rice seedlings, at the 6th or 7th leaf-stage, which were treated with nutrient solution containing butachlor 0, 1.8, 3.6, 7.2, 10.8 or 14.4 ppm for 1, 2 or 4 days, in other case, the solutions were thereafter renewed with the untreated nutrient solution for further growth. Uptake of butachlor by rice seedlings increased linearly with increase of its concentration and duration of uptake. Butachlor inhibited root growth more than shoot growth, furthermore, the inhibitory effect on the shoot growth was greater in height than in weight or leafing rate. After 4 day-treatment, the rates of shoot growth in weight were delayed for 4 days. Butachlor inhibited water uptake rapidly and linearly with increase of its external concentration. The reduced uptake of water was followed by slow increase in the stomatal resistance of leaves. Upon completion of butachlor treatment, rate of water uptake was recovered rapidly, but the stomatal resistance with lag in time. Butachlor did not affect the uptake of cation such as ammonium, potassium and calcium, but inhibited substantially uptake of nitrate in proportion to its concentration. Especially, butachlor did not affect synthesis and degradation of nitrate reductase. In addition, butachlor has shown much greater binding to the lipidic substances from rice roots than the proteinous material. The primary mechanism of phytotoxic action of butachlor does not seem to be its effect on the protein synthesis, but great affinity to membranes. The inhibition of water uptake, and its subsequent closure of stomates is thought very important for reduced growth under mild phytotoxicity.

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Studies on the Mechanism of Varietal Resistance of Rice to the Brown Planthopper(Nilaparvata lugens $ST{\AA}L$ (벼멸구에 대한 수도품종(水稻品種)의 저항성기작(抵抗性機作)에 관(關)한 연구(硏究))

  • Kim, J.W.;Choi, S.Y.;Park, J.S.
    • Korean journal of applied entomology
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    • v.24 no.2 s.63
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    • pp.51-60
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    • 1985
  • This paper was performed to study the nature of varietal resistance of some Korean-new rice cultivars to the brown planthopper (BPH), Nilaparvata lugens ($ST{\AA}L$). The rice cultivars tested were Cheongcheong, Gaya, Hangangchal, Samgang, Nampoong and Yeongpoong which have been reported as having resistant genes for the BPH. The check varieties were Jinheung, Sangpoong and Chucheong for susceptible and IR-36 for resistant. The factors studied were referred to the seedling responses, preference in feeding and oviposition of BPH, antibiosis (nymphal development, adult emergence and sex ratio, adult body weight, population build-up, feeding amount and amylase activity), and chemical composition (inorganic components, chlorophyll contents, cell wall components, amino acids and esterase isozymes) of leaf- sheath and/or roots of rice plants. In conclusion, the natures of varietal resistance of rice cultivars to the BPH were not only correlated with the resistant reaction of rice plant, but also they were related with the non preference in feeding and oviposition and those resistant cultivars had the antibiotic effects to the insects. Their antibiotic effects of rice cultivars to the BPH would be related with some of the chemical components of rice plants, such as the contents of magnesium oxide (MgO), and chlorophyll and the different esterase isozymes.

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Characterization of SID2 that is required for the production of salicylic acid by using β-GLUCURONIDASE and LUCIFERASE reporter system in Arabidoposis (리포트 시스템을 이용한 살리실산 생합성 유전자 SID2의 발현 해석)

  • Hong, Mi-Ju;Cheong, Mi-Sun;Lee, Ji-Young;Kim, Hun;Jeong, Jae-Cheol;Shen, Mingzhe;Ali, Zahir;Park, Bo-Kyung;Choi, Won-Kyun;Yun, Dae-Jin
    • Journal of Plant Biotechnology
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    • v.35 no.3
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    • pp.169-176
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    • 2008
  • Salicylic acid(SA) is a phytohormone that is related to plant defense mechanism. The SA accumulation is triggered by abiotic and biotic stresses. SA acts as a signal molecular compound mediating systemic acquired resistance and hypersensitive response in plant. Although the role of SA has been studied extensively, an understanding of the SA regulatory mechanism is still lacking in plants. In order to comprehend SA regulatory mechanism, we have been transformed with a SID2 promoter:GUS::LUC fusion construct into siz1-2 mutant and wild plant(Col-0). SIZ1 encodes SUMO E3 ligase and negatively regulates SA accumulation in plants. SID2(SALICYLIC ACID INDUCTION DEFICIENT2) is a crucial enzyme of SA biosynthesis. The Arabidopsis SID2 gene encodes isochorismate synthase(ICS) that controls SA level by conversion of chorismate to isochorismate. We compared the regulation of SID2 in wild-type and siz1-2 transgenic plants that express SID2 promoter:GUS::LUC constructs respectively. The expressions of $\beta$-GLUCURONIDASE and LUCIFERASE were higher in siz 1-2 transgenic plant without any stress treatment. SID2 promoter:GUS::LUC/siz1-2 transgenic plant will be used as a starting material for isolation of siz1-2 suppressor mutants and genes involved in SA-mediated stress signaling pathway.

A Research on Ball-Balancing Robot (볼 벨런싱 로봇에 관한 연구)

  • Kim, Ji-Tae;Kim, Dae-young;Lee, Won-Joon;Jin, Tae-Seok
    • Proceedings of the Korean Institute of Information and Commucation Sciences Conference
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    • 2017.05a
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    • pp.463-466
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    • 2017
  • The purpose of this paper is to develop a module capable of all-directional driving different from conventional wheeled robots, and to solve the problems of the conventional mobile robot with side driving performance degradation, It is possible to overcome the disadvantages such as an increase in the time required for the unnecessary driving. The all - direction spherical wheel drive module for driving a ball - balancing robot is required to develop a power transfer mechanism and a driving algorithm for driving the robot in all directions using three rotor casters. 3DoF (Axis) A driver with built-in forward motion algorithm is embedded in the module and a driving motor module with 3DoF (axis) for driving direction and speed is installed. The movement mechanism depends on the sum of the rotation vectors of the respective driving wheels. It is possible to create various movement directions depending on the rotation and the vector sum of two or three drive wheels. It is possible to move in different directions according to the rotation vector field of each driving wheel. When a more innovative all-round spherical wheel drive module for forward movement is developed, it can be used in the driving part of the mobile robot to improve the performance of the robot more technically, and through the forward-direction robot platform with the drive module Conventional wheeled robots can overcome the disadvantage that the continuous straightening performance is lowered due to resistance to various environments. Therefore, it is necessary to use a full-direction driving function as well as a cleaning robot and a mobile robot applicable in the Americas and Europe It will be an essential technology for guide robots, boarding robots, mobile means, etc., and will contribute to the expansion of the intelligent service robot market and future automobile market.

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The Role of NF-${\kappa}B$ in the TNF-$\alpha$-induced Apoptosis of Lung Cancer Cell Line (폐암세포주의 TNF-$\alpha$ 유발 apoptosis에서 NF-${\kappa}B$의 역할)

  • Kim, J.Y.;Lee, S.H.;HwangBo, B.;Lee, C.T.;Kim, O.H.;Han, S.K.;Shim, O.S.;Yoo, C.G.
    • Tuberculosis and Respiratory Diseases
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    • v.48 no.2
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    • pp.166-179
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    • 2000
  • Background: The main reason for the failure of anti-cancer chemotherapy is the build up of resistance by cancer cells to apoptosis. The activation of NF-${\kappa}B$ in many cancer cell lines is reported to be underlying mechanism behind the build up of resistance of cancer cells to apoptosis. However, this relationship varied depending on the cells used in the experiments. In this study, the role of NF-${\kappa}B$ activation in the TNF-$\alpha$-induced apoptosis in lung cancer cell line was evaluated. Methods: NCI-H157 cells were used in all experiments. Cells were exposed to a high dose of TNF-$\alpha$(20 ng/ml) for 24 or 48 hours with or without blocking NF-${\kappa}B$ activation. TNF-$\alpha$-induced activation of NF-${\kappa}B$ was inhibited either by overexpression of $I{\kappa}B{\alpha}$-super repressor($I{\kappa}B{\alpha}$-SR) or by pre-treatment with proteasome inhibitor. Cell viability and apoptosis were evaluated with MTT assay and Western blot analysis for PARP fragment, respectively. Results: Cell viability of NCI-H157 cells was not affected by TNF-$\alpha$ treatment alone; however, combined treatment with TNF-$\alpha$ and cycloheximide reduced cell viability significantly, indicating that resistance to TNF-$\alpha$ is mediated by the new proteins synthesized after TNF-$\alpha$ stimulation. To evaluate the role of NF-${\kappa}B$ in the transcription of anti-apoptotic proteins. delete NF-${\kappa}B$ activation was inhibited before TNF-$\alpha$ stimulation. as described above. $AD5I{\kappa}B{\alpha}$-SR-transduction inhibited TNF-$\alpha$-induced nuclear translocation of p65. TNF-$\alpha$-induced cell death and apoptosis increased after inhibition of TNF-$\alpha$-induced activation of NF-${\kappa}$ by methods. Conclusion: These results suggest that TNF-$\alpha$-induced activation of NF-${\kappa}B$ may be closely related to the acquisition of the resistance to TNF-$\alpha$-induced apoptosis in lung cancer cells. Therefore. blocking of NF-${\kappa}B$ pathway can be a useful therapeutic modality in the treatment of lung cancer.

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